Re: plant 2차 대사산물 - 폴리페놀 분류, 생체이용율... 2024

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Polyphenols: From Classification to Therapeutic Potential and Bioavailability

by 

Daria Ciupei

 1,†,

Alexandru Colişar

 2,†,

Loredana Leopold

 3

1

Life Science Institute, University of Agricultural Sciences and Veterinary Medicine, Manastur 3-5, 400372 Cluj-Napoca, Romania

2

Faculty of Forestry and Cadastre, University of Agricultural Sciences and Veterinary Medicine, Manastur 3-5, 400372 Cluj-Napoca, Romania

3

Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, Manastur 3-5, 400372 Cluj-Napoca, Romania

*

Author to whom correspondence should be addressed.

†

These authors contributed equally to this work.

Foods 2024, 13(24), 4131; https://doi.org/10.3390/foods13244131

Submission received: 22 November 2024 / Revised: 14 December 2024 / Accepted: 18 December 2024 / Published: 20 December 2024

(This article belongs to the Special Issue Dietary Polyphenols in Foods)

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Abstract

Though ubiquitous in nature, polyphenols gained scientific prominence only after the pioneering work of researchers like E. Fischer and K. Freudenberg, who demonstrated their potential beyond traditional applications, such as in the leather industry. Today, these bioactive compounds are recognized for their diverse therapeutic roles, including their use as adjuvants in cancer treatment, cancer prevention, and their anti-inflammatory and antioxidant properties. Additionally, polyphenols have demonstrated benefits in managing obesity, cardiovascular diseases, and neuromodulation. Their synthesis is influenced by environmental and genetic factors, with their concentrations varying based on the intensity of these variables, as well as the stage of ripening. This review provides a comprehensive overview of polyphenols, covering their classification, chemical structures, and bioavailability. The mechanisms influencing bioavailability, bioaccessibility, and bioactivity are explored in detail, alongside an introduction to their bioactive effects and associated metabolic pathways. Specific examples, such as the bioavailability of polyphenols in coffee and various types of onions, are analyzed. Despite their promising biological activities, a significant limitation of polyphenols lies in their inherently low oral bioavailability. However, their systemic circulation and the bioactive by-products formed during digestion present exciting opportunities for further research and application.

요약

폴리페놀은 

자연계에 널리 존재하지만, 

가죽 산업과 같은 전통적인 응용 분야를 넘어 그 잠재력을 입증한 

E. Fischer와 K. Freudenberg 같은 선구적인 연구자들의 업적 이후에야 

과학적으로 주목을 받게 되었습니다. 

오늘날, 이러한 생체 활성 화합물은 

암 치료, 암 예방, 항염증 및 항산화 특성의 보조제로서의 사용을 포함하여 

다양한 치료적 역할로 인정받고 있습니다. 

또한, 

폴리페놀은 비만, 심혈관 질환, 신경 조절 관리에 도움이 되는 것으로 나타났습니다. 

폴리페놀의 합성은 

환경적 요인과 유전적 요인에 의해 영향을 받으며, 

이러한 변수의 강도와 숙성 단계에 따라 농도가 달라집니다. 

이 리뷰는 

폴리페놀의 분류, 화학 구조, 생체 이용률을 포괄적으로 다루고 있습니다. 

생체 이용률, 생체 접근성, 생체 활성에 영향을 미치는 메커니즘을 

생체 활성 효과와 관련된 대사 경로에 대한 소개와 함께 자세히 살펴봅니다. 

커피와 다양한 종류의 양파에 함유된 폴리페놀의 

생체 이용률과 같은 구체적인 예를 분석합니다. 

폴리페놀의 생물학적 활성은 매우 유망하지만, 

폴리페놀의 중요한 한계는 본질적으로 구강 생체 이용률이 낮다는 점입니다. 

그러나, 

폴리페놀의 전신 순환과 소화 과정에서 생성되는 생체 활성 부산물은 

추가 연구와 적용을 위한 흥미로운 기회를 제공합니다.

Keywords: 

polyphenols; bioavailability; metabolism; quercetin; chlorogenic acid

1. Introduction

In ancient times, people firmly believed that diet and exercise were the most important sources of well-being. Hippocrates, the father of medicine, said in his Greek oath: “I will use the diet that will benefit my patients to the best of my knowledge and belief, and I will do them neither harm nor injustice” [1]. Their eating behaviors and focus on health led to better and longer possible lives, while medication was administered second, only in times of need. BC mankind did not have the advance on research and medicine available nowadays to know exactly the benefits of foods and the power they possess on human health, but throughout the decades, these benefits have been proven through research. The significant abilities of secondary metabolites like polyphenols were first noticed in the leather industry under the name “vegetable tannins” [2], later called “vegetable polyphenols” by Emil Fischer and Karl Freudenberg, but were restrained by the lack of analytical tools [3], an issue we do not encounter at this moment in time. After multiple formulations and reformulations, the definitions it is presented as are known today: polyphenols are secondary metabolites that are formed in plants and are generally involved in protection from excessive exposure from UV radiation or different disease-causing microorganisms [4]. When plants are exposed to UV radiation, environmental factors, microbes, or stresses that occur during its life, it accretes a significantly higher number of phenols. There are studies that support the argument that plants grown in soil poor in nutrients and in higher temperatures accumulate a higher content in phenolic compounds. Polyphenols are phytochemicals that have health-benefiting potential, from being used in chronic disease or cancer treatment [5,6] to simply being used as preserving agents [7,8] or antioxidants [8]. They are the highest source of antioxidants in the nourishment of human species, favoring well-being. Although they are the largest known source of antioxidants for humans, their disadvantage is their low bioavailability and rapid absorption, which leads to excretion via urine [9]. The aim of this paper is to eval‎uate the bioavailability of two significant classes of polyphenols known for their substantial health benefits. Additionally, this study seeks to provide a comprehensive understanding of the importance of polyphenol consumption by highlighting their bioactivity and the health effects mediated by the metabolites formed during digestion.

1. 서론

고대에는 식단과 운동이 웰빙의 가장 중요한 원천이라고 굳게 믿었습니다.

의학의 아버지 히포크라테스는 그리스어로 된 선서에서 이렇게 말했습니다:

“나는 내가 아는 한도 내에서,

그리고 내가 믿는 한도 내에서,

환자에게 도움이 되는 식단을 사용할 것이며,

그들에게 해를 끼치거나 불공평한 일을 하지 않을 것이다” [1].

“I will use the diet that will benefit my patients to the best of my knowledge and belief,

and I will do them neither harm nor injustice”

그들의 식습관과 건강에 대한 관심은 더 좋고 더 긴 삶을 가능하게 만들었고, 약은 필요할 때만 두 번째로 투여되었습니다. 기원전 인류는 오늘날과 같은 수준의 연구와 의학이 없었기 때문에 식품의 이점과 식품이 인간의 건강에 미치는 영향에 대해 정확히 알지 못했습니다. 그러나 수십 년에 걸쳐 이러한 이점이 연구를 통해 입증되었습니다.

폴리페놀과 같은 2차 대사 산물의 중요한 능력은

가죽 산업에서 “식물성 탄닌”이라는 이름으로 처음 발견되었으며[2],

나중에 에밀 피셔와 칼 프로이덴베르크에 의해 “식물성 폴리페놀”로 불리게 되었지만,

분석 도구의 부족으로 인해 제한을 받았습니다[3].

여러 번의 공식화와 재공식화를 거쳐,

폴리페놀은 오늘날 알려진 대로 정의되었습니다:

폴리페놀은 식물에서 형성되는 2차 대사 산물로,

일반적으로 자외선이나 다양한 질병을 유발하는 미생물에 과다 노출되는 것을 막는 데 관여합니다 [4].

식물이

자외선, 환경 요인, 미생물 또는 생애 동안 발생하는 스트레스에 노출되면,

폴리페놀의 수가 상당히 증가합니다.

영양분이 부족하고 온도가 높은 토양에서 자란 식물이

페놀 화합물의 함량이 더 높다는 주장을 뒷받침하는 연구가 있습니다.

폴리페놀은

만성 질환이나 암 치료에 사용될 수 있을 정도로

건강에 유익한 잠재력을 가진 식물 화학 물질입니다 [5,6]

단순히 보존제 [7,8] 또는 항산화제 [8]로 사용될 수도 있습니다.

폴리페놀은 인류의 영양 공급원 중

가장 높은 항산화제 공급원이며,

웰빙에 도움이 됩니다.

비록 인간에게 알려진 가장 큰 항산화제 공급원이지만,

생체 이용률이 낮고 흡수가 빠르기 때문에

소변을 통해 배설된다는 단점이 있습니다 [9].

이 논문의 목적은

상당한 건강상의 이점으로 알려진

두 가지 중요한 폴리페놀 종류의 생체 이용률을 평가하는 것입니다.

또한, 이 연구는

폴리페놀의 생체 활성과 소화 과정에서 형성된 대사 산물에 의해 매개되는

건강 효과를 강조함으로써 폴리페놀 섭취의 중요성에 대한 포괄적인 이해를 제공하고자 합니다.

2. Structure of Polyphenols: Classification

Polyphenols represent a diverse group of plant secondary metabolites with widespread occurrence in nature. Structurally, they are made of phenol units (Figure 1). More commonly, they exist in conjugated forms, with sugar residues linked to hydroxyl groups; direct links between sugar and aromatic carbon also exist. More than 8000 varieties of polyphenols have been identified in different plants throughout the years [10]. As they are considered the biggest class of phytochemicals, they ought to have another classification, dividing them into four most important subgroups: flavonoids, phenolic acids, stilbenes, and lignans, as presented in Figure 1.

2. 폴리페놀의 구조: 분류

폴리페놀은

자연계에 널리 분포하는 다양한 식물 2차 대사 산물 그룹을 나타냅니다.

구조적으로,

이들은

페놀 단위로 이루어져 있습니다(그림 1).

더 일반적으로,

이들은 수산기와 연결된 당 잔기가 있는

공액 형태로 존재합니다;

당과 방향족 탄소 사이의 직접적인 연결도 존재합니다.

수년에 걸쳐 다양한 식물에서

8000가지 이상의 폴리페놀이 확인되었습니다 [10].

폴리페놀은

식물성 화학물질의 가장 큰 부류로 간주되기 때문에,

그림 1에 나타난 것처럼

플라보노이드, 페놀산, 스틸벤, 리그난의

네 가지 가장 중요한 하위 그룹으로 나누어 다른 분류를 해야 합니다.

Figure 1. Polyphenol structures and representatives, along with some illustrations on where they could be found in plant-derived foods.

2.1. Phenolic Acids (PA)

Phenolic acids can be defined as derivates of the benzoic acid or cinnamic acid. Hydroxycinnamic acids are more likely to be encountered in different plant species than hydroxybenzoic acids, and are predominately encountered in PA such as p-coumaric, caffeic, ferulic, and sinapic acids [11]. Mo often than not, they are found bound to an amine, ester, or glycoside. The literature highlights the great absorption of hydroxycinnamic as well as hydroxybenzoic acids, even though most information is known about hydroxycinnamic acids. Hydroxybenzoic acid (HBA) generally comes in small quantities, but it can be found in some red fruits, herbs, radishes, or onions, and it exists in some alcoholic beverages like wine or beer [12,13].

Hydroxycinnamic acids (HCAs) are merely found in their bound forms, rarely in their free one. Caffeic acid is the main compound, representing over 70% of the total hydroxycinnamic acid of most fruits, concentrations that decrease during the ripening. Ferulic acid is abundant in cereal, found in the aleurone layer and pericarp, averaging around 98% of PA [14]. HCAs are absorbed easily by the stomach and small intestine; afterwards, the conjugation process is catalyzed by detoxifying enzymes. Consumption of HCA has been associated with lowering rates of cardiovascular disease, skin cancer, Alzheimer’s disease, and other brain dysfunctions, as well as obesity and diabetes, when in vivo orally administrated to rodents [11,15]. Chlorogenic acids are abundant in fruit and vegetable species. The most representative sources of CGAs are coffee beans, potatoes, eggplants, and sunflower seeds. They exist displayed as four different isomers of caffeoylquinic acid, 1-CQA, 3-CQA, 4-CQA, 5-CQA (Figure 2). Coffee is considered to be the main source with the largest amount of CGAs, their concentration being 6–12%. Their properties were discovered in 1837 in the work conducted by Robiquet and Bourton, but the name “chlorogenic acid” was given by Payen in 1846. Later along the decades, isomers of CGAs were discovered, and given names by the IUPAC commission [16]. Table 1 describes HCA-rich foods and their importance on health management.

2.1. 페놀산(PA)

페놀산은

벤조산 또는 신남산 benzoic acid or cinnamic acid 의 유도체로 정의할 수 있습니다.

하이드록시신남산은

하이드록시벤조산보다 다양한 식물 종에서 발견될 가능성이 더 높으며,

주로 p-쿠마르산, 카페산, 페룰산, 신남산과 같은

PA(페놀산)에서 발견됩니다 [11].

Mo는

종종 아민, 에스테르 또는 배당체에 결합되어 발견됩니다. 이 문헌은 하이드록시신남산과 하이드록시벤조산의 흡수율이 매우 높다는 점을 강조하고 있지만, 하이드록시신남산에 대한 정보가 가장 많이 알려져 있습니다.

하이드록시벤조산(HBA)은 일반적으로 소량으로 존재하지만, 일부 붉은 과일, 허브, 무, 양파에서 발견될 수 있으며, 와인이나 맥주와 같은 일부 알코올 음료에도 존재합니다 [12,13].

하이드록시신남산(HCA)은

결합된 형태로만 발견되며,

자유 형태로 발견되는 경우는 거의 없습니다.

카페산은

대부분의 과일에서 전체 하이드록시신남산의 70% 이상을 차지하는

주요 화합물이며,

숙성 과정에서 그 농도가 감소합니다.

페룰산은

곡물에 풍부하게 함유되어 있으며,

배젖층과 과피에서 발견되며,

평균적으로 PA의 약 98%를 차지합니다 [14].

HCA는

위와 소장에서 쉽게 흡수되며,

이후 해독 효소에 의해 대사 과정이 촉진됩니다.

HCA의 섭취는 설치류에 경구 투여했을 때

비만과 당뇨병뿐만 아니라 심혈관 질환, 피부암, 알츠하이머병,

기타 뇌 기능 장애의 발생률을 낮추는 것과 관련이 있습니다 [11,15].

클로로겐산은

과일과 채소에 풍부하게 함유되어 있습니다.

CGA의 가장 대표적인 공급원은

커피 원두, 감자, 가지, 해바라기 씨입니다.

이들은

카페인산(caffeoylquinic acid)의 네 가지 이성질체,

1-CQA, 3-CQA, 4-CQA, 5-CQA로 존재합니다(그림 2).

커피는

CGA의 양이 가장 많은 주요 공급원으로 간주되며,

그 농도는 6-12%입니다.

그 성분은 1837년 Robiquet과 Bourton이 수행한 연구에서 발견되었지만,

“클로로겐산”이라는 이름은 1846년 Payen에 의해 붙여졌습니다.

그 후 수십 년 동안 CGA의 이성질체가 발견되었고, IUPAC 위원회에 의해 이름이 부여되었습니다 [16].

표 1은 HCA가 풍부한 식품과 건강 관리에 대한 중요성을 설명합니다.

Figure 2. Chlorogenic acid and its isomers.

Table 1. HCA-rich foods and effects on health after consumption.

2.2. Flavonoids

Flavonoids are made of two aromatic rings linked by three carbon atoms forming an oxygenated heterocycle. Researchers over the decades have discovered over 4000 flavonoids. Their name derives from the latin “flavus”, signifying yellow or golden. Given their abundance, they have been divided into the following subclasses: flavonols, flavones, isoflavones, flavanones, flavanols, and anthocyanins. Most commonly, we encounter flavonol glycosides, between five and ten different compounds, mainly representatives of the group being quercetin and kaempferol. Flavanols were detected as both monomers (catechins) or polymers (proanthocyanidins). Epicatechins are remarkable in tea, being stable to heat exposure, while proanthocyanidins are known for formatting complexes with salivary proteins, and giving an intense and astringent taste that changes with ripening [28]. Anthocyanins are pigments found in the epiderma of the fruit, as vacuolar juice. They are responsible for the coloration of red fruits, berries, grapes, and many other fruits and vegetables.

Being the most studied of the polyphenols means not only basic information about their coloring properties and flavoring capacity is known, but also about their enzyme-blocking properties, used as a treatment for dementia by blocking the Acetylcholinesterase enzyme in the brain. The inhibition of enzymes (COX) for anti-inflammatory purposes has been studied, as well as steroid genesis modulating, countering antibiotic resistance, disease-combating activity, and combating neurodegenerative diseases [29,30]. Another important study underlines the possibility of using scavenging enzymes that detoxify cancerogenic cells, followed by their elimination. Flavonoids are claimed to be useful in inducing apoptosis, suppressing invasiveness and autophagy [31].

Recent mechanistic studies by Sitarek et al. (2024) have revealed new insights into flavonoids’ action as DNA topoisomerase inhibitors, demonstrating their potential through multiple-cell models. This work has identified novel pathways through which flavonoids exert their anticancer effects, particularly highlighting their role in DNA topology modulation [32]. Quercetin is a flavonol found in more than 20 plant species of fruits, vegetables, or grains. The main sources of flavonoids and their biological activities are shown in Table 2.

2.2. 플라보노이드

플라보노이드는

3개의 탄소 원자가 연결된 두 개의 방향족 고리로 구성되어 있으며,

산소화 헤테로사이클을 형성합니다.

수십 년 동안 연구자들은

4,000개 이상의 플라보노이드를 발견했습니다.

플라보노이드라는 이름은

노란색 또는 금색을 의미하는 라틴어 “플라부스(flavus)”에서 유래했습니다.

풍부한 종류를 고려하여

플라보놀, 플라본, 이소플라본, 플라바논, 플라바놀, 안토시아닌 등의 하위 분류로 나뉩니다.

가장 일반적으로 접할 수 있는 것은

플라보놀 배당체로서,

주로 케르세틴과 캠퍼롤을 대표하는 5~10가지의 다른 화합물로 구성되어 있습니다.

플라바놀은

단량체(카테킨) 또는 중합체(프로안토시아니딘)로 검출됩니다.

에피카테킨은

열에 안정적이어서 차에 많이 들어 있는 성분이고,

프로안토시아니딘은 타액 단백질과 복합체를 형성하는 것으로 알려져 있으며,

숙성에 따라 변화하는 강렬하고 떫은 맛을 냅니다 [28].

안토시아닌은

과일의 표피에 있는 색소로,

진액으로 존재합니다.

이 성분은

붉은 과일, 베리류, 포도, 그리고 다른 많은 과일과 채소의 색을 냅니다.

폴리페놀 중에서 가장 많이 연구된 물질이라는 것은

색상 특성과 향미 능력에 대한 기본적인 정보뿐만 아니라,

뇌의 아세틸콜린에스테라아제 효소를 차단하여

치매 치료제로 사용되는 효소 차단 특성에 대한 정보도 알려져 있다는 것을 의미합니다.

항염증 목적으로

효소(COX)의 억제에 대한 연구가 진행되고 있으며,

스테로이드 생성 조절, 항생제 내성 대응, 질병 퇴치 활동, 신경 퇴행성 질환 퇴치 등도 연구되고 있습니다 [29,30].

또 다른 중요한 연구는

암세포를 해독하고 제거하는 청소 효소의 사용 가능성을 강조하고 있습니다.

플라보노이드는

세포 자멸사 유도, 침입 억제, 자가포식 억제 등에

유용하다고 알려져 있습니다 [31].

Sitarek et al. (2024)의 최근 기계적 연구에 따르면

플라보노이드가

DNA 토포이소머라제 억제제로 작용하는 새로운 통찰력을 밝혀냈으며,

다중 세포 모델을 통해 그 잠재력을 입증했습니다.

이 연구는

플라보노이드가 항암 효과를 발휘하는 새로운 경로를 확인했으며,

특히 DNA 토폴로지 조절에 미치는 역할을 강조했습니다 [32].

케르세틴은

과일, 채소, 곡물 등 20여 종의 식물에서 발견되는 플라보놀입니다.

플라보노이드의 주요 공급원과 생물학적 활동은 표 2에 나와 있습니다.

Table 2. Main sources of flavonoids and their biological activities.

Quercetin and naringenin are two of the most well-researched and potent flavonoids, known for their wide range of health benefits. Quercetin, found in foods like apples, onions, and berries, is celebrated for its powerful antioxidant and anti-inflammatory properties, which help reduce the risk of chronic diseases like heart disease and diabetes [45]. Naringenin, primarily found in citrus fruits such as grapefruit, has similar antioxidant benefits and is also known for its ability to support metabolic health by improving insulin sensitivity and reducing inflammation. The selection of quercetin and naringenin for investigation or inclusion in health interventions is grounded in their substantial therapeutic potential, widespread presence in commonly consumed foods, and their demonstrated capacity to support cardiovascular health, regulate glycemic control, and mitigate oxidative stress. These properties position quercetin and naringenin as significant contributors to preventive healthcare strategies, offering promising avenues for the management of chronic conditions and the enhancement of overall wellness [46]. Quercetin is a flavonol found in more than 20 plant species of fruits, vegetables, or grains, and its chemical structure is presented in Figure 3.

케르세틴과 나린게닌은

가장 많이 연구된 강력한 플라보노이드 중 하나로,

다양한 건강상의 이점으로 잘 알려져 있습니다.

사과, 양파, 베리류와 같은 식품에 함유된 케르세틴은

강력한 항산화 및 항염 작용으로 유명하며,

심장병과 당뇨병과 같은 만성 질환의 위험을 줄이는 데 도움이 됩니다 [45].

주로

자몽과 같은 감귤류 과일에서 발견되는 나린게닌은

항산화 효과가 있으며,

인슐린 감수성을 개선하고

염증을 줄임으로써 대사 건강을 지원하는 능력으로도 알려져 있습니다.

건강 개입에 대한 연구 또는 포함을 위해 케르세틴과 나린게닌을 선택하는 것은

상당한 치료 잠재력,

일반적으로 소비되는 식품에 널리 존재하는 것,

그리고 심혈관 건강을 지원하고,

혈당 조절을 조절하며,

산화 스트레스를 완화하는 것으로 입증된 능력에 근거합니다.

이러한 특성 때문에 케르세틴과 나린게닌은

예방적 건강 관리 전략에 중요한 기여를 하는 것으로 평가되며,

만성 질환 관리와 전반적인 건강 증진을 위한 유망한 수단으로 제시되고 있습니다 [46].

케르세틴은

과일, 채소, 곡물 등 20여 종의 식물에서 발견되는 플라보놀(flavonol)이며,

그 화학 구조는 그림 3에 나와 있습니다.

Figure 3. Quercetin according to IUPAC.

The word “quercetin” derives from the Latin word “Quercetum”, meaning oak, or oak forest, not being able to be produced in the human body. It is yellow-colored and liposoluble—soluble in alcohol and insoluble in water depending on its temperature (being lightly soluble in hot water). The International Union of Pure and Applied Chemistry (IUPAC) gave quercetin the following name and chemical formula: 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one and C15H10O7. It has been used for its properties for a long time, as listed in Table 3.

“케르세틴"이라는 단어는

‘Quercetum’이라는 라틴어 단어에서 유래한 것으로,

참나무 또는 참나무 숲을 의미하며,

인체에서 생성되지 않습니다.

노란색을 띠고 있으며,

지용성입니다(알코올에 용해되고 온도에 따라 물에 용해되지 않음(뜨거운 물에 약간 용해됨)).

국제 순수 및 응용 화학 연합(IUPAC)은

케르세틴에 다음과 같은 이름과 화학식을 부여했습니다:

2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one 및 C15H10O7.

표 3에 나열된 바와 같이,

케르세틴은 그 특성 때문에 오랫동안 사용되어 왔습니다.

Table 3. Pharmaceutical properties of quercetin-rich foods in different health afflictions.

Plant NameFamilyPharmacological ActivityReferencesApium graveolensApiaceaeLowers blood pressure, anti-inflammatory, antibacterial[47,48]Hypericum perforatumHypericaceaeMental disorders, neurological effects, antimicrobial[49]Brassica oleracea var. sabellicaBrassicaceaeOxidative stress[50]Brassica oleracea var. italicaOleaceaePromotes weight loss and prevents cancer[51,52]Nasturtium officinaleLauraceaePrevents risk of colorectal cancer and breast cancer,[53,54]Prunus domesticaRosaceaehepatoprotective, antimicrobial, osteoporosis, laxative[55,56]

Naringenin is another valuable flavonoid compound, specifically, a primary flavanone. It has been reported in higher quantities in citrus fruits like oranges, grapefruit, and lemon or lime peels. Concentration depends on the harvesting method and environmental conditions. Naringenin is the aglycone of naringin. Naringin is the inactive form that will further be transformed into naringenin by gut bacteria. It is known for its antioxidant capacity and many other pharmaceutical benefits. The compound’s chemical formula is 5,7-dihydroxy-2-(4-hydroxyphenyl)-2,3-dihydrochromen-4-one, or C15H12O5. Lipophilic propriety gives the compound the characteristic of being soluble in organic solvents, such as polar alcohols (e.g., ethanol). Naringenin has been intensely studied for its neurological modulations against diseases and disorders [57]. An interesting aspect of naringenin found in tomatoes during ketchup making is its conversion from naringenin chalcone to naringenin [58]. The following provides an overview of naringenin-type flavonoids, including key compounds such as naringenin, naringin, hesperidin, and others, along with their primary sources and associated pharmacological activities (Table 4).

나린게닌은

또 다른 중요한 플라보노이드 화합물,

특히 1차 플라바논입니다.

오렌지, 자몽, 레몬 또는 라임 껍질과 같은

감귤류 과일에서 더 많이 발견된다고 합니다.

농도는 수확 방법과 환경 조건에 따라 달라집니다.

나린게닌은

나린진의 아글리콘입니다.

나린진은

비활성 형태이며,

장내 세균에 의해 나린게닌으로 변형됩니다.

항산화 능력과 여러 가지 다른 약리학적 효능으로 잘 알려져 있습니다. 이 화합물의 화학식은 5,7-디하이드록시-2-(4-하이드록시페닐)-2,3-디하이드로크로멘-4-온 또는 C15H12O5입니다.

친유성 특성은

극성 알코올(예: 에탄올)과 같은 유기 용매에 용해되는 특성을

화합물에 부여합니다.

나링게닌은

질병과 장애에 대한 신경학적 조절에 대해 집중적으로 연구되어 왔습니다 [57].

케첩을 만들 때 토마토에서 발견되는 나링게닌의 흥미로운 측면은

나링게닌 칼콘이 나링게닌으로 전환된다는 점입니다 [58].

다음은

나링게닌, 나링인, 헤스페리딘 등의 주요 화합물을 포함한

나링게닌 계열 플라보노이드의 개요와

주요 공급원 및 관련 약리 작용을 제공합니다 (표 4).

Table 4. Overview of naringenin-type flavonoids.

2.3. Stilbenes

These compounds can act as an antifungal, synthetized in cases of injury or infected tissue. Structurally, they have a C6–C2–C6 skeleton, most often presented with two isomeric forms (Figure 4). Stilbenes are biosynthesized in times of biotic and abiotic stress that occurs in the plant’s life, such as microbial attacks, extreme heat exposure, and oxidation [67]. A more intensely studied stilbene is resveratrol (3,4′,5-trihydroxystilbene), that naturally occurs in grapes [68]. Moreover, resveratrol acts as an antioxidant agent, fights cancer cells, improves lipid metabolism, and holds anti-aging and cardioprotective properties [69]. It is found abundantly in grapes, peanuts, wine, and berries. Resveratrol inhibits low-density lipoprotein (LDL) oxidation and therefore shows great importance in lowering rates of cardiovascular diseases. Its help in the obesity epidemic is linked to improving calorie restriction by stimulating Silent information regulator 2 (Sir2) [70,71].

2.3. 스틸벤

이 화합물은

상처나 감염된 조직에서 합성되어 항진균 작용을 할 수 있습니다.

구조적으로,

이 화합물은 C6-C2-C6 골격을 가지고 있으며,

대부분 두 가지 이성질체 형태로 나타납니다(그림 4).

스틸벤은

미생물 공격, 극심한 열 노출, 산화 등 식물의 생애에서 발생하는

생물적 및 비생물적 스트레스가 있을 때 생합성됩니다[67].

보다 집중적으로 연구된 스틸벤은

레스베라트롤(3,4′,5-trihydroxystilbene)로,

포도에서 자연적으로 발생합니다 [68].

또한,

레스베라트롤은

항산화 작용을 하고, 암세포와 싸우며, 지질 대사를 개선하고,

노화 방지 및 심장 보호 특성을 가지고 있습니다 [69].

레스베라트롤은

포도, 땅콩, 와인, 베리류에 풍부하게 함유되어 있습니다.

레스베라트롤은

저밀도 지단백(LDL)의 산화를 억제하기 때문에

심혈관 질환의 발생률을 낮추는 데 매우 중요한 역할을 합니다.

비만 유행에 대한 레스베라트롤의 도움은

침묵 정보 조절자 2(Sir2)를 자극하여

칼로리 제한을 개선하는 것과 관련이 있습니다 [70,71].

Figure 4. Structure of stilbenes.

2.4. Lignans

Lignans possess a unique chemical structure characterized by two phenylpropanoid units (C6-C3) connected at their β carbons (C8-C8′). Their basic skeleton consists of two coniferyl alcohol residues joined in a 2,3-dibenzylbutane structure. The diversity in lignan structures arises from different oxidation patterns and varying substitutions on the aromatic rings, typically including methoxy (-OCH3) and hydroxyl (-OH) groups [72]. The major dietary lignans can be classified based on their oxidation level and substitution patterns:

Secoisolariciresinol diglucoside (SDG) contains two glucose molecules attached to the main structure through ester bonds. Its aglycone form has two hydroxyl groups on each aromatic ring and two methoxy groups.

Matairesinol features a more complex structure with a lactone ring formed between the two phenylpropanoid units, containing two methoxy and two hydroxyl groups.

Pinoresinol has a unique furofuran structure formed by two tetrahydrofuran rings, with methoxy and hydroxyl substitutions on the aromatic rings.

Lariciresinol represents an intermediate oxidation state between pinoresinol and secoisolariciresinol, containing one tetrahydrofuran ring.

During microbial metabolism in the gut, these plant lignans undergo several biotransformation steps. The key process involves demethylation, dehydroxylation, and reduction reactions that convert them into enterolignans enterodiol (ED) and enterolactone (EL). This transformation significantly alters their chemical structure and biological activity compared to the parent compounds [73,74]. Recent research by Berenshtein et al. (2024) has provided additional insights into how these transformations are influenced by external factors, demonstrating that food processing and storage conditions significantly impact lignan stability and bioaccessibility. Their findings emphasize the importance of proper handling and processing methods in optimizing dietary lignan intake and maintaining their biological potential [74].

They are considered phytoestrogens, as they can stimulate the secretion of certain hormones. Structurally, they are a linkage of a 2,3-dibenzylbutane resulted after the dimerization of two cinnamic acid residues [75]. Lignans are weakly estrogenic or anti-estrogenic, found mostly in seeds such as flaxseeds and sesame seeds, and less in legumes and other plant-derived foods. Their estrogenic mechanism and other bioactivity-linked mechanisms offer lignans potential in preventing heart diseases and other chronic diseases. Most commonly in foods, lignans such as lariciresinol, matairesinol, pinoresinol, and secoisolariciresinol have been identified. Flaxseeds and sesame seeds contain exceptionally high lignan concentrations (335 mg/100 g and 373 mg/100 g, respectively), exhibiting up to 100-fold higher content compared to other dietary sources. Following ingestion, these plant lignans undergo biotransformation by gut microbiota to produce enterolignans, their bioactive metabolites [76]. They are often found in human urine or plasma and are correlated with decreasing risks of coronary heart disease [77]. The microbial metabolism of lignans is particularly interesting, as studies have shown that their bioavailability and therapeutic effects are highly dependent on gut microbiota composition. Recent research indicates that specific bacterial strains, including Bacteroides, Clostridium, and Eubacterium species, are crucial for converting plant lignans into bioactive enterolignans. The efficiency of this conversion varies significantly among individuals, with factors such as diet, antibiotic use, and overall gut health influencing the process. Additionally, the presence of dietary fiber alongside lignans may enhance their biotransformation and absorption, as demonstrated in studies with whole grain and flaxseed consumption. The enterolignans ED and EL exhibit different biological activities compared to their parent compounds, with research suggesting they may have stronger antioxidant and anti-inflammatory properties. Moreover, their structural similarity to endogenous estrogens allows them to modulate estrogen-signaling pathways, contributing to their potential protective effects against hormone-dependent cancers and cardiovascular diseases [78,79,80]. Figure 5 shows the chemical structure of four more common lignans.

2.4. 리그난

리그난은

β 탄소(C8-C8′)에 연결된 두 개의 페닐프로판올 단위(C6-C3)가 특징인

독특한 화학 구조를 가지고 있습니다.

그들의 기본 골격은 2,3-디벤질부탄 구조에 결합된

두 개의 콘피네릴 알코올 잔기로 구성되어 있습니다.

리간 구조의 다양성은

일반적으로 메톡시(-OCH3) 및 하이드록실(-OH) 그룹을 포함하는

방향족 고리에 대한 다양한 산화 패턴과 치환으로 인해 발생합니다 [72].

주요 식이 리간은 산화 수준과 치환 패턴에 따라 분류할 수 있습니다.

세코이솔라리시레시놀 디글루코사이드(SDG)는 에스테르 결합을 통해 주 구조에 부착된 두 개의 포도당 분자를 포함합니다. 아글리콘 형태는 각 방향족 고리에 두 개의 수산기와 두 개의 메톡시기를 가지고 있습니다.

마테이시놀은 두 개의 페닐프로파노이드 단위 사이에 형성된 락톤 고리를 포함하는 더 복잡한 구조를 가지고 있으며, 두 개의 메톡시와 두 개의 수산기를 포함합니다.

피노레시놀은 두 개의 테트라하이드로푸란 고리에 메톡시와 하이드록실 치환기가 있는 독특한 푸로푸란 구조를 가지고 있습니다.

라리시레시놀은 피노레시놀과 세코이솔라리시레시놀 사이의 중간 산화 상태를 나타내며, 하나의 테트라하이드로푸란 고리를 포함하고 있습니다.

장내 미생물 대사 과정에서,

이 식물성 리그난은 여러 가지 생체 변형 단계를 거칩니다.

핵심적인 과정은

데메틸화, 탈수산화, 그리고 엔테로리난 엔테로디올(ED)과 엔테롤락톤(EL)으로 전환하는

환원 반응입니다.

이러한 변형은

모 화합물에 비해 화학적 구조와 생물학적 활성을 크게 변화시킵니다 [73,74].

Berenshtein et al. (2024)의 최근 연구는 이러한 변형이 외부 요인에 의해 어떻게 영향을 받는지에 대한 추가적인 통찰력을 제공하여 식품 가공 및 저장 조건이 리그난 안정성과 생체 접근성에 상당한 영향을 미친다는 것을 보여줍니다.

그들의 연구 결과는

식이 리그난 섭취를 최적화하고

생물학적 잠재력을 유지하기 위한 적절한 취급 및 가공 방법의 중요성을 강조합니다 [74].

그들은

특정 호르몬의 분비를 자극할 수 있기 때문에

식물성 에스트로겐으로 간주됩니다.

구조적으로,

그들은

두 개의 신남산 잔기(cinnamic acid residue)의 이량체화(dimerization) 후에 생성된

2,3-디벤질부탄(2,3-dibenzylbutane)의 결합체입니다 [75].

리그난은

약한 에스트로겐 또는 항에스트로겐으로,

아마씨와 참깨와 같은 씨앗에 주로 존재하며,

콩과 식물 및 기타 식물성 식품에는 거의 존재하지 않습니다.

그들의 에스트로겐 작용 기전과 다른 생체 활성 작용 기전은

심장병과 다른 만성 질환을 예방하는 데 잠재적인 가능성을 제공합니다.

가장 일반적으로 식품에서

라리시레시놀, 마타이레시놀, 피노레시놀, 세코이솔라리시레시놀과 같은

리그난이 확인되었습니다.

아마씨와 참깨에는

매우 높은 농도의 리그난(각각 335mg/100g과 373mg/100g)이 함유되어 있어

다른 식이 공급원보다 최대 100배 더 높은 함량을 나타냅니다.

섭취 후, 이 식물성 리그난은

장내 미생물총에 의해 생체 변형을 거쳐

생체 활성 대사 산물인 엔테롤리난을 생성합니다 [76].

엔테롤리난은

사람의 소변이나 혈장에서 흔히 발견되며,

관상 동맥 심장 질환의 위험 감소와 관련이 있습니다 [77].

연구 결과에 따르면,

리그난의 생체 이용률과 치료 효과는

장내 미생물총의 구성에 크게 좌우된다는 사실이 밝혀졌기 때문에,

미생물 대사 작용이 특히 흥미롭습니다.

최근 연구에 따르면,

박테로이드(Bacteroides), 클로스트리듐(Clostridium), 유박테리움(Eubacterium) 종을 포함한

특정 박테리아 균주가 식물 리그난을 생체 활성 장내 리그난으로 전환하는 데

중요한 역할을 한다고 합니다.

이러한 전환의 효율성은 개인마다 크게 다르며,

식단, 항생제 사용, 전반적인 장 건강과 같은 요인들이

이 과정에 영향을 미칩니다.

또한,

통곡물과 아마씨 섭취에 대한 연구에서 입증된 바와 같이,

리그난과 함께 식이섬유를 섭취하면

생체 내 전환과 흡수가 향상될 수 있습니다.

엔테롤리난 ED와 EL은

모 화합물에 비해 다른 생물학적 활동을 나타내며,

연구 결과에 따르면 항산화 및 항염 작용이 더 강할 수 있다고 합니다.

또한,

내인성 에스트로겐과 구조적으로 유사하기 때문에

에스트로겐 신호 전달 경로를 조절할 수 있어

호르몬 의존성 암과 심혈관 질환에 대한 잠재적 보호 효과에 기여할 수 있습니다 [78,79,80].

그림 5는 더 일반적인 4가지 리간드의 화학 구조를 보여줍니다.

Figure 5. Structure of lignans.

3. Dietary Intake of Polyphenols

Dietary intake of polyphenols varies from culture to culture, from one’s eating habits and preferences to another’s, making it extremely difficult to estimate the average daily intake. In 1976, researcher Kuhnau determined the total polyphenol daily intake in the United States to land approximately at 1 g/d [81], this value remaining the most used etalon for most researchers. Flavonol intake in the U.S., Denmark, and Holland is about 20–25 mg/d, while in Italy, it was estimated a mean, with 15 mg/d higher. Current dietary reference intakes for anthocyanins have not been established in most countries. China is the only nation that has proposed a specific intake level of 50 mg/day. According to NHANES 2007–2008 data, the estimated average intake in the United States for adults aged ≥ 20 years is 11.6 ± 1.1 mg/day, with women showing higher consumption (12.6 ± 1.5 mg/day) compared to men (10.5 ± 0.8 mg/day). Regarding safety, the Joint FAO/WHO Expert Committee on Food Additives has established an acceptable daily intake of 2.5 mg/kg body weight per day, specifically for anthocyanins derived from grape-skin extracts. Due to high coffee consumption, the hydroxycinnamic acid intake for several cups of coffee may result in ingesting > 500 mg/d [28,81].

3. 폴리페놀의 섭취량

폴리페놀의 섭취량은

문화마다, 그리고 개인마다 먹는 습관과 선호도에 따라 다르기 때문에

일일 평균 섭취량을 추정하기가 매우 어렵습니다.

1976년, 쿠나우(Kuhnau) 연구원은

미국에서 섭취되는 폴리페놀의 총량을 하루 1g으로 추정했으며,

이 수치는 대부분의 연구자들이 가장 많이 사용하는 기준치로 남아 있습니다.

미국, 덴마크, 네덜란드에서 플라보놀 섭취량은

하루 평균 20-25mg 정도인 반면,

이탈리아에서는 하루 평균 15mg 정도 더 많은 것으로 추정됩니다.

현재 대부분의 국가에서 안토시아닌의 하루 영양소 기준치 섭취량은 정해지지 않았습니다. 중국만이 하루 50mg의 특정 섭취량을 제안한 유일한 국가입니다. 2007-2008년 미국 국민건강영양조사(NHANES)에 따르면, 미국에서 20세 이상 성인의 평균 일일 섭취량은 11.6±1.1mg으로, 여성(12.6±1.5mg)이 남성(10.5±0.8mg)보다 더 많이 섭취하는 것으로 나타났습니다. 안전성 측면에서, FAO/WHO 합동 식품첨가물 전문가위원회는 포도 껍질 추출물에서 추출한 안토시아닌에 대해 하루 체중 1kg당 2.5mg의 일일 허용 섭취량을 설정했습니다.

커피를 많이 마시는 경우,

커피 몇 잔에 해당하는 하이드록시신남산의 섭취량은

하루 500mg을 초과할 수 있습니다 [28,81].

3.1. Bioavailability

Referring to bioavailability indicates the capacity of the substance/compound to be assimilated and metabolized by the host that ingested the supposedly bioavailable matter in question. Because bioavailability is tightly linked to the terms bioactivity and bioaccessibility, it is necessary to take into consideration the way the substance is transformed during transformations, conversions, and metabolization, the pathways it reaches, but also the effect it possesses on the host’s ailment (Figure 6).

3.1. 생체 이용률

생체 이용률을 언급하는 것은

해당 물질/화합물이 생체 이용 가능한 것으로 추정되는 물질을 섭취한 숙주에 의해

동화되고 대사되는 능력을 나타냅니다.

생체 이용률은

생체 활성 및 생체 접근성과 밀접하게 연관되어 있기 때문에,

물질이 변형, 전환, 대사되는 동안 변형되는 방식,

도달하는 경로, 숙주의 질병에 미치는 영향(그림 6)을 고려해야 합니다.

Figure 6. Bioavailability and term appliance.

Bioavailability of polyphenols can be affected by a number of factors, the main one being the interaction between other compounds in the food matrix, as well as their chemical structure. The impact that the food matrix can have on the accessibility of polyphenols and its absorption is highly dependent on the food matrix from where it is released [82]. This interconnection between their bioaccessibility and bioactivity will be affected positively or negatively by these intermolecular interplays. There are three main classes of macromolecules: carbohydrates, lipids, and proteins, each having their own particular way of interaction with polyphenols. Interaction with macromolecules is of great interest, being one of the main factors that can impact the effect polyphenols possess. The average human diet is most likely to be abundant in carbohydrates, with proteins and lipids following in second and third place, respectively. Since polyphenols have been recognized for their potency of being aids as immune system boosters, eval‎uation of their interaction with the main classes that characterize the human diet was emphasized thoroughly in the last century. Food matrixes’ interactions with phenolics can serve as carrier agents through the digestion, making them less prone to oxidation [83].

폴리페놀의 생체 이용률은

여러 가지 요인에 의해 영향을 받을 수 있는데,

그 중에서도 식품 매트릭스 내의

다른 화합물과의 상호작용과

화학적 구조가 가장 큰 영향을 미칩니다.

식품 매트릭스가 폴리페놀의 접근성과 흡수에 미치는 영향은

폴리페놀이 방출되는 식품 매트릭스에 크게 의존합니다 [82].

이러한 생체 접근성과 생체 활성 사이의 상호 연결은

분자 간의 상호 작용에 의해 긍정적 또는 부정적으로 영향을 받습니다.

거대 분자는 크게 세 가지 종류로 나뉩니다:

탄수화물, 지질, 단백질.

각각의 거대 분자는

폴리페놀과 상호작용하는 방식이 다릅니다.

거대 분자와의 상호작용은

폴리페놀의 효능에 영향을 미치는 주요 요인 중 하나이기 때문에

매우 중요합니다.

인간의 평균적인 식단은 탄수화물이 가장 많고,

그 다음으로 단백질과 지질이 각각 두 번째와 세 번째로 많습니다.

폴리페놀은

면역 체계를 강화하는 데 도움이 된다는 효능이 인정되어

지난 세기에는 인간의 식단을 특징짓는 주요 영양소와의 상호작용에 대한 평가가

철저히 이루어졌습니다.

식품 매트릭스와 페놀류의 상호작용은

소화 과정을 통해 운반제 역할을 할 수 있어 산화되기 어렵게 만듭니다 [83].

The interaction between carbohydrates and polyphenols is likely linked to their frail hydrophobic and hydrogen bonds. An important factor of this reaction refers to the phenolic structure; favorable compounds are flavonoids and catechins, unfavorable reactions were shown in the methoxylation of phenolic acids. One of the most abundant carbohydrates found in plants, starch, has been studied over the years in this scope. Interaction with polyphenols show gelatinization and retrogradation of starch when interacting with flavonoids; gelatinization is increased in quercetin and green tea flavan-3-ol, while retrogradation is repressed [82]. Other functions of starch are affected, such as thermal, physiochemical, or digestibility. Main changes that affect digestibility rate are starch structure, granule surface smoothness, relative crystallinity, and short range molecular order [83]. If it were to give the simplest definition of what starch is, it would have to be that it represents the stored energy of different plants reserved as feed when other resources are not available. Chemically, it is a polymer made out of linear and branched microstructures linked through α-d-(1-4) glucose bonds. The linear structure is called amylose, with α-1,4 glucose bonds. The branched one is called amylopectin, characterized by its α-1,4 chain bonded by α-1,6 glucose links. The amylose/amylopectin proportion is influenced by its source and age, but also, its evolution is dependent on the survival needs of the plant in question, so it can highly differ from region to region [84]. Interplay of polyphenols and starch is concluded to be due to the hydroxyl-group-containing polyphenols and non-covalent bonds of the polymer discussed (hydrogen bonds and electrostatic and ionic interactions). End products can be V-type inclusions with hydrophobic contacts or non-inclusion with weaker binding forces. Notably, V-type inclusion can restrict hydrolysis of the starch molecule.

Furthermore, phenols can also bind directly to the target enzyme, decreasing its activity and, therefore, the starch’s digestibility. This aspect is notable in tea polyphenols, flavonoids, ferulic acid, quercetin, gallic acid, tannic acid, p-coumaric acid, or sinnapic acid. Another mechanism of action is amylase, which lowers the activity during hydrolysis. In the case of excessive supplementation of polyphenols, it may enhance digestibility as a result of high complexation with a looser structure [83]. In the case of flavonoids interacting with different starch-rich foods, Shanshan Gao et al., while studying quercetin and starch from Tartary buckwheat, managed to highlight the bonding through non-covalent linkages during the process of gelatinization, resulting in a V-type structure [85]. Libo Wang et al. showed the diminished digestibility of quercetin–starch (Tartary buckwheat) complexes by modifying the polymer’s structure and limiting the specific enzyme activity. Compared to rutin, quercetin had a stronger effect [86]. Interaction of tea polyphenols with wheat starch showed a reducing rate of retrogradation in their interaction. Studies show the interaction of these two compounds to be through hydrogen links, having almost an identical effect to quercetin without forming the V-type, resulting in an increasing content of resistant starch and reducing digestibility [83,87]. Due to these interactions, there could potentially be a loss in polyphenol content.

For non-starch compounds, such as fiber-rich foods, interaction of polyphenols might act as carrier agents for these bioactive compounds [82]. Dietary fibers are categorized as carbohydrate polymers susceptible of low digestibility in the upper-digestive path of the digestive system, but it can be highly transformed and metabolized in the large intestine. The literature shows that dietary fiber has the capacity of modulating the microbiome, but can also aid in the colonization of the intestinal microbiota. The final products of fermentation in the colon are short-chain fatty acids, gas, and water [88]. Commonly, the linkage is formed through non-covalent bonds, including hydrogen bonds, van der Waals forces, and hydrophobic interplays. Van der Waals forces occur through the existence of functional groups that are capable of creating polarized molecules; in the case in which hydrogen bonds are previously formed, it results in a shorter distance, permitting van der Waals forces to take effect. Insoluble polyphenols and dietary fiber have the capacity to aggregate [88,89]. Of great impact on the bondage are ionic strength, temperature, or pH level. Due to a high ionic strength, the association of molecules is increased, leading to a higher probability of formation of hydrophobic interactions, since hydrophobic molecules aggregate together to minimize exposure to the ionic force. In the case of hydrogen bonds, exothermal reaction is needed, and the opposite, endothermal reaction, for hydrophobic ones. With a higher temperature that results in the association of molecules, hydrophobic bonds have a more plausible forming capacity, while in H bonds, when the temperature increases, the association decreases, and thus, so does the formation of the link. The increase in size of the polyphenols’ molecules can positively affect the degree of the bonding. The solubility of the phenol is also important: the hydrophobic character of fiber is complexed by hydrophobic polyphenols and likewise in the case of hydrophilic polyphenols. The carrier agent effects of polyphenol–fiber complexes throughout the digestive tract are remarked: it is shown that they possess a low bioavailability in the small intestine, but it increases in the colon, having a higher dose released [90,91].

A decrease in particle size can show positive results in the availability in the upper digestive tract. In the lower digestive tract, polyphenol–fibers are released (seemingly in a higher dose due to the carrier-like capacity of the fiber) and the complexes undergo the process of fermentation and transformation in catabolites that are bioaccessible [88]. Short-chain fatty acids are a result of the fermentation process of dietary fibers, and their increase might be a result of linkage with the phenol group [88,90].

Proteins mostly interact through non-covalent bonding and hydrophobic bonds, followed by a stabilization by hydrogen bonds. In the case of oxidized flavonoids, the compounds formed, quinones, can form irreversible covalent bonds. Interplays of these two classes of compounds can be specific or non-specific. Specific interaction refers mostly to enzymes/proteins with a strong tertiary structure (immunoglobulin in milk, myoglobin in muscle). Larger polyphenols have a better binding capacity; molecular weight is taken into account when discussing this type of interaction [82]. Other factors to take into account are temperature, ionic strength, and pH. In the case of pH, it is observed that pH levels for binding in tea polyphenols range from 3.6 to 8. Biological effects are often seen in the case of interaction between phenols and proteins; a significant one is the astringency, as a consequence of salivary proteins and polyphenols in red wine, tea, or coffee, causing the preserving of dry mouth and a tightening sensation. The interaction with salivary proteins is mostly encountered in tannins [92,93]. In the case of tea, with addition of milk, it results in a lower astringency feeling, binding the flavan-3-ol to the caseins and whey proteins. A considerable aspect is the functionality of proteins: studies show that the binding of these molecules with polyphenols can result in blocking their amino acid functions, thus decreasing their bioavailability. Polyphenol’s bioavailability can increase through linking with proteins. Stabilization, in this case, means enhancing the antioxidant capacity, preventing the polyphenols from oxidation. Reports show that milk proteins and catechins from tea can bind and better the intestinal transportation and absorption of the tea polyphenols. In animal studies, soy proteins and polyphenols showed an increase in bioavailability and transport throughout the GI tract from these forms of complexes [82].

Interaction with lipids has been highlighted in the case of plant oils. It was demonstrated that some lipids could increase acute absorption of flavonoids, like quercetin. Green tea catechins can serve as food additives to fatty products that are easily oxidized. As a downside, tea catechins can affect the pH and microstructure of milk products such as cheese, causing changes in organoleptic characteristics and hardness. It has been noted that polyphenols can influence triglyceride and fatty-acid synthesizing, increasing levels in rat models when incubation of resveratrol and hepatic cells was conducted, but also decreasing enzyme activity of acetyl-coA carboxylase. One mechanism of action that authors have noted throughout their research along the years is the lowered or later absorption of lipids in the gut as a result of the inhibition of pancreatic lipase (that breaks down lipids). Polyphenols can also incorporate in the lipid layer, grow in size, and modify the physiological and chemical characteristics of the fat droplets. Also, a possible way of stabilizing the polyphenols could be taken into account—incorporating them into lipid particles, making them less prone to degradation in the GI tract, but also the possibility of the formation of liposomes, that might be a possibility of slow and controlled release of the polyphenols [82].

탄수화물과 폴리페놀의 상호작용은

약한 소수성 및 수소 결합과 관련이 있을 가능성이 큽니다.

이 반응의 중요한 요소는 페놀 구조를 참조합니다.

유리한 화합물은

플라보노이드와 카테킨이고,

페놀산의 메톡시화에 불리한 반응이 나타났습니다.

식물에서 가장 풍부한 탄수화물 중 하나인 전분은

수년 동안 이 범위에서 연구되어 왔습니다.

폴리페놀과의 상호작용은 플라보노이드와 상호작용할 때

전분의 젤라틴화와 역행화를 보여줍니다.

젤라틴화는

케르세틴과 녹차 플라반-3-올에서 증가하는 반면,

역행화는 억제됩니다 [82].

전분의 다른 기능, 즉

열적, 물리화학적, 소화성 등이 영향을 받습니다.

소화율에 영향을 미치는 주요 변화는

전분 구조, 과립 표면의 매끄러움, 상대적 결정화도, 단거리 분자 순서입니다 [83].

전분이 무엇인지 가장 간단하게 정의한다면,

다른 자원이 없을 때 식량으로 저장된 다양한 식물의 저장 에너지를 나타낸다고 할 수 있습니다.

화학적으로,

전분은 α-d-(1-4) 포도당 결합을 통해 연결된 선형 및 분지 미세 구조로 이루어진 중합체입니다.

선형 구조는 α-1,4 포도당 결합을 가진 아밀로오스라고 불립니다.

분지형은 α-1,6 포도당 결합에 의해 α-1,4 사슬이 결합된 것이 특징인 아밀로펙틴이라고 불립니다.

아밀로오스와 아밀로펙틴의 비율은 그 원료와 나이에 영향을 받지만,

그 진화 과정은 해당 식물의 생존 필요성에 따라 달라지기 때문에 지역마다 크게 다를 수 있습니다 [84].

폴리페놀과 전분의 상호작용은

수산기를 포함하는 폴리페놀과 논의된 고분자의 비공유 결합(수소 결합, 정전기 및 이온 상호작용)에

기인하는 것으로 결론지었습니다.

최종 생성물은

소수성 접촉을 갖는 V형 내포물 또는 약한 결합력을 갖는 비내포물이 될 수 있습니다.

특히,

V형 내포물은 전분 분자의 가수분해를 제한할 수 있습니다.

또한,

페놀은

표적 효소에 직접 결합하여 그 활성을 감소시키고,

따라서 전분의 소화율을 감소시킵니다.

이러한 측면은

차 폴리페놀, 플라보노이드, 페룰산, 케르세틴, 갈산, 탄닌산, p-쿠마르산, 신나픽산에서 두드러집니다.

또 다른 작용 메커니즘은 아밀라아제인데,

이는 가수분해 과정에서 활성을 감소시킵니다.

폴리페놀의 과다 보충의 경우,

느슨한 구조와 높은 복합화로 인해 소화율이 향상될 수 있습니다 [83].

다양한 전분 함량이 높은 식품과 상호 작용하는 플라보노이드의 경우,

Shanshan Gao 등은 타타르 메밀의 케르세틴과 전분을 연구하면서 젤라틴화 과정에서 비공유 결합을 통한 결합을 강조하여 V형 구조를 생성했습니다 [85]. Libo Wang 등은 폴리머의 구조를 변형하고 특정 효소의 활성을 제한함으로써 케르세틴과 전분(타타리 메밀) 복합체의 소화율이 감소하는 것을 보여주었습니다. 루틴에 비해 케르세틴은 더 강력한 효과를 보였습니다 [86]. 차 폴리페놀과 밀 전분의 상호작용은 상호작용에서 역행의 감소율을 보여주었습니다. 연구에 따르면 이 두 화합물의 상호 작용은 수소 결합을 통해 이루어지며, V형 구조를 형성하지 않고 퀘르세틴과 거의 동일한 효과를 나타내어 저항성 전분 함량을 증가시키고 소화율을 감소시킵니다 [83,87]. 이러한 상호 작용으로 인해 폴리페놀 함량이 감소할 수 있습니다.

섬유질이 풍부한 식품과 같은 비전분 화합물의 경우, 폴리페놀의 상호작용이 이러한 생체 활성 화합물의 운반체 역할을 할 수 있습니다 [82]. 식이 섬유는 소화 기관의 상부 소화 경로에서 소화율이 낮은 탄수화물 중합체로 분류되지만, 대장에서는 높은 수준으로 변형 및 대사될 수 있습니다. 문헌에 따르면 식이 섬유는 미생물 군집을 조절하는 능력이 있지만, 장내 미생물 군집의 식민지화를 도울 수도 있습니다. 결장에서 발효의 최종 산물은 단쇄 지방산, 가스, 물입니다 [88]. 일반적으로 결합은 수소 결합, 반 데르 발스 힘, 소수성 상호 작용을 포함한 비공유 결합을 통해 형성됩니다. 반데르발스 힘은 분극된 분자를 생성할 수 있는 작용기(functional group)의 존재를 통해 발생합니다. 수소 결합이 이미 형성된 경우, 반데르발스 힘이 작용할 수 있도록 거리가 짧아집니다. 불용성 폴리페놀과 식이섬유는 응집할 수 있는 능력을 가지고 있습니다 [88,89]. 결합에 큰 영향을 미치는 것은 이온 강도, 온도, pH 수준입니다. 이온 강도가 높으면 분자 결합이 증가하여 소수성 분자가 이온력에 노출되는 것을 최소화하기 위해 함께 모이는 경향이 있기 때문에 소수성 상호작용이 형성될 가능성이 높아집니다. 수소 결합의 경우 발열 반응이 필요하지만, 소수성 상호작용의 경우에는 반대로 흡열 반응이 필요합니다. 온도가 높아지면 분자가 결합하기 때문에, 소수성 결합은 더 확실하게 결합할 수 있는 능력을 가지지만, H 결합의 경우 온도가 높아지면 결합이 감소하고, 따라서 결합의 형성도 감소합니다. 폴리페놀 분자의 크기가 커지면 결합 정도에 긍정적인 영향을 미칠 수 있습니다. 페놀의 용해도 또한 중요합니다: 섬유질의 소수성 특성은 소수성 폴리페놀에 의해 복합화되며, 친수성 폴리페놀의 경우에도 마찬가지입니다. 소화관 전체에 걸쳐 폴리페놀-섬유 복합체의 운반체 작용이 주목받고 있습니다: 이들은 소장에서 생체이용률이 낮지만, 결장에서 증가하여 더 많은 양이 방출된다는 사실이 밝혀졌습니다 [90,91].

입자 크기가 작아지면 상부 소화관에서 가용성이 향상될 수 있습니다. 하부 소화관에서는 폴리페놀 섬유질이 방출되고(섬유질이 운반체 역할을 하기 때문에 더 많은 양이 방출되는 것 같습니다), 복합체는 생체 접근성 대사 산물에서 발효 및 변형 과정을 거칩니다[88]. 단쇄 지방산은 식이 섬유의 발효 과정의 결과물이며, 이들의 증가는 페놀기와의 결합의 결과일 수 있습니다 [88,90].

단백질은 대부분 비공유 결합과 소수성 결합을 통해 상호 작용하며, 그 다음으로 수소 결합에 의한 안정화가 뒤따릅니다. 산화된 플라보노이드의 경우, 형성된 화합물인 퀴논은 비가역적인 공유 결합을 형성할 수 있습니다. 이 두 종류의 화합물 간의 상호 작용은 특이적이거나 비특이적일 수 있습니다. 특정 상호작용은 주로 강한 3차 구조를 가진 효소/단백질(우유의 면역글로불린, 근육의 미오글로빈)을 가리킵니다. 폴리페놀의 크기가 클수록 결합력이 더 좋습니다. 이러한 유형의 상호작용을 논의할 때 분자량을 고려합니다 [82]. 고려해야 할 다른 요소로는 온도, 이온 강도, pH가 있습니다. pH의 경우, 차 폴리페놀의 결합에 대한 pH 수준은 3.6에서 8 사이인 것으로 관찰됩니다. 생물학적 효과는 종종 페놀과 단백질 간의 상호 작용의 경우에 나타납니다. 중요한 효과 중 하나는 떫은맛인데, 이는 레드 와인, 차 또는 커피에 있는 타액 단백질과 폴리페놀의 결과로, 구강 건조와 조임감을 유발합니다. 타닌은 타닌 단백질과 상호작용을 일으키는 경우가 대부분입니다 [92,93]. 차의 경우, 우유를 첨가하면 플라반-3-올이 카제인과 유청 단백질에 결합하여 떫은맛이 덜하게 됩니다. 단백질의 기능성은 중요한 측면입니다: 연구 결과에 따르면, 이러한 분자들이 폴리페놀과 결합하면 아미노산 기능이 차단되어 생체이용률이 감소할 수 있다고 합니다. 폴리페놀의 생체 이용률은 단백질과 결합함으로써 증가할 수 있습니다. 이 경우 안정화란 항산화 능력을 강화하여 폴리페놀의 산화를 방지하는 것을 의미합니다. 연구 결과에 따르면, 우유 단백질과 차의 카테킨은 차 폴리페놀의 장내 운반과 흡수를 향상시킬 수 있는 결합력을 가지고 있습니다. 동물 실험에서, 콩 단백질과 폴리페놀은 이러한 형태의 복합체를 통해 생체 이용률과 위장관 전체의 수송이 증가하는 것으로 나타났습니다 [82].

식물성 기름의 경우, 지질과의 상호작용이 강조되었습니다. 일부 지질이 케르세틴과 같은 플라보노이드의 급성 흡수를 증가시킬 수 있다는 사실이 입증되었습니다. 녹차 카테킨은 쉽게 산화되는 지방 제품에 식품 첨가물로 사용될 수 있습니다. 단점은, 녹차 카테킨이 치즈와 같은 유제품의 pH와 미세구조에 영향을 미쳐 관능적 특성과 경도에 변화를 일으킬 수 있다는 것입니다. 폴리페놀은 트리글리세라이드와 지방산 합성에 영향을 미쳐, 레스베라트롤과 간세포의 배양 실험을 진행했을 때 쥐 모델에서 레스베라트롤의 수치가 증가하는 한편, 아세틸-CoA 카복실레이스의 효소 활성이 감소하는 것으로 나타났습니다. 저자들이 수년 동안 연구를 진행하면서 발견한 작용 메커니즘 중 하나는 췌장 리파제(지질을 분해하는 효소)의 억제로 인해 장에서 지질의 흡수가 감소하거나 지연된다는 것입니다. 폴리페놀은 또한 지질층에 통합되어 크기가 커지고, 지방 방울의 생리적, 화학적 특성을 변화시킬 수 있습니다. 또한, 폴리페놀을 안정화시키는 방법도 고려할 수 있습니다. 폴리페놀을 지질 입자에 통합하여 위장관에서 분해되기 어렵게 만들 수 있으며, 폴리페놀을 서서히 방출할 수 있는 리포좀 형성 가능성도 있습니다 [82].

3.2. Bioavailability of Phenolic Compounds

3.2.1. Phenolic Acids

Phenolic acid sources vary, as they are commonly found in all food groups; higher concentration has been reported in cereal, legumes, oilseeds, beverages, and herbs [94]. They contribute to nutritional and organoleptic properties, but they are significantly used for their health contribution, as they are powerful antioxidants [11,95]. Bioavailability of these compounds depends on their free form, level of conjugation, or different treatments they might undergo. In the processing of cereal, preliminary methods can increase the amount of free form PAs. Even though milling, air-classification, and dehulling can either increase the bound-forms of PAs or decrease them overall, further bioprocessing like germination, fermentation, or enzyme treatments can impact the increase in free form phenolics. In dough, the fermentation process aids in destroying the cell wall, as most phenolic acids are esterified to it. The further absorption by the host through GI barrier, entering the bloodstream, could be the perceiving of the absorbed phenolics as xenobiotics and the body’s response of removing these substances. HCAs suffer transformations under the processes of glucuronidation, sulfation, and further oxidation to benzoic acid (and derivates) that are glycinated into hippuric acid derivates. These transformations enhance elimination through phase I or II. One of the major enzymes responsible for the metabolization of xenobiotics is cytochrome P450 monooxygenase. Debrisoquine hydroxylase and mephenytoin hydroxylase depend on the gene expression‎ variability of the host. Acetylation enzymes are dependent on the phenotype that is influenced by the territory in which the host is living in. Slower acetylator phenotypes can have a decreased activity in the liver’s NAT1 and NAT2 genes, essential in the transformation of acetate into acetyl-CoA [95]. Thermo liability has been proved in a study conducted by Yu and Beta, showing an increase in free ferulic acid and p-hydroxybenzoic acids during baking [96]. Because free form is less common, bound forms of dietary fiber compounds reach the intestinal microbiota and are, therefore, degraded by it. Hydrolysis by microbial esterase is the proposed pathway, conducting in the release of conjugated/bound form and liberating the free form of HCAs in vivo [95]. A study conducted in 2021 by Wenfei Tiai et al. regarding phenolic acids’ in vitro digestion of whole wheat products showed an increase in the first hour of digestion. Trans-ferulic acid increased throughout the Gastric phase (44.82 to 63.36 µg/g), but also significantly though the Intestinal phase (85.10 µg/g). Similarly, 4-hydroxybenzoic acid, vanillic acid, and sinapic acid showed an increased activity. An important mention from this study is the fact that digestive enzymes and dramatically reduced pH were catalysts for the releasing of PA. Alkaline conditions may help break the insoluble bond, but not in all cases. In the case of vanillic acid, because of the entrapment in the fiber–protein matrix, these conditions might not help releasing the insoluble form. Colonic fermentation of probiotic strains with the whole wheat products show production of PAs from the digested residues [97].

3.2. 페놀 화합물의 생체 이용률

3.2.1. 페놀산

페놀산은

모든 식품군에 존재하기 때문에 그 공급원이 다양합니다.

곡류, 콩류, 유지 종자, 음료, 허브에

더 많이 함유되어 있는 것으로 보고되었습니다 [94].

페놀산은

영양적, 감각적 특성에 기여하지만,

강력한 항산화제이기 때문에 건강에 기여하는 면에서 상당히 많이 사용됩니다 [11,95].

이러한 화합물의 생체 이용률은

자유 형태, 결합 수준, 또는 다른 처리에 따라 달라집니다.

곡물 가공 과정에서 예비적인 방법을 사용하면

자유 형태의 PA의 양을 늘릴 수 있습니다.

분쇄, 공기 분류, 껍질 제거는

PA의 결합 형태를 늘리거나 전체적으로 줄일 수 있지만,

발아, 발효, 효소 처리와 같은 추가적인 생물학적 처리는

자유 형태의 페놀의 증가에 영향을 미칠 수 있습니다.

반죽에서 발효 과정은

대부분의 페놀산이 에스테르화되어 세포벽을 파괴하는 데 도움이 됩니다.

위장 장벽을 통해 숙주에 의해 흡수되어 혈류로 들어가면

흡수된 페놀산을 이종생체로 인식하고

신체가 이러한 물질을 제거하는 반응을 일으킬 수 있습니다.

HCAs는

글루쿠로니드화, 설파화, 그리고 히푸르산 유도체로 글리시네이트화되는 벤조산(및 유도체)으로의

추가 산화 과정을 통해 변형됩니다.

이러한 변형은 1단계 또는 2단계의 배설을 촉진합니다.

이종물질의 대사를 담당하는 주요 효소 중 하나는

사이토크롬 P450 모노옥시게나제입니다.

데브리오신 하이드록실라제와 메페니토인 하이드록실라제는

숙주의 유전자 발현 변동성에 의존합니다.

아세틸화 효소는

숙주가 살고 있는 지역에 영향을 받는 표현형에 의존합니다.

느린 아세틸화 표현형은 아세테이트를 아세틸-CoA로 전환하는 데 필수적인 간 NAT1 및 NAT2 유전자의 활성이 감소할 수 있습니다 [95]. Yu와 Beta가 실시한 연구에서 열에 의한 손상이 입증되었으며, 베이킹 과정에서 유리 페룰산과 p-하이드록시벤조산이 증가하는 것으로 나타났습니다 [96]. 유리 형태는 흔하지 않기 때문에, 결합된 형태의 식이섬유 화합물은 장내 미생물에 도달하여 분해됩니다. 미생물 에스테라아제에 의한 가수분해가 제안된 경로로, 결합/결합된 형태의 방출을 통해 생체 내에서 유리 형태의 HCA를 방출합니다 [95]. Wenfei Tiai 등이 2021년에 수행한 연구에 따르면, 페놀산의 통밀 제품에 대한 체외 소화 과정에서 소화 첫 시간 동안 증가하는 것으로 나타났습니다. 트랜스페룰산은 위장 단계(44.82~63.36 µg/g) 전반에 걸쳐 증가했지만, 장 단계(85.10 µg/g)에서도 유의미한 증가를 보였습니다. 마찬가지로, 4-하이드록시벤조산, 바닐산, 신남산도 활동이 증가했습니다. 이 연구에서 중요한 점은 소화 효소와 극적으로 감소된 pH가 PA의 방출을 촉진한다는 사실입니다. 알칼리성 조건은 불용성 결합을 끊는 데 도움이 될 수 있지만, 모든 경우에 그런 것은 아닙니다. 바닐산(vanillic acid)의 경우, 섬유질-단백질 매트릭스에 갇혀 있기 때문에 이러한 조건이 불용성 형태를 방출하는 데 도움이 되지 않을 수 있습니다. 통밀 제품에 대한 프로바이오틱 균주의 대장 발효는 소화된 잔여물로부터 PA의 생성을 보여줍니다 [97].

3.2.2. Flavonoids

Flavonoids are commonly found in teas, citrus fruits, berries, and leafy vegetables responsible for exerting health benefits upon the host [98]. Even though some of them are easily found in food, others are solely found in a certain group; for example, isoflavones are only found in legumes. The low bioavailability is caused mainly by phase II metabolism. In most cases, they suffer from sulfation, methylation, and glucuronidation in the upper part of the GI tract and liver and conjugated forms exist in plasma after flavonoids are ingested. A critical factor for the bioavailability of flavonoids is represented by their molecular weight: the bigger the weight, the harder the absorption. Polymeric proanthocyanidins have a large molecular weight, making it an inconvenience in their metabolization in the stomach or small intestine, passing right through, reaching the colon and getting catabolized by the microbiota. The produced microbial metabolites could be subjected to entering the bloodstream and urinal excretion. Variation in means of absorption can differ even on the same compound within conjugates. In the case of glycosides, it might vary; reports show that bioavailability of apple quercetin glycosides was 30% of that from onions. Sugar linkage can also affect the rate of absorption of flavonoids [99]. Quercetin glucosides are absorbed faster and the plasma concentration peak was significantly higher than its rutinosides in humans. Glucosides are supposedly in the small intestine, whilst rutinosides are absorbed in the colon, post deglycosylation [99,100]. Another important factor is metabolic conversion. For quercetin, encountered in plasma were sulfate or methyl conjugates, but not its aglycone or glycosides. Also, in the case of cathechins, only conjugates were found in plasma. Colonic metabolization heavily impacts polyphenols, as a tremendous amount of polyphenols do not get metabolized in the stomach or small intestine, reaching the colon intact [99]. The degradation of the bacteria present in the gut results in simple phenolic acids and absorption in the bloodstream [101]. Proanthocyanidins were known to be catabolized to phenylacetic acid, mono- and dihydroxyphenylacetic acids, mono- and dihydroxyphenylpropionic acids, and hydroxybenzoic acid; anthocyanins were catabolized mainly to protocatechuic acid [102].

3.2.2. 플라보노이드

플라보노이드는 일반적으로 차, 감귤류, 베리류, 잎채소에 함유되어 있으며, 숙주에게 건강상의 이점을 제공하는 역할을 합니다 [98]. 일부 플라보노이드는 식품에서 쉽게 발견되지만, 일부는 특정 그룹에서만 발견됩니다. 예를 들어, 이소플라본은 콩과 식물에서만 발견됩니다. 낮은 생체 이용률은 주로 2단계 대사에 의해 발생합니다. 대부분의 경우, 위장관 상부와 간에서 황산화, 메틸화, 글루쿠로니드화 과정을 거치며, 플라보노이드를 섭취한 후에는 플라즈마에 결합된 형태가 존재합니다. 플라보노이드의 생체 이용률에 중요한 요소는 분자량입니다. 분자량이 클수록 흡수하기가 더 어렵습니다. 다당류 프로안토시아니딘은 분자량이 크기 때문에 위나 소장에서 대사되어 결장으로 바로 통과한 후 미생물 군집에 의해 분해되는 과정에서 불편함이 발생합니다. 생성된 미생물 대사 산물은 혈류로 들어가거나 소변으로 배출될 수 있습니다. 흡수 수단의 변화는 복합체 내의 동일한 화합물에서도 다를 수 있습니다. 글리코사이드의 경우, 사과 케르세틴 글리코사이드의 생체 이용률은 양파의 30%에 불과하다는 보고가 있습니다. 당 결합은 플라보노이드의 흡수율에도 영향을 미칠 수 있습니다 [99]. 케르세틴 글루코사이드의 흡수 속도가 더 빠르며, 혈장 농도 피크가 루티노사이드보다 훨씬 더 높았습니다. 글루코사이드가 소장에서 흡수되는 반면, 루티노사이드는 탈당화 후 결장에서 흡수되는 것으로 추정됩니다 [99,100]. 또 다른 중요한 요소는 대사 전환입니다. 플라즈마에서 발견된 케르세틴은 황산염 또는 메틸 접합체였지만, 아글리콘 또는 배당체는 발견되지 않았습니다. 또한, 카테킨의 경우, 플라즈마에서 접합체만 발견되었습니다. 대장에서의 대사는 폴리페놀에 큰 영향을 미칩니다. 엄청난 양의 폴리페놀이 위나 소장에서 대사되지 않고 그대로 결장에 도달하기 때문입니다 [99]. 장내에 존재하는 박테리아의 분해는 단순한 페놀산과 혈류로의 흡수를 초래합니다 [101]. 프로안토시아니딘은 페닐아세트산, 모노- 및 디하이드록시페닐아세트산, 모노- 및 디하이드록시페닐프로피온산, 하이드록시벤조산으로 분해되는 것으로 알려져 있습니다. 안토시아닌은 주로 프로카테츄산으로 분해됩니다 [102].

3.2.3. Stilbenes

Stilbenes are polyphenols; their production de novo is caused as a mechanism of protection in situations of stress, such as fungal infections, toxins or to inhibit bacterial growth [103]. They are known under the name of allelochemicals [104] or phytoalexins [103]. Sources are usually represented by grapes (skin), peanuts, rhubarb, blueberries, or raspberries [103,104]. Most representative for this group is resveratrol; this compound can be found in two conformations, predominantly being in the trans- form (found in red grapes and peanuts, naturally). The cis- form of resveratrol can be encountered in wine. Moreover, the cis- form molecule might present a decreased bioactivity compared to the trans- due to its isomerization [103]. The absorption of resveratrol is high, but its bioavailability is poor, being easily concluded in phase II conjugation. After ingestion of resveratrol, conjugates are present in serum within 30–60 min [105]. Circadian rhythm and type of meal (highly lipidic foods, bondage to proteins) can influence bioavailability [103]. It was concluded that the best time for administering resveratrol was in the morning, being careful of not exceeding dosage, as it might be harmful, causing digestive issues, headaches, and nausea [103,106]. The dosage recommended is 100–1000 mg/day [103].

Stilbenes suffer different transformations after ingestion, like oxidation, reduction, conjunction mostly in the liver. For resveratrol, post oral ingestion, 70% is absorbed but only a small amount is available (5 ng/mL) with a 9 h half-life in plasma. Extensive hepatic conversions are responsible for the formation of sulfo- and glucorono-conjugates. Through phase II conjugation, compounds formed are hydrosoluble and easily eliminated [104]. Only 2% of resveratrol conjugates are detected in plasma and urine post-ingestion; major compounds found in urine are monoglucuronides, dihydroresveratrol monoglucuronide, resveratrol monosulphate, and dihydroresveratrol sulphate, according to Walle T. et al. [103,105]. When resveratrol passes through the upper part of the GI tract and arrives in the colon, about 75% can enter the coloncytes, metabolization by microbiome occurs, and transformation in metabolites such as dihydroresveratrol or lunularin can take place [103]. Pterostilbenes are also rapidly absorbed, with a faster rate compared to resveratrol, with four times the bioavailability. The methoxy groups attached to it give it an increased lipophilicity characteristic. Half-time rises up to 104 min. Its stability and bioavailability is higher due to lack of hydroxyl groups available for sulfation, owning only one [104]. Oligomerization and its degree also affects the bioavailability of these polyphenols, as a higher level determines a lowered bioavailability [107].

3.2.3. 스틸벤

스틸벤은 폴리페놀의 일종입니다. 스틸벤의 생성은 곰팡이 감염, 독소 또는 세균의 성장을 억제하는 것과 같은 스트레스 상황에서 보호 메커니즘으로 작용합니다 [103]. 스틸벤은 알레로케미컬 [104] 또는 피토알렉신 [103]이라는 이름으로 알려져 있습니다. 원료는 보통 포도(껍질), 땅콩, 대황, 블루베리, 라즈베리 등으로 표현됩니다 [103,104]. 이 그룹을 대표하는 것은 레스베라트롤입니다. 이 화합물은 두 가지 형태로 존재할 수 있으며, 주로 트랜스 형태로 존재합니다(자연적으로 붉은 포도와 땅콩에서 발견됨). 레스베라트롤의 cis- 형태는 와인에서 발견될 수 있습니다. 게다가, cis- 형태 분자는 이성질체화로 인해 trans- 형태에 비해 생체 활성이 감소할 수 있습니다 [103]. 레스베라트롤의 흡수율은 높지만, 생체 이용률은 낮아서 쉽게 2단계 결합으로 마무리됩니다. 레스베라트롤을 섭취한 후, 30~60분 내에 혈청에 결합체가 존재합니다 [105]. 일주기 리듬과 식사 유형(고지방 음식, 단백질에 대한 의존)은 생체 이용률에 영향을 미칠 수 있습니다 [103]. 레스베라트롤을 투여하는 가장 좋은 시간은 아침이며, 복용량을 초과하지 않도록 주의해야 한다는 결론을 내렸습니다. 복용량을 초과하면 소화 장애, 두통, 메스꺼움과 같은 부작용이 발생할 수 있기 때문입니다 [103,106]. 권장 복용량은 하루 100-1000mg입니다 [103].

스틸벤은 섭취 후 산화, 환원, 결합과 같은 다양한 변형을 겪으며, 대부분 간에서 일어납니다. 레스베라트롤의 경우, 경구 섭취 후 70%가 흡수되지만, 혈장 내 반감기가 9시간이고 이용 가능한 양은 소량(5ng/mL)에 불과합니다. 광범위한 간 전환이 설포-글루코로노-접합체의 형성에 기여합니다. 2단계 접합을 통해 형성된 화합물은 수용성이며 쉽게 제거됩니다 [104]. 섭취 후 혈장과 소변에서 검출되는 레스베라트롤의 2%만이 결합체입니다. Walle T. et al. [103,105]에 따르면, 소변에서 발견되는 주요 화합물은 모노글루쿠로니드, 디하이드로레스베라트롤 모노글루쿠로니드, 레스베라트롤 모노설페이트, 디하이드로레스베라트롤 설페이트입니다. 레스베라트롤이 위장관의 상부를 통과하여 결장에 도달하면 약 75%가 결장세포에 들어가 미생물 군집에 의한 대사가 일어나고, 디하이드로레스베라트롤이나 루눌라린과 같은 대사 산물로 변형될 수 있습니다 [103]. 프테로스틸벤도 레스베라트롤에 비해 흡수 속도가 빠르며, 생체 이용률이 4배 더 높습니다. 그것에 부착된 메톡시 그룹은 친지방성 특성을 증가시킵니다. 반감기는 104분까지 올라갑니다. 황산화 작용에 사용할 수 있는 수산기가 하나밖에 없기 때문에 안정성과 생체 이용률이 더 높습니다. 올리고머화와 그 정도도 이러한 폴리페놀의 생체 이용률에 영향을 미치는데, 그 정도가 높을수록 생체 이용률이 낮아집니다 [107].

3.2.4. Lignans

Lignans are phytoestrogens with a steroid-like structure, found in various seeds, grains, fruits, or vegetables in relatively low concentration, with importance due to a higher concentration being flaxseeds and sesame seeds [77,108]. Secoisolariciresinol has glycosidic bonds that are hard to hydrolyze, being unsusceptible of undergoing hydrolysis when passing through the upper part of the GI tract. Its diglucoside release, whatsoever, gets released in this portion depending on the food matrix it is linked with; deglycosilation of secoisolariciresinol could occur thanks to the brush border enzymes, in vivo study shows exitance of secoisolariciresinol in biofluids after high intake of SDG [108]. Significant for these compounds are the conversions occurring in the colon. Metabolization by intestinal microbiome leads to transformation in enterolignans, respectively enterodiol (ED) and entrolactone (EL) (also known under the name of mammalian lignans) [77,108]. The half-life of these compounds is between 5–13 h, remaining able to be detected even 8–10 h post ingestion. The cell density of entero-ligan-producing bacteria strains is more pronounced in women rather than in men, depending on their menstrual cycle (mid-luteal phase) and early pregnancy [109]. The bacterial metabolization of secoisolariciresinol can be a model for most common plant lignans. Luminal secoisolariciresinol can be sourced from the microbial transformation of plant precursors, or secoisolariciresinol diglucoside that was not absorbed. SDG is subjected to two consecutive deglycosilations and the end product is secoisolariciresinol monoglycoside (SDG). Demethylation of secoisolariciresinol results in demethyl-SECO, followed by transformation through demethylation and dihydroxylation into demethyl-dehydroxy-SECO, didemethyl-SECO (dihydroxy-ED), didemethyl-dehydroxy-SECO (hydroxy-ED), and ED. The oxidation of ED leads to EL. Obtaining EL can be described through mechanisms such as the generation of MAT after the dehydrogenation of SECO [108]. Another factor that might impact the bioavailability of lignans is the matrix of interlinkage, as positive results are obtained in patients with a diet rich in fiber [77]. The absorption of enterolignan after their production by bacteria in the large intestine is efficient; EL-sulfate, EL-glucuronide and ED-glucuronide were successfully detected after exposure of colonic cells to enterolignans. Conjugation and excretion happened within an 8 h window, remarkable being the fact that EL was eliminated with a faster rate than ED, as observed in in vitro studies. In one in vivo study conducted on blood samples from 27 female subjects, Adlercreutz et al. manage to show that the biologically active fraction of ED and EL, mainly being represented by their free, mono- and di-sulfated forms, adds up to 21–25% of the total (conjugated and non-conjugated) enterolignans. A total of 80% were biologically inactive [109,110].

3.2.4. 리그난

리그난은 스테로이드와 유사한 구조를 가진 식물성 에스트로겐으로, 다양한 씨앗, 곡물, 과일 또는 채소에서 비교적 낮은 농도로 발견되며, 아마씨와 참깨의 농도가 더 높기 때문에 중요합니다 [77,108]. 세코이솔라리시레시놀은 가수분해가 어려운 글리코시드 결합을 가지고 있어 위장관의 상부를 통과할 때 가수분해되지 않습니다. 이 디글루코사이드의 방출은 그것이 결합된 식품 매트릭스에 따라 이 부분에서 방출됩니다. 생체 내 연구에 따르면, SDG의 높은 섭취 후 세코이솔라리시레시놀의 브러시 보더 효소 덕분에 세코이솔라리시레시놀의 탈글리코실화가 일어날 수 있습니다 [108]. 이러한 화합물에서 중요한 것은 결장에서 일어나는 전환입니다. 장내 미생물 군집에 의한 대사는 장내 리그난, 즉 엔테로디올(ED)과 엔테로락톤(EL)(포유류 리그난으로도 알려져 있음)의 변형을 유도합니다 [77,108]. 이 화합물의 반감기는 5-13시간이며, 섭취 후 8-10시간 후에도 검출이 가능합니다. 엔테로리간을 생산하는 박테리아 균주의 세포 밀도는 월경 주기(황체기 중기)와 임신 초기[109]에 따라 남성보다 여성에게서 더 두드러집니다. 세코이솔라리시레시놀의 박테리아 대사는 가장 일반적인 식물성 리그난의 모델이 될 수 있습니다. 루미날 세코이솔라리시레시놀은 식물 전구체의 미생물 변형 또는 흡수되지 않은 세코이솔라리시레시놀 디글루코사이드에서 얻을 수 있습니다. SDG는 두 번의 연속적인 탈글리코실화 과정을 거치며, 최종 생성물은 세코이솔라리시레시놀 모노글리코사이드(SDG)입니다. 세코이솔라리시레시놀의 탈메틸화는 탈메틸-SECO를 생성하고, 그 다음 탈메틸화와 디하이드록실화를 거쳐 탈메틸-데하이드록시-SECO, 디메틸-SECO(디하이드록시-ED), 디메틸-데하이드록시-SECO(하이드록시-ED), 그리고 ED로 변형됩니다. ED의 산화는 EL로 이어집니다. EL을 얻는 것은 SECO의 탈수소화 후 MAT의 생성과 같은 메커니즘을 통해 설명할 수 있습니다 [108]. 리그난의 생체 이용률에 영향을 미칠 수 있는 또 다른 요인은 섬유질이 풍부한 식단을 섭취하는 환자들에게서 긍정적인 결과가 얻어지는 것처럼, 상호 연결의 매트릭스입니다 [77]. 대장에서 박테리아에 의해 생성된 후 장리닌의 흡수가 효율적입니다. 장리닌에 노출된 결장 세포에서 EL-황산염, EL-글루쿠로니드, ED-글루쿠로니드가 성공적으로 검출되었습니다. 결합과 배설은 8시간 이내에 이루어졌으며, 시험관 내 연구에서 관찰된 바와 같이 EL이 ED보다 더 빠른 속도로 제거되었다는 사실이 주목할 만합니다. 27명의 여성 피험자의 혈액 샘플을 대상으로 한 생체 내 연구에서, Adlercreutz 등은 ED와 EL의 생물학적 활성 부분이 주로 유리, 모노- 및 디설페이트 형태로 나타나며, 총 엔테롤리난(결합 및 비결합)의 21-25%를 차지한다는 것을 증명했습니다. 총 80%가 생물학적으로 비활성이었습니다 [109,110].

3.3. Bioactivity of Polyphenols

Polyphenols exert their bioactivity primarily through their interaction with biological systems at the molecular level, often mediated by their metabolites formed during digestion. They play a critical role in scavenging reactive oxygen species (ROS) and chelating metal ions, thereby reducing oxidative stress, a key factor in the pathogenesis of various chronic diseases. Specific pathways, such as the inhibition of lipid peroxidation and upregulation of endogenous antioxidant enzymes (e.g., superoxide dismutase and catalase), underscore their antioxidant properties.

These general mechanisms are well illustrated in specific plant sources. A 2024 review by Olas has expanded our understanding of Asparagus officinalis polyphenols, demonstrating their multifaceted health benefits, including antioxidant, anti-inflammatory, and anticancer properties. This work provides new evidence for the bioactivity of asparagus-derived compounds and their potential therapeutic applications through multiple molecular pathways, particularly highlighting their role in oxidative stress reduction and inflammatory response modulation [40]. Additionally, polyphenols influence inflammation by modulating cytokine production, suppressing proinflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and inhibiting the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Their anticancer effects include inducing apoptosis through caspase activation, inhibiting angiogenesis by targeting vascular endothelial growth factor (VEGF), and suppressing metastasis via the modulation of matrix metalloproteinases (MMPs).

Cardiometabolic benefits are also significant, with polyphenols shown to improve lipid profiles, enhance insulin sensitivity, and regulate blood pressure through their interaction with nitric oxide (NO) pathways. Emerging research highlights their neuroprotective effects, including the modulation of neuroinflammatory processes and promotion of synaptic plasticity, making them promising agents for mitigating neurodegenerative diseases. Moreover, the interaction of polyphenols with gut microbiota contributes to their bioactivity, as microbial fermentation produces bioactive metabolites that influence systemic health.

These multifaceted bioactivities emphasize the importance of understanding not just the chemistry of polyphenols but also their dynamic interactions within the human body to fully harness their therapeutic potential.

3.3. 폴리페놀의 생체 활성

폴리페놀은 주로 분자 수준에서 생물학적 시스템과의 상호 작용을 통해 생체 활성을 발휘하며, 종종 소화 과정에서 형성된 대사 산물에 의해 매개됩니다. 이들은 반응성 산소 종(ROS)을 제거하고 금속 이온을 킬레이트화하여 다양한 만성 질환의 발병 기전에 중요한 역할을 하는 산화 스트레스를 감소시킵니다. 지질 과산화 억제 및 내인성 항산화 효소(예: 슈퍼옥사이드 디스뮤타제 및 카탈라제)의 상향 조절과 같은 특정 경로는 이들의 항산화 특성을 강조합니다.

이러한 일반적인 메커니즘은 특정 식물 출처에서 잘 설명되어 있습니다. Olas의 2024년 리뷰는 아스파라거스 오피시날리스 폴리페놀에 대한 이해를 넓혀 항산화, 항염증, 항암 특성을 포함한 다각적인 건강상의 이점을 입증했습니다. 이 연구는 아스파라거스에서 추출한 화합물의 생체 활성 및 여러 분자 경로를 통한 잠재적인 치료 적용에 대한 새로운 증거를 제공하며, 특히 산화 스트레스 감소 및 염증 반응 조절에 대한 역할을 강조합니다 [40]. 또한, 폴리페놀은 사이토카인 생성을 조절하고, 인터루킨-6(IL-6)과 종양 괴사 인자-알파(TNF-α)와 같은 전염증 매개체를 억제하고, 활성화된 B 세포의 핵 인자 kappa 경쇄 강화 인자(NF-κB) 경로를 억제함으로써 염증에 영향을 미칩니다. 항암 효과로는 카스파제 활성화를 통한 세포자살 유도, 혈관 내피 성장 인자(VEGF)를 표적으로 하는 혈관 신생 억제, 매트릭스 메탈로프로테이나제(MMP) 조절을 통한 전이 억제 등이 있습니다.

심혈관 대사 효과도 중요합니다. 폴리페놀은 산화질소(NO) 경로와의 상호 작용을 통해 지질 프로파일을 개선하고, 인슐린 감수성을 향상시키며, 혈압을 조절하는 것으로 나타났습니다. 최근 연구에 따르면 폴리페놀은 신경염증 과정의 조절과 시냅스 가소성의 촉진 등 신경 보호 효과가 있어 신경 퇴행성 질환을 완화하는 데 유망한 약제로 여겨지고 있습니다. 또한, 폴리페놀과 장내 미생물 간의 상호 작용은 미생물 발효를 통해 전신 건강에 영향을 미치는 생체 활성 대사 산물을 생성하기 때문에 생체 활성에 기여합니다.

이러한 다각적인 생체 활성은 폴리페놀의 화학적 특성뿐만 아니라 인체 내에서의 역동적인 상호 작용을 이해하는 것이 치료 잠재력을 완전히 활용하는 데 중요하다는 것을 강조합니다.

3.3.1. Cardiovascular Protection

Cardiovascular Diseases (CVD) involve the circulatory system’s malfunction. CVD include several diseases, including coronary artery disease, stroke, heart failure, or high blood pressure. Consumption of polyphenols is reported to reduce and prevent the risk of developing or aggravating the symptoms of the preexistent disease [111].

Resveratrol can be most significantly found in grapes, specifically in their skin. Other sources for resveratrol can be peanuts, berries, or medicinal plants [112,113]. Since resveratrol is found in higher concentration in grape skin, red wine can be considered abundant in this polyphenol. Low mortality rate as a cause of CVD in France has been associated with the consumption of red wine. This phenomenon has been named “The French Paradox” due to their high-fat diet, but with a low incidence of deaths caused by coronary heart disease. Explanation of this paradoxal event suggests that moderate consumption of wine can provide anti-inflammatory effects, decrease platelet aggregation, increase high-density lipoprotein and decrease low-density lipoprotein, as these are causes of developing the disease. Resveratrol fights proinflammatory cytokines through its mechanisms of action through the decreasing of NLR family pyrin domain that consists of three inflammasome routes, therefore decreasing levels of interleukin (IL)-1β production and gene expression‎. The mechanism of action for resveratrol involves action upon molecular sites to stimulate endothelial production of NO, reduction of oxidative stress, inhibition of vascular inflammation, and prevention of platelet aggregation. Studies on resveratrol’s antioxidant potency suggest that it inhibits nicotidamide adenine dinucleotide phosphate oxidase and further limits the production of ROS [112]. Studies show that resveratrol consumption is connected to lowering the expression‎ of inflammatory markers (e.g., intercellular adhesion molecules and interleukin-8) in endothelial cells and lower diastolic blood pressure in systemic circulation, these two being causes of ischemic stroke and hypertension [114]. Resveratrol upregulates endothelial nitric oxide synthase expression‎ followed by NO production from endothelial cells [115]. The inhibition of platelet aggregation begins through cellular signaling through the inhibition of p38 mitogen-activated protein kinase pathway, activating the NO production/cyclic guanoside monophosphate with resulting phospholipase C and protein kinase C inhibition, decreasing intracellular calcium concentration or ROS formation. As an anti-inflammatory agent, it acts similarly to aspirin: target of cyclooxygenase-1 and 2, hindering prostaglandin activity. Sirtuin-1 can be another route for obtaining the anti-inflammatory effects given by resveratrol [112]. SIRT-1 is an NAD+ dependent protein deacetylase that regulates aging, transcription, proliferation, apoptosis, and inflammation. Loss of SIRT-1 leads to vascular and cardiac aging. Activation of SIRT-1 through resveratrol implies modulation of enzyme activity, protein phosphorylation, and transcription factor function, deriving its properties in regard to modulation of the cardiovascular system. The post-transitional deacetylation of lysine residues by means of resveratrol-SIRT-1 activation increases the activity of endothelial nitric oxide synthase. Superoxide anions are scavenged by NO; the duality of these two mechanisms provide balance for endothelial health, and besides its malfunctioning being associated as an early sign of hypertension, it is responsible for upping the rate of vascular tone and prompting vascular remodel [114,116]. AMP- activated protein kinase (AMPK) is a cellular-signaling mechanism for regulating energy and cellular pathways, being activated in periods of metabolic stress, such as depletion of nutrients, hypoxia, and intoxications [117]. The indirect modulation of AMPK conducted by the ingestion of resveratrol can be explained by the SIRT-1 pathway activated by the phenolic compound, and the deacetylation of LKB1 serine–threonine kinase that directly phosphorylates and stimulates inactive AMPK. Activating AMPK provides antioxidant and anti-inflammatory characteristics, for a well-functioning and balanced in-cell environment of the CVS [114,118].

Resveratrol at 10–100 µM provides cardiac safety insulin resistance syndrome (metabolic syndrome) in human aortic endothelial cells and salvianolic acid A (natural polyphenol used in Chinese medicine) shows benefits for CVD protection against lipotoxicity-induced myocardial damage at >5µM, as presented in some in vitro studies [119].

As for other human studies, an impressing study conducted by Rafael Moreno-Luna et al., shows the reduction of diastolic blood pressure (BP) after treatment with polyphenol-rich olive oil [120]. Changes in lipid metabolism in adults with CVD are potent in a study prescribing a polyphenolic-abundant drink of cranberries [111]. The consumption of polyphenols gave a positive response in lowering inflammatory risk factors such as human C-reactive (CRP) and fibrinogen protein destruction, mitigating atherosclerosis and, ultimately, CVDs [121]. Flavonoids such as quercetin and kaempferol are supportive of cardiac cell function in mitochondria. ROS species degenerate this function by ischemia-reperfusion damage [122].

3.3.2. Neuroprotection

Neurodegenerative diseases that appear in older populations as a consequence of aging is characterized by loss of brain function. Brain function is degraded when neurons and neutral stem cells are destroyed, modulated by a cellular and molecular system: glutamate excitotoxicity, oxidative stress, and abnormal apoptosis; other than genetic and environmental influences [123,124]. Polyphenols enhance detoxification and antioxidation enzyme activity as well as regulation of reactive oxygen activity. They also inhibit glutamate-induced apoptosis [119]. In the case of hereditary chronic diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and dementia, inflammation and oxidative stress play a huge role in further degenerating the brain’s function [124]. In human trials, studies show dietary α-linolenic acid’s intake as successful on a lower education and lower background group. Inhibition of these problems may aid in brain health, ease the symptoms, and ultimately make the patient’s life easier. The consumption of resveratrol, curcumin, quercetin, or catechins shows cognitive improvement, inhibits apoptosis (and therefore limits the destruction of dopaminergic cells), and promotes antioxidant activity. Administering quercetin in human subjects improved cells’ life and antioxidant activity [111,124]. Because of the attention the gut–brain axis has been given in the recent years in the field of neurological studies, it is important to mention that gut microbiota can modulate activity in the brain, and therefore, can be a great influence on neurodegenerative diseases such as the ones previously mentioned. A healthy gut microbiota can influence one’s being, from physical to mental health. The article “Polyphenols-gut microbiota interplay and brain neuromodulation” by S. Filosa et al. mentions the role of polyphenols as prebiotics, a critical aspect for an optimal microflora. The enzymatic transformation of microorganisms from the gut improves bioavailability of polyphenols; subsequently, these key secondary metabolites will be modulating the microbiome community, avoiding the risk of pathogenic microbes [125]. Only recently, scientists have begun to take in consideration not only the administration of probiotics and probiotic-rich foods, but also the importance of including prebiotics into this class of psychobiotics. A remarkable and well-recognized study was conducted by Aurelijus Burokas and collaborators, studying the administration and the beneficial effect of administering prebiotics in mice. The results are as follows: “reduced chronic stress-induced elevations in corticosterone and proinflammatory cytokine levels and depression-like and anxiety-like behavior in addition to normalizing the effects of stress on the microbiota” [126]. Different studies show that different bacteria strains can produce doses and different types of neurotransmitters that are secreted by the brain: Escherichia and Enterococcus spp.- serotonin and Lactobacillus and Bifidobacterium- γ-aminobutyric acid (GABA) [124].

Neuromodulation through the gut–brain axis and administration of polyphenols has been proven along the years through research, and due to the fact that most polyphenols are not absorbed, they get metabolized by the microbiome [127]. Through the ingestion and metabolization of polyphenols by intestinal bacteria existing in the gut, they improve the diversity of the microbiota, production of important metabolites such as SCFAs, assist in the production of different hormones and neurotransmitters, and also play an important role in contributing to neurodegenerative disease treatment [128]. SCFA production has been linked to neuroactive attributes, and its production is linked to the microorganisms’ influence on CNS via the vagus nerve. In the colon, SCFA production mainly include its acetate, propionate, and butyrate form through the fermentation of different substrates like fiber or resistant starch [129,130]. The importance of the vagus nerve has been underlined to aid in satiety, stress, and mood; therefore, bacteria in the gut interacting to activate it can have an impact on CNS. After their production through fermentation, they are absorbed by colonocytes via 𝐻+H+-dependent or sodium-dependent monocarboxylate transporters. SCFAs do not enter through colonocytes but get transported to hepatocytes via portal circulation and used as an energy source. SCFAs bind G-protein-coupled receptors (GPRs), particularly the intensely studied GPR43 and GPR41, GPR109a/HCAR2 (hydrocarboxylic acid receptor) and GPR164, expressed in various cells across the GI mucosa to the immune and nervous systems. The cell of expression‎ will determine the effects of activation of these different types of receptors. Regulating systemic functions via histone deacetylase activity promotes the acetylation of lysine residues from nucleosomal histones; this particular signaling mechanism has been linked to modulating the peripheral NS and CNS [130]. The SCFA–Microglia interlink has been studied; microglial maturation and function can be modulated through microbiota production of SCFA acetate, butyrate, and propionate, as they could determine it through the activation of FFAR2 (free fatty acid receptor-2) in FFAR2-deficient mice [131]. Glial and microglial cells are responsible for the elimination of unnecessary synaptic connections, necessary for the maturation and refining of the circuits and connections in the NS. In the same interaction between microglial cells and SCFAs, their acetate form provides information on reducing inflammation through IL-1b, IL-6, and TNF-a expression‎ and p38 MAPK, JNK, and NF-kB phosphorylation. SCFAs can modulate neurotrophic factors, that are factors for regulating growth, survival, and to differentiate neurons and synapses in the CNS, supposedly through GPR41 or GPR43 receptors. SCFAs have a positive effect on different mental disorders by improving the activity of the brain through its discussed mechanisms, and therefore, being a great tool in their treatment. Successful data conclude their help in autism spectrum disorders, balancing the microbes in the colon, usually a common trait found in individuals suffering from autism disorder. The same goes for mood disorders; in depressed patients it was found that commonly, proinflammatory cytokines were present and patients suffering from depression had lower SCFAs in stool than non-depressed patients. The current literature shows that butyrate can act as an antidepressant, creating changes in energy levels, cognitive functioning and sociability inadaptation [130]. Quercetin-3-O-glucuronide is one of the most abundant metabolites of quercetin in vivo. Its administration might restore dysbiosis of the microbiome by restoring normal levels of bacteria in the colon, as an abnormal composition could lead to neuroinflammation. Quercetin-3-O-glucuronide has the ability to restore Aβ43 (amyloid β-43- characteristic for Alzheimer’s disease) and induce low levels of SCFAs, being associated with changes in the gut microbiome [128]. Anthocyanidins are also powerful in exerting neuroinflammatory properties with effects on the CNS as a result of modulation of the gut microbiota. Kynurenic acid resulting from metabolizing of the phenols generated from tryptophan metabolism could be used as a therapeutic tool for psychiatric diseases for its antagonist properties in regards to excitatory Aa receptors [132].

3.3.3. Antioxidant and Anti-Inflammatory Effects

Imbalance in free radicals in the body leads to oxidative stress. As a defense mechanism, the body releases cells that might come from enzymes, bacterial cells, mammalian cells, and polyphenols. In oxidative stress, the mechanism of cell damage occurs due to the different chemical actions of oxygen-based free radicals. Scavenging of free radicals, preventing oxidation of lipids, and inhibiting the secondary products of oxygen reactions—hydrogen peroxides produced by NADPH oxidases and xanthine oxidase—are one the main characteristics of the antioxidant properties of polyphenols [119,121]. The advantage of hydroxyl groups present in polyphenols gives them the propriety to scavenge free radicals and chelate ions. Their nature allows them to be providers of electrons or hydrogen for reactive oxygen species (ROS). For chelation of metal ions, they act by giving the peroxide compound or metal oxides stability. Increasing the activity of certain enzymes, polyphenols restore a balance of the enzymatic redox system, an oxidative defense mechanism, averting inflammation. Although they play their role in this scenario, it is important to consider their potential in becoming pro-oxidant substances, when they lose electrons or when they are reducing agents [111,119]. Excessive production of ROS can be associated with the development of metabolic disorders and inflammation [133]. Therefore, it is important to combat this imbalance and treat the root cause to prevent further health implications. Polyphenols can modulate the immune system in NOD-like receptors, Toll-like receptors, NF-ĸB, proinflammatory chemokines, cytokines, and adhesion molecules, because of the existence of 4–5 hydroxyl groups in their molecule, resulting in antioxidant potential [121].

3.3.4. Anticancer Activity

A cancerous cell is defined as a life unit that is prone to proliferation, motivated by the genetic history of the individual or other habitual or environmental factors (diet, lifestyle, pollution, radiation, and many others). In 35% of cancer cases, the causes are dietary habits and patterns [134]. Since phytochemicals like polyphenols are great anticancer agents, after being studied for their properties, they could be used as support for cancer treatment [135]. With their affinity for protein macromolecules, polyphenols exert benefits in the field of interest of cellular effects.

Mainly, they are used as an aid in chemotherapy side effects, or preventive tool to ameliorate chemotherapeutics. In animal models, they show inhibition of cell proliferation, differentiation, apoptosis, angiogenesis, or metastasis. Moreover, they can reduce the possibility of different types of cancers to develop [119,134]. As anticancerogenics, some polyphenols demonstrate important effects on certain types of cancers. Quercetin and green tea catechins can be inhibitors for the tumor’s activity in colon cancer and protection from different GI cancers [134], supposedly having a local antibiotic effect. Injection with resveratrol in breast cancer reduces the carcinogenic activity of immunosuppressor dimethylbenz[α]anthracene, used in animal studies. Genistein also has successful attribution for mammary cancer [134].

Polyphenols are responsible for the modulation of cytokine-signaling pathways that involve cancerogenic cells. Green tea polyphenols, especially Epigallocatechin-3-gallate and other tea catechins, are important for their antioxidant, anti-inflammatory, and anticancer capacities due to the multitude of OH groups [121]. Chung S. Yang et al. demonstrated the effectiveness of tea catechins in suppressing proliferation of cancer cells and inflammation [136]. Red wine interactions with colon cancer and tumors have been studied, and the researchers showed the success of phenols present in the beverage in carcinogenesis suppression. Polyphenols are capable of lowering DNA damage caused by ROS formation, and therefore inhibit cancerous cells and their multiplication [121].

Inhibiting angiogenesis can be used in cancer treatments as the process itself involves generating new blood vessels from already existing ones. Unregulated angiogenesis is described in diseases like psoriasis, hemangioma, tumor growth, and metastasis. Inhibiting this process could prevent these cancerogenic cells from spreading, and therefore, inhibit their way of getting to other organs in the body. Factors of this process include vascular endothelial growth (VEGFs) and basic fibroblast factor (bFGF) [137,138]. Both of them are important for the endothelial cell’s survival, differentiating, and migrating. Enzymes in collagen degradation such as matrix metalloproteins (MMPs) are secreted by endothelial cells and they are responsible for the cell’s movement, because for that to take place, it previously is in need of degradation to happen. Polyphenols can inhibit angiogenesis via direct suppressive effects. Resveratrol is used as a suppressant for malignant tumors (leukemia, neuroblastoma, breast cancer, intestine cancer, liver cancer, colon cancer). Resveratrol is known to cause apoptosis and G1/S-phase cell cycle arrest in cancer cells. It downregulates the activating of kappa B (NF-κB) and the expression‎ of MMP-9, survivin, cyclin D1, COX-2, and intracellular adhesion molecule 1. Antiangiogenics are complex and include the downregulating of VEGFs and FGFs in endothelial cells, mediated by the reduction of hypoxia-inducible factor-1α and the suppression of thrombospondin-1 and tumor suppressor factor 53. Other compounds, such as genistein found in soybeans, can be tools for prostate, breast, gastric, and colon cancer, with anticancer mechanisms that include the inhibition of tyrosin kinase, topoisomerase 20S, proteasomal activity, and FoxM1 upregulation of p27Kip-1, IKB and Bax; as angiogenetic inhibitors, the polyphenol downregulates MMP-2, HIF-1α, and VEGFs [138]. Caffeic acid phenethyl ester, existing in propolis, diminishes the cell’s capacity for proliferation in PC-3 human prostate cancer cells through reducing the phosphorylation of p-ERK1/2 (Thr202/Tyr204), p-Akt (Ser473), p-mTOR (Ser2448, Ser24981), p-GSK3α (Ser21), and p-GSK3β (Ser9) [139]. Another study shows inhibition of tumor growth in mice with the reduction of signaling molecules from the Akt pathway [140], an important protein kinase B pathway involved in cell growth, death, and survival, regulation of glucose uptake in muscle or fat cells, or suppression of neuronal cell death; dysregulation of this pathway is associated with diseases such as cancer [141].

3.4. Bioaccessibility of Polyphenols

The bioaccessibility of polyphenols refers to their release from the food matrix and their subsequent modifications in the gastrointestinal (GI) tract, which affect their absorption and bioavailability. Bioavailability is influenced by factors such as the molecular structure of polyphenols, the interactions they have with other dietary components, and the mechanisms they undergo in the body. When bioavailability is studied, it is essential to first understand the resealing from the food matrix and the modifications the compound undergoes in the gastrointestinal tract. The majority of polyphenols ingested are not excreted through urine, meaning that they either have not been absorbed properly in the gut, absorbed, and excreted in the bile, or metabolized by the colon microflora or by the tissues. The molecular structure of polyphenols in their free form gives them the benefit to pass through plasmatic membranes by diffusion, unlike the case when they form complexes with other compounds, changing the way they get assimilated [111]. The availability of the compound is bound to the presence of other molecules interacting with the phenolic compound: dietary fiber reduces the absorption rate, trapping the phenols in the matrix due to their polysaccharides and the polar groups of the polyphenols; lipids increase absorption in the intestine for non-polar phenol groups (curcumin, resveratrol, xanthones, and some flavonoid aglycones); dietary proteins, on the other hand, interact with the hydroxyl groups of the polyphenols, forming hydron bonds and hydrophobic ones with the carboxyl groups of different protein chains, increasing absorption 1.5-10 times [142]; dietary carbohydrates can increase absorption of flavanols to 40%, whereas generic absorption of polyphenols is also increased due to high GI motility and action of enzymes [10,111].

3.4. 폴리페놀의 생체 접근성

폴리페놀의 생체 접근성은

식품 매트릭스로부터의 방출과 위장관(GI)에서의 후속 변형에 의해

흡수 및 생체 이용률에 영향을 미칩니다.

생체 이용률은

폴리페놀의 분자 구조,

다른 식이 성분과의 상호 작용,

체내에서 겪는 메커니즘과 같은 요인에 의해 영향을 받습니다.

생체 이용률을 연구할 때,

먼저 식품 매트릭스로부터의 재밀봉과 위장관에서 겪는 화합물의 변형을 이해하는 것이 필수적입니다.

섭취된 폴리페놀의 대부분은 소변을 통해 배출되지 않습니다.

즉, 장에서 제대로 흡수되지 않았거나,

흡수되어 담즙으로 배출되거나,

대장 미생물이나 조직에 의해 대사되었음을 의미합니다.

자유 형태의 폴리페놀의 분자 구조는

다른 화합물과 복합체를 형성하여 동화되는 방식을 바꾸는 경우와 달리

확산에 의해 혈장막을 통과할 수 있는 이점을 제공합니다 [111].

이 화합물의 이용 가능성은

페놀 화합물과 상호 작용하는 다른 분자의 존재 여부에 달려 있습니다:

식이 섬유는

흡수율을 감소시켜, 다당류와 폴리페놀의 극성 그룹 때문에

매트릭스에 페놀을 가두어 둡니다;

지질은 비극성 페놀 그룹(커큐민, 레스베라트롤, 잔톤, 일부 플라보노이드 아글리콘)에 대한 장내 흡수를 증가시킵니다;

식이 단백질은,

반면에, 폴리페놀의 하이드록실 그룹과 상호 작용하여 하이드론 결합과 소수성 결합을 형성하고,

다른 단백질 사슬의 카르복실 그룹과 소수성 결합을 형성하여 흡수율을 1.5-10배 증가시킵니다 [142];

식이 탄수화물은 플라바놀의 흡수율을 40%까지 증가시킬 수 있으며, 높은 GI 운동성과 효소의 작용으로 인해 폴리페놀의 일반적인 흡수율도 증가합니다 [10,111].

3.4.1. Absorption in Stomach

Mechanic action that happens to the ingested foodstuff, such as chewing, the crushing process, gastric motility, and abrasion between the aliments can ease the liberation and assimilation of polyphenols [111]. The stomach can only accept the free form of polyphenol for absorption. It has been proved that acidic pH does not affect the stability of polyphenol and that, depending on the complex form, the aglycon can be liberated [28]. If the polyphenol has an affinity to the mucus excreted when chewing, the mucins act as a protective layer, not allowing the gastric absorption to take place. The phenols or flavonoids found in the extracellular matrix could only be dissolved in alkaline conditions, but not in acid ones. However, they might provide local activity, protecting the GI tract of oxidizing agents’ exposure, inflammation, and intestinal diseases. Chlorogenic acids undergo hydrolysis, resulting in the release of caffeic acid and quinic acid [83,115]. It is important to note that, unlike flavonoid glycosides, chlorogenic acids are esters formed by the conjugation of caffeic acid and quinic acid. Therefore, their hydrolysis produces specific hydrolysates (caffeic acid and quinic acid) rather than aglycones [111,143].

The complexes polyphenols form in the stomach make it difficult to understand the GI pathway and its mechanism in human trials. In vitro studies provide an understanding of gastric uptake. In most cases, absorption of polyphenols in the stomach does not occur. Only in the case of free and conjugated Hydroxytyrosol and Tyrosol is encountered a hydrolysis of phenolic compound conjugates, according to Mireille Koudoufio and collaborators. The hydrolyzation of procyanidins occurs as a time-dependent hydrolysis of oligomers, and achieves polyphenol stability when faced with a low pH [143].

3.4.1. 위장에서의 흡수

씹기, 분쇄 과정, 위 운동성, 음식물 간의 마찰과 같이 섭취된 음식물에 일어나는 기계적 작용은 폴리페놀의 방출과 동화를 촉진할 수 있습니다 [111]. 위는 흡수를 위해 폴리페놀의 자유 형태만 받아들일 수 있습니다. 산성 pH가 폴리페놀의 안정성에 영향을 미치지 않으며, 복합 형태에 따라 아글리콘이 분리될 수 있다는 것이 증명되었습니다 [28]. 폴리페놀이 씹을 때 배출되는 점액과 친화성이 있다면, 점액질은 보호막 역할을 하여 위장 흡수를 허용하지 않습니다. 세포 외 기질에서 발견되는 페놀 또는 플라보노이드는 알칼리성 조건에서만 용해될 수 있지만, 산성 조건에서는 용해되지 않습니다. 그러나, 그들은 산화제의 노출, 염증, 장 질환으로부터 위장관을 보호하는 지역 활동을 제공할 수 있습니다. 클로로겐산은 가수분해되어 카페산과 퀴닉산을 방출합니다 [83,115]. 플라보노이드 배당체와는 달리, 클로로겐산은 카페산과 퀴닉산의 결합에 의해 형성된 에스테르라는 점에 유의해야 합니다. 따라서, 이들의 가수분해는 아글리콘(aglycones)이 아닌 특정 가수분해물(카페인산과 퀴닉산)을 생성합니다 [111,143].

위장에서 형성되는 복합 폴리페놀은 인간 대상 실험에서 위장 경로와 그 메커니즘을 이해하는 것을 어렵게 만듭니다. 체외 연구에서는 위장 흡수에 대한 이해를 제공합니다. 대부분의 경우, 위장에서 폴리페놀의 흡수는 일어나지 않습니다. Mireille Koudoufio와 공동 연구진에 따르면, 자유 상태의 복합체 형태의 하이드록시티로졸과 티로졸의 경우에만 페놀 화합물 복합체의 가수분해가 발생합니다. 프로시아니딘의 가수분해는 시간 의존적 올리고머의 가수분해로 발생하며, 낮은 pH에 직면했을 때 폴리페놀의 안정성을 달성합니다 [143].

3.4.2. Absorption in the Small Intestine

The first step in the intestinal process, due to sugar linkage of polyphenols, would be glycosylation by the intestinal mucosa, or by microorganisms existent in the gut. Rhamnose-linked phenols cannot be metabolized in the intestine, and therefore, will further be transported in the colon. In the duodenum, most polyphenolic compounds pass by intact, while high-molecular-weight ones are hydrolyzed into dimers or monomers by bile salts and pancreatin-stimulated dialyze and non-dialyze [143]. Whereas the other polyphenols, like aglycones and some glucosides [28], have two possible pathways for absorption in the jejunum and ileum segments. One is the transportation in intact state to enterocytes (IPEC, a strain of cells existing in human GI tract [143]) by sodium-dependent glucose transporter, followed by hydrolyzation by cytosolic β-glucosidase, resulting in their aglycone. The second one is the glucosidase of the brush border membrane, lactase phlorizin hydrolase (LPH), that catalyzes extracellular hydrolysis of some glucosides, and then diffusion of the aglycone [28,143]. Flavonoid glucosides involve both pathways: Quercetin 3-glucoside, mono-glucosides of genistein and daidzein with LPH, cytosolic β-glucosidase (CBG) for hydrolyzing Q4’G, genistein 7-O-glucoside (genistein), and daidzein 7-O-glucoside (daidzein); quercetin-4′-glucoside seems to use both [28,144].

After entering the villi (epithelial of the small intestine), conjugation occurs through either methylation, sulfation, or glucuronidation [144]. The type of conjugation is related to the dose, and the nature of substrate of the ingested compound. Sulfation takes place in cases of lower-dose high-affinity substrates, shifting towards glucuronidation when a dose increases [28]. In a study regarding the Spanish diet, it is estimated that 48% of the total polyphenols from vegetables are bioaccessible in the small intestine. A considerate number of studies show that only 5–10% of the bioaccessible polyphenols get to be metabolized through absorption in the intestinal villi [145].

3.4.2. 소장에서의 흡수

폴리페놀의 당 결합으로 인해 장에서 일어나는 과정의 첫 번째 단계는 장 점막 또는 장에 존재하는 미생물에 의한 당화 작용입니다. 람노오스 연결 페놀은 장에서 대사될 수 없기 때문에, 결장으로 이동하게 됩니다. 십이지장에서 대부분의 폴리페놀 화합물은 그대로 통과하지만, 고분자량 화합물은 담즙산과 췌장 자극 투석 및 비투석에 의해 이량체 또는 단량체로 가수분해됩니다 [143]. 다른 폴리페놀인 아글리콘과 일부 글루코사이드[28]는 공장 및 회장에서 흡수될 수 있는 두 가지 경로를 가지고 있습니다. 하나는 나트륨 의존성 포도당 수송체에 의해 장내 상피세포(IPEC, 인간 위장관에 존재하는 세포의 일종[143])로 온전한 상태로 운반된 다음, 세포질 β-글루코시다아제에 의해 가수분해되어 아글리콘이 되는 것입니다. 두 번째는 일부 글루코사이드의 세포외 가수분해를 촉매하고, 그 다음에 아글리콘의 확산(28,143)을 촉매하는 브러시 보더 막의 글루코시다아제, 락타아제 플로리진 가수분해효소(LPH)입니다. 플라보노이드 글루코사이드에는 두 가지 경로가 모두 관여합니다: 케르세틴 3-글루코사이드, 제니스테인과 다이제인의 모노글루코사이드와 LPH, Q4'G 가수분해를 위한 세포질 β-글루코시다아제(CBG), 제니스테인 7-O-글루코사이드(제니스테인), 다이제인 7-O-글루코사이드(다이제인); 케르세틴-4'-글루코사이드가 둘 다 사용하는 것으로 보임 [28,144].

빌리(소장의 상피)에 들어간 후, 메틸화, 황산화, 글루쿠로니드화 중 하나를 통해 접합이 일어납니다 [144]. 접합 유형은 섭취된 화합물의 용량과 기질의 특성과 관련이 있습니다. 황산화는 저용량 고친화성 기질의 경우에 일어나며, 용량이 증가하면 글루쿠로니드화로 전환됩니다 [28]. 스페인 식단에 관한 연구에 따르면, 채소에서 추출한 폴리페놀의 48%가 소장에서 생체 이용 가능하다고 추정됩니다. 많은 연구에 따르면, 생체 이용 가능한 폴리페놀 중 5~10%만이 장 융모에서 흡수되어 대사된다고 합니다 [145].

3.4.3. Colon Absorption

Polyphenols that are not metabolized in the stomach or the small bowel will pass further into the colon, where they are subjects of destruction until reaching phenolic acid compounds (Figure 7).

3.4.3. 결장 흡수

위나 소장에서 대사되지 않은 폴리페놀은 결장으로 더 이동하여 페놀산 화합물에 도달할 때까지 파괴됩니다(그림 7).

Figure 7. Representation of the general absorption of polyphenols.

Glycosides that arrived from the small intestine, undigested, will be transformed into aglycones by hydrolyzation with the help of the colonic microflora, catalyzed by β-glucosidase, β-rhamnosidase, or esterase. The aglycones resulted will be absorbed via the portal vein to the liver, either execrated in the bile back into the small intestine, creating an enterohepatic cycle while also creating a synergetic relationship between the gut microbiota and polyphenols [143]. In the liver, like in the intestine, after absorption, resulted fractions of polyphenols undergo the same types of conjugations (also called phase II enzymatic conversion) [144]. A possible pathway is simply by excretion into feces, along with the undigestible fraction present in plant tissue, but according to studies, only 10% of polyphenols experience this type of elimination, resulting in the utility of gut-assimilated polyphenols up to 90%. Hepatic function also implies that polyphenols can be transported to tissues or by renal pathway (phase I conversions) into urine. The interaction of microbiota and polyphenols has a great interest in the use of these phytochemicals as prebiotics. Studies conducted in vivo and in vitro show the modulation of gut metabolism and inflammatory pathway by inhibiting mast cell degranulation. They also show potential in improving gut barrier protection, and improvement in metabolic homeostasis. As a first conclusion so far, polyphenols go through changes from the moment they encounter the enzymes present in saliva. They get liberated from conjunction, re-conjugate in the liver or the intestine, get used up by microflora’s bacteria after assimilation by the GI tract, enter the composition of plasmatic proteins, and at last, incorporate in adipose tissues [111]. In vitro studies show ideal course of metabolic reactions happening in the human body, at level of digestion and possibly target-action of polyphenols towards tissues and cells, exerting beneficial effects. In vivo cases, however, cannot always be the most accurate, due to individuality. Each organism differs in one way or another, and human metabolism is harder to understand fully because of the many possible interactions and structures that form through the catabolism’s (and anabolism’s) track.

Even though in vitro studies do not give us exact data about human bioavailability of polyphenols, they help know how many beans make five, meaning that they give us an idea of the asset that are these compounds for health.

소장에서 소화되지 않은 상태로 도착한 배당체는 β-글루코시다아제, β-람노시다아제, 또는 에스테라아제의 촉매 작용을 받아 결장 미생물의 도움을 받아 가수분해에 의해 아글리콘으로 변형됩니다. 그 결과 생성된 아글리콘은 간으로 가는 문맥을 통해 흡수되어 담즙을 통해 소장으로 다시 배출되면서 장간 순환을 형성하는 동시에 장내 미생물과 폴리페놀 사이에 시너지 효과를 일으킵니다 [143]. 장과 마찬가지로, 간에서도 흡수된 폴리페놀의 일부는 동일한 유형의 결합(2단계 효소 전환이라고도 함)을 거칩니다 [144]. 가능한 경로는 식물 조직에 존재하는 소화되지 않는 부분과 함께 대변으로 배설되는 것입니다. 그러나 연구에 따르면, 폴리페놀의 10%만이 이러한 유형의 배설을 경험하며, 장에서 흡수된 폴리페놀의 효용성은 최대 90%에 달합니다. 간 기능은 또한 폴리페놀이 조직으로 운반되거나 신장 경로를 통해 소변으로 배출될 수 있음을 의미합니다(1단계 전환). 미생물군과 폴리페놀의 상호작용은 이러한 식물성 화학물질을 프리바이오틱스로 사용하는 데 큰 관심을 불러일으킵니다. 생체 내 및 생체 외에서 수행된 연구에 따르면, 비만세포 탈과립화를 억제함으로써 장내 대사와 염증 경로를 조절하는 것으로 나타났습니다. 또한 장벽 보호 개선과 대사 항상성 개선에 잠재력이 있는 것으로 나타났습니다. 지금까지 나온 첫 번째 결론은 폴리페놀은 타액에 존재하는 효소와 접촉하는 순간부터 변화를 겪는다는 것입니다. 이들은 결합에서 해방되고, 간이나 장에서 재결합하며, 위장관에 흡수된 후 미생물 군집의 박테리아에 의해 소모되고, 혈장 단백질의 구성에 들어가며, 마지막으로 지방 조직에 통합됩니다 [111]. 체외 연구에서는 소화 수준에서 인체에서 일어나는 이상적인 대사 반응 과정과 조직과 세포에 대한 폴리페놀의 표적 작용이 유익한 효과를 발휘하는 것을 보여줍니다. 그러나 체내 사례는 개체성 때문에 항상 가장 정확한 것은 아닙니다. 각 유기체는 어떤 면에서든 다르며, 인체 대사는 이화 작용(및 동화 작용)의 경로를 통해 형성되는 많은 상호 작용과 구조 때문에 완전히 이해하기가 더 어렵습니다.

체외 연구가 폴리페놀의 생체 이용률에 대한 정확한 데이터를 제공하지는 않지만, 콩 다섯 개로 얼마나 많은 콩을 만들 수 있는지를 알려줌으로써, 이 화합물이 건강에 얼마나 유익한지를 알려줍니다.

4. Major Polyphenol Food Sources and Their Bioavailability

Due to their consumption in a larger quantity, two food sources of major polyphenol compounds were analyzed, in hopes for a better understanding of the polyphenols’ bioavailability. Their everyday consumption leads to daily CGA and quercetin sources, each of the chosen foodstuff having a corresponding polyphenolic group in a significant amount. The impact on well-being is linked to the quantity ingested and the metabolism’s capacity of utilizing the compounds in their free form or metabolites formed throughout the digestion. For coffee and onion, we demonstrated the bioaccessibility from the moment of ingestion through the GI tract, but we also appreciated the bioactivity these compounds possess.

4.1. Coffee—Coffea Arabica and Coffea Robusta

Coffee, a simple infusion of ground coffee beans, as it is seen by most people. In reality, coffee is a complex antioxidant bomb, containing high amounts of polyphenolic compounds. Besides giving a boost of energy, it offers benefits regarding the neurological system, cardiovascular system, and also digestive system (and many others). Green coffee, less accepted by the population due to intense body and spicy aftertaste, confers maximum antioxidant activities and better absorption. Roasted coffee, on the other hand, is a well-liked beverage, appreciated all over the world. The downside is that in the process of roasting the beans, it loses a few of the antioxidant properties, depending on the assortment (Arabica, Robusta, Excelsa and Liberica), origin (country where it has been grown), preparation (brewing, boiling, filtering) also influences the polyphenolic quality and grade of roasting. Besides roasting, coffee can undergo other types of processing such as washing, introduction of carbon dioxide (Anaerobic Processing), natural drying and aerobic fermentation. In coffee, in the highest amount, is encountered chlorogenic acid (CGA). CGAs are abundant in fruit and vegetable species. The most representative sources of CGAs are coffee beans, potatoes, eggplants, and sunflower seeds. They exist displayed as four different isomers, 1-CQA, 3-CQA, 4-CQA, 5-CQA, caffeoylquinic acid. Coffee is considered to be the main source, with the largest amount of CGAs, with concentration being 6–12% [16].

Research shows the most common in coffee beans is 5-CQA, representing 76–84% of the total CGAs, an approximate value of 10 g/100 bg coffee beans, and total CGAs ranging from 1.76–88.0 mg/g. A study was conducted by Huijie Lu et al., where they interpreted the data from two other studies conducted in 1984 and 2008 [16]. Close values were obtained by Joanna Grzelczyk and collaborators, when testing samples of Arabica (C. Arabica, fam. Rubiaceae) and Robusta (C. Canephora, fam. Rubiaceae) on different roasting levels [146]. In a study focusing only on the ways in which roasting affects coffee beans, they also have given the conclusion that roasting level decreases levels of 5-CQAs and other CGAs. This means that CGAs are easily denaturized at high temperatures, the denaturation being directly proportional to the exposure time. Josiane Alessandra Vignoli et al. managed to use the HPLC method to determine the downfall of 5-CQAs, decreasing from 5.96 to 0.22 g/100 g for C. Arabica and from 6.19 to 0.13 g/100 g for C. Canephora [147].

A 2020 study by Vamanu et al. in Bucharest analyzed polyphenol content in brewed coffee, reporting notably low values: 135.07 ± 2.04 µg/mL (0.135 mg/g) for light roast and 56.67 ± 1.32 µg/mL (0.056 mg/g) for dark roast [148]. These values are significantly lower than typical CGA concentrations in brewed coffee, which range from 187.7 to 295.6 mg/100 mL for light roasts and 24.2 to 41.3 mg/100 mL for dark roasts [143]. Considering that 5-CQAs represent 76–84% of total CGAs, their expected content would be approximately 192.8 mg/100 mL (1.92 mg/g) for light roast and 26.2 mg/100 mL (0.26 mg/g) for dark roast [144]. The discrepancy might be attributed to factors such as processing methods, roasting intensity, or coffee bean quality [149,150].

In Table 5, the differences between coffee types and roasting methods can be observed; we highlight that in Robusta coffee, the quantity of 5-CQAs is higher than in Arabica coffee. The difference that appears in roasting, as the level of roasting increases, decreases the CGA content due to loss of carbon–carbon bond between the CGAs caused by heat exposure, a common trait of polyphenols.

Table 5. Content of 5-CQAs found in coffee, ranked by roasting level.

While non-ingested quantity of polyphenol content is satisfactory, in the digestion phase, the situation changes. Bioavailability depends on an amalgam of intrinsic and extrinsic factors, when it is proposed discussion of in vivo digestion and absorption. In vitro, the ideal case of digestion, studies show that in the Gastric phase, concentrations of 5-CQA were low, followed by an increase in the Small Intestine phase, and another decrease in the Colonic phase, according to studies conducted by Joanna Grzelczyk et al. on Caco-2 and HT29 cells, according to roasting levels [146] and another study on digestion of coffee pulp extract conducted by Silvia Cañas and collaborators. These two studies highlight the affinity of phenolic acids for the upper part of the gastrointestinal tract, phenolic acids being characterized of it [146,151]. They are susceptive of fast and effective enterohepatic circulation, peaking at 5 min after administration.

Moreover, they are likely to “experience a rapid permeation system for intact phenolic acids and a slow permeation system for the conjugated derivatives” resulting in “conjugated phenolic acids detected in the portal vein and abdominal artery were derived from metabolism in the liver and/or re-absorption by enterohepatic circulation”, says Konishi et al. in a study conducted on rats in 2006 [152].

The study conducted by Joanna Grzelczyk et al. showed information on decreasing/increasing levels of 5-CQAs in different stages of digestion on different coffee types at various levels of roasting. Robusta green coffee managed to reach 8.24 ± 0.02 g/100 g 5-CQA in the Intestinal phase, while Arabica Green, the daughter of Robusta coffee, only had 2.61 ± 0.02 g/100 g 5-CQA concentration. Higher levels in all coffee types were observed at the Colonic phase, with probiotic cultures after 10 h, with a mean of 8.7 g/100 g 5-CQA. Light and dark roast concentrations decrease in all phases for both types, due to processing (roasting). An exception is the Colonic phase where it increases [146], probably because of the interaction with the gut microbiota. Joanna Grzelczyk et al. and Silvia Cañas et al. showed the same conclusion: the highest level of absorption is at the Intestinal phase [146,151]. In the case of phenolic acids, studies show that chlorogenic acids can pass through the stomach in intact form, reaching the small intestine where they undergo passive diffusion, reach the portal vein, and are further subjected to phase II conjugation [153,154] mediated by LPH by glucuronidation by UDP glucuronosyltransferase (UGT) and sulfidation by sulfotransferases (SULTs) [155]. Also, in the small intestine, CGAs with enzymatic catalysis of estrearase enzyme go through a transformation and their molecular weight lowers, thus being able to reach the liver. Transformation of CGA to caffeic acid must be transformed by colonic bacteria to m-coumaric acid and phenylpropionic derivative [153]. The Colonic phase enterprises other transformations: absorption or further metabolization, by reduction, demethylation, dihydroxylation, isomerization, and many more. Moreover, a study from 2015 by Adriana Farah and Giselle Duarte supports the statement that 90% of CGAs from coffee can be absorbed in their free form by gastrointestinal mucosa [155], due to lipophilic character, meaning that only 10% of CGAs undergo colonic phase.

In a study for quantification of tissue distribution and pharmacokinetics of CGAs focused on rodents, Yulu Zhou et al. showed that 5-O-caffeoylquinic acid had a rapid metabolization due to not being detected in organs after 4 h. This study also managed to indicate affinity for well-perfused organs, thus the benefits of a good operating system [156]. Excretion of chlorogenic acids can lead up to 48 h via renal pathway [157], CGAs being susceptible that they are highly implicated in the enterohepatic cycle (Figure 8).

Figure 8. Representation of the circuit of CGAs in the GI tract. (SP—Stomach phase; IP—Intestinal phase; CP—Colonic phase).

4.2. Onion—Genus Allium

Most often than not, the onion is an item in the cupboard that tends to be looked down upon. Its composition proves otherwise: it is an extremely powerful one, being filled with antioxidants that fight free radicals that form in our body for different environmental influences, lifestyle choices, or diseases.

The Allium genus contains over 700 species, making it the largest existing category of plants [158]. It includes species such as: A. cepa (onion), A. ascalonicum (shallot), A. sativum (garlic), A. schoenoprasum L. (chives), A. chinense (scallion), A. neapolitanum (white garlic), and A. moly (lily leek). The focus in the following paragraphs are three species of the Allium genera, Allium schoenoprasum—chives, which are considered to have the strongest antioxidant power—followed by Allium cepa—red onion—and then Allium cepa L.—yellow onion [159].

Chives are plants that originated in cold regions of Europe and Asia; making an analogy to the known fact that polyphenol accumulation is linked to stress factors that are exerted on the plant, it can be a plausible reason for its highest antioxidant capacity. Chives are characterized by their thin and long leaves, with a purple inflorescence. In older times, chives were used as medicine to treat different problems like anemia, high blood pressure, act as a digestive aid, and flu treatments [159,160].

It is important to mention the existence of Sulphur compounds, as they are responsible for some biological activity of Allium schoenoprasum; for example, enrichment of volatile compounds. Marianna Lenkovà et al. studied the total polyphenol content (TPC) using Folin–Ciocalteu reagent and measured the Antioxidant Activity (AOA) using DPPH (2.2-diphenyl-1-picrylhydrazyl), and then, they used spectrophotometry UV/VIS at 1240–515.6 nm. The results show that the higher the number of polyphenols, the higher the antioxidant activity. Chives ranged at 1591 ± 10.89 mg∗kg−1∗kg−1 TPC and 76.57 ± 0.67% AOA [159]. Quercetin and kaempferol are two of the most important flavonoids found in the Allium family. In chives, average concentration of quercetin is at 10.4 mg/100 g fresh product, and kaempferol 12.5 g/100 g fresh product, as presented in a review conducted by Wijdan M. Dabeek and Melissa Ventura Marr in 2019 [161].

Red onions are a great source of phytochemicals that aid in human health, being anti-inflammatory, anti-obesity, antifungal, anticancerogenic, and antidiabetic. They are mostly rich in quercetin, but they are also a source of anthocyanins, giving them different nuances of red, unlike yellow onions. Yellow onions have the same benefits, to some extent, but it has been proven that red onions’ TPC and AOA are higher. In a study comparing two types of red onions, it was proven that the Sweet Italian red onion subclass had a higher level of sugar, therefore a good development of phenolic content, as we discussed about the ripening (higher sugar levels) affecting the levels of phenolic content. Rita Metrani et al. discovered, using ABTS with analysis of antioxidant activity by the power to scavenge free radicals on hydrophobic and hydrophilic constituents, that Sweet Italian had a higher AOA, while with DPPH (applicable to hydrophobic compounds) Honeysuckle had a higher activity. TPC was higher in Honeysuckle, with a possible reason that Sweet Italian had passed the certain maturity stage of maximum phenol content [162]. Marianna Lenkovà et al. reported phenolic content for the red onion variety Red Mate at 1313 ± 29.74 mg∗kg−1∗kg−1 and AOA 40.58 ± 1.157%, while for the yellow onion type Sherpa, it reached 935.2 ± 9.23 mg∗kg−1∗kg−1 and AOA 21.09 ± 2.418% [159].

In a study conducted by Jihun Lee and Alyson E. Mitchell comparing different varieties of onions, the main view upon them is comparing different layers and quercetin derivates and aglycone, measured in mg/100 g dry weight (DW). After analysis of the data provided by the study, the conclusion that the predominant quercetin-derived compound is the glycoside quercetin 4′-O-glucoside. In all four onions studied, it appears that high concentrations of the glucoside are found in the first and paper (skin) layer. Astounding results were achieved by the Chief variety, with 2392 ± 79 mg/100 g DW in the first layer and 1612 ± 18.5 mg/100 g DW. Satisfying results were presented for the Cowboy and Denali varieties, reaching up to 706 ± 3 mg/100 g DW in the skin, and 688 ± 11 mg/100 g DW in the first layer. Aglycones of quercetin were found in the skin for the most part, the Chief variety acquiring 423 ± 7 mg/100 g DW, while the Denali variety 326 ± 2 mg/100 g DW; Sequoia (that achieved concentrations of quercetin 3,4′-O-diglucoside higher comparing to quercetin 4′-O-glucoside) reached an aglycone concentration of 289 ± 6 mg/100 g DW. In the Denali and Cowboy varieties, aglycone concentrations were not determined [163].

These results conclude and complete the theory that environmental factors have an impact on the development of polyphenolic compounds—in this case, quercetin—with influences such as plant genetics, soil nutrients, temperature (in growth time but also storage temperature), and nitrogen concentration, according to a review conducted by Khalid Mahmud Khokhar [164]. In analogy, these factors can potentially be some of the reasons for the accumulation of phenolic content in the plants. Given that the predominant compound is quercetin, the next paragraphs explain the metabolism of quercetin.

Quercetin is hardly absorbed in the stomach, therefore transported, and primarily absorbed in the small intestine. Bondage of sugars must be removed before absorption of the quercetin aglycon. For glycosylation, LPH of the brush border removes the glucose attached, transporting it into the colon where it will undergo hydrolysis under bacteria’s action, either being completely hydrolyzed before absorption, or priorly transformed into aglycone before entering the large intestine and be absorbed by it, given the phospholipid bilayer of cellular membranes, or be transformed into aglycone by bacteria. These transformations depend on the type of sugar unit that is linked to the aglycone (Figure 9) [100]. In a study using Caco-2 cells, researchers showed that quercetin glucosides pass through the epithelial membrane easier than the aglycone, driven by the LPH, β-glucosidase hydrolysis, sodium-dependent glucose transporter1(SGLT-1) and their carbohydrate-opposing abilities to utilize the saccharides and transform them into aglycones [165]. Quercetin is degraded by gut microbiota (e.g., Streptococcus spp., Lactobacillus spp., Pediococcus spp., Bifidobacterium spp.) into phenolic acids [166].

Figure 9. Representation of quercetin absorption.

In the intestinal lumen, they will be conjugated by glucuronidation by UDP glucuronosyltransferase (UGT), sulfidation by sulfotransferases (SULTs), and/or methylation by catechol-O-methyl transferase (COMT) present in intestinal and hepatic cells and further entering circulation. Galindo et al., in 2012, and Menendez et al., in 2011, claimed that quercetin glucuronides are more stable as phase II conjugates, but they might suffer deconjugation in vascular smooth muscle cells [167,168]. UGT-mediated glucuronidation and metabolism in the livers’ hepatocyte cells has been underlined. After passing diffusion through the portal vein, they pass through the sinusoidal membrane, and, modulated by multidrug resistance-associated protein-2 (MRP-2), arrive in the bile where they can be secreted back into the intestinal lumen [165]. The most common dietary source of quercetin is the O-glycosidic form. It includes quercetin-3-O-rutinoside, quercetin-3-O-glucoside, and quercetin-3,4′-O-diglucoside [161].

Intensive metabolism of quercetin is proved due to low quantities in the urine via the renal pathway; therefore, the amount of quercetin in plasma is quite high (up to 50%), as the two of them are inversely proportional [169].

For quercetin, absorption is relatively high, whilst in a slower rate, elimination half-life being of 25 h [170], the average terminal half-life (the necessary time to divide the plasma concentration by two, after the achievement of stability [171]) of quercetin is 3.5 h [172].

5. Methods of Improving the Bioavailability of Polyphenols

As previously mentioned, the bioavailability of polyphenols is low, and therefore, to enhance the benefits of these phytochemicals, scientists have elaborated a series of techniques for improvement of their bioavailability and delivery systems. With the creation of these delivery systems for polyphenols, their bioavailability increases, as well as their absorption in the GI tract and their organ-targeted action. Bio-based macromolecules are characterized for their affinity for molecules with a high number of hydroxyl groups, like polyphenols. The combination of these two results in increased stability and bioavailable material. Interaction with macromolecules causes the formation of these delivery systems in different ways, forming emulsions, nanoparticles, microcapsules, or liposomes [173]. Encapsulations can be emulsion-based systems or nanoparticle-based systems. Characteristic to each system is its loading capacity, encapsulation efficiency, particle size, and zeta potential. Emulsion-based systems require high-speed homogenization, ultrasonic emulsification, or other stabilizing technologies for achieving a proper desired emulsion. Liposomes can be used because of their capacity for self-assembly, modification acceptability, and compatibility [174]. Liposomes are defined as self-assembled amphiphilic spherical vesicles with at least one phospholipid bilayer, similar to the cell membrane, that is designed to separate the internal/external aqueous phase [119]. The preparation of these systems provides increased Aa activity after digestion after stimulation with intestinal fluid in the case of EGCG. In recent studies, modified liposome systems created by incorporation of the xenobiotics on the liposome surface improved the stability of the liposomes, increased the release control, and had a higher encapsulation efficiency of the tea polyphenols [174]. The importance of this method is highlighted by Minneli et al., with a success rate for encapsulation efficiency of 100% after incorporation of EGCG with Polaxomer-407 (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, and cholesteryl hemisuccinate). Furthermore, magnesium salt was used for maximizing EGCG internalization, obtaining in the end result a multilamellar structure through analysis with X-ray diffraction [175]. Nanoemulsions usually present themselves as a system containing an aqueous phase, oil phase, and stabilizers. They present the benefit of having a higher thermodynamic stability compared to the other emulsion types. Studies show that using hydrogel combined with water in oil emulsion increases the emulsion stability with increasing either the emulsifier used or the hydrogel, while the hydrogel shows importance in retaining the polyphenols during storing. Using oil in water emulsions is also possible, but due to the polar nature of some polyphenols (such as tea polyphenols), this process can be challenging. Pickering emulsions are stabilized by particles from protein or starch from the food matrix. They form very strong bonds between the molecule of protein/starch and the compound of interest, making it hard for them to get detached [174]. They are recognized for their high internal phase that helps them have a higher loading for polyphenols. Nonetheless, these types of emulsions can be used stabilizer-free due to the character of the bounding molecule. These systems present high ionic strength and stability against pH changes, with sizes larger than the other emulsion types, up to micron array [174,176]. Nanoparticle-based systems are made of biodegradable polymers in which polyphenols are entrapped in a particle matrix. Techniques used include spray drying, extrusion, crosslinking reactions, electrospinning, and layer-by-layer self-assembly. The nature of the polymers can be protein/carbohydrate/by-polymer-based. Protein-based systems are a good alternative thanks to their emulsification, gelatinization, and binding properties [174,177]. Milk proteins are a promising alternative, providing the formation of a complex and stable end product. EGCG-loaded casein systems have shown efficacy for their nano-structure as well as anticancer ability. Carbohydrate-based systems are biodegradable and biocompatible, forming complexes with polyphenols through non-covalent bonds, hydrogen binding, and weak ionic interactions. Starch is widely studied for its capacity for binding and forming complexes with different polyphenols. Apart from starch, alginate, inulin, cyclodextrin, and maltodextrin are other carbohydrate matrixes used in fabricating these carb-based nano-emulsions [174]. Last but not least, bi-polymeric systems are a combination of protein/peptide and polysaccharide that lead to electrostatic complexes through self-assembly. The advantages of these types of delivery systems are high encapsulation efficiency, high loading capacity, and a probable controlled release from the system [178]. They can be formed through non-covalent and covalent bonds, although a covalent bond between the protein and polysaccharide is preferred as it is demonstrated to be more stable in different environment changes and has a slower release. Covalent bonds can be obtained with chemical crosslinking agents or through Maillard reaction [174].

6. Toxicity of Polyphenols

Toxicity assessment of any compound advised as a treatment or adjuvant of treatment directed for human consumption is essential due to possible unwanted outcomes. The testing of compounds is required for the development of drugs and usually is achieved by testing the activity in vitro on living cells. The requirements include metabolic activity of the cells, morphology, cell growth/proliferation, or mechanisms implicated in death of the cells. Most indicated for cytotoxicity examination are human primary hepatocytes and HepG2 cell lines that provide the closest alternative to the in vivo models of the human liver. Magdalena Boncler et al. eval‎uated the toxicity of different polyphenols on cell cultures (HepG2, Caco-2, A549, and 3T3) using high-content screening assay. They observed that in regard to mitochondrial activity, kaempferol and four extracts of buckthorn bark, walnut husk, hollyhock flower, and silverweed herb were the most cytotoxic. The silverweed herb was one of the most toxic especially in Caco-2 cells. Membrane integrity cytotoxic activity was notably for kaempferol. In the case of nuclear area, resveratrol and kaempferol are the most concerning, in all cell lines. Omnivir R represented the most toxic compound in the nuclear area in case of HepG2 human hepatocytes. In Caco-2 cells, in comparison, Omnivir R was one of the least toxic, as well as in A549 epithelial cells. For A549 cells, Ominivir R was least toxic only in the nuclear area assay, proving information about a risk in the membrane integrity and mitochondrial membrane potential. High toxicity in these cells was represented by resveratrol and walnut husk extract. In 3T3 mouse fibroblasts, kaempferol and resveratrol possessed the highest toxicity activity in the nuclear area test. Oak bark was remarked with a high activity in all three tests [179]. Polyphenols’ capacity to chelate transition metal’s ions can be an incredible downside for people suffering with iron deficiency, as the xerobiotic can bind to iron in the intestine, thus making it impossible for Fe to be absorbed. Another effect of this interaction could lead to the dysregulation of iron homeostasis. Tea polyphenol, (-)-epigallocatechin-3-gallate, was found to be responsible for the decrease in transepithelial iron transport in Caco-2 intestinal cells. Proposed trajectory for the iron is the basolateral exit via ferroportin, which is affected by the complex formed with the polyphenol, making it unable to transport [180]. In the case of quercetin, it was observed that the complex compound formed with iron was not in the size range to be able to exit via ferropotin, and also, that the decrease in iron in Caco-2 cells was linked to a decrease in ferroportin protein and mRNA, as a mediator being miRNA with 3′UTR of ferroportin mRNA [181]. It is possible that the iron–quercetin compound formed to be retained in the enterocyte cytosol leads to iron deficiency, and is known to have an impact on the ferritin decrease. The ability of polyphenols to form complexes with proteins impairs an issue when it comes to digestive enzymes, as it could affect their normal functioning and assimilating of different food nutrients. People with food intolerances, like gluten/lactose intolerance, celiac disease exocrine pancreatic insufficiency, and complex carbohydrate intolerance, have a deficit in enzymes needed to metabolize certain food groups. Even though it is recommended for patients suffering with food intolerances to conduct a healthy lifestyle, certain polyphenols naturally found in plants (like condensed tannins, which are known to inhibit enzymes α-amylase, α-glycosidase, pepsin, trypsin, lipase, and chymotrypsin) could present an issue. Another factor to be considered is the polyphenols’ ability to stimulate and inhibit certain strains of bacteria in the microbiota. Changing the ratio in favor of non-beneficial bacteria creates dysbiosis in the gut, creating an imbalance. Dysbiosis is tightly linked to different diseases such as irritable bowel syndrome (IBS), functional dyspepsia, metabolic disorders (diabetes, obesity), inflammatory bowel diseases, colorectal cancer, and intestinal bacterial overgrowth (SIBO) [180].

6. 폴리페놀의 독성

인간의 섭취를 목적으로 하는 치료 또는 보조 치료제로 권장되는 모든 화합물의 독성 평가는 원치 않는 결과가 발생할 수 있기 때문에 필수적입니다. 화합물의 테스트는 약물의 개발을 위해 필요하며, 일반적으로 살아있는 세포에 대한 시험관 내 활성을 테스트함으로써 이루어집니다. 요구 사항에는 세포의 대사 활동, 형태, 세포 성장/증식 또는 세포의 죽음과 관련된 메커니즘이 포함됩니다. 세포 독성 검사에 가장 많이 사용되는 것은 인간 간세포와 HepG2 세포주인데, 이 세포주는 인간 간을 모델로 한 생체 내 모델에 가장 근접한 대체물을 제공합니다. Magdalena Boncler 외.는 고함량 스크리닝 분석을 사용하여 세포 배양(HepG2, Caco-2, A549, 3T3)에 대한 다양한 폴리페놀의 독성을 평가했습니다. 그들은 미토콘드리아 활동과 관련하여, 캠퍼롤과 4가지 추출물(갈매나무 껍질, 호두 껍질, 도라지 꽃, 쇠비름)이 가장 세포 독성이 있는 것으로 나타났습니다. 쇠비름은 특히 Caco-2 세포에서 가장 독성이 강한 것으로 나타났습니다. 세포막 무결성 세포 독성 활동은 특히 캠퍼롤에 대한 것이었습니다. 핵 영역의 경우, 레스베라트롤과 캠퍼롤이 모든 세포주에서 가장 우려되는 것으로 나타났습니다. Omnivir R은 HepG2 인간 간세포의 경우 핵 영역에서 가장 독성이 강한 화합물을 나타냈습니다. 이에 비해 Caco-2 세포에서 Omnivir R은 A549 상피 세포뿐만 아니라 독성이 가장 낮은 화합물 중 하나였습니다. A549 세포의 경우, Ominivir R은 핵 영역 분석에서만 독성이 가장 낮았으며, 이는 세포막의 완전성과 미토콘드리아 막 잠재력에 대한 위험을 입증하는 정보입니다. 이 세포에서 높은 독성은 레스베라트롤과 호두 껍질 추출물로 나타났습니다. 3T3 마우스 섬유 아세포에서, 캄페롤과 레스베라트롤은 핵 영역 테스트에서 가장 높은 독성 활성을 나타냈습니다. 참나무 껍질은 세 가지 테스트에서 모두 높은 활성을 보였습니다 [179]. 폴리페놀의 전이 금속 이온 킬레이트화 능력은 철분 결핍으로 고통받는 사람들에게 놀라운 단점이 될 수 있습니다. 왜냐하면, 폴리페놀은 장에서 철분과 결합하여 철분의 흡수를 불가능하게 만들기 때문입니다. 이러한 상호작용의 또 다른 효과는 철분 항상성의 조절 장애로 이어질 수 있습니다. 차 폴리페놀인 (-)-에피갈로카테킨 갈레이트가 Caco-2 장 세포의 상피 철분 수송 감소의 원인으로 밝혀졌습니다. 철분의 이동 경로는 페로포르틴을 통한 기저측 출구로 알려져 있는데, 폴리페놀과 결합된 복합체의 영향을 받아 페로포르틴이 철분을 수송할 수 없게 됩니다 [180]. 케르세틴의 경우, 철과 함께 형성된 복합 화합물이 페로포틴을 통해 빠져나갈 수 있는 크기 범위에 있지 않다는 것이 관찰되었고, 또한 Caco-2 세포에서 철의 감소가 페로포틴 단백질과 mRNA의 감소와 관련이 있다는 것이 밝혀졌습니다. 이는 페로포틴 mRNA의 3′UTR에 miRNA가 매개체로서 관여하기 때문입니다 [181]. 장세포의 세포질에 형성된 철-케르세틴 화합물이 철분 결핍을 유발할 수 있으며, 페리틴 감소에 영향을 미치는 것으로 알려져 있습니다. 폴리페놀이 단백질과 복합체를 형성하는 능력은 소화 효소에 문제가 생길 수 있습니다. 정상적인 기능과 다양한 식품 영양소의 동화에 영향을 미칠 수 있기 때문입니다. 글루텐/락토스 불내증, 셀리악병, 외분비 췌장 기능 부전, 복합 탄수화물 불내증과 같은 음식 불내증이 있는 사람들은 특정 식품군을 대사하는 데 필요한 효소가 부족합니다. 음식 과민증을 앓고 있는 환자에게는 건강한 생활 방식을 권장하지만, 식물에서 자연적으로 발견되는 특정 폴리페놀(효소 α-아밀라제, α-글리코시다아제, 펩신, 트립신, 리파제, 키모트립신을 억제하는 것으로 알려진 응축 탄닌 등)은 문제가 될 수 있습니다. 고려해야 할 또 다른 요소는 폴리페놀이 미생물 군집의 특정 세균을 자극하고 억제하는 능력입니다. 유익균의 비율을 높이는 대신 비유익균의 비율을 높이면 장내 미생물 불균형이 발생하여 장내 환경이 불균형해집니다. 장내 미생물 불균형은 과민성 대장 증후군(IBS), 기능성 소화 불량, 대사 장애(당뇨병, 비만), 염증성 장 질환, 대장암, 과다 장내 세균 증식(SIBO) 등 다양한 질병과 밀접한 관련이 있습니다 [180].

7. Conclusions

The purpose of this study is to underline the remarkable properties of polyphenols, while also focusing on their bioavailability, as it is crucial for exerting their benefits on humans. Throughout the years, consumers have been looking for sustainable and natural medicine or treatments for diseases and thanks to the evolution of biotechnology, now they can choose from a variety of alternatives to treat or ameliorate their symptoms, conducting to a better health. Polyphenols are secondary metabolites of plants, formed in times of defense against different environmental and/or genetic factors. Hundreds of years were needed to quantify and classify them and to determine their contribution to well-being. As for their bioavailability, it is certain from the research conducted that polyphenols are quickly absorbed and assimilated, a reason for their low oral bioavailability. Most of the polyphenols are not absorbed in their free form; nevertheless, the benefits of consumption still exist, being transformed and converted into metabolites that reach the liver, kidneys, and other organs in the body, exerting different actions like antioxidant (scavenging ROS), antimicrobial, and anticancerogenic. The scavenging of ROS is incredibly important since most chronic diseases and metabolic dysbiosis are linked to oxidative stress and inflammation. Their action has also been linked to the gut–brain axis by reducing the gut microbiota imbalance, improving the neurological health of the host. Discussing elimination, it depends on their circulation, implication in the enterohepatic cycle, metabolization by microbiota, and many other unknown factors implicated in digestion that are hard to put a pin into due to the complexity of the process.

Author Contributions

Conceptualization, writing—review and editing Z.M.D., A.S. and L.L.; writing—original draft preparation, D.C. and A.C.; funding acquisition Z.M.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Romanian National Authority for Scientific Research (UEFISCDI) Grant Number PN-III-P1-1.1-TE-2021-1585.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

PA	Phenolic acids
HBA	Hydroxybenzoic acid
HCA	Hydroxycinnamic acid
CQA	Caffeoylquinic acid
SDG	Secoisolariciresinol diglucoside
ED	Enterodiol
EL	Entrolactone
CGA	Chlorogenic acid
IUPAC	International Union of Pure and Applied Chemistry
LDL	Low-density lipoprotein
Sir2	Silent information regulator 2
CVD	Cardiovascular diseases
BP	Blood pressure
GABA	γ-aminobutyric acid
ROS	Reactive oxygen species
NLR	Neutrophil to lymphocyte ratio
NADPH	Nicotinamide-adenine dinucleotide phosphate
NOD	Nucleotide oligomerization domain
NF-ĸB	Nuclear factor kappa-light-chain-enhancer of activated B cells
GI	Gastrointestinal
IPEC	Intestinal porcine enterocyte cell line
LPH	Lactase phlorizin hydrolase
CBG	Cytosolic β-glucosidase
Caco2	Immortalized cell line of human colorectal adenocarcinoma cells
HT29	Human colorectal adenocarcinoma cell line with epithelial morphology
UGT	UDP glucuronosyltransferase
SULTs	Sulfotransferases
COMT	Catechol-O-methyl transferase
AOA	Antioxidant Activity
TPC	Total polyphenol content
DW	Dry weight
MRP-2	Multidrug resistance-associated protein-2

References