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Health Benefits of Grapes: Unpacking Resveratrol, Skin Health, and Cardiovascular Benefits – Medriva

Grapes, particularly red and purple ones, are more than just tasty fruits. They carry an impressive array of potential health benefits, thanks to the high levels of resveratrol they contain. This antioxidant is linked to the prevention of various types of cancer, including breast, liver, and stomach cancer. But the power of grapes and resveratrol extends far beyond this, offering a range of other health and wellness advantages.

Resveratrol is a powerful phytonutrient found in certain plants and fruits, including grapes. It boasts antioxidant and anti-inflammatory effects, contributing significantly to its health benefits. Not only can resveratrol protect the body from oxidative stress and inflammation, but it also aids in the prevention of some types of cancer. Its antioxidant capacities also improve skin appearance, reduce blood cholesterol levels, and promote overall well-being. Although resveratrol can be consumed through supplements, it is also abundant in natural grape juice, red wine, and cocoa. However, it is important to note that excess resveratrol can cause gastrointestinal disorders and that supplements should be used under the guidance of a healthcare professional.

Its not just the fruit of the grape vine that carries health benefits. Grape stems, rich in phenolic compounds, have emerged as a valuable natural ingredient in the cosmetics industry. These compounds have strong antioxidant and anti-inflammatory properties, promoting skin health, combatting signs of aging, and shielding skin from environmental stressors. The antioxidant abilities of these compounds effectively fight free radicals, which can accelerate aging. Moreover, grape stem extracts can soothe irritated skin and reduce redness, offering effective and eco-friendly solutions for skin care.

Resveratrols health benefits extend to the cardiovascular system. This chemical compound is known for its effectiveness in treating cardiovascular diseases, allergies, and obesity. Its anti-obesity properties aid in lowering insulin levels and improving glycemic control. While generally safe, high dosages of resveratrol can lead to gastrointestinal issues. Pregnant women, infants, and people with bleeding disorders should exercise caution.

Among the different types of grapes, red grapes stand out for their health benefits. They contain higher resveratrol content compared to green and black grapes, making them a healthier choice. The resveratrol in red grapes is linked to heart health, antioxidant properties, anti-inflammatory effects, and potential cancer prevention. Incorporating red grapes into daily diets can be an easy and delicious way to boost health.

Polyphenols, a group of naturally occurring antioxidants found in plant-based foods and supplements, are another health benefit of grapes. These compounds have anti-inflammatory benefits and protect against diseases like cancer, cardiovascular diseases, and neurodegenerative diseases. Over 8,000 unique polyphenols are found in foods like fruits, vegetables, teas, wines, olive oil, and spices. Consuming polyphenols can reduce the risk of chronic diseases, improve vascular function, and have anti-cancer effects. They can also reduce oxidative stress and have anti-aging properties. Incorporating polyphenols into your diet can provide many health benefits.

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The New Addition to Caudalie’s Resveratrol-Lift Collection – Who What Wear

One of the main reasons so many of us tend to steer clear of retinol isthat while the popular ingredient may be a holy grail when it comes to reversing signs of aging, not all skin responds well to such a powerful vitamin. Caudalie's newest serum was made with everyone in mind. It'sformulated with resveratrol as a high-performing retinol alternative. "The patented combination of resveratrol, micro hyaluronic acid, and new vegan collagen 1 works synergistically to deliver the best results,"Kwitman tells us.Resveratrol and retinol may work in a similar way, but to an in vitro test on ingredients association, one is much more versatile than the other.

But what is resveratrol? According to Kwitman, it's harnessed from the grapevine stalk and works to increase activity in the anti-aging cells. Made from 98% natural origin ingredients, the Resveratrol-Lift Instant Firming Serum also happens to be vegan, recyclable, and gentle, which makes it an effective alternative for retinol. "The serum is clinically proven to be three times more effective than retinol to firm and lift," she says. "This is critical because by the time you reach 40 years old, you have lost nearly 40% of your collagen and 50% of your hyaluronic acid." In other words, the older you get, the more changes you'll notice to the skin. Using Caudalie's patented resveratrol formula can help pump the breaks.

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Best Resveratrol Supplements 2024 – Top Product Brands on the Market – Deccan Herald

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The manufacturers of Glucotrust ensure that they integrate the best natural ingredients to craft this unique product for tackling diabetes. The product contains no parabens or preservatives that could deteriorate the health condition in the long run. All the benefits derived from the product come from natural sources. Let us take a glance at them;

Gymnema Sylvestre: Gymnema Sylvestre is the main component in numerous sugar-controlling pills. The rich content of antioxidants in the natural ingredient ensures that no inflammation or injury can be sustained. Consequently, the rich content of vitamins, minerals, and amino acids cannot be ignored as they increase the ingredient's potency by manifolds.

Biotin Vitamin B7: Biotin Vitamin B7 plays a crucial role in the absorption of natural glucose into the bloodstream and converting the same for energy. It also stimulates the stem cells to produce beta cells, aggravating insulin production and diverting complications.

Chromium: Chromium nullifies all the complications and deficiencies related to diabetes. In addition, it propels better sugar absorption and usage for energy requirements. There is an increased insulin production and enhanced sensitivity that can regulate sugar levels.

Manganese: Numerous medical health experts promote the consumption of manganese for a better nervous system, guided by the aggravated brain's cognitive functioning. It increases the production of leptin in the body, which defers the cravings for fast food or excessive carbohydrates. Such functionality prevents the sugar from getting oxidized into the bloodstream and promotes better sleep for energy recovery.

Licorice Root: Glucotrust shares the inclusion of Licorice root into its manufacture in consonance with its predecessors. Licorice root is an undeniable part of staple Ayurvedic medicine. Not many know that Licorice harbors glycyrrhizin, which inhibits glucose absorption into the bloodstream.

Cinnamon: Also known as the king of spices, Cinnamon promotes better digestion and healthy sugar levels in the body. It stimulates increased insulin production and better glucose metabolism that promotes the overall well-being of a diabetic individual. The presence of antioxidant properties helps tackle issues like inflammation, diseases, and irregular sleep schedules to give a better life.

Zinc: Zinc has a plethora of never-ending benefits. Industry experts feel that there is not one aspect of human health that zinc does not help improve. Three hundred working enzymes in the human body require an adequate supply of zinc for promoting metabolism, reproduction, growth, and immune system functionalities. Besides reducing the sugar levels, it also tackles the triglycerides that keep the cholesterol levels under check.

Juniper Berries: Do you know an evergreen shrub that offers multiple health benefits besides being a natural sugar inhibitor? Juniper berries are a great anti-diabetic ingredient that can reduce sugar cravings by manifolds. Its combination with chromium aids in aggravated fat loss and assists in the diabetic journey.

Glucotrust promotes numerous advantages of its consumption, making it one of the most sought-after products for diabetic patients. Knowing the benefits can convince any individual to give this product a try.

Weight loss

People suffering from obesity or carrying more body weight than recommended are the ones who suffer from ailments like diabetes. Glucotrust aids in reducing sugar consumption and promotes increased metabolism for getting rid of excess weight.

Controlling Appetite

The major reason behind people gaining extra weight is their lack of tongue control. People crave good food that has a lot of spices and carbohydrates to treat their taste buds. However, such food remains detrimental to health and opens the door for numerous ailments. Glucotrust prohibits food cravings and lowers the appetite to a considerable level.

Diabetic Assistance

The main benefit of Glucotrust is to keep diabetes under control. It facilitates better sugar absorption in the human body and converts it into energy required to fulfill the day's responsibilities. The extensive set of ingredients included in Glucotrust's manufacture substantiates the effectiveness concerning its sugar control.

Boosted Immune System

One of the vital benefits of Glucotrust is to offer a better immune system. Ever since the onslaught of COVID-19, people understood the importance of building immunity for sustaining in a world vulnerable to viruses. Glucotrust offers an amalgamation of immunity and weight loss to keep the diabetes level under control. Thus, the benefits are multiple.

Promotes Deep Sleep

Increased sugar levels can mess with the hormonal secretion in the human body. Hormonal disbalance often causes an increase in cortisol levels that puts people under extreme stress. Such a situation deprives them of the necessary sleep to sustain. Glucotrust mitigates cortisol levels and enhances sleep quality.

Is Glucoredi safe?

Yes, Glucoredi is safe for human consumption and remains devoid of side effects.

What is the main benefit of Glucoredi?

Glucoredi helps control type-2 diabetes.

How to consume Glucoredi?

According to the manufacturers, consuming Glucoredi twice a day will give optimal results.

Make your life better with the best resveratrol supplement of your choice! The options mentioned above are the most trusted ones and have passed the necessary tests for approval.

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Global Resveratrol Market is projected to reach US$ 278.3 Million by 2033 at a moderate CAGR of 8% | Get In-depth Report by Future Market Insights,…

Future Market Insights Global and Consulting Pvt. Ltd.

According to Future Market Insights, the North American region is forecast to lead the resveratrol market in 2023 and is likely do so throughout the forecast period. United States is a promising market in this region, which was estimated to have acquired 17.3% market share in 2022.

NEWARK, Del, May 09, 2023 (GLOBE NEWSWIRE) -- The estimated worth of the worldwide resveratrol market in 2022 was US$ 118.60 Million. Sales of dietary supplements is likely to increase to US$ 278.3 Million by 2033 thanks to shifting customer tastes, with a CAGR of 8% predicted for the forecast period of 2023 to 2033.

The growing demand for nutritional supplements among consumers is one of the main factors driving up the price of resveratrol on the international market. The market is expected to grow due to the product's high anti-antioxidant content and phenolic activities, which are popular with older consumers and sportsmen, as well as the increased prevalence of health issues including cardiovascular diseases. The increasing usage of nutraceuticals by the populace and the increasing reliance of the beauty sector on resveratrol all have an effect on the market's growth.

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The use of this substance has been associated with a wide range of implications, including anti-angiogenic, estrogen-like effects, skin-whitening, anti-aging, collagen I activation, and its capacity to protect cells from oxidative damage and UV radiations-mediated cell death. It is well-liked in dermatology as well as cosmetology due to its ability to penetrate the skin barrier and its anti-aging properties.

Resveratrol has experienced extraordinary penetration in developed North American economies due to growing consumer demand for natural and healthy products. Consumers are turning to resveratrol supplementation for its antioxidant as well as anti-inflammatory qualities. Cardiovascular issues have increased in frequency in the United States as a result of the people's sedentary lifestyles, poor eating patterns, and hectic schedules. Resveratrol is a common ingredient in dietary supplements, which is anticipated to fuel the growth of the resveratrol market over the forecasted time period due to its multiple health benefits.

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Key Takeaways:

The global resveratrol market is expected to be valued at US$ 123 Million by 2023.

From 2018 to 2022, the market demand expanded at a CAGR of 3.1%.

In 2022, the United States market for resveratrol accounted for about 17.3% of the global market share.

The Indian resveratrol market to experience a rapid CAGR of 14% from 2023 to 2033.

By product type, the extract or plant-based resveratrol was estimated to acquire more than 40% share in 2022.

By Isomer, the trans-resveratrol had acquired a market share of 87%.

Resveratrol is gaining traction owing to its health benefits and having antioxidant, anti-inflammatory and anti-aging properties, says an analyst at FMI.

Competitive Landscape:

Prominent players in the resveratrol market are:

DSM Nutritionals

Evolva

Endurance Product Company

Great Forest Biomedical

Laurus Labs Limited

JF-NATURAL

Sabinsa Corporation

Resvitale LLC

Shanghai Natural Bio-engineering Co., Ltd.

Some key developments in this market are:

In 2021, Lonza, a worldwide manufacturing partner to the pharmaceutical, biotechnology, and nutrition sectors, declared it is likely to invest to build its production capabilities for pharmaceutical products at its facility in Guangzhou, China.

The fill as well as finish production line is likely to provide clinical trial and commercialization batches in China as well as local and international clients. In keeping with Lonza's objective to provide clients integrated end-to-end solutions, the launch of drug product manufacturing at the Guangzhou (CN) facility is likely to provide customers with a unified drug substance as well as drug product manufacturing service option.

More Valuable Insights Available:

Future Market Insights offers an unbiased analysis of the global resveratrol market, providing historical data for 2018 to 2022 and forecast statistics from 2023 to 2033.

To understand opportunities in the resveratrol market, the market is segmented on the basis of resveratrol by product (extract, fermentation, synthetic), form (powder and liquid), isomer (trans-resveratrol and cis-resveratrol), end-use and across five major regions (North America, Latin America, Europe, Asia Pacific and Middle East & Africa).

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Key Segments Profiled:

By Product:

Extract

Fermentation

Synthetic

By Form:

By Isomer:

Trans-Resveratrol

Cis-Resveratrol

By End Use:

Skin Care

Cream & Lotion

Scrub Exfoliator

Cleanser & Toner

Balm & Butter

Serum & Mask

Makeup Remover

Others

Hair Care

Shampoo

Conditioner

Essential Oil

Hair Color

Hair Stylist Products

Hair Oil

Makeup

Facial Makeup

Eye Makeup

Lip Makeup

Nail Makeup

Bath Care

Shower Products

Liquid Bath Products

Bath Additives

Bar Soaps

Fragrance

Tools

Dietary Supplements

Pharmaceuticals

Others

Table of Content (ToC):

1. Executive Summary | Resveratrol Market

1.1. Global Market Outlook

1.2. Demand-side Trends

1.3. Supply-side Trends

1.4. Technology Roadmap Analysis

1.5. Analysis and Recommendations

2. Market Overview

2.1. Market Coverage / Taxonomy

2.2. Market Definition / Scope / Limitations

3. Market Background

3.1. Market Dynamics

3.1.1. Drivers

3.1.2. Restraints

3.1.3. Opportunity

3.1.4. Trends

3.2. Scenario Forecast

3.2.1. Demand in Optimistic Scenario

3.2.2. Demand in Likely Scenario

3.2.3. Demand in Conservative Scenario

3.3. Opportunity Map Analysis

3.4. Product Life Cycle Analysis

3.5. Supply Chain Analysis

3.5.1. Supply Side Participants and their Roles

3.5.1.1. Producers

3.5.1.2. Mid-Level Participants (Traders/ Agents/ Brokers)

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Global Resveratrol Market is projected to reach US$ 278.3 Million by 2033 at a moderate CAGR of 8% | Get In-depth Report by Future Market Insights,...

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Therapeutic effects and molecular mechanisms of resveratrol | IJWH – Dove Medical Press

Introduction

Endometriosis (EMS), a hormone-dependent gynecological inflammatory disease, is defined as the endometrium, including both stroma and glands, presenting at the extrauterine sites, mostly involving pelvic organs and peritoneum.1 It may also affect external pelvic organs and even the central and peripheral nervous systems.1 Endometriosis affects 10% of women of reproductive age.2 Approximately 3080% of women with this disease experience pelvic pain, and 3040% of women are accompanied by infertility, representing the two major clinical symptoms.3,4 In addition to the aforementioned symptoms and phenomena, endometriosis also has adverse effects on the quality of life, such as sleep quality, physical and psychological well-being, sexual function, and interpersonal relationships, resulting in a large economic burden to individuals, the healthcare system, and society.5,6 Furthermore, some studies have reported that endometriosis is closely correlated with the elevated incidence rate of endometrial and ovarian malignant tumors, which may be implicated as a precursor to epithelial ovarian cancer and may have a tumor-promoting effect on ovarian cancer.7,8

At present, pharmacotherapy and surgical resection are the main therapeutic approaches for endometriosis. Pharmacotherapy mainly consists of hormone therapies that induce hypoestrogenism or antagonize estrogen effects, such as progestines (including the levonorgestrel-releasing intrauterine system (LNG-IUS), dienogest and medroxyprogesterone acetate), combined oral contraceptive pills (COCs), aromatase inhibitors, danazol, gestrinone, gonadotropin-releasing hormone agonist (GnRH-a) and GnRH antagonist (GnRH-ant), selective estrogen/progestogen receptor modulators (SERMs/SPRMs), and nonhormone therapy for alleviating endometriosis-related pain, such as nonsteroidal anti-inflammatory drugs (NSAIDs).9 However, the efficacies of conventional medications are limited or discontinuous in the majority of patients, as long-term usage of these drugs will bring about perimenopausal symptoms, breakthrough bleeding and osteoporosis due to the hypoestrogenic status, as well as other adverse effects such as thrombosis, and liver function damage.10,11 Although surgical management aims to completely destroy or remove visible ectopic lesions, restore normal anatomy, alleviate pain, and ameliorate infertility,12 the recurrence rate and reoperation rate of endometriosis after surgery are relatively high. It has been shown that the incidence of disease relapse is 21.5% within 2 years after surgery, and 4050% within 5 years,13 and the reoperation rate is 2758%.13,14 Surgery combined with hormonal maintenance treatment reduces the risk of disease recurrence,13 but hormonal treatment inhibits follicular development and ovulation, which opposes reproductive requirements in some patients. In recent years, several emerging nonhormonal therapeutic strategies, such as dopamine agonists and bentamapimod, have achieved prospective outcomes and may become complementary treatment options for endometriosis.15

Due to the limitations of existing therapeutic strategies, it is necessary to exploit new supplementary and alternative drugs to improve the treatments of endometriosis. In the past few decades, natural compounds mainly obtained from herbs have been increasingly studied. Natural compounds have potential advantages over synthetic drugs that are developed via target-based assays in terms of tolerance, side effects, and cost-effectiveness, promising to be new therapeutic options for endometriosis. Among them, resveratrol has attracted tremendous attention due to its wide range of biological activities, including anti-neoplastic, anti-oxidant, anti-angiogenic, anti-proliferative, anti-inflammatory, antiglycosylated, antiaging, and pro-apoptotic activities.1621 Resveratrol (3,5,4-trihydroxysilbene) is a natural dietary phytochemical mainly found in beans, peanuts, wine, tea, and some fruits,2225 and it is also found in several microorganisms, such as Botulinum, Penicillium and Cephalosporium.26 Structurally, resveratrol belongs to phenols, existing as cis- or trans-isomers, and it is composed of two aromatic rings linked by an ethylene bridge. Trans-resveratrol can be isomerized into cis-resveratrol when exposed to heat, light, or ultraviolet radiation, of which trans-resveratrol is the major natural form,27,28 and the biological activities of trans-resveratrol are more significant than cis-resveratrol.29,30 Resveratrol has been confirmed to have pleiotropic properties that significantly depend on its structures, including hydroxyl groups, hydrogen bonds and double bonds.31 Some researchers have indicated the possible mechanisms by which resveratrol treats cancers, thereby decreasing the incidence rate and inhibiting the development of diseases. Thus, resveratrol is considered a prospective agent for the treatment of various malignant tumors, such as cervical cancer, breast cancer, liver cancer, pancreatic cancer, colorectal cancer and prostate cancer.17,3235 Other biological activities of resveratrol have also been reported, including cardioprotective, vasorelaxant, phytoestrogenic and neuroprotective activities.3639

Based on the available in vitro, in vivo, and clinical studies as well as the pathology and pathogenesis of endometriosis, this review generalizes the efficacies of resveratrol against endometriosis and its possible molecular mechanisms, highlighting the underlying efficacy of resveratrol in the treatment of endometriosis. This review also provides a comprehensive overview of the theoretical foundation of resveratrol in clinical trials for endometriosis (Figure 1, Table 1).

Table 1 Researches Investigating the Effects and Potential Molecular Mechanisms of Resveratrol Against Endometriosis

Figure 1 Potential molecular mechanisms of resveratrol on endometriosis. This figure was created with MedPeer (www.medpeer.cn).

Abbreviations: , increase; , decrease; Ang-1, angiotensin-1; CAT, catalase; COX-2, Cyclooxygenase-2; ER, estrogen receptor alpha; GLUT, glucose transporters; GSH-Px, glutathione peroxidase; HGF, hepatocyte growth factor; ICAM-1, Intercellular cell adhesion molecule-1; IGF-1, insulin-like growth factor-1; IL, interleukin; INF-, Interferon gamma; M, macrophage; MCP-1, monocyte chemotactic protein 1; MCT, monocarboxylate transporters; MDA, malonyl dialdehyde; MMP, matrix metalloproteinase; MTA1, metastasis-associated protein 1; NK cell, natural killer cell; NO, nitric oxide; PCNA, proliferating cell nuclear antigen; RANTES, regulated upon activation, normal T-cell expressed and secreted; SIRT1, Sirtuin 1; SOD, superoxide dismutase; TGF-, transforming growth factor-beta; TIMP, tissue inhibitors of metalloproteinase; TNF-, tumor necrosis factor-alpha; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; VEGF, vascular endothelial growth factor; ZEB2, zinc finger E-box binding homeobox 2.

Despite research efforts and extensive investigations, the unequivocal etiologies and pathogenesis of endometriosis remain elusive. Currently, several hypotheses have been proposed for endometriosis to illustrate the pathological mechanism as follows: retrograde menstruation, lymphatic and hematogenous dissemination, peritoneal metaplasia, activation of Mullerian residues, and cellular immunity.40,41 However, none of these theories comprehensively accounts for the mechanism and the different biological and clinical characteristics of endometriosis alone. According to literature, the formation and maintenance of ectopic endometrial lesions at ectopic sites are the most basic characteristics of endometriosis and are strongly correlated with the pathology and pathogenesis, such as inflammation, oxidative stress, proliferation, apoptosis, angiogenesis, immunity, invasion, and adhesion.4247 It has also been found that some other factors, such as hormones, heredity, and environment, are implicated in the formation and/or advancement of this disease. Local estrogen augmentation and progesterone resistance are observed in endometriosis, thus promoting the survival, migration, proliferation, and adhesion of ectopic endometrial cells. According to a previous report, first-degree relatives of patients affected by endometriosis have a 710 times increased risk of developing endometriosis,48 and studies in female twins have revealed that the heritability of endometriosis may be up to 50%.2 Several experimental studies on primates and rodents have shown that exposure to tetrachlorodibenzo-p-dioxin (TCDD) and other organochlorine environments (particularly dioxin-like compounds) during adulthood interfere with hormone regulation and immune function, thereby facilitating endometriosis.49

Endometriosis is a proliferative chronic disorder that is mainly characterized by the abnormal endometrial growth at ectopic sites outside the uterine cavity.42 Previous studies have shown an incremental cell proliferation rate of ectopic endometrium in endometriotic patients, which is conductive to survival and implantation into the ectopic site.50 Proliferating cell nuclear antigen (PCNA), a sensitive indicator of proliferation and DNA restoration, exists in the G1, S and G2 phases of the cell cycle, while Ki-67 exists in all active phases and is a more specific proliferative marker than PCNA.51 The proliferative ability of cells is usually be assessed by detecting the expression of proliferative markers.

Bruner-Tran et al firstly evaluated the curative potential of resveratrol on endometriosis in an animal model of endometriosis and endometrial tissues, and they reported that resveratrol reduces the incidence of experimental endometriosis and also decreases the invasion of normal endometrial stromal cells (NESCs) in vitro.51 Additionally, they demonstrated that resveratrol attenuates the formation and advancement of endometriosis by suppressing cell proliferation, promoting apoptosis, and reducing invasiveness. However, the efficacy of resveratrol against proliferation in ectopic endometrial lesions remains unclear as they reported to upregulate expression of PCNA but to downregulate expression of Ki-67 in implants.51

In peritoneal and mesenteric endometriosis rat model, Rudzitis-Auth et al reported that resveratrol treatment reduces the number of PCNA+ and Ki-67+ endometrial cells, thereby mitigating the growth rate of endometriotic implants compared to the control group. In addition, they demonstrated that resveratrol suppresses the formation of novel microvasculature in endometriotic implants by inhibiting the proliferative activity of CD31+ endothelial cells.52

Apoptosis is the process of programmed cell death, that helps sustain intracellular homeostasis by scavenging dysfunctional cells from the endometrium during the menstrual cycle.43 Compared to healthy participants, patients affected by endometriosis have impaired spontaneous apoptosis of ectopic and eutopic endometrium, leading to growth and implantation of endometrial tissues at ectopic areas.53 This resistance to apoptosis is associated with increased expression of anti-apoptotic factors (eg, B-cell lymphoma-2 (Bcl-2)) and decreased expression of pro-apoptotic factors (eg, caspase-3, Bcl-2 associated X (Bax)).53,54

To date, the effect of resveratrol on cell apoptosis in endometriosis has been evaluated through several animal models and in vitro experiments. Madanes et al investigated the mechanism of resveratrol in endometrial cells, and they reported that this compound remarkably reduces cell viability and induces apoptosis by increasing caspase-3 cleavage in two cell lines, namely, endometriotic epithelial cells (12Z) and endometrial stromal cells (St-T1b).55 The property of invasiveness depends on the ratio of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs).56 Furthermore, resveratrol mitigates the ability of invasion and angiogenesis by lowering the gene expression ratio of MMP-2/TIMP-1 and suppressing the mRNA expression of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1).55

In an in vitro three-dimensional culture model of endometriosis, Khazaei et al investigated the effects of resveratrol at various doses on human endometrial overgrowth, neovascularization, and the expression of apoptosis-related genes, and they reported that resveratrol attenuates the growth of endothelial cells, stromal and epithelial cells in a dose-dependent manner.57 Furthermore, these researchers demonstrated that resveratrol fully inhibits growth and angiogenesis at a concentration of 200 M. They also reported that resveratrol decreases the level of nitric oxide (NO, a vasodilator and messenger molecule in the process of angiogenesis), and significantly increases the expression levels of pro-apoptotic genes, such as Sirtuin-1 (SIRT1), Bax, caspase-3 and p53, and decreases the ratio of Bax/Bcl-2.57 Additionally, another study has assessed the influence of resveratrol on Bax and Bcl-2 gene expression within ectopic endometrial stromal cells (EcESCs), eutopic endometrial stromal cells (EuESCs), and NESCs, demonstrating that resveratrol intervention effectively decreases the gene expression ratio of Bax/Bcl-2 in EuESCs and NESCs but not in EcESCs.58

In addition to the aforementioned effects of resveratrol on endometriosis, a previous study has demonstrated that pretreatment with resveratrol diminishes the level of the anti-apoptotic protein, survivin, as well as suppresses the apoptosis resistance of EcESCs and accelerates apoptosis induced by tumor necrosis factor-alpha (TNF-) related apoptosis-inducing ligand (TRAIL).59

Angiogenesis, the formation of neovascularization, is a sophisticated multistage procedure that includes the following processes: coordinated expression of genes encoding angiogenic growth factors, disintegration of extracellular matrix, migration and proliferation of endothelial cells, and formation of capillary tubes.60 Because the implantation, proliferation, and growth of endometriotic lesions require a new blood supply, angiogenesis plays an essential role in the establishment and maintenance of endometriotic lesions.44 Based on the literature, increased levels of cytokines related to angiogenesis, such as VEGF, MMPs, TNF-, interleukin-6 (IL-6), IL-8, transforming growth factor-beta (TGF-), hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), platelet-derived growth factor (PDGF), angiopoietin, macrophage migration inhibitory factor (MIF), erythropoietin, neutrophil activating factor, and tissue factor (TF), have been measured in the peritoneal fluid (PF) of endometriotic patients compared to disease-free women.6163 Moreover, inflammation, oxygen deficiency, endothelial cell damage, and disturbances in acid-base imbalance also facilitate the formation of new blood vessels.64,65 These factors are collectively implicated in the angiogenesis of endometriosis.

VEGF, the most prominent angiogenic factor in endometriosis,63 which is produced by EcESCs, EuESCs, peritoneal macrophages, and neutrophils, triggers endothelial cell proliferation, migration, and survival during the process of angiogenesis, and it increases vascular permeability, thus enhancing the development of endometriosis.66,67 Compared to the non-endometriotic controls, markedly increased levels of VEGF have been detected in the PF, serum, EcESCs and EuESCs of endometriotic women, and the level is linked to the clinical stage.6870 However, there is no distinction in VEGF levels in either blood or urine.71 TGF- is involved in mediating numerous cell functions, such as cell proliferation, apoptosis, angiogenesis, inflammation, migration, adhesion, differentiation, tumor inhibition, and immune functions. TGF- may promote the survival of ectopic endometrial cells, strengthen apoptosis resistance, accelerate invasion, and initiate neoangiogenesis by inducing alterations in cellular metabolism, thereby leading to the progression of endometriosis.72 Compared to the non-endometriotic controls, the levels of TGF- in serum, PF, ectopic endometriotic lesions, and peritoneal tissue of endometriotic patients are higher, and it is linked to the degree of inflammation.73,74

To evaluate the anti-angiogenic effects of resveratrol, a previous study applied resveratrol to treat endometriosis in a mesenteric endometriosis rat model as well as treated EuESCs and NESCs with resveratrol. Ricci et al suggested that resveratrol diminishes the vascular density and reduces the numbers and volumes of endometriotic lesions.75 They also reported that resveratrol suppresses cell proliferation and promotes cell apoptosis, further inhibiting the occurrence and development of endometriotic lesions.75

Two studies have evaluated the therapeutic efficacy of resveratrol in an experimental rat model and compared this effect to leuprolide acetate, a GnRH analog, demonstrating that the effectiveness of resveratrol on endometriosis is equivalent to that of leuprolide acetate. Both resveratrol and leuprolide acetate have the following effects: significantly decrease the volume and histopathological scores of endometriotic lesions, downregulate the expression of VEGF, MMP-2, and MMP-9 in implants, reduce the levels of monocyte chemoattractant protein-1 (MCP-1) and VEGF in serum and PF, and reduce the levels of TNF-, IL-6, and IL-8 in plasma and PF. Interestingly, the drug combination of resveratrol and leuprolide acetate represses the anti-angiogenic and anti-inflammatory efficacy compared to treatment with each drug alone.76,77 Additionally, Ergenolu et al reported that resveratrol treatment in a rat endometriosis model minimizes the size of endometriosis lesions and decreases VEGF level in the PF and plasma as well as downregulates VEGF expression in endometriotic lesions.78

Bahrami et al reported that resveratrol, atorvastatin alone, and particularly the combination of resveratrol and atorvastatin diminish the size of endometriotic lesions, reduce the number of new blood vessels, and inhibit the expression of glycolysis-related proteins, such as glucose transporters-1 (GLUT-1) and GLUT-3 and monocarboxylate transporters-1 (MCT-1) and MCT-4 in a rat model of endometriosis, suggesting that resveratrol inhibits the establishment and development of ectopic endometrial tissue by suppressing glycolysis and angiogenesis.79

In vitro experiments have revealed higher basic gene and protein expression levels of VEGF, MMP-9, IGF-1, and HGF in EcESCs compared to EuESCs and NESCs, and resveratrol intervention significantly reduces the gene and protein expression levels of VEGF, MMP-9, and TGF- in EcESCs and EuESCs, as well as downregulates the gene expression levels of VEGF and MMP-9 in NESCs.80,81 Reduced expression of IGF-1 and HGF has also been observed in EcESCs and EuESCs after resveratrol intervention, especially in EcESCs, which are effective promotors of ectopic endometrial lesions, owing to their role in growth, proliferation, invasion, and angiogenesis.80,81

Khodarahmian et al conducted a randomized exploratory clinical study, in which endometriotic patients with stage IIIIV were treated with resveratrol (400 mg) or placebo for 12 to 14 weeks in addition to COCs.82 The results show that resveratrol remarkably reduced the protein and gene expression levels of TNF- and VEGF in eutopic endometrial tissues, compared to the control group and before intervention. Thus, they suggested that resveratrol mitigates angiogenesis and inflammation in the endometrium of endometriotic patients by undermining the expression of TNF- and VEGF.82

Endometriosis, an inflammatory disease, is relevant to chronic inflammation and immune dysregulation in the peritoneal microenvironment.45 Several studies have reported that levels of pro-inflammatory cytokines and chemokines, such as IL-1, IL-4, IL-6, IL-8, IL-12, TGF-, TNF-, prostaglandin (PG), growth factor, MCP-1, and regulated upon activation, normal T cell expressed and secreted (RANTES), are higher in the PF of women affected by endometriosis compared to disease-free participants.8385 These inflammatory mediators may participate in the establishment and advancement of endometriosis, and they are secreted by activated macrophages, lymphocytes, endometriotic lesions, and peritoneal mesothelial cells, thereby promoting the viability, proliferation, adhesion, invasiveness, and angiogenesis of endometrial cells.86

Macrophages are the most common member of the immune cell family in endometriosis, and activated macrophages modulate the peritoneal microenvironment through phagocytosis and secretion of immune mediators.85 M1 and M2 are two main categories of activated macrophages, M1 predominantly participate in the pro-inflammatory response, inhibit cell proliferation, and exacerbate tissue damage, while M2 mainly participate in anti-inflammatory reactions, tissue repair, and angiogenesis.87,88 Evidences suggest that in endometriotic women, the macrophages in the eutopic endometrium are mostly M1-polarized, while those in the ectopic endometrium are mostly M2-polarized.89 Macrophages depletion tests have demonstrated that M2 enhance the growth and vascularization of endometriotic lesions, while M1 effectively protect mice from endometriosis.90 In an experimental endometriosis rat model, Wang et al reported that the number of activated macrophages is increased in the PF, which agreed with other studies. However, they reported that M1/M2 polarization in the PF is increased and resveratrol reduces the M1/M2 polarization, which contradicts other studies.91 The inconsistent conclusions may be explained by the measurement of different samples. Wang et al detected macrophage polarization in the PF, while other researchers detected macrophage polarization in endometriotic lesions. Additionally, Wang et al reported that resveratrol decreases the mRNA expression levels of the pro-inflammatory cytokines IL-6, TNF-, and interferon gamma (INF-) but increases the mRNA expression levels of the anti-inflammatory IL-10.91

MCP-1, also known as chemokine (C-C motif) ligand 2 (CCL2), binds to its receptor, CCR2, and then activates the signaling pathways regulating cell migration, further promoting the migration of inflammatory cells, such as monocytes/macrophages, and infiltration of other cytokines in the inflammatory site.92 MCP-1 is generated by fibroblasts, macrophages, endothelial cells, epithelial cells, EcESCs, and EuESCs.86,92 Some studies have demonstrated that the expression level of MCP-1 in the serum, PF, and EcESCs is higher in endometriotic patients than in non-endometriotic controls.93,94 Heidari et al assessed the effects of resveratrol on endometriosis by isolating EcESCs and EuESCs from endometriotic patients and NESCs from disease-free participants.87 They demonstrated that the protein and gene expression levels of MCP-1 were higher in EcESCs compared to EuESCs and NESCs under basic conditions, but that resveratrol (100 M) intervention significantly downregulates the expression of MCP-1 and RANTES in EcESCs.87 Similarly, other studies have reported that resveratrol reduces MCP-1 level in the PF of endometriotic animal models.76,78

IL-6, an inflammatory cytokine, stimulates M2 polarization of peritoneal macrophages, weakens phagocytosis of macrophages, reduces cytotoxicity of natural killer (NK) cells, and facilitates the synthesis of aromatase, consequently promoting the progression of endometriotic lesions.89,9597 IL-8, a pro-inflammatory, pro-angiogenic, and growth-promoting cytokine, enhances the expression of various adhesion molecules and neutrophil chemotaxis, and it may also promote the initial adherence of endometrial cells to the peritoneum surfaces.98 Numerous studies have reported that the levels of IL-6 and IL-8 in the PF and serum of endometriotic patients are significantly higher than those in individuals without endometriosis and they increase correspondingly with the aggravation of endometriosis stage.93,98,99 Additionally, the levels of IL-6 and IL-8 are higher in EcESCs compared to EuECSs,100 and the increased expression of IL-6 and IL-8 increases the migration and invasion abilities of EcESCs.99,101 Using an experimental endometriosis model, Bayoglu Tekin et al revealed that resveratrol reduces the levels of IL-6 and IL-8 in the PF and serum compared to the control group.77 Consistent with their findings, another study has evaluated the impacts of resveratrol on IL-6 and IL-8 mRNA and protein expression in EcESCs, EuESCs, and NESCs, demonstrating that resveratrol reduces the expression of IL-6 and IL-8 in EcESCs compared to the EuESCs and NESCs groups.86

TNF- is implicated as a pivotal factor in the inflammatory response and immunopathological injury.102 Previous studies have reported that ectopic endometrial tissue stimulates humoral and cellular immunity, acting as an antigen, which results in an increased number and activity of macrophages and lymphocytes, thereby increasing the expression of TNF-.103 The level of TNF- is increased in the PF and serum of endometriotic women, and it is closely related to the stage of endometriosis, which may contribute to the production of other cytokines and the proliferation, adhesion, and angiogenesis of endometrial cells.103,104 Similarly, in vitro, animal, and clinical exploratory experiments have demonstrated that resveratrol decreases the levels of TNF- in the PF and endometrial tissues of the endometriosis groups.77,91,105 Other studies have reported that resveratrol alleviates TNF--stimulated inflammatory injury in late-stage endothelial progenitor cells (EPCs) by reducing the expression of intercellular adhesion molecule 1 (ICAM-1) and MCP-1.106 Additionally, resveratrol suppresses the invasiveness of human hepatoma cells by inhibiting nuclear factor-kappa B (NF-B) activity to reduce TNF--mediated MMP-9 expression.107

SIRT1 is involved in the modulation of inflammation. The increased activity and overexpression of SIRT1 suppresses the production of inflammatory cytokines,108,109 while SIRT1 deficiency stimulates the inflammatory response.110 SIRT1 also has a role in oxidative stress. Resveratrol treatment can reverse the experimental induced oxidative stress condition and upregulate SIRT1 expression.111 Taguchi et al reported that resveratrol ameliorates local inflammation in endometriosis by suppressing TNF--induced IL-8 release in a dose-dependent manner via the SIRT1 pathway.112

Cyclooxygenase-2 (COX-2), a rate-limiting enzyme of prostaglandin E2 (PGE2) biosynthesis,113 is an essential part of the positive feedback circulation of estradiol (E2)-COX-2-PGE2-aromatase-E2, and upregulated COX-2 expression decreases apoptosis and promotes proliferation, invasiveness, angiogenesis, endometriosis-related pain, and infertility.114 The expression of COX-2 in the ectopic and eutopic endometrium of endometriotic women is upregulated compared to the normal endometrium of disease-free individuals.115 In a clinical trial, Maia et al reported that resveratrol promotes the effectiveness of COCs to alleviate dysmenorrhea by downregulating the expression of COX-2 and aromatase in the endometrium.116 Nonetheless, another clinical study has reported that resveratrol has no advantage over placebo in treating endometriosis-related pain.117

Oxidative stress is characterized by an imbalance between anti-oxidant defense and oxidation,118 resulting in the accumulation of ROS and oxidation products as well as causing damage to molecules, cells, and the organisms. ROS mediate cytotoxicity by interacting with lipids, proteins (especially cysteine residues), and nucleic acids.119 Based on data from previous research, the oxidative stress of endometriosis is associated with increased ROS and oxidation products, reduced anti-oxidant enzymes and detoxifying enzymes, disordered iron metabolism, and elevated number of activated macrophages. An increased level of oxidative stress gives rise to inflammation, angiogenesis, cell proliferation, cell adhesion, and extracellular matrix degradation, resulting in endometriosis and infertility.47,120,121

NF-B, a transcription factor, modulates the expression of a variety of genes encoding angiogenic factors, growth factors, pro-inflammatory factors, chemokines, and adhesion molecules, such as ICAM-1, as well as inducible enzymes, such as inducible nitric oxide synthase (iNOS) and COX-2.122,139 These gene products facilitate cell proliferation, adhesion, inflammation, angiogenesis, and oxidative stress, thereby implicating the progression of endometriosis.123 NF-B initiates gene transcription of gp91-phox, the catalytic subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which is implicated in the electron transport chain of oxidative phosphorylation and responsible for donating electrons from NADPH to molecular oxygen to generate superoxide anion, consequently increasing oxidative stress.119 Another study has reported that NF-B-mediated transcriptional activation of COX-2 also inhibits apoptosis and promotes cell proliferation in endometriosis.124 Oxidative stress and iron overload activate the NF-B signaling pathway and elevate IL-10 levels in the serum and PF of patients affected by endometriosis, leading to MMPs activation, extracellular matrix (ECM) remodeling, and neovascularization.115 Elevated levels of INF- and IL-10 resulting from increased IL-2 and IL-27 are able to collaboratively accelerate the proliferation and invasion of endometrial stromal cells.125

The role of oxidative stress in endometriosis is generally assessed by ROS markers, including malondialdehyde (MDA), oxidative products, and enzyme antioxidants, such as glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD).126 Using resveratrol in experimental endometriosis rats, Yavuz et al showed that resveratrol increases SOD and GSH-Px activities in ectopic endometrial tissues and serum in a dose-dependent manner as well as increases CAT levels in tissues.127 And they reported that resveratrol reduces MDA levels in tissues and serum but not to a significant extent compared to the control group. Whats more, resveratrol effectively diminishes implant sizes, histological scores, and PCNA expression levels were observed. And they demonstrated that resveratrol inhibits oxidative stress by activating endogenous antioxidant capacity to ameliorate endometriosis.127 In diazinon (DZN)-induced oxidative stress rat models, Mehri et a reported that DZN inhibits serum acetylcholinesterase (AChE) as well as serum and liver CAT, GSH-Px, and total antioxidant abilities, and they also demonstrated that resveratrol reverses the oxidative stress conditions, improves the activity of antioxidant enzymes, and lower MDA level in the serum and liver.111

In view of Sampsons theory, invasion and adhesion are key processes in the establishment of endometriosis.128 Elevated levels of MMPs, especially MMP-2 and MMP-9, as well as cell adhesion molecules, such as ICAM-1, integrin, and cadherin, have been reported in the PF of endometriotic women, which collectively exert influences on the invasion and adhesion of ectopic endometrium.46,129,130

MMPs, a group of zinc-dependent proteolytic enzymes, play an important role in the degradation of ECM, which is a vital step of ectopic endometrial cell implantation and endometriosis formation.131 A comprehensive analysis of previous studies has revealed that MMPs are implicated in multiple stages associated with endometriosis formation as follows: endometrial cells migrating from the uterine cavity and implanting in peritoneal surfaces, vascular endothelial cells migrating to new blood vessels, macrophages distinguishing and phagocytizing escape cells, and NK cells killing target cells. These stages promote cell migration, cell invasion, angiogenesis, ephemeral mesenchymal transformation (EMT), fibrosis, and regulation of immune cells or autoimmune factors, ultimately inducing endometriosis.132 ECM protein degradation and tissue remodeling play pivotal roles in ectopic endometrial cell implantation and endometriotic lesion formation, and the extent of which is generally determined by the MMP/TIMP ratio.133 PGE2 and COX-2 can facilitate angiogenesis indirectly by mediating MMP-2 activity.113 Chen et al revealed that resveratrol reduces invasiveness and proliferation as well as induces early apoptosis of EcESCs in a dose-dependent manner.134 Moreover, they reported that resveratrol effectively reduces the gene expression of VEGF, Bcl-2 and MMP-2 as well as the protein expression levels of ICAM-1 and MMP-2. Additionally, they showed that resveratrol corrects aberrant lipid distribution in endometriosis model rats.134 An exploratory clinical trial has indicated that the gene and protein expressions levels of MMP-2 and MMP-9 are significantly decreased within endometrial tissues, endometrial fluid, and serum after resveratrol intervention compared to controls.105

EMT is the trans-differentiation of epithelial cells into mesenchymal cells. Zinc-finger E-box-binding (ZEB) and other transcription factors drive EMT by increasing mesenchymal maker (eg, vimentin) expression and decreasing epithelial marker (eg, E-cadherin) expression, which further degrades the extracellular matrix, promoting invasion ability.132,135 To the best of our knowledge, metastasis-associated protein 1 (MTA1) induces EMT in a variety of cancers to promote disease progression and metastasis,136 and it is overexpressed in endometrial cancer to promote carcinoma cell proliferation, migration, and invasion.137 A thorough exploration of the Gene Expression Omnibus (GEO) database has indicated that the expression levels of MTA1 and ZEB2 are upregulated in ectopic endometrial tissues.138 Kong et al found that MTA1 interacts with ZEB2 to induce EMT, thus facilitating the proliferation, migration, and invasiveness of NESCs, while resveratrol downregulates the expression of MTA1 and ZEB2 as well as inhibits their promoting function.138 In an endometriosis mouse model, compared with the eutopic endometrium, the expression of MTA1, ZEB2, and vimentin is increased in endometriotic implants, but E-cadherin expression is decreased, however, resveratrol reverses these phenomena by inhibiting the growth of ectopic endometrium and suppressing the expression of MTA1, ZEB2, and vimentin as well as promoting the expression of E-cadherin.138

Endometriosis is regarded as hormone-dependent as several studies have reported that the endometrium is modulated by steroid hormones, mainly including estrogen and progesterone, which regulate the expression of various genes at diverse stages of the menstrual cycle.140 The level of estrogen detected in the ectopic endometrium of endometriotic women is elevated compared to that in the eutopic endometrium or normal endometrium, which depends on local estrogen metabolism rather than circulating levels.141 Ectopic endometrial tissues can synthesize abundant E2 de novo from cholesterol, resulting from the high expression of aromatase (the key enzyme for estrogen biosynthesis) and steroidogenic acute regulatory protein (StAR), while normal endometrial tissues cannot synthesize estrogen due to the lack of these enzymes.142 Moreover, some inflammatory factors are also involved in the synthesis of local E2. The elevated level of COX-2 increases the expression of PGE2, which activates the aromatase gene promoter, resulting in aromatase overexpression and accumulation. Furthermore, E2 stimulates the expression of COX-2 by binding to its receptor, estrogen receptor beta (ER). Thus, estrogen generation and chronic inflammation form a vicious spiral under the positive feedback cycle of E2-COX-2-PGE2-aromatase-E2.114

Because immunoreactive ER and progesterone receptor (PR) exist in ectopic and eutopic endometrium, they show similar histological changes in response to estrogen and progesterone.143 PR-A and PR-B are the main subtypes of PRs in the endometrium, of which PR-B plays more important biological functions. In EcESCs of endometriotic patients, the methylation of the PR-B transcription factor is enhanced, resulting in progesterone resistance, which is consistent with the report that EuESCs of women with endometriosis are less responsive to progesterone.144 ERs in the endometrium mainly consist of ER and ER. The expression of ER is more prominent in healthy endometrial tissues, while the expression of ER is more prominent in ectopic endometrial tissues.145 The ER level in EcESCs cultured in vitro is 142 times higher than that in NESCs, while the ER level in EcESCs is 9 times lower than that in NESCs.146 ER and ER may be cooperatively responsible for the regulation of proliferation, adhesion, and inflammation in the initiation of endometriotic lesions. Besides, ER principally triggers angiogenesis, and ER exerts a leading role in the pro-invasive capability, anti-apoptotic effects and activation of inflammatory bodies to maintain survival.147

Using an experimental animal model, Han et al showed that overexpressed ER in ectopic endometrium attenuates TNF--induced apoptosis, elevates the level of IL-1 to promote inflammation, and enhances EMT to facilitate invasion and adhesion.147 Amaya et al suggested that resveratrol is an estrogen agonist or antagonist at lower or higher levels, respectively.39 Their another study using a recombination activating gene-2 mouse model of endometriosis has demonstrated that the expression of Ki-67 and ER in the endometrial epithelium is downregulated, and that ER is reduced to a level similar to that with progesterone treatment. However, progesterone treatment dose not decrease the Ki-67 expression level. Therefore, these researchers proposed that high-dose resveratrol reduces proliferation activity of the endometrial epithelium by inhibiting ER expression.39

Resveratrol mostly exists in dietary foods in a glycosylated form, which prevents resveratrol from enzymatic oxidation in the digestive tract, thus preserving its biological activity and overall stability.148,149 However, intestine cells absorb only resveratrol aglycone via transepithelial diffusion with an absorption rate of approximately 75%. Pharmacokinetics studies have confirmed that resveratrol is rapidly and comprehensively metabolized through the intestine and liver, and the main glucoside and sulfate metabolites of resveratrol are produced through glucuronidation and sulfation.149,150 Therefore, it has been proposed that improving the content of resveratrol glycosylation and aglycone may increase its absorption rate in foods and beverages.151 Despite good lipophilicity and a high absorption rate, these coupling reactions (glucuronidation and sulfation) also decrease cell permeability to the drug, increase the polarity of the drug, and promote drug excretion from the body. Evidence suggests that after extensive metabolism of resveratrol in the intestines and liver, nearly 75% of the metabolites are scavenged from the body through urine and feces, ultimately, the oral bioavailability of resveratrol is less than 1%.149,152 Thus, the limited effect of resveratrol results from its rapid metabolic rate in vivo.153

Walle et al reported that the plasma concentration of resveratrol is less than 10 ng/mL following oral administration of 25 mg resveratrol in humans, and the plasma concentration is 500 ng/mL after taking 5000 mg of high-dose resveratrol, indicating that increased or repeated dose of resveratrol does not significantly improve the bioavailability.149 To date, it is generally believed that the limited bioavailability of resveratrol is largely due to its poor water solubility, thus, a variety of formulations and strategies have been developed, including nanocarriers, liposomes, and synthetic derivatives (aromatic rings contain different substituents, such as methoxy, hydroxyl, or halogen), to improve the bioavailability.154156 Compared to free resveratrol, some studies have reported that resveratrol nanoparticles increase the uptake and sustained release in target cells as well as the toxicity of resveratrol to these cells, thereby improving the bioavailability,157 and the absorption rate of resveratrol nanoparticles conjugated with polyethylene glycol is increased by 7-fold.158 Methylation of resveratrol enhances the water solubility and bioavailability of resveratrol, and Summerlin et al proposed that methylated resveratrol synthesized by in vitro metabolic engineering (recombinant Escherichia coli) is superior to chemosynthesis in biological activity.157 Importantly, in the process of drug research and development, attention should be focused on amending the structure, bioavailability and activity of resveratrol.

Comprehensive testing has indicated that oral administration of resveratrol is considered safe.159 A previous rat experiment has demonstrated that resveratrol effectively suppresses the growth of ovarian cancer but does not affect normal tissues.160 Another study has reported that resveratrol regulates the proliferation and apoptosis of cancer cells and epithelial cells in a dose-dependent manner. Resveratrol exerts a time- and concentration-dependent pro-apoptotic impact on cancer cells.161 Besides, resveratrol protects healthy cells and induces cancer cell death, which may be due to its inconsistent molecular targets and metabolic pathways within these cells.162 Experimental animal models have shown good tolerance to resveratrol. For instance, CD rats receiving resveratrol at a daily dosage of 200 mg/kg and beagle dogs receiving resveratrol at a daily dosage of 600 mg/kg for 90 days do not show any obvious biological adverse effects.163 In CD rats, a high daily dose of resveratrol (1000 mg/kg, lasting for 1013 weeks) increases the level of bilirubin without any gross or microscopic changes associated with liver injury, and the high dose of resveratrol administration reduces the incidence of cardiomyopathy. Notably, elevated bilirubin has not been reported in beagle dogs exposed to any dose level of resveratrol.163

By evaluating the potential toxicity of resveratrol, Crowell et al reported that rats fed resveratrol at a high daily dosage (3000 mg/kg, lasting for 4 weeks) show elevated levels of transaminase, bilirubin, creatinine, and blood urea nitrogen (BUN) as well as increased incidence and severity of nephrosis but with no histological changes in the liver.164 Liu et al used an experimental renal fibrosis mouse model to estimate the impact of resveratrol on renal fibrosis.165 They found that resveratrol at low dosage (25 mg/kg) partially ameliorates kidney function by mitigating unilateral ureteric blockage, while a high dosage (50 mg/kg) fails to prevent fibrosis and aggravates renal fibrosis in mice. These researchers also concluded that mice with ureteric blockage are more predisposed to kidney injuries induced by high-dose resveratrol than normal mice.165 Some researchers have considered that the effective dosage range of this compound in cells is inconsistent with the concentration in the human body, therefore, it is difficult to ascertain the efficacious concentration range of resveratrol in participants.166 The safety of resveratrol in humans has been assessed at different doses in several clinical studies, and these studies have indicated that resveratrol has no obvious adverse effects.167173 Resveratrol is safe and well-tolerated in a disease-free population following a single dose of 500 mg resveratrol tablet.172 Another study has suggested that resveratrol is considered to be safe at daily doses up to 5000 mg and these slight adverse effects, such as alopecia, nausea, headache, and diarrhea, occur only when taking a high oral dose of resveratrol (>2500 mg, every 4 hours).173 Since these studies on the toxicity of resveratrol were conducted in endometriosis-free participants, it is possible that the side effects of resveratrol may vary in patients with endometriosis.

As a substitute or supplement treatment for endometriosis, resveratrol is a promising candidate. To date, however, the clinical trials evaluating the role of resveratrol in endometriosis have been small samples and lack an assessment of its side effects. 82,105,116,117 The optimal drug dosage to maximize the health benefits of resveratrol without causing toxicity requires further supporting evidence, suggesting that additional comprehensive studies are needed.29,166 Furthermore, it is not easy to determine the therapeutic effect of resveratrol at a specific dosage as well as the precise dosage safety range in patients with endometriosis. Thus, the optimum dosage and preparation method of resveratrol need to be further explored.

Botanical therapies (or herbal medicines) have been used to combat diseases for a long time in human history, especially for infectious diseases, cancer, and other chronic ailments. The basis of these synergistic therapeutic effects of the therapies and herbal medicines is bioactive compounds within the mixtures or crude preparations. More precisely and scientifically, compounds found in the natural sources (eg, plants, animals, microorganisms, and minerals) are defined as natural products (NPs). Due to their vast scaffold diversity, structural complexity, and stability, NPs have received much attention in the drug discovery process. To date, many successfully approved drugs have been derived from NPs, such as Taxol (oncology), Fumagillin (antiparasitic), Trabectedin (oncology).

Resveratrol, a natural product, is mainly found in the grapes and red wines, and it also exists in some other plants and several genera of microorganisms. Based on in vitro, animal, and clinical studies associated with endometriosis, resveratrol has been reported to have multiple biological functions, such as anti-proliferative, pro-apoptotic, anti-angiogenic, anti-oxidant, anti-invasive, and anti-adhesive effects. Accumulated evidences confirm that resveratrol is a relatively safe and well-tolerated compound for humans, but it is also an inefficient agent due to its rapid metabolic rate in vivo. Nanocarriers, liposomes, and synthetic derivatives of resveratrol have been explored to increase its biological availability. In the light of existing evidence, resveratrol is effective and potential in endometriosis, we speculate that resveratrol may be a new supplementary and adjuvant drug for the treatment of endometriosis. However, the exact molecular mechanisms are not fully elucidated, and the majority of studies have been conducted on in vitro and rodent animal models, with a few clinical studies. Furthermore, there are distinctions in the reproductive physiology between humans and rodents because rodents never develop endometriosis spontaneously due to a lack of menstruation. Consequently, caution is always warranted when extrapolating results obtained from in vitro experiments or animal models to humans, and further high-quality clinical trials with large sample sizes should be implemented to assess the effectiveness and clinical application feasibility of resveratrol in endometriosis.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

This research was funded by the Doctoral Research Initiation Fund of the Affiliated Hospital of Southwest Medical University (No. 18061), the Fund for High-level Talents in Luzhou City (No. 02/00180117).

The authors report no conflicts of interest in this work.

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Key themes from Vitafoods 2023 – NutraIngredients.com

Here is a whistle-stop tour of some of the innovations which exemplify these themes.

"Instagrammable" capsules:

Lonza provided a fun twist on capsule formats with capsugel liquid-filled capsules.The duocap capsule-in-capsule, means that the outer capsule can

be liquid or semi-solid, and the inner capsule can contain liquid, semi-solids, powder or beadlets.Joris Dewit, Executive Director and Head of Dosage Form Solutions and Ingredients at Lonza, said: Theyre intagrammable, can combine incompatible ingredients, and can come in many bespoke profiles.

Chewing gum to cut cravings:

Israeli startup Sweet Victory presented in the Startup Innovation Challenge introducing GymnemaSylvestre extract in chewing gum format. With itsglucose like moleculesit works to block sugar receptors to curb cravings. The founders claim consumers need only chew on one piece of gum for a few minutes to reduce sugar cravings.

Coffee gummies:

And for those needing a pep-up, Israeli company TopGum has released high caffeine 'cappuccino gummies'.In addition to providing the full coffee sensory experience, TopGum's gummies deliver a functional dose of caffeine: Each serving of two coffee gummies contains 40 mg of caffeine, which is equivalent to a standard espresso shot.Eli Edri, TopGum's COO and VP of strategic partnerships said: "Over the last couple of years, we worked on the development of a state-of-the-art microencapsulation technology called TopCaps that is uniquely tailored for gummies. This innovative technology allows consumers to savour the flavour and aroma of coffee-on-the-go, while energising themselves with a single chewy treat."

Marshmallow collagen:

EssentiaProtein Solutions showcased its Omnicol bovine collagen peptides in a marshmallow from. They note the concept is a nearly fat free treat providing 19 grams of collagen per 100 grams.

Calming gummies:

Herbaland calm & chill gummies for kids includeMagnesium and Chamomile Extract andpromise to help relieve restlessness and nervousness andrelieve inflammatory conditions of the gastrointestinal tract.Consumers are directed to take two of the strawberry flavour gummies per day to add a little 'calm to their day'.

Meanwhile Finzelberg showcased their Concental gummies. Utilising the company's Sideritis scardicaGreek tea extract, the gummies provide a tasty solution for increasing attention and reducing anxiety levels via the regulation of blood flow in the brain.

And Kerry created lemongrass-flavoured gummies with the firm's Sensoril Ashwagandha ingredient for a stress-relieving tasty supplement solution.

Chill out chocolate:

Providing an indulgent solution with calming benefits, Prinova developed a high protein plant-based recovery hot chocolate concept, including AlphaTea, the firm's branded L-Theanine sourced from green tea extract, shown to reduce stress and anxiety levels.

Resveratrol:

Resveratrol has been found to improve brain functionality through SIRT1 activation and inflammation modulation, prevention of oxidative stress, and via regulation of some signalling pathways. This ingredient was spotlighted at many stands including Veri-te, where the team showcased a range of food and drink formats, including chocolate truffles.

Gut-Brain:

NovozymesOneHealth showcased its ProbioBrain ingredient, a probiotic for mental wellness featuringBifidobacterium longum1714, targeting the gut-brain axis.Manel Berga, head of sales operations, told NutraIngredients: Sleep, mood, and stress are of particular interest to us. And we see that continuing togather interest in the industry. Brain health is a trend that is here to stay.

Low-stress sport:

Discussing the importance of adding additional functional benefits to protein powders, Fonterra highlighted its 'Nutiani Body + Brain'

range - in powder,drink and bar formats - offering protein alongside phospholipids to support cognition, focus and reduce stress. Alex Williams, marketing manager Europe, told NutraIngredients: "We are seeing other protein powders on the market with cognitive health benefits and they are performing very well but this is the first protein powder with phospholipids."

Gut-skin axis:

ADM brought its VitaSkin capsules to the show, formulated to target skin vitality, while also supporting the gut-skin axis using a blend of probiotics, zinc and vitamins A and C.

Nutraceutical gummies:

Sirio created gummy solutions for the beauty-from-within consumer withtwo new products. Its Jumping Jacks gummy is a type II collagen-powered sports nutrition gummy for joint health. Sirio partnered with Lonza for the inclusion of its patented UC-II collagen which is effective at just 40 mg per day and backed by 11 clinical trials. ItsPerfect Glow gummy is the "worlds first" full-spectrum (type I, II and III) collagen-based gummy for visible effects on skin elasticity, smoothness and glow.

Postbiotic gummies:

ADM concentrated on microbiome modulating solutions providing a range of scientifically backed benefits. Offering metabolic health benefits,ADMs apple and blackcurrant Bio Trinity Gummies featured a combination of fiber, plant extracts and vitamin E. And with a 'healthy living' focus,the firm showed its balanced wellness Red Beat Walk beverage concept supporting weight management, skin health, energy, immune function and metabolic health with probiotics, green tea extract, fiber, botanicals and vitamins B and D.

Carob prebiotics:

Foodtech startup Carobway joined the show to spotlight its potential in the prebiotic space.One formulation under development is a prebiotic powder enriched with fibers and polyphenols that possess anti-inflammatory properties and support a healthy gut microbiome. Following bioavailability and bio-accessibility studies, the start-up will advance a series of microbiome studies to explore the effect of its prebiotic on human microbiota diversity and specificmicrobes.

Menopause gummies:

A number of exhibitors showed awareness of the growing interest in menopause supporting solutions, ncluding HTC who showcased menopause gummies. The firm makes us of a range of hormone influencing ingredients including: starflower oil (aka borage oil) which is a rich source of gamma-linoleic acid (GLA); andEvening Primrose Oil, which is rich in omega-6and there is some evidence to suggest it could help relieve hot flashes and the symptoms of premenstrual syndrome (PMS).

Balancing botanicals:

Tilmans' brought its Pre-ms product to the show, combining evening primrose oil and lavender oil in capsule format to contribute to hormonal balance during the premenstrual period.

Hot flash relief treat:

Focusing ontheir Novasoy soy isoflavone concentrate, ADM produced a chocolate concept to deliver extracted genistein, an ingredient important for relief of hot flashes.

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