폴리페놀(플라보노이드)- 항산화, 항염증, 항암효과 - 카테킨, 레스베라트롤, 케르세틴, 이소플라본, 안토시아닌!!

[문형철]

미량원소의 치유세계

beyond reason

자연이 우리에게 준 선물 'phytochemicals' - 파이토케미칼

파이토케미칼 안에는 인류가 아직 알지 못하는 수많은 질병치유성분이 들어있다.

폴리페놀이외에도 카로테노이드(carotenoid), 이노시톨(inositol), 리그난(lignan), 인돌(indole), 테르펜(terpene) 등 다양한 파이토케미칼이 존재

폴리페놀(polyphenol)은 식물에서 발견되는 화학성분 중 하나. 

- 탄닌(Tannin)과 플라보노이드로 크게 분류

참고) 탄닌

Review Article

Recent Advances in Anticancer Activities and Drug Delivery Systems of Tannins

Yuee Cai 

 

Jinming Zhang 

 

Nelson G. Chen 

 

Zhi Shi 

 

Jiange Qiu 

 

Chengwei He 

 

Meiwan Chen

First published: 22 December 2016

 

https://doi.org/10.1002/med.21422

Citations: 34

Abstract

Tannins, polyphenols in medicinal plants, have been divided into two groups of hydrolysable and condensed tannins, including gallotannins, ellagitannins, and (–)‐epigallocatechin‐3‐gallate (EGCG). Potent anticancer activities have been observed in tannins (especially EGCG) with multiple mechanisms, such as apoptosis, cell cycle arrest, and inhibition of invasion and metastases. Furthermore, the combinational effects of tannins and anticancer drugs have been demonstrated in this review, including chemoprotective, chemosensitive, and antagonizing effects accompanying with anticancer effect. However, the applications of tannins have been hindered due to their poor liposolubility, low bioavailability, off‐taste, and shorter half‐life time in human body, such as EGCG, gallic acid, and ellagic acid. To tackle these obstacles, novel drug delivery systems have been employed to deliver tannins with the aim of improving their applications, such as gelatin nanoparticles, micelles, nanogold, liposomes, and so on. In this review, the chemical characteristics, anticancer properties, and drug delivery systems of tannins were discussed with an attempt to provide a systemic reference to promote the development of tannins as anticancer agents.

아래 그림처럼 폴리페놀 5가지로 분류할 수 있음.

1) lignans - 아마씨에 풍부한 폴리페놀

2) phenolic acids(페놀산) - 사람의 소변에도 존재함. 

3) 플라보노이드 - anthocyanidins , flavanones, flavonols, flavones, isoflavones, flavanols(카테킨, 안토시아닌)

4) Ellagic acid(엘라그산) - 많은 과일, 야채에 존재하는 천연 phenol antioxidant

5) stilbenes

지구상에는 4000여종의 플라보노이드가 있는데 안토시아닌, 카테킨, 플라보논, 플라본, 이소플라본 등이 대표적이다. 플라보노이드는 “강력한 항산화 효과”를 가지고 있다

Phenolic acids or phenolcarboxylic acids are types of aromatic acid compound. Included in that class are substances containing a phenolic ring and an organic carboxylic acid function (C6-C1 skeleton). Two important naturally occurring types of phenolic acids are hydroxybenzoic acids and hydroxycinnamic acids, which are derived from non-phenolic molecules of benzoic and cinnamic acid, respectively. Phenolic acids can be found in many plant species. Their content in dried fruits can be high. Natural phenols in horse grams (Macrotyloma uniflorum) are mostly phenolic acids, namely 3,4-dihydroxy benzoic, p-hydroxy benzoic, vanillic, caffeic, p-coumaric, ferulic, syringic, and sinapinic acids. Phenolic acids can be found in mushroom Basidiomycetes species.^[2] It is also a part of the humic substances, which are the major organic constituents of soil humus. Many phenolic acids can be found in human urine

- 폴리페놀은 식물에서 발견되는 파이토케미칼

- 페놀은 벤젠의 수소원자 하나가 히드록시기로 치환된 것

- 폴리페놀은 두개이상 수소원자가 히드록시기로 치환된 것. 

- 녹차의 카테킨, 포도주의 레스베트롤, 양파의 퀘르세틴은 폴리페놀의 종류

- 과일의 플라보노이드와 콩의 이소플라본도 폴리페놀의 일종

폴리페놀(polyphenol)은 식물에서 발견되는 화학물질의 일종으로서 분자 하나에 페놀 그룹이 두 개 이상 있는 것이 특징이다. 폴리페놀은 일반적으로 타닌, 페닐프로파노이드 (플라보노이드, 리그린 등)으로 분류된다. 페놀은 벤젠의 수소원자 하나가 히드록시기로 치환된 것이며, 폴리페놀은 두 개 이상의 히드록시기로 치환된 것이다. 폴리페놀의 종류는 수천 가지가 넘는데 녹차에 든 카테킨, 포도주의 레스베라트롤, 사과.양파의 쿼세틴 등이 있다. 과일에 많은 플라보노이드와 콩에 많은 이소플라본도 폴리페놀의 일종이다.

폴리페놀은 광합성에 의해 생성된 식물의 색소와 쓴맛의 성분이므로, 포도처럼 색이 선명하고 떫은맛이나 쓴맛이 나는 식품에 많다.

우리 몸에 있는 활성 산소(유해 산소)를 해가 없는 물질로 바꾸어 주는 항산화 효과가 있어 노화를 방지한다. 또한 활성 산소에 노출되어 손상되는 DNA 보호, 세포구성 단백질 및 효소를 보호하는 기능이 뛰어나 다양한 질병에 대한 위험도를 낮춘다고 보고된다. 또한 항암 작용과 함께 심장 질환을 막아주는 것으로 알려져 있다.^[1]

폴리페놀은 주로 과일의 껍질부분에 많이 들어있다. 왜 일까?
인간은 따가운 자외선을 피해 동굴이나 집으로 들어갈 수 있지만 식물은 그 자리에 꿋꿋이 버티면서 자외선에 의해 발생하는 활성산소의 피해를 극복해야 한다. 그러다 보니 햇빛을 직접 받는 열매의 껍질이나 잎사귀에는 강력한 항산화 물질들이 만들어져야 활성산소로 인한 피해를 줄일 수 있다. 뿐만아니라 세균이나 곰팡이가 침투하지 못하게 해야 하고 홍수, 가뭄, 폭염 같은 극한 상황에서도 버텨내야 한다. 식물이 꿋꿋이 버틸 수 있도록 스스로 만들어낸 영양소들이 바로 파이토케미칼(식물영양소)이다.
 
폴리페놀은 수많은 파이토케미칼 중 가장 중요한 부분을 차지한다. 폴리페놀 이외에도 카로테노이드(carotenoid), 이노시톨(inositol), 리그난(lignan), 인돌(indole), 테르펜(terpene) 등 다양한 파이토케미칼이 존재한다.
 
폴리페놀이 인체 내에 들어오면 “강력한 항산화제”로 작용해 세포 DNA와 세포막의 산화를 억제한다. 활성산소에 의한 단백질, 지질의 손상을 막아주고 혈관손상을 보호한다. 또한 암세포의 증식을 억제하며, 발암물질을 불활성화시키고 세포의 변이를 방지해 암을 예방하는 효과를 나타낸다.
 
그런데 폴리페놀에는 비(非)플라보노이드(non-flavonoids)와 플라보노이드(flavonoids) 두 종류가 있다.
 
1) 비플라보노이드
비플라보노이드 폴리페놀 엘라그산(ellagic acid)이 대표적인데 포도, 딸기, 블루베리, 라스베리, 체리, 석류 등에 존재한다. 항산화, 항바이러스, 항돌연변이, 항암기능을 가지고 있으며 유방 및 식도, 피부, 결장, 전립선과 췌장에서의 암세포 활동을 억제하는 역할을 하는 것으로 보고되어 있다.
 
2) 플라보노이드
지구상에는 4000여종의 플라보노이드가 있는데 안토시아닌, 카테킨, 플라보논, 플라본, 이소플라본 등이 대표적이다. 플라보노이드는 “강력한 항산화 효과”를 가지고 있다.
 
예를 들어 레드와인에 풍부한 레스베라트롤은 플라보노이드계 폴리페놀에 속하며 항산화효과를 가지고 있는 파이토케미칼이라 할 수 있다.
 
아싸이베리주스와 깻잎에는 안토시아닌이 풍부하게 들어있는데 이것은 다른 플라보노이드 보다 5배나 강력한 항산화력을 가지고 있다. 특히 들깻잎에는 안토시아닌, 플라본, 플라본배당체 등 안토시아닌계 색소가 다른 식물에 비해 특히 많이 들어있다.
 
연구결과 안토시아닌은 인슐린 분비능력을 개선시키고 인슐린수용체 기능을 좋게 하여 체내 호르몬 작동능력을 향상시킨다. 따라서 렙틴 저항성을 개선시키고 비만치료에도 도움을 줄 수 있다

cereals(시리얼,  곡물류) - barley 보리, millet( 수수), sorghum(사탕수수)에 플라보노이드가 많음. 

legumes(콩과식물) - black gram(검은콩), pigeon peas(완두콩), green gram(녹두)

nuts(견과류) - betel nuts(빈랑), cashew nets(캐슈넛), pecan nuts(피칸)

vegetable(야채) - brussels sprouts(브뤼셀 콩나물), onion(양파), parsley(파슬리)

fruits(과일) - 사과, apricot(살구), blackcurrant(블랙커런트), blueberry, 포도, 오렌지 등

레드와인, 커피 등

플라보노이드(flavonoids)

플라보노이드는 과일과 채소의 향기, 맛, 색깔에 기여하는 폴리페놀균을 지칭함.

음식내 플라보노이드의 주요군은 '산딸기류의 열매, 녹차와 초콜린, 브로콜리, 케일, 부추, 양파, 포도와 사과껍질.

몇종류의 플라보노이드는 항산화작용을 하며 세포의 신호전달에 영향을 미침. 

플라보노이드에 대한 연구는 부족하지만 '신경퇴행성 질환, 당뇨병, 골다공증'을 포함한 만성질환의 예방에 효과가 있을 것으로 추정됨. 

삼성 서울병원의 플라보노이드 - 항산화, 암예방에 효과가 있다고 밝힘

Medicines (Basel). 2018 Sep; 5(3): 93. 

Published online 2018 Aug 25. doi: 10.3390/medicines5030093

PMCID: PMC6165118

PMID: 30149600

Flavonoids and Other Phenolic Compounds from Medicinal Plants for Pharmaceutical and Medical Aspects: An Overview

Duangjai Tungmunnithum,1,2,* Areeya Thongboonyou,1 Apinan Pholboon,1 and  Aujana Yangsabai1

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Abstract

Phenolic compounds as well as flavonoids are well-known as antioxidant and many other important bioactive agents that have long been interested due to their benefits for human health, curing and preventing many diseases. This review attempts to demonstrate an overview of flavonoids and other phenolic compounds as the interesting alternative sources for pharmaceutical and medicinal applications. The examples of these phytochemicals from several medicinal plants are also illustrated, and their potential applications in pharmaceutical and medical aspects, especially for health promoting e.g., antioxidant effects, antibacterial effect, anti-cancer effect, cardioprotective effects, immune system promoting and anti-inflammatory effects, skin protective effect from UV radiation and so forth are highlighted.

- 플라보노이드(폴리페놀)은 잘 알려진 항산화제, 중요한 생화학물질로서 인체의 건강과 많은 질병예방 물질임. 이 논문은 플라보노이드와 페놀화합물의 제약과 의학적용의 관점에 대해서 연구함. 

- 항산화 효과, 항박테리아 효과, 항암효과, 심혈관계 보호효과, 면역력 증진효과, 항염증효과, 피부보효효과 등

Keywords: flavonoid, medicinal and pharmaceutical applications, medicinal plants, phenolics

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1. Introduction

Flavonoids and the other phenolic compounds are commonly known as plant secondary metabolites that hold an aromatic ring bearing at least one hydroxyl groups. More than 8000 phenolic compounds as naturally occurring substances from plants have been reported [1,2]. It is very interesting to note that half of these phenolic compounds are flavonoids presenting as aglycone, glycosides and methylated derivatives [1,2]. These phytochemical substances are presented in nutrients and herbal medicines, both flavonoids and many other phenolic components have been reported on their effective antioxidants, anticancer, antibacteria, cardioprotective agents, anti-inflammation, immune system promoting, skin protection from UV radiation, and interesting candidate for pharmaceutical and medical application [1,3,4,5,6]. Since a few decades ago, the research studies focusing on flavonoids and the other phenolic compounds from medicinal plant species have increased considerably, because of their versatile benefits for human health [1,2,7,8,9,10,11]. Most of the recent reviews focused on one precise aspect of flavonoids or phenolics action on human health.

-8천가지 폴리페놀이 식물에 존재함. 

- 플라보노이드는 항산화, 항암, 항박테리아, 심장보호, 항염증, 면역증진, 피부보호 효과가 있음. 

This work aims to provide an overview of flavonoids and other phenolic phytochems as the potential sources of pharmaceutical and medical applications from the recent published studies as well as some interesting directions for future researches. The key word searches for flavonoids, phenolics, medicinal plant were performed on June, 2018 using Scopus, Google scholar and PubMed. The 351 resulted publications were found and carefully read, in order to find the more recent and non-redundant publications meeting the objective of this work with a few older publications to highlight some necessary points were also used. The 105 selected publications were employed in this review.

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2. Effects of Plant Flavonoids and Other Phenolics on Human Health Promoting, Diseases Curing and Preventing

2.1. Antioxidant Effects

During the production of adenosine triphosphate (ATP) to generate energy for the cells by using oxygen, reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced as the by-products from these cellular redox reaction. At the balance level, ROS and RNS are beneficial compounds for cellular functions and immune responses, but the unbalance concentration of ROS and RNS will lead to oxidative stress which can cause chronic and degenerative disorders [12,13]. 

- ATP를 생산하는 과정에서 활성산소, 반응성산화질소가 생성되고 세포에 산화환원 반응을 일으키.

- ROS와 RNS의 균형은 세포기능과 면역반응에 유용한 역할을 하는데 불균형이 발생하면 산화 스트레스로 작용하여 많은 만성, 퇴행성 질병이 발생함.

The naturally occurring antioxidant molecules have significantly increased in both usages and research studies; many natural antioxidant compounds have been employed in medical and pharmaceutical products as the substitute compounds for artificial antioxidant ones which have suspected to be one of the major causes for carcinogenesis [14]. Medicinal plants have long been reported as a prospective hub of natural antioxidant compounds, particularly plant secondary metabolites i.e., phenolic compounds and flavonoids which are generated by plant to defend itself or to promote the growth under unfavorable conditions. In addition, functional group arrangement, configuration, substitution, the number of hydroxyl groups were also influenced by antioxidant activity of flavonoids, for example radical scavenging activity and/or metal ion chelation ability [15]. Phenolics and flavonoids are commonly known as the largest phytochemical molecules with antioxidant properties from plants [5,9,10,16,17,18,19].

- 많은 식물은 자연의 항산화물질의 허브이고 그중 폴리페놀과 플라보노이드는 ...

Oki and his team examined antioxidant activity of anthocyanins and other phenolic compounds from various cultivars of purple-fleshed sweet potato (Ipomoea batatas (L.) Lam.), an edible and economic medicinal species in Japan by diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity; the obtained results showed the positive correlation between phenolic content and the activity of free-radical scavenging. In addition, chlorogenic acid was the phenolic compounds that acted as dominant DPPH radical-scavenger in “Miyanou-36” and “Bise” cultivars of I. batatas, whereas anthocyanins were the dominant DPPH radical-scavengers of “Ayamurasaki” and “Kyushu-132” cultivars [11]. Bauhinia variegata L., a medicinal plant that was used in traditional medicine in Pakistan, India and other Asian countries, was studied by Mishra and his group. The researchers found that leaf extracts of B. variegatecontained flavonoid compounds, and presented antioxidant properties against oxidative damage by radical neutralization, iron binding and reducing power abilities [17]. The antioxidant activity and phytochemical characterization of young and adult cladodes, peel of the fruit and pulp of the fruits from six Spanish Mediterranean cultivars of Opuntia ficus-indica (L.) Mill. were analyzed by Andreu and his team. This research team discovered that the significant levels of total phenolic compounds in the best antioxidant cultivar played a significant role against oxidative stress [5]. The antioxidant property and bioactive compounds from the fruits of Aesculus indica (Wall. ex Cambess.) Hook, a medicinal plant from temperate regions of Asia i.e., Pakistan, Nepal, India and Afghanistan, were analyzed by the research group of Zahoor; their results indicated that 2-hydroxy-2-phenyle acetic acid (mandelic acid) and 2-(3,4-dihydroxy phenyl)-3,5,7-trihydroxy-4H-Chromen-4-one (quercetin) were the major bioactive molecules with significant antioxidant property to decrease oxidative stress caused by ROS [19]. Furthermore, the rhizomes extracts of Polygonatum verticillatum (L.) All., an Indian medicinal plant, were also exhibited antioxidant activity which is associated with the level of phenolic composition [20]. The research group of Meng eval‎uated the biological activity and phytochemical profiling from the leaves extract of Camellia fangchengensis S. Ye Liang and Y.C. Zhong, a wild tea species which local people have been used for green tea or black tea production, that is an endemic tea species in Guangxi province, Republic of China. The acquired results proved that flavan-3-ol oligomers and monomers were the potent antioxidant compounds and abundantly found in this species [6].

Besides the angiosperms or flowering plants, the antioxidant property of phenolic compounds was also reported in gymnosperms, the necked-seed plants. Ustun and his research group studied twig and needle extracts and essential oils of the 5 Turkish Pinus species such as P. brutia Tenore (Turkish pine), P. pineaL. (stone pine or umbrella pine), P. halepensis Miller (Aleppo pine), P. sylvestris L. (Scots pine) and P. nigra J.F. Arnold (European black pine), as well as pycnogenol which is the bark extract from P. pinaster,in order to investigate their phytochemical compounds and antioxidant activities by using DPPH and N,N-dimethyl-p-phenylendiamine (DMPD) radical scavenging, ferric-reducing antioxidant power (FRAP), and metal-chelating assays. Their results indicated that pycnogenol had the richest total phenol content, and revealed effective antioxidant effects [21]. Likewise, Apetrei and his collaborators conducted their study on phytochemical compounds and biological activity of Pinus cembra L., a native species of Central European Alps and the Carpathian mountains; they discovered that hydromethanolic extract from bark provided higher concentration of total phenolics and flavonoids than that of needle extract. Additionally, the bark extract showed better ability as free radical scavenger [22].

2.2. Antibacterial Effect

Interestingly, there are a large number of flavonoids and phenolics which exhibit antibacterial effect; such those compounds can be widely found in non-flowering medicinal plants to the flowering ones. The fern(고사리), Aspleniumnidus nidus L., contained gliricidin 7-O-hexoside and quercetin-7-O-rutinoside that can fight against the 3 pathogens e.g., Proteus mirabilis Hauser, Proteus vulgaris Hauser and Pseudomonas aeruginosa (Schroeter) Migula [23]. Moreover, flavonoid and phenolic compounds are synthesized by various plant groups including many medicinal plant species that are employed in traditional medicine or dietary consumption. 

-  흥미롭게도 플라보노이드와 폴리페놀은 항박테리아 효과가 있음.

- 고사리(fern)는 gliricidin 7-O-hexoside and quercetin-7-O-rutinoside 를 함유하여 박테리아에 대항함. 

An obvious example is nutmeg or Myristica fragrans Houtt.; this plant is mostly used traditionally as flavoring agent in Indonesia and other countries in South East Asia [24,25]. However, ethanolic extract of the nutmeg seed which contained 3′,4′,7-trihydroxyflavone showed effective potential against MDR gram-negative bacteria e.g., Providencia stuartii Ewing and Escherichia coli (Migula) Castellani and Chalmers. [25]. Similarly, Pseudarthria hookeri Wight and Arn which has been used as traditional herbal medicine in Africa [26,27] for the treatment of pneumonia, abdominal pains, cough and diarrhea. According to the antibacterial study of this medicinal species, Dzoyem and his team found that flavonoids from this plant showed the highest antibacterial effect against both gram-positive and gram-negative bacteria e.g., E. coli, Klebsiella pneumonia (Schroeter) Trevisan, Pseudomonas aeruginosa(Schroeter) Migula, Enterococcus faecalis (Andrew and Horder) Schleifer and Kilpper-Blazand, and Staphylococcus aureus Rosenbach; the highest antibacterial activities found in pseudarflavone A and 6-prenylpinocembrin [27]. In addition, Rajarathinam and his group found that Pseudomonas aeruginosa(Schroeter) Migula, an important resistant strain that caused many problems in medical treatment can be eliminated by 2-(3′,4′ dihydroxy-phenyl) 3,5,7-trihydroxy-chromen-4-one from the aerial part extract of Trianthema decandra L.; this phytochemical compound showed antibacterial activity against this pathogen comparing to chloremphenical, an antibiotic [28]. Flavonoids and other phenolics have also been reported as antibacterial agent against P. acnes which are the major cause of skin acne problems. Kaempferol that isolated from the Impatiens balsamina L. exhibited potential activity to inhibit the growth of P. acnes; its combination with clindamycin and quercetin combined with clindamycin were reported as a better synergic effects [29]. Moreover, flavones which were isolated from the root of Scutellaria baicalensis Georgi were proved as potential antibacterial agents against P. acnes-induced skin inflammation both in vitro and in vivo models [30]. The study of Hsieh and his team focused on strictinin, the main phenolic compound isolated from the leaves of Camellia sinensis var. assamica (J.W. Mast.) Kitam which is a raw plant material of Pu’er teas. They discovered that strictinin was a good candidate for antibacterial molecule against this bacteria [31]. Phenolics from kernel extract of Mangifera indica L. were also showed anti-acne property to inhibit the growth of P. acnes [32].

2.3. Anti-Cancer Effect

It is no denying that cancer is one of the major causes of death worldwide; the imbalance and high level of free radicals such as ROS and RNS can also become mutagenic or carcinogenic agents which lead to the cancer development. Chemotherapy is globally employed in cancer treatment, however a large number of drawbacks is its limitation. For example, sometimes the undesired side effects occur during chemotherapeutic treatment. Thus, it is interesting to seek for the alternative treatments for cancer that are no side effects and not so expensive cost. 

- 프리라디칼(활성산소와 산화질소)의 불균형은 암을 유발함. 

Flavopiridol, a flavonoid-derived drugs from Dysoxylum binectariferum (Roxb.) Hook.f. ex Bedd. [Currently the correct scientific name is Dysoxylum gotadhora(Buch.-Ham.) Mabb. (http://www.theplantlist.org/tpl1.1/record/kew-2607025)] is an example of anticancer drugs originated from phytochemical compound for lymphomas and leukemia treatments [33,34]. In addition, dietary supplements also play an important role in preventing and curing various kinds of cancer. Phenolic compounds especially flavonoids have long been reported as chemopreventive agents in cancer therapy [2,17,35,36].

Likewise, Danciu and colleagues researched on the phenolic compounds and biological activities of ethanolic extracts from rhizome of Zingiber officinale Roscoe and Curcuma longa L. which are the core representative species of Zingiberaceae family. This research team proposed the extract of C. longarhizome as the promising source of natural active compounds to fight against malignant melanoma due to its potential anticancer property on B164A5 murine melanoma cell line. The authors also suggested that the increase in anticancer activity was correlated with the increase in amount of polyphenol compounds [37]. Moreover, the results from many biomedical research teams indicated that various kinds of flavonoids can promote apoptosis in various cancer cells [17,35,38]. Quercetin, a flavonol member, is reported as an interesting anticancer substance against prostate and breast cancers [1,38]. Gliricidin7-O-hexoside and Quercetin 7-O-rutinoside which were the flavonoids isolated from the medicine fern (Asplenium nidus) was also purposed as the potential chemopreventive against human hepatoma HepG2 and human carcinoma HeLa cells [23]. According to the intense studied of Hashemzaei and his research group on quercetin and apoptosis-inducing ability both in vitro and in vivo levels. For in vitro studies, they tested anticancer activity of quercetin in 9 cancer cell lines: prostate adenocarcinoma LNCaP cells, colon carcinoma CT-26 cells, pheocromocytoma PC12 cells, human prostate PC3 cells, acute lymphoblastic leukemia MOLT-4 T-cells, estrogen receptor-positive breast cancer MCF-7 cells, ovarian cancer CHO cells, human myeloma U266B1 cells and human lymphoid Raji cells; the obtained results proved that quercetin can significantly induce apoptosis of every tested cell lines at p < 0.001 comparing with control group [39]. The in vivo experiments conducted in mouse models i.e., mice bearing MCF-7 tumors and mice bearing CT-26 tumors; the quercetin-treated group exhibited a significant decrease in tumor size and volume at p < 0.001 compared to the control group. The survival period of the quercetin-tested animals were also prolonged [39]. Besides, the research team of Clifford conducted their research to eval‎uate anticancer benefits of quercetin on patient-derived pancreatic tissue and 3 established pancreatic cancer cell lines: primary pancreatic cancer cell line ASANPaCa, AsPC1 and PANC1 to go deeper on the cross talk between quercetin a polyphenol phytochemical compound, microRNAs and Notch signaling in the regulation of self-renewing cancer stem cell divisions [40]. Notch is known as an important gene for signaling receptor encoding, which leads to proper development, the decision of cell fate, cell proliferation and survival [41,42]; it is suggested as a good marker of oncogene and symmetric cell division [43]. Clifford team showed that quercetin can induced miR-200b-3p to regulate the mode of self-renewing divisions of the tested pancreatic cancer [40]. The intense reviewed on genistein and its molecular effects on prostate cancer by Adjakly and his group pointed out that a soy isoflavone genistein inhibited the activation of Nuclear factor kappa B (NF-κB) signaling pathway that is occupied the balance of cell survival and apoptosis, this soy isoflavone could also take its action to fight against cell growth, apoptotic and metastasis processes, including epigenetic modifications in prostate cancer [44]. Curcumin is one of natural phenolic compounds exhibiting anticancer effects towards skin cancers, this phenolic can influence the cell cycle by acting as a pro-apoptotic agent [4]. Abusnina and his team investigated the antiproliferative effect of curcumin on melanoma cancer in in vitro level using B16F10 murine melanoma cells. They showed that curcumin acted as non-selective cyclic nucleotide phosphodiesterases (PDE) inhibitor to inhibit melanoma cell proliferation which is related to epigenetic integrator UHRF1; these researchers also suggested that curcumin occurring in diets might be help to prevent this cancer and contribute in the gene expression‎ via epigenetic control [45]. Interestingly, Hisamitsu group investigated prostate cancer therapeutic potential of curcumin on the inhibitory effect of intracrine androgen synthesis using both in vitro and in vivo models. Their in vitro experiments conducted on human prostate cancer cell lines such as LNCaP and 22Rv1 cells; curcumin decreased the expression‎ of genes evolving in steroidogenic acute regulatory proteins, supporting the decline of testosterone synthesis. Curcumin inhibited proliferation of the selected cell lines in this experiment and induced apoptosis of the cancer cells with dose-dependent response. Their in vivo study on transgenic adenocarcinoma of the mouse prostate (TRAMP) model with 1-month oral administration of curcumin displayed that the phytochemical compound regulate the expression‎ of steroidogenic enzyme, including AKR1C2, and suppressed the growth prostate cancer cells by decreasing testosterone levels in prostate tissues of TRAMP mice [46].

2.4. Cardioprotective Effects

The cardioprotective effects from various kinds of phenolics and/or flavonoids occurring in medicinal plants have been investigated from many researches since many decades ago [1,47,48,49,50,51,52,53,54,55,56,57]. The comprehensive review of Razavi-Azarkhiavi and his team illustrated cardioprotective role of various phenolic compounds against cardiotoxicity of doxorubicin which is the extensively used anticancer medicine for lymphomas, leukemia and breast cancers in clinical application that contains vulnerable side effect as cardiotoxicity such as pericarditis, arrhythmias, myocarditis, and acute heart failure [52]. They found that antioxidant phenolics have been recommended as a promising approach to reduce adverse effects of this anticancer drug; many phenolic and flavonoid compounds have been studied and reported their cardioprotective properties via various mechanisms including inhibition of ROS generation, mitochondrial dysfunction, apoptosis, NF-kB, p53, and DNA damage both in vitro, in vivo, and clinical studies. Razavi-Azarkhiavi team also found that many flavonoid and phenolics i.e., kaempferol, rutin, luteolin and resveratrol showed their efficacy against doxorubicin-induced cardiotoxicity, but do not affect on the antitumor activity of this medicine [58,59,60]. The most interesting reported compound was isorhamnetin. Because, it provided cardioprotective effect against cardiotoxicity of doxorubicin, and potentiated the anticancer efficacy of this drug [52,61]. Recently, there is the research on phenolic composition from methanolic extracts of the aerial parts of the two medicinal plants in Poland: Centaurea borysthenica Gruner and C. daghestanica (Lipsky) Wagenitz [At present, the corrected scientific name of this plant is Centaurea transcaucasica Sosn. ex Grossh. (http://www.theplantlist.org/tpl1.1/record/gcc-95497? ref=tpl1)] were analyzed together with their protective effects on cardiomyocytes treated with doxorubicin [53]. The obtained results from oxidative stress, cell viability, and mitochondrial membrane potential tests displayed their cardioprotective activity of both C. borysthenica and C. daghestanica extracts on rat cardiomyocytes treated with doxorubicin anticancer drug. According to this study, they found an attractive point that C. daghestanica methanolic extracts did not affect on efficacy of doxorubicin in this experiment [53].

In addition, the research group of Alhaider eval‎uated the cardioprotective potential of Phoenix dactyliferaL. or date palm in English name or Nakl in Arabic name. The total flavonoid, total phenolic, in vitro antioxidant capacity and in vivo rodent myocardial infarction models with fruit extracts from 4 different varieties of date palm in eastern provision of Saudi Arabia were confirmed. The high concentrations of phenolics and flavonoids were detected in the fruit extracts that contributed the potential antioxidant activities and high cardioprotective effect against various induced factors in vivo myocardial infarction models by mobilizing the circulating progenitor cells from both bone marrow to the site of myocardial infraction, in order to promote tissue repairing from ischemic injury [56]. Syama and his colleagues eval‎uated the major phenolic acids and flavonoids from the different fractions of seeds extract from Syzygium cumini (L.) Skeels, and their cardioprotective potential in in vitro H9c2 cardiac cell lines such as tertiary butyl hydrogen peroxide induced oxidative stress, LDL oxidation, HMG-CoA reductase and angiotensin converting enzyme modulation. The major phytochemical compounds from the analyzed fractions were gellagic acid, syringic acid, gallic acid, ferulic acid, cinnamic acid and quercetin. These fractions attenuated oxidative stress in H9c2 cardiomyoblasts and molecular docking demonstrated the positive correlation between the major phytochemical compounds and key enzymes for preventing cardiovascular diseases i.e., angiotensin converting enzyme [57]. Moreover, the research group of Garjani investigated the potential of aerial parts extract from Marrubium vulgare L., a medicinal plant from Iran focusing on its cardioprotective effects against ischemia-reperfusion injury in vivo Wistar rat model. They determined total phenolic and flavonoids content of aqueous fraction of the extract, and their effect on ischemia-reperfusion injury of the rat hearts using Langendroff method; the obtained result proved that aqueous fraction from M. vulgare consisting of cardioprotective potential against this cardiac injury [48]. Aspalathin and phenylpyruvic acid-2-O-β-d-glucoside, the two of the major compounds from Aspalathus linearis (Burm.f.) R. Dahlgren were demonstrated as potential protective compounds to protect myocardial infarction caused by chronic hyperglycemia [49]. Likewise, puerarin is a potential isoflavones that was reported as an interesting candidate for cardioprotection by protecting myocardium from ischemia and reperfusion damage by means of opening the Ca2+-activated K+ channel and activating the protein kinase C [51]; this research team conducted their study using in vivo Sprague–Dawley rats model. Tian and his group compared the cardioprotective effects between polyphenolic extracts from apple peel and apple flesh in in vivo mice model with cardiovascular risk factors; they found that the extracts of apple peels exhibited better cardioprotective ability than that of apple flesh in mice model [54]. This may probably due to the higher amount of both total phenolics and total flavonoids consisting in polyphenolic extracts from apple peel.

2.5. Immune System Promoting and Anti-Inflammatory Effects

Medicinal and pharmacological agents, nutrients, pollutants and other environmental factors play a necessary role in the human immune system. A large number of flavonoids and other phenolics have been proved their noteworthy effects on immune system function and inflammatory processes [62,63]. Quercetin, apigenin, hesperidin and luteolin were reported as flavonoids containing potential anti-inflammatory effects [1]. 

- 케르세틴, 아피기닌, 헤스페리딘, 루테올린은 플라보노이드가 함유하고 있는 항염증 효과...

The research group of Rupasinghe examined the anti-inflammatory properties of Canadian medicinal plant extracts, Lonicera caerulea L. or haskap berry in various cultivars focusing on pro-inflammatory cytokines using in vitro human monocytic cell line THP-1 derived macrophages which stimulated by lipopolysaccharide. Borealis cultivar of Haskap berry presented the highest phenolic, flavonoid and anthocyanin content (p < 0.05), and exhibited comparable anti-inflammatory effects to diclofenac which is a COX inhibitory medicine [64]. In addition, the synergistic effects on immune and health promoting properties of bioactive compounds and probiotic bacteria are also currently interested by the scientists. For example, the study of Sisto’s group to investigate effect of Lactobacillus paracaseiculture filtrates and Cynara scolymus L. or artichoke phenolic extract from edible part of its fresh buds on cytokine producing by dendritic cells. The experimental result pointed out the interesting anti-inflammatory effect of a culture filtrate obtained after probiotic L. paracasei strain growing in the media supplemented with artichoke phenolic extract [65]. Moreover, the anti-inflammatory activity of polyphenolic compounds in Gaillardia grandiflora Hort. ex Van Houte and Gaillardia pulchella Foug from Egypt were reported with nontoxicity test in in vivo mice model; the newly reported compound, 8-hydroxyapigenin 6-O-β-d-apiofuranosyl-(1′′′→6”)-C-β-d-4C1-glucopyranoside, from G. grandiflora and other known compound i.e., luteolin 6-C-β-d-4C1-glucopyranoside 8-methyl ether, schaftoside, isoorientin, apigenin 6-C-β-d-4C1- glucopyranoside 8-methyl ether, 6-methoxyluteolin isovitexin and hispidulin were also isolated and tested in this research [66]. The inflammatory inhibition ability both tumor necrosis factor- (TNF-) and interleukin-6 (IL-6) of polyphenol fractions from sixteen cultivars of Chinese blueberries including 14 commercialized ones such as Bluecrop, Bluesource, Berkeley, Brigitta, Duke, Darrow, Misty, Northblue, Northland, Northcountry, O’Neal, Patriot, Reka and Southgood from China were employed in the study of Ma and his team. Their anti-inflammatory effect of these blueberry samples were tested using lipopolysaccharide induced RAW 264.7 macrophages; anti-inflammatory potential of the polyphenol fractions were in the same trend of their phenolic acid contents [67]. Likewise, anti-inflammatory activities of two medicinal plant species: Bidens engleri O.E. Schulz from Asteraceae family as well as Boerhavia erecta L. from Nyctaginaceae family were tested in various fractions and eval‎uated their total phenolic and total flavonoid contents [68]. This research team found that dichloromethane was the highest potential solvent to extract flavonoid compounds in both species and this fraction also exhibited anti-inflammatory effect via COX-2 and LOX-15 inhibition. Macrophages play an important role in controlling the switches of immune system by means of maintaining the balance of pro-inflammatory and anti-inflammatory activities. Dugo and his team proved that polyphenol extract from roasted cocoa beans (Theobroma cacao L.) significantly lowered pro-inflammatory cytokines secretion in in vitro THP-1 cells, as well as suppressed inflammation by promoting oxidative pathways, which lead to the increase in oxygen consumption by mitochondria and ATP production via oxidative phosphorylation [69]. Additionally, Lopes and his team characterized phenolic composition of Lavandula pedunculata (Mill.) Cav. samples from various different geographical origins in Portugal, and compared their bioactive activities in aqueous and hydroethanolic extracts. The obtained results pointed out that the L. pedunculata hydroethanolic extract from Alentejo area exhibited highest anti-inflammatory activity in rat RAW 264.7 macrophages by inhibiting nitric oxide production [70].

It is known that COX-2 syntheses prostaglandin E2 is an endogenous pain-producing substance, while COX-1 is a house-keeping enzyme. According to the molecular mechanism of some anti-inflammatory medicines which inhibit both cyclooxygenase-2 (COX-2) and COX-1 enzymes. Consequently, the medicines that inhibits both COX-1 and COX-2 concurrently can cause adverse side effects i.e., renal dysfunction or gastrointestinal bleeding. Therefore, the researchers have challenged to seek for the better candidate for drug development; some phenolics have been reported as the selective inhibiting compounds toward COX-2 expression‎. An interesting example is the study Ma and his team which aimed to validate the potential and mechanisms of polyphenols from inner bark of Tabebuia avellanedae Lorentz ex Griseb [Currently, the corrected species name of this plant is Handroanthus impetiginosus (Mart. ex DC.) Mattos; http://www.theplantlist.org/tpl1.1/record/kew-317146], a medicinal plant with extensively use as folk medicine in Central and South America, as an anti-inflammation agent without undesirable side effects from COX-1 inhibition. This work was conducted using in vitro free fatty acid-stimulated macrophage cell lines and combined molecular docking to investigate the interactions between the phenolic compounds and COX-2; the obtained results illustrated anti-inflammatory effects of phenolics from this medicinal plant to regulate macrophages by targeting COX-2 activity inhibition without any action on COX-1 activity [71]. Furthermore, phenolics and flavonoids from bark of Vitex peduncularis Wall. ex Schauer, a herbal drug, were characterization together with their anti-inflammatory activity by the research group of Ferreres. They found high content of apigenin, C-rhamnosyl flavones and luteolin derivatives in this methanolic bark extract which reduced nitric oxide levels in macrophages and significantly inhibited the activity of phospholipase A2, a mediate enzyme in inflammatory processes [72]. Additionally, Lu and his research group optimized the ethanolic rhizome extract of astilbin, a dihydroflavonol, from Smilax glabra Roxb and eval‎uated its anti-inflammatory effects in in vitro lipopolysaccharide-induced RAW264.7 macrophages. Their results pointed out that astilbin significantly suppressed nitric oxide production, tumor necrosis factor-α (TNF-α), mRNA expression‎ of inducible nitric oxide synthase and TNF-α in the tested cells [73]. Recently, the isolated astilbin flavonoid from rhizome of S. glabra in China and its anti-inflammatory potential was also investigated by Dong and his group in in vivo complete Freund’s adjuvant-induced adjuvant arthritis rats (AA rats) model. Their results showed noteworthy inhibitory properties of astilbin on TNF-α, IL-1β as well as IL-6 mRNA expression‎; serum cytokine levels of TNF-α, IL-1β, and IL-6 were also decreased in treated AA rats. They also proved that oral treatment of astilbin daily at 5.3 mg/kg can reduce joint damage in hind paw of the animal model; this therapeutic properties of astilbin flavonoid on the inhibition of cytokines production and reduction of inflammatory response in in vivo AA rats model were effective as equal as leflunomide, the frequently used antirheumatic drug [74]. Moreover, the double-blind, randomized, placebo-controlled clinical trial on inflammation of ferulic acid, an abundant phenolic compound from various plant including edible medicinal plant and cereal grains, were eval‎uated in hyperlipidemic subjects by the research team of Bumrungpert. They randomly divided hyperlipidemia subjects into 2 groups i.e., treatment group (n = 24) with ferulic acid 1000 mg daily and the control group (n = 24) with a placebo for six weeks; ferulic acid supplementation significantly decreased in the inflammatory markers with statistic different comparing with the control group [75].

2.6. Skin Protective Effect from UV Radiation

Overexposure to ultraviolet (UV) radiation can harm to skin. It induces extensive production of reactive oxygen species (ROS) and eventually causes skin damages [76]. However, there are several strategies applicable for skin protection. Phytochemical compound, especially phenolics and flavonoids is one of the most interesting choices that exhibits beneficial effects on UV-irradiated skin [77,78,79]. Flavonoids have photoprotective effects that are antioxidant properties by their capacity to chelate iron which can damage lipid and protein on cell membrane, and modulate several signaling pathways, for example, inhibit xanthine oxidase which is considered as a source of ROS that contributes to oxidative stress [80,81]. Several phenolic compounds are reported as potential antioxidant molecules for treatment of various skin disorders including diseases which caused by UV radiation [4,78].

Apigenin is a major flavones with skin protective effect from UV light; this flavone can be found in many edible medicinal plants or plants-derived beverages e.g., red wine, beer and chamomile tea [82,83]. Quercetin is a flavonols which can be found in onion skin, apple peel and Hypericum perforatum L. leaves [84]. Topical application with quercitin effectively inhibited UVB-induced skin damage in hairless mice [85]. In addition, Ginkgo biloba L. extract (EGb 761) that contains a lot of quercetin derivatives had an ability to decrease sunburn symptoms UVB-induced skin in in vivo study using UVB irradiated-skin mice model; the results indicated that oral intake of EGb 761 may act as a protective and therapeutic agent [86]. Silymarin, a standardized extract of flavonolignans from the milk thistle (Silybum marianum (L.) Gaernt.) fruits contains silybin, a major active component [87]. The topical treatment with silymarin stimulated the repair of UVB-induced DNA damage that leads to the prevention of apoptosis in UVB-exposed human epidermal keratinocytes as well as fibroblasts in in vitro study [88]. Genistein is a soybean isoflavone that was also reported as photoprotective molecule against photocarcinogenesis by inhibiting UV-induced DNA damage in human skin equivalent in vitro model [89]. Moreover, Wang and his team examined effect of genistein in human dermal fibroblasts on UVB-induced senescence via the mechanism of oxidative pathway; they found that genistein was able to maintain activities of antioxidant enzymes and modulate mitochondrial oxidative stress [90]. Equol is known as an isoflavonoid metabolite from isoflavone daidzein or genistein producing by gut microflora [91,92]. An in vivo study in hairless mice reported that topical application with equol prior to UV-irradiation can prevent UV-induced erythema-associated edema, immunosuppression and skin cancer by acting as a sunscreen and inhibiting DNA photodamage [92]. Additionally, the study of Choi and his group to eval‎uate skin protective effects of spent coffee ground on ultraviolet UVB-induced photo aging in in vivo hairless mice model showed that topical application of spent coffee ground extracts consisting of flavonoids and caffeine which were able to protect mouse skin by down-regulating of matrix metalloproteinases [93]. Interestingly, the research team of Kano investigated protective effect of isoflavones from fermented soymilk products on photodamage in the skin of ovariectomized hairless by oral administration for 28 days. The results indicated the increases of isoflavone concentration on mice skin and in their blood can effectively scavenge reactive oxygen species generating by UV irradiation, and also exerting estrogenic activity, resulting in photoprotective effect on skin of the animal model [94].

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3. Naturally Occurring Plant Phenolics and Flavonoids for Menopausal and Post-Menopausal Women

There is pros and cons between using synthetic chemical compounds and phytochemical substances in pharmacy and medicine. Synthetic substances or medicines are easy and quickly to produce in large scale of drug development process and modify as many forms of consumption for patients. Conversely, many non-natural (or synthetic chemical compounds) cause several undesirable side effects, particularly long-term treatments [95]. Some synthetic medicines were not accept for clinical treatments because of their harmful side effects. An obvious example is synthetic estrogen which was commonly used in menopause women for hormone replacement therapy a few decades ago. This synthetic chemical compounds could work well to reduce menopause symptoms, long before there were a number of researches discovered its unwanted side effects i.e., an increase in the risk of breast, uterus and ovarian cancers [95,96,97].

Estrogen is a sex hormone mainly responsible for reproductive functions and the menstrual cycle of women. In postmenopausal women, estrogen is depleted due to the failure of the response of ovary to pituitary. When the level of estrogen decreases, it leads to many postmenopausal symptoms including cardiovascular disease. In particular, postmenopausal woman who also has metabolic syndrome (MetS) will increase in the risk of cardiovascular disease [98]. The research study of Squadrito and his group showed that flavonoid supplementation can also improve cardiovascular function in postmenopausal woman with metabolic syndrome [99]. Genistein is an obvious example of interesting choice of flavonoid phytoestrogen for improving endothelial functions in postmenopausal women with MetS [100]. Gregorio and his research team investigated the effects of genistein supplement on cardiac function of postmenopausal women with MetS; postmenopausal women patients with type-2 Diabetes mellitus and free from previous cardiovascular disease 120 subjects were employed in this study [98]. The patients were equally divided into 2 groups: Genistein supplementation group and control group who have got placebo by using a computer-generated double-blind randomization. The result indicated that genistein can improve the cardiac function in postmenopausal women with MetS [98].

The decrease of estrogen leads to postmenopausal bone loss or osteoporosis. Morabito research team found that genistein can be used as hormone-replacement therapy (HRT) for preventing osteoporosis in postmenopausal women [101]. This research team aims to compare the effect of genistein phytoestrogen with HRT (estrogen and its derivatives). The study conducted on 90 healthy women between 47–57 years who had bone mineral density at femoral neck of <0.795 g/cm2. The 90 participant subjects were randomly and equally divided into three groups: Genistein, HRT and control group treating with placebo continuously for 1 year. The result indicated that using genistein in postmenopausal bone loss is more effective than HRT, because the undesirable side effects were not found in genistein group. Kruger and his team investigated the effects of bone turnover and the change in microflora between the groups of healthy New Zealand post-menopausal women who received daily isoflavone supplementation (daidzein and genistein) alone and those who consumed green kiwifruit combined with isoflavones for 4 months; their results indicated that the second group of post-menopausal women significantly improved bone health [102]. Nevertheless, the minimum and optimum dose are the essential point to concern. The concreted example can be seen in the study of Kaczmarczyk-Sedlak and his research group; their results indicated that moderate dose of isoflavane glabridin from root of Glycyrrhiza glabra L. or licorice plant showed no effect on bone loss in ovariectomized rats, an in vivo model of osteoporosis from estrogen deficiency in postmenopausal women [103]. The secondary metabolites discovered in medicinal plants such as flavonoids and other phenolics may avoid the negative side effect of synthetic medicines, because they must accumulate within the cells and tissues of living organisms [71,95,96]. Moreover, many medicinal herbs contain novel or valuable secondary metabolites with different biological properties, and a huge numbers of them are waiting for discovery.

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4. Profiling Works and the Survey of Flavonoids and Other Phenolics from Medicinal Plants

For over four million years, flavonoids and other phenolic substances from medicinal herbs have been used or consumed by humans so as to live healthy and fight against undesirable diseases [1,22,51]. As a plant secondary metabolites, flavonoids and the other phenolics are found in several plant species, type and amount of the chemical components are vary depending on species and affecting by environmental factors i.e., mineral at the growth locality and geographic origin [70]. Nowadays, there is a significant increase in the number of research on potential of medicinal plant species for pharmaceutical and medical purposes focusing on natural phenolic compounds and flavonoids [1,4,9,16,18,51,63,71,73,104].

Though many flavonoids and other phenolic compounds were examined from medicinal plant species, a large amount of native or endemic medicinal herbs are still waiting for being survey and observing their novel compounds from profiling works. These processes are an indispensable step to promote the progression in drug discovery and development using phytochemical compounds. Asian region is well-known as one of the greatest hotspot of plant biodiversity including medicinal species, especially Japan, China, Thailand and related areas in tropical and sub-tropical regions [6,54,67,74,104,105]. However, a comprehensive profiling of many medicinal plants and functional eval‎uation of their chemical compound has not been completely conducted. According to our intense review in more than one hundred scientific publications, it is clear that the different parts of medicinal species such as floral parts, leaves, stems, root or rhizome consisting of different types and amount of phenolics and flavonoids. Furthermore, the harvesting season, cultivar and variety of the targeted plant species should be accounted and compared in phytochemical profiling works.

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5. Future Perspectives and Interesting Directions for Future Researches

(1) The low cost of medicines and many other medical products is very important to allow all people to access to the drug. Consequently, the flavonoid and phenolic compounds which are abundant found in a large number of plant may possible be an interesting choice of molecules for drug and medical product development.

(2) In the same species of medicinal plants, the different cultivars may provide different amount of flavonoid and phenolic compounds as well as the biological activities. Thus, the cultivars of medicinal plant should be taken into account for the future medical and pharmaceutical research studies.

(3) The geographic areas of raw plant material should also be analyzed and compared in the future research. Since the environmental factors e.g., nutrients and mineral in soil are also effect on the quality and quantity of phytochemical compounds in some species of medicinal plant as discussed in this work.

(4) Not only local medicinal plant species but also the wild or endemic species are interesting for the future studies, in order to discover the novel phytochemical compounds to increase the alternative sources of raw material for medical and pharmaceutical applications.

(5) The molecular mechanism and signaling pathway of many known flavonoid and phenolic compounds are need to be done in the future, so as to apply this knowledge to the drug development processes.

(6) The need of purified compounds to confirm‎ data obtained with the plant extracts.

(7) Epidemiological and in vitro studies are sometimes contradictory. In part because of the calculation of the intake based on general table estimated content without taking into account genetic variation among cultivars, geographic variations and so on. Also because of the possible need of metabolization by gut microflora for activation. Those of gut microflora are not taken into account, and quantification of the active circulating forms was not eval‎uated most of the time.

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6. Conclusions

To recapitulate, the use of phenolic compounds and flavonoids are the potential candidate of bioactive agents in pharmaceutical and medicinal sectors to promote human health, prevent and cure various diseases. In order to discover and progress these alternative choice of using phytochemical compounds, the survey of medicinal plants together with intense profiling research needs to be done. The targeted compounds should be employed in biomedical and pharmaceutical research ranging from in vitro, in vivo, and clinical trial step to eval‎uate the safety, efficacy and also the side effects of the tested candidate compounds.

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Acknowledgments

Duangjai Tungmunnithum would like to express her sincere thanks to the Development and the Promotion of Science and Technology Talent Project (DPST) from the Royal Thai Government for financial support for her collaborative research in Japan. Nonetheless, the funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results. She also thanks to Tsukasa Iwashina, the director of Tsukuba Botanical Garden, and head of Department of Botany, National Museum of Nature and Science, Japan for broadening her horizons in phytochemistry of medicinal plants during the fruitful period of her post-doctoral research in Japan.

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Author Contributions

D.T. conceived, designed, proved and edited the whole review manuscript. A.P. wrote the topic of “Antibacterial effect”, A.T. wrote the topic of “Skin protective effect from UV radiation”, A.Y. wrote a second half part of the topic ‘’Naturally occurring plant phenolics and flavonoids for menopause and post-menopausal women’’, and D.T. wrote the remaining topics of the review.

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