한의사가 많이 쓰는 '산사' 치료효과 및 에탄올 추출법 2024년 review

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REVIEW ARTICLE

Open Access

The hawthorn (Crataegus pinnatifida Bge.) fruit as a new dietary source of bioactive ingredients with multiple beneficial functions

Jin-Xin Ma, Wei Yang, Chester Yan Jie Ng, Xu-Dong Tang, Sunny Wong, Ren-You Gan, Linda Zhong

First published: 07 May 2024

https://doi.org/10.1002/fft2.413

Citations: 3

Jin-Xin Ma and Wei Yang contributed equally to the work.

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Abstract

The discovery of new natural sources has brought increased attention to the development of functional foods. The hawthorn (Crataegus pinnatifida Bge.) fruit is an underutilized fruit due to its benefits for human health and good taste. It contains a variety of bioactive ingredients, contributing to its multiple beneficial functions and applications. This review summarized and discussed the main bioactive ingredients, beneficial functions based on in vitro, in vivo, and human studies, and different applications of the hawthorn fruit according to the updated literature in the past 3 years. Hawthorn berries contain phenolic acids, flavonoids, proanthocyanidins, pectin, and many other bioactive components, which have a variety of beneficial functions, such as antioxidant, anti-inflammatory, antibacterial, antidiabetic, intestinal protection, cardiovascular protection, hepatoprotection, anti-cancer, and neuroprotection. Its potential molecular mechanism and different food-related applications such as hawthorn wine and antioxidant drink are discussed in detail in this review. Additionally, hawthorn berries are shown to be safe when consumed within the proper dosage. Collectively, this updated review indicates that the hawthorn fruit can be a new dietary source of bioactive ingredients with multiple beneficial functions and can be affordably developed into functional and medicinal foods for the prevention and management of certain chronic diseases.

요약

새로운 천연 원료의 발견으로 기능성 식품 개발에 대한 관심이 높아지고 있습니다.

산사나무(Crataegus pinnatifida Bge.) 열매는

인체 건강에 유익하고 맛이 좋아서

충분히 활용되지 못하고 있는 과일입니다.

이 과일에는 다양한 생체 활성 성분이 함유되어 있어

여러 가지 유익한 기능과 용도에 기여합니다.

이 리뷰는 지난 3년 동안 업데이트된 문헌에 근거하여 생체 내, 생체 외, 인간 연구에 근거한 주요 생체 활성 성분, 유익한 기능, 산사나무 열매의 다양한 응용에 대해 요약하고 논의했습니다.

산사나무 열매에는

페놀산, 플라보노이드, 프로안토시아니딘, 펙틴, 그리고

항산화, 항염증, 항균, 항당뇨, 장 보호, 심혈관 보호, 간 보호, 항암, 신경 보호 등

다양한 유익한 기능을 가진 많은 다른 생체 활성 성분이 함유되어 있습니다.

이 리뷰에서는

산사나무의 잠재적인 분자 메커니즘과

산사나무 와인, 항산화 음료 등 식품 관련 응용 사례에 대해 자세히 설명합니다.

또한,

산사나무 열매는

적절한 양을 섭취할 경우 안전하다는 것이 입증되었습니다.

종합적으로,

이 업데이트된 검토 결과는

산사나무 열매가 여러 가지 유익한 기능을 가진 새로운 생리 활성 성분의 식이 공급원이 될 수 있으며,

특정 만성 질환의 예방과 관리를 위한 기능성 및 약용 식품으로 저렴하게 개발될 수 있음을 보여줍니다.

1 INTRODUCTION

Hawthorn, also known as Crataegus pinnatifida Bge., belongs to the Rosaceae family and is a deciduous tree (Hamza et al., 2020). The hawthorn fruit, with both medicinal and edible characteristics, has a long history of use as Traditional Chinese Medicine and has been proven to possess many health benefits. According to the theory of Traditional Chinese Medicine, it has the functions of promoting digestion, invigorating the spleen, nourishing vitality, and removing blood stasis (Hou et al., 2020). Modern research has also discovered that it contains phenolic acids, flavonoids, proanthocyanidins, pectin, and other bioactive ingredients (Li, Gao et al., 2022; Li et al., 2021). In the past decade of research, hawthorn berries and their bioactive constituents have been shown to possess many beneficial functions, such as antioxidant, anti-inflammatory, antibacterial, intestinal protection, modulation of intestinal microbiota, cardiovascular protection, and antidiabetic and neuroprotective effects. It also has a broad prospect in drug and food research and development (Lin et al., 2022; Schandry et al., 2018; Wang, Wang et al., 2021). As a kind of food with the same origin of food and medicine, the hawthorn fruit has gradually received more attention in the modern life, which emphasizes a healthy diet.

However, there is still a lack of a state-of-the-art review to better understand its main bioactive ingredients and beneficial functions. Hence, our study retrieved relevant literature regarding the hawthorn fruit published in the past 3 years from the Web of Science Core Collection and PubMed databases. Our study first summarizes the main bioactive components of the whole hawthorn fruit, then comprehensively discusses the health effects of the whole hawthorn fruit and its main bioactive components from in vitro, in vivo, and clinical studies, focusing on hawthorn berries and their main bioactive components and their antioxidant, anti-inflammatory, antimicrobial, intestinal protection, regulation of intestinal microbiota, cardiovascular protection, and antidiabetic effects. Finally, the application of hawthorn berries in food products is introduced, and the potential safety issues of hawthorn are discussed. We hope that this review paper can attract more attention to the hawthorn fruit and promote its further research and application in the prevention and management of certain chronic diseases.

1 서론

산사나무(Crataegus pinnatifida Bge.)는 장미과에 속하는 낙엽수입니다(Hamza et al., 2020). 약용과 식용으로 모두 사용되는 산사나무 열매는 중국 전통 의학에서 오랫동안 사용되어 왔으며, 많은 건강상의 이점이 있는 것으로 입증되었습니다. 한의학 이론에 따르면, 이 약재는 소화를 촉진하고, 비장을 활성화하며, 활력을 공급하고, 혈액 정체를 제거하는 기능을 가지고 있습니다(Hou et al., 2020).

현대 연구에 따르면, 이 약재에는

페놀산, 플라보노이드, 프로안토시아니딘, 펙틴, 그리고

기타 생체 활성 성분이 포함되어 있는 것으로 밝혀졌습니다(Li, Gao et al., 2022; Li et al., 2021).

지난 10년간의 연구에서

산사나무 열매와 그 생체 활성 성분은

항산화, 항염증, 항균, 장 보호, 장내 미생물 조절, 심혈관 보호, 항당뇨 및 신경 보호 효과 등

많은 유익한 기능을 가지고 있는 것으로 나타났습니다.

또한, 의약품 및 식품 연구 및 개발 분야에서 폭넓은 전망을 가지고 있습니다(Lin et al., 2022; Schandry et al., 2018; Wang, Wang et al., 2021). 식품과 약의 기원이 같은 식품의 일종인 산사나무 열매는 건강한 식생활을 강조하는 현대 생활에서 점차 더 많은 관심을 받고 있습니다.

그러나, 주요 생리 활성 성분과 유익한 기능을 더 잘 이해하기 위한 최첨단 검토가 아직 부족합니다. 따라서, 저희의 연구는 Web of Science Core Collection과 PubMed 데이터베이스에서 지난 3년 동안 출판된 산사나무 열매에 관한 관련 문헌을 검색했습니다. 이 연구는 먼저 산사나무 열매 전체의 주요 생체 활성 성분을 요약한 다음, 체외, 생체, 임상 연구에서 산사나무 열매 전체와 그 주요 생체 활성 성분의 건강 효과를 종합적으로 논의합니다. 이 연구는 산사나무 열매와 그 주요 생체 활성 성분, 그리고 항산화, 항염증, 항균, 장 보호, 장내 미생물 조절, 심혈관 보호, 항당뇨 효과에 중점을 둡니다. 마지막으로, 식품에 산사나무 열매를 사용하는 것이 소개되고, 산사나무의 잠재적인 안전성 문제가 논의됩니다. 이 리뷰 논문이 산사나무 열매에 대한 관심을 더 끌고, 특정 만성 질환의 예방과 관리에 대한 추가 연구와 적용을 촉진할 수 있기를 바랍니다.

2 BIOACTIVE INGREDIENTS IN THE WHOLE HAWTHORN FRUIT

The whole hawthorn fruit contains various bioactive ingredients, like polyphenols, polysaccharides, terpenoids, essential oils, and lignans, with representative compounds shown in Figure 1. Different factors, such as the varieties, cultivation regions, and postharvest drying methods, can influence the bioactive ingredients and their content in the whole hawthorn fruit, and they are discussed in the following sections.

2 가지 생체 활성 성분 함유 호손 열매

산사나무 열매 전체에는

폴리페놀, 다당류, 테르페노이드, 에센셜 오일, 리그난 등

다양한 생체 활성 성분이 함유되어 있으며, 대표적인 화합물은 그림 1에 나와 있습니다.

품종, 재배 지역, 수확 후 건조 방법 등 다양한 요인이

산사나무 열매 전체의 생체 활성 성분과 그 함량에 영향을 미칠 수 있으며,

이에 대해서는 다음 섹션에서 설명합니다.

FIGURE 1

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Chemical structures of bioactive compounds in the hawthorn fruit.

2.1 Polyphenols

Polyphenols are a large family of organic compounds that are characterized by at least one hydroxyl group in the benzene ring. Polyphenols are abundant in many plant-based foods (Lund, 2021). Usually, methanol and ethanol are common solvents for the extraction of polyphenols from plants. A study by Sultana et al. (2009) found that aqueous methanol was comparatively more efficient than ethanol and acerone for polyphenol extraction from different medicinal plant extracts. The predominant polyphenolic compounds in whole hawthorn fruits include phenolic acids, flavonoids, and proanthocyanidins, and the main compounds and chemical structures are shown in Figure 1.

2.1 폴리페놀

폴리페놀은

벤젠 고리에 적어도 하나의 수산기가 있는

유기 화합물의 큰 계열입니다.

폴리페놀은

많은 식물성 식품에 풍부하게 함유되어 있습니다(Lund, 2021).

일반적으로,

식물에서 폴리페놀을 추출하는 데

메탄올과 에탄올이 일반적으로 사용됩니다.

Sultana 외(2009년)의 연구에 따르면,

수성 메탄올은 에탄올과 아세론보다

다양한 약용 식물 추출물에서 폴리페놀을 추출하는 데 더 효율적이라고 합니다.

산사나무 열매 전체에 함유된 주요 폴리페놀 화합물에는

페놀산, 플라보노이드, 프로안토시아니딘이 있으며,

주요 화합물과 화학 구조는 그림 1에 나와 있습니다.

2.1.1 Phenolic acids

Phenolic acids are one of the main categories of phenolic compounds in the whole hawthorn fruit. Besides the Soxhlet extraction and ultrasonic-assisted extraction that are commonly used in phenolic acid extraction, supercritical fluid extraction and accelerated solvent extraction are also developed as alternative techniques (Arceusz et al., 2013). Gallic acid, caffeic acid, and syringic acid were found in fresh and dehydrated whole hawthorn fruits (Benabderrahmane et al., 2021). In addition, gallic acid, neochlorogenic acid, and cryptochlorogenic acid were revealed to be active components of the whole hawthorn fruit for the treatment of hyperlipidemia and cardiovascular diseases (CVDs) (Sun, Zeng et al., 2022).

2.1.1 페놀산

페놀산은 산사나무 열매 전체에 함유된 페놀 화합물의 주요 범주 중 하나입니다. 페놀산 추출에 일반적으로 사용되는 Soxhlet 추출과 초음파 보조 추출 외에도 초임계 유체 추출과 가속 용매 추출이 대안 기술로 개발되었습니다(Arceusz et al., 2013).

갈릭산, 카페산, 그리고 시링산은

신선한 산사나무 열매와 건조된 산사나무 열매에서 발견되었습니다(Benabderrahmane et al., 2021).

또한,

갈릭산, 네오클로로겐산, 크립토클로로겐산은

고지혈증과 심혈관 질환(CVD) 치료를 위한

전체 산사나무 열매의 활성 성분으로 밝혀졌습니다(Sun, Zeng et al., 2022).

2.1.2 Flavonoids

Flavonoids are another important category of polyphenols that have important biological effects. Flavonoids are usually extracted by a combination of ethanol and water in different proportions and can also be extracted by the natural deep eutectic solvents, which could solubilize moderately polar flavonoids in a low-cost and environment-friendly manner (Chaves et al., 2020). It was found that (+)-catechin was a main flavonoid compound in hawthorn pulp, ranging from 9.57 to 29.9 mg/100 g based on different extraction methods (Özcan et al., 2022). In addition, apigenin, luteolin, chrysin, and quercetin were also found in the whole hawthorn fruit (Li, Gao et al., 2022). Moreover, vitexin 2″-O-rhamnoside, rutin, vitexin, and hyperoside were identified in three different varieties of whole hawthorn fruit (Agiel et al., 2022). The cultivation regions can influence the total flavonoid content (TFC) in the whole hawthorn fruit. For example, Hou et al. (2020) eval‎uated the TFC in the whole hawthorn fruits from five places in China, and they found that the TFC in samples from Henan was the highest, whereas the TFC of the Jiangsu samples was the lowest, and epicatechin was the predominant flavonoid in all samples from all regions.

2.1.2 플라보노이드

플라보노이드는

중요한 생물학적 효과를 가진 폴리페놀의

또 다른 중요한 범주입니다.

플라보노이드는

보통 에탄올과 물의 다양한 비율의 조합으로 추출되며,

적당한 극성의 플라보노이드를 저렴한 비용과 환경 친화적인 방식으로 가용화할 수 있는

천연 심층 공융 용매로도 추출할 수 있습니다(Chaves et al., 2020).

(+)-카테킨은

산사나무 펄프의 주요 플라보노이드 화합물이며,

추출 방법에 따라 9.57~29.9mg/100g에 이르는 것으로 밝혀졌습니다(Özcan et al., 2022).

또한,

전체 산사나무 열매에서

아피제닌, 루테올린, 크리신, 케르세틴도 발견되었습니다(Li, Gao et al., 2022).

게다가, 세 가지 다른 품종의 전체 산사나무 열매에서 비텍신 2″-O-람노사이드, 루틴, 비텍신, 하이페로사이드가 확인되었습니다(Agiel et al., 2022). 재배 지역은 산사나무 열매 전체의 총 플라보노이드 함량(TFC)에 영향을 미칠 수 있습니다. 예를 들어, Hou et al. (2020)은 중국 내 다섯 곳의 산사나무 열매 전체의 TFC를 평가한 결과, 허난성 샘플의 TFC가 가장 높았고, 장쑤성 샘플의 TFC가 가장 낮았으며, 모든 지역의 모든 샘플에서 에피카테킨이 가장 많은 플라보노이드임을 발견했습니다.

2.1.3 Proanthocyanidins

Proanthocyanidins, also called condensed tannins, are a category of polyphenols with higher molecular weights compared with common phenolic acids and flavonoids. They are oligomeric compounds with a basic framework structure consisting of epicatechin or catechin. Procyanidins are members of proanthocyanidins that are found in the whole hawthorn fruit. Liquid/Liquid extraction is the main method for proanthocyanidin isolation. In addition, ethyl acetate and water are the most commonly used solvent systems for liquid/liquid extraction (Liu, 2012). Procyanidin dimers (e.g., procyanidins B2 and B5), dimer hexosides, and trimers (e.g., procyanidins C1 and C5) are shown to be the major procyanidins in whole hawthorn fruits (Liu et al., 2009). Liu et al. (2010) optimized the extraction and purification methods of procyanidins from whole hawthorn fruits and found that the content of procyanidins was 2.96% ± 0.14%, and the oligomeric procyanidins/procyanidins ratio was 61.6%, which was the highest in their screening sources.

2.2 Polysaccharides

Most of the cellulosic polysaccharides are polar macromolecules and soluble in water. Thus, polysaccharides are usually extracted using hot water according to the principle of “similar compatibility.” On top of hot water extraction, some other methods, such as microwave-assisted extraction, ultrasonic-assisted extraction, acid–base extraction, enzymatic extraction, and ultrahigh-pressure extraction, have also been developed for polysaccharide extraction (Liu & Huang, 2019). The common methods for the separation and purification of polysaccharides include precipitation, ultrafiltration, and gel chromatography (Zhan et al., 2023; Wang et al., 2010; Luo et al., 2010). The whole hawthorn fruit is also rich in polysaccharides. Its pulps contain 82.35% of total carbohydrates and 29.39% of uronic acid contents, which is higher than its seeds (Rjeibi et al., 2020). In addition, pectin is the predominant polysaccharide in the whole hawthorn fruit. Guo et al. (2019) extracted a high-methoxylated pectic polysaccharide with the mild acid extraction method from hawthorn wine residues and found that the pectic polysaccharide had a relatively lower molecular weight and higher polydispersity index when compared with pectin from the whole hawthorn fruit, indicating that the wine-making processing degraded the chain of polysaccharides originally existing in the whole hawthorn fruit. Another study obtained the whole hawthorn fruit pectin by ultrasound-sodium citrate assisted extraction and divided it into quaternized hawthorn pectin (QHP) by (3-chlom-2-hydroxypropyl) trimethylammonium chloride under alkaline conditions according to different degrees of substitution, and the quaternary ammonium modification was found to improve the water solubility and water holding capacity of the pectin (Qin et al., 2022). The weight-average molecular weight (Mw) of its pectin was 379.35 ± 0.57 KDa, and the number-average molecular weight (Mn) was 147.72 ± 1.40; thus, the Mw/Mn values indicate that the molecular weight distribution was 2.57 ± 0.03. Li, Zhang et al. (2022) extracted, purified, and analyzed the hawthorn pectic polysaccharide and found that its Mw ranged from 73.67 × 103 to 464.42 × 103 KDa, depending on the type of extraction method. Zhu et al. (2019) found that the monosaccharide composition of HP polysaccharides included d-galacturonic acid, d-glucuronic acid, d-glucose, l-rhamnose, d-galactose, d-xylose, and d-arabinose.

2.3 Other ingredients

The whole hawthorn fruit also contains other bioactive ingredients, like terpenoids, volatile compounds, and lignans. Two triterpenoids, oleanic acid and corosolic acid, were identified in the whole hawthorn fruit (Li, Gao et al., 2022). The volatile compounds of the whole hawthorn fruits vary at each maturity stage, and some esters (e.g., butyl and hexyl hexanoates, hexyl, and cis-3-hexenyl acetates) gradually increased in the Sultan cultivar (Dursun et al., 2021). In addition, beta-thujene (17.21%), alpha-pinene (15.40%), 2-hexenal (12.42%), trans-caryophyllene (8.76%), beta-myrcene (7.89%), 1-pentacene (5.89%), sabinene (4.33%), and trans-beta-farnesene were identified as the major essential oil compounds in the whole hawthorn fruit (Bazgir et al., 2020). Besides, Shang et al. (2020) isolated two pairs of new lignan enantiomers (1a/1b, 2a/2b) from the whole hawthorn fruit, and Xin et al. (2022) isolated seven lignans, including six new compounds, from the whole hawthorn fruit.

3 BIOACTIVITIES BASED ON IN VITRO AND IN VIVO STUDIES

The whole hawthorn fruit has been reported to contain many bioactive components (Figure 2), such as phenolic acids, flavonoids, proanthocyanidins, and pectin, which are intensively discussed as follows. The underlying molecular mechanisms will also be highlighted.

FIGURE 2

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Food-related applications of the hawthorn fruit.

3.1 Antioxidant activity

Oxidative stress is a redox imbalance accompanied by increased production of reactive oxygen species (ROS) and overwhelming antioxidant defenses (He et al., 2021). Free radical–induced oxidative stress is closely associated with many human diseases like CVD, autoimmune disease, and age-related sexual decline. The antioxidant effects of plant flavonoids have been frequently reported, and possible mechanisms include inhibiting the production or direct elimination of free radicals, or inhibiting lipid peroxidation (Huang et al., 2022).

Recent studies have reported that the hawthorn pulp and its polyphenols exhibit potent antioxidant activity in vitro. It was shown that the total antioxidant capacity of the hawthorn pulp was 0.32–1.84 mmol Fe2+/g dry weight (DW) (Alirezalu et al., 2020), and it had a more stable anti-lipid peroxidation capacity than vitamin C (Feng et al., 2022). The antioxidant activity of the hawthorn pulp was mainly attributed to its free phenolics, accounting for 35.3%–37.8% of its antioxidant activity, followed by insoluble-bound, soluble esterified–bound, and soluble glycosylated–bound phenolics, accounting for 25.0%–27.0%, 23.4%–25.7%, and 9.4%–15.7% of its antioxidant activity, respectively (Feng et al., 2022). Interestingly, the antioxidant activity of insoluble-bound phenolics in its peel (103–125 μmol Trolox/g DW) was significantly higher than that in its pulp (61.3–67.3 μmol Trolox/g DW) (Lou et al., 2020). Moreover, polyphenols in the hawthorn pulp also exhibited obvious scavenging activities against 1-diphenyl-2-picrylhydrazyl radical, 2,2′-Azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), and hydroxyl radicals (Lin et al., 2022). Chlorogenic acid and chrysin showed potential antioxidant activity in ABTS and superoxide radical scavenging assays (Lin et al., 2022). Chlorogenic acid, epicatechin, and procyanidin B2 were found to be the predominant antioxidant contributors in hawthorn pulp (Lou et al., 2021).

The hawthorn extract and its polyphenols also exhibited antioxidant activities in cells and animals. The whole hawthorn extract significantly increased cell viability and enhanced the activities of superoxide dismutase, catalase, and glutathione peroxidase, while decreasing lactate dehydrogenase release, ROS levels, and peroxide (H2O2)-induced malondialdehyde (MDA) content in rat pheochromocytoma cells (PC12 cells) (Wang et al., 2022). Treatment using the whole hawthorn fruit extract (HFE) increased the antioxidant capacity of human hepatocellular carcinoma cells (HepG2 cells) and reduced oleic acid–induced hyperlipidemia by activating the nuclear factor erythropoietin-2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway (Feng et al., 2022). Hawthorn flavonoids were also discovered to possess powerful Peroxyl radical scavenging activity and strong intracellular antioxidant activity in cells (Huang et al., 2022). The whole hawthorn fruit promoted the antioxidant capacity of both plasma and liver (He et al., 2021) and could inhibit lipid peroxidation in liver tissue and red blood cells (Feng et al., 2022).

These results suggest that polyphenols are the main antioxidants in the whole hawthorn fruit, and the underlying antioxidant mechanisms involve the activation of the Nrf2/HO-1 signaling pathway, enhancement of antioxidant enzyme activity, and ultimately induction of cellular antioxidant defense systems. Further studies are needed to verify whether other signaling pathways and oxidative stress molecules are involved in the in vivo antioxidant effects of whole hawthorn fruit and their polyphenols and to provide more reliable evidence for the development of natural antioxidant functional foods in the future.

3.2 Anti-inflammatory activity

Inflammation is an unavoidable consequence of normal cellular activity, and it can cause acute and chronic diseases and accelerate the aging process. Many studies have reported the anti-inflammatory effects of the whole hawthorn fruit and its bioactive components in vitro and in vivo. The whole HFE is rich in phenolic compounds, especially chlorogenic acid and (−)-epicatechin, which are widely known for their anti-inflammatory effects (Abdel-Rahman et al., 2021; Nguyen et al., 2021).

The whole HFE and its compounds can inhibit inflammation in vitro. Its flavonoids were reported to inhibit the production of inflammatory cytokines, including IL-6, IL-8, and IL-1β in human colorectal adenocarcinoma cells, possibly by suppressing the upregulation of myosin light chain kinase (MLCK)/myosin regulatory light chain (MLC) phosphorylation and inhibiting the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor kappa-light chain enhancer of activated B cells (NF-κB) signaling (Liu, Zhang et al., 2020). The whole HFE also inhibited ROS formation and mRNA production of protein kinase (MAPK)/activator protein-1 (AP-1), NF-κB, and lipopolysaccharide (LPS)-stimulated keratinocytes nuclear factor levels of activated T cells (NFAT) and interleukins in keratinocytes in a dose-dependent manner (Nguyen et al., 2021). Moreover, four new biphenyl derivatives (1–4) as well as two known compounds (5 and 6) extracted from the whole hawthorn fruit also showed anti-inflammatory activities in mouse mononuclear macrophage leukemia cells (RAW264.7 cells) (Wang et al., 2020).

Similarly, the hawthorn pulp can also block inflammation in vivo, contributing to its therapeutic effects on inflammation-related chronic diseases. It was reported that the hawthorn pulp significantly reduced the pro-inflammatory mediators of prostaglandin E2, tumor necrosis factor-α (TNF-α), and myeloperoxidase (MPO) by modulating NF-κB in vivo, thus showing high potency in inhibiting keratin-induced inflammation (Abdel-Rahman et al., 2021). Meanwhile, it could also significantly lower plasma levels of TNF-α and monocyte chemoattractant protein 1 (MCP-1) and downregulate the hepatic expression‎ of MCP-1 and IL-1β in type 2 diabetes (T2D) rats (He et al., 2021). Moreover, the hawthorn pulp could reduce plasma myeloperoxidase, C-reactive protein, and alkaline phosphatase (ALP) levels, suggesting its potential to block or regulate intestinal inflammation in a castor oil–induced rat model (Nascimento et al., 2021; Sammari et al., 2021). In addition, a series of animal experiments have demonstrated that hawthorn pulp can alleviate chronic diseases associated with inflammation, such as osteoarthritis, ulcerative colitis, atherosclerosis (AS), chronic heart failure, hepatic fibrosis, and obesity, but the specific mechanism of action has not yet been completely revealed (Alsharif et al., 2022; Cheng et al., 2020; Hamza et al., 2020; He et al., 2021; Nguyen et al., 2021).

Overall, a large number of studies support the anti-inflammatory activity of the whole HFE and hawthorn pulp, and its anti-inflammatory mechanism is related to the regulation of NF-κB, ERK1/2, MLCK-pMLC, MAPK, and TLR4 signaling pathways, leading to the downregulation of related pro-inflammatory cytokines, such as TNF-α, IL-6, IL-8, and IL-1β. However, as mentioned earlier, the mechanism by which hawthorn pulp alleviates inflammation-associated chronic diseases is not fully understood and requires further validation in animal experiments. It is well known that a series of symptoms caused by inflammation have a great impact on human health; therefore, nutraceuticals and foods containing hawthorn pulp can be developed to reduce inflammation and prevent related symptoms.

3.3 Antibacterial activity

The whole hawthorn fruit has been reported to possess antibacterial activity. It displayed good inhibitory effects against both Gram-positive and Gram-negative bacteria, with the antibacterial mechanism of inducing oxidative stress via ROS production (Golabiazar et al., 2021). Similarly, it enhanced the resistance of Exopalaemon carinicauda to Vibrio parahaemolyticus, as evidenced by an improved immune response and growth of the shrimp (Cao et al., 2022). It also exhibited antibacterial effects against Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, Acinetobacter baumannii, and Escherichia coli, with the minimum inhibitory concentration of 0.11 μg/mL (Ebrahimzadeh et al., 2020). In addition, it was reported that the QHP derivative exhibited a certain inhibitory effect on E. coli and S. aureus (Qin et al., 2022).

In general, the whole hawthorn fruit exhibits broad antimicrobial spectra by inhibiting the growth of bacteria. However, there is no specific study on its main bacteriostatic components or potential bacteriostatic mechanisms, and future studies may focus on the active components and specific targets of its bacteriostatic effects.

3.4 Intestinal health

Intestinal health is related to many factors, such as intestinal morphology, intestinal barrier, and gastrointestinal dynamics. Intestinal diseases are related to these factors and are one of the major diseases that threaten human health. The whole hawthorn fruit and its constituent polyphenols and polysaccharides have been reported to be beneficial for intestinal health.

Researchers found that dietary supplementation with the hawthorn pulp improved intestinal morphology by increasing villi length, villi width, and muscle thickness, and enhanced gut barrier integrity by increasing the mRNA expression‎ of zonula occludens-3 in golden pompano (Tan et al., 2020). It also improved intestinal health by improving duodenal lipase and trypsin activity and jejunal morphology, as well as higher ileal valproic acid, colonic propionic acid, and isobutyric acid concentrations (Fu et al., 2022). In addition, hawthorn extract can promote gastrointestinal motility by increasing the number of gastrointestinal Cajal (interstitial cell of Cajal [ICC]) mesenchymal cells through upregulation of c-kit expression‎ (Wang, Luo et al., 2021). Besides, it could prevent diarrhea and the accumulation of interstitial fluid (Sammari et al., 2021). Furthermore, hawthorn seeds have also been found to be beneficial for intestinal health. Hawthorn seed ethyl acetate extract improved gastrointestinal motility in rats with diabetic gastroparesis (DGP), and its potential mechanism might be related to the upregulation of n-NOS and c-kit expression‎ and ICCs in the stomach and the regulation of motilin, gastrin, and 5-HT (Niu et al., 2020). The supplementation of hawthorn seed oils could selectively alter the abundance of gut bacteria, including unclassified Christensenellaceae, Ruminococcaceae, Gastranaerophilales, Faecalibaculum, Peptococcus, Clostridiales, and Ruminococcus, which were correlated with cholesterol metabolism (Kwek et al., 2022).

Flavonoids extracted from the whole hawthorn fruit may reverse intestinal flora disorders and metabolic disorders in mice by increasing the proportion of Dubosiella, Alloprevotella, and Bifidobacterium, as well as the levels of docosapentaenoic acid, sphingolipids (SM), and phosphatidylcholine (PC), while decreasing the proportion of immobile bacteria (Zhang et al., 2022). Hawthorn polyphenols were found to shorten the length of lesions formed in colitis rat colon, in addition to decreasing the levels of myeloperoxidase and interleukin-1β (Nascimento et al., 2021). Simultaneously, they could improve the diversity of gut microbial species by altering the abundance of the Bacteroidetes and Firmicutes microorganisms in the gut (Yu et al., 2022). They also increased the abundance of Lactobacillus, but reduced the production of Gram-negative bacteria, thereby reducing the abnormal increase in bacterial diversity caused by alcohol (Wang, Wang et al., 2021).

Polysaccharides have been demonstrated to regulate gut microbiota. Current studies suggest that the hawthorn polysaccharide could directly modify the intestine, particularly by enriching Alistipes and Odoribacter, and produce short-chain fatty acids to inhibit colitis (Guo et al., 2021). Furthermore, it was found to increase the abundance of Micrococcus, Acidaminococcus, and Mitsuokella while decreasing the abundance of E. coli and Clostridium, thus regulating the proportion of beneficial bacteria in the intestine (Han, Zhou, et al., 2022). It also increased the abundance of Akkermansia, Bacteroides, and Adlercreutzia but decreased the abundance of Lactobacillus, Bifidobacterium, Blautia, Lachnospiraceae, and Subdoligranulum to restore the balance of gut microbiota (Han, Zhao, et al., 2022).

Overall, the whole hawthorn fruit exhibits beneficial effects on intestinal health with mechanisms related to the regulation of intestinal morphology, motility, and microbiota abundance. Polyphenols and polysaccharides are the main contributors to its intestinal protection, whereas the underlying mechanisms remain unclear, which needs additional investigation in the future. Moreover, current studies mainly focus on the first messenger, and there are no relevant studies on the specific activated signaling pathways. As a recognized food for promoting digestion and absorption, it would be beneficial to develop hawthorn to promote human gastrointestinal health.

3.5 Antidiabetic effect

Diabetes mellitus is a metabolic disease characterized by hyperglycemia that can be caused by rapid glucose uptake in the intestine. In recent years, the antidiabetic effects of the whole hawthorn fruit and its components have received increasing attention.

α-Amylase and α-glucosidase are two key glucoside hydrolases that catalyze the conversion of starch, disaccharides, or oligosaccharides to glucose during carbohydrate digestion. An important approach to controlling diabetes is to reduce postprandial hyperglycemia by delaying carbohydrate digestion and glucose absorption. The whole hawthorn fruit exhibited excellent hypoglycemic ability due to its ability to resist α-amylase and α-glucosidase (Mecheri et al., 2021). Polysaccharides, a major component of the whole hawthorn fruit, were reported to have high α-amylase inhibitory activity (Rjeibi et al., 2020). In a recent study by Aad et al. (2021), it was found that hawthorn flavonoids could dose-dependently inhibit α-amylase and α-glucosidase. Hypericin, a component extracted from the whole hawthorn fruit, was found to have significant anti-α-glucosidase activity (Lin et al., 2022). In addition, the B-type proanthocyanidin, one of the hawthorn phytochemicals, is a potent, reversible, and competitive inhibitor of α-glucosidase (Liang et al., 2022). Screening and identification of α-glucosidase inhibitors in the whole hawthorn fruit also showed that polyphenols containing mainly quercetin (74.58%) and chrysin (9.58%) played an important role in α-glucosidase inhibition (Xin et al., 2021).

Insulin is the most critical hormone in regulating blood sugar and maintaining normal blood sugar levels. Insulin resistance occurs when insulin regulation becomes delayed and insufficient to inhibit glucose processing. A complex hypoglycemic complex consisting of hawthorn polyphenols, d-chiral inositol, and epigallocatechin gallate increased glucose consumption and glycogen levels and inhibited hepatic gluconeogenesis in HepG2 cells (Xin et al., 2021). Hawthorn polyphenols improved insulin resistance, decreased fasting glucose and hepatic gluconeogenesis, and increased hepatic glycogen synthesis and storage by downregulating phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Forkhead box protein O1 (FOXO1)-mediated phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase and upregulating PI3K/Akt/glycogen synthase (GS) kinase-3–mediated GS activation in STZ/high-fat diet (HFD)-induced mice. Polyphenols in the whole hawthorn fruit significantly reduced insulin resistance by upregulating phosphorylation of glucose uptake protein (GLUT4) and insulin resistance–related proteins phosphorylated insulin receptor substrate (p-IRS1), phosphorylated serthreonine protein kinase (p-AKT), and phosphorylated inositol 3 kinase (p-PI3K) in rat liver (Liu, Yu, et al., 2021). Procyanidins in whole hawthorn berries are involved in fatty acid biosynthesis, MAPK, and lipopolysaccharide biosynthesis pathways to ameliorate hormone-associated insulin resistance (Han, Zhao, et al., 2022).

Furthermore, the whole hawthorn fruit and its constituent polyphenols improved secondary complications of diabetes in vitro and in vivo. Hawthorn pulp treatment and moderate-intensity interval running training simultaneously improved myocardial ischemia-reperfusion-induced renal injury via the miR-126/Nrf-2 pathway and improved insulin sensitivity and renal function in type 1 diabetic rats (Asgari et al., 2022). In addition, the hawthorn seed improved gastrointestinal motility in DGP rats, and its potential mechanism may be related to inhibiting oxidative stress damage caused by hyperglycemia (Niu et al., 2020). On the other hand, hawthorn polyphenols attenuated hyperglycemia-induced retinal damage, possibly through inhibition of the adenosine monophosphate-activated protein kinase (AMPK)/mitochondrial acetylase (SIRT1)/NF-κB and miR-34a/SIRT1/p53 pathways, and attenuated hyperglycemia-induced inflammation and apoptosis in human retinal pigment epithelial cells (ARPE-19 cells) (Liu, Fang, et al., 2021).

Overall, the whole hawthorn berry and its constituents have good antidiabetic potential to prevent and improve diabetes and its complications, including diabetic nephropathy, cardiomyopathy, and DGP, which involve a variety of signaling pathways, such as PI3K/Akt/FOXO1-mediated/PEPCK, AMPK/SIRT/NF-κB, and miR-34a/SIRT1/p53. Polyphenols and polysaccharides are the main hypoglycemic components of the whole hawthorn fruit, but few experiments have been conducted to study their mechanisms of action individually. The development of nutraceuticals from hawthorn and its constituents is a focus of subsequent research.

3.6 Cardiovascular protection

CVD is the leading cause of death in humans. Hypertension, hyperlipidemia, and AS are the main risk factors for CVD, which can be inhibited by the whole hawthorn fruit and its constituents, contributing to its cardiovascular protective effect.

The whole hawthorn extract has potential preventive and therapeutic effects on AS. In golden Syrian hamsters, it might regulate AS by controlling cell survival and proliferation, reducing the levels of enzymes 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) and lipoprotein lipase, and inhibiting inflammatory response (Li, Gao et al., 2022). The promotion of thrombosis induced by platelet aggregation plays an important role in the development of AS in rats. The whole hawthorn extract could reduce thromboxane B2 release, P-selectin expression‎, and activation of cAMP and Akt signaling through the mechanisms of downregulating platelet receptor (P2Y12) (chemoreceptor for adenosine diphosphate) signaling and inhibiting ROS-induced NF-κB activation (Shatoor, Shati, et al., 2021). The whole HFE also produces endothelium-dependent vasodilation in porcine coronary, which is partially dependent on estrogen receptors and is sensitive to the inhibition of the ROS/Src/PI3K/NO pathway (Younis et al., 2021). Its extract had the potential benefit of alleviating endothelial dysfunction in isolated aortic rings from Sprague–Dawley rats, possibly related to the inhibition of arginase (Bujor et al., 2020).

The antihypertensive effects of the hawthorn pulp and its compounds have also been demonstrated. Combination of the hawthorn pulp with vitamin C inhibited heat exposure-induced oxidative changes in vascular tissues under hypertension, contributing to its antihypertensive activities without signs of toxicity, which involved the activation of nitric oxide pathway by muscarinic receptors and/or inhibition of angiotensin-converting enzymes (Zhu et al., 2022). The hawthorn pulp as a parent tincture for the initial treatment of heart failure significantly reduces systolic blood pressure in normotensive rats (Balbueno et al., 2020). Incidentally, the whole hawthorn fruit vinegar could achieve antihypertensive effects by inhibiting the activity of angiotensin-converting enzyme II (Sayin & Gunes, 2021). Specifically, hawthorn berry flavonoid extracts can positively affect the electrocardiogram of oiled chickens reared at high altitude, thereby preventing the complications of pulmonary hypertension and heart wave disorders (Younis et al., 2020).

Hyperlipidemia is another high-risk factor for CVD, and consumption of the hawthorn pulp may regulate blood lipids based on in vitro and in vivo studies. Molecular docking results suggested that acetyl-CoA carboxylase might be the target of the hypolipidemic activity of hawthorn triterpenoids, which is verified in HepG2 cells (Zhu et al., 2022). In addition, hawthorn pectic acid inhibited lipid accumulation in HepG2 cells by upregulating low-density lipoprotein (LDL) receptor and downregulating HMG-CoA reductase gene expression‎ (Feng et al., 2022). The whole hawthorn fruit and its compounds can also regulate blood lipids in animal models. Treatment of the hawthorn pulp also reduced golden pompano's plasma cholesterol, triglycerides, and LDL levels to lower blood lipids (Tan et al., 2020). Hawthorn polyphenol extracts were reported to significantly improve total cholesterol and total triglycerides in T2D rats (Liu, Yu, et al., 2021). Besides, it showed significant lipid-lowering activities (40 mg/kg) in male albino Wistar rats compared to atorvastatin (80 mg/kg) (Zahra et al., 2021). Hawthorn proanthocyanidins significantly alleviated lipid accumulation in the serum and liver through modulation of NF-κB and AMPK pathways and protected liver structure in rats with lipid metabolism disorders (LMDs) (Han, Zhao, et al., 2022). The hawthorn pulp also effectively reduced lipid synthesis in HFD rats by downregulating hepatocyte ER stress-induced peroxisome proliferator–activated receptor-γ (PPAR-γ) expression‎ (Mao et al., 2022). It also ameliorated some of the disordered metabolic pathways in spontaneously hypertensive rats by interfering with sphingolipid, glycerophospholipid, and glycerolipid metabolism (Sun, Chi et al., 2022). Hawthorn seed oils could also reduce plasma cholesterol and non-HDL cholesterol by up to 15% in hypercholesterolemia hamsters (Kwek et al., 2022).

In general, the whole hawthorn fruit and its components can alleviate cardiovascular risk factors, such as AS, vascular strain, vascular tension, and hyperlipidemia, without significant side effects. The mechanism is related to the regulation of cAMP, Akt, P2Y12, NF-κB, ROS/Src/PI3K/NO signaling pathways, which lead to the downregulation of HMG-CoAR, angiotensin-converting enzyme II, and other related enzymes. Hawthorn is worth developing nutraceuticals for due to its multi-targeted treatment of CVDs.

3.7 Hepatoprotective effect

The whole hawthorn fruit and its components have been reported to exhibit hepatoprotective effects on acute liver injury as well as chronic liver diseases, which are discussed as follows.

The protective ability of hawthorn pulp and its components on acute liver injury caused by drugs and alcohol has been demonstrated in vivo. Treatment with the ethanolic extract of the whole hawthorn fruit reduced total bilirubin concentration, increased total protein ratio, altered serum ALP, aspartate aminotransferase, and alanine aminotransferase levels, and improved liver tissue morphology in isoniazid and rifampicin, which caused hepatotoxicity in rats (Han, Zhao, et al., 2022). Lactobacillus rhamnosus 217-1 fermented mixture of Pueraria lobata, Lonicera japonica, and hawthorn pulp improved liver indexes, increased the activities of liver tissue superoxide dismutase and glutathione, and decreased the levels of MDA in a mouse model of alcoholic liver disease (Wang, Wang et al., 2021).

The hawthorn pulp also exhibited excellent protective effects against chronic liver diseases. It could ameliorate obesity-related hepatic steatosis in HFD rats by reducing hepatic endoplasmic reticulum (ER) stress through the downregulation of PPAR-γ and glucose regulatory protein 78 (a major regulator of ER homeostasis) (Mao et al., 2022). Another study also confirmed that it ameliorated HFD-induced hepatic steatosis via the prevention of elevated serum and hepatic lipids, and the mechanism could be associated with the activation of AMPK signaling and the subsequent blocking of its downstream molecules, such as hepatic expression‎ of sterol regulatory element–binding protein 1/2, fatty acid synthase, and 3-hydroxy-3-methylglutaryl coenzyme A reductase (Shatoor, Al Humayed, et al., 2021). In addition, proanthocyanidins in the whole hawthorn fruit could protect the liver structure and reduce liver inflammation and lipid accumulation by regulating LM-related NF-κB and AMPK pathways in LMD rats (Han, Zhao, et al., 2022).

In brief, the whole hawthorn fruit and its constituents, mainly proanthocyanidins, showed potential to treat the liver injury caused by alcohol, isoniazid, rifampin, and HFD while improving liver steatosis and functional indices; the protective mechanism is mainly related to resistance to oxidative stress and impaired lipid metabolism in the liver. However, the specific targets of its action have not been fully revealed, and subsequent studies can utilize relevant cell models to investigate the specific targets of its action.

3.8 Anti-cancer effect

Current studies have shown that the whole hawthorn fruit and its components, especially proanthocyanidins, have anti-cancer activity.

The whole HFE and its components have been reported to have anti-cancer activity against different cancer cells in vitro. Methanolic extracts of the whole hawthorn fruit rich in polyphenols were found to be cytotoxic against human breast cancer cells (MCF-7) hormone receptor-positive and human breast cancer cells (MDA-MB-231) triple-negative breast cancer cell lines, effectively inhibiting tumor cell proliferation and arresting the cell cycle at the G1/S transition, possibly associated with the regulation of Wnt signaling pathway (Kombiyil & Sivasithamparam, 2023). Polyphenols also inhibited apoptosis through the AMPK/SIRT1/NF-κB pathway and reduced miR-34a/SIRT1/p53 pathway activation in human retinal pigment epithelial cells (ARPE-19 cells) (Liu, Fang, et al., 2021). Homogeneous polysaccharides extracted from the whole hawthorn fruit also possessed anti-cancer effects on colon cancer cells by upregulating caspase 3, 7, 8, 9, and Fas, fas-associating protein with death domain, TNF-R1, and TNF receptor-1-associated death domain protein, and downregulating cyclin A1/D1/E1 and cyclin-dependent kinase-1/2 (Ma et al., 2020). Hawthorn B–type proanthocyanidin polymorphs composed of epicatechin strongly inhibited intracellular tyrosinase activity and melanogenesis and induced apoptosis in mouse melanoma cells (Liang et al., 2022). It blocked the HCT116 cell cycle in the G2/M phase through the p53-cyclin B pathway and promoted apoptosis partly through the mitochondrial (cysteine 9-cysteine 3) and death receptor (cysteine 8-cysteine 3) pathways (Sun, Wang et al., 2022). Meanwhile, two new pairs of lignan enantiomers (1a/1b and 2a/2b) isolated from the whole hawthorn fruit were cytotoxic to Hep3B hepatoma cells with IC50 values of 34.97 ± 2.74 and 17.42 ± 0.71 μM, respectively. In addition, 1b induced more apoptotic and autophagic cells than 1a in Hep3B cells, which may be related to the activation of p38 to promote 1b-induced apoptosis and autophagy (Shang et al., 2020). The HFE inhibited the proliferative and invasive potential of glioblastoma cells by promoting the cleavage of poly (ADP-ribose) polymerase 1 (PARP1) associated with apoptosis and significantly inhibiting pro-survival kinase, adherent plaque kinase (FAK), and Akt (Żurek et al., 2021). Silver nanoparticles (CME@Ag-NPs) prepared from the HFE were very effective in inhibiting the growth of gastric and mammary gland cancer cell lines in vitro (Shirzadi-Ahodashti et al., 2020).

In summary, the whole HFE and its components are potential anti-cancer natural products. They have a positive effect on the prevention and treatment of a variety of cancers in vitro, including gastric, colon, liver, breast, and mammary cancers. Their anti-cancer mechanisms include the inhibition of cancer cell growth and induction of apoptosis, in part through p53-cyclin B, AMPK/SIRT1/NF-κB, miR-34a/SIRT1/p53, mitochondrial (cysteine 9-cysteine 3), and death receptor (cysteine 8-cysteine 3) signaling pathways. These findings open up the possibility that whole hawthorn extract and its components can be used for the prevention and management of different cancers.

3.9 Neuroprotective activity

The whole HFE and its components have been found to have neuroprotective effects on nerve injury in vitro and in vivo.

Acetylcholinesterase (AChE) plays an important role in neurodegenerative diseases that affect memory. Hawthorn's components showed significant AChE inhibitory activities. The phenolic compounds of the whole hawthorn fruit have been shown to possess stronger AChE inhibitory activity than donepezil (Liu, Zhang et al., 2020). Polysaccharides from the pulp exhibited higher AChE inhibitory activity (Rjeibi et al., 2020).

Lignans, isolated from the whole hawthorn fruits, were reported to protect against H2O2-induced damage in human neuroblastoma SH-SY5Y cells (Zhang et al., 2023). In addition, the whole HFE prevented traumatic brain injury–mediated reduction in neuronal survival and inhibited neuronal death in the rat cerebral cortex by activating Nrf2 pathways and inhibiting NF-κB expression‎ (Gao et al., 2022).

Therefore, the whole hawthorn fruit and its components, mainly lignans and polysaccharides, have significant neuroprotective activity, implying that they may be potential inhibitors of AChE and beneficial for human memory. However, its specific mechanism of action and target of action have not been described in detail, which is worth exploring in depth in the future.

3.10 Other bioactivities

The whole hawthorn extract and its components exhibited other bioactivities in vitro. The whole hawthorn extract inhibited osteoclast differentiation by suppressing the nuclear factor of activated T cells (NFATc1) and c-Fos expression‎ and suppressing the expression‎ of osteoclast-related genes, such as NFATc1, Ca2, Acp5, mmp9, cathepsin K (CtsK), Oscar, and Atp6v0d2 (Kim et al., 2021). Proanthocyanidins and phenylpropanoids extracted from the whole hawthorn fruit exhibited moderate tyrosinase inhibitory activity (Liang et al., 2022) (Table 1).

TABLE 1. Bioactivities and related molecular mechanisms of the hawthorn fruit based on in vitro and in vivo studies.

Extracts/CompoundsSubjects/Cell linesDosesMain effectsMechanismsReferences

• Abbreviations: AChE, acetylcholinesterase; AMPK, activated protein kinase; ABTS, 2,2′-Azino-bis(3-ethylbenzthiazoline-6-sulfonic acid); AGS, growth of gastric; ALP, alkaline phosphatase; AP-1, activator protein-1; BDNF, brain-derived neurotrophic factor; CtsK, cathepsin K; CAT, catalase; CRP, C-reactive protein; DPPH, 1-diphenyl-2-picrylhydrazyl radical; DSS, dextran sulfate sodium; FAK, adherent plaque kinase; FOS, fructooligosaccharides; GSH-Px3, glutathione peroxidase 3; HO-1, heme oxygenase 1; H2O2, hydrogen peroxide; HFD, high-fat diet; ICC, interstitial cell of Cajal; LPS, lipopolysaccharide; MARK, protein kinase; MCF, mammary gland; MCP-1, monocyte chemoattractant protein 1; MDA, malondialdehyde; MIC, minimum inhibitory concentration; MPO, myeloperoxidase; NFATc1, nuclear factor of activated T cells; NFAT, nuclear factor levels of activated T cells; NF-κB, nuclear factor kappa-light chain enhancer of activated B cells; Nrf2, nuclear factor erythropoietin-2-related factor; 2PFC, prefrontal cortex; PPAR-γ, peroxisome proliferator–activated receptor-γ; PI3K, phosphoinositide 3-kinase; PGE2, prostaglandin E2; PKB, protein kinase B; ROS, reactive oxygen species; SOD, superoxide dismutase; T2D, type 2 diabetes; TC, total cholesterol; TG, total triglyceride; TMAO, trimethylamine-N-oxide; TNF-α, tumor necrosis factor-α; XOS, xylooligosaccharides.

The whole hawthorn fruit and its components also had other in vivo beneficial functions. The whole hawthorn extract could also enhance immune response and growth performance (Fu et al., 2022). Hawthorn pulp was sufficient to produce anxiolytic and antidepressant-like effects by activating 5-HT1A receptors and elevating brain-derived neurotrophic factor, increasing urinary serotonin levels, and decreasing urinary NE and DA levels (Nitzan et al., 2022). The defatted methanolic extract of the whole hawthorn had excellent anti-injury sensitizing ability (Abdel-Rahman et al., 2021). Incidentally, hawthorn polyphenol microcapsules (HPMs) improved swimming ability and skeletal muscle substrate depletion as well as product metabolism, enhanced antioxidant capacity in fatigued mice, possibly through activation of AMPK pathways to improve mitochondrial dysfunction and cellular metabolism, inhibition of NF-κB inflammatory conserved pathways, and improved the diversity of gut microbial species (Yu et al., 2022).

4 HEALTH BENEFITS BASED ON HUMAN STUDIES

The whole hawthorn fruit has also been demonstrated to possess health benefits for humans, especially with cardiovascular protective effects. It was reported to regulate blood pressure on humans. The HFE exhibited significant hypotensive effects in diabetic patients taking medication, especially in lowering resting diastolic blood pressure (Hu et al., 2014). A combination of natural d-camphor and fresh HFE could improve hypotension in adolescents, adults, and the elderly (Schandry et al., 2018). It could also regulate blood lipids. A polyherbal formula containing the hawthorn pulp (1 g daily), Alisma orientalis, Stigma maydis, Ganoderma lucidum, Polygonum multiflorum, and Morus alba reduced LDL cholesterol and glycated hemoglobin in patients with dyslipidemia (Holubarsch et al., 2008). Besides, the HFE might reduce the incidence of sudden cardiac death in patients with less impaired left ventricular function (Holubarsch et al., 2008).

Limited clinical studies indicate that the whole hawthorn fruit possesses beneficial effects on mental health. It was reported that the extracts of the whole hawthorn fruit and Eschscholtzia californica significantly reduced total somatic Hamilton scale scores and self-rated anxiety in mild-to-moderate anxiety patients (Hanus et al., 2004).

In summary, the whole hawthorn fruit has been demonstrated to benefit the cardiovascular system, mainly through regulating blood pressure, regulating blood lipids, and alleviating heart failure symptoms (Table 2). However, its other health benefits on humans require further studies for verification. For example, the beneficial effects of the whole hawthorn fruit on human intestinal health and its anti-inflammatory effects need to be confirmed in more clinical trials.

TABLE 2. Health benefits of the hawthorn fruit based on human studies.

Extracts/CompoundsParticipantsControlTreatmentsMain effectsReferences

Antihypertensive effects
Hawthorn extract	Patients with type 2 diabetes	Placebo	Daily 1200 mg	Antihypertensive	Hu et al. (2014)
Korodin, a combination of camphor and hawthorn extract	Adolescent participants in the age range of 14– 17 years having a systolic blood pressure below 118 mmHg (boys) or 110 mmHg (girls)	Placebo	A single dose of 20 drops	Blood pressure ↑	Schandry et al. (2018)
Hypolipidemic effects
The multiherb formula containing hawthorn, Alisma orientalis, Stigma maydis, Ganoderma lucidum, Polygonum multiflorum, and Morus alba	Patients with dyslipidemia	Placebo	800 mg (two capsules), three times a day, 15 days	Lipoprotein cholesterol ↓ Glycated hemoglobin ↓	Holubarsch et al. (2008)
Anti-heart failure effects
Neuroprotective effects
Extracts of hawthorn and Eschscholtzia California	Patients presenting with generalized anxiety (DSM-III-R) of mild-to-moderate intensity	Placebo	NA	Total and somatic Hamilton scale scores ↓ Subjective patient-rated anxiety ↓	Hanus et al. (2004)

5 FOOD-RELATED APPLICATIONS

Studies have demonstrated various food-related applications of the whole hawthorn fruit (Figure 3). pH-sensitive films are thin and transparent layers that can change color or fluorescence in response to changes in pH. In a study conducted by Yan et al. (2021), the incorporation of the whole HFE into gelatin/chitosan/nanocellulose composite films yielded positive pH-sensitive films, suggesting that the developed films could be used to indicate the changes in food quality. Another interesting food application is the usage of hawthorn wine pomace. It demonstrated the sustainable use of hawthorn wine pomace for HP synthesis, which acted as an effective and antioxidative stabilizer (Jiang et al., 2020). Lastly, a study by Liu, Yang et al. (2020) showed that the antioxidant ability of HP helped preserve the Pickering emulsion from its lipid oxidation, thus stabilizing Pickering emulsions as particle shell materials while protecting lipid components from oxidation.

FIGURE 3

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Bioactivities of the hawthorn fruit and its compounds based on in vitro and in vivo studies. ABTS, 2,2′-Azino-bis(3-ethylbenzthiazoline-6-sulfonic acid); ALP, alkaline phosphatase; AP-1, activator protein-1; CAT, catalase; CRP, C-reactive protein; DPPH, 1-diphenyl-2-picrylhydrazyl radical; FAK, adherent plaque kinase; FOS, fructooligosaccharides; GSH-Px3, glutathione peroxidase 3; LPS, lipopolysaccharide; MARK, protein kinase; MCF, mammary gland; MCP-1, monocyte chemoattractant protein 1; MDA, malondialdehyde; MPO, myeloperoxidase; NFAT, nuclear factor levels of activated T cells; PFC, prefrontal cortex; PGE2, prostaglandin E2; PKB, protein kinase B; ROS, reactive oxygen species; SOD, superoxide dismutase; T2D, type 2 diabetes; TBI, traumatic brain injury; TC, total cholesterol; TG, total triglyceride; TMAO, trimethylamine-N-oxide; TNF-α, tumor necrosis factor-α; XOS, xylooligosaccharides.

Recent studies have also explored the use of the whole hawthorn fruit in the development of food products. A study by Ozcelik et al. (2021) investigated the properties of hawthorn juice-based water kefir, indicating the potential of hawthorn juice-based water kefir as an effective antioxidant beverage. Another interesting food application is the manufacturing of hawthorn wine as a new beverage. Collectively, these studies demonstrate positive results in hawthorn wine production and quality.

6 THE SAFETY ISSUE

In terms of safety, the whole hawthorn fruit is generally regarded as a safe fruit for consumption, and the European Medicines Agency's Committee for Herbal Medicinal Products has also classified hawthorn as a “Traditional Herbal Medicinal Product” and deemed it safe for consumption due to its long history of use (Distefano, 2021). Various systematic reviews have shown that the whole hawthorn fruit is generally safe for consumption. For instance, a systematic review conducted by Daniele et al. (2006) showed that the whole hawthorn is well tolerated, even if several adverse events were reported. It was found that the most frequent adverse events included dizziness/vertigo, gastrointestinal complaints, headache, migraine, and palpitation. There were also no reports of herb–drug interactions. Another review conducted by Cloud et al. (2020) also showed that the whole hawthorn fruit is considered a relatively safe herb without severe adverse effects for consumption up to 24 months. Despite the favorable indications that the whole hawthorn fruit may be safe for consumption and development into medicinal food products, further research is required to properly examine the safety of hawthorn-containing formulations. Future studies can also focus on investigating possible herb–drug interactions of the whole hawthorn fruit if consumed with other concomitant medications.

In addition, optimal dosage is another potential concern for the safety of the whole hawthorn fruit. For instance, a study conducted on whole HFE showed that it did not produce marked genotoxic effects at concentrations of 2.5 or 5 μg/mL in leukocytes or human liver hepatocellular carcinoma cells (HepG2 cells) (de Quadros et al., 2017), however, at concentrations of 10 μg/mL or higher, significant DNA damage and clastogenic/aneugenic responses were observed. Furthermore, the whole HFE was also found to exhibit weak clastogenic and/or aneugenic effects in bone marrow cells of male mice, suggesting that prolonged or high-dose use of such extracts needs to be undertaken with caution (Yonekubo et al., 2018). Therefore, it is also crucial to eval‎uate the optimal dosage of the whole HFEs for safe human consumption.

7 CONCLUSION AND PERSPECTIVES

Recent research progress indicates that the whole hawthorn fruit can be a new natural source of functional foods. Its main bioactive components are polyphenols and polysaccharides. The fruit and its bioactive compounds have also been discovered to have numerous beneficial bioactivities that may be useful in the prevention and management of certain diseases. Some of the most critical biological activities are anti-inflammatory, antimicrobial, gut-protective, antidiabetic, cardioprotective, hepatoprotective, and anti-cancer properties that may prevent or even treat diseases, indicating an impact on the management of health problems. However, the underlying mechanisms of their relevant functions are not fully understood, such as the mechanisms and targets of anti-cancer and neuroprotective effects, requiring further research. A better understanding of the bioavailability, pharmacokinetics, and metabolic pathways of the whole hawthorn extract and the main bioactive compounds in the human body is important for the development of hawthorn-related nutraceuticals. In today's society, diseases and sub-health phenomena occur frequently, and more and more people seek to prevent and maintain health from the diet. Therefore, hawthorn, as an edible and medicinal fruit, contains a large number of naturally occurring bioactive components with abundant beneficial functions that are generally safe and reliable to be used to gradually improve health in daily life. It is also a valuable source of dietary bioactive components for the development of functional foods or other nutraceuticals and for the prevention and management of certain chronic diseases.

AUTHOR CONTRIBUTIONS

Ren-You Gan and Li-Dan Zhong conceived this paper; Jin-Xin Ma, Wei Yang, and Chester Yan Jie Ng wrote this paper; Ren-You Gan, Li-Dan Zhong, Xu-Dong Tang, and Sunny Wong provided critical comments and revised the paper. The final version was approved by all the authors.

ACKNOWLEDGMENTS

This study was supported by the Qi Huang Young Scholar Programme (National Administration of Traditional Chinese Medicine), The 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-Hong Kong-Macau Joint Lab) [grant number 2020B1212030006], and the China Scholarship Council [grant number

REVIEW ARTICLE

Open Access

The hawthorn (Crataegus pinnatifida Bge.) fruit as a new dietary source of bioactive ingredients with multiple beneficial functions

Jin-Xin Ma, Wei Yang, Chester Yan Jie Ng, Xu-Dong Tang, Sunny Wong, Ren-You Gan, Linda Zhong

First published: 07 May 2024

https://doi.org/10.1002/fft2.413

Citations: 3

Jin-Xin Ma and Wei Yang contributed equally to the work.

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Abstract

The discovery of new natural sources has brought increased attention to the development of functional foods. The hawthorn (Crataegus pinnatifida Bge.) fruit is an underutilized fruit due to its benefits for human health and good taste. It contains a variety of bioactive ingredients, contributing to its multiple beneficial functions and applications. This review summarized and discussed the main bioactive ingredients, beneficial functions based on in vitro, in vivo, and human studies, and different applications of the hawthorn fruit according to the updated literature in the past 3 years. Hawthorn berries contain phenolic acids, flavonoids, proanthocyanidins, pectin, and many other bioactive components, which have a variety of beneficial functions, such as antioxidant, anti-inflammatory, antibacterial, antidiabetic, intestinal protection, cardiovascular protection, hepatoprotection, anti-cancer, and neuroprotection. Its potential molecular mechanism and different food-related applications such as hawthorn wine and antioxidant drink are discussed in detail in this review. Additionally, hawthorn berries are shown to be safe when consumed within the proper dosage. Collectively, this updated review indicates that the hawthorn fruit can be a new dietary source of bioactive ingredients with multiple beneficial functions and can be affordably developed into functional and medicinal foods for the prevention and management of certain chronic diseases.

1 INTRODUCTION

Hawthorn, also known as Crataegus pinnatifida Bge., belongs to the Rosaceae family and is a deciduous tree (Hamza et al., 2020). The hawthorn fruit, with both medicinal and edible characteristics, has a long history of use as Traditional Chinese Medicine and has been proven to possess many health benefits. According to the theory of Traditional Chinese Medicine, it has the functions of promoting digestion, invigorating the spleen, nourishing vitality, and removing blood stasis (Hou et al., 2020). Modern research has also discovered that it contains phenolic acids, flavonoids, proanthocyanidins, pectin, and other bioactive ingredients (Li, Gao et al., 2022; Li et al., 2021). In the past decade of research, hawthorn berries and their bioactive constituents have been shown to possess many beneficial functions, such as antioxidant, anti-inflammatory, antibacterial, intestinal protection, modulation of intestinal microbiota, cardiovascular protection, and antidiabetic and neuroprotective effects. It also has a broad prospect in drug and food research and development (Lin et al., 2022; Schandry et al., 2018; Wang, Wang et al., 2021). As a kind of food with the same origin of food and medicine, the hawthorn fruit has gradually received more attention in the modern life, which emphasizes a healthy diet.

However, there is still a lack of a state-of-the-art review to better understand its main bioactive ingredients and beneficial functions. Hence, our study retrieved relevant literature regarding the hawthorn fruit published in the past 3 years from the Web of Science Core Collection and PubMed databases. Our study first summarizes the main bioactive components of the whole hawthorn fruit, then comprehensively discusses the health effects of the whole hawthorn fruit and its main bioactive components from in vitro, in vivo, and clinical studies, focusing on hawthorn berries and their main bioactive components and their antioxidant, anti-inflammatory, antimicrobial, intestinal protection, regulation of intestinal microbiota, cardiovascular protection, and antidiabetic effects. Finally, the application of hawthorn berries in food products is introduced, and the potential safety issues of hawthorn are discussed. We hope that this review paper can attract more attention to the hawthorn fruit and promote its further research and application in the prevention and management of certain chronic diseases.

2 BIOACTIVE INGREDIENTS IN THE WHOLE HAWTHORN FRUIT

The whole hawthorn fruit contains various bioactive ingredients, like polyphenols, polysaccharides, terpenoids, essential oils, and lignans, with representative compounds shown in Figure 1. Different factors, such as the varieties, cultivation regions, and postharvest drying methods, can influence the bioactive ingredients and their content in the whole hawthorn fruit, and they are discussed in the following sections.

FIGURE 1

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Chemical structures of bioactive compounds in the hawthorn fruit.

2.1 Polyphenols

Polyphenols are a large family of organic compounds that are characterized by at least one hydroxyl group in the benzene ring. Polyphenols are abundant in many plant-based foods (Lund, 2021). Usually, methanol and ethanol are common solvents for the extraction of polyphenols from plants. A study by Sultana et al. (2009) found that aqueous methanol was comparatively more efficient than ethanol and acerone for polyphenol extraction from different medicinal plant extracts. The predominant polyphenolic compounds in whole hawthorn fruits include phenolic acids, flavonoids, and proanthocyanidins, and the main compounds and chemical structures are shown in Figure 1.

2.1.1 Phenolic acids

Phenolic acids are one of the main categories of phenolic compounds in the whole hawthorn fruit. Besides the Soxhlet extraction and ultrasonic-assisted extraction that are commonly used in phenolic acid extraction, supercritical fluid extraction and accelerated solvent extraction are also developed as alternative techniques (Arceusz et al., 2013). Gallic acid, caffeic acid, and syringic acid were found in fresh and dehydrated whole hawthorn fruits (Benabderrahmane et al., 2021). In addition, gallic acid, neochlorogenic acid, and cryptochlorogenic acid were revealed to be active components of the whole hawthorn fruit for the treatment of hyperlipidemia and cardiovascular diseases (CVDs) (Sun, Zeng et al., 2022).

2.1.2 Flavonoids

Flavonoids are another important category of polyphenols that have important biological effects. Flavonoids are usually extracted by a combination of ethanol and water in different proportions and can also be extracted by the natural deep eutectic solvents, which could solubilize moderately polar flavonoids in a low-cost and environment-friendly manner (Chaves et al., 2020). It was found that (+)-catechin was a main flavonoid compound in hawthorn pulp, ranging from 9.57 to 29.9 mg/100 g based on different extraction methods (Özcan et al., 2022). In addition, apigenin, luteolin, chrysin, and quercetin were also found in the whole hawthorn fruit (Li, Gao et al., 2022). Moreover, vitexin 2″-O-rhamnoside, rutin, vitexin, and hyperoside were identified in three different varieties of whole hawthorn fruit (Agiel et al., 2022). The cultivation regions can influence the total flavonoid content (TFC) in the whole hawthorn fruit. For example, Hou et al. (2020) eval‎uated the TFC in the whole hawthorn fruits from five places in China, and they found that the TFC in samples from Henan was the highest, whereas the TFC of the Jiangsu samples was the lowest, and epicatechin was the predominant flavonoid in all samples from all regions.

2.1.3 Proanthocyanidins

Proanthocyanidins, also called condensed tannins, are a category of polyphenols with higher molecular weights compared with common phenolic acids and flavonoids. They are oligomeric compounds with a basic framework structure consisting of epicatechin or catechin. Procyanidins are members of proanthocyanidins that are found in the whole hawthorn fruit. Liquid/Liquid extraction is the main method for proanthocyanidin isolation. In addition, ethyl acetate and water are the most commonly used solvent systems for liquid/liquid extraction (Liu, 2012). Procyanidin dimers (e.g., procyanidins B2 and B5), dimer hexosides, and trimers (e.g., procyanidins C1 and C5) are shown to be the major procyanidins in whole hawthorn fruits (Liu et al., 2009). Liu et al. (2010) optimized the extraction and purification methods of procyanidins from whole hawthorn fruits and found that the content of procyanidins was 2.96% ± 0.14%, and the oligomeric procyanidins/procyanidins ratio was 61.6%, which was the highest in their screening sources.

2.2 Polysaccharides

Most of the cellulosic polysaccharides are polar macromolecules and soluble in water. Thus, polysaccharides are usually extracted using hot water according to the principle of “similar compatibility.” On top of hot water extraction, some other methods, such as microwave-assisted extraction, ultrasonic-assisted extraction, acid–base extraction, enzymatic extraction, and ultrahigh-pressure extraction, have also been developed for polysaccharide extraction (Liu & Huang, 2019). The common methods for the separation and purification of polysaccharides include precipitation, ultrafiltration, and gel chromatography (Zhan et al., 2023; Wang et al., 2010; Luo et al., 2010). The whole hawthorn fruit is also rich in polysaccharides. Its pulps contain 82.35% of total carbohydrates and 29.39% of uronic acid contents, which is higher than its seeds (Rjeibi et al., 2020). In addition, pectin is the predominant polysaccharide in the whole hawthorn fruit. Guo et al. (2019) extracted a high-methoxylated pectic polysaccharide with the mild acid extraction method from hawthorn wine residues and found that the pectic polysaccharide had a relatively lower molecular weight and higher polydispersity index when compared with pectin from the whole hawthorn fruit, indicating that the wine-making processing degraded the chain of polysaccharides originally existing in the whole hawthorn fruit. Another study obtained the whole hawthorn fruit pectin by ultrasound-sodium citrate assisted extraction and divided it into quaternized hawthorn pectin (QHP) by (3-chlom-2-hydroxypropyl) trimethylammonium chloride under alkaline conditions according to different degrees of substitution, and the quaternary ammonium modification was found to improve the water solubility and water holding capacity of the pectin (Qin et al., 2022). The weight-average molecular weight (Mw) of its pectin was 379.35 ± 0.57 KDa, and the number-average molecular weight (Mn) was 147.72 ± 1.40; thus, the Mw/Mn values indicate that the molecular weight distribution was 2.57 ± 0.03. Li, Zhang et al. (2022) extracted, purified, and analyzed the hawthorn pectic polysaccharide and found that its Mw ranged from 73.67 × 103 to 464.42 × 103 KDa, depending on the type of extraction method. Zhu et al. (2019) found that the monosaccharide composition of HP polysaccharides included d-galacturonic acid, d-glucuronic acid, d-glucose, l-rhamnose, d-galactose, d-xylose, and d-arabinose.

2.3 Other ingredients

The whole hawthorn fruit also contains other bioactive ingredients, like terpenoids, volatile compounds, and lignans. Two triterpenoids, oleanic acid and corosolic acid, were identified in the whole hawthorn fruit (Li, Gao et al., 2022). The volatile compounds of the whole hawthorn fruits vary at each maturity stage, and some esters (e.g., butyl and hexyl hexanoates, hexyl, and cis-3-hexenyl acetates) gradually increased in the Sultan cultivar (Dursun et al., 2021). In addition, beta-thujene (17.21%), alpha-pinene (15.40%), 2-hexenal (12.42%), trans-caryophyllene (8.76%), beta-myrcene (7.89%), 1-pentacene (5.89%), sabinene (4.33%), and trans-beta-farnesene were identified as the major essential oil compounds in the whole hawthorn fruit (Bazgir et al., 2020). Besides, Shang et al. (2020) isolated two pairs of new lignan enantiomers (1a/1b, 2a/2b) from the whole hawthorn fruit, and Xin et al. (2022) isolated seven lignans, including six new compounds, from the whole hawthorn fruit.

3 BIOACTIVITIES BASED ON IN VITRO AND IN VIVO STUDIES

The whole hawthorn fruit has been reported to contain many bioactive components (Figure 2), such as phenolic acids, flavonoids, proanthocyanidins, and pectin, which are intensively discussed as follows. The underlying molecular mechanisms will also be highlighted.

FIGURE 2

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Food-related applications of the hawthorn fruit.

3.1 Antioxidant activity

Oxidative stress is a redox imbalance accompanied by increased production of reactive oxygen species (ROS) and overwhelming antioxidant defenses (He et al., 2021). Free radical–induced oxidative stress is closely associated with many human diseases like CVD, autoimmune disease, and age-related sexual decline. The antioxidant effects of plant flavonoids have been frequently reported, and possible mechanisms include inhibiting the production or direct elimination of free radicals, or inhibiting lipid peroxidation (Huang et al., 2022).

Recent studies have reported that the hawthorn pulp and its polyphenols exhibit potent antioxidant activity in vitro. It was shown that the total antioxidant capacity of the hawthorn pulp was 0.32–1.84 mmol Fe2+/g dry weight (DW) (Alirezalu et al., 2020), and it had a more stable anti-lipid peroxidation capacity than vitamin C (Feng et al., 2022). The antioxidant activity of the hawthorn pulp was mainly attributed to its free phenolics, accounting for 35.3%–37.8% of its antioxidant activity, followed by insoluble-bound, soluble esterified–bound, and soluble glycosylated–bound phenolics, accounting for 25.0%–27.0%, 23.4%–25.7%, and 9.4%–15.7% of its antioxidant activity, respectively (Feng et al., 2022). Interestingly, the antioxidant activity of insoluble-bound phenolics in its peel (103–125 μmol Trolox/g DW) was significantly higher than that in its pulp (61.3–67.3 μmol Trolox/g DW) (Lou et al., 2020). Moreover, polyphenols in the hawthorn pulp also exhibited obvious scavenging activities against 1-diphenyl-2-picrylhydrazyl radical, 2,2′-Azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), and hydroxyl radicals (Lin et al., 2022). Chlorogenic acid and chrysin showed potential antioxidant activity in ABTS and superoxide radical scavenging assays (Lin et al., 2022). Chlorogenic acid, epicatechin, and procyanidin B2 were found to be the predominant antioxidant contributors in hawthorn pulp (Lou et al., 2021).

The hawthorn extract and its polyphenols also exhibited antioxidant activities in cells and animals. The whole hawthorn extract significantly increased cell viability and enhanced the activities of superoxide dismutase, catalase, and glutathione peroxidase, while decreasing lactate dehydrogenase release, ROS levels, and peroxide (H2O2)-induced malondialdehyde (MDA) content in rat pheochromocytoma cells (PC12 cells) (Wang et al., 2022). Treatment using the whole hawthorn fruit extract (HFE) increased the antioxidant capacity of human hepatocellular carcinoma cells (HepG2 cells) and reduced oleic acid–induced hyperlipidemia by activating the nuclear factor erythropoietin-2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway (Feng et al., 2022). Hawthorn flavonoids were also discovered to possess powerful Peroxyl radical scavenging activity and strong intracellular antioxidant activity in cells (Huang et al., 2022). The whole hawthorn fruit promoted the antioxidant capacity of both plasma and liver (He et al., 2021) and could inhibit lipid peroxidation in liver tissue and red blood cells (Feng et al., 2022).

These results suggest that polyphenols are the main antioxidants in the whole hawthorn fruit, and the underlying antioxidant mechanisms involve the activation of the Nrf2/HO-1 signaling pathway, enhancement of antioxidant enzyme activity, and ultimately induction of cellular antioxidant defense systems. Further studies are needed to verify whether other signaling pathways and oxidative stress molecules are involved in the in vivo antioxidant effects of whole hawthorn fruit and their polyphenols and to provide more reliable evidence for the development of natural antioxidant functional foods in the future.

3.2 Anti-inflammatory activity

Inflammation is an unavoidable consequence of normal cellular activity, and it can cause acute and chronic diseases and accelerate the aging process. Many studies have reported the anti-inflammatory effects of the whole hawthorn fruit and its bioactive components in vitro and in vivo. The whole HFE is rich in phenolic compounds, especially chlorogenic acid and (−)-epicatechin, which are widely known for their anti-inflammatory effects (Abdel-Rahman et al., 2021; Nguyen et al., 2021).

The whole HFE and its compounds can inhibit inflammation in vitro. Its flavonoids were reported to inhibit the production of inflammatory cytokines, including IL-6, IL-8, and IL-1β in human colorectal adenocarcinoma cells, possibly by suppressing the upregulation of myosin light chain kinase (MLCK)/myosin regulatory light chain (MLC) phosphorylation and inhibiting the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor kappa-light chain enhancer of activated B cells (NF-κB) signaling (Liu, Zhang et al., 2020). The whole HFE also inhibited ROS formation and mRNA production of protein kinase (MAPK)/activator protein-1 (AP-1), NF-κB, and lipopolysaccharide (LPS)-stimulated keratinocytes nuclear factor levels of activated T cells (NFAT) and interleukins in keratinocytes in a dose-dependent manner (Nguyen et al., 2021). Moreover, four new biphenyl derivatives (1–4) as well as two known compounds (5 and 6) extracted from the whole hawthorn fruit also showed anti-inflammatory activities in mouse mononuclear macrophage leukemia cells (RAW264.7 cells) (Wang et al., 2020).

Similarly, the hawthorn pulp can also block inflammation in vivo, contributing to its therapeutic effects on inflammation-related chronic diseases. It was reported that the hawthorn pulp significantly reduced the pro-inflammatory mediators of prostaglandin E2, tumor necrosis factor-α (TNF-α), and myeloperoxidase (MPO) by modulating NF-κB in vivo, thus showing high potency in inhibiting keratin-induced inflammation (Abdel-Rahman et al., 2021). Meanwhile, it could also significantly lower plasma levels of TNF-α and monocyte chemoattractant protein 1 (MCP-1) and downregulate the hepatic expression‎ of MCP-1 and IL-1β in type 2 diabetes (T2D) rats (He et al., 2021). Moreover, the hawthorn pulp could reduce plasma myeloperoxidase, C-reactive protein, and alkaline phosphatase (ALP) levels, suggesting its potential to block or regulate intestinal inflammation in a castor oil–induced rat model (Nascimento et al., 2021; Sammari et al., 2021). In addition, a series of animal experiments have demonstrated that hawthorn pulp can alleviate chronic diseases associated with inflammation, such as osteoarthritis, ulcerative colitis, atherosclerosis (AS), chronic heart failure, hepatic fibrosis, and obesity, but the specific mechanism of action has not yet been completely revealed (Alsharif et al., 2022; Cheng et al., 2020; Hamza et al., 2020; He et al., 2021; Nguyen et al., 2021).

Overall, a large number of studies support the anti-inflammatory activity of the whole HFE and hawthorn pulp, and its anti-inflammatory mechanism is related to the regulation of NF-κB, ERK1/2, MLCK-pMLC, MAPK, and TLR4 signaling pathways, leading to the downregulation of related pro-inflammatory cytokines, such as TNF-α, IL-6, IL-8, and IL-1β. However, as mentioned earlier, the mechanism by which hawthorn pulp alleviates inflammation-associated chronic diseases is not fully understood and requires further validation in animal experiments. It is well known that a series of symptoms caused by inflammation have a great impact on human health; therefore, nutraceuticals and foods containing hawthorn pulp can be developed to reduce inflammation and prevent related symptoms.

3.3 Antibacterial activity

The whole hawthorn fruit has been reported to possess antibacterial activity. It displayed good inhibitory effects against both Gram-positive and Gram-negative bacteria, with the antibacterial mechanism of inducing oxidative stress via ROS production (Golabiazar et al., 2021). Similarly, it enhanced the resistance of Exopalaemon carinicauda to Vibrio parahaemolyticus, as evidenced by an improved immune response and growth of the shrimp (Cao et al., 2022). It also exhibited antibacterial effects against Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, Acinetobacter baumannii, and Escherichia coli, with the minimum inhibitory concentration of 0.11 μg/mL (Ebrahimzadeh et al., 2020). In addition, it was reported that the QHP derivative exhibited a certain inhibitory effect on E. coli and S. aureus (Qin et al., 2022).

In general, the whole hawthorn fruit exhibits broad antimicrobial spectra by inhibiting the growth of bacteria. However, there is no specific study on its main bacteriostatic components or potential bacteriostatic mechanisms, and future studies may focus on the active components and specific targets of its bacteriostatic effects.

3.4 Intestinal health

Intestinal health is related to many factors, such as intestinal morphology, intestinal barrier, and gastrointestinal dynamics. Intestinal diseases are related to these factors and are one of the major diseases that threaten human health. The whole hawthorn fruit and its constituent polyphenols and polysaccharides have been reported to be beneficial for intestinal health.

Researchers found that dietary supplementation with the hawthorn pulp improved intestinal morphology by increasing villi length, villi width, and muscle thickness, and enhanced gut barrier integrity by increasing the mRNA expression‎ of zonula occludens-3 in golden pompano (Tan et al., 2020). It also improved intestinal health by improving duodenal lipase and trypsin activity and jejunal morphology, as well as higher ileal valproic acid, colonic propionic acid, and isobutyric acid concentrations (Fu et al., 2022). In addition, hawthorn extract can promote gastrointestinal motility by increasing the number of gastrointestinal Cajal (interstitial cell of Cajal [ICC]) mesenchymal cells through upregulation of c-kit expression‎ (Wang, Luo et al., 2021). Besides, it could prevent diarrhea and the accumulation of interstitial fluid (Sammari et al., 2021). Furthermore, hawthorn seeds have also been found to be beneficial for intestinal health. Hawthorn seed ethyl acetate extract improved gastrointestinal motility in rats with diabetic gastroparesis (DGP), and its potential mechanism might be related to the upregulation of n-NOS and c-kit expression‎ and ICCs in the stomach and the regulation of motilin, gastrin, and 5-HT (Niu et al., 2020). The supplementation of hawthorn seed oils could selectively alter the abundance of gut bacteria, including unclassified Christensenellaceae, Ruminococcaceae, Gastranaerophilales, Faecalibaculum, Peptococcus, Clostridiales, and Ruminococcus, which were correlated with cholesterol metabolism (Kwek et al., 2022).

Flavonoids extracted from the whole hawthorn fruit may reverse intestinal flora disorders and metabolic disorders in mice by increasing the proportion of Dubosiella, Alloprevotella, and Bifidobacterium, as well as the levels of docosapentaenoic acid, sphingolipids (SM), and phosphatidylcholine (PC), while decreasing the proportion of immobile bacteria (Zhang et al., 2022). Hawthorn polyphenols were found to shorten the length of lesions formed in colitis rat colon, in addition to decreasing the levels of myeloperoxidase and interleukin-1β (Nascimento et al., 2021). Simultaneously, they could improve the diversity of gut microbial species by altering the abundance of the Bacteroidetes and Firmicutes microorganisms in the gut (Yu et al., 2022). They also increased the abundance of Lactobacillus, but reduced the production of Gram-negative bacteria, thereby reducing the abnormal increase in bacterial diversity caused by alcohol (Wang, Wang et al., 2021).

Polysaccharides have been demonstrated to regulate gut microbiota. Current studies suggest that the hawthorn polysaccharide could directly modify the intestine, particularly by enriching Alistipes and Odoribacter, and produce short-chain fatty acids to inhibit colitis (Guo et al., 2021). Furthermore, it was found to increase the abundance of Micrococcus, Acidaminococcus, and Mitsuokella while decreasing the abundance of E. coli and Clostridium, thus regulating the proportion of beneficial bacteria in the intestine (Han, Zhou, et al., 2022). It also increased the abundance of Akkermansia, Bacteroides, and Adlercreutzia but decreased the abundance of Lactobacillus, Bifidobacterium, Blautia, Lachnospiraceae, and Subdoligranulum to restore the balance of gut microbiota (Han, Zhao, et al., 2022).

Overall, the whole hawthorn fruit exhibits beneficial effects on intestinal health with mechanisms related to the regulation of intestinal morphology, motility, and microbiota abundance. Polyphenols and polysaccharides are the main contributors to its intestinal protection, whereas the underlying mechanisms remain unclear, which needs additional investigation in the future. Moreover, current studies mainly focus on the first messenger, and there are no relevant studies on the specific activated signaling pathways. As a recognized food for promoting digestion and absorption, it would be beneficial to develop hawthorn to promote human gastrointestinal health.

3.5 Antidiabetic effect

Diabetes mellitus is a metabolic disease characterized by hyperglycemia that can be caused by rapid glucose uptake in the intestine. In recent years, the antidiabetic effects of the whole hawthorn fruit and its components have received increasing attention.

α-Amylase and α-glucosidase are two key glucoside hydrolases that catalyze the conversion of starch, disaccharides, or oligosaccharides to glucose during carbohydrate digestion. An important approach to controlling diabetes is to reduce postprandial hyperglycemia by delaying carbohydrate digestion and glucose absorption. The whole hawthorn fruit exhibited excellent hypoglycemic ability due to its ability to resist α-amylase and α-glucosidase (Mecheri et al., 2021). Polysaccharides, a major component of the whole hawthorn fruit, were reported to have high α-amylase inhibitory activity (Rjeibi et al., 2020). In a recent study by Aad et al. (2021), it was found that hawthorn flavonoids could dose-dependently inhibit α-amylase and α-glucosidase. Hypericin, a component extracted from the whole hawthorn fruit, was found to have significant anti-α-glucosidase activity (Lin et al., 2022). In addition, the B-type proanthocyanidin, one of the hawthorn phytochemicals, is a potent, reversible, and competitive inhibitor of α-glucosidase (Liang et al., 2022). Screening and identification of α-glucosidase inhibitors in the whole hawthorn fruit also showed that polyphenols containing mainly quercetin (74.58%) and chrysin (9.58%) played an important role in α-glucosidase inhibition (Xin et al., 2021).

Insulin is the most critical hormone in regulating blood sugar and maintaining normal blood sugar levels. Insulin resistance occurs when insulin regulation becomes delayed and insufficient to inhibit glucose processing. A complex hypoglycemic complex consisting of hawthorn polyphenols, d-chiral inositol, and epigallocatechin gallate increased glucose consumption and glycogen levels and inhibited hepatic gluconeogenesis in HepG2 cells (Xin et al., 2021). Hawthorn polyphenols improved insulin resistance, decreased fasting glucose and hepatic gluconeogenesis, and increased hepatic glycogen synthesis and storage by downregulating phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Forkhead box protein O1 (FOXO1)-mediated phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase and upregulating PI3K/Akt/glycogen synthase (GS) kinase-3–mediated GS activation in STZ/high-fat diet (HFD)-induced mice. Polyphenols in the whole hawthorn fruit significantly reduced insulin resistance by upregulating phosphorylation of glucose uptake protein (GLUT4) and insulin resistance–related proteins phosphorylated insulin receptor substrate (p-IRS1), phosphorylated serthreonine protein kinase (p-AKT), and phosphorylated inositol 3 kinase (p-PI3K) in rat liver (Liu, Yu, et al., 2021). Procyanidins in whole hawthorn berries are involved in fatty acid biosynthesis, MAPK, and lipopolysaccharide biosynthesis pathways to ameliorate hormone-associated insulin resistance (Han, Zhao, et al., 2022).

Furthermore, the whole hawthorn fruit and its constituent polyphenols improved secondary complications of diabetes in vitro and in vivo. Hawthorn pulp treatment and moderate-intensity interval running training simultaneously improved myocardial ischemia-reperfusion-induced renal injury via the miR-126/Nrf-2 pathway and improved insulin sensitivity and renal function in type 1 diabetic rats (Asgari et al., 2022). In addition, the hawthorn seed improved gastrointestinal motility in DGP rats, and its potential mechanism may be related to inhibiting oxidative stress damage caused by hyperglycemia (Niu et al., 2020). On the other hand, hawthorn polyphenols attenuated hyperglycemia-induced retinal damage, possibly through inhibition of the adenosine monophosphate-activated protein kinase (AMPK)/mitochondrial acetylase (SIRT1)/NF-κB and miR-34a/SIRT1/p53 pathways, and attenuated hyperglycemia-induced inflammation and apoptosis in human retinal pigment epithelial cells (ARPE-19 cells) (Liu, Fang, et al., 2021).

Overall, the whole hawthorn berry and its constituents have good antidiabetic potential to prevent and improve diabetes and its complications, including diabetic nephropathy, cardiomyopathy, and DGP, which involve a variety of signaling pathways, such as PI3K/Akt/FOXO1-mediated/PEPCK, AMPK/SIRT/NF-κB, and miR-34a/SIRT1/p53. Polyphenols and polysaccharides are the main hypoglycemic components of the whole hawthorn fruit, but few experiments have been conducted to study their mechanisms of action individually. The development of nutraceuticals from hawthorn and its constituents is a focus of subsequent research.

3.6 Cardiovascular protection

CVD is the leading cause of death in humans. Hypertension, hyperlipidemia, and AS are the main risk factors for CVD, which can be inhibited by the whole hawthorn fruit and its constituents, contributing to its cardiovascular protective effect.

The whole hawthorn extract has potential preventive and therapeutic effects on AS. In golden Syrian hamsters, it might regulate AS by controlling cell survival and proliferation, reducing the levels of enzymes 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) and lipoprotein lipase, and inhibiting inflammatory response (Li, Gao et al., 2022). The promotion of thrombosis induced by platelet aggregation plays an important role in the development of AS in rats. The whole hawthorn extract could reduce thromboxane B2 release, P-selectin expression‎, and activation of cAMP and Akt signaling through the mechanisms of downregulating platelet receptor (P2Y12) (chemoreceptor for adenosine diphosphate) signaling and inhibiting ROS-induced NF-κB activation (Shatoor, Shati, et al., 2021). The whole HFE also produces endothelium-dependent vasodilation in porcine coronary, which is partially dependent on estrogen receptors and is sensitive to the inhibition of the ROS/Src/PI3K/NO pathway (Younis et al., 2021). Its extract had the potential benefit of alleviating endothelial dysfunction in isolated aortic rings from Sprague–Dawley rats, possibly related to the inhibition of arginase (Bujor et al., 2020).

The antihypertensive effects of the hawthorn pulp and its compounds have also been demonstrated. Combination of the hawthorn pulp with vitamin C inhibited heat exposure-induced oxidative changes in vascular tissues under hypertension, contributing to its antihypertensive activities without signs of toxicity, which involved the activation of nitric oxide pathway by muscarinic receptors and/or inhibition of angiotensin-converting enzymes (Zhu et al., 2022). The hawthorn pulp as a parent tincture for the initial treatment of heart failure significantly reduces systolic blood pressure in normotensive rats (Balbueno et al., 2020). Incidentally, the whole hawthorn fruit vinegar could achieve antihypertensive effects by inhibiting the activity of angiotensin-converting enzyme II (Sayin & Gunes, 2021). Specifically, hawthorn berry flavonoid extracts can positively affect the electrocardiogram of oiled chickens reared at high altitude, thereby preventing the complications of pulmonary hypertension and heart wave disorders (Younis et al., 2020).

Hyperlipidemia is another high-risk factor for CVD, and consumption of the hawthorn pulp may regulate blood lipids based on in vitro and in vivo studies. Molecular docking results suggested that acetyl-CoA carboxylase might be the target of the hypolipidemic activity of hawthorn triterpenoids, which is verified in HepG2 cells (Zhu et al., 2022). In addition, hawthorn pectic acid inhibited lipid accumulation in HepG2 cells by upregulating low-density lipoprotein (LDL) receptor and downregulating HMG-CoA reductase gene expression‎ (Feng et al., 2022). The whole hawthorn fruit and its compounds can also regulate blood lipids in animal models. Treatment of the hawthorn pulp also reduced golden pompano's plasma cholesterol, triglycerides, and LDL levels to lower blood lipids (Tan et al., 2020). Hawthorn polyphenol extracts were reported to significantly improve total cholesterol and total triglycerides in T2D rats (Liu, Yu, et al., 2021). Besides, it showed significant lipid-lowering activities (40 mg/kg) in male albino Wistar rats compared to atorvastatin (80 mg/kg) (Zahra et al., 2021). Hawthorn proanthocyanidins significantly alleviated lipid accumulation in the serum and liver through modulation of NF-κB and AMPK pathways and protected liver structure in rats with lipid metabolism disorders (LMDs) (Han, Zhao, et al., 2022). The hawthorn pulp also effectively reduced lipid synthesis in HFD rats by downregulating hepatocyte ER stress-induced peroxisome proliferator–activated receptor-γ (PPAR-γ) expression‎ (Mao et al., 2022). It also ameliorated some of the disordered metabolic pathways in spontaneously hypertensive rats by interfering with sphingolipid, glycerophospholipid, and glycerolipid metabolism (Sun, Chi et al., 2022). Hawthorn seed oils could also reduce plasma cholesterol and non-HDL cholesterol by up to 15% in hypercholesterolemia hamsters (Kwek et al., 2022).

In general, the whole hawthorn fruit and its components can alleviate cardiovascular risk factors, such as AS, vascular strain, vascular tension, and hyperlipidemia, without significant side effects. The mechanism is related to the regulation of cAMP, Akt, P2Y12, NF-κB, ROS/Src/PI3K/NO signaling pathways, which lead to the downregulation of HMG-CoAR, angiotensin-converting enzyme II, and other related enzymes. Hawthorn is worth developing nutraceuticals for due to its multi-targeted treatment of CVDs.

3.7 Hepatoprotective effect

The whole hawthorn fruit and its components have been reported to exhibit hepatoprotective effects on acute liver injury as well as chronic liver diseases, which are discussed as follows.

The protective ability of hawthorn pulp and its components on acute liver injury caused by drugs and alcohol has been demonstrated in vivo. Treatment with the ethanolic extract of the whole hawthorn fruit reduced total bilirubin concentration, increased total protein ratio, altered serum ALP, aspartate aminotransferase, and alanine aminotransferase levels, and improved liver tissue morphology in isoniazid and rifampicin, which caused hepatotoxicity in rats (Han, Zhao, et al., 2022). Lactobacillus rhamnosus 217-1 fermented mixture of Pueraria lobata, Lonicera japonica, and hawthorn pulp improved liver indexes, increased the activities of liver tissue superoxide dismutase and glutathione, and decreased the levels of MDA in a mouse model of alcoholic liver disease (Wang, Wang et al., 2021).

The hawthorn pulp also exhibited excellent protective effects against chronic liver diseases. It could ameliorate obesity-related hepatic steatosis in HFD rats by reducing hepatic endoplasmic reticulum (ER) stress through the downregulation of PPAR-γ and glucose regulatory protein 78 (a major regulator of ER homeostasis) (Mao et al., 2022). Another study also confirmed that it ameliorated HFD-induced hepatic steatosis via the prevention of elevated serum and hepatic lipids, and the mechanism could be associated with the activation of AMPK signaling and the subsequent blocking of its downstream molecules, such as hepatic expression‎ of sterol regulatory element–binding protein 1/2, fatty acid synthase, and 3-hydroxy-3-methylglutaryl coenzyme A reductase (Shatoor, Al Humayed, et al., 2021). In addition, proanthocyanidins in the whole hawthorn fruit could protect the liver structure and reduce liver inflammation and lipid accumulation by regulating LM-related NF-κB and AMPK pathways in LMD rats (Han, Zhao, et al., 2022).

In brief, the whole hawthorn fruit and its constituents, mainly proanthocyanidins, showed potential to treat the liver injury caused by alcohol, isoniazid, rifampin, and HFD while improving liver steatosis and functional indices; the protective mechanism is mainly related to resistance to oxidative stress and impaired lipid metabolism in the liver. However, the specific targets of its action have not been fully revealed, and subsequent studies can utilize relevant cell models to investigate the specific targets of its action.

3.8 Anti-cancer effect

Current studies have shown that the whole hawthorn fruit and its components, especially proanthocyanidins, have anti-cancer activity.

The whole HFE and its components have been reported to have anti-cancer activity against different cancer cells in vitro. Methanolic extracts of the whole hawthorn fruit rich in polyphenols were found to be cytotoxic against human breast cancer cells (MCF-7) hormone receptor-positive and human breast cancer cells (MDA-MB-231) triple-negative breast cancer cell lines, effectively inhibiting tumor cell proliferation and arresting the cell cycle at the G1/S transition, possibly associated with the regulation of Wnt signaling pathway (Kombiyil & Sivasithamparam, 2023). Polyphenols also inhibited apoptosis through the AMPK/SIRT1/NF-κB pathway and reduced miR-34a/SIRT1/p53 pathway activation in human retinal pigment epithelial cells (ARPE-19 cells) (Liu, Fang, et al., 2021). Homogeneous polysaccharides extracted from the whole hawthorn fruit also possessed anti-cancer effects on colon cancer cells by upregulating caspase 3, 7, 8, 9, and Fas, fas-associating protein with death domain, TNF-R1, and TNF receptor-1-associated death domain protein, and downregulating cyclin A1/D1/E1 and cyclin-dependent kinase-1/2 (Ma et al., 2020). Hawthorn B–type proanthocyanidin polymorphs composed of epicatechin strongly inhibited intracellular tyrosinase activity and melanogenesis and induced apoptosis in mouse melanoma cells (Liang et al., 2022). It blocked the HCT116 cell cycle in the G2/M phase through the p53-cyclin B pathway and promoted apoptosis partly through the mitochondrial (cysteine 9-cysteine 3) and death receptor (cysteine 8-cysteine 3) pathways (Sun, Wang et al., 2022). Meanwhile, two new pairs of lignan enantiomers (1a/1b and 2a/2b) isolated from the whole hawthorn fruit were cytotoxic to Hep3B hepatoma cells with IC50 values of 34.97 ± 2.74 and 17.42 ± 0.71 μM, respectively. In addition, 1b induced more apoptotic and autophagic cells than 1a in Hep3B cells, which may be related to the activation of p38 to promote 1b-induced apoptosis and autophagy (Shang et al., 2020). The HFE inhibited the proliferative and invasive potential of glioblastoma cells by promoting the cleavage of poly (ADP-ribose) polymerase 1 (PARP1) associated with apoptosis and significantly inhibiting pro-survival kinase, adherent plaque kinase (FAK), and Akt (Żurek et al., 2021). Silver nanoparticles (CME@Ag-NPs) prepared from the HFE were very effective in inhibiting the growth of gastric and mammary gland cancer cell lines in vitro (Shirzadi-Ahodashti et al., 2020).

In summary, the whole HFE and its components are potential anti-cancer natural products. They have a positive effect on the prevention and treatment of a variety of cancers in vitro, including gastric, colon, liver, breast, and mammary cancers. Their anti-cancer mechanisms include the inhibition of cancer cell growth and induction of apoptosis, in part through p53-cyclin B, AMPK/SIRT1/NF-κB, miR-34a/SIRT1/p53, mitochondrial (cysteine 9-cysteine 3), and death receptor (cysteine 8-cysteine 3) signaling pathways. These findings open up the possibility that whole hawthorn extract and its components can be used for the prevention and management of different cancers.

3.9 Neuroprotective activity

The whole HFE and its components have been found to have neuroprotective effects on nerve injury in vitro and in vivo.

Acetylcholinesterase (AChE) plays an important role in neurodegenerative diseases that affect memory. Hawthorn's components showed significant AChE inhibitory activities. The phenolic compounds of the whole hawthorn fruit have been shown to possess stronger AChE inhibitory activity than donepezil (Liu, Zhang et al., 2020). Polysaccharides from the pulp exhibited higher AChE inhibitory activity (Rjeibi et al., 2020).

Lignans, isolated from the whole hawthorn fruits, were reported to protect against H2O2-induced damage in human neuroblastoma SH-SY5Y cells (Zhang et al., 2023). In addition, the whole HFE prevented traumatic brain injury–mediated reduction in neuronal survival and inhibited neuronal death in the rat cerebral cortex by activating Nrf2 pathways and inhibiting NF-κB expression‎ (Gao et al., 2022).

Therefore, the whole hawthorn fruit and its components, mainly lignans and polysaccharides, have significant neuroprotective activity, implying that they may be potential inhibitors of AChE and beneficial for human memory. However, its specific mechanism of action and target of action have not been described in detail, which is worth exploring in depth in the future.

3.10 Other bioactivities

The whole hawthorn extract and its components exhibited other bioactivities in vitro. The whole hawthorn extract inhibited osteoclast differentiation by suppressing the nuclear factor of activated T cells (NFATc1) and c-Fos expression‎ and suppressing the expression‎ of osteoclast-related genes, such as NFATc1, Ca2, Acp5, mmp9, cathepsin K (CtsK), Oscar, and Atp6v0d2 (Kim et al., 2021). Proanthocyanidins and phenylpropanoids extracted from the whole hawthorn fruit exhibited moderate tyrosinase inhibitory activity (Liang et al., 2022) (Table 1).

TABLE 1. Bioactivities and related molecular mechanisms of the hawthorn fruit based on in vitro and in vivo studies.

Extracts/CompoundsSubjects/Cell linesDosesMain effectsMechanismsReferences

• Abbreviations: AChE, acetylcholinesterase; AMPK, activated protein kinase; ABTS, 2,2′-Azino-bis(3-ethylbenzthiazoline-6-sulfonic acid); AGS, growth of gastric; ALP, alkaline phosphatase; AP-1, activator protein-1; BDNF, brain-derived neurotrophic factor; CtsK, cathepsin K; CAT, catalase; CRP, C-reactive protein; DPPH, 1-diphenyl-2-picrylhydrazyl radical; DSS, dextran sulfate sodium; FAK, adherent plaque kinase; FOS, fructooligosaccharides; GSH-Px3, glutathione peroxidase 3; HO-1, heme oxygenase 1; H2O2, hydrogen peroxide; HFD, high-fat diet; ICC, interstitial cell of Cajal; LPS, lipopolysaccharide; MARK, protein kinase; MCF, mammary gland; MCP-1, monocyte chemoattractant protein 1; MDA, malondialdehyde; MIC, minimum inhibitory concentration; MPO, myeloperoxidase; NFATc1, nuclear factor of activated T cells; NFAT, nuclear factor levels of activated T cells; NF-κB, nuclear factor kappa-light chain enhancer of activated B cells; Nrf2, nuclear factor erythropoietin-2-related factor; 2PFC, prefrontal cortex; PPAR-γ, peroxisome proliferator–activated receptor-γ; PI3K, phosphoinositide 3-kinase; PGE2, prostaglandin E2; PKB, protein kinase B; ROS, reactive oxygen species; SOD, superoxide dismutase; T2D, type 2 diabetes; TC, total cholesterol; TG, total triglyceride; TMAO, trimethylamine-N-oxide; TNF-α, tumor necrosis factor-α; XOS, xylooligosaccharides.

The whole hawthorn fruit and its components also had other in vivo beneficial functions. The whole hawthorn extract could also enhance immune response and growth performance (Fu et al., 2022). Hawthorn pulp was sufficient to produce anxiolytic and antidepressant-like effects by activating 5-HT1A receptors and elevating brain-derived neurotrophic factor, increasing urinary serotonin levels, and decreasing urinary NE and DA levels (Nitzan et al., 2022). The defatted methanolic extract of the whole hawthorn had excellent anti-injury sensitizing ability (Abdel-Rahman et al., 2021). Incidentally, hawthorn polyphenol microcapsules (HPMs) improved swimming ability and skeletal muscle substrate depletion as well as product metabolism, enhanced antioxidant capacity in fatigued mice, possibly through activation of AMPK pathways to improve mitochondrial dysfunction and cellular metabolism, inhibition of NF-κB inflammatory conserved pathways, and improved the diversity of gut microbial species (Yu et al., 2022).

4 HEALTH BENEFITS BASED ON HUMAN STUDIES

The whole hawthorn fruit has also been demonstrated to possess health benefits for humans, especially with cardiovascular protective effects. It was reported to regulate blood pressure on humans. The HFE exhibited significant hypotensive effects in diabetic patients taking medication, especially in lowering resting diastolic blood pressure (Hu et al., 2014). A combination of natural d-camphor and fresh HFE could improve hypotension in adolescents, adults, and the elderly (Schandry et al., 2018). It could also regulate blood lipids. A polyherbal formula containing the hawthorn pulp (1 g daily), Alisma orientalis, Stigma maydis, Ganoderma lucidum, Polygonum multiflorum, and Morus alba reduced LDL cholesterol and glycated hemoglobin in patients with dyslipidemia (Holubarsch et al., 2008). Besides, the HFE might reduce the incidence of sudden cardiac death in patients with less impaired left ventricular function (Holubarsch et al., 2008).

Limited clinical studies indicate that the whole hawthorn fruit possesses beneficial effects on mental health. It was reported that the extracts of the whole hawthorn fruit and Eschscholtzia californica significantly reduced total somatic Hamilton scale scores and self-rated anxiety in mild-to-moderate anxiety patients (Hanus et al., 2004).

In summary, the whole hawthorn fruit has been demonstrated to benefit the cardiovascular system, mainly through regulating blood pressure, regulating blood lipids, and alleviating heart failure symptoms (Table 2). However, its other health benefits on humans require further studies for verification. For example, the beneficial effects of the whole hawthorn fruit on human intestinal health and its anti-inflammatory effects need to be confirmed in more clinical trials.

TABLE 2. Health benefits of the hawthorn fruit based on human studies.

Extracts/CompoundsParticipantsControlTreatmentsMain effectsReferences

Antihypertensive effects
Hawthorn extract	Patients with type 2 diabetes	Placebo	Daily 1200 mg	Antihypertensive	Hu et al. (2014)
Korodin, a combination of camphor and hawthorn extract	Adolescent participants in the age range of 14– 17 years having a systolic blood pressure below 118 mmHg (boys) or 110 mmHg (girls)	Placebo	A single dose of 20 drops	Blood pressure ↑	Schandry et al. (2018)
Hypolipidemic effects
The multiherb formula containing hawthorn, Alisma orientalis, Stigma maydis, Ganoderma lucidum, Polygonum multiflorum, and Morus alba	Patients with dyslipidemia	Placebo	800 mg (two capsules), three times a day, 15 days	Lipoprotein cholesterol ↓ Glycated hemoglobin ↓	Holubarsch et al. (2008)
Anti-heart failure effects
Neuroprotective effects
Extracts of hawthorn and Eschscholtzia California	Patients presenting with generalized anxiety (DSM-III-R) of mild-to-moderate intensity	Placebo	NA	Total and somatic Hamilton scale scores ↓ Subjective patient-rated anxiety ↓	Hanus et al. (2004)

5 FOOD-RELATED APPLICATIONS

Studies have demonstrated various food-related applications of the whole hawthorn fruit (Figure 3). pH-sensitive films are thin and transparent layers that can change color or fluorescence in response to changes in pH. In a study conducted by Yan et al. (2021), the incorporation of the whole HFE into gelatin/chitosan/nanocellulose composite films yielded positive pH-sensitive films, suggesting that the developed films could be used to indicate the changes in food quality. Another interesting food application is the usage of hawthorn wine pomace. It demonstrated the sustainable use of hawthorn wine pomace for HP synthesis, which acted as an effective and antioxidative stabilizer (Jiang et al., 2020). Lastly, a study by Liu, Yang et al. (2020) showed that the antioxidant ability of HP helped preserve the Pickering emulsion from its lipid oxidation, thus stabilizing Pickering emulsions as particle shell materials while protecting lipid components from oxidation.

FIGURE 3

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Bioactivities of the hawthorn fruit and its compounds based on in vitro and in vivo studies. ABTS, 2,2′-Azino-bis(3-ethylbenzthiazoline-6-sulfonic acid); ALP, alkaline phosphatase; AP-1, activator protein-1; CAT, catalase; CRP, C-reactive protein; DPPH, 1-diphenyl-2-picrylhydrazyl radical; FAK, adherent plaque kinase; FOS, fructooligosaccharides; GSH-Px3, glutathione peroxidase 3; LPS, lipopolysaccharide; MARK, protein kinase; MCF, mammary gland; MCP-1, monocyte chemoattractant protein 1; MDA, malondialdehyde; MPO, myeloperoxidase; NFAT, nuclear factor levels of activated T cells; PFC, prefrontal cortex; PGE2, prostaglandin E2; PKB, protein kinase B; ROS, reactive oxygen species; SOD, superoxide dismutase; T2D, type 2 diabetes; TBI, traumatic brain injury; TC, total cholesterol; TG, total triglyceride; TMAO, trimethylamine-N-oxide; TNF-α, tumor necrosis factor-α; XOS, xylooligosaccharides.

Recent studies have also explored the use of the whole hawthorn fruit in the development of food products. A study by Ozcelik et al. (2021) investigated the properties of hawthorn juice-based water kefir, indicating the potential of hawthorn juice-based water kefir as an effective antioxidant beverage. Another interesting food application is the manufacturing of hawthorn wine as a new beverage. Collectively, these studies demonstrate positive results in hawthorn wine production and quality.

6 THE SAFETY ISSUE

In terms of safety, the whole hawthorn fruit is generally regarded as a safe fruit for consumption, and the European Medicines Agency's Committee for Herbal Medicinal Products has also classified hawthorn as a “Traditional Herbal Medicinal Product” and deemed it safe for consumption due to its long history of use (Distefano, 2021). Various systematic reviews have shown that the whole hawthorn fruit is generally safe for consumption. For instance, a systematic review conducted by Daniele et al. (2006) showed that the whole hawthorn is well tolerated, even if several adverse events were reported. It was found that the most frequent adverse events included dizziness/vertigo, gastrointestinal complaints, headache, migraine, and palpitation. There were also no reports of herb–drug interactions. Another review conducted by Cloud et al. (2020) also showed that the whole hawthorn fruit is considered a relatively safe herb without severe adverse effects for consumption up to 24 months. Despite the favorable indications that the whole hawthorn fruit may be safe for consumption and development into medicinal food products, further research is required to properly examine the safety of hawthorn-containing formulations. Future studies can also focus on investigating possible herb–drug interactions of the whole hawthorn fruit if consumed with other concomitant medications.

In addition, optimal dosage is another potential concern for the safety of the whole hawthorn fruit. For instance, a study conducted on whole HFE showed that it did not produce marked genotoxic effects at concentrations of 2.5 or 5 μg/mL in leukocytes or human liver hepatocellular carcinoma cells (HepG2 cells) (de Quadros et al., 2017), however, at concentrations of 10 μg/mL or higher, significant DNA damage and clastogenic/aneugenic responses were observed. Furthermore, the whole HFE was also found to exhibit weak clastogenic and/or aneugenic effects in bone marrow cells of male mice, suggesting that prolonged or high-dose use of such extracts needs to be undertaken with caution (Yonekubo et al., 2018). Therefore, it is also crucial to eval‎uate the optimal dosage of the whole HFEs for safe human consumption.

7 CONCLUSION AND PERSPECTIVES

Recent research progress indicates that the whole hawthorn fruit can be a new natural source of functional foods. Its main bioactive components are polyphenols and polysaccharides. The fruit and its bioactive compounds have also been discovered to have numerous beneficial bioactivities that may be useful in the prevention and management of certain diseases. Some of the most critical biological activities are anti-inflammatory, antimicrobial, gut-protective, antidiabetic, cardioprotective, hepatoprotective, and anti-cancer properties that may prevent or even treat diseases, indicating an impact on the management of health problems. However, the underlying mechanisms of their relevant functions are not fully understood, such as the mechanisms and targets of anti-cancer and neuroprotective effects, requiring further research. A better understanding of the bioavailability, pharmacokinetics, and metabolic pathways of the whole hawthorn extract and the main bioactive compounds in the human body is important for the development of hawthorn-related nutraceuticals. In today's society, diseases and sub-health phenomena occur frequently, and more and more people seek to prevent and maintain health from the diet. Therefore, hawthorn, as an edible and medicinal fruit, contains a large number of naturally occurring bioactive components with abundant beneficial functions that are generally safe and reliable to be used to gradually improve health in daily life. It is also a valuable source of dietary bioactive components for the development of functional foods or other nutraceuticals and for the prevention and management of certain chronic diseases.

AUTHOR CONTRIBUTIONS

Ren-You Gan and Li-Dan Zhong conceived this paper; Jin-Xin Ma, Wei Yang, and Chester Yan Jie Ng wrote this paper; Ren-You Gan, Li-Dan Zhong, Xu-Dong Tang, and Sunny Wong provided critical comments and revised the paper. The final version was approved by all the authors.

ACKNOWLEDGMENTS

This study was supported by the Qi Huang Young Scholar Programme (National Administration of Traditional Chinese Medicine), The 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-Hong Kong-Macau Joint Lab) [grant number 2020B1212030006], and the China Scholarship Council [grant number

REVIEW ARTICLE

Open Access

The hawthorn (Crataegus pinnatifida Bge.) fruit as a new dietary source of bioactive ingredients with multiple beneficial functions

Jin-Xin Ma, Wei Yang, Chester Yan Jie Ng, Xu-Dong Tang, Sunny Wong, Ren-You Gan, Linda Zhong

First published: 07 May 2024

https://doi.org/10.1002/fft2.413

Citations: 3

Jin-Xin Ma and Wei Yang contributed equally to the work.

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Abstract

The discovery of new natural sources has brought increased attention to the development of functional foods. The hawthorn (Crataegus pinnatifida Bge.) fruit is an underutilized fruit due to its benefits for human health and good taste. It contains a variety of bioactive ingredients, contributing to its multiple beneficial functions and applications. This review summarized and discussed the main bioactive ingredients, beneficial functions based on in vitro, in vivo, and human studies, and different applications of the hawthorn fruit according to the updated literature in the past 3 years. Hawthorn berries contain phenolic acids, flavonoids, proanthocyanidins, pectin, and many other bioactive components, which have a variety of beneficial functions, such as antioxidant, anti-inflammatory, antibacterial, antidiabetic, intestinal protection, cardiovascular protection, hepatoprotection, anti-cancer, and neuroprotection. Its potential molecular mechanism and different food-related applications such as hawthorn wine and antioxidant drink are discussed in detail in this review. Additionally, hawthorn berries are shown to be safe when consumed within the proper dosage. Collectively, this updated review indicates that the hawthorn fruit can be a new dietary source of bioactive ingredients with multiple beneficial functions and can be affordably developed into functional and medicinal foods for the prevention and management of certain chronic diseases.

1 INTRODUCTION

Hawthorn, also known as Crataegus pinnatifida Bge., belongs to the Rosaceae family and is a deciduous tree (Hamza et al., 2020). The hawthorn fruit, with both medicinal and edible characteristics, has a long history of use as Traditional Chinese Medicine and has been proven to possess many health benefits. According to the theory of Traditional Chinese Medicine, it has the functions of promoting digestion, invigorating the spleen, nourishing vitality, and removing blood stasis (Hou et al., 2020). Modern research has also discovered that it contains phenolic acids, flavonoids, proanthocyanidins, pectin, and other bioactive ingredients (Li, Gao et al., 2022; Li et al., 2021). In the past decade of research, hawthorn berries and their bioactive constituents have been shown to possess many beneficial functions, such as antioxidant, anti-inflammatory, antibacterial, intestinal protection, modulation of intestinal microbiota, cardiovascular protection, and antidiabetic and neuroprotective effects. It also has a broad prospect in drug and food research and development (Lin et al., 2022; Schandry et al., 2018; Wang, Wang et al., 2021). As a kind of food with the same origin of food and medicine, the hawthorn fruit has gradually received more attention in the modern life, which emphasizes a healthy diet.

However, there is still a lack of a state-of-the-art review to better understand its main bioactive ingredients and beneficial functions. Hence, our study retrieved relevant literature regarding the hawthorn fruit published in the past 3 years from the Web of Science Core Collection and PubMed databases. Our study first summarizes the main bioactive components of the whole hawthorn fruit, then comprehensively discusses the health effects of the whole hawthorn fruit and its main bioactive components from in vitro, in vivo, and clinical studies, focusing on hawthorn berries and their main bioactive components and their antioxidant, anti-inflammatory, antimicrobial, intestinal protection, regulation of intestinal microbiota, cardiovascular protection, and antidiabetic effects. Finally, the application of hawthorn berries in food products is introduced, and the potential safety issues of hawthorn are discussed. We hope that this review paper can attract more attention to the hawthorn fruit and promote its further research and application in the prevention and management of certain chronic diseases.

2 BIOACTIVE INGREDIENTS IN THE WHOLE HAWTHORN FRUIT

The whole hawthorn fruit contains various bioactive ingredients, like polyphenols, polysaccharides, terpenoids, essential oils, and lignans, with representative compounds shown in Figure 1. Different factors, such as the varieties, cultivation regions, and postharvest drying methods, can influence the bioactive ingredients and their content in the whole hawthorn fruit, and they are discussed in the following sections.

FIGURE 1

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Chemical structures of bioactive compounds in the hawthorn fruit.

2.1 Polyphenols

Polyphenols are a large family of organic compounds that are characterized by at least one hydroxyl group in the benzene ring. Polyphenols are abundant in many plant-based foods (Lund, 2021). Usually, methanol and ethanol are common solvents for the extraction of polyphenols from plants. A study by Sultana et al. (2009) found that aqueous methanol was comparatively more efficient than ethanol and acerone for polyphenol extraction from different medicinal plant extracts. The predominant polyphenolic compounds in whole hawthorn fruits include phenolic acids, flavonoids, and proanthocyanidins, and the main compounds and chemical structures are shown in Figure 1.

2.1.1 Phenolic acids

Phenolic acids are one of the main categories of phenolic compounds in the whole hawthorn fruit. Besides the Soxhlet extraction and ultrasonic-assisted extraction that are commonly used in phenolic acid extraction, supercritical fluid extraction and accelerated solvent extraction are also developed as alternative techniques (Arceusz et al., 2013). Gallic acid, caffeic acid, and syringic acid were found in fresh and dehydrated whole hawthorn fruits (Benabderrahmane et al., 2021). In addition, gallic acid, neochlorogenic acid, and cryptochlorogenic acid were revealed to be active components of the whole hawthorn fruit for the treatment of hyperlipidemia and cardiovascular diseases (CVDs) (Sun, Zeng et al., 2022).

2.1.2 Flavonoids

Flavonoids are another important category of polyphenols that have important biological effects. Flavonoids are usually extracted by a combination of ethanol and water in different proportions and can also be extracted by the natural deep eutectic solvents, which could solubilize moderately polar flavonoids in a low-cost and environment-friendly manner (Chaves et al., 2020). It was found that (+)-catechin was a main flavonoid compound in hawthorn pulp, ranging from 9.57 to 29.9 mg/100 g based on different extraction methods (Özcan et al., 2022). In addition, apigenin, luteolin, chrysin, and quercetin were also found in the whole hawthorn fruit (Li, Gao et al., 2022). Moreover, vitexin 2″-O-rhamnoside, rutin, vitexin, and hyperoside were identified in three different varieties of whole hawthorn fruit (Agiel et al., 2022). The cultivation regions can influence the total flavonoid content (TFC) in the whole hawthorn fruit. For example, Hou et al. (2020) eval‎uated the TFC in the whole hawthorn fruits from five places in China, and they found that the TFC in samples from Henan was the highest, whereas the TFC of the Jiangsu samples was the lowest, and epicatechin was the predominant flavonoid in all samples from all regions.

2.1.3 Proanthocyanidins

Proanthocyanidins, also called condensed tannins, are a category of polyphenols with higher molecular weights compared with common phenolic acids and flavonoids. They are oligomeric compounds with a basic framework structure consisting of epicatechin or catechin. Procyanidins are members of proanthocyanidins that are found in the whole hawthorn fruit. Liquid/Liquid extraction is the main method for proanthocyanidin isolation. In addition, ethyl acetate and water are the most commonly used solvent systems for liquid/liquid extraction (Liu, 2012). Procyanidin dimers (e.g., procyanidins B2 and B5), dimer hexosides, and trimers (e.g., procyanidins C1 and C5) are shown to be the major procyanidins in whole hawthorn fruits (Liu et al., 2009). Liu et al. (2010) optimized the extraction and purification methods of procyanidins from whole hawthorn fruits and found that the content of procyanidins was 2.96% ± 0.14%, and the oligomeric procyanidins/procyanidins ratio was 61.6%, which was the highest in their screening sources.

2.2 Polysaccharides

Most of the cellulosic polysaccharides are polar macromolecules and soluble in water. Thus, polysaccharides are usually extracted using hot water according to the principle of “similar compatibility.” On top of hot water extraction, some other methods, such as microwave-assisted extraction, ultrasonic-assisted extraction, acid–base extraction, enzymatic extraction, and ultrahigh-pressure extraction, have also been developed for polysaccharide extraction (Liu & Huang, 2019). The common methods for the separation and purification of polysaccharides include precipitation, ultrafiltration, and gel chromatography (Zhan et al., 2023; Wang et al., 2010; Luo et al., 2010). The whole hawthorn fruit is also rich in polysaccharides. Its pulps contain 82.35% of total carbohydrates and 29.39% of uronic acid contents, which is higher than its seeds (Rjeibi et al., 2020). In addition, pectin is the predominant polysaccharide in the whole hawthorn fruit. Guo et al. (2019) extracted a high-methoxylated pectic polysaccharide with the mild acid extraction method from hawthorn wine residues and found that the pectic polysaccharide had a relatively lower molecular weight and higher polydispersity index when compared with pectin from the whole hawthorn fruit, indicating that the wine-making processing degraded the chain of polysaccharides originally existing in the whole hawthorn fruit. Another study obtained the whole hawthorn fruit pectin by ultrasound-sodium citrate assisted extraction and divided it into quaternized hawthorn pectin (QHP) by (3-chlom-2-hydroxypropyl) trimethylammonium chloride under alkaline conditions according to different degrees of substitution, and the quaternary ammonium modification was found to improve the water solubility and water holding capacity of the pectin (Qin et al., 2022). The weight-average molecular weight (Mw) of its pectin was 379.35 ± 0.57 KDa, and the number-average molecular weight (Mn) was 147.72 ± 1.40; thus, the Mw/Mn values indicate that the molecular weight distribution was 2.57 ± 0.03. Li, Zhang et al. (2022) extracted, purified, and analyzed the hawthorn pectic polysaccharide and found that its Mw ranged from 73.67 × 103 to 464.42 × 103 KDa, depending on the type of extraction method. Zhu et al. (2019) found that the monosaccharide composition of HP polysaccharides included d-galacturonic acid, d-glucuronic acid, d-glucose, l-rhamnose, d-galactose, d-xylose, and d-arabinose.

2.3 Other ingredients

The whole hawthorn fruit also contains other bioactive ingredients, like terpenoids, volatile compounds, and lignans. Two triterpenoids, oleanic acid and corosolic acid, were identified in the whole hawthorn fruit (Li, Gao et al., 2022). The volatile compounds of the whole hawthorn fruits vary at each maturity stage, and some esters (e.g., butyl and hexyl hexanoates, hexyl, and cis-3-hexenyl acetates) gradually increased in the Sultan cultivar (Dursun et al., 2021). In addition, beta-thujene (17.21%), alpha-pinene (15.40%), 2-hexenal (12.42%), trans-caryophyllene (8.76%), beta-myrcene (7.89%), 1-pentacene (5.89%), sabinene (4.33%), and trans-beta-farnesene were identified as the major essential oil compounds in the whole hawthorn fruit (Bazgir et al., 2020). Besides, Shang et al. (2020) isolated two pairs of new lignan enantiomers (1a/1b, 2a/2b) from the whole hawthorn fruit, and Xin et al. (2022) isolated seven lignans, including six new compounds, from the whole hawthorn fruit.

3 BIOACTIVITIES BASED ON IN VITRO AND IN VIVO STUDIES

The whole hawthorn fruit has been reported to contain many bioactive components (Figure 2), such as phenolic acids, flavonoids, proanthocyanidins, and pectin, which are intensively discussed as follows. The underlying molecular mechanisms will also be highlighted.

FIGURE 2

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Food-related applications of the hawthorn fruit.

3.1 Antioxidant activity

Oxidative stress is a redox imbalance accompanied by increased production of reactive oxygen species (ROS) and overwhelming antioxidant defenses (He et al., 2021). Free radical–induced oxidative stress is closely associated with many human diseases like CVD, autoimmune disease, and age-related sexual decline. The antioxidant effects of plant flavonoids have been frequently reported, and possible mechanisms include inhibiting the production or direct elimination of free radicals, or inhibiting lipid peroxidation (Huang et al., 2022).

Recent studies have reported that the hawthorn pulp and its polyphenols exhibit potent antioxidant activity in vitro. It was shown that the total antioxidant capacity of the hawthorn pulp was 0.32–1.84 mmol Fe2+/g dry weight (DW) (Alirezalu et al., 2020), and it had a more stable anti-lipid peroxidation capacity than vitamin C (Feng et al., 2022). The antioxidant activity of the hawthorn pulp was mainly attributed to its free phenolics, accounting for 35.3%–37.8% of its antioxidant activity, followed by insoluble-bound, soluble esterified–bound, and soluble glycosylated–bound phenolics, accounting for 25.0%–27.0%, 23.4%–25.7%, and 9.4%–15.7% of its antioxidant activity, respectively (Feng et al., 2022). Interestingly, the antioxidant activity of insoluble-bound phenolics in its peel (103–125 μmol Trolox/g DW) was significantly higher than that in its pulp (61.3–67.3 μmol Trolox/g DW) (Lou et al., 2020). Moreover, polyphenols in the hawthorn pulp also exhibited obvious scavenging activities against 1-diphenyl-2-picrylhydrazyl radical, 2,2′-Azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), and hydroxyl radicals (Lin et al., 2022). Chlorogenic acid and chrysin showed potential antioxidant activity in ABTS and superoxide radical scavenging assays (Lin et al., 2022). Chlorogenic acid, epicatechin, and procyanidin B2 were found to be the predominant antioxidant contributors in hawthorn pulp (Lou et al., 2021).

The hawthorn extract and its polyphenols also exhibited antioxidant activities in cells and animals. The whole hawthorn extract significantly increased cell viability and enhanced the activities of superoxide dismutase, catalase, and glutathione peroxidase, while decreasing lactate dehydrogenase release, ROS levels, and peroxide (H2O2)-induced malondialdehyde (MDA) content in rat pheochromocytoma cells (PC12 cells) (Wang et al., 2022). Treatment using the whole hawthorn fruit extract (HFE) increased the antioxidant capacity of human hepatocellular carcinoma cells (HepG2 cells) and reduced oleic acid–induced hyperlipidemia by activating the nuclear factor erythropoietin-2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway (Feng et al., 2022). Hawthorn flavonoids were also discovered to possess powerful Peroxyl radical scavenging activity and strong intracellular antioxidant activity in cells (Huang et al., 2022). The whole hawthorn fruit promoted the antioxidant capacity of both plasma and liver (He et al., 2021) and could inhibit lipid peroxidation in liver tissue and red blood cells (Feng et al., 2022).

These results suggest that polyphenols are the main antioxidants in the whole hawthorn fruit, and the underlying antioxidant mechanisms involve the activation of the Nrf2/HO-1 signaling pathway, enhancement of antioxidant enzyme activity, and ultimately induction of cellular antioxidant defense systems. Further studies are needed to verify whether other signaling pathways and oxidative stress molecules are involved in the in vivo antioxidant effects of whole hawthorn fruit and their polyphenols and to provide more reliable evidence for the development of natural antioxidant functional foods in the future.

3.2 Anti-inflammatory activity

Inflammation is an unavoidable consequence of normal cellular activity, and it can cause acute and chronic diseases and accelerate the aging process. Many studies have reported the anti-inflammatory effects of the whole hawthorn fruit and its bioactive components in vitro and in vivo. The whole HFE is rich in phenolic compounds, especially chlorogenic acid and (−)-epicatechin, which are widely known for their anti-inflammatory effects (Abdel-Rahman et al., 2021; Nguyen et al., 2021).

The whole HFE and its compounds can inhibit inflammation in vitro. Its flavonoids were reported to inhibit the production of inflammatory cytokines, including IL-6, IL-8, and IL-1β in human colorectal adenocarcinoma cells, possibly by suppressing the upregulation of myosin light chain kinase (MLCK)/myosin regulatory light chain (MLC) phosphorylation and inhibiting the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor kappa-light chain enhancer of activated B cells (NF-κB) signaling (Liu, Zhang et al., 2020). The whole HFE also inhibited ROS formation and mRNA production of protein kinase (MAPK)/activator protein-1 (AP-1), NF-κB, and lipopolysaccharide (LPS)-stimulated keratinocytes nuclear factor levels of activated T cells (NFAT) and interleukins in keratinocytes in a dose-dependent manner (Nguyen et al., 2021). Moreover, four new biphenyl derivatives (1–4) as well as two known compounds (5 and 6) extracted from the whole hawthorn fruit also showed anti-inflammatory activities in mouse mononuclear macrophage leukemia cells (RAW264.7 cells) (Wang et al., 2020).

Similarly, the hawthorn pulp can also block inflammation in vivo, contributing to its therapeutic effects on inflammation-related chronic diseases. It was reported that the hawthorn pulp significantly reduced the pro-inflammatory mediators of prostaglandin E2, tumor necrosis factor-α (TNF-α), and myeloperoxidase (MPO) by modulating NF-κB in vivo, thus showing high potency in inhibiting keratin-induced inflammation (Abdel-Rahman et al., 2021). Meanwhile, it could also significantly lower plasma levels of TNF-α and monocyte chemoattractant protein 1 (MCP-1) and downregulate the hepatic expression‎ of MCP-1 and IL-1β in type 2 diabetes (T2D) rats (He et al., 2021). Moreover, the hawthorn pulp could reduce plasma myeloperoxidase, C-reactive protein, and alkaline phosphatase (ALP) levels, suggesting its potential to block or regulate intestinal inflammation in a castor oil–induced rat model (Nascimento et al., 2021; Sammari et al., 2021). In addition, a series of animal experiments have demonstrated that hawthorn pulp can alleviate chronic diseases associated with inflammation, such as osteoarthritis, ulcerative colitis, atherosclerosis (AS), chronic heart failure, hepatic fibrosis, and obesity, but the specific mechanism of action has not yet been completely revealed (Alsharif et al., 2022; Cheng et al., 2020; Hamza et al., 2020; He et al., 2021; Nguyen et al., 2021).

Overall, a large number of studies support the anti-inflammatory activity of the whole HFE and hawthorn pulp, and its anti-inflammatory mechanism is related to the regulation of NF-κB, ERK1/2, MLCK-pMLC, MAPK, and TLR4 signaling pathways, leading to the downregulation of related pro-inflammatory cytokines, such as TNF-α, IL-6, IL-8, and IL-1β. However, as mentioned earlier, the mechanism by which hawthorn pulp alleviates inflammation-associated chronic diseases is not fully understood and requires further validation in animal experiments. It is well known that a series of symptoms caused by inflammation have a great impact on human health; therefore, nutraceuticals and foods containing hawthorn pulp can be developed to reduce inflammation and prevent related symptoms.

3.3 Antibacterial activity

The whole hawthorn fruit has been reported to possess antibacterial activity. It displayed good inhibitory effects against both Gram-positive and Gram-negative bacteria, with the antibacterial mechanism of inducing oxidative stress via ROS production (Golabiazar et al., 2021). Similarly, it enhanced the resistance of Exopalaemon carinicauda to Vibrio parahaemolyticus, as evidenced by an improved immune response and growth of the shrimp (Cao et al., 2022). It also exhibited antibacterial effects against Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, Acinetobacter baumannii, and Escherichia coli, with the minimum inhibitory concentration of 0.11 μg/mL (Ebrahimzadeh et al., 2020). In addition, it was reported that the QHP derivative exhibited a certain inhibitory effect on E. coli and S. aureus (Qin et al., 2022).

In general, the whole hawthorn fruit exhibits broad antimicrobial spectra by inhibiting the growth of bacteria. However, there is no specific study on its main bacteriostatic components or potential bacteriostatic mechanisms, and future studies may focus on the active components and specific targets of its bacteriostatic effects.

3.4 Intestinal health

Intestinal health is related to many factors, such as intestinal morphology, intestinal barrier, and gastrointestinal dynamics. Intestinal diseases are related to these factors and are one of the major diseases that threaten human health. The whole hawthorn fruit and its constituent polyphenols and polysaccharides have been reported to be beneficial for intestinal health.

Researchers found that dietary supplementation with the hawthorn pulp improved intestinal morphology by increasing villi length, villi width, and muscle thickness, and enhanced gut barrier integrity by increasing the mRNA expression‎ of zonula occludens-3 in golden pompano (Tan et al., 2020). It also improved intestinal health by improving duodenal lipase and trypsin activity and jejunal morphology, as well as higher ileal valproic acid, colonic propionic acid, and isobutyric acid concentrations (Fu et al., 2022). In addition, hawthorn extract can promote gastrointestinal motility by increasing the number of gastrointestinal Cajal (interstitial cell of Cajal [ICC]) mesenchymal cells through upregulation of c-kit expression‎ (Wang, Luo et al., 2021). Besides, it could prevent diarrhea and the accumulation of interstitial fluid (Sammari et al., 2021). Furthermore, hawthorn seeds have also been found to be beneficial for intestinal health. Hawthorn seed ethyl acetate extract improved gastrointestinal motility in rats with diabetic gastroparesis (DGP), and its potential mechanism might be related to the upregulation of n-NOS and c-kit expression‎ and ICCs in the stomach and the regulation of motilin, gastrin, and 5-HT (Niu et al., 2020). The supplementation of hawthorn seed oils could selectively alter the abundance of gut bacteria, including unclassified Christensenellaceae, Ruminococcaceae, Gastranaerophilales, Faecalibaculum, Peptococcus, Clostridiales, and Ruminococcus, which were correlated with cholesterol metabolism (Kwek et al., 2022).

Flavonoids extracted from the whole hawthorn fruit may reverse intestinal flora disorders and metabolic disorders in mice by increasing the proportion of Dubosiella, Alloprevotella, and Bifidobacterium, as well as the levels of docosapentaenoic acid, sphingolipids (SM), and phosphatidylcholine (PC), while decreasing the proportion of immobile bacteria (Zhang et al., 2022). Hawthorn polyphenols were found to shorten the length of lesions formed in colitis rat colon, in addition to decreasing the levels of myeloperoxidase and interleukin-1β (Nascimento et al., 2021). Simultaneously, they could improve the diversity of gut microbial species by altering the abundance of the Bacteroidetes and Firmicutes microorganisms in the gut (Yu et al., 2022). They also increased the abundance of Lactobacillus, but reduced the production of Gram-negative bacteria, thereby reducing the abnormal increase in bacterial diversity caused by alcohol (Wang, Wang et al., 2021).

Polysaccharides have been demonstrated to regulate gut microbiota. Current studies suggest that the hawthorn polysaccharide could directly modify the intestine, particularly by enriching Alistipes and Odoribacter, and produce short-chain fatty acids to inhibit colitis (Guo et al., 2021). Furthermore, it was found to increase the abundance of Micrococcus, Acidaminococcus, and Mitsuokella while decreasing the abundance of E. coli and Clostridium, thus regulating the proportion of beneficial bacteria in the intestine (Han, Zhou, et al., 2022). It also increased the abundance of Akkermansia, Bacteroides, and Adlercreutzia but decreased the abundance of Lactobacillus, Bifidobacterium, Blautia, Lachnospiraceae, and Subdoligranulum to restore the balance of gut microbiota (Han, Zhao, et al., 2022).

Overall, the whole hawthorn fruit exhibits beneficial effects on intestinal health with mechanisms related to the regulation of intestinal morphology, motility, and microbiota abundance. Polyphenols and polysaccharides are the main contributors to its intestinal protection, whereas the underlying mechanisms remain unclear, which needs additional investigation in the future. Moreover, current studies mainly focus on the first messenger, and there are no relevant studies on the specific activated signaling pathways. As a recognized food for promoting digestion and absorption, it would be beneficial to develop hawthorn to promote human gastrointestinal health.

3.5 Antidiabetic effect

Diabetes mellitus is a metabolic disease characterized by hyperglycemia that can be caused by rapid glucose uptake in the intestine. In recent years, the antidiabetic effects of the whole hawthorn fruit and its components have received increasing attention.

α-Amylase and α-glucosidase are two key glucoside hydrolases that catalyze the conversion of starch, disaccharides, or oligosaccharides to glucose during carbohydrate digestion. An important approach to controlling diabetes is to reduce postprandial hyperglycemia by delaying carbohydrate digestion and glucose absorption. The whole hawthorn fruit exhibited excellent hypoglycemic ability due to its ability to resist α-amylase and α-glucosidase (Mecheri et al., 2021). Polysaccharides, a major component of the whole hawthorn fruit, were reported to have high α-amylase inhibitory activity (Rjeibi et al., 2020). In a recent study by Aad et al. (2021), it was found that hawthorn flavonoids could dose-dependently inhibit α-amylase and α-glucosidase. Hypericin, a component extracted from the whole hawthorn fruit, was found to have significant anti-α-glucosidase activity (Lin et al., 2022). In addition, the B-type proanthocyanidin, one of the hawthorn phytochemicals, is a potent, reversible, and competitive inhibitor of α-glucosidase (Liang et al., 2022). Screening and identification of α-glucosidase inhibitors in the whole hawthorn fruit also showed that polyphenols containing mainly quercetin (74.58%) and chrysin (9.58%) played an important role in α-glucosidase inhibition (Xin et al., 2021).

Insulin is the most critical hormone in regulating blood sugar and maintaining normal blood sugar levels. Insulin resistance occurs when insulin regulation becomes delayed and insufficient to inhibit glucose processing. A complex hypoglycemic complex consisting of hawthorn polyphenols, d-chiral inositol, and epigallocatechin gallate increased glucose consumption and glycogen levels and inhibited hepatic gluconeogenesis in HepG2 cells (Xin et al., 2021). Hawthorn polyphenols improved insulin resistance, decreased fasting glucose and hepatic gluconeogenesis, and increased hepatic glycogen synthesis and storage by downregulating phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Forkhead box protein O1 (FOXO1)-mediated phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase and upregulating PI3K/Akt/glycogen synthase (GS) kinase-3–mediated GS activation in STZ/high-fat diet (HFD)-induced mice. Polyphenols in the whole hawthorn fruit significantly reduced insulin resistance by upregulating phosphorylation of glucose uptake protein (GLUT4) and insulin resistance–related proteins phosphorylated insulin receptor substrate (p-IRS1), phosphorylated serthreonine protein kinase (p-AKT), and phosphorylated inositol 3 kinase (p-PI3K) in rat liver (Liu, Yu, et al., 2021). Procyanidins in whole hawthorn berries are involved in fatty acid biosynthesis, MAPK, and lipopolysaccharide biosynthesis pathways to ameliorate hormone-associated insulin resistance (Han, Zhao, et al., 2022).

Furthermore, the whole hawthorn fruit and its constituent polyphenols improved secondary complications of diabetes in vitro and in vivo. Hawthorn pulp treatment and moderate-intensity interval running training simultaneously improved myocardial ischemia-reperfusion-induced renal injury via the miR-126/Nrf-2 pathway and improved insulin sensitivity and renal function in type 1 diabetic rats (Asgari et al., 2022). In addition, the hawthorn seed improved gastrointestinal motility in DGP rats, and its potential mechanism may be related to inhibiting oxidative stress damage caused by hyperglycemia (Niu et al., 2020). On the other hand, hawthorn polyphenols attenuated hyperglycemia-induced retinal damage, possibly through inhibition of the adenosine monophosphate-activated protein kinase (AMPK)/mitochondrial acetylase (SIRT1)/NF-κB and miR-34a/SIRT1/p53 pathways, and attenuated hyperglycemia-induced inflammation and apoptosis in human retinal pigment epithelial cells (ARPE-19 cells) (Liu, Fang, et al., 2021).

Overall, the whole hawthorn berry and its constituents have good antidiabetic potential to prevent and improve diabetes and its complications, including diabetic nephropathy, cardiomyopathy, and DGP, which involve a variety of signaling pathways, such as PI3K/Akt/FOXO1-mediated/PEPCK, AMPK/SIRT/NF-κB, and miR-34a/SIRT1/p53. Polyphenols and polysaccharides are the main hypoglycemic components of the whole hawthorn fruit, but few experiments have been conducted to study their mechanisms of action individually. The development of nutraceuticals from hawthorn and its constituents is a focus of subsequent research.

3.6 Cardiovascular protection

CVD is the leading cause of death in humans. Hypertension, hyperlipidemia, and AS are the main risk factors for CVD, which can be inhibited by the whole hawthorn fruit and its constituents, contributing to its cardiovascular protective effect.

The whole hawthorn extract has potential preventive and therapeutic effects on AS. In golden Syrian hamsters, it might regulate AS by controlling cell survival and proliferation, reducing the levels of enzymes 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) and lipoprotein lipase, and inhibiting inflammatory response (Li, Gao et al., 2022). The promotion of thrombosis induced by platelet aggregation plays an important role in the development of AS in rats. The whole hawthorn extract could reduce thromboxane B2 release, P-selectin expression‎, and activation of cAMP and Akt signaling through the mechanisms of downregulating platelet receptor (P2Y12) (chemoreceptor for adenosine diphosphate) signaling and inhibiting ROS-induced NF-κB activation (Shatoor, Shati, et al., 2021). The whole HFE also produces endothelium-dependent vasodilation in porcine coronary, which is partially dependent on estrogen receptors and is sensitive to the inhibition of the ROS/Src/PI3K/NO pathway (Younis et al., 2021). Its extract had the potential benefit of alleviating endothelial dysfunction in isolated aortic rings from Sprague–Dawley rats, possibly related to the inhibition of arginase (Bujor et al., 2020).

The antihypertensive effects of the hawthorn pulp and its compounds have also been demonstrated. Combination of the hawthorn pulp with vitamin C inhibited heat exposure-induced oxidative changes in vascular tissues under hypertension, contributing to its antihypertensive activities without signs of toxicity, which involved the activation of nitric oxide pathway by muscarinic receptors and/or inhibition of angiotensin-converting enzymes (Zhu et al., 2022). The hawthorn pulp as a parent tincture for the initial treatment of heart failure significantly reduces systolic blood pressure in normotensive rats (Balbueno et al., 2020). Incidentally, the whole hawthorn fruit vinegar could achieve antihypertensive effects by inhibiting the activity of angiotensin-converting enzyme II (Sayin & Gunes, 2021). Specifically, hawthorn berry flavonoid extracts can positively affect the electrocardiogram of oiled chickens reared at high altitude, thereby preventing the complications of pulmonary hypertension and heart wave disorders (Younis et al., 2020).

Hyperlipidemia is another high-risk factor for CVD, and consumption of the hawthorn pulp may regulate blood lipids based on in vitro and in vivo studies. Molecular docking results suggested that acetyl-CoA carboxylase might be the target of the hypolipidemic activity of hawthorn triterpenoids, which is verified in HepG2 cells (Zhu et al., 2022). In addition, hawthorn pectic acid inhibited lipid accumulation in HepG2 cells by upregulating low-density lipoprotein (LDL) receptor and downregulating HMG-CoA reductase gene expression‎ (Feng et al., 2022). The whole hawthorn fruit and its compounds can also regulate blood lipids in animal models. Treatment of the hawthorn pulp also reduced golden pompano's plasma cholesterol, triglycerides, and LDL levels to lower blood lipids (Tan et al., 2020). Hawthorn polyphenol extracts were reported to significantly improve total cholesterol and total triglycerides in T2D rats (Liu, Yu, et al., 2021). Besides, it showed significant lipid-lowering activities (40 mg/kg) in male albino Wistar rats compared to atorvastatin (80 mg/kg) (Zahra et al., 2021). Hawthorn proanthocyanidins significantly alleviated lipid accumulation in the serum and liver through modulation of NF-κB and AMPK pathways and protected liver structure in rats with lipid metabolism disorders (LMDs) (Han, Zhao, et al., 2022). The hawthorn pulp also effectively reduced lipid synthesis in HFD rats by downregulating hepatocyte ER stress-induced peroxisome proliferator–activated receptor-γ (PPAR-γ) expression‎ (Mao et al., 2022). It also ameliorated some of the disordered metabolic pathways in spontaneously hypertensive rats by interfering with sphingolipid, glycerophospholipid, and glycerolipid metabolism (Sun, Chi et al., 2022). Hawthorn seed oils could also reduce plasma cholesterol and non-HDL cholesterol by up to 15% in hypercholesterolemia hamsters (Kwek et al., 2022).

In general, the whole hawthorn fruit and its components can alleviate cardiovascular risk factors, such as AS, vascular strain, vascular tension, and hyperlipidemia, without significant side effects. The mechanism is related to the regulation of cAMP, Akt, P2Y12, NF-κB, ROS/Src/PI3K/NO signaling pathways, which lead to the downregulation of HMG-CoAR, angiotensin-converting enzyme II, and other related enzymes. Hawthorn is worth developing nutraceuticals for due to its multi-targeted treatment of CVDs.

3.7 Hepatoprotective effect

The whole hawthorn fruit and its components have been reported to exhibit hepatoprotective effects on acute liver injury as well as chronic liver diseases, which are discussed as follows.

The protective ability of hawthorn pulp and its components on acute liver injury caused by drugs and alcohol has been demonstrated in vivo. Treatment with the ethanolic extract of the whole hawthorn fruit reduced total bilirubin concentration, increased total protein ratio, altered serum ALP, aspartate aminotransferase, and alanine aminotransferase levels, and improved liver tissue morphology in isoniazid and rifampicin, which caused hepatotoxicity in rats (Han, Zhao, et al., 2022). Lactobacillus rhamnosus 217-1 fermented mixture of Pueraria lobata, Lonicera japonica, and hawthorn pulp improved liver indexes, increased the activities of liver tissue superoxide dismutase and glutathione, and decreased the levels of MDA in a mouse model of alcoholic liver disease (Wang, Wang et al., 2021).

The hawthorn pulp also exhibited excellent protective effects against chronic liver diseases. It could ameliorate obesity-related hepatic steatosis in HFD rats by reducing hepatic endoplasmic reticulum (ER) stress through the downregulation of PPAR-γ and glucose regulatory protein 78 (a major regulator of ER homeostasis) (Mao et al., 2022). Another study also confirmed that it ameliorated HFD-induced hepatic steatosis via the prevention of elevated serum and hepatic lipids, and the mechanism could be associated with the activation of AMPK signaling and the subsequent blocking of its downstream molecules, such as hepatic expression‎ of sterol regulatory element–binding protein 1/2, fatty acid synthase, and 3-hydroxy-3-methylglutaryl coenzyme A reductase (Shatoor, Al Humayed, et al., 2021). In addition, proanthocyanidins in the whole hawthorn fruit could protect the liver structure and reduce liver inflammation and lipid accumulation by regulating LM-related NF-κB and AMPK pathways in LMD rats (Han, Zhao, et al., 2022).

In brief, the whole hawthorn fruit and its constituents, mainly proanthocyanidins, showed potential to treat the liver injury caused by alcohol, isoniazid, rifampin, and HFD while improving liver steatosis and functional indices; the protective mechanism is mainly related to resistance to oxidative stress and impaired lipid metabolism in the liver. However, the specific targets of its action have not been fully revealed, and subsequent studies can utilize relevant cell models to investigate the specific targets of its action.

3.8 Anti-cancer effect

Current studies have shown that the whole hawthorn fruit and its components, especially proanthocyanidins, have anti-cancer activity.

The whole HFE and its components have been reported to have anti-cancer activity against different cancer cells in vitro. Methanolic extracts of the whole hawthorn fruit rich in polyphenols were found to be cytotoxic against human breast cancer cells (MCF-7) hormone receptor-positive and human breast cancer cells (MDA-MB-231) triple-negative breast cancer cell lines, effectively inhibiting tumor cell proliferation and arresting the cell cycle at the G1/S transition, possibly associated with the regulation of Wnt signaling pathway (Kombiyil & Sivasithamparam, 2023). Polyphenols also inhibited apoptosis through the AMPK/SIRT1/NF-κB pathway and reduced miR-34a/SIRT1/p53 pathway activation in human retinal pigment epithelial cells (ARPE-19 cells) (Liu, Fang, et al., 2021). Homogeneous polysaccharides extracted from the whole hawthorn fruit also possessed anti-cancer effects on colon cancer cells by upregulating caspase 3, 7, 8, 9, and Fas, fas-associating protein with death domain, TNF-R1, and TNF receptor-1-associated death domain protein, and downregulating cyclin A1/D1/E1 and cyclin-dependent kinase-1/2 (Ma et al., 2020). Hawthorn B–type proanthocyanidin polymorphs composed of epicatechin strongly inhibited intracellular tyrosinase activity and melanogenesis and induced apoptosis in mouse melanoma cells (Liang et al., 2022). It blocked the HCT116 cell cycle in the G2/M phase through the p53-cyclin B pathway and promoted apoptosis partly through the mitochondrial (cysteine 9-cysteine 3) and death receptor (cysteine 8-cysteine 3) pathways (Sun, Wang et al., 2022). Meanwhile, two new pairs of lignan enantiomers (1a/1b and 2a/2b) isolated from the whole hawthorn fruit were cytotoxic to Hep3B hepatoma cells with IC50 values of 34.97 ± 2.74 and 17.42 ± 0.71 μM, respectively. In addition, 1b induced more apoptotic and autophagic cells than 1a in Hep3B cells, which may be related to the activation of p38 to promote 1b-induced apoptosis and autophagy (Shang et al., 2020). The HFE inhibited the proliferative and invasive potential of glioblastoma cells by promoting the cleavage of poly (ADP-ribose) polymerase 1 (PARP1) associated with apoptosis and significantly inhibiting pro-survival kinase, adherent plaque kinase (FAK), and Akt (Żurek et al., 2021). Silver nanoparticles (CME@Ag-NPs) prepared from the HFE were very effective in inhibiting the growth of gastric and mammary gland cancer cell lines in vitro (Shirzadi-Ahodashti et al., 2020).

In summary, the whole HFE and its components are potential anti-cancer natural products. They have a positive effect on the prevention and treatment of a variety of cancers in vitro, including gastric, colon, liver, breast, and mammary cancers. Their anti-cancer mechanisms include the inhibition of cancer cell growth and induction of apoptosis, in part through p53-cyclin B, AMPK/SIRT1/NF-κB, miR-34a/SIRT1/p53, mitochondrial (cysteine 9-cysteine 3), and death receptor (cysteine 8-cysteine 3) signaling pathways. These findings open up the possibility that whole hawthorn extract and its components can be used for the prevention and management of different cancers.

3.9 Neuroprotective activity

The whole HFE and its components have been found to have neuroprotective effects on nerve injury in vitro and in vivo.

Acetylcholinesterase (AChE) plays an important role in neurodegenerative diseases that affect memory. Hawthorn's components showed significant AChE inhibitory activities. The phenolic compounds of the whole hawthorn fruit have been shown to possess stronger AChE inhibitory activity than donepezil (Liu, Zhang et al., 2020). Polysaccharides from the pulp exhibited higher AChE inhibitory activity (Rjeibi et al., 2020).

Lignans, isolated from the whole hawthorn fruits, were reported to protect against H2O2-induced damage in human neuroblastoma SH-SY5Y cells (Zhang et al., 2023). In addition, the whole HFE prevented traumatic brain injury–mediated reduction in neuronal survival and inhibited neuronal death in the rat cerebral cortex by activating Nrf2 pathways and inhibiting NF-κB expression‎ (Gao et al., 2022).

Therefore, the whole hawthorn fruit and its components, mainly lignans and polysaccharides, have significant neuroprotective activity, implying that they may be potential inhibitors of AChE and beneficial for human memory. However, its specific mechanism of action and target of action have not been described in detail, which is worth exploring in depth in the future.

3.10 Other bioactivities

The whole hawthorn extract and its components exhibited other bioactivities in vitro. The whole hawthorn extract inhibited osteoclast differentiation by suppressing the nuclear factor of activated T cells (NFATc1) and c-Fos expression‎ and suppressing the expression‎ of osteoclast-related genes, such as NFATc1, Ca2, Acp5, mmp9, cathepsin K (CtsK), Oscar, and Atp6v0d2 (Kim et al., 2021). Proanthocyanidins and phenylpropanoids extracted from the whole hawthorn fruit exhibited moderate tyrosinase inhibitory activity (Liang et al., 2022) (Table 1).

TABLE 1. Bioactivities and related molecular mechanisms of the hawthorn fruit based on in vitro and in vivo studies.

Extracts/CompoundsSubjects/Cell linesDosesMain effectsMechanismsReferences

• Abbreviations: AChE, acetylcholinesterase; AMPK, activated protein kinase; ABTS, 2,2′-Azino-bis(3-ethylbenzthiazoline-6-sulfonic acid); AGS, growth of gastric; ALP, alkaline phosphatase; AP-1, activator protein-1; BDNF, brain-derived neurotrophic factor; CtsK, cathepsin K; CAT, catalase; CRP, C-reactive protein; DPPH, 1-diphenyl-2-picrylhydrazyl radical; DSS, dextran sulfate sodium; FAK, adherent plaque kinase; FOS, fructooligosaccharides; GSH-Px3, glutathione peroxidase 3; HO-1, heme oxygenase 1; H2O2, hydrogen peroxide; HFD, high-fat diet; ICC, interstitial cell of Cajal; LPS, lipopolysaccharide; MARK, protein kinase; MCF, mammary gland; MCP-1, monocyte chemoattractant protein 1; MDA, malondialdehyde; MIC, minimum inhibitory concentration; MPO, myeloperoxidase; NFATc1, nuclear factor of activated T cells; NFAT, nuclear factor levels of activated T cells; NF-κB, nuclear factor kappa-light chain enhancer of activated B cells; Nrf2, nuclear factor erythropoietin-2-related factor; 2PFC, prefrontal cortex; PPAR-γ, peroxisome proliferator–activated receptor-γ; PI3K, phosphoinositide 3-kinase; PGE2, prostaglandin E2; PKB, protein kinase B; ROS, reactive oxygen species; SOD, superoxide dismutase; T2D, type 2 diabetes; TC, total cholesterol; TG, total triglyceride; TMAO, trimethylamine-N-oxide; TNF-α, tumor necrosis factor-α; XOS, xylooligosaccharides.

The whole hawthorn fruit and its components also had other in vivo beneficial functions. The whole hawthorn extract could also enhance immune response and growth performance (Fu et al., 2022). Hawthorn pulp was sufficient to produce anxiolytic and antidepressant-like effects by activating 5-HT1A receptors and elevating brain-derived neurotrophic factor, increasing urinary serotonin levels, and decreasing urinary NE and DA levels (Nitzan et al., 2022). The defatted methanolic extract of the whole hawthorn had excellent anti-injury sensitizing ability (Abdel-Rahman et al., 2021). Incidentally, hawthorn polyphenol microcapsules (HPMs) improved swimming ability and skeletal muscle substrate depletion as well as product metabolism, enhanced antioxidant capacity in fatigued mice, possibly through activation of AMPK pathways to improve mitochondrial dysfunction and cellular metabolism, inhibition of NF-κB inflammatory conserved pathways, and improved the diversity of gut microbial species (Yu et al., 2022).

4 HEALTH BENEFITS BASED ON HUMAN STUDIES

The whole hawthorn fruit has also been demonstrated to possess health benefits for humans, especially with cardiovascular protective effects. It was reported to regulate blood pressure on humans. The HFE exhibited significant hypotensive effects in diabetic patients taking medication, especially in lowering resting diastolic blood pressure (Hu et al., 2014). A combination of natural d-camphor and fresh HFE could improve hypotension in adolescents, adults, and the elderly (Schandry et al., 2018). It could also regulate blood lipids. A polyherbal formula containing the hawthorn pulp (1 g daily), Alisma orientalis, Stigma maydis, Ganoderma lucidum, Polygonum multiflorum, and Morus alba reduced LDL cholesterol and glycated hemoglobin in patients with dyslipidemia (Holubarsch et al., 2008). Besides, the HFE might reduce the incidence of sudden cardiac death in patients with less impaired left ventricular function (Holubarsch et al., 2008).

Limited clinical studies indicate that the whole hawthorn fruit possesses beneficial effects on mental health. It was reported that the extracts of the whole hawthorn fruit and Eschscholtzia californica significantly reduced total somatic Hamilton scale scores and self-rated anxiety in mild-to-moderate anxiety patients (Hanus et al., 2004).

In summary, the whole hawthorn fruit has been demonstrated to benefit the cardiovascular system, mainly through regulating blood pressure, regulating blood lipids, and alleviating heart failure symptoms (Table 2). However, its other health benefits on humans require further studies for verification. For example, the beneficial effects of the whole hawthorn fruit on human intestinal health and its anti-inflammatory effects need to be confirmed in more clinical trials.

TABLE 2. Health benefits of the hawthorn fruit based on human studies.

Extracts/CompoundsParticipantsControlTreatmentsMain effectsReferences

Antihypertensive effects
Hawthorn extract	Patients with type 2 diabetes	Placebo	Daily 1200 mg	Antihypertensive	Hu et al. (2014)
Korodin, a combination of camphor and hawthorn extract	Adolescent participants in the age range of 14– 17 years having a systolic blood pressure below 118 mmHg (boys) or 110 mmHg (girls)	Placebo	A single dose of 20 drops	Blood pressure ↑	Schandry et al. (2018)
Hypolipidemic effects
The multiherb formula containing hawthorn, Alisma orientalis, Stigma maydis, Ganoderma lucidum, Polygonum multiflorum, and Morus alba	Patients with dyslipidemia	Placebo	800 mg (two capsules), three times a day, 15 days	Lipoprotein cholesterol ↓ Glycated hemoglobin ↓	Holubarsch et al. (2008)
Anti-heart failure effects
Neuroprotective effects
Extracts of hawthorn and Eschscholtzia California	Patients presenting with generalized anxiety (DSM-III-R) of mild-to-moderate intensity	Placebo	NA	Total and somatic Hamilton scale scores ↓ Subjective patient-rated anxiety ↓	Hanus et al. (2004)

5 FOOD-RELATED APPLICATIONS

Studies have demonstrated various food-related applications of the whole hawthorn fruit (Figure 3). pH-sensitive films are thin and transparent layers that can change color or fluorescence in response to changes in pH. In a study conducted by Yan et al. (2021), the incorporation of the whole HFE into gelatin/chitosan/nanocellulose composite films yielded positive pH-sensitive films, suggesting that the developed films could be used to indicate the changes in food quality. Another interesting food application is the usage of hawthorn wine pomace. It demonstrated the sustainable use of hawthorn wine pomace for HP synthesis, which acted as an effective and antioxidative stabilizer (Jiang et al., 2020). Lastly, a study by Liu, Yang et al. (2020) showed that the antioxidant ability of HP helped preserve the Pickering emulsion from its lipid oxidation, thus stabilizing Pickering emulsions as particle shell materials while protecting lipid components from oxidation.

FIGURE 3

Open in figure viewerPowerPoint

Bioactivities of the hawthorn fruit and its compounds based on in vitro and in vivo studies. ABTS, 2,2′-Azino-bis(3-ethylbenzthiazoline-6-sulfonic acid); ALP, alkaline phosphatase; AP-1, activator protein-1; CAT, catalase; CRP, C-reactive protein; DPPH, 1-diphenyl-2-picrylhydrazyl radical; FAK, adherent plaque kinase; FOS, fructooligosaccharides; GSH-Px3, glutathione peroxidase 3; LPS, lipopolysaccharide; MARK, protein kinase; MCF, mammary gland; MCP-1, monocyte chemoattractant protein 1; MDA, malondialdehyde; MPO, myeloperoxidase; NFAT, nuclear factor levels of activated T cells; PFC, prefrontal cortex; PGE2, prostaglandin E2; PKB, protein kinase B; ROS, reactive oxygen species; SOD, superoxide dismutase; T2D, type 2 diabetes; TBI, traumatic brain injury; TC, total cholesterol; TG, total triglyceride; TMAO, trimethylamine-N-oxide; TNF-α, tumor necrosis factor-α; XOS, xylooligosaccharides.

Recent studies have also explored the use of the whole hawthorn fruit in the development of food products. A study by Ozcelik et al. (2021) investigated the properties of hawthorn juice-based water kefir, indicating the potential of hawthorn juice-based water kefir as an effective antioxidant beverage. Another interesting food application is the manufacturing of hawthorn wine as a new beverage. Collectively, these studies demonstrate positive results in hawthorn wine production and quality.

6 THE SAFETY ISSUE

In terms of safety, the whole hawthorn fruit is generally regarded as a safe fruit for consumption, and the European Medicines Agency's Committee for Herbal Medicinal Products has also classified hawthorn as a “Traditional Herbal Medicinal Product” and deemed it safe for consumption due to its long history of use (Distefano, 2021). Various systematic reviews have shown that the whole hawthorn fruit is generally safe for consumption. For instance, a systematic review conducted by Daniele et al. (2006) showed that the whole hawthorn is well tolerated, even if several adverse events were reported. It was found that the most frequent adverse events included dizziness/vertigo, gastrointestinal complaints, headache, migraine, and palpitation. There were also no reports of herb–drug interactions. Another review conducted by Cloud et al. (2020) also showed that the whole hawthorn fruit is considered a relatively safe herb without severe adverse effects for consumption up to 24 months. Despite the favorable indications that the whole hawthorn fruit may be safe for consumption and development into medicinal food products, further research is required to properly examine the safety of hawthorn-containing formulations. Future studies can also focus on investigating possible herb–drug interactions of the whole hawthorn fruit if consumed with other concomitant medications.

In addition, optimal dosage is another potential concern for the safety of the whole hawthorn fruit. For instance, a study conducted on whole HFE showed that it did not produce marked genotoxic effects at concentrations of 2.5 or 5 μg/mL in leukocytes or human liver hepatocellular carcinoma cells (HepG2 cells) (de Quadros et al., 2017), however, at concentrations of 10 μg/mL or higher, significant DNA damage and clastogenic/aneugenic responses were observed. Furthermore, the whole HFE was also found to exhibit weak clastogenic and/or aneugenic effects in bone marrow cells of male mice, suggesting that prolonged or high-dose use of such extracts needs to be undertaken with caution (Yonekubo et al., 2018). Therefore, it is also crucial to eval‎uate the optimal dosage of the whole HFEs for safe human consumption.

7 CONCLUSION AND PERSPECTIVES

Recent research progress indicates that the whole hawthorn fruit can be a new natural source of functional foods. Its main bioactive components are polyphenols and polysaccharides. The fruit and its bioactive compounds have also been discovered to have numerous beneficial bioactivities that may be useful in the prevention and management of certain diseases. Some of the most critical biological activities are anti-inflammatory, antimicrobial, gut-protective, antidiabetic, cardioprotective, hepatoprotective, and anti-cancer properties that may prevent or even treat diseases, indicating an impact on the management of health problems. However, the underlying mechanisms of their relevant functions are not fully understood, such as the mechanisms and targets of anti-cancer and neuroprotective effects, requiring further research. A better understanding of the bioavailability, pharmacokinetics, and metabolic pathways of the whole hawthorn extract and the main bioactive compounds in the human body is important for the development of hawthorn-related nutraceuticals. In today's society, diseases and sub-health phenomena occur frequently, and more and more people seek to prevent and maintain health from the diet. Therefore, hawthorn, as an edible and medicinal fruit, contains a large number of naturally occurring bioactive components with abundant beneficial functions that are generally safe and reliable to be used to gradually improve health in daily life. It is also a valuable source of dietary bioactive components for the development of functional foods or other nutraceuticals and for the prevention and management of certain chronic diseases.

AUTHOR CONTRIBUTIONS

Ren-You Gan and Li-Dan Zhong conceived this paper; Jin-Xin Ma, Wei Yang, and Chester Yan Jie Ng wrote this paper; Ren-You Gan, Li-Dan Zhong, Xu-Dong Tang, and Sunny Wong provided critical comments and revised the paper. The final version was approved by all the authors.

ACKNOWLEDGMENTS

This study was supported by the Qi Huang Young Scholar Programme (National Administration of Traditional Chinese Medicine), The 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-Hong Kong-Macau Joint Lab) [grant number 2020B1212030006], and the China Scholarship Council [grant number