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Resveratrol and endometriosis: In vitro and animal studies and underlying mechanisms (Review)
Abstract
Endometriosis is characterized by the existence of endometrial tissue and stroma exterior to the uterus. Despite the high prevalence, the etiology of endometriosis remains elusive. The search for the most promising compounds for treatment of endometriosis has led to the identification of resveratrol. Resveratrol, a plant-derived polyphenolic phytoalexin, demonstrates broad-spectrum health beneficial effects, including anti-proliferative, anti-inflammatory, antineoplastic and antioxidant. Because of these properties and its wide distribution in plants, resveratrol is proposed as a great potential to treat endometriosis.
In animal models of endometriosis, resveratrol supplementation has displayed beneficial results as it decreased the number and volume of endometrial implants, suppressed proliferation, vascularization, inflammation, cell survival and increased apoptosis. On the other hand, resveratrol treatment in-vitro studies, reduced invasiveness of endometriotic stromal cells (ESCs) and suppressed their inflammatory responses.
In this review, we will summarize the recent studies in in-vitro and animal studies on resveratrol and endometriosis.
... therapeutic effects in women with diminished ovarian function, polycystic ovary syndrome (PCOS), endometriosis, or uterine fibroids. [4][5][6][7] In addition, resveratrol may improve testicular function and sperm quality. 8,9 Therefore, resveratrol supplementation may help to treat both male and female infertility based on animal studies. ...
... 52 Also, resveratrol has antiapoptosis and antiproliferative effects, and it can inhibit progression of ectopic endometrium (endometriosis). 6 These reports suggest beneficial therapeutic effects of resveratrol on infertility with endometriosis. ...
... Our study focused on pregnancy outcomes after ET, and we had no data on ovarian function before and after resveratrol intake. Resveratrol treatment has been shown to protect against ovarian aging and to improve PCOS and endometriosis; [4][5][6] therefore, resveratrol intake may have benefits for some patients. ...
Background:
Resveratrol is an antiaging, antioxidant, anti-inflammatory, and insulin-sensitizing natural polyphenolic compound. Growing evidence indicates that resveratrol has potential therapeutic effects in infertile women with diminished ovarian function, polycystic ovary syndrome (PCOS), or endometriosis. However, only one clinical trial in women undergoing in vitro fertilization (IVF) cycles using resveratrol has ever been reported. This review focuses on the potential therapeutic effects of resveratrol on pregnancy and on its advantages and disadvantages in pregnancy outcomes during infertility treatment.
Methods:
We performed a literature review to describe the known impacts of resveratrol on the ovary and endometrium.
Results:
Resveratrol upregulates sirtuin (SIRT)1 expression in ovaries, which is associated with protection against oxidative stress. It leads to the activation of telomerase activity and mitochondrial function, improving ovarian function. In the endometrium, resveratrol downregulates the CRABP2-RAR pathway leading to suppressing decidual and senescent changes of endometrial cells, which is essential for embryo implantation and placentation. Moreover, resveratrol may also induce deacetylation of important decidual-related genes.
Conclusions:
Resveratrol has potential therapeutic effects for improving ovarian function; however, it also has anti-deciduogenic actions in uterine endometrium. In addition, its teratogenicity has not yet been ruled out; thus, resveratrol should be avoided during the luteal phase and pregnancy.
... 11 Protective effects of resveratrol on various diseases have been widely investigated in preclinical and clinical studies and attributed to anti-oxidative, anti-inflammatory, anti-tumorigenic, anti-atherogenic and anti-ageing properties of resveratrol. 12 The first animal study of the effect of resveratrol on endometriosis was reported by Bruner-Tran et al in 2011. 13 In that study, resveratrol treatment decreased the number and volume of endometriotic lesions in a nude mouse model of endometriosis. ...
... 13 In that study, resveratrol treatment decreased the number and volume of endometriotic lesions in a nude mouse model of endometriosis. In subsequent studies, resveratrol treatment in animal models of endometriosis decreased the number and size of endometriotic implants and showed anti-inflammatory, anti-angiogenic, anti-proliferative, anti-oxidative, and pro-apoptotic activities 12 and in just one in vitro study resveratrol treatment showed anti-inflammatory effect through suppression of IL-8 expression in endometriotic stromal cells. 14 So in this study, for the first time, we sought to investigate and compare the effect of resveratrol treatment on MCP-1, IL-6, and IL-8 gene expression and protein production and RANTES protein expression in ectopic and eutopic endometrial stromal cells of endometriotic women (EESCs and EuESCs, respectively) and non-endometriotic control endometrial stromal cells (CESCs). ...
Endometriosis is an inflammatory disease affecting reproductive‐aged women. Immunologic disturbance, as well as inflammation, have crucial roles in the pathogenesis of endometriosis. In this study, we evaluated the effects of resveratrol treatment on expression of monocyte chemotactic protein‐1 (MCP‐1), interleukin‐6 (IL‐6), IL‐8, and regulated upon activation, normal T cell expressed and secreted (RANTES) in endometrial stromal cells from patients with endometriosis compared with non‐endometriotic controls. Thirteen eutopic (EuESCs) and nine ectopic (EESCs) endometrial stromal cells from endometriotic patients as well as eleven endometrial stromal cells from non‐endometriotic controls (CESCs) were treated with resveratrol (100 μmol/L) or ethanol, and gene and/or protein expression of MCP‐1, IL‐6, IL‐8 and RANTES was examined at 6, 24 and 48 hours following treatment in the cells from all origins. Resveratrol treatment significantly reduced gene and protein expression of MCP‐1, IL‐6, and IL‐8 in EuESCs and EESCs compared with CESCs (P < .05‐.001, P < .05‐.001 and P < .05‐<.01, respectively), and this reduction was more noticeable in EESCs than EuESCs (P < .05‐<.001). Besides, resveratrol treatment significantly reduced RANTES protein expression in EESCs in all time intervals (P < .05). Resveratrol treatment significantly reduced the expression of MCP‐1, IL‐6, IL‐8 and RANTES in EESCs.
... [11][12][13][14] It is also effective in treating endometriosis. [15][16][17][18][19][20][21][22] Resveratrol not only increases antioxidant capacity and decreases lipid peroxidation, 15 but it also exhibits anti-inflammatory activity by suppressing nuclear factor kB (NF-kB), tumor necrosis factor (TNF)-a, and inflammatory cytokines in endometriosis. 20 More importantly, resveratrol has the activities of anti-proliferation and anti-invasion in endometriosis through inhibiting the expressions of VEGF, MMP-2, and MMP-9. ...
... Resveratrol is considered to be effective in preventing and treating endometriosis. [15][16][17][18][19][20][21][22] In the present study, we showed that resveratrol inhibited the proliferation, migration, and invasion of ESCs in cell cultures ( Figures 4A, 4C, and 4E) and suppressed the growth of ectopic endometrium in the mouse endometriosis model ( Figure 7B). Then, we demonstrated that resveratrol decreased MTA1 expression and suppressed EMT induced by MTA1-ZEB2 in endometrial cells ( Figure 3G) and endometriosis mice ( Figures 7C and 7D). ...
Endometriosis is a benign disease that shares some malignant features. Epithelial-mesenchymal transition (EMT) is involved in the pathogenesis of endometriosis. Metastasis-associated protein 1 (MTA1) plays an important role in various cancers by promoting EMT, yet there are no studies on its function in endometriosis. In the present study, we found that MTA1 was highly expressed in the ectopic endometrium of endometriosis patients and that the expression of MTA1 was related to the revised American Fertility Society stage. MTA1 facilitated endometrial stroma cell proliferation, migration, and invasion by inducing EMT, and the promotion function and MTA1 expression were suppressed by resveratrol, a natural polyphenol. Moreover, we revealed that MTA1 induced EMT through interaction with ZEB2. The findings in a mouse endometriosis model further showed that MTA1 and ZEB2 were upregulated in ectopic tissues and that resveratrol inhibited the growth of ectopic lesions and expression of MTA1 and ZEB2. Taken together, we demonstrate that MTA1 is a protein that promotes EMT via interacting with ZEB2 in the pathogenesis of endometriosis, and may be a target of resveratrol.
... Over the past decade, resveratrol has emerged as a therapeutic treatment for many diseases due to its anti-aging, antioxidant, anti-inflammatory, insulin-sensitizing, cardioprotective, vasodilating, and anti-neoplastic properties [56]. In the reproductive field, resveratrol may benefit women with diminished ovarian function, PCOS, endometriosis, and uterine fibroids [55,[57][58][59]. Resveratrol may improve age-related decline in ovarian function through the activation of sirtuin 1 (SIRT1) [60], a molecule that protects mitochondrial function from oxidative stress and whose levels are undetectable in aged oocytes [61]. ...
... In the endometrium, resveratrol's antiapoptotic and anti-proliferative effects inhibited the progression of ectopic endometrium, countering endometriosis [58]. In addition, resveratrol reduced vascular endothelial growth factor (VEGF) expression [74], improving the treatment of ovarian hyperstimulation syndrome (OHSS) and endometriosis, both gynecologic disorders associated with excessive VEGF activity [55]. ...
Mitochondria produce adenosine triphosphate (ATP) while also generating high amounts of reactive oxygen species (ROS) derived from oxygen metabolism. ROS are small but highly reactive molecules that can be detrimental if unregulated. While normally functioning mitochondria produce molecules that counteract ROS production, an imbalance between the amount of ROS produced in the mitochondria and the capacity of the cell to counteract them leads to oxidative stress and ultimately to mitochondrial dysfunction. This dysfunction impairs cellular functions through reduced ATP output and/or increased oxidative stress. Mitochondrial dysfunction may also lead to poor oocyte quality and embryo development, ultimately affecting pregnancy outcomes. Improving mitochondrial function through antioxidant supplementation may enhance reproductive performance. Recent studies suggest that antioxidants may treat infertility by restoring mitochondrial function and promoting mitochondrial biogenesis. However, further randomized, controlled trials are needed to determine their clinical efficacy. In this review, we discuss the use of resveratrol, coenzyme-Q10, melatonin, folic acid, and several vitamins as antioxidant treatments to improve human oocyte and embryo quality, focusing on the mitochondria as their main hypothetical target. However, this mechanism of action has not yet been demonstrated in the human oocyte, which highlights the need for further studies in this field.
... Resveratrol, a natural polyphenolic compound, is widely studied for its anti-inflammatory, antisenescent, and anticarcinogenic properties [1]. Growing evidence indicates that resveratrol has therapeutic effects in women with diminished ovarian reserve, polycystic ovary syndrome (PCOS), and endometriosis [2][3][4]. Recently, two studies reported seemingly conflicting findings on the actions of resveratrol on decidualization of human endometrial stromal cells (HESCs). One study, from our group, demonstrated that resveratrol inhibits decidual transformation of primary cultured HESCs [5]. ...
... In agreement with our in vitro study, resveratrol supplementation may negatively impact on pregnancy outcomes in embryo transfer cycles. However, resveratrol treatment potentially protects against ovarian aging and may be beneficial in the treatment of PCOS and endometriosis [2][3][4]. These effects appear dependent on resveratrol-mediated activation of ovarian sirtuin, which in tune confers protection against oxidative stress and glycation stress, promotes telomerase activity, and enhances mitochondrial function [28]. ...
Resveratrol, a natural polyphenolic compound, is widely studied for its anti-inflammatory and antisenescent properties. Recently, two studies reported seemingly conflicting findings on the actions of resveratrol on decidualization of human endometrial stromal cells (HESCs). One study by Ochiai et al. demonstrated that resveratrol inhibits decidual transformation of primary cultured HESCs. The other study by Mestre Citrinovitz et al., showed that resveratrol enhances decidualization of HESCs in culture. At a glance, the reason for these opposing observations seems puzzling. However, recent studies demonstrated that decidualization is a multistep process, which starts with an acute proinflammatory stress response that lasts for several days and is followed by the emergence of stress-resistant decidual cells as well as senescent decidual cells. The balance between these decidual subpopulations may determine if the cycling endometrium can successfully transition into the decidua of pregnancy upon embryo implantation. Here, we explore the importance of timing of drugs aimed at modulating the decidual response. We posit that resveratrol treatment during the initial proinflammatory decidual phase, i.e., coinciding with the implantation window in vivo, inhibits decidual transformation of the endometrium. However, when given after the initial phase, resveratrol may promote decidualization by inhibiting decidual senescence. Further, if restricted to the proliferative phase, resveratrol may promote ovarian function without adversely impacting on embryo implantation or decidualization. Thus, failure to align drug interventions with the correct phase of the menstrual cycle may negate beneficial clinical effects and results in adverse reproductive outcomes.
... • Resveratrol is a natural substance obtained from red wine that has anti-proliferative and anti-inflammatory properties [28]. The mechanisms/pathways of action of this naturally occurring compound have also shown that, in animal models of endometriosis, resveratrol supplementation displays beneficial results by decreasing the number and volume of endometrial implants, suppressing proliferation, vascularization, inflammation, cell survival, and increasing apoptosis [29]. On the other hand, in vitro resveratrol treatment reduces invasiveness of endometriotic stromal cells (ESCs) and suppresses their inflammatory responses. ...
... On the other hand, in vitro resveratrol treatment reduces invasiveness of endometriotic stromal cells (ESCs) and suppresses their inflammatory responses. [29]. A 2011 study by Bruner-Tran et al. has demonstrated that resveratrol inhibits development of experimental endometriosis in vivo and reduces endometrial stromal cell invasiveness in vitro [30]. ...
Endometriosis, an inflammatory, non-lethal, non-malignant disease, still has unjustified etiology. Among many, the theory dealing with this review claims that a suppressed or incompetent immune system that is totally unable to eradicate the non-hemopoietic mesenchymal endometriotic stem cell (MESC) escapes immune surveillance. As a result, there is migration and invasion of the aforementioned cell to ectopic tissues causing the disease. This review focuses on bioactive compounds (i.e. vitamins and minerals) that may have the potential to boost the immune system rendering it capable to fight the MESC and, consequently, endometriosis. The use of vitamins and minerals, also called meganutrients, constitutes the known approach of orthomolecular medicine. However, when scrutinized these methods yield contradicting results but still merit attention. According to our review of the available scientific literature, compared to traditional medicine, which only regulates hormonal imbalances and alleviates pain, the orthomolecular approach is promising for successfully strengthening the immune system towards a curative outcome. However, the underlying mechanisms behind the action of the abovementioned natural bioactive ingredients appear numerous and often speculative, thereby remaining under examination.
... Resveratrol (RES) is a kind of polyphenolic phytoalexin that is derived from plants. It exhibits broad health benefits, such as antioxidative, anti-inflammatory, and anti-proliferative activities and tyrosinase inhibition [13]. Oxyresveratrol (OXYR) is a powerful inhibitor of tyrosinase and can be used as a skin-whitening and anti-browning agent [14]. ...
... The activity of tyrosinase is the first step in melanogenesis, indicating the oxidation of phenols to ortho-quinones by oxy-tyrosinase [47,48]. The activity mentioned above also shows the oxidation of bisphenol to quinone at the same time [2,3,5,13,14,18,32,34,37,38,49]. Thus, the activity of tyrosinase reflects the whole oxidation process of phenol to quinone through monooxygenase activity. ...
When exposed to ultraviolet radiation, the human skin produces profuse reactive oxygen species (ROS), which in turn activate a variety of biological responses. Mounting ROS levels activate tyrosinase by mobilizing α-melanocyte-stimulating hormone in the epidermis and finally stimulates the melanocytes to produce melanin. Meanwhile, the Keap1-Nrf2/ARE pathway, which removes ROS, is activated at increased ROS levels, and antioxidant compounds facilitates the dissociation of Nrf2. In this study, we explored the possible suppressing effects of antioxidant compounds and tyrosine inhibitors on melanin formation and the promotory effects of these compounds on ROS scavenging. The antioxidant activity of glabridin (GLA), resveratrol (RES), oxyresveratrol (OXYR), and phenylethylresorcinol (PR) were investigated via the stable free radical 2,2-diphenyl-1-picrylhydrazyl method. The inhibitory effects of the four compounds and their mixtures on tyrosinase were evaluated. l-Tyrosine or 3-(3,4-dihydroxyphenyl)-l-alanine (l-DOPA) was used as a substrate. The results showed that all mixtures did not exhibit synergistic effects with the l-tyrosine as a substrate, suggesting that l-tyrosine is not suitable as a substrate. However, the mixtures of "GLA:RES," "GLA:OXYR," "OXYR:RES," and "PR:RES" demonstrated synergistic effects (CI < 0.9, p < 0.05), whereas "GLA:RES" and "PR:OXYR" indicated an additive effect (0.9 ditive1, p < 0.05). Furthermore, we used a molecular docking strategy to study the interactions of the four compounds with tyrosinase and l-DOPA. The molecular docking result is consistent with that of the experiment. Finally, we selected RES + OXYR and used PIG1 cells to verify whether OXYR synergistically promotes RES activity on tyrosinase. The two agents had a synergistic inhibitory effect on tyrosinase activity. These results provided a novel synergistic strategy for antioxidants and tyrosinase inhibitors, and this strategy is useful in skin injury treatment.
... Phytoestrogens are compounds from plants that act as selective estrogen modulators in a tissue-specific manner [12]. Phytoestrogens can offer anti-proliferative, anti-inflammatory, antioxidant, and analgesic properties [13]. Specifically, formononetin, a phytoestrogen derived from Pongamia pinnata, Astragalus membranaceus, Ononis angustissima, and Trifolium pratense (T. ...
Objectives:
Formononetin is one of the phytoestrogens that functions like a selective estrogen receptor modulator (SERM). In this study, we evaluated the effects of formononetin on endometriosis progression in vitro and in vivo.
Materials and methods:
After pathological confirmation, 10 eutopic and ectopic endometria were collected from patients with endometriosis. Ten eutopic endometria samples were collected from patients who did not have endometriosis. To determine the cytotoxic dose and therapeutic dose of formononetin, the concentration of 70% of the cells that survived after formononetin administration was estimated using a Cell counting kit-8 (CCK 8) assay. Western blot analysis was used to determine the relative expression levels of BAX, p53, pAKT, ERK, pERK, p27, and pSTAT3 in the eutopic endometria without endometriosis, eutopic endometria with endometriosis, and ectopic endometria with endometriosis as the formononetin concentration was increased. We confirmed the effect of formononetin on apoptosis and migration in endometriosis using fluorescence-activated cell sorting (FACS) and wound healing assays, respectively. A mouse model of endometriosis was prepared using a non-surgical method, as previously described. The mice were intraperitoneally administered formononetin for four weeks after dividing them into control, low-dose formononetin (40 mg/kg/day) treatment, and high-dose (80 mg/kg/day) formononetin treatment groups. All the mice were euthanized after formononetin treatment. Endometriotic lesions were retrieved and confirmed using hematoxylin and eosin (H&E) staining. Immunohistochemical (IHC) staining of p27 was performed.
Results:
We set the maximum concentration of formononetin administration to 80 μM through the CCK8 assay. Based on formononetin concentration, the expression levels of BAX, p53, pAKT, ERK, pERK, p27, and pSTAT3 proteins were measured using Western blot analysis (N = 4 per group). The expression level of pERK, p27, and pSTAT3 in eutopic endometrium with endometriosis tended to decrease with increasing formononetin concentration, and a significant decrease was noted at 80 μM. The expression of p27 in ectopic endometrium with endometriosis was also significantly decreased at 80 μM of formononetin. FACS analysis revealed that formononetin did not significantly affect apoptosis. In the wound healing assay, formononetin treatment revealed a more significant decrease in the proliferation of the eutopic endometrium in patients with endometriosis than in the eutopic endometrium without endometriosis. Relative expression of sex hormone receptors decreased with increasing formononetin doses. Although no significant differences were observed in the ER, PR-A, ERβ/ERα, and PR-B/PR-A, significant down-regulation of PR-B expression was noted after formononetin treatment at 80 μM. In the in vivo study, endometriotic lesions in the formononetin-treated group significantly decreased compared to those in the control group. The relative expression of p27 using IHC was highest in the control group and lowest in the high-dose formononetin treatment group.
Conclusions:
Formononetin treatment was shown to inhibit the proliferation of eutopic and ectopic endometria in patients with endometriosis through the regulation of p27, pSTAT3, and PR-B. In an endometriosis mouse model, formononetin treatment significantly reduced the number of endometriotic lesions with decreased p27 expression. The results of this study suggest that formononetin may be used as a non-hormonal treatment option for endometriosis.
... It was demonstrated that RES, when combined with E 2 , may act as an estrogen agonist and antagonist in low and high concentrations, respectively [121]. In addition to this action on ERs, RES may also play a role in endometriosis treatment interfering with others pathogenetic pathways involved in the disease, including induction of apoptosis, reduction of inflammation and angiogenesis, inhibition of adhesion and invasion [122]. In animal models, RES supplementation decreased the number and volume of endometrial implants, suppressed proliferation, vascularization, inflammation, cell survival, and increased apoptosis [123][124][125]. ...
Introduction:
Endometriosis is an estrogen-dependent disease on the background of progesterone resistance. Increased estrogen production, low estrogen metabolization, and altered estrogen receptors (ERs) expression contribute to the hyperestrogenic milieu within endometriotic lesions. Since estrogens play a crucial role in the pathogenesis of the disease, inhibition of estrogen production is one of the main targets of available and emerging drugs.
Areas covered:
Firstly, we described the molecular alterations responsible for estrogen dependence. Secondly, we reviewed available and emerging treatments that interfere, through central (gonadotropin-releasing hormone analogs (GnRH-a), GnRH antagonists) or local mechanisms (aromatase inhibitors (AIs), inhibitors of steroid sulfatase (STS) and hydroxysteroid dehydrogenase type 1 (17β-HSD1)), with estrogen dependence. Finally, we focused on emerging treatments targeting ERs (selective estrogen receptor modulators (SERMs), estrogen receptors agonists, and antagonists).
Expert opinion:
Available treatments interfering with estrogen pathways exert a contraceptive effect, have hypoestrogenic side effects, and cannot prevent or definitively treat the disease. Preclinical and animal studies are focusing on emerging drugs targeting ERs in order to overcome limitations of available treatments. These treatments may represent a promising option, as they may produce a more specific inhibition of disease activity within endometriotic implants, avoiding prolonged hypoestrogenic status and limiting systemic side effects.
... Many studies address phytotherapy as a therapeutic alternative for endometriosis treatment. In this vein, some studies corroborate our findings, evidencing the antiendometriotic effects of various extracts and plant actives [32][33][34][35][36][37][38][39][40]. Likewise, our results are in accordance with a reduction in cell viability as found by Cao et al. [41], as well as a decrease in the expression of several molecules involved in the pathophysiology of endometriosis (VCAM-1, ICAM-1, TNF-α, IL-1, IL-6, IL-8, and MCP-1) in cell cultures obtained from endometriotic lesions after treatment with curcumin [36]. ...
Background:
Current drugs for the treatment of endometriosis are not able to completely cure the condition, and significant side effects hinder the continuation of treatment. Therefore, it is necessary to search for new drug candidates. In the present paper, the use of plant extracts is highlighted. Babassu oil and Copaiba oil resin have several therapeutic properties. We investigated the in vitro effects of two nanoemulsions containing oil extracted from Babassu (Orbignya speciosa) nuts (called SNEDDS-18) and/or oil resin extracted from Copaiba trunk (Copaifera langsdorffii) (called SNEDDS-18/COPA) on cultured human eutopic endometrium stromal cells from endometrial biopsies of patients without (CESC) and with (EuESC) endometriosis as well as human stromal cells from biopsies of endometriotic lesions (EctESC).
Methods:
CESC, EuESC, and EctESC were taken and treated with SNEDDS-18 and SNEDDS-18/COPA to evaluate their effects on cytotoxicity, cell morphology, proliferation, and signaling pathways.
Results:
After 48 h of incubation with SNEDDS-18 and SNEDDS-18/COPA, cell viability and proliferation were inhibited, especially in EctESC. The lowest concentration of both nanoemulsions reduced cell viability and proliferation and broke down the cytoskeleton in EctESCs. After 24 h of treatment a decrease in IL-1, TNF-α, and MCP-1 was observed, as well as an increase in IL-10 production.
Conclusions:
Both nanoemulsions can affect endometriotic stromal cell behaviors, thus revealing two potential candidates for new phytotherapeutic agents for the management of endometriosis.
... Retinoic acid and Elocalcitol reduced the size and weight of endometriotic lesions in a mouse model [143,164] . The administration of the natural antioxidant resveratrol reduced the size and number of endometrial lesions in endometriosis-prone animals and in vitro models [165] . Resveratrol significantly improved pain scores when used in combination with oral contraceptives (COCs) in patients with endometriosis pain who failed to respond to COCs alone. ...
Endometriosis is a chronic gynecological disorder that affects approximately 10% of women of reproductive age. Most medical
treatments used today for endometriosis pain are hormonal therapies, which are not an option for those trying to conceive
and are not tolerated by a subset of patients due to side effects. In this article, we offer a comprehensive review of current and
investigational medical therapeutic options used to treat endometriosis pain, as well as a symptom-based systematic approach
for patients with painful endometriosis. We have also included recommendations for research to enhance the evolution of novel
therapeutic options. A thorough literature search was carried out, and the data were synthesized using a synthesis matrix that
classifies and categorizes various arguments.
... Trapp et al. (2010) observed a decrease in endothelial cell viability (by apoptosis) after RSV treatment (50 µM, 48 h) when the cell was co-cultured with A375, YUZAZ6, or WM3211 melanoma cells [33]. Mohammadi and Arablou in 2017 reviewed the effect of RSV on endometriosis and found that the polyphenol not only decreased the proliferation of endometrial cells (through apoptosis induction) but also affected endothelial cells (decreased proliferating activity associated with decreased VEGF level) [34]. Contrarily, some studies indicate that RSV may reveal proangiogenic properties in other cell lines. ...
Age-related macular degeneration (AMD) and diabetic retinopathy are the leading cause of blindness in developed countries. Pathological angiogenesis has a causal role in these eye diseases. Resveratrol (RSV), a plant-derived polyphenol, has anti-proliferative and anti-angiogenic properties that could improve its management. Here, the effects of various concentrations of RSV (1, 5, 10, 50, 100 µM) were compared in two types of cell lines: HECa10 (endothelial cell line) and ARPE-19 (retinal pigment epithelial cell line). We assayed the impact on proliferation rate, viability, cell cycle progression, and secretion of selected proangiogenic factors VEGF and bFGF. We show that lower concentrations of RSV (1, 5, 10 µM) had no effect on proliferation, viability or cell cycle progression in HECa10 cells. However, higher concentrations (50, 100 µM) significantly enhanced the reduction in the cell number and stimulated apoptosis. In ARPE-19 cells, lower concentrations of RSV increased the rate of proliferation, while higher concentrations had no effect on proliferation and viability. Both ARPE-19 and HECa10 cell lines were affected to different degrees in the secretion of proangiogenic cytokines: reducing VEGF and enhancing bFGF secretion. These results suggest that RSV may be useful in the prevention or treatment of pathological angiogenesis in eye disorders.
... Resveratrol's use as an antioxidant has already been suggested in various other conditions such as cardiovascular disease, metabolic syndrome, and chronic obstructive pulmonary disease (COPD) [157][158][159]. A similar diet or use of supplements could be beneficial for women with endometriosis as they have immunological processes and elevated pro-inflammatory cytokines like that of other chronic inflammatory diseases [160]. Pycnogenol is another plant-derived mixture of polyphenols and procyanidins (bark of the pine tree Pinus pinaster) that have both antioxidant and anti-inflammatory properties by inhibiting the NF-kB pathway. ...
Endometriosis is a common gynecological disorder seen in women and is characterized by chronic pelvic pain and infertility. This disorder is becoming more prevalent with increased morbidity. The etiology of endometriosis remains to be fully elucidated, which will lead to improved therapeutic options. In this review, we will evaluate the biochemical mechanisms leading to oxidative stress and their implication in the pathophysiology of endometriosis, as well as potential treatments that target these processes. A comprehensive exploration of previous research revealed that endometriosis is associated with elevated reactive oxygen species and oxidation products, decreased antioxidants and detoxification enzymes, and dysregulated iron metabolism. High levels of oxidative stress contributed to inflammation, extracellular matrix degradation, angiogenesis, and cell proliferation, which may explain its role in endometriosis. Endometriosis-associated pain was attributed to neurogenic inflammation and a feed-forward mechanism involving macrophages, pro-inflammatory cytokines, and pain-inducing prostaglandins. N-acetylcysteine, curcumin, melatonin, and combined vitamin C and E supplementation displayed promising results for the treatment of endometriosis, but further research is needed for their use in this population.
... O papel do resveratrol também repercute em melhorias da fertilização mas ainda são resultados inconclusivos (Ochiai & Kuroda, 2019). Os achados semelhantes ao presente estudo foram abordados por Dull et al. (2019), Hung et al. (2021) e Kolahdouz-Mohammadi e Arablou (2017). No entanto, é válido ressaltar que apesar da eficácia dos resultados obtidos, os estudos disponíveis são muito escassos, principalmente ao avaliar os seres humanos. ...
A endometriose é uma desordem ginecológica caracterizada pela presença de tecido endometrial fora da cavidade uterina relacionado com predisposição genética, dependência de estrogênio, resistência à progesterona e inflamação. A teoria da menstruação retrógrada, formulada por Sampson, é a etiologia cientificamente mais aceitável devido mecanismos semelhantes que ocorreram em mulheres saudáveis. Entretanto, diversas outras teorias foram levantadas com diferentes focos fisiopatológicos. A patogênese da doença contribui para um desequilíbrio imunológico, culminando no aumento da expressão de mediadores inflamatórios, angiogênicos e alterações em diversas vias metabólicas. O resveratrol é um polifenol que tem sido amplamente estudado pelos seus benefícios no controle de mediadores inflamatórios. Nesta revisão, nós resumimos os achados mais recentes que interligam os efeitos do resveratrol e possíveis melhorias na sintomatologia da doença alvo. Estudos experimentais e in vitro mostraram resultados benéficos quando avaliados em modelos endometrióticos. No entanto, os mesmos resultados não foram obtidos em humanos, especialmente quando avaliaram os limiares de dor antes e depois da suplementação do resveratrol. Em conclusão, os resultados para a prática clínica ainda são inconclusivos.
... Resveratrol, has previously been highlighted as apotential supplement for the treatment of cancers, 8 cardiovascular disease 9 and EMs. 10 Pharmacological effects of resveratrol on the energy and lipid metabolism have been highlighted in animal models, particularly related to the human eutopic endometrial stromal cells (HESCs) of EMs. 11 The highlighted benefits relating to lipid metabolism and other aspects in this study contain little overlap with findings from the other potential compounds. ...
Introduction:
Endometriosis (EMs) is associated with severe chronic pelvic pain and infertility and the development of improved EMs treatment options is an ongoing focus. In this study, we investigated the effects of resveratrol on EMs and analyzed transcriptional changes in the lesions of model rats before and after resveratrol treatment.
Methods:
We established arat model of endometriosis through the trans-implantation of endometrial fragments to the peritoneal wall and then used resveratrol as treatment. We then analyzed the results using RNA sequencing of the lesion tissues of each of the model rats before resveratrol treatment and the reduced lesion tissues after the treatment. Examinations of anatomy, biochemistry, immunohistochemical staining and flow cytometry examinations were also conducted. Other trans-implanted rats were also given sham treatments as sham-treatment control and other untrans-implanted rats served as sham-operation controls.
Results:
In addition to the obvious lesions observed in the model rats, there were significant differences in the glucose tolerance, macrophage M1/M2 polarization, and adipocyte sizes between the treated model rats and sham (control) rats. Resveratrol treatment in the model rats showed significant efficacy and positive therapeutic effect. Transcriptional analysis showed that the effects of resveratrol on the endometriosis model rats were manifested by alterations in the PPAR, insulin resistance, MAPK and PI3K/Akt signaling pathways. Correspondingly, changes in PPARγ activation, M1/M2 polarization and lipid metabolism were also detected after resveratrol treatment.
Discussion:
Our study revealed that resveratrol treatment displayed efficient therapeutic effects for EMs model rats, probably through its important roles in anti-inflammation, immunoregulation and lipid-related metabolism regulation.
... Resveratrol is a natural polyphenol and phytoalexin, which has abundant biological properties as antiinflammatory, antioxidant, anti-tumor, anti-aging, cardiovascular protective and chemo-protective, antidiabetes, etc [14][15][16]. Zhao et al. suggested that DNA demethylation may create a positive link for reactivating the Nrf2 signaling in Alzheimer's disease cellular model [20]. ...
Non-alcoholic fatty liver disease has become one of the common illnesses among urban dwellers worldwide. Many consider natural products as better options for medicine and diet supplements. In recent years, researchers found that natural products can prevent human diseases by reactivating silencing genes through epigenetic regulation. They also discovered nuclear factor erythroid-2-related factor-2 (Nrf2) as is an important factor in the response of anti-oxidation has a close relation to lipogenesis. Studies showed with the higher expression of DNA methyl-transferases, the higher methylation of Nrf2 promoter occurred. With the high methylation rate of the Nrf2 promoter, the expression of Nrf2 reduced thus enhanced lipid accumulation, which may cause NAFLD. Furthermore, with lower expression of Nrf2, the downstream antioxidant genes’ expression decreased, which may cause oxidative stress to human body cells. Understanding the pathway of Nrf2 and NAFLD can shed a light on discovering new development of drugs. This paper reviews several natural products and their mechanisms of alleviating NAFLD and hopes to bring in new perspectives on the treatment and the development of new drugs on NAFLD.
... Therefore, manipulation of programmed cell death processes by enhancing endogenous or exogenous apoptotic stimulants in the lesions could be used to treat endometriosis. In recent years, naturally occurring phytochemicals such as resveratrol have gained considerable attention because of their health-promoting properties (7). Resveratrol (trans-3,4',5-trihydroxystilbene, C14H12O3) is a phytoalexin synthesized by plants in response to fungal infection or exposure to ultraviolet light and is present in dietary products such as grapes and red wine (8). ...
Background:
We aimed to examine resveratrol effects on gene expression of Bcl-2, Bax and Bcl-2/Bax ratio in endometrial stromal cells derived from women with and without endometriosis.
Methods:
Endometrial tissues were obtained from 40 endometriotic patients and 15 non-endometriotic controls undergoing laparoscopic surgery or hysterectomy in the gynecology ward of Rassoul Akram Hospital, Tehran, Iran from 2015 to 2017. After the enzymatic digestion, eutopic (EuESCs) and ectopic (EESCs) endometrial stromal cells from patients with endometriosis as well as endometrial stromal cells from non-endometriotic controls (CESCs) were treated with or without resveratrol (100 μM) and the levels of Bcl-2, Bax and Bcl-2/Bax gene expression ratio in the cells from all origins were examined at 6, 24 and 48 h post-treatment by real-time PCR.
Results:
Resveratrol treatment increased Bcl-2 expression in CESCs at 24 and 48 h and in EuESCs at 48 h (P<0.05), but had no significant effects on the expression of this gene in EESCs. On the other hand, resveratrol treatment increased Bax expression in EuESCs at 6 h and decreased its expression in EESCs at 48 h (P<0.05). Regarding the Bcl-2/Bax gene expression ratio, resveratrol treatment increased Bcl-2/Bax gene expression ratio in CESCs and EuESCs at 48 h (P<0.01). However, this treatment had no significant differential effect on Bcl-2 and Bcl-2/Bax gene expression ratio between CESCs and EuESCs at 48 h.
Conclusion:
Resveratrol treatment significantly increased Bcl-2/Bax gene expression ratio in EuESCs and CESCs but had no significant effect in EESCs.
... In recent years, many studies have been conducted to verify the effect of RVT on EMS and to elucidate the mechanism of action. [53] RVT exerts its antioxidant effect through increased expression of SOD, GPx, glutathione-S-transferase, nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase 1 (NQO1), and heme oxygenase-1, and heme oxygenase-1. In mice models of EMS, RVT showed significantly reduced endometriotic implant volumes compared with controls and significant increase in SOD and GPx activities in a dose-dependent manner in the serum and tissue in the RVT (10 mg/kg) and RVT (100 mg/ kg) groups. ...
Endometriosis (EMS) is a common gynecological disorder characterized by the presence of endometrial tissue outside the uterine cavity. It is commonly associated with pelvic pain and infertility. The exact pathogenesis remains unclear and many hypotheses have been suggested. In recent years, accumulating evidence indicates that oxidative stress (OS) plays a role in the development of EMS. The treatment of EMS remains a challenge. Antioxidant therapies for effective management of reactive oxygen species and inflammation have generated considerable research interest. Antioxidant agents such as Vitamins C and E, resveratrol, curcumin, melatonin, epigallocatechin‑3‑gallate, and others have been studied for the treatment of EMS. This review presents the role of OS in pathophysiology of EMS and the antioxidant therapies in its management.
... In recent years, many studies have been conducted to verify the effect of RVT on EMS and to elucidate the mechanism of action. [53] RVT exerts its antioxidant effect through increased expression of SOD, GPx, glutathione-S-transferase, nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase 1 (NQO1), and heme oxygenase-1, and heme oxygenase-1. In mice models of EMS, RVT showed significantly reduced endometriotic implant volumes compared with controls and significant increase in SOD and GPx activities in a dose-dependent manner in the serum and tissue in the RVT (10 mg/kg) and RVT (100 mg/ kg) groups. ...
Endometriosis (EMS) is a common gynecological disorder characterized by the presence of endometrial tissue outside the uterine cavity. It is commonly associated with pelvic pain and infertility. The exact pathogenesis remains unclear and many hypotheses have been suggested. In recent years, accumulating evidence indicates that oxidative stress (OS) plays a role in the development of EMS. The treatment of EMS remains a challenge. Antioxidant therapies for effective management of reactive oxygen species and inflammation have generated considerable research interest. Antioxidant agents such as Vitamins C and E, resveratrol, curcumin, melatonin, epigallocatechin-3-gallate, and others have been studied for the treatment of EMS. This review presents the role of OS in pathophysiology of EMS and the antioxidant therapies in its management.
... This application is rational for the purpose of improving ovarian function, but may be out of scope for embryo transfer. Resveratrol treatment has been demonstrated to reduce weight in obesity (Tabrizi et al., 2018), ameliorate hyperandrogenemia and insulin resistance in polycystic ovary syndrome (Banaszewska et al., 2016), as well as suppress ectopic endometrial invasiveness and inflammation in endometriosis (Kolahdouz Mohammadi and Arablou, 2017). Due to the negative influences of these diseases on pregnancy outcomes (Rittenberg et al., 2011;Katulski et al., 2015;Saraswat et al., 2017), resveratrol may be of more benefit for certain populations in embryo transfer cycles. ...
... Resveratrol has been mooted as a potentially therapeutic agent for infertile patients with diminished ovarian reserve, obesity, and polycystic ovary syndrome (PCOS) [6][7][8][9][10] . In addition, a number of studies pointed towards the therapeutic potential of resveratrol in improving testicular function and sperm quality as well as in the management of pelvic endometriosis and uterine leiomyomas [11][12][13] . However, the potential impact of resveratrol on endometrial preparation for embryo implantation has not yet been evaluated. ...
Pregnancy critically depends on the transformation of the human endometrium into a decidual matrix that controls embryo implantation and placenta formation, a process driven foremost by differentiation and polarization of endometrial stromal cells into mature and senescent decidual cells. Perturbations in the decidual process underpin a spectrum of prevalent reproductive disorders, including implantation failure and early pregnancy loss, emphasizing the need for new therapeutic interventions. Resveratrol is a naturally occurring polyphenol, widely used for its antioxidant and anti-inflammatory properties. Using primary human endometrial stromal cell (HESC) cultures, we demonstrate that resveratrol has anti-deciduogenic properties, repressing not only the induction of the decidual marker genes PRL and IGFBP1 but also abrogating decidual senescence. Knockdown of Sirtuin 1, a histone deacetylase activated by resveratrol, restored the expression of IGFBP1 but not the induction of PRL or senescence markers in decidualizing HESCs, suggesting involvement of other pathways. We demonstrate that resveratrol interferes with the reprogramming of the retinoic acid signaling pathway in decidualizing HESCs by accelerating down-regulation of cellular retinoic acid-binding protein 2 (CRABP2) and retinoic acid receptor (RAR). Notably, knockdown of CRABP2 or RAR in HESCs was sufficient to recapitulate the anti-deciduogenic effects of resveratrol. Thus, while resveratrol has been advanced as a potential fertility drug, our results indicate it may have detrimental effects on embryo implantation by interfering with decidual remodeling of the endometrium.
... Resveratrol has an anti-inflammatory effect; thus, it may also inhibit embryo attachment directly. Treatment of endometriosis with resveratrol demonstrates the suppression of proliferation, vascularization and inflammation of ectopic endometriotic tissue (Kolahdouz Mohammadi and Arablou, 2017). Therefore, resveratrol has beneficial therapeutic effects on endometriosis; however, in eutopic endometrium, it may have detrimental effects on decidualization and embryo implantation. ...
Research question:
Does resveratrol, a polyphenolic compound, affect IVF-embryo transfer outcomes?
Design:
This single-centre, cross-sectional retrospective study was designed to compare the outcomes of embryo transfer cycles in women receiving resveratrol supplementation (200 mg/day) continuously (RES group) with a control group (non-RES group). Of 8686 embryo transfer cycles, 1409 cycles with poor prognostic factors were excluded, including cycles in women aged ≥43 years and those with poor-quality embryos. The RES group (204 cycles, 102 women) was compared with the non-RES group (7073 cycles, 2958 women).
Results:
After matching patients by age at the time of oocyte retrieval, grade and developmental stage of embryos, number of embryos transferred, and fresh or vitrified-warmed embryo transfer, multivariate logistic regression analysis showed that resveratrol supplementation is strongly associated with a decrease in clinical pregnancy rate [odds ratio (OR) 0.539, 95% confidence interval (CI) 0.341-0.853] and an increased risk of miscarriage (OR 2.602, 95% CI 1.070-6.325).
Conclusions:
Resveratrol supplementation during embryo transfer cycles appears to be detrimental for pregnancy outcomes. An analysis of the supplementation protocol and randomized controlled studies are needed.
... Many fungal species were also found to possess it, such as Botryosphaeria, Penicillium, Cephalosporium, Aspergillus, Geotrichum, Mucor and Alternaria. Resveratrol was isolated from a Chinese medicinal plant named Polygonum cuspidatum for the first time [1][2][3][4][5][6][7][8][9][10]. It exists in both cis and trans configurations, both of which have aboundant biological activities, despite the fact that those of trans-resveratrol have been credited to have more prominent potential than its cis-isomer [11][12][13][14][15]. Surprisingly, on exposure of trans-resveratrol to UV light, it is changed to its cis-isomer [11,16]. ...
Several phenolic compounds bind to protein (enzymes) and interfere in their catalytic mechanism. Interaction studies of natural polyphenol; Resveratrol with various targets like with tubulin, Protein Kinase C alpha (PKCα), phosphodiesterase-4D, human oral cancer cell line proteins, DNA sequences having AATT/TTAA segments, protein kinase C alpha, Lysine-specific demethylase 1 has been reviewed in this article. Simulation studies indicate that resveratrol and its analogs/ derivatives show good interaction with the target receptor through its hydroxyl groups by forming hydrogen bonds and hydrophobic interactions with amino acid residues at binding site. Binding geometry and stability of complex formed by resveratrol shows that it is a good inhibitor for many pathogenic targets. Further studies in the direction are however needed to develop many more ligands based on resveratrol skeleton which can further serve more in the treatment of ailments.
... [4,5] There is a popular belief that endometriosis is caused by the activated endometrial cells grows outside the endometrium. [6] The development of endometriosis is similar to the malignant tumors. [7,8] Many hypotheses have been put forward to explain the etiology of it. ...
This study was aimed to explore the correlation between catechol-O-methyltransferase (COMT) gene polymorphisms and endometriosis susceptibility in Chinese Han population.
This case-control study recruited 134 endometriosis patients and 139 healthy individuals. COMT gene rs4680, rs2020917, and rs4646312 polymorphisms in the subjects were genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. Association between COMT polymorphisms and endometriosis susceptibility was evaluated by χ² test and adjusted by Logistic regression. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to present the relative risk of endometriosis.
A allele of rs4680 was distinctly correlated with increased susceptibility of endometriosis (OR = 1.450, 95% CI = 1.012–2.076). However, when adjusted by the confounding factors, these associations become not significant. We failed to find any significant association between rs2020917 and endometriosis risk in the crude results. The adjusted results suggested that rs2020917 TT genotype and T allele were distinctly correlated with enhanced endometriosis risk (TT vs CC: P = .038, OR = 2.894, 95% CI = 1.060–7.903; T vs C: P = .039, OR = 1.481, 95% CI = 1.021–2.149). Besides, rs4646312 C allele was significantly correlated with endometriosis risk both in the crude (P = .027, OR = 1.502, 95% CI = 1.047–2.154) and adjusted (P = .019, OR = 1.564, 95% CI = 1.078–2.269) results.
COMT polymorphisms might predict the occurrence of endometriosis.
... Resveratrol, 3,4,5-trihydroxy-trans-stilbene, a phytoalexin derived from grapes and other food products, is a plantderived polyphenolic phytoalexin that inhibits angiogenesis in peritoneal and mesenteric endometriotic lesions, significantly reduces micro-vessel density, inhibits proliferation, and increases apoptosis [77,78]. Furthermore, resveratrol has been shown to reduce in vitro invasiveness of endometriotic stromal cells (ESCs) and suppress the inflammatory response [79]. Resveratrol has also been shown to significantly reduce histopathological grade, as well as the expression of matrix metalloproteinases-2 (MMP-2), matrix metalloproteinases-9 (MMP-9), and VEGF in a rat model of endometriosis; this drug also reduced levels of interleukin-6 (IL-6), IL-8, and TNF-× levels in plasma and peritoneal fluid [80]. ...
Endometriosis is caused by the growth or infiltration of endometrial tissues outside of the endometrium and myometrium. Symptoms include pain and infertility. Surgery and hormonal therapy are widely used in Western medicine for the treatment of endometriosis; however, the side effects associated with this practice include disease recurrence and menopause, which can severely influence quality of life. Angiogenesis is the main biological mechanism underlying the development of endometriosis. Numerous natural products and Chinese medicines with potent anti-angiogenic effects have been investigated, and the molecular basis underlying their therapeutic effects in endometriosis has been explored. This review aims to describe natural products and compounds that suppress angiogenesis associated with endometriosis and to assess their diverse molecular mechanisms of action. Furthermore, this review provides a source of information relating to alternative and complementary therapeutic products that mediate anti-angiogenesis. An extensive review of the literature and electronic databases, such as the China National Knowledge Infrastructure, PubMed, and Embase, was conducted using the keywords ‘endometriosis,’ ‘traditional Chinese medicine,’ ‘Chinese herbal medicine,’ ‘natural compounds,’ and ‘anti-angiogenic’ therapy. Anti-angiogenic therapy is an emerging strategy for the treatment of endometriosis. Natural anti-angiogenic products and Chinese medicines provide several beneficial clinical effects, including pain relief. In this review, we summarize clinical trials and experimental studies of endometriosis using natural products and Chinese medicines. In particular, we focus on anti-angiogenic products and alternative and complementary medicines for the treatment of endometriosis and additionally examine their therapeutic efficacy and mechanisms of action. Anti-angiogenic natural products and/or compounds provide a new approach for the treatment of endometriosis. Future work will require randomized trials with larger numbers of subjects, as well as long-term follow-up to confirm the findings described here.
... Hence, they may be more effective and, thus, applied in lower, well-tolerated doses. Interesting candidates of such compounds can be found in the large group of phytochemicals with anti-angiogenic, anti-inflammatory, antiproliferative and anti-oxidative properties, such as epigallocatechin-3gallate (Laschke et al., 2008) or resveratrol (Kolahdouz Mohammadi and Arablou, 2017). ...
... Cytokines, angiogenic factors and adhesion promotion factors, including interleukin (IL)-6, IL-8, tumor growth factor-β and vascular endothelial growth factor, contribute to cell attachment, proliferation and invasion, and neovascularization (8,9). It is also considered that various factors, including inflammatory, genetic, epigenetic, hormonal, immune, anatomic and lifestyle factors, are associated with the etiology of endometriosis (6,10,11). However, despite the various hypotheses, the exact pathogenesis of endometriosis remains unclear. ...
Endometriosis is a common gynecological disease, affecting 6‑10% of women of reproductive age. The precise mechanisms underlying the development of endometriosis remain unclear. In the present study, a bioinformatics approach was applied to systematically identify the pathways and genes involved in the development of endometriosis and to discover potential biomarkers. The gene expression profiles of GSE6364, a microarray dataset of endometrial biopsies obtained from women with or without endometriosis, was downloaded from the Gene Expression Omnibus DataSets database that stores original submitter‑supplied records (series, samples and platforms), as well as curated datasets. Differentially expressed gene (DEG) analysis was performed with GEO2R. DAVID was used to analyze the gene ontology enrichment of the DEGs. Gene Set Enrichment Analysis (GSEA) was conducted using the GSEA v3.0 software. Protein‑protein interactions (PPI) were evaluated with the Search Tool for the Retrieval of Interacting Genes, and PPI network visualization was performed with Cytoscape. In addition, Cell Counting kit‑8 and Transwell assays were performed on human endometrial stromal cells (HESCs). A total of 172 DEGs were extracted. Inflammatory response genes were significantly upregulated in the endometriosis tissues and C‑X‑C motif chemokine receptor 2 (CXCR2), was one of the most up‑regulated genes according to DEG analysis. Cell‑based experiments confirmed that CXCR2 promoted the proliferation, migration and invasion of HESCs. In conclusion, a bioinformatics approach combined with in vitro experiments in the present study revealed that CXCR2 may be associated with the development of endometriosis and has potential as a biomarker for the diagnosis of endometriosis.
... Its anti-inflammatory effect of resveratrol is mediated by several mechanisms including the inhibition of (NF)-kB activation. In animal models of endometriosis, the supplementation of resveratrol displayed to decrease the number and volume of endometrial implants, suppressing inflammation and decreasing cell proliferation and survival of ectopic endometriotic cells [154]. In a small open-label clinical trial, 12 women with endometriosis who failed to obtain pain relief during COC use (drosperinone 3 mg and EE 30 μg) received the addition of resveratrol (30 mg/day). ...
Introduction: Endometriosis is a hormone-dependent benign chronic disease that requires a chronic medical therapy. Although currently available drugs are efficacious in treating endometriosis-related pain, some women experience partial or no improvement. Moreover, the recurrence of symptoms is expected after discontinuation of the therapies. Currently, new drugs are under intense clinical investigation for the treatment of endometriosis.
Areas covered: This review aims to offer the reader a complete and updated overview on new investigational drugs and early molecular targets for the treatment of endometriosis. The authors describe the pre-clinical and clinical development of these agents.
Expert opinion: Among the drugs under investigation, late clinical trials on gonadotropin-releasing hormone antagonists (GnRH-ant) showed the most promising results for the treatment of endometriosis. Aromatase inhibitors (AIs) are efficacious in treating endometriosis related pain symptoms but they cause significant adverse effects that limit their long-term use. New targets have been identified to produce drugs for the treatment of endometriosis, but the majority of these new compounds have only been investigated in laboratory studies or early clinical trials. Thus, further clinical research is required in order to elucidate their efficacy and safety in human.
... RSV, also referred to as 3,5,4'-trihydroxystilbene, is one of the natural phytoalexin extracted from some kinds of plant seeds such as grape seeds [27]. Many previous studies have suggested that RSV has the ability to interfere with the pathological processes in neurodegenerative diseases [28]. ...
Background
Traumatic brain injury (TBI) is characterized by cognitive deficits, which was associated with brain oxidative stress and apoptosis. Resveratrol (RSV) is an anti-apoptotic and anti-oxidative. This study aimed to investigate neuroprotective effects and involved molecular mechanisms in TBI.
Material/Methods
RSV and p38 inhibitor were administrated to TBI rats. Cognitive deficits were evaluated by Morris water maze assay. Reactive oxygen species (ROS) and apoptosis were detected in rat brains by fluorescent staining. Western blotting was used to assess the phosphorylation of p38 and the expression levels of Nrf2, HO1, and activated caspase-3.
Results
RSV administration attenuated cognitive deficits of TBI rats. The ROS generation and apoptosis in the brain of TBI rats were suppressed by RSV treatment. Moreover, RSV treatment recovered activation of p38/Nrf2/HO1 signaling pathway. The co-administration of p38 inhibitor impaired RSV’s attenuating effects on cognitive deficits, brain apoptosis, and ROS generation.
Conclusions
RSV attenuated cognitive deficits of TBI by inhibiting oxidative stress-mediated apoptosis via targeting p38/Nrf2 signaling.
... The introduction of new agents can be effective in improving the condition of patients. Diet is a potentially modifiable risk factor for endometriosis and recently, dietary components and phytochemicals are considered as preventive and therapeutic agents in endometriosis [2,18]. ...
Endometriosis, an estrogen-dependent inflammatory disease, is one of the most common chronic gynecological disorders affecting women in reproductive age. It is characterized by the presence of endometrial-like tissue outside the uterus. The exact pathophysiology of endometriosis is not still well-known, but the immune system and inflammation have been considered as pivotal factors in disease progression.
Turmeric, an important spice all around the world, is obtained from the rhizomes of Curcuma longa, a member of the Zingiberaceae family. It has been used in the prevention and treatment of many diseases since ancient times. Curcumin is the principal polyphenol isolated from turmeric. Several evidences have shown the anti-inflammatory, antioxidant, anti-tumor, anti-angiogenesis, and anti-metastatic activities of curcumin. In this review, relevant articles on the effect of curcumin on endometriosis and possible molecular mechanisms are discussed.
... We discussed the role of APE1 in resveratrol-elicited protective effect in cerebral ischemia injury only in terms of its antioxidant stress activity. Many researches revel that both APE1 and resveratrol have anti-apoptotic and anti-inflammatory activities (41)(42)(43), implying that apoptosis may also contribute to the role of APE1 in these. In addition, we only use HT22 cells to test the hypothesis. ...
Resveratrol, a naturally occurring polyphenolic compound, exhibits a neuroprotective role in models of central nervous system diseases, including cerebral ischemia/reperfusion injury. Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme that contributes to base excision repair of oxidative DNA damage and redox activation of transcription factors, associated with neuronal survival against hypoxic‑ischemic injury. It was hypothesized that resveratrol protects HT22 cells against oxygen‑glucose deprivation and re‑oxygenation (OGD/R)‑induced injuries through upregulation of APE1. It was demonstrated that resveratrol pretreatment significantly increased the viability of HT22 cells and decreased the release of lactate dehydrogenase (LDH), accompanied by the upregulation of APE1 mRNA, and protein levels, as well as the activity of APE1 under OGD/R conditions. In addition, resveratrol reversed OGD/R‑induced oxidative DNA damage as evidenced by the decreases in the levels of 8‑hydroxy‑2'‑deoxyguanosine and APE sites. However, APE1 knockdown using short hairpin RNA sequence targeting APE1 abolished resveratrol‑elicited beneficent effects against OGD/R‑induced cytotoxicity and oxidative stress. This was indicated by decreased cell viability, superoxide dismutase activity and glutathione levels, and increased LDH release and reactive oxygen species levels. The results of the present study indicate that APE1 contributes to the protective effects of resveratrol against neonatal hypoxic‑ischemic brain injuries, and suggest that DNA repair enzymes, including APE1, may be a unique strategy for neuroprotection against this disease.
... This polyphenol can be found in many plant species, but mainly in grapes and red wine. Heat and ultraviolet radiation can cause isomerization of trans-resveratrol into cis-resveratrol [25]. Resveratrol is a potent antioxidant and scavenger of superoxide, hydroxyl and metal-induced radicals. ...
At present time it is noticed significant interest for ability of biologically active compounds usage not only for prevention but also for therapy of human diseases. Traditionally medical plants with high pharmacological potential are rich source for them. Therapeutical features of plants were demonstrated on example of many widespread human diseases. In this systematic review perspectives of plant extracts application in lung cancer therapy has been discussed. It was carried out research of scientific publications using Medline, Scopus, WoS, Pubmed databases. Their text was published in open access in English. As a result of analysis it was made a conclusion about significant therapeutical potential of plant extracts and perspectives of development of new strategies of lung cancer treatment, that are included biologically active compounds with classical approaches (chemoterapeutical agents, target substances and radiation).
Endometriosis is a disease with a heterogeneous pathogenesis, explained by multiple theories, and also with a polymorphic presentation. The purpose of this literature review is to systematize the genetic, inflammatory, and environmental factors related to the pathophysiology of endometriosis. Current evidence suggests that endometriosis is a complex inherited genetic condition, in which the genes that determine susceptibility to the disease interact with the environment to develop different phenotypes. Genetic variants associated with risk of endometriosis have been identified in several genome‐wide association studies, in addition to a group of genes related to the pathophysiology of endometriosis, namely the estrogen, progesterone and androgen receptors and the cytochrome P450 gene, as well as the p53 gene. The role of inflammation is controversial; however, it is an essential process, both in the initiation and perpetuation of the disease, in and outside the pelvis. Alterations in reactive oxygen species pathways that consequently determine oxidative stress are typical in the inflammatory environment of endometriosis. The role of environmental factors is a relatively new and broad‐spectrum topic, with inconsistent evidence. Multiple factors have been studied such as endocrine‐disrupting chemicals, metals, intrauterine exposure to diethylstilbesterol and lifestyle risk factors. In conclusion, endometriosis remains a mysterious condition, with multifactorial factors involved in its pathophysiology. The progress that has been made in the genetic predisposition to endometriosis may allow the establishment of new therapeutic targets. On the other hand, understanding the role of the environment in this disease may allow preventive intervention, minimizing its incidence and/or severity.
This article is categorized under: Reproductive System Diseases > Molecular and Cellular Physiology
Reproductive System Diseases > Environmental Factors
Reproductive System Diseases > Genetics/Genomics/Epigenetics
Endometriosis is a chronic and complex endocrine disorder that affects women of reproductive age. This syndrome is benign and is characterized by a combination of ovarian dysfunction and estrogen dependency symptoms, as well as pain and infertility. The most commonly stated symptoms include dysmenorrhea, significant dyspareunia, dyschezia, and dysuria. It is a severe public health issue. The prevalence rate is quite high and continues to rise on a daily basis. Starting with its diagnosis, pathophysiology, repercussions, and treatment options, there are numerous areas of disagreement. This study aims to provide an overview of the development of endometriosis diagnosis, symptoms, risk factors, etiology, medicinal plants, phytochemicals, and treatment, with a focus on research and the creation of novel therapeutic strategies. We conclude by making predictions and recommendations for the future of endometriosis-related research and prospective therapy approaches.
Endometriosis is an estrogen-dependent chronic inflammatory gynecological disease defined by the presence of endometrial glands and mesenchyme outside the uterine cavity, named ectopic endometrium. Recent studies show that endometriosis is...
Resveratrol is a polyphenolic phytochemical found in fruits, nuts and vegetables that contributes to the remarkable dietary effects of polyphenolic as inhibitors aging and multiple aging related diseases. In addition, resveratrol has been extensively investigated as an inhibitor of inflammatory diseases including cancer, however, the underlying mechanisms of these chemotherapeutic effects of resveratrol are not completely understood. In cancer cells resveratrol inhibits cell growth, survival, migration and invasion, and many of the effects of resveratrol resemble those observed for bis-indole derived (CDIM) compounds that bind the pro-oncogenic nuclear receptor 4A1 (NR4A1, Nur77) and act as receptor antagonists. Using an isothermal titration calorimetry binding assay, we observed that resveratrol bound to the ligand binding domain of NR4A1 with a KD value of 2.4 µM and a ΔG of -32.2 kJ/mol. Resveratrol also inhibited NR4A1-dependent transactivation in H460 and H1299 lung cancer cells suggesting that resveratrol is an NR4A1 antagonist. This observation was confirmed in a series of functional (cell proliferation, survival, migration and invasion) and gene expression assays in H460 and H1299 cells showing that treatment with resveratrol mimicked the effects of NR4A1 knockdown and were similar to results of previous studies using CDIM/NR4A1 antagonists. These data indicate that applications of resveratrol may be more effective in patients that overexpress NR4A1 which is a negative prognostic factor for patients with some solid tumor-derived cancers. Significance Statement We have examined the mechanism of action of resveratrol and show binding to NR4A1 (KD = 2.4 µM) and inhibition of NR4A1-dependent transactivation in lung cancer cells. Treatment of H460 and H1299 lung cancer cells with resveratrol inhibits cell growth, survival, migration/invasion and related genes, and acts as an NR4A1 antagonist. Resveratrol can now be used more effectively in cancer chemotherapy by targeting patients that overexpress NR4A1 in lung cancer.
Endometriosis, a gynecological disease that affects reproductive age women is difficultly controlled in the long term by currently available treatments, prompting patients to adopt self‐controlled interventions including dietary changes. The aim of this review is to provide evidence of how curcumin, quercetin, and resveratrol can act as natural interventions to control endometriosis. The review followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) guidelines. A comprehensive search was carried out in PubMed, Scopus, and Web of Science to gather together all the articles that study the specific actions of curcumin, resveratrol, or quercetin in endometriosis pathophysiology. All types of study designs including experimental data were considered. Thirty articles, including a clinical trial, were included. For the assessment of the quality of the selected studies that globally have “good quality”, the GRADE (Grading of Recommendations Assessment, Development and Evaluation) and the SYRCLE ROB tool criteria were used. By acting on mechanisms of inflammation, oxidative stress, cell proliferation, invasion and adhesion, apoptosis, angiogenesis and glucose and lipid metabolism, curcumin, quercetin, and resveratrol showed to have beneficial effects, evidencing their potential application in the endometriosis treatment. However, future clinical studies are necessary to determine the real efficacy of these compounds in human endometriosis.
Resveratrol obtained in grape seed and skin is structurally similar to a synthetic estrogen diethylstilbestrol. The endogenous estrogen, 17β-estradiol, induces cellular responses by binding to the estrogen receptor alpha and beta. The bone fracture due to decreased bone mineral density in postmenopausal women is linked to reduced estrogen. The adverse drug reactions of hormone replacement therapy warrant identifying unique natural compounds with ER-subtype specificity to improve bone health. Resveratrol is considered a phytoestrogen; however, its isoform selectivity has not yet been established on osteoblast cell lines. Therefore, in vitro and in silico docking studies were performed to analyze the binding affinity and selectivity of resveratrol towards receptor alpha and β-isoforms. Resveratrol was evaluated for its actions on the proliferation and differentiation in the primary rat calvarial osteoblasts and bone marrow cells. Osteoblasts specifically increased receptor alpha expression in rat calvarial osteoblasts cells; however, there was no effect on receptor beta expression. In silico studies further confirmed receptor alpha isoform specificity. The observed differences in the orientation, interaction pattern, and binding affinity of resveratrol at the active site of receptor alpha and beta are supported by the western blot analysis. The estrogen mimetic action of resveratrol suggests its therapeutic potential as a bone anabolic agent for postmenopausal osteoporosis.
Graphical abstract
Endometriosis is an estrogen-dependent chronic inflammatory disease that affects approximately 10% of women of reproductive age and up to 50% of women with infertility. The heterogeneity of the disease makes accurate diagnosis and treatment a clinical challenge. In this study, we generated two models of endometriosis: the first in rats and the second using human ectopic endometrial stromal cells (HEcESCs) derived from the lesion tissues of endometriosis patients. We then applied resveratrol to assess its therapeutic potential. Resveratrol intervention had significant efficacy to attenuate lesion size and to rectify aberrant lipid profiles of model rats. Lipidomic analysis revealed significant lipidomic alterations, including notable increases of sphingolipids and decreases of both glycerolipids and most phospholipids. Upon resveratrol application, both proliferation capacity and invasiveness parameters decreased, and the early apoptosis proportion increased for HEcESCs. The activation of PPARα was also noted as a factor potentially contributing to recovery from endometriosis in both models. Our study provides valuable insight into the mechanisms of resveratrol in endometriosis and therefore strengthens the potential for optimizing resveratrol treatment for this disease.
Endometriosis is a chronic benign disease that affects women of reproductive age. Medical therapy is often the first line of management for women with endometriosis in order to ameliorate symptoms or to prevent post-surgical disease recurrence. Currently, there are several medical options for the management of patients with endometriosis and long-term treatments should balance clinical efficacy (controlling pain symptoms and preventing recurrence of disease after surgery) with an acceptable safety-profile. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of chronic inflammatory conditions, being efficacious in relieving primary dysmenorrhea. Combined oral contraceptives and progestins, available for multiple routes of administration, are commonly administered as first-line hormonal therapies. Several studies demonstrated that they succeed in improving pain symptoms in the majority of patients; moreover, they are well tolerated and not expensive. Gonadotropin-releasing hormone-agonists are prescribed when first line therapies are ineffective, not tolerated or contraindicated. Even if these drugs are efficacious in treating women not responding to COCs or progestins, they are not orally available and have a less favorable tolerability profile (needing an appropriate add-back therapy). Because few data are available on long-term efficacy and safety of aromatase inhibitors they should be reserved only for women with symptoms who are refractory to other treatments only in a research environment. Almost all of the currently available treatment options for endometriosis suppress ovarian function and are not curative. For this reason, research into new drugs is unsurprisingly demanding. Amongst the drugs currently under investigation, gonadotropin-releasing hormone antagonists have shown most promise, currently in late-stage clinical development. There is a number of potential future therapies currently tested only in vitro, in animal models of endometriosis or in early clinical studies with a small sample size. Further studies are necessary to conclude whether these treatments would be of value for the treatment of endometriosis.
Endometriosis represents an often painful, estrogen-dependent gynecological disorder, defined by the existence of endometrial glands and stroma exterior to the uterine cavity. The disease provides a wide range of symptoms and affects women’s quality of life and reproductive functions. Despite research efforts and extensive investigations, this disease’s pathogenesis and molecular basis remain unclear. Conventional endometriosis treatment implies surgical resection, hormonal therapies, and treatment with nonsteroidal anti-inflammatory drugs, but their efficacy is currently limited due to many side effects. Therefore, exploring complementary and alternative therapy strategies, minimizing the current treatments’ adverse effects, is needed. Plants are sources of bioactive compounds that demonstrate broad-spectrum health-promoting effects and interact with molecular targets associated with endometriosis, such as cell proliferation, apoptosis, invasiveness, inflammation, oxidative stress, and angiogenesis. Anti-endometriotic properties are exhibited mainly by polyphenols, which can exert a potent phytoestrogen effect, modulating estrogen activity. The available evidence derived from preclinical research and several clinical studies indicates that natural biologically active compounds represent promising candidates for developing novel strategies in endometriosis management. The purpose of this review is to provide a comprehensive overview of polyphenols and their properties valuable for natural treatment strategy by interacting with different cellular and molecular targets involved in endometriosis progression.
Resveratrol is a phytochemical with anti-angiogenic, anti-inflammatory, and antioxidant properties. The present study has evaluated the effect of resveratrol on the expression of vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β) and matrix metalloproteinase-9 (MMP-9) as factors related to endometriosis progression. Thirteen eutopic (EuESCs) and 8 ectopic (EESCs) endometrial stromal cells from women with endometriosis and 11 control endometrial stromal cells (CESCs) were treated with resveratrol (100 µM) for 6, 24 and 48 h. The gene and protein expression levels of VEGF, TGF-β, and MMP-9 were measured using real-time PCR and ELISA methods, respectively. Results showed that the basal gene and protein expression of VEGF and MMP-9 were higher in EESCs compared to EuESCs and CESCs (P < 0.01 to < 0.001 and P < 0.05 to < 0.01 respectively). Also, resveratrol treatment decreased the gene and protein expression of VEGF and MMP-9 in EuESCs, EESCs and CESCs (P < 0.05 to < 0.01 and P < 0.05 to < 0.01 respectively) and gene and protein expression of TGF-β in EESCs and EuESCs (P < 0.05 to < 0.01). The effect of resveratrol in reduction of VEGF gene expression was statistically more noticeable in EESCs compared to EuESCs and CESCs (P < 0.05). According to the findings, resveratrol may ameliorate endometriosis progression through reducing the expression of VEGF, TGF-β, and MMP-9 in endometrial stromal cells (ESCs).
Although endometriosis is a disease that affects a large percentage of women, studies demonstrating the relationship between certain foods or lifestyle modifications are limited. Data from the Nurses’ Health Study II cohort allowed for retrospective observation of certain dietary measures and risk of developing endometriosis utilizing a large sample size over a span of 4 years. Analysis has found that increasing consumption of certain fruits, omega-3 fatty acids, and dairy foods may reduce the risk of developing endometriosis. Dietary and lifestyle modifications and how they relate to endometriosis risk and/or symptoms associated with endometriosis are discussed in this chapter.
Endometriosis is a benign gynecological condition prevalent among reproductive-aged women. Although active research and studies have been carried out to discover new drugs, surgery and hormone therapy are still the gold standard for endometriosis treatment. Nowadays, various flavonoids are considered long-term supplements for different diseases. Myricetin, a flavonol, has antiproliferative, anti- or pro-oxidant, and anticancer effects in gynecological diseases. Here, we reveal for the first time, to our knowledge, the antigrowth effects of myricetin in endometriosis. Myricetin inhibited cell proliferation and cell cycle progression of human VK2/E6E7 and End1/E6E7 cells and induced apoptosis, with the loss of mitochondrial membrane potential and accumulation of reactive oxygen species and calcium ions. Additionally, myricetin decreased the activation of AKT and ERK1/2 proteins, whereas it induced p38 activation in both cell lines. Moreover, myricetin decreased lesion size in the endometriosis mouse model via Ccne1 inhibition. Thus, myricetin has antiproliferative effects on endometriosis through cell cycle regulation.
Endometriosis is a common disease in women of reproduction age. It causes pain and difficulty in getting pregnant. However the exact causes of infertility associated with endometriosis still remain controversial. The treatment of endometriosis consists of medical treatment of pain as well as medical and surgical treatment of infertility caused by endometriosis and assisted reproduction techniques. Since the treatment of endometriosis is often connected with diminishing ovarian reserve, the techniques for ovarian tissue preservation and oocyte and embryo freezing are used to maintain the ability for childbearing.
Resveratrol, a phytoalexin polyphenol, has antiproliferative, antiangiogenic, anti‐inflammatory, and antioxidant properties. The present study has assessed the effect of resveratrol treatment on the expression of insulin‐like growth factor‐1 (IGF‐1) and hepatocyte growth factor (HGF) in endometrial stromal cells (ESCs) from women with and without endometriosis. Endometrial tissues were obtained from 40 endometriotic patients and 15 nonendometriotic control women. After the enzymatic digestion, 13 eutopic ESCs (EuESCs), 8 ectopic ESCs (EESCs), and 11 control ESCs (CESCs) were treated with resveratrol (100 μM) for 6, 24, and 48 hr. The gene and protein expressions of IGF‐1 and HGF were measured using real‐time polymerase chain reaction and enzyme‐linked immunosorbent assay methods, respectively. Results showed that resveratrol treatment decreased significantly the gene expression of IGF‐1 and HGF in EuESCs, EESCs, and CESCs (p < 0.05). The effect of resveratrol treatment on the reduction of IGF‐1 gene expression was statistically more noticeable in EESCs compared with CESCs (p < 0.05). Also, in the case of HGF gene expression, the reducing effect of resveratrol treatment was statistically more considerable in EESCs compared with EuESCs and CESCs (p < 0.05 and p < 0.01, respectively). The IGF‐1 and HGF protein production decreased significantly in EuESCs and EESCs (p < 0.05) but not in CESCs. These findings suggest that resveratrol treatment could reduce the expression of IGF‐1 and HGF in ESCs especially in EESCs, which play a pivotal role in disease progression.
Deep eutectic solvents (DESs), a new group of ecofriendly solvent combined with the ultrasonic-assisted extraction (UAE) technique, were first successfully used for extraction of resveratrol from peanut roots. Resveratrol in the extract was analyzed and quantified using a HPLC-UV method. A series of DESs consisting of choline chloride (ChCl) and 1,4-butanediol, citric acid, and ethylene glycol were formulated, finding ChCl/1,4-butanediol was a most proper extraction system. The optimal extraction parameters were obtained using a Box–Behnken design (BBD) test combined with response surface methodology as follows: 40% of water in ChCl/1,4-butanediol (1/3, g/g) at 55°C for 40 min and solid/liquid ratio of 1:30 g/mL. The total extraction content and extraction yield of resveratrol from peanut roots could reach 38.91 mg/kg and 88.19%, respectively, under such optimal conditions. The present study will provide a typical example for using DESs to extract natural bioactive compounds from plants.
Introduction: Pharmacotherapy has a pivotal role in the management of endometriosis with long-term treatments balancing clinical efficacy (control of pain symptoms and prevention of recurrence of the disease after surgery) with an acceptable safety profile. Treatment choice is based on several factors including age and patient preference, reproductive plans, intensity of pain, severity of disease and incidence of adverse effects.
Areas covered: The aim of this review is to provide the reader with a complete overview of drugs that are currently available or are under investigation for the treatment of endometriosis highlighting on-going clinical trials.
Expert opinion: Almost all of the available treatment options for endometriosis suppress ovarian function and are not curative. Combined oral contraceptives and progestins are commonly administered to these patients in order to ameliorate pain symptoms. Gonadotropin-releasing hormone-agonists are prescribed when first-line therapies are ineffective, not tolerated or contraindicated. Aromatase inhibitors should be reserved only for women who are refractory to other treatments. Amongst the drugs under development, gonadotropin-releasing hormone antagonists have shown the most promising results. Presently, are a number of potential therapies currently in pre-clinical or early clinical studies which may alter treatment strategies in the future although further studies are necessary.
Resveratrol (RSV), a polyphenolic compound derived from red wine, inhibits the proliferation of various types of cancer. RSV induces apoptosis in cancer cells, while enhancing autophagy. Autophagy promotes cancer cell growth by driving cellular metabolism, which may counteract the effect of RSV. The present study aimed to elucidate the correlation between RSV and autophagy and to examine whether autophagy inhibition may enhance the antitumor effect of RSV in endometrial cancer cells. Cell proliferation, cell cycle progression and apoptosis were examined, following RSV exposure, by performing MTT assays, flow cytometry and annexin V staining, respectively, in an Ishikawa endometrial cancer cell line. Autophagy was evaluated by measuring the expression levels of light chain 3, II (LC3-II; an autophagy marker) by western blotting and immunofluorescence. Chloroquine (CQ) and small interfering RNAs targeting autophagy related (ATG) gene 5 (ATG5) or 7 (ATG7) were used to inhibit autophagy, and the effects in combination with RSV were assessed using MTT assays. RSV treatment suppressed cell proliferation in a dose-dependent manner in Ishikawa cells. In addition, RSV exposure increased the abundance of the sub-G1 population and induced apoptosis. LC3-II accumulation was observed following RSV treatment, indicating that RSV induced autophagy. Combination treatment with CQ and RSV more robustly suppressed growth inhibition and apoptosis, compared with RSV treatment alone. Knocking down ATG5 or ATG7 expression significantly augmented RSV-induced apoptosis. The results of the present study indicated that RSV-induced autophagy may counteract the antitumor effect of RSV in Ishikawa cells. Combination treatment with RSV and an autophagy inhibitor, such as CQ, may be an attractive therapeutic option for treating certain endometrial cancer cells.
Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.
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Abstract The aim of our study was to evaluate the effectiveness of resveratrol in experimentally induced endometrial implants in rats through inhibiting angiogenesis and inflammation. Endometrial implants were surgically induced in 24 female Wistar-Albino rats in the first surgery. After confirmation of endometriotic foci in the second surgery, the rats were divided into resveratrol (seven rats), leuprolide acetate (eight rats), and control (seven rats) groups and medicated for 21 d. In the third surgery, the measurements of mean areas and histopathological analysis of endometriotic lesions, VEGF, and MCP-1 measurements in blood and peritoneal fluid samples, and immunohistochemical staining were evaluated. After treatment, significant reductions in mean areas of implants (p < 0.01) and decreased mean histopathological scores of the implants (p < 0.05), mean VEGF-staining scores of endometriotic implants (p = 0.01), and peritoneal fluid levels of VEGF and MCP-1 (p < 0.01, for VEGF and p < 0.01, for MCP-1) were found in the resveratrol and leuprolide acetate groups. Serum VEGF (p = 0.05) and MCP-1 (p = 0.01) levels after treatment were also significantly lower in the resveratrol and leuprolide acetate groups. Resveratrol appears to be a potential novel therapeutic agent in the treatment of endometriosis through inhibiting angiogenesis and inflammation. Further studies are needed to determine the optimum effective dose in humans and to evaluate other effects on reproductive physiology.
Resveratrol is a natural phytoestrogen with antiproliferative properties present in red wine, grapes, and berries. Published reports on the effects of resveratrol in human endometrial function are limited. The objective of this study was to investigate the expression of estrogen receptor α (ESR1), Ki-67 (a proliferative marker), aryl hydrocarbon receptor (AhR), and members of the cytochrome P450 superfamily of enzymes (CYP1A1 and CYP1B1) in an in vitro and vivo assay. Alkaline phosphatase assay of estrogenicity was used to compare estrogen activity of different concentrations of resveratrol to estradiol (E2) and diethylstilbestrol (DES), using Ishikawa cell culture. Immunohistochemical expression of ESR1 and Ki67, and reverse transcriptase polymerase chain reaction of AhR, CYP1A1, and CYP1B1 were analyzed from xenograft implants of human endometrial tissue in ovariectomized immunodeficient RAG-2-γ(c) mice, after 30 days of treatment with subcutaneous pellets of E2, E2 plus progesterone (P4), or E2 plus resveratrol (6, 30, or 60 mg) for 30 days. Compared to E2, resveratrol acted as an agonist and antagonist of estrogen in low and high concentrations, respectively, when combined with E2. Xenografts of human endometrial tissues in RAG-2 mice exhibited reduced expression of ESR1 and proliferative activity (Ki67) with 60 mg of resveratrol. This study suggests that resveratrol, at high doses, has the potential benefit to reduce proliferation of human endometrium through ESR1.
In this study, resveratrol (RSV) - a potent sirtuin 1 activator - was found to have beneficial effects on glucolipid metabolism and improve inflammatory mediators and markers of oxidative stress. Diabetic (db/db) mice and non-diabetic C57BL/6J mice were used in the study. The db/db mice were treated with or without 0.3% RSV mixed with chow for 8 weeks. Dietary RSV significantly lowered blood glucose, plasma lipid and free fatty acid levels in db/db mice. RSV markedly inhibited the expression of intercellular adhesion molecule-1 (ICAM-1), endothelial vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) in the aorta and the blood plasma of db/db mice (p < 0.05). Levels of mac-3-positive macrophages (measure of the infiltration of activated macrophages) were lower in RSV-treated diabetic mice than in their untreated counterparts (p < 0.05). RSV treatment reduced the activity of the transcriptional regulator nuclear factor kappa B (NF-κB) in aortic tissues (p < 0.05). Thus, RSV treatment reduced ICAM-1, VCAM-1 and MCP-1 expression in the aorta and ICAM-1, VCAM-1 and MCP-1 levels in the plasma of diabetic mice. Since dietary supplementation with RSV also reduced NF-κB activities in the aorta, the therapeutic effects of RSV might be associated with the downregulation of NF-κB.
Can we use chemokines as biomarkers to diagnose patients with endometriosis in clinical practice?
Some chemokines, especially CXCL8 (IL-8), CCL-2 (MCP-1) and CCL5 (RANTES), have the potential to work as biomarkers to identify patients with endometriosis but their accuracy could be improved by combination with other non-inflammatory markers in a panel of biomarkers.
The need for a good marker to diagnose endometriosis has increased in recent years and research in this field has intensified. Chemokines have been reported to be associated with endometriosis in several studies over the last 20 years. Many of these studies measured one or more chemokines in peritoneal fluid (PF) and peripheral blood (PB) or through endometrial biopsies in patients with and without endometriosis.
A systematic review was done on all published studies that compared chemokine concentrations in patients with and without endometriosis to evaluate their potential as biomarkers for the disease.
Using MEDLINE database from December 1993 to August 2013 and the MeSH terms 'Endometriosis' and 'Chemokines', we identified relevant studies to include in the present review, which was based on the PRISMA statement. Studies that measured at least one chemokine in patients with endometriosis and matching controls in PB, PF or endometrial samples were included. We did not include samples from ectopic lesions. All review articles as well as studies with animals and those not written in English were excluded from this systematic review. The studies were assessed using a modified version of the Quality Assessment of Diagnostic Accuracy Studies criteria. Two authors independently assessed studies for inclusion and risk of bias, and extracted data.
After inclusion and exclusion criteria, 62 studies were selected to be included in this systematic review. A total of 27 different chemokines or their receptors were evaluated in the reviewed studies. The most studied chemokines (including their receptors) were CXCL8 (51.6%), CCL2 (38.7%) and CCL5 (19.3%) (% of studies). CXCL8 (IL-8) appears to have the best results among all the other chemokines as a marker for endometriosis.
Some studies included have low power due to small sample size and study designs vary in the assessment criteria for the markers, the state of the patients (e.g. phase of the cycle and stage of disease) and the nature of the controls.
Our findings could guide future research in this field to select the chemokines with the best potential, and to stimulate better-designed studies to determine whether they can become a useful diagnostic tool in clinical practice.
There was no funding to support this systematic review. The authors have no competing interest to declare.
In the past decades, a greater understanding of acute pancreatitis has led to improvement in mortality rates. Nevertheless, this disease continues to be a health care system problem due to its economical costs. Future strategies such as antioxidant supplementation could be very promising, regarding to beginning and progression of the disease. For this reason, this study was aimed at assessing the effect of exogenous administration of resveratrol during the induction process of acute pancreatitis caused by the cholecystokinin analog cerulein in rats. Resveratrol pretreatment reduced histological damage induced by cerulein treatment, as well as hyperamylasemia and hyperlipidemia. Altered levels of corticosterone, total antioxidant status, and glutathione peroxidase were significantly reverted to control levels by the administration of resveratrol. Lipid peroxidation was also counteracted; nevertheless, superoxide dismutase enzyme was overexpressed due to resveratrol pretreatment. Related to immune response, resveratrol pretreatment reduced pro-inflammatory cytokine IL-1β levels and increased anti-inflammatory cytokine IL-10 levels. In addition, pretreatment with resveratrol in cerulein-induced pancreatitis rats was able to reverse, at least partially, the abnormal calcium signal induced by treatment with cerulein. In conclusion, this study confirms antioxidant and immunomodulatory properties of resveratrol as chemopreventive in cerulein-induced acute pancreatitis.
Hepatocellular carcinoma (HCC), a hypervascular tumor, is one of the most common and lethal cancers worldwide.We previously showed that resveratrol, a dietary polyphenol, inhibits rat liver carcinogenesis through antioxidative and antiinfl ammatory mechanisms. As resveratrol possesses antiangiogenic properties, we hypothesize that it may exert chemoprevention of hepatocarcinogenesis by suppressing angiogenesis. The antiangiogenic effect of resveratrol was investigated by analyzing livers from our previous study in which resveratrol (50-300 mg/kg) exerted chemopreventive action against diethylnitrosamine (DENA)-induced rat liver tumorigenesis. Hepatic angiogenesis was evaluated by microvessel density (MVD) based on immunohistochemical staining of CD31-positive endothelial cells. The expression of hepatic vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) were determined by
immunohistochemistry. Sixteen weeks following the administration of DENA, there was a substantial increase in hepatic MVD as compared to normal liver. A dramatic increase in hepatic VEGF and HIF-1α was observed in DENA-treated animals compared to normal counterparts. Treatment with resveratrol dose-dependently abrogated the DENA-induced increased MVD as well as the elevated expression of VEGF and HIF-1α. DENA-initiated hepatocarcinogenesis in rats exhibits substantial neovascularization possibly due to overexpression of VEGF upregulated by HIF-1α. Resveratrol exerts a remarkable angiosuppressive effect in DENA-evoked hepatocellular carcinogenesis. Resveratrol-mediated inhibition of angiogenesis could be achieved by suppressing VEGF expression through downregulation of HIF- 1α. These results, in conjunction with our previous fi ndings, provide evidence that angiosuppression is involved in resveratrol-mediated chemoprevention of rat liver carcinogenesis and support the potential use of this natural agent in the prevention and therapy of HCC.
Objective:
To evaluate the effect of resveratrol on an experimentally induced endometriosis rat model.
Study design:
After endometriotic implants were surgically formed, rats were randomly divided into 2 groups as control group (saline treated, n = 6) and resveratrol group (10 mg/kg/d, n = 6). The inflammatory markers and histopathological changes were assessed at the end of the treatment period. Results Our results showed (1) significant reduction in the implant size (P < .0005); (2) significantly decreased levels of vascular endothelial growth factor (VEGF) in the peritoneal fluid and plasma (P < .005); and monocyte chemotactic protein 1 (MCP-1) in the peritoneal fluid (P < .05), (3) highly significant suppression of VEGF expression in the endometriotic tissue (P < .0005); and (4) considerable histological changes in the endometriotic foci following resveratrol treatment.
Conclusion:
Resveratrol appears to be effective on the development of endometriosis through its antiangiogenic and anti-inflammatory properties. Future studies with different doses of resveratrol might provide more comprehensive results regarding the treatment of endometriosis.
Study question:
Can resveratrol and epigallocatechin-3-gallate (EGCG) inhibit the growth and survival of endometriotic-like lesions in vivo in a BALB/c model of endometriosis, and in vitro in primary cultures of human endometrial epithelial cells (EECs)?
Summary answer:
Resveratrol and EGCG exerted a potent inhibitory effect on the development of endometriosis in a BALB/c murine model and on the survival of EECs.
What is known already:
Endometriosis is a common condition associated with infertility and pelvic pain in women of reproductive age. Resveratrol and EGCG are two polyphenols with anticarcinogenic and antioxidant properties that have been proposed as natural therapies to treat endometriosis.
Study design, size, duration:
Fifty-six 2-month-old female BALB/c mice underwent surgical induction of endometriosis. Treatments with resveratrol or EGCG started 15 days post-surgery and continued for 4 weeks. Human biopsies were taken with a metal Novak curette from the posterior uterine wall from 16 patients with untreated endometriosis and 15 controls who underwent diagnostic laparoscopy for infertility.
Materials, setting, methods:
After the treatments, animals were sacrificed and lesions were counted, measured, excised and fixed. Immunohistochemistry for proliferating cell nuclear antigen and CD34 was performed for cell proliferation and vascularization assessment in the lesions. The terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) technique was performed for apoptosis evaluation. Peritoneal fluid was collected to analyze vascular endothelial growth factor levels. Human EECs were purified from proliferative-phase endometrial biopsies and cultured. The effect of both polyphenols on cell proliferation was determined by a colorimetric assay using the CellTiter 96®AQueous One Solution Cell Proliferation Assay kit and on apoptosis by the TUNEL technique, using an In Situ Cell Death Detection Kit with Fluorescein.
Main results:
In the mouse model, both treatments significantly reduced the mean number (P < 0.05 versus control) and the volume of established lesions (P < 0.05 versus control). Treatments consistently statistically significantly diminished cell proliferation (resveratrol P < 0.01 and EGCG P < 0.05, versus control), reduced vascular density (resveratrol P < 0.01 and EGCG P < 0.001, versus control) and increased apoptosis within the lesions (resveratrol P < 0.01 and EGCG P < 0.05, versus control). Both compounds induced reduction in human EEC proliferation (P < 0.05 versus basal) and increased apoptosis (P < 0.05 versus basal) in primary cultures.
Limitations:
In vitro studies were only carried out in epithelial cells from human eutopic endometrium.
Wider implications of the findings:
The present findings are promising and will assist the development of novel natural treatments for endometriosis.
Study funding:
This study was supported by ANPCYT (PICT 6384 BID 1201 OC-AR) and CONICET (PIP 5471), Argentina. None of the authors has any conflict of interest to declare.
We investigated the effects of resveratrol on metastasis in in vitro and in vivo systems. 4T1 cells were cultured in the presence of various concentrations (0-30 µmol/L) of resveratrol. For experimental metastasis, BALB/c mice were injected intravenously with 4T1 cells in the tail vein, and were orally administered various concentrations (0, 100, or 200 mg/kg Body weight) of resveratrol for 21 days. After resveratrol treatment, cell adhesion, wound migration, invasion, and MMP-9 activity were significantly decreased in a dose-dependent manner in 4T1 cells (P < 0.05). The numbers of pulmonary nodules were significantly decreased in mice fed the resveratrol (P < 0.05). The plasma MMP-9 activity was decreased in response to treatment with resveratrol in mice (P < 0.05). We conclude that resveratrol inhibits cancer metastasis both in vitro and in vivo, and this inhibition is likely due to the decrease in MMP-9 activity caused by resveratrol.
How is the expression of nectins and nectin-like molecules (Necls) detected by immunostaining altered by endometriosis? SUMMARY ANSWER: Our results suggest that Nectin-1, -3, -4 and Necl-2 may contribute to the pathogenesis of endometriosis. Immunostaining of nectins and Necls varies according to the anatomical location of endometriosis. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Nectin and Necl molecules are immunoglobulin-like cell adhesion molecules involved in apoptosis, cell proliferation and in metastases. Previous studies have demonstrated the involvement of adhesion molecules in the development of endometriotic lesions but no data exist on immunostaining of nectins and Necls molecules in endometriosis.
This retrospective study was conducted in a tertiary-care hospital (Tenon Hospital, Paris, France). Samples were collected from 55 women undergoing endometrial biopsy or surgery for endometriosis and 20 controls having hysterectomy or endometrial biopsy for other reasons; multiple samples were collected from 15 women. We studied the immunostaining of Nectin-1, -3, -4 and Necl-2 in secretory and proliferative endometrium from women with (n = 20) or without endometriosis (i.e. control group, n = 20), and in peritoneal (n = 20), ovarian (n = 20) and colorectal endometriosis (n = 20).
Semi-quantitative immunostaining demonstrated that (1) Necl-2 staining was stronger in all types of endometriotic lesions than in the eutopic endometrium from patients with endometriosis (P < 0.0125) and in ovarian endometriotic cysts compared with other locations (P < 0.001); (2) Nectin-3 staining was stronger in the eutopic endometrium of patients with endometriosis compared with controls (P = 0.03) and in all endometriotic lesions compared with the eutopic endometrium from patients with endometriosis (P < 0.0125); (3) Nectin-4, staining was stronger in the eutopic endometrium of patients with endometriosis compared with controls (P = 0.04) and (4) Nectin-1 staining was significantly increased in colorectal endometriosis compared with other locations (P = 0.004). BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: We did not assess the pattern of expression in endometriosis of all nectins and Necl molecules. Indeed, Necl-5 is implicated in many pathophysiological processes such as cell movement and proliferation with potential relevance to endometriosis. GENERALISABILITY TO OTHER POPULATIONS: At present, few data on implication of nectins and Necl molecules in endometriosis exist. Hence, our results should be confirmed by further quantitative studies at protein or RNA levels. STUDY FUNDING/COMPETING INTEREST(S): No funding source. All the authors declare no conflict of interest.
Since the first description about oxygen toxicity made by Joseph Priestley, the oxidative stress has been enrolled as a key factor in the pathogenesis of endometriosis. Our aim was to review oxidative stress biomarkers measured in patients with endometriosis.
Relevant studies were identified by searches of the MEDLINE database from 1990 to March 2011 using endometriosis, free radical and oxidative stress as mesh terms. We only included manuscripts in English, and review articles were excluded. In addition, free radical chemistry and oxidative stress history were discussed.
After inclusion and exclusion criteria, 19 articles were selected to be included in this systematic review. A total of 36 oxidative stress biomarkers (20 different markers) were measured in patients with endometriosis. Some of the markers were measured in more than one manuscript. They were arranged in five subgroups: Enzymatic activity (n = 3), Anions/free radicals (n = 5), Lipoperoxidation markers (n = 7), DNA Damage markers (n = 1), and Protein oxidation (n = 4). Of those 36 markers, 23 were found to be significantly higher in patients with endometriosis comparing with control patients.
Oxidative stress plays an important role in the pathogenesis and progression of endometriosis.
Resveratrol is a naturally occurring polyphenol that exhibits pleiotropic health beneficial effects, including anti-inflammatory, cardio-protective, and cancer-protective activities. It is recognized as one of the more promising natural molecules in the prevention and treatment of chronic inflammatory and autoimmune disorders. Ulcerative colitis is an idiopathic, chronic inflammatory disease of the colon associated with a high colon cancer risk. Here, we used a dextran sulfate sodium (DSS) mouse model of colitis, which resembles human ulcerative colitis pathology. Resveratrol mixed in food ameliorates DSS-induced colitis in mice in a dose-dependent manner. Resveratrol significantly improves inflammation score, downregulates the percentage of neutrophils in the mesenteric lymph nodes and lamina propria, and modulates CD3(+) T cells that express tumor necrosis factor-alpha and IFN-gamma. Markers of inflammation and inflammatory stress (p53 and p53-phospho-Ser(15)) are also downregulated by resveratrol. Because chronic colitis drives colon cancer risk, we carried out experiments to determine the chemopreventive properties of resveratrol. Tumor incidence is reduced from 80% in mice treated with azoxymethane (AOM) + DSS to 20% in mice treated with AOM + DSS + resveratrol (300 ppm). Tumor multiplicity also decreased with resveratrol treatment. AOM + DSS-treated mice had 2.4 +/- 0.7 tumors per animal compared with AOM + DSS + 300 ppm resveratrol, which had 0.2 +/- 0.13 tumors per animal. The current study indicates that resveratrol is a useful, nontoxic complementary and alternative strategy to abate colitis and potentially colon cancer associated with colitis.
Due to its potential in preventing or slowing the occurrence of many diseases, resveratrol (3,5,4'-trihydroxystilbene) has attracted great research interest. The objective of this study was to identify microorganisms from selected plants that produce resveratrol and to optimize the conditions for resveratrol production. Endophytes from Merlot wine grapes (Vitis vinifera L. cv. Merlot), wild Vitis (Vitis quinquangularis Rehd.), and Japanese knotweed (Polygonum cuspidatum Siebold & Zucc.) were isolated, and their abilities to produce resveratrol were evaluated. A total of 65 isolates were obtained and 21 produced resveratrol (6-123 μg/L) in liquid culture. The resveratrol-producing isolates belonged to seven genera, Botryosphaeria, Penicillium, Cephalosporium, Aspergillus, Geotrichum, Mucor, and Alternaria. The resveratrol-producing capability decreased or was completely lost in most isolates after three rounds of subculture. It was found that only the strain Alternaria sp. MG1 (isolated from cob of Merlot using GA1 medium) had stable and high resveratrol-producing capability in all subcultures. During liquid cultivation of Alternaria sp. MG1 in potato dextrose medium, the synthesis of resveratrol began on the first day, increased to peak levels on day 7, and then decreased sharply thereafter. Cell growth increased during cultivation and reached a stable and high level of biomass after 5 days. The best fermentation conditions for resveratrol production in liquid cultures of Alternaria sp. MG1 were an inoculum size of 6 %, a medium volume of 125 mL in a 250-mL flask, a rotation speed of 101 rpm, and a temperature of 27 °C.
Endometriosis is a common gynecologic disorder characterized by ectopic attachment and growth of endometrial tissues. Resveratrol is a natural polyphenol with antiproliferative and anti-inflammatory properties. Our objective was to study the effects of resveratrol on human endometriotic implants in a nude mouse model and to examine its impact on human endometrial stromal (HES) cell invasiveness in vitro. Human endometrial tissues were obtained from healthy donors. Endometriosis was established in oophorectomized nude mice by intraperitoneal injection of endometrial tissues. Mice were treated with 17β-estradiol (8 mg, silastic capsule implants) alone (n = 16) or with resveratrol (6 mg/mouse; n = 20) for 10-12 and 18-20 days beginning 1 day after tissue injection. Mice were killed and endometrial implants were evaluated. A Matrigel invasion assay was used to examine the effects of resveratrol on HES cells. We assessed number and size of endometriotic implants in vivo and Matrigel invasion in vitro. Resveratrol decreased the number of endometrial implants per mouse by 60% (P < 0.001) and the total volume of lesions per mouse by 80% (P < 0.001). Resveratrol (10-30 μM) also induced a concentration-dependent reduction of invasiveness of HES by up to 78% (P < 0.0001). Resveratrol inhibits development of endometriosis in the nude mouse and reduces invasiveness of HES cells. These observations may aid in the development of novel treatments of endometriosis.
Endometriosis is estimated to affect 1 in 10 women during the reproductive years. There is often delay in making the diagnosis, mainly due to the non-specific nature of the associated symptoms and the need to verify the disease surgically. A biomarker that is simple to measure could help clinicians to diagnose (or at least exclude) endometriosis; it might also allow the effects of treatment to be monitored. If effective, such a marker or panel of markers could prevent unnecessary diagnostic procedures and/or recognize treatment failure at an early stage.
We used QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria to perform a systematic review of the literature over the last 25 years to assess critically the clinical value of all proposed biomarkers for endometriosis in serum, plasma and urine.
We identified over 100 putative biomarkers in publications that met the selection criteria. We were unable to identify a single biomarker or panel of biomarkers that have unequivocally been shown to be clinically useful.
Peripheral biomarkers show promise as diagnostic aids, but further research is necessary before they can be recommended in routine clinical care. Panels of markers may allow increased sensitivity and specificity of any diagnostic test.
Endometriosis is a prevalent but enigmatic gynecologic disorder for which few modifiable risk factors have been identified. Fish oil consumption has been associated with symptom improvement in studies of women with primary dysmenorrhea and with decreased endometriosis risk in autotransplantation animal studies.
To investigate the relation between dietary fat intake and the risk of endometriosis, we analyzed 12 years of prospective data from the Nurses' Health Study II that began in 1989. Dietary fat was assessed via food frequency questionnaire in 1991, 1995 and 1999. We used Cox proportional hazards models adjusted for total energy intake, parity, race and body mass index at age 18, and assessed cumulatively averaged fat intake across the three diet questionnaires.
During the 586 153 person-years of follow-up, 1199 cases of laparoscopically confirmed endometriosis were reported. Although total fat consumption was not associated with endometriosis risk, those women in the highest fifth of long-chain omega-3 fatty acid consumption were 22% less likely to be diagnosed with endometriosis compared with those with the lowest fifth of intake [95% confidence interval (CI) = 0.62-0.99; P-value, test for linear trend (Pt) = 0.03]. In addition, those in the highest quintile of trans-unsaturated fat intake were 48% more likely to be diagnosed with endometriosis (95% CI = 1.17-1.88; Pt = 0.001).
These data suggest that specific types of dietary fat are associated with the incidence of laparoscopically confirmed endometriosis, and that these relations may indicate modifiable risk. This evidence additionally provides another disease association that supports efforts to remove trans fat from hydrogenated oils from the food supply.
Decreased susceptibility of endometrial tissue to apoptosis may contribute to the pathogenesis of endometriosis. We investigate the role of survivin in the pathophysiology of endometriosis through the ability of ectopic and eutopic endometrial stromal cells (ESCs) to resist apoptosis.
Ectopic ESCs were obtained from ovarian chocolate cysts in patients undergoing laparoscopic surgery (n = 22). Eutopic ESCs were isolated from endometrial tissue of cyclic premenopausal women undergoing hysterectomy for fibroids (n = 22). Purified stromal cells were studied in vitro. The number of surviving cells and activation of caspases were assessed by WST-8 assay and immunoblotting. Expression of inhibitor of apoptosis proteins (IAP) family members: cIAP1 (birc2), cIAP2 (birc3), XIAP (birc4), survivin (birc5) were examined using cDNA array and real-time RT-PCR. Effects of gene silencing by small inhibitor RNAs (siRNA) were examined by WST-8-assay, Annexin-V staining and immunoblotting.
After staurosporine (SS) treatment, 55% of eutopic ESCs survived versus 70% of ectopic ESCs. Procaspase-3 or -7 was more intensely activated by SS treatment in eutopic than in ectopic ESCs (P < 0.01). mRNAs for IAP-family genes, such as cIAP-1, XIAP and survivin, were highly expressed in ectopic ESCs before SS treatment. The fold induction of survivin expression after SS treatment was higher in ectopic than eutopic ESCs (2.8 +/- 0.27 versus 0.69 +/- 0.07, respectively). Survivin gene silencing in SS-treated ectopic ESCs led to an increase of apoptotic cells (P < 0.05, versus control siRNA).
We demonstrated that survivin plays a critical role in susceptibility of ESCs to apoptosis. Our results indicate that a survivin inhibitor may be effective as a novel treatment for endometriosis.
Several studies have cited the Mediterranean diet as an example of healthy eating. In fact, the Mediterranean diet has become the reference diet for the prevention of cardiovascular disease. Red wine seems to be an essential component of the diet, since moderate consumption of wine is associated with lower risk and mortality from cardiovascular disease. Evidence is also accumulating that wine helps prevent the development of certain cancers. Of all the many components of wine, resveratrol, which is a natural component specifically present in wine, has been identified as being mainly responsible for these health-promoting properties. Many valuable properties such as cardioprotective and anticarcinogenic activity have been attributed to resveratrol; however, its bioavailability is quite low. The bioactivity of metabolites derived from resveratrol, and the accumulation of resveratrol in vital organs are still under study, but there are high expectations of positive results. Other stilbene compounds are also considered in this review, despite being present in undetectable or very small quantities in wine. The present paper reviews all aspects of the health properties of wine, bioactive compounds found in wine, and their concentrations, bioavailability and possible synergistic effects.
Resveratrol, a natural polyphenol, has a variety of effects including protection against ischemia-reperfusion injury, and antitumor and chemopreventive action against malignant tumors. In recent years, resveratrol has been found to exert pro- and anti-angiogenic effects, depending on the situation. For example, pro-angiogenic effects are noted in the peri-infarct myocardium, whereas resveratrol inhibits angiogenesis in tumors. In this article, a review of the literature concerning both pro-angiogenic and anti-angiogenic effects of resveratrol and the underlying mechanisms of its effects on angiogenesis is presented.
Problem:
Resistance to apoptosis, together with inflammatory and invasive activity, contributes to the pathogenesis of endometriosis; therefore, approaches that can safely enhance apoptosis in endometriotic tissue are highly sought after as a means of managing the disease. Although resveratrol (RVT) is known to induce apoptosis or increase sensitivity to apoptotic stimuli in various cancer cell types, its effect on human endometriosis has remained uncertain. This study aimed to investigate whether RVT induces or enhances apoptosis in human endometriotic stromal cells (ESCs).
Method of study:
Endometriotic tissues were collected, during laparoscopies, from women affected by ovarian endometriosis. ESCs were prepared, cultured, and treated with RVT. Apoptosis was assessed by annexin V-PI staining. Survivin mRNA expression in ESCs was examined using RT-PCR. ESCs were pre-treated with or without RVT and then incubated with TNF-α-related-apoptosis-inducing ligand (TRAIL), which is a known pro-apoptotic molecule.
Results:
RVT alone did not induce apoptosis in ESCs. RVT significantly reduced survivin mRNA expression (P < 0.05). Pre-treatment with RVT significantly enhanced TRAIL-induced apoptosis (8.13 ± 0.83% (control) versus 29.19 ± 7.39% (pre-treated with RVT), P < 0.05).
Conclusion:
This study indicates that RVT suppresses survivin expression and enhances TRAIL-induced apoptosis in ESCs.
Introduction:
Endometriosis affects 10% of women of reproductive age. It is defined as the presence of implanted active endometrial tissue outside the uterine cavity. The exact pathophysiology of endometriosis is still uncertain, although several optional etiological theories have been suggested. Being so common, a novel treatment for endometriosis is widely quested. Recent studies addressing the pathological characteristics of endometriosis have revealed a vicious cycle in which oxidative stress (OS) is generated, which in turn facilitates the implantation of the ectopic endometrium. At the same time, the generation of high amounts of reactive oxygen species further triggers a state of OS. Areas covered: The author examined the evidence associating OS and endometriosis. After establishing an association, a search for antioxidant agents that were investigated specifically on endometriosis patients are described including Vitamins C and E, melatonin, resveratrol, xanthohumol and epigallocatechin-3-gallate. A significant effect of all the reviewed antioxidants on endometriosis is reported. Expert opinion: Aiming for the reduction of OS as the treatment goal for endometriosis looks promising. However, since most of the studies are either in vitro or are animal based, further studies on human subjects are deemed necessary to elucidate the impact of OS reduction on patients with endometriosis.
Resveratrol (3,5,4'-trihydroxystilbene) is a natural compound found in several plants, including grapes, peanuts, and pines, and in their related products. Red wine is probably the most frequently consumed drink that is enriched in resveratrol. We investigated whether drinking resveratrol could suppress angiogenesis, a process of blood vessel growth involved in initiation, development, and progression of many diseases, including cancer, metastasis, and diabetic retinopathy. We found that resveratrol suppresses the growth of new blood vessels in animals. It directly inhibits capillary endothelial cell growth. It blocks both VEGF- and FGF-receptormediated angiogenic responses. In addition, resveratrol inhibits the phosphorylation of mitogenactivated kinase isoforms (MAPK p44 /MAPK p42 ) induced by fibroblast growth factor-2 in proliferating endothelial cells in a dose-dependent manner. Oral administration of resveratrol significantly inhibits the growth of a murine fibrosarcoma in mice, and it significantly delays angiogenesis-dependent wound healing in mice. Our findings suggest that ingestion of resveratrol-enriched food could be beneficial for the prevention of cancer. However, its antiangiogenic effect could delay wound healing and possibly other angiogenesis-dependent processes under physiological conditions.
Endometriosis, an oestrogen-dependent disorder affecting women of reproductive age, is associated with active angiogenesis and an increased recruitment of leukocyte into the peritoneal cavity where the implants often develop. The role of oestrogens in the development of endometriosis has been clearly established, but the biochemical mechanisms of their action are still not clearly elucidated. The present study shows that interleukin-1 (IL-1) induces interleukin-8 (IL-8) secretion by endometriotic cells and that oestradiol enhances endometriotic cell responsiveness to IL-1. In contrast, no significant cell responsiveness to progesterone either alone in the culture medium or in combination with oestradiol was noted. Positive immunostaining for IL-8 was observed throughout endometriotic tissue, and no perceptible difference in the intensity of staining regarding the menstrual cycle phase was observed. Together with the in-vitro data, this suggests that IL-8 expression in endometriotic tissue is not subject to cyclic variation. Furthermore, this study provides evidence that oestradiol indirectly up-regulates the expression by ectopic endometrial cells of IL-8, a cytokine endowed with neutrophil chemotactic and angiogenic properties. This may contribute to peritoneal leukocyte recruitment and to the growth of endometriotic implants, and may be a new mechanism for oestradiol action in endometriosis.
Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive
activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen
and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited
cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation
(antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse
mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a
common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.
This Review Article is focused on the action of the reactive oxygenated species in inducing oxidative injury of the lipid membrane components, as well as on the ability of antioxidants (of different structures and sources, and following different mechanisms of action) in fighting against oxidative stress. Oxidative stress is defined as an excessive production of reactive oxygenated species that cannot be counteracted by the action of antioxidants, but also as a perturbation of cell redox balance. Reactive oxygenated/nitrogenated species are represented by superoxide anion radical, hydroxyl, alkoxyl and lipid peroxyl radicals, nitric oxide and peroxynitrite. Oxidative stress determines structure modifications and function modulation in nucleic acids, lipids and proteins. Oxidative degradation of lipids yields malondialdehyde and 4-hydroxynonenal, but also isoprostanes, from unsaturated fatty acids. Protein damage may occur with thiol oxidation, carbonylation, side-chain oxidation, fragmentation, unfolding and misfolding, resulting activity loss. 8-hydroxydeoxyguanosine is an index of DNA damage. The involvement of the reactive oxygenated/nitrogenated species in disease occurrence is described. The unbalance between the oxidant species and the antioxidant defense system may trigger specific factors responsible for oxidative damage in the cell: over-expression of oncogene genes, generation of mutagen compounds, promotion of atherogenic activity, senile plaque occurrence or inflammation. This leads to cancer, neurodegeneration, cardiovascular diseases, diabetes, kidney diseases. The concept of antioxidant is defined, along with a discussion of the existent classification criteria: enzymatic and non-enzymatic, preventative or repair-systems, endogenous and exogenous, primary and secondary, hydrosoluble and liposoluble, natural or synthetic. Primary antioxidants are mainly chain breakers, able to scavenge radical species by hydrogen donation. Secondary antioxidants are singlet oxygen quenchers, peroxide decomposers, metal chelators, oxidative enzyme inhibitors or UV radiation absorbers. The specific mechanism of action of the most important representatives of each antioxidant class (endogenous and exogenous) in preventing or inhibiting particular factors leading to oxidative injury in the cell, is then reviewed. Mutual influences, including synergistic effects are presented and discussed. Prooxidative influences likely to occur, as for instance in the presence of transition metal ions, are also reminded.
Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Cancer stem cells (CSCs) are considered to contribute to the poor prognosis of ovarian cancer as a major cause of fatal recurrence. Identification of effective measures to eliminate ovarian CSCs through induction of cell death and/or loss of self-renewal capacity would, therefore, be key to successful management of ovarian cancer.
The effects of resveratrol on the viability and self-renewal capacity of CSCs derived from A2780 human ovarian cancer cells were examined. The involvement of reactive oxygen species (ROS) was also investigated.
At a non-toxic to normal human fibroblasts concentration, resveratrol effectively killed ovarian CSCs independently of ROS, while ROS-dependently impaired the self-renewal capacity of ovarian CSCs that survived resveratrol treatment.
Our findings not only shed light on a novel mechanism of action for resveratrol but also suggest that resveratrol, or its analogs, may be useful for CSC-directed therapy against ovarian cancer.
Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
Background and Aims: The purpose of this study was to investigate the potential therapeutic efficiency of resveratrol in the treatment of experimental endometriosis in rats.
Settings and Design: Experimental study was carried out in a University hospital.
Materials and Methods: Endometriosis was surgically induced in 24 female rats. Four weeks after this procedure, the viability and dimensions of the endometriosis foci were recorded. Rats were then randomly divided into three groups: (1) Control group (n = 8); (2) low dose (10 mg/kg) resveratrol group (n = 8); (3) high dose (100 mg/kg) resveratrol group (n = 8). At the end of the 7-day treatment, blood samples were taken and laparotomy was performed. The endometrial implants were processed for biochemical, histological and immunohistochemical studies.
Statistical Analysis Used: The Kruskal-Wallis H test and one-way ANOVA test were used.
Results: Resveratrol-treated rats showed significantly reduced endometriotic implant volumes (P = 0.004). After treatment, a significant and dose-dependent increase in activities of superoxide dismutase and glutathione peroxidase in serum and tissue of the rats in Group 2 and Group 3 was detected. Similarly, serum and tissue malonyl dialdehyde levels and tissue catalase levels were significantly higher in Group 3 than that of control animals. Histological scores and proliferating cell nuclear antigen expression levels were also significantly reduced in Group 2 and Group 3 than that of control group.
Conclusion: In a rat endometriosis model, resveratrol showed potential ameliorative effects on endometriotic implants probably due to its potent antioxidative properties.