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Abstract
The development of new blood vessels plays an essential role in growth and survival of endometriosis. Epigallocatechin gallate (EGCG) from green tea has powerful anti-angiogenic properties and our aim was to evaluate these properties in experimental endometriosis.
Eutopic endometrium from endometriosis patients was transplanted s.c. to severely compromised immunodeficient mice, randomly treated i.p. with EGCG (anti-angiogenic and -oxidant), Vitamin E (a non-angiogenic antioxidant) or saline for 2 weeks. The endometrial implant, including adjacent host outer skin and subcutaneous layers plus inner abdominal muscle and peritoneum, was collected. New microvessels were determined by species-specific immunohistochemistry. Angiogenic factors in lesions and abdominal muscle were detected by quantitative real-time PCR. Apoptosis was studied by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling and quantitative real-time PCR. In saline control, endometrial implants developed new blood vessels with proliferating glandular epithelium and were tightly adhered to host subcutaneous and abdominal muscle layers. After EGCG, endometriotic lesions were smaller than control (P < 0.05), and glandular epithelium was smaller and eccentrically distributed. Angiogenesis in lesions from the implant and adjacent tissues was under-developed, and microvessel size and density were lower (both P < 0.01) than control. mRNA for angiogenic vascular endothelial growth factor A, but not hypoxia inducible factor 1, alpha subunit, was significantly down-regulated in lesions after EGCG (P < 0.05). In addition, apoptosis in the lesions was more obvious, and nuclear factor kappa B and mitogen activated protein kinase 1 mRNA levels were up-regulated (P < 0.05) after EGCG treatment. No differences were observed with Vitamin E treatment.
EGCG significantly inhibits the development of experimental endometriosis through anti-angiogenic effects.
... The proapoptotic role of EGCG has been previously demonstrated in different cancer cells such as breast, pancreatic, hepatic, and prostate cancer cells, as well as ovarian and cervical cancer cells [94,95,157,158]. Although endometriosis is a benign disease, three studies have shown that EGCG treatment drove apoptosis in endometriosis cells [62,159,160] and increased the expression of apoptotic factors like NF-κB and mitogen-activated protein kinase 1 (MAPK1) ( Figure 5; Table 2) [159]. ...
... The proapoptotic role of EGCG has been previously demonstrated in different cancer cells such as breast, pancreatic, hepatic, and prostate cancer cells, as well as ovarian and cervical cancer cells [94,95,157,158]. Although endometriosis is a benign disease, three studies have shown that EGCG treatment drove apoptosis in endometriosis cells [62,159,160] and increased the expression of apoptotic factors like NF-κB and mitogen-activated protein kinase 1 (MAPK1) ( Figure 5; Table 2) [159]. ...
... Many of these studies have also explored specific cellular signaling pathways targeted by EGCG in endometrial cells. First, EGCG was found to downregulate the expression of pro-angiogenic factors like vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor C (VEGF-C), and the tyrosine kinase receptor VEGF receptor 2 (VEGFR2) in murine endometriosis models [159,161]. Interestingly, EGCG did not affect the expression of hypoxia-inducible factor 1 (HIF1A), another important regulator of angiogenesis [159]. EGCG was shown to inhibit specific key factors of the VEGF/VEGFR2 angiogenesis signaling pathway like matrix metalloproteinase-9, c-JUN, interferon-g, and chemokines (C-X-C motif) [161]. ...
Green tea is harvested from the tea plant Camellia sinensis and is one of the most widely consumed beverages worldwide. It is richer in antioxidants than other forms of tea and has a uniquely high content of polyphenolic compounds known as catechins. Epigallocatechin-3-gallate (EGCG), the major green tea catechin, has been studied for its potential therapeutic role in many disease contexts, including pathologies of the female reproductive system. As both a prooxidant and antioxidant, EGCG can modulate many cellular pathways important to disease pathogenesis and thus has clinical benefits. This review provides a synopsis of the current knowledge on the beneficial effects of green tea in benign gynecological disorders. Green tea alleviates symptom severity in uterine fibroids and improves endometriosis through anti-fibrotic, anti-angiogenic, and pro-apoptotic mechanisms. Additionally, it can reduce uterine contractility and improve the generalized hyperalgesia associated with dysmenorrhea and adenomyosis. Although its role in infertility is controversial, EGCG can be used as a symptomatic treatment for menopause, where it decreases weight gain and osteoporosis, as well as for polycystic ovary syndrome (PCOS).
... Seven studies investigated the effects of EGCG on endometriosis development, five in mice and one in hamsters. ECGC was administered either orally [35] or through an intraperitoneal injection [23,24,29,35,37,40,45]. In all the studies in which endometriotic lesions were measured, ECGC induced the regression of lesions. ...
... The compound could suppress E2-stimulated activation, proliferation and VEGF expression of endometrial cells in vitro isolated from hamsters. When evaluated by intravital fluorescence microscopy and histology, in vivo treatment with ECGC mediated a selective inhibition of angiogenesis and blood perfusion of endometriotic lesions without affecting blood vessel development in ovarian follicles [23,24,35,37]. Moreover, EGCG showed to increase total apoptotic cell numbers in the lesions [24,35,37]. ...
... When evaluated by intravital fluorescence microscopy and histology, in vivo treatment with ECGC mediated a selective inhibition of angiogenesis and blood perfusion of endometriotic lesions without affecting blood vessel development in ovarian follicles [23,24,35,37]. Moreover, EGCG showed to increase total apoptotic cell numbers in the lesions [24,35,37]. Molecular mechanisms put forward to explain these phenomena in the lesions include: selective inhibition of VEGFC expression; down-regulation of MMP-9, chemokine (C-X-C motif) ligand 3 (CXCL3), c-JUN, and interferon-γ expression, decreased ROS generation and lipid peroxidation and reduced MMP-2 and MMP-9 activity [29,45]. ...
The aim of this systematic review was to provide comprehensive and available data on the possible role of phytoestrogens (PE) for the treatment of endometriosis. We conducted an advanced, systematic search of online medical databases PubMed and Medline. Only full-length manuscripts written in English up to September 2020 were considered. A total of 60 studies were included in the systematic review. According to in vitro findings, 19 out of 22 studies reported the ability of PE in inducing anti-proliferative, anti-inflammatory and proapoptotic effects on cultured cells. Various mechanisms have been proposed to explain this in vitro action including the alteration of cell cycle proteins, the activation/inactivation of regulatory pathways, and modification of radical oxidative species levels. Thirty-eight articles on the effects of phytoestrogens on the development of endometriotic lesions in in vivo experimental animal models of endometriosis have been included. In line with in vitro findings, results also derived from animal models of endometriosis generally supported a beneficial effect of the compounds in reducing lesion growth and development. Finally, only seven studies investigated the effects of phytoestrogens intake on endometriosis in humans. The huge amount of in vitro and in vivo animal findings did not correspond to a consistent literature in the women affected. Therefore, whether the experimental findings can be translated in women is currently unknown.
... 66 EGCG inhibited E 2 -stimulated proliferation and VEGF expression in cultured endometriotic glandular cells as well as angiogenesis and lesion growth via VEGF in mouse models. 70,129,167 3.1.2 | NF-κB pathway NF-κB is a protein that promotes cell proliferation and inhibits apoptosis in endometrial and endometriotic cells. ...
... Overexpression of VEGFC induces migration of endothelial cells, increases vascular permeability, and induces angiogenesis and endometriotic lesions growth. 70,129 Prodrug of EGCG (ProEGCG), reduced lesion size, weight, and VEGF concentrations in plasma to a greater extent than the parent EGCG molecule. More importantly, there were no signs of side effects on reproductive tissues. ...
... It exerts efficacy against diseases including cancer, diabetes, and inflammation. 306 In EM, it exerts ant antiangiogenetic effect via the VEGFC/VEGFR2 pathways, 70,129 antioxidant effects via ROS-scavenging mechanism, 130 antiproliferative effect via reduction of E 2 production, and anti-migration and anti-invasion effects via TGF-β1-induced phosphorylation of ERK1/2 and MAPK pathways, 167 thus inhibiting the development and growth of lesions. Promising evidence of its high potency and efficacy, and without major side effects in reproductive functions were reported. ...
Endometriosis (EM) is defined as endometrial tissues found outside the uterus. Growth and development of endometriotic cells in ectopic sites can be promoted via multiple pathways, including MAPK/MEK/ERK, PI3K/Akt/mTOR, NF‐κB, Rho/ROCK, reactive oxidative stress, tumor necrosis factor, transforming growth factor‐β, Wnt/β‐catenin, vascular endothelial growth factor, estrogen, and cytokines. The underlying pathophysiological mechanisms include proliferation, apoptosis, autophagy, migration, invasion, fibrosis, angiogenesis, oxidative stress, inflammation, and immune escape. Current medical treatments for EM are mainly hormonal and symptomatic, and thus the development of new, effective, and safe pharmaceuticals targeting specific molecular and signaling pathways is needed. Here, we systematically reviewed the literature focused on pharmaceuticals that specifically target the molecular and signaling pathways involved in the pathophysiology of EM. Potential drug targets, their upstream and downstream molecules with key aberrant signaling, and the regulatory mechanisms promoting the growth and development of endometriotic cells and tissues were discussed. Hormonal pharmaceuticals, including melatonin, exerts proapoptotic via regulating matrix metallopeptidase activity while nonhormonal pharmaceutical sorafenib exerts antiproliferative effect via MAPK/ERK pathway and antiangiogenesis activity via VEGF/VEGFR pathway. N‐acetyl cysteine, curcumin, and ginsenoside exert antioxidant and anti‐inflammatory effects via radical scavenging activity. Natural products have high efficacy with minimal side effects; for example, resveratrol and epigallocatechin gallate have multiple targets and provide synergistic efficacy to resolve the complexity of the pathophysiology of EM, showing promising efficacy in treating EM. Although new medical treatments are currently being developed, more detailed pharmacological studies and large sample size clinical trials are needed to confirm the efficacy and safety of these treatments in the near future.
... Endometriosis is a chronic disorder characterised by the implantation of endometrial glands and stroma outside the uterine cavity [33]. It affects adolescents and reproductiveaged women and is commonly associated with chronic pelvic pain and infertility [34]. ...
... Endometriosis is a chronic disorder characterised by the implantation of endometrial glands and stroma outside the uterine cavity [33]. It affects adolescents and reproductive-aged women and is commonly associated with chronic pelvic pain and infertility [34]. ...
... The anti-proliferative effect of EGCG against endometriosis was reported in most of the studies. EGCG causes regression in the development of endometriosis lesions assessed by size, number, volume, weight and cell proliferation [33,[35][36][37][38]. Figure 2 illustrates a simplified version of the mechanism related to the beneficial effects of green tea catechins on endometriosis. ...
Tea is one of the most widely consumed beverages worldwide after water, and green tea accounts for 20% of the total tea consumption. The health benefits of green tea are attributed to its natural antioxidants, namely, catechins, which are phenolic compounds with diverse beneficial effects on human health. The beneficial effects of green tea and its major bioactive component, (−)-epigallocatechin-3-gallate (EGCG), on health include high antioxidative, osteoprotective, neuroprotective, anti-cancer, anti-hyperlipidemia and anti-diabetic effects. However, the review of green tea’s benefits on female reproductive disorders, including polycystic ovary syndrome (PCOS), endometriosis and dysmenorrhea, remains scarce. Thus, this review summarises current knowledge on the beneficial effects of green tea catechins on selected female reproductive disorders. Green tea or its derivative, EGCG, improves endometriosis mainly through anti-angiogenic, anti-fibrotic, anti-proliferative and proapoptotic mechanisms. Moreover, green tea enhances ovulation and reduces cyst formation in PCOS while improving generalised hyperalgesia, and reduces plasma corticosterone levels and uterine contractility in dysmenorrhea. However, information on clinical trials is inadequate for translating excellent findings on green tea benefits in animal endometriosis models. Thus, future clinical intervention studies are needed to provide clear evidence of the green tea benefits with regard to these diseases.
... Xu et al. 46 Xu et al. 47 NF-κB: nuclear factor-κB; TGF-β: transforming growth factor-β; TNF-α: tumor necrosis factor-α; IL-6: interleukin-6; MMP: matrix metalloproteinase; VEGF: vascular endothelial growth factor; MAPK: mitogen-activated protein kinase; TRAIL: tumor necrosis factor-related apoptosis-inducing ligand; STAT-3: signal transducer and activator of transcription-3; iNOS: inducible nitric oxide synthase; COX2: cyclooxygenase 2; AMPK: 5' adenosine monophosphate-activated protein kinase. ...
... Transplanted eutopic endometria isolated from patients with endometriosis generated smaller lesions with significantly reduced microvessel size and density and lower VEGF-B/C expression in nude mice ip injected with EGCG than with vehicle alone. 46 The reduced macrovascular network in lesions was shown to be mediated by EGCG inhibition of VEGF/ VEGF receptor signaling occurring through interferon-γ, MMP9, and chemokine ligand 3 pathways. 47 Interestingly, vitamin E (a non-angiogenic anti-oxidant) did not mimic EGCG-elicited effects on lesions, suggesting angiogenesis as a major target of EGCG actions. ...
... 47 Interestingly, vitamin E (a non-angiogenic anti-oxidant) did not mimic EGCG-elicited effects on lesions, suggesting angiogenesis as a major target of EGCG actions. 46 Of high relevance to endometriosis is consumption of a HFD, given the latter's known effects in promoting metabolic dysfunction. Studies on the consequences of fat consumption (e.g. ...
... Xu et al. 46 Xu et al. 47 NF-κB: nuclear factor-κB; TGF-β: transforming growth factor-β; TNF-α: tumor necrosis factor-α; IL-6: interleukin-6; MMP: matrix metalloproteinase; VEGF: vascular endothelial growth factor; MAPK: mitogen-activated protein kinase; TRAIL: tumor necrosis factor-related apoptosis-inducing ligand; STAT-3: signal transducer and activator of transcription-3; iNOS: inducible nitric oxide synthase; COX2: cyclooxygenase 2; AMPK: 5' adenosine monophosphate-activated protein kinase. ...
... Transplanted eutopic endometria isolated from patients with endometriosis generated smaller lesions with significantly reduced microvessel size and density and lower VEGF-B/C expression in nude mice ip injected with EGCG than with vehicle alone. 46 The reduced macrovascular network in lesions was shown to be mediated by EGCG inhibition of VEGF/ VEGF receptor signaling occurring through interferon-γ, MMP9, and chemokine ligand 3 pathways. 47 Interestingly, vitamin E (a non-angiogenic anti-oxidant) did not mimic EGCG-elicited effects on lesions, suggesting angiogenesis as a major target of EGCG actions. ...
... 47 Interestingly, vitamin E (a non-angiogenic anti-oxidant) did not mimic EGCG-elicited effects on lesions, suggesting angiogenesis as a major target of EGCG actions. 46 Of high relevance to endometriosis is consumption of a HFD, given the latter's known effects in promoting metabolic dysfunction. Studies on the consequences of fat consumption (e.g. ...
Endometriosis is a chronic inflammatory condition that may cause pelvic pain, dysmenorrhea, and/or infertility in women of reproductive age. While treatments may include medical or surgical management, the majority of therapeutic options are non-curative, and women may experience longstanding pain and/or disability. In general, chronic diseases are believed to result from modifiable risk factors, including diet. In this review, we discuss recent data on evidence-based associations between diet and endometriosis and the mechanistic points of action of constituent dietary factors with emphasis on inflammatory events that may contribute to the promotion or inhibition of the disease. Understanding the convergence of diet and endometriosis may lead to the development of clinical strategies to improve the quality of life for symptomatic women.
... It has been reported that both of IP and SC model exhibits similar development of endometriosis in respect with the cyst-like growth, and glandular and epithelial structures of the lesions [27,29]. The same strain C57BL/6 mice were used to establish SC endometriosis mouse model as described before [30,31]. Briefly, uterus was dissected out from donor mice and endometrial tissues were prepared as IP model mentioned above. ...
... For SC model, medication lasted for 21 days. The endometriotic lesion growth was determined by measuring longest length and perpendicular width of the lesions every 3 days in SC model and at the end of intervention in IP model using caliper as described before [31]. Then all the mice were sacrificed and lesions were removed and washed in sterilize PBS, then weighted on balance. ...
... Data were analyzed using relative expression level and comparison was performed between different groups after normalized to the β-actin expression. The markers had been shown to play important role in the pathogenesis of endometriosis were chosen to screen the therapeutic actions [31]. Mmp2 and Plau play key role in breaking down the endometrial stroma and extracellular basement membrane [35,36]. ...
Background:
Current medical treatments for endometriosis are very limited. Progestin and selective progesterone receptor modulators (SPRM) are developed but their efficacy, safety, mechanism and recurrence in endometriosis are not fully studied.
Methods:
In order to compare therapeutic, side effects and therapeutic actions of Esmya, Duphaston and Dienogest in endometriosis. Experimental endometriosis was induced by either intraperitoneal or subcutaneous mouse endometrium transplantation. Lesion size, weight and histology at the end of intervention were compared. Expression of related markers in the endometriotic lesions were examined. Body, uterus and ovary weights, endometrial glands and thickness (ETI), and follicle count were measured. For recurrent study, lesion growth before and after intervention was monitored.
Results:
After Esmya, Duphaston, Dienogest treatment, lesion size and weight were significantly decreased. Proliferation Pcna expression was significantly decreased in all groups, but proliferation cells were significantly decreased only in Duphaston group. Apoptosis Mapk1 expression and TUNEL-positive cells were significantly increased in Duphaston group. Adhesion Mmp2 and Itgavβ3 expression were significantly increased in Esmya group. Plau, Hif1α and Vegfa expression, peritoneal fluid PGE2 levels, and ERα and ERβ expression were not affected; while PR expression was significantly lower in all groups. Endometrial gland count in uterus was significantly increased in Dienogest group, ETI was significantly decreased in Duphaston group, and AFC were significantly increased in Esmya group. Upon treatment cessation, lesion growth rebound quickly in Dienogest and Duphaston groups, but slowly in Esmya group.
Conclusion:
Esmya, Duphaston and Dienogest are effective anti-endometriosis drugs targeting proliferation, apoptosis and adhesion. Esmya, Duphaston and Dienogest are all well tolerable, although endometrial glandular hyperplasia was found in Dienogest, endometrial atrophy in Duphaston, follicle accumulation in Esmya.
... [15] In previous studies, it was reported that EGCG suppressed the angiogenesis signaling pathway and inhibited neovascularization and the growth of experimental endometriosis in mice. [16,17] Due to the similarity in nature and histologic features of endometrial and endometriosis lesions and considering the fact that angiogenesis plays a major role in endometrial receptivity and thickening of the endometrium immediately before implantation, it is critically important to investigate the study that shows whether the contents of green tea can inhibit angiogenesis and subsequent reduction of implantation. The endometrium is one of the most interesting tissues in the human body. ...
... Our results had many similarities with the results of studies of EGCG on endometriosis lesions. [16] Optical microscopy studies revealed that PAS positive granules are mainly placed in the basal cell surface in the control group, while PAS positive granules are placed in supranuclear and subnuclear area in other groups. Xu et al. in 2009 reported that EGCG with dose of 50 mg/kg IP has antiangiogenic effects on an experimental endometriosis mouse model. ...
... [16] Optical microscopy studies revealed that PAS positive granules are mainly placed in the basal cell surface in the control group, while PAS positive granules are placed in supranuclear and subnuclear area in other groups. Xu et al. in 2009 reported that EGCG with dose of 50 mg/kg IP has antiangiogenic effects on an experimental endometriosis mouse model. [16] Although Nakae, et al. in 2008 demonstrated the dose-dependent antiangiogenic effects, they proved that EGCG at the lower dose of 5 mg/kg IP also had the same result. ...
Background
Angiogenesis plays a major role in endometrial receptivity and thickening of the endometrium immediately before implantation. The aim of the present work was to evaluate the antiangiogenic properties of epigallocatechin-3-gallate (EGCG) from green tea in angiogenesis of endometrium.
Materials and Methods
In this study, forty adult female NMARI mice randomly divided into four groups. Control group received vehicle; human menopausal gonadotropin/human chorionic gonadotropin (HMG/HCG) group received 7.5 IU HMG intraperitoneal (IP) and 48 h later 7.5 IU HCG was injected (IP) for ovarian stimulation; HMG/HCG + EGCG group received HMG and HCG in the same manner as the previous group and also received 5 mg/kg EGCG at 0, 24, 48, and 72 h after injection of HMG; and the group EGCG received 5 mg/kg EGCG. A male mouse was kept with two female animals in the same cage for mating. Mice were dissected 96 h after administration of HMG (immediately before implantation) and tissue processing was carried out for the uterine specimens. CD31-positive cells were counted by use of histological and immunohistochemical methods.
Results
Angiogenesis in EGCG-treated group was less than that of control and gonadotropin group (P < 0.05). The number of endothelial cells was counted by CD31 marker under a light microscope and showed significant differences between all groups (P < 0.05).
Conclusion
EGCG significantly inhibited the angiogenesis in endometrium (in natural cycles) through antiangiogenic effects.
... In a BALB/c mouse model, it safely suppressed endometriotic implant growth [168] . Epigallocatechin-3-gallate (EGCG) is an antioxidant compound found in green tea that has been shown to decrease the size of both in vitro and animal endometriotic lesions [169][170][171] . A RCT of green tea extract to evaluate its effectiveness and tolerability against placebo in endometriosis treatment is currently underway (NCT02832271). ...
... Inhibits cell migration and invasion of endometrial and endometriotic stromal cells; selectively inhibits angiogenesis; inhibits fibrosis formation through reducing mRNA levels of TGF-β [169][170][171] . ...
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.
... All of them used a mouse model for endometriosis. Six studies performed the method of autotransplantation of uterine tissue to peritoneum [53][54][55][56][57][58], three studies used endometrial tissue from endometriosis-free women and implanted it to the abdominal cavity [59][60][61], one study used eutopic endometrial tissue from women with endometriosis [62] and two other studies transplanted the uterus from a donor mice [63,64]. In two studies, the mice underwent overectomy [56,60]. ...
... Moreover, omega-3 polyunsaturated fatty acids (PUFA) were shown to induce the regression of endometriosis [54,56,58], which is partially in line with the human studies. Finally, several natural components found in plants such as resveratrol (natural phenol found in grapes and red wine) [60], quercetin (a plant flavonol) [55], xanthohumol (found in beer) [53], and epigallocatechingallate (found in green tea) [62] seem to inhibit endometriosis. However, due to the way of inducing endometriosis in animals, the route of nutrition administration in some studies and the lack of symptom measurement, all of which do not reflect the reality in humans, the results of the animal studies cannot be extrapolated to changes in the patients' diet. ...
A patients’ increasing interest in dietary modifications as a possible complementary or alternative treatment of endometriosis is observed. Unfortunately, the therapeutic potential of dietary interventions is unclear and to date no guidelines to assist physicians on this topic exist. The aim of this study, therefore, was to systematically review the existing studies on the effect of dietary interventions on endometriosis. An electronic-based search was performed in MEDLINE and COCHRANE. We included human and animal studies that evaluated a dietary intervention on endometriosis-associated symptoms or other health outcomes. Studies were identified and coded using standard criteria, and the risk of bias was assessed with established tools relevant to the study design. We identified nine human and 12 animal studies. Out of the nine human studies, two were randomized controlled trials, two controlled studies, four uncontrolled before-after studies, and one qualitative study. All of them assessed a different dietary intervention, which could be classified in one of the following principle models: supplementation with selected dietary components, exclusion of selected dietary components, and complete diet modification. Most of the studies reported a positive effect on endometriosis; they were however characterized by moderate or high-risk bias possibly due to the challenges of conducting dietary intervention trials. According to the available level of evidence, we suggest an evidence-based clinical approach for physicians to use during consultations with their patients. Further well-designed randomized controlled trials are needed to accurately determine the short-term and long-term effectiveness and safety of different dietary interventions.
... Angiogenesis has been clear in its pathophysiological nature [24]. Epigallocatechin gallate (EGCG) has been known to suppress estrogen-induced endothelial cell activation [25]. VEGF levels decreased in the mRNA, and apoptotesis of endometriosis mouse model increased with the Nucleic Factor (NF-SB) and ...
... Mitogen-activated Protein kinase 1(MAPK1)mRNA.. [25]. ...
... In vivo, EGCG inhibited angiogenesis, blood perfusion and growth of endometriotic lesions within dorsal skinfold chambers (Laschke et al., 2008). Xu et al. (2009) subcutaneously transplanted eutopic endometrium from patients with endometriosis into immunodeficient mice, which were intraperitoneally treated with EGCG for 2 weeks. This treatment significantly suppressed the development of endometriotic lesions by inhibition of angiogenesis, as indicated by a decreased microvessel density and reduced mRNA levels of VEGF within the lesions. ...
... This treatment significantly suppressed the development of endometriotic lesions by inhibition of angiogenesis, as indicated by a decreased microvessel density and reduced mRNA levels of VEGF within the lesions. In addition, the lesions contained higher numbers of apoptotic cells when compared to controls (Xu et al., 2009). In a follow-up study, Xu et al. (2011) further reported that EGCG selectively suppresses VEGFC/VEGF receptor-2 (VEGFR-2) expression and signalling in experimental endometriosis in vivo and in endothelial cells in vitro . ...
Background:
Given the disadvantages and limitations of current endometriosis therapy, there is a progressive increase in studies focusing on plant-derived agents as a natural treatment option with the intention of achieving high efficiency, avoiding adverse effects and preserving the chance for successful pregnancy. The heterogeneity of these studies in terms of evaluated agents, applied approaches and outcomes illustrates the need for an up-to-date summary and critical view on this rapidly growing field in endometriosis research.
Objective and rationale:
This review provides a comprehensive overview of plant-derived agents and natural treatment strategies that are under preclinical or clinical investigation and critically evaluates their potential for future endometriosis therapy.
Search methods:
An English language PubMed literature search was performed using variations of the terms 'endometriosis', 'natural therapy', 'herb/herbal', 'plant', 'flavonoid', 'polyphenol', 'phytochemical', 'bioactive', 'Kampo' and 'Chinese medicine'. It included both animal and human studies. Moreover, the Clinicaltrials.gov database was searched with the term 'endometriosis' for clinical trials on plant-derived agents. No restriction was set for the publication date.
Outcomes:
Natural therapies can be assigned to three categories: (i) herbal extracts, (ii) specific plant-derived bioactive compounds and (iii) Chinese herbal medicine (CHM). Agents of the first category have been shown to exert anti-proliferative, anti-inflammatory, anti-angiogenic and anti-oxidant effects on endometrial cells and endometriotic lesions. However, the existing evidence supporting their use in endometriosis therapy is quite limited. The most studied specific plant-derived bioactive compounds are resveratrol, epigallocatechin-3-gallate, curcumin, puerarin, ginsenosides, xanthohumol, 4-hydroxybenzyl alcohol, quercetin, apigenin, carnosic acid, rosmarinic acid, wogonin, baicalein, parthenolide, andrographolide and cannabinoids, with solid evidence about their inhibitory activity in experimental endometriosis models. Their mechanisms of action include pleiotropic effects on known signalling effectors: oestrogen receptor-α, cyclooxygenase-2, interleukin-1 and -6, tumour necrosis factor-α, intercellular adhesion molecule-1, vascular endothelial growth factor, nuclear factor-kappa B, matrix metalloproteinases as well as reactive oxygen species (ROS) and apoptosis-related proteins. Numerous studies suggest that treatment with CHM is a good choice for endometriosis management. Even under clinical conditions, this approach has already been shown to decrease the size of endometriotic lesions, alleviate chronic pelvic pain and reduce postoperative recurrence rates.
Wider implications:
The necessity to manage endometriosis as a chronic disease highlights the importance of identifying novel and affordable long-term safety therapeutics. For this purpose, natural plant-derived agents represent promising candidates. Many of these agents exhibit a pleiotropic action profile, which simultaneously inhibits fundamental processes in the pathogenesis of endometriosis, such as proliferation, inflammation, ROS formation and angiogenesis. Hence, their inclusion into multimodal treatment concepts may essentially contribute to increase the therapeutic efficiency and reduce the side effects of future endometriosis therapy.
... EGCG is the main and most significantly bioactive polyphenol found in solid green tea extract, accounting for ~65% of the catechin content; 250 mg EGCG is present in a brewed cup of green tea (22). Several previous studies showed that EGCG has important anti-atherogenic and anti-inflammatory properties (23,24). The anti-inflammatory effects of EGCG have been demonstrated in numerous previous studies related to the pathological conditions where inflammation is a core-driving factor (23,24). ...
... Several previous studies showed that EGCG has important anti-atherogenic and anti-inflammatory properties (23,24). The anti-inflammatory effects of EGCG have been demonstrated in numerous previous studies related to the pathological conditions where inflammation is a core-driving factor (23,24). For example, previous studies identified that EGCG was effective in preventing IL-8 production in airway epithelial cells through stimulation of IL-1β, restraining the development of respiratory inflammation (25,26). ...
The inflammatory response has been implicated in various cardiac and systemic diseases. Epigallocatechin-3-gallate (EGCG), the major polyphenol extracted from green tea, has various biological and pharmacological properties, such as anti-inflammation, anti-oxidative and anti-tumorigenesis. To some extent, the mechanism of EGCG in the inflammatory response that characterizes myocardial dysfunction is not fully understood. The present study aimed to investigate the inhibiting effect of EGCG on lipopolysaccharide (LPS)-induced inflammation in vitro. Treatment with LPS affected rat H9c2 cardiomyocytes and induced an inflammatory response. However, the LPS-induced effects were attenuated after treatment with EGCG. The present results demonstrated that EGCG treatment repressed several inflammatory mediators, such as vascular endothelial growth factor, chemokine ligand 5, chemokine ligand 2, intercellular adhesion molecule-1, matrix metalloproteinase-2, tumor necrosis factor-α and nitric oxide (induced by LPS), and the repressing effect of EGCG on inflammatory response was dose-dependent in the range of 6.25-100 µM. EGCG inhibited these marked inflammatory key signaling molecules by reducing the expression of phospho-nuclear factor-κB p65, -Akt, -ERK and -MAPK p38 while the total protein level of these signal proteins were not affected. In conclusion, the present findings suggested that EGCG possesses cardiomyocyte-protective action in reducing the LPS-induced inflammatory response due to the inhibition of the phosphorylation of Akt and ERK signaling molecules.
... Green tea has a significant chemical component called EGCG which has been shown high antioxidant capacity and also demonstrated anti-angiogenic capability. It may also represent (Xu et al., 2009;Xu et al., 2011;Laschke et al., 2008). We found MDA serum level in KGE or GTE group was lower compared to the control. ...
... 35 Some previous studies examined the advantages of GTE for endometriosis shown that green tea catechins particularly EGCG have anti-angiogenic effects on microvascular endothelium and suppressed the expansion and survival of experimental endometriosis in severely compromised immunodeficient mice. Mouse VEGFA mRNA expression in lesions with EGCG treatment was considerably down-regulated and decreased (Xu at al., 2009). A study analyzed the effect of EGCG on the eutopic endometrium, treated endometriosis model mice with 65 mg/kg EGCG daily for three days. ...
The pathological pathway of endometriosis remains unclear and involves complex etiologies. Increased oxidative stress is understood to be related to this disease. Oxidative stress produces reactive oxygen species, causes inflammation that is characterized by recruiting lymphocytes and phagocyte activation, produces cytokines that induce oxidation enzyme, and supports epithelium growth. Oxidative stress conjointly will increase angiogenesis and promotes the proliferation of endometriosis tissue within the peritoneal cavity. Kebar grass and green tea contain high antioxidants, are expected to extend antioxidant defense leading to reduced oxidative stress, inflammation, angiogenesis, and reduced endometriosis tissue implants. The objective is to analyze the consequences of Kebar grass and green tea extract to MDA serum level, TNF-α, and VEGF expression, and the area of the endometriotic implants in the mice models. The study was an experiment designed. It has been conducted within the. Twenty-one mice were divided into three groups, i.e., the first group of mouse models was given Kebar extract 3 mg/day; the second group was assigned green tea extract 1.1 mg/day; therefore the third group was a control group contains the untreated endometriosis mice. Each treatment was given for fourteen days. MDA serum level was measured by specto-photometric examination, the area of the endometriotic implants was measured by computer tracing technique, whereas TNF-α and VEGF expression of endometriotic implants were measured by IHC using Rammele Scale Index (ImmunoReactive Score). The MDA serum levels of the groups treated with Kebar grass extract and green tea extract were significantly lower than the control group (0.090.022 mmol, 0.070.019 mmol, and 0.300.062 mmol, respectively; p=0.001). TNF-α expression of the groups supplied with each treatment also lower than the control groups (2.431.521, 3.661.422, and 7.262.898, respectively; p=0.002). However, VEGF expression was not significantly different between Kebar grass extract group, green tea group, and the control (4.342.402, 4.571.998, 7.403.495, respectively; p=0.089). Finally, the area of the endometriotic implants of the mice models administered with all treatment was smaller than the control group (0.010.025 mm2, 8.7618.776 mm2, and 34.8013.079 mm2, respectively; p=0.003). Conclusion: Kebar grass extract, as well as green tea extract administration to endometriosis model mice, resulted in lower MDA serum level and TNF-α expression, smaller the area of endometriotic implants compared, but not resulted in a significant difference of VEGF expression.
... It may also represent a promising therapeutic agent in the treatment of endometriosis. [16][17][18] The combination of Cucumis melo-gliadin, a commercial pharmaceutical product that contains antioxidant orally available. CMEgliadin combination affects general antioxidant defences, its increase endogenous SOD activity, and prevent cellular damage after induction of oxidative stress. ...
... Mouse VEGFA mRNA expression in lesions with EGCG treatment was significantly down-regulated and decreased. 16 A study analysed the effect of EGCG on the eutopic endometrium, treated endometriosis model mice with 65 mg/kg EGCG daily for three days. Their study resulted in EGCG inhibits E2-induced activation, proliferation and VEGF expression of endometrial cells. ...
Background: Increased oxidative stress causes inflammation and increases angiogenesis. It presumed to promote the proliferation of endometriosis tissue. Kebar grass (Biophytum petersianum) and other herbs such as green tea and Cucumis melo, which contain high antioxidants, are expected to decrease oxidative stress, inflammation, angiogenesis, and reduced endometriosis implants.
Objective: To investigate the effects of Kebar grass, green tea, and Cucumis melo to malondialdehyde serum, tumor necrosis factor alpha, and vascular endothelial growth factor expression, and the area of the endometriotic implants.
Methods: Twenty-eight mice were divided into four groups, i.e., the first group of endometriosis mice was given Kebar grass extract; the second group was assigned green tea extract, the third group was given the combination of Cucumis melo extract–gliadin, and the last containing the untreated endometriosis mice as the control. Each treatment was given for 14 days. The data of MDA serum level, the area of the endometriotic implants, TNF-α, and VEGF expression were collected and analyzed.
Results: The MDA serum levels of the groups treated with Kebar grass extract, green tea extract, and Cucumis melo extract – gliadin were significantly lower (p=0.001) than the control group. TNF-α expression of the groups provided with each treatment also lower than the control groups (p=0.002). However, only the administration of the Cucumis melo extract–gliadin resulted in lower VEGF expression compare with the control (p=0.017). Finally, the area of the endometriotic implants of the mice models administered with each treatment was smaller than the control group (p=0.003).
Conclusion: Kebar grass as well as green tea and Cucumis melo–gliadin inhibits endometriotic implants extension by decreasing MDA serum and TNF-α expression.
... Moreover, EGCG selectively suppresses the expression of VEGF-C and VEGF receptor 2 and reduces extracellular regulated kinase activation in endothelial cells (Table 1) [154]. Another study demonstrated that endometriotic lesions and glandular epithelium reduced after treatment with EGCG for 2 weeks by downregulating angiogenic VEGF A mRNA levels and upregulating NF-!B and mitogen-activated protein kinase 1 mRNA levels in lesions [156]. Laschke et al. found that EGCG might diminish E2-stimulated activation, proliferation, and VEGF expression in endometrial cells of rat endometriosis models, therefore inhibiting the formation of new endometriotic lesions [157]. ...
... EGCG has earlier been found to exert anticancer effects [147,152]. Some latest trials displayed its antiangiogenic effects on endometriosis [154,156]. The antiproliferative and proapoptotic effects of EGCG on endometriosis were consistent with the findings of previous experimental trials [149,151]. ...
Endometriosis is a disease in which the lining of the endometrium is found outside of the uterus. Recent medical treatments for endometriosis have adverse effects, limiting their long-term use. Furthermore, the recurrence of the disease after the cessation of therapy is quite common, and most patients need to continue treatment to maintain a hypoestrogenic environment till conception. Notwithstanding recent advances in computational and chemical practices, traditional medicines are considered the most consistent sources for the discovery of new drugs. Numerous medicinal plants and plant-derived compounds have been tested against gynecological disorders, mainly endometriosis. This review aimed to describe the pharmacological activity profile of the medicinal plants and their active ingredients and draw attention to the discovery of multitargeted drug molecules for rational therapy.
... In a study published in 2009, microvessels' size and density and mRNA levels of VEGF in endometriotic lesions have been found to be significantly reduced after EGCG treatment. 87 In 2011, the same research group found that EGCG significantly reduces the expression of vascular endothelial growth factor C (VEGFC) and VEGF receptor 2 (VEGFR2), and down-regulates the VEGFC/VEGFR2 angiogenic pathway. 88 Two other studies on animal models observed a reduction in size and weight of endometriotic Table 2. Main characteristics of studies conducted in vitro or on animal models focused on green tea effects. ...
... Laschke et al. 86 In vitro (endometrial cells) ↓ E2-stimulated activation ↓ Proliferation ↓ VEGF expression In vivo (endometriotic lesions) ↓ Angiogenesis ↓ Blood perfusion Induces regression of the lesion Xu et al. 87 Animal study (subcutaneous transplant of human endometrial tissue from women with endometriosis in immunocompromised mice) ...
Endometriosis is a chronic, inflammatory, estrogenic-dependent disease characterized by the presence of endometrial glands outside the uterine cavity, affecting approximately 2%–10% of women in reproductive age and 30%–50% of women in general. Despite the high prevalence of the disease, not much is known about etiology, possible risk factors, and an adequate and satisfactory therapy. In the past years, many studies have focused on food intake (nutrients and food groups) and on its possible correlation with endometriosis, demonstrating how diet could be identified as a possible risk factor. Comprehensive searches in the largest medical information databases (Medline-PubMed, Embase, Lilacs, and Cochrane Library) were conducted using the Medical Subject Heading terms “diet,” “food,” “nutrition,” “fatty acids,” vitamins,” “fruit,” “vegetables,” “coffee,” “caffeine,” “fish,” “soy food,” “dairy products,” “tea,” “curcumin” combined with “endometriosis.” Purpose of this review is to revise the literature, in order to determine potential modifiable risk factors of the disease.
... Angiogenesis is widely believed to play a crucial role in the development of endometriosis lesions. Levels of VEGF A and C mRNA decreased after EGCG therapy, which suggested that EGCG inhibited angiogenesis to reduce endometriosis damage [100,101]. However, EGCG is easily oxidized in neutral or alkaline environments, and its bioavailability in humans is low [102]. ...
Reactive oxygen species (ROS) are mainly produced in mitochondria and are involved in various physiological activities of the ovary through signaling and are critical for regulating the ovarian cycle. Notably, the imbalance between ROS generation and the antioxidant defense system contributes to the development of ovarian diseases. These contradictory effects have critical implications for potential antioxidant strategies that aim to scavenge excessive ROS. However, much remains to be learned about how ROS causes various ovarian diseases to the application of antioxidant therapy for ovarian diseases. Here, we review the mechanisms of ROS generation and maintenance of homeostasis in the ovary and its associated physiological effects. Additionally, we have highlighted the pathological mechanisms of ROS in ovarian diseases and potential antioxidant strategies for treatment.
... In the network pharmacology study, baicalein, sitosterol, β-sitosterol, (+)-catechin, and other active compounds inhibited the invasion and metastasis of AM ectopic lesions, possibly by acting on MMP-2, MMP-9, and VEGF. Some mechanisms have been confirmed, (+)-catechin decreased VEGF levels in vivo and inhibited the growth of ectopic endometrium [47]. Stigmasterol can inhibit angiogenesis, reduce the invasive ability of tumor cells, promote the apoptosis of abnormal cells, and improve the immunity of the body [48]. ...
Background:
The effect of GuizhiFuling Wan (GFW) on adenomyosis (AM) is definite. This study aimed to explore the mechanism and key therapeutic targets of GFW in treating AM through network pharmacology combined with molecular docking and experimental verification.
Materials and methods:
In network pharmacology, firstly, the active components of GFW, its drug, and disease targets were screened through several related public databases, and GFW-AM common targets were obtained after the intersection. Then, the biological function (Gene Ontology, GO) and pathway (Kyoto Encyclopedia of Genes and Genomes, KEGG) of GFW in treating AM were enriched and analyzed. Finally, the interaction and binding force between key components and key targets of GFW were verified by molecular docking. In the animal part, the effect of GFW on the expression of matrix metallopeptidase 2 (MMP-2), matrix metallopeptidase 9 (MMP-9), and vascular endothelial growth factor (VEGF) in mice with AM was observed by HE staining, ELISA, and immunohistochemistry.
Results:
In this study, 89 active components of GFW, 102 related targets, and 291 targets of AM were collected. After the intersection, 26 common targets were finally obtained. The key active compounds were baicalein, sitosterol, and β-sitosterol, and the key targets were MMP-2, MMP-9, and VEGF. GO and KEGG enrichment analyses showed that biological processes such as the positive regulation of vascular endothelial migration and signaling pathways such as TNF and HIF-1 were involved in regulating angiogenesis, invasion, and metastasis in AM. The molecular docking results showed that baicalein, β-sitosterol, and stigmasterol had better binding potential with MMP-2, MMP-9, and VEGF. The results of in vivo analysis showed that GFW could decrease the serum content and protein expression of MMP-2, MMP-9, and VEGF in mice with AM.
Conclusions:
GFW could reduce the expression of MMP-2, MMP-9, and VEGF, which might be an essential mechanism for GFW to inhibit the invasion and metastasis of ectopic tissues of AM.
... In the cited study, reduced expression of oestrogen and progesterone receptors, as well as the arrest of cells in the G0/G1 phase of the cell cycle, was also observed. In an animal study, EGCG inhibited angiogenesis [227,228], preventing the formation of new blood vessels needed to support large tumours. A study utilising a xenograft model revealed that the administration of a prodrug form of EGCG inhibited the proliferation of tumour cells and enhanced apoptosis in a time and dose-dependent manner, with the significant effect of reducing the formation of microvessels and therefore hindering blood flow to the xenografts [229]. ...
Endometrial cancer (EC) is second only to cervical carcinoma among the most commonly diagnosed malignant tumours of the female reproductive system. The available literature provides evidence for the involvement of 32 genes in the hereditary incidence of EC. The physiological markers of EC and coexisting diet-dependent maladies include antioxidative system disorders but also progressing inflammation; hence, the main forms of prophylaxis and pharmacotherapy ought to include a diet rich in substances aiding the organism’s response to this type of disorder, with a particular focus on ones suitable for lifelong consumption. Tea polyphenols satisfy those requirements due to their proven antioxidative, anti-inflammatory, anti-obesogenic, and antidiabetic properties. Practitioners ought to consider promoting tea consumption among individuals genetically predisposed for EC, particularly given its low cost, accessibility, confirmed health benefits, and above all, suitability for long-term consumption regardless of the patient’s age. The aim of this paper is to analyse the potential usability of tea as an element of prophylaxis and pharmacotherapy support in EC patients. The analysis is based on information available from worldwide literature published in the last 15 years.
... Formulated as two phenolic hydroxyl groups containing 2-3 endiol-L gluconic acid lactone, vitamin C is a powerful reductive and is one of the most important antioxidants in the human body (87). Antioxidants inhibit lipid peroxidation by inhibiting the peroxidation estrogen-related activation, proliferation, and VEGF expression of endometrial cells in vitro (103,104). It also significantly reduced the mean number and the volume of endometriotic implants, inhibited cell proliferation, reduced vascularization, and increased apoptosis (105). ...
As search for optimal therapy continues for endometriosis, aid of dietary supplements is gaining attention. Supplements can be used for their anti-inflammatory, anti-oxidant, anti-proliferative and immune modulatory charactheristics. We reviewed the literature, evaluated and synthesized effects of vitamin D, zinc, magnesium, omega 3, propolis, quercetin, curcumin, N-acetylcysteine, probiotics, resveratrol, alpha lipoic acid, vitamin C, vitamin E, selenium and epigallocatechin-3-gallate. Based on results of in vitro, animal and human studies, it might be safe to say that dietary supplements can be used as a complementary treatment for endometriosis.
... EGCG treatment substantially decreased the expression of markers αSMA, collagen-I, fibronectin (FN), and connective tissue growth factor (CTGF) known to be involved in fibrogenesis in endometriotic stromal cells [106]. Another study demonstrated that treatment with EGCG for two weeks reduced endometriotic lesions by downregulating angiogenic VEGFA mRNA expression and upregulating NF-κB and MAPK 1 mRNA expression [153]. The subsequent experiments showed that EGCG exerted an inhibitory effect on endometriosis-associated angiogenesis by decreasing the number and size of microvessels and VEGF-C/VEGF receptor 2 (VEGFR-2) expression and signaling [107]. ...
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.
... It was also reported that gallic acid exhibits various biological properties such as anticancer, antimicrobial, anti-inflammatory, antitumor, anti-neoplastic and anti-diabetic effects (Kroes et al., 1992;Kawada et al., 2001;Fiuza et al., 2004;Chia et al., 2010;Liu et al., 2013;Sun et al., 2014;Zhang et al., 2019). In addition to its high antioxidant activity; catechin was reported to exhibit several activities such as anti-inflammatory, antipandemic, anti-metastatic, anti-ulcer, anti-angiogenic, anti-allergic, anti-mutagenic, anti-proliferative, antimicrobial effects (Nagabhushan and Bhide, 1988;Maeda-Yamamoto et al., 2007;Xu et al., 2008;Chunmei et al., 2010;Delgado et al., 2014;You et al., 2018;Nakano et al., 2019). It was reported that p-coumaric acid exhibited immunomodulatory activity, antioxidant, antiinflammatory and antiangiogenic properties (Etoh et al., 2004;Kong et al., 2013;Pragasam et al., 2013). ...
Wild edible mushrooms have been gathered and consumed by humans since ancient times. In addition to their nutritional properties, many mushrooms are known to possess medicinal properties. The present study aimed to determine antioxidant and antimicrobial activities and phenolic content of the wild edible mushroom Melanoleuca melaleuca (Pers.) Murrill. All experiments were performed 5 times, and results expressed as mean ± standard deviation unless otherwise stated (p ≤ 0:05). The present study findings demonstrated that the antioxidant potential of the mushroom was high. It was determined that the TAS value of ethanol extract of the M. melaleuca mushroom was 3.393±0.098 mmol/L, TOS value was 6.460±0.121 µmol/L and OSI value was 0.190±0.002. Furthermore, it was determined that the mushroom extracts were effective against test microorganisms at 25-400 µg/mL concentrations. HPLC scans revealed that the mushroom contained gallic, catechin, p-coumaric, syringic and protocatechuic acids. Thus, it was determined that the mushroom had antioxidant and antimicrobial potential. It was also determined that the mushroom could serve as a natural source for phenolic content.
... It has also been reported that green tea polyphenols possess anticolorectal cancer activity, by altering intestinal microbiota and intestinal colonization of oral cavity bacteria that are associated with gastrointestinal malignancies [10]. Studies have also revealed anti-angiogenic effects for green tea catechins, which can suppress tumor growth [11][12][13][14]. Cardio-protective [15][16], cholesterol lowering [17][18][19][20], anti-hypertensive [21][22][23], and antidiabetic [24][25] properties of polyphenols has also been indicated in many clinical studies and literature reviews. ...
Herbal products are increasingly growing in the oral care market. Some of the related herbal compounds in this field have considerable clinical evidence for use in mouthwashes in their background. Camellia sinensis or tea plant has attracted numerous researchers of dentistry and pharmaceutical sciences, in recent years, for its biologic and medicinal properties. The effects such as anti-septic, anti-oxidative, and anti-inflammatory activities have made this plant a suitable candidate for preparation of mouthwashes. In this systematic review, we tried to find, evaluate, and categorize the sparse evidence in medical literature about Camellia sinensis mouthwashes. We explored three scientific databases with keywords including tea, dental care, Camellia sinensis, and mouthwashes and found 69 relevant studies including 41 randomized controlled trials (RCTs), which are generally proposing anti-microbial, anti-plaque, and analgesic indications for these tea formulations. Considering the main trend in clinical evidence and favorable safety profile, Camellia sinensis products are able to act as antiseptic, anti-plaque, and anti-inflammatory agents and can be used as useful mouthwashes in the future clinical studies and practice.
... The in vitro effect of EGCG in concentrates of 50 µM inhibits the expression of PDGF-induced VEGF mRNA, PDGFinduced activation of Erk-1/2, and Active-1/2 (Park, eet al. 2006). Injecting 5mg/kg and 50mg/kg of EGCG in rats inhibits the dose-dependent angiogenesis (Xu, et al. 2009). EGCG is excreted through bile while the other polyphenols are excreted through urine. ...
Background: Polyphenols contained in tea have anti-angiogenesis effects. Epigallocatechin-3-gallate (EGCC) extracted from green tea is a strong inhibitor of neutrophil-mediated angiogenesis, both in vitro and in vivo. Some studies have shown that oral or IP injection of ECGC could be a strong angiogenesis inhibition. Purpose: This study aims to determine the effect of green tea extract on angiogenesis in bone fracture healing. Method: The study utilized the Randomized Control Group Post Test-Only Design research. In the first draft, the sample was divided into several groups, i.e., K1 as a control group, and P1, P2, P3, and P4 as treatment groups. For the first draft, the experimental animals were terminated on the 10th day. The termination was undertaken on the 14th day for the second draft. This study utilized the Anova test to analyze the data. Results: The recommended dose for administering the green tea extract was 20 mg (p=0.447), then there would be a significant reduction (p=0.034) of cell numbers that represented VEGF if the dose was 25 mg or more. A significant reduction of blood vessel numbers (p=0.009) was indicated after administering 25 mg or more. Conclusion: The cross-sectional area of blood vessels decreases when transferring 20 mg of the extract, while the blood vessels and cells number that represented VEGF decrease when administering 25 mg of the extract. The blood vessels contained in the callus also decrease after injecting 25 mg of green tea extract.
... Other compounds are moscatin; 7-hydroxy-2,3,4-trimethoxy-9,10-dihydrophenanthrene, coelonin; densiflorol B; gigantol; batatasin III; tristin; vanillic acid and syringaldehyde; 3,7-dihydroxy-2-4-6trimethoxyphenanthrene; bulbophyllanthrone; coelonin Majumder and Sen (1991); Xu et al. (2009) 5 Bulbophyllum triste Tristin Majumder and Pal (1993) 6 Coelogyne cristata Coelogin, coeloginin, coeloginanthridin, and coeloginanthrin; phytoalexins; combretastatinC-1 Majumder et al. (2001) 7 Coelogyne flaccida Flaccidin (9,10-dihydrophenanthropyran derivative) Majumder and Maiti (1988) Homoeridictyol;scoparone;bibenzyl,densiflorol a,phenanthrenedione,densiflorol b,dendroflorin,dengibsin,cypripedin,gigantol,moscatilin,tristin,naringenin,homoeriodictyol,moscatin,2,5,4, Lam et al. (2015) 20 Dendrobium macraei Lindl Alkaloids: Jebantine, jibantic acid Khasin and Rao (1999); Khory (1982);Lam et al. (2015) 21 Dendrobium monoliforme Sw. Dendromoniliside A, dendromoniliside B, dendromoniliside C; moniliformin (2,6-dimethoxy-1,4,5,8phenanthradiquinone); 7-hydroxy-5,6-dimethoxy-1, 4-phenanthranequinone; (+)-syringaresinol, aloifol I; daucosterol Gutiérrez (2010); Arora et al. (2017) 22 Dendrobium moschatum Phenanthrenes: rotundatin, moscatin; moscatilin (4,4-dihydroxy-3,3,5-trimethoxybibenzyl) Miyazawa et al. (1997) 23 Dendrobium nobile Bibenzyls: gigantol, moscatilin Alkaloids: dendrobinae; mucilage, alkaloid: dendrobine, 1-4: phenanthrenequinone: denbinobine, gigantol bibenzyl compound: moscatilin; (−)-dendrobine; denbinobin (5-hydroxy-3,7-dimethoxy-1,4-phenanthraquinone); dendroside A, dendroside D; dendroside E; dendroside F; dendroside G; dendronobiloside A; 4,7-dihydroxy-2-methoxy-9, 10-dihydrophenanthrene; nobilin D, nobilin E; nobilone; Lee et al. (1995); Miyazawa et al. (1997); Khory (1982); Arditti (1992); Matsuda et al. (2004) 24 Dendrobium plicata Ephemeranthoquinone Yamaki and Honda (1996); Arora et al. ...
In the last century, nearly all compounds of medicinal value were derived from naturally occurring compounds found in plants, bacteria, and fungi. Yet even today several interesting plant species with potential medicinal value remain underutilized and neglected. In a changing world, where unfavorable climatic and anthropogenic scenarios threaten natural vegetation across the globe, there is an urgent need to identify and investigate underutilized medicinal plants. Also, the utilization of such species should go hand in hand with their conservation. With the island territory of Puerto Rico as an example, we present a case for such underutilized medicinal plant species which could end up being the source of the next wonder drug for humanity. We also emphasize the need for sustainable utilization of such resources to go hand in hand with their conservation.
... Proliferation, fibrosis, and angiogenesis each plays a role in uterine fibroid growth and formation (Islam et al. 2014). Studies have shown that all of these processes can be inhibited by EGCG (Xu et al. 2009;Larsen and Dashwood 2010;Matsuzaki and Darcha 2014). We first studied EGCG in comparison to pro-EGCG and analogs 2a and 4a with regard to their effect on proliferation of human uterine leiomyoma cell lines (Ahmed et al. 2016). ...
Green tea polyphenols, especially catechins, have shown great promise for use as anticancer agents. One such catechin, epigallocatechin-3 gallate (EGCG), is of particular interest due to mounting evidence of its ability to interrupt a variety of essential signaling pathways in cancer cells and target multiple tumor-specific proteins, and its synergistic effects when paired with commonly used anticancer therapies. However, EGCG has a number of disadvantages, e.g., low stability and poor bioavailability, as well as rapid metabolic transformations in vivo. We previously developed a prodrug of EGCG (Pro-EGCG or 1) which shows increased levels of stability, bioavailability, and biological activity in human cancer cells and xenografts as compared to EGCG. In order to potentially reduce the susceptibility of EGCG analogs to be methylated and thus inhibited by catechol-O-methyltransferase (COMT), we synthesized novel analogs and prodrugs where one or two hydroxyl or acetoxy groups, respectively, have been removed from the gallate ester moiety. Such prodrugs (2a and 4a) were reported recently to have potent antiproliferative, antiangiogenic, and antifibrotic properties. We previously also reported that synthetic EGCG analogs 4 and 6 were more potent AMPK activators than metformin and EGCG. Here we review the activity of 4 and 6 in inhibiting growth of uterine fibroid cells. We also review the potential of these novel EGCG analogs and prodrugs as anticancer drugs and discuss the potential mechanisms of action involved.
... The results of the present study suggested that both R-GT and SE-GT water extracts have an anti-angiogenic effect. Using different Experimental studies using different tumour angiogenic models, have shown that green tea extract and/or its polyphenolic substances such as catechins have strong anti-angiogenic effects [18][19][20][21]. Although the mechanism of the anti-angiogenic activity was not investigated in this study, some previous studies have shown that it seems that it is to be associated with inhibitory effects on VEGF production and VEGF receptor activity [22][23][24][25][26]. ...
... The results of the present study suggested that both R-GT and SE-GT water extracts have an anti-angiogenic effect. Using different Experimental studies using different tumour angiogenic models, have shown that green tea extract and/or its polyphenolic substances such as catechins have strong anti-angiogenic effects [18][19][20][21]. Although the mechanism of the anti-angiogenic activity was not investigated in this study, some previous studies have shown that it seems that it is to be associated with inhibitory effects on VEGF production and VEGF receptor activity [22][23][24][25][26]. ...
... 32 33 On the other hand, an animal study has shown that green tea catechins inhibited the development of endometriosis through antiangiogenic effects. 34 Thus, it is possible that green tea may potentially be beneficial to both primary and secondary dysmenorrhoea. Third, we did not include information on oral contraceptive pills use, which may cause potential bias due to residual confounding. ...
Objectives
To investigate the association between tea drinking and dysmenorrhoea among women of reproductive age.
Design
A cross-sectional study based on Shanghai Birth Cohort Study.
Setting
Two preconceptional care clinics in Shanghai, China.
Participants
1183 women of reproductive age who sought preconceptional care were recruited from August 2013 to April 2015.
Primary and secondary outcome measures
Participants were asked if they had pelvic pain associated with menstrual bleeding during the past 12 months and to further grade the intensity of menstrual cramp as mild, moderate and severe. Multinomial logistic regression was performed to assess the association of tea drinking and dysmenorrhoea. Other information, such as demographic and lifestyle factors, was also collected and assessed in relation to dysmenorrhoea.
Results
The prevalence of dysmenorrhoea was 57.8%, among whom 10.4% and 3.5% had moderate and severe dysmenorrhoea, respectively. Tea drinking was associated with a lower prevalence of dysmenorrhoea (adjusted OR [aOR]=0.68, 95% CI 0.50 to 0.93 for mild dysmenorrhoea; aOR=0.59 (95% CI 0.32 to 1.04) for moderate-to-severe dysmenorrhoea). Green tea and oolong tea appeared to have most reduction in the prevalence of dysmenorrhoea (for mild dysmenorrhoea: green tea: aOR=0.63 (95% CI 0.44 to 0.90) and oolong tea: aOR=0.60 (95% CI 0.35 to 1.03); for moderate-to-severe dysmenorrhoea: green tea: aOR=0.42 (95% CI 0.20 to 0.85) and oolong tea: aOR=0.34 (95% CI 0.11 to 1.09)).
Conclusions
Consumptions of green tea and possibly oolong tea were associated with a lower prevalence of dysmenorrhoea.
... Epigallocatechin-3-gallate (EGCG) is one of the most abundant polyphenols present in green tea. It has been reported that EGCG reduces the size of endometriotic implants by inhibition of cell proliferation, angiogenesis, and induction of apoptosis in mouse endometriotic implants [249][250][251][252]. Furthermore, EGCG treatment significantly decreased the TGF-β1-induced in the mRNA expression of fibrotic markers, and the TGF-β1-stimulated activation of MAPK and Smad signaling pathways in endometriotic ESCs, suggesting that anti-fibrosis activity of EGCG may be dependent on the suppression of TGF-β1 in endometriosis [188]. ...
Although the pathogenesis of endometriosis is not fully understood, it is often considered to be an inflammatory disease. An increasing number of studies suggest that differential expression of anti-inflammatory cytokines (e.g., interleukin-4 and -10, and transforming growth factor-β1) occurs in women with endometriosis, including in serum, peritoneal fluid and ectopic lesions. These anti-inflammatory cytokines also have indispensable roles in the progression of endometriosis, including by promoting survival, growth, invasion, differentiation, angiogenesis, and immune escape of the endometriotic lesions. In this review, we provide an overview of the expression, origin, function and regulation of anti-inflammatory cytokines in endometriosis, with brief discussion and perspectives on their future clinical implications in the diagnosis and therapy of the disease.
... 59 Human tissues were subcutaneously implanted in the pockets made through less than 3 mm midline ventral incision in NOD-SCID mice; ideal results were concluded. 60 The allograft models in mice have been proposed elsewhere. ...
Although endometriosis is not a newly discovered disease, it has still remained enigmatic. Understanding the pathophysiology of this disease is still one of the challenges of gynecology and reproductive medicine. Therefore, the subject of endometriosis
treatment faces many questions to be answered. Even though this is not considered to be a rare disease, testing novel treatments on subjects is defnitely contrary to medical ethics. This is where importance of animal studies is emphasized. History of animal studies on endometriosis dates back to the time when the young John Sampson presented his theory of retrograde flow of menstruation to the gynecologic society of his time to explain the mechanism of endometriosis. However, most of the medical society of that time favored metaplasia as the main mechanism over the new theory. In order to prove Sampson’s theory, animal models were used to induce endometriosis, and that was the frst study of experimental endometriosis. Nowadays, although no one uses animals to
evaluate Sampson theory of endometriosis, however, experimental endometriosis is widely used to study many different aspects of the disease from pathogenesis to possible options for treatments. Also, since then, various animals and different techniques
have been proposed and so there is a huge body of literature on experimental endometriosis. Contrary to many countries, Iranian medical societies have neglected animal models for endometriosis until recently. This review article aims to go through the
prominent articles on the subject and introduce different animals and methods to its readers and have a special look at Iranian literature on experimental endometriosis.
... Many studies have demonstrated that the peritoneal fluid contains elevated concentrations of different angiogenesis-promoting factors besides VEGF and NGF, including angiopoietin, IL-4, activin A, and IL-17A [30][31][32][33]. These efforts contribute to therapies for endometriosis to develop anti-angiogenic treatment strategies [34][35][36][37]. As lesions must be vascularized to survive, the blood vessels are presumably innervated by sensory and sympathetic fibers, as many studies demonstrated that nerve fibers are thought to sprout from perivascular and paravascular blood vessels as they vascularize growths [38,39]. ...
Endometriosis is a common multifactorial gynecological disorder defined as the proliferation of endometrial tissue outside of the uterine cavity. Neuroangiogenesis (co-recruitment of nerves and blood vessels) is believed to play an integral part in the establishment and growth of endometriotic lesions. We hypothesized that exosomes derived from abnormal endometrium may serve as the second identifier of endometriosis and play an important role in the development of endometriosis by regulating neuroangiogenesis. Primary human endometrial stromal cells (ESCs) were isolated from eutopic endometrium (EmESC, n = 22) with endometriosis and normal endometrium (CoESC, n = 6). Exosomes were isolated from ESCs using “standard” ultracentrifugation method, and the characterization of exosomes were identified through transmission electron microscopy, nanoparticle tracking analysis, and western blot. The role of exosomes in regulating neuroangiogenesis was determined through in vitro tube formation assay, neurite outgrowth assay, and dorsal root ganglion (DRG) neuron apoptosis analysis. The data showed that EmESCs could secrete exosomes with a diameter of approximately 100 nm and a biconcave morphological feature; they were internalized by human umbilical vein endothelial cells (HUVECs) and DRG neurons and enhanced neuroangiogenic effects. We further validated the role of exosomes through blocking experiments. We found that when the exosome secretion was blocked, the pro-neuroangiogenesis effects were decreased. In conclusion, these data suggested that exosomes may play a key role in endometriosis by promoting neuroangiogenesis.
... Epigallocatechin Gallate (EGCG), which is derived from green tea, has powerful anti-angiogenic properties. It may be effective against endometriosis through inhibition of angiogenesis, adhesions, and invasion by endometriotic lesions on an endometriosis mouse model transplanting human eutopic endometrium [71]. EGCG selectively inhibits the expression of vascular endothelial growth factor VEGF-C (VEGFC) and the tyrosine kinase receptor, VEGFR2, by inhibition of the VEGFC/VEGFR2 signaling pathways, which inhibits endometriosis-associated angiogenesis of endothelial cells [72]. ...
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.
... Clearly, development of a vascular supply is essential for ectopic endometrial survival. Therefore, a large number of studies have utilized murine models to examine the potential therapeutic value of angiogenesis inhibitors [101,[110][111][112][113][114][115][116][117]. Collectively, these studies indicate that both natural and pharmaceutical agents that inhibit angiogenesis can impede maintenance and growth of experimental endometriosis and support investigation of angiostatic agents as potential therapeutic agents for women with this disease. ...
Background
Although it has been more than a century since endometriosis was initially described in the literature, understanding the etiology and natural history of the disease has been challenging. However, the broad utility of murine and rat models of experimental endometriosis has enabled the elucidation of a number of potentially targetable processes which may otherwise promote this disease.
Objective
To review a variety of studies utilizing rodent models of endometriosis to illustrate their utility in examining mechanisms associated with development and progression of this disease.
Results
Use of rodent models of endometriosis has provided a much broader understanding of the risk factors for the initial development of endometriosis, the cellular pathology of the disease and the identification of potential therapeutic targets.
Conclusion
Although there are limitations with any animal model, the variety of experimental endometriosis models that have been developed has enabled investigation into numerous aspects of this disease. Thanks to these models, our under-standing of the early processes of disease development, the role of steroid responsiveness, inflammatory processes and the peritoneal environment has been advanced. More recent models have begun to shed light on how epigenetic alterations con-tribute to the molecular basis of this disease as well as the multiple comorbidities which plague many patients. Continued de-velopments of animal models which aid in unraveling the mechanisms of endometriosis development provide the best oppor-tunity to identify therapeutic strategies to prevent or regress this enigmatic disease.
... Green tea has a lot of catechins and several other trace components having physiological functions like caffeine, theanine, and vitamins. Among green tea components, green tea catechins have many physiological effects such as anti-angiogenesis, 1) anti-oxidation, 2) cholesterol blood disease onset inhibition, 3) anticancer, 4) and apoptosis induction. 5) In particular, the formation of oxidized LDL is inhibited by catechins through their strong antioxidant action. ...
Atherosclerosis is one of the diseases related to metabolic syndrome which is caused by obesity. Previous reports have shown that green tea and its components have anti-obesity effect. We examined whether catechins and caffeine can prevent the development of atherosclerosis by oral administration, singly or in combination to the atherosclerosis model mice. Results demonstrated that the number of atherosclerotic regions in the aorta was significantly reduced by the combined treatment, and the atherosclerotic area was also improved. Serum HDL-C increased by caffeine single treatment, but no effect on the TG and TC by any treatments. Moreover, ECG illuviated to atheromatous lesions in aorta and the illuviation was enhanced by caffeine. The mRNA expression levels of LOX-1 and TNF-α showed a tendency to suppress by the combined treatment. These results indicated that the combined administration of catechins and caffeine has the inhibitory effect on the development of atherosclerosis in mice.
... The ester of epigallocatechin and gallic acid, (−)-Epigallocatechin-3-Gallate [EGCG; (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate] (Pubchem CID: 65,064), represents the principal bioactive polyphenol in the solid GTE (65% catechin content). Several studies showed that EGCG has important anti-atherogenic and anti-inflammatory properties [14,15] with potential neuroprotective effects against cerebrovascular diseases. For examples, Ahn et al. showed that EGCG was able to inhibit the production of TNFα-induced monocyte chemotactic protein-1 from vascular endothelial cells [16], whereas Lee et al. studied the protective effects of EGCG against brain edema and neuronal damage after unilateral cerebral ischemia in gerbils [17]. ...
Alzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia characterized by cognitive and memory impairment. One of the mechanism involved in the pathogenesis of AD, is the oxidative stress being involved in AD's development and progression. In addition, several studies proved that chronic viral infections, mainly induced by Human herpesvirus 1 (HHV-1), Cytomegalovirus (CMV), Human herpesvirus 2 (HHV-2), and Hepatitis C virus (HCV) could be responsible for AD's neuropathology. Despite the large amount of data regarding the pathogenesis of Alzheimer's disease (AD), a very limited number of therapeutic drugs and/or pharmacological approaches, have been developed so far. It is important to underline that, in recent years, natural compounds, due their antioxidants and anti-inflammatory properties have been largely studied and identified as promising agents for the prevention and treatment of neurodegenerative diseases, including AD. The ester of epigallocatechin and gallic acid, (−)-Epigallocatechin-3-Gallate (EGCG), is the main and most significantly bioactive polyphenol found in solid green tea extract. Several studies showed that this compound has important anti-inflammatory and antiatherogenic properties as well as protective effects against neuronal damage and brain edema. To date, many studies regarding the potential effects of EGCG in AD's treatment have been reported in literature. The purpose of this review is to summarize the in vitro and in vivo pre-clinical studies on the use of EGCG in the prevention and the treatment of AD as well as to offer new insights for translational perspectives into clinical practice.
... Because it inhibits cell proliferation, promotes apoptosis and has antioxidative effects, researchers have studied it as a possible treatment for endometriosis. Animal studies showed that it signifi cantly suppressed angiogenesis in endometrial tissue without affecting blood vessel development in ovarian follicles [ 91 ] and reduced the size and activity of the endometrial implants [ 92 ]. The authors concluded that Epigallocatechin-3-gallate has the potential to be an effective treatment by inhibiting the formation of new endometriotic lesions [ 91 ]. ...
Reactive oxygen species (ROS) are highly reactive oxidizing agents which play certain physiological and pathological roles in the human body [1]. These substances are normally present within the cells. ROS are mostly free radicals. Free radicals have been labeled as molecular entities containing at least one unpaired electron which gives rise to a highly reactive group of compounds [2]. Moderate concentrations of ROS are vital in maintaining a number of physiologic processes in both male and female reproductive systems. ROS can be acquired through two different classes of sources, either endogenous (cellular) or exogenous. Unlike endogenous ROS, exogenous sources such as ultraviolet light, chemotherapeutic agents and inflammatory cytokines do not play a major role in generating ROS in the female reproductive system [3]. Endogenous sources, however, are the most prominent birthplace from which ROS are derived. The major intracellular sources of ROS include the electron transport chain in the mitochondria, endoplasmic reticulum as well as the peroxisomes [4]. Conversely, other extra-mitochondrial ROS sources exist through numerous enzymatic pathways. Examples include NADPH oxidase, xanthine oxidase, lipoxygenases, cyclooxygenases and the cytochrome P450 systems [5].
The Camellia sinensis plant provides a wide diversity of black, green, oolong, yellow, brick dark, and white tea. Tea is one of the majorly used beverages across the globe, succeeds only in the water for fitness and pleasure. Generally, green tea has been preferred more as compared to other teas due to its main constituent e.g. polyphenols which contribute to various health benefits. The aim of this updated and comprehensive review is to bring together the latest data on the phytochemistry and pharmacological properties of Camellia sinensis and to highlight the therapeutic prospects of the bioactive compounds in this plant so that the full medicinal potential of Camellia sinensis can be realised. A review of published studies on this topic was performed by searching PubMed/MedLine, Scopus, Google scholar, and Web of Science databases from 1999-2022. The results of the analysed studies showed that the main polyphenols of tea are the four prime flavonoids catechins: epigallocatechin gallate (EGCG), epicatechin gallate (ECG), epigallocatechin (EGC), and epicatechin (EC) along with the beneficial biological properties of tea for a broad heterogeneity of disorders, including anticancer, neuroprotective, antibacterial, antiviral, antifungal, antiobesity, antidiabetes and antiglaucoma activities. Poor absorption and low bioavailability of bioactive compounds from Camellia sinensis are limiting aspects of their therapeutic use. More human clinical studies and approaching the latest nanoformulation techniques in nanoparticles to transport the target phytochemical compounds to increase therapeutic efficacy are needed in the future.
Endometriosis represents an estrogen-dependent disorder with a complex pathophysiology. Phytochemicals are promising candidates for endometriosis therapy, because they simultaneously target different cellular processes involved in the pathogenesis of endometriosis. Herein, we analyzed whether indole-3-carbinol (I3C) suppresses the development of endometriotic lesions, which were surgically induced by fixation of uterine tissue samples (diameter: 2 mm) from female BALB/c donor mice to the peritoneum of recipient animals. The mice received either I3C or vehicle (control) by peroral administration once per day. Growth, cyst formation, cell proliferation, microvascularization and protein expression of the lesions were assessed by high-resolution ultrasound imaging, caliper measurements, histology, immunohistochemistry and Western blotting. I3C inhibited the vascularization and growth of endometriotic lesions without inducing anti-angiogenic and anti-proliferative side effects on reproductive organs. This was associated with a significantly reduced number of proliferating stromal and endothelial cells and a lower expression of the pro-angiogenic signaling molecules vascular endothelial growth factor receptor-2 (VEGFR2), phosphoinositide 3-kinase (PI3K) and phosphorylated extracellular signal-regulated kinase (pERK) within I3C-treated lesions when compared to controls. These findings indicate that I3C effectively inhibits endometriotic lesion formation in mice. Thus, further studies should clarify whether I3C may be also beneficial for the prevention and therapy of the human disease.
Background: Diabetes is one of the most challenging health problems in 21st century. It is a group of endocrine-metabolic disorder characterized by high glucose level (hyperglycemia) due to insufficient insulin secretion/action or both. It causes multi-organ failure viz hepatorenal damage, adult-onset blindness, lower-limb amputations, heart diseases and stroke, high blood pressure and nerve damage. Moreover, diabetic patients are having higher risk of cardiovascular complications including atherosclerosis, hypertension, lipoprotein abnormalities and cerebrovascular disease.
Study design: Considering the potencies of currently available drugs for the treatment of diabetes and associated complications, present study was focussed to explore the role of plant bioactive components as alternative and easily accessible therapeutic remedies.
Hypothesis/Purpose: This study the pooled status of diabetes, available treatments, attitude and traditional herbal polyphenols regarding diabetes.
Results: This study was aimed to summarize the natural polyphenols having anti-diabetic, anti-inflammatory, anti-apoptotic and anti-cancerous activities. Polyphenols can decrease other metabolic diseases such as insulin resistance, hyperglycemia, hyperlipidemic, and obesity and Type-2 diabetes.
Conclusion: Polyphenols are promising alternatives that can decrease the severity of diabetes and promote the other protective roles by decreasing the adverse effects of diabetes on other metabolic organs and their functions.
Endometriosis is a chronic disorder characterized by the presence of endometrial glands and stroma outside the uterine cavity. It affects 8%-10% of women in their reproductive years, and represents a major clinical problem with deleterious social, sexual and reproductive consequences. Current treatment options include pain relief, hormonal intervention and surgical removal. However, these treatments are deemed unsatisfactory owing to varying success, significant side effects and high recurrence rates. Green tea and its major bioactive component, (-)-epigallocatechin gallate (EGCG), possess diverse biological properties, particularly anti-angiogenic, anti-proliferation, anti-metastasis, and apoptosis induction. In recent years, preclinical studies have proposed the use of green tea to inhibit the growth of endometriosis. Herein, the aim of this review is to summarize the potential therapeutic effects of green tea on molecular and cellular mechanism through inflammation, oxidative stress, invasion and adhesion, apoptosis and angiogenesis in endometriosis.
Research question
Does sodium tanshinone IIA sulfonate (STS) induce cellular senescence in endometriotic lesions and thus curtail lesional development and fibrogenesis in a recently established mouse model of deep endometriosis?
Design
A prospective randomized animal experimentation. Forty-eight female Balb/C mice were induced with deep endometriosis, and they were then randomly divided into 3 groups, low-dose STS, high-dose STS, and untreated, and received respective treatment for 2 weeks. Then all mice were sacrificed and their lesions were excised and harvested. Lesion weight was quantified, and all lesion samples were subjected to histochemistry analysis of the extent of lesional fibrosis by Masson trichrome staining and of cellular senescence by senescence-associated β-galactosidase (SA-β-gal), along with immunohistochemistry analyses of p53, CCN1, activate Salvador 1 (Sav1), hyaluronan synthase 2 (HAS2), Survivin, GM-CSF and CD163-positive M2 macrophages. Plasma P-selectin and hyaluronic acid (HA) levels were also quantified. Hotplate test was also administered before the induction, before and after the treatment.
Results
STS treatment resulted in significantly reduced lesion weight, stalled lesional fibrogenesis and improved hyperalgesia seemingly through the induction of cellular senescence by activating p53, Sav1 and CCN1 while suppressing HAS2, Survivin and GM-CSF, resulting in increased apoptosis and reduced lesional infiltration of alternatively activated macrophages. In addition, STS treatment significantly reduced the plasma concentration of P-selectin and HA, possibly leading to reduced lesional platelet aggregation.
Conclusions
STS appears to be a promising compound for treating endometriosis. Our results suggest that senescence may restrain lesional progression and fibrogenesis, and targeting the senescence pathway may have desirable therapeutic potential.
Metastasis of cells from primary site to distant organs involves a series of sequential steps, and molecules responsible for all these events are understandably considered as potential targets for metastasis management. Tea polyphenols, the secondary metabolites of the tea leaf Camellia sinensis, are increasingly being studied for their antimetastatic properties. In this article, effects of green tea polyphenols (GTP) and black tea polyphenols (BTP) on the molecules and events involved in metastasis are discussed in detail. As tea is a very popular beverage, tea polyphenols are expected to be potential chemopreventive agents that can be taken with normal diet and can be nontoxic due to their natural origin. However, individual variations in metabolic pathways, bioavailability, dose, and toxicity are some important factors that can modify the effectiveness of tea polyphenols within the human system.
Neovascularization causes serious oculopathy related to upregulation of vascular endothelial growth factor (VEGF) causing new capillary growth by endothelial cells. Green tea extract (GTE) constituents possess anti-angiogenesis properties. We used VEGF to induce human umbilical vein endothelial cells (HUVEC) and applied GTE, epigallocatechin gallate (EGCG), and different composition of purified catechins mixtures (M1 and M2) to evaluate the efficacy of inhibition and their underlying mechanisms using cell cycle analysis and untargeted metabolomics technique. GTE, EGCG, M1 and M2 induced HUVEC apoptosis by 22.1±2%, 20.0±0.7%, 50.7±8.5% and 69.8±4.1% respectively. GTE exerted a broad balanced metabolomics spectrum involving suppression of biosynthesis of cellular building blocks and oxidative phosphorylation metabolites but promoting biosynthesis of membrane lipids and growth factors. M2 mainly induced mechanisms associated with energy and biosynthesis suppression. Therefore, GTE exerted mechanisms involving both promotion and suppression activities, while purified catechins induced extensive apoptosis. GTE could be a more promising anti-neovascularization remedy for ocular treatment.
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.
Introduction:
Increasing evidence has expanded the role of green tea from a traditional beverage to a source of pharmacologically active molecules with diverse health benefits. However, conclusive clinical results are needed to better elucidate the cancer-preventive and therapeutic effects of green tea polyphenols (GTPs). Areas covered: The authors describe GTPs' chemical compositions and metabolic biotransformations, and their recent developments in drug discovery, focusing on their cancer chemopreventive and therapeutic effects. They then review the recent development of GTP-loaded nanoparticles and GTP prodrugs. Expert opinion: GTPs possess potent anticarcinogenic activities through interfering with the initiation, development and progression phases of cancer. There are several challenges (e.g. poor bioavailability) in developing GTPs as therapeutic agents. Use of nanoparticle-based delivery systems has provided unique advantages over purified GTPs. However, there is still a need to determine the actual magnitude and pharmacological mechanisms of GTPs encapsulated in nanoparticles, in order to address newly emerging safety issues associated with the potential 'local overdose' effect. The use of Pro- epigallocatechin gallate (Pro-EGCG) as a prodrug appears to offer improved in vitro stability as well as better in vivo bioavailability and efficacies in a number of animal studies, suggesting its potential as a therapeutic agent for further study and development.
The study was conducted to assess the phytochemical components and properties of herbal plant extracts, such as (a) sabungai (Gynura nepalensis DC), (b) pandan (Pandanus odoratissimus L.) and (c) tsaang-gubat (Carmona retusa (Vahl.) Masam.), as potential angiogenesis inhibitors using the Chick Chorioallantoic Membrane (CAM) assay. Phytochemical analysis showed that the three extracts were found to have alkaloids, tannins and flavonoids. Only pandan extract was assessed to contain anthraquinones and steroids. The treatments were individually compared to the positive control and negative control of the study. Statistical analysis showed significant difference on the mean number of branching points of eggs treated sabungai extract, pandan extract and tsaang-gubat as compared to negative control of the study. Sabungai extract was found significantly different to the positive control. On the other hand, no significant difference is seen in the mean number of the branching points of the eggs treated with pandan and tsaang-gubat extracts when individually compared to the positive control. Using the formula for CAM Vascularity that determines the inhibition properties of the extracts, it was found out that tsaang-gubat gained the highest inhibition of vascularity followed by pandan, then sabungai.
Study question:
Does the flavonoid naringenin inhibit proliferation of human endometriosis cells?
Summary answer:
Naringenin suppresses proliferation and increases apoptosis via depolarization of mitochondrial membrane potential and generation of reactive oxygen species (ROS) in human endometriosis cells.
What is known already:
For management of endometriosis, hormonal therapy is commonly used to decrease production of estrogens by the ovaries, but that has limitations including undesirable side effects with long-term therapies. To overcome these limitations, it is important to discover novel compounds which have no adverse effects, but inhibit expression of target molecules involved in the pathogenesis of endometriosis.
Study design size, duration:
Well-established endometriosis cell lines (VK2/E6E7 and End1/E6E7) were purchased from the American Type Culture Collection. Effects of naringenin on VK2/E6E7 and End1/E6E7 cells were assessed in diverse assays in a dose- and time-dependent manner.
Participants/materials, setting, methods:
Effects of naringenin on viability, apoptosis (Annexin V expression, propidium iodide staining, TUNEL and invasion assays), mitochondria-mediated apoptosis, production of ROS and endoplasmic reticulum (ER) stress proteins of VK2/E6E7 and End1/E6E7 cells were determined. Signal transduction pathways in VK2/E6E7 and End1/E6E7 cells in response to naringenin were determined by western blot analyses.
Main results and the role of chance:
In the present study, we demonstrated that naringenin suppressed proliferation and increased apoptosis through depolarization of mitochondrial membrane potential and inducing pro-apoptotic proteins, Bax and Bak, in both endometriosis cell lines. In addition, naringenin increased ROS, ER stress, through activation of eIF2α and IRE1α, GADD153 and GRP78 proteins in a dose-dependent manner. Furthermore, the induction of apoptosis by naringenin involved activation of MAPK and inactivation of PI3K pathways in VK2/E6E7 and End1/E6E7 cells.
Limitations reasons for caution:
Lack of in vivo animal studies is a major limitation of this research. Effectiveness of naringenin to induce apoptosis of human endometriosis cells requires further investigation.
Wider implications of the findings:
Our results suggest that naringenin is a promising therapeutic compound for treatment of endometriosis in women.
Study funding/competing interest(s):
This work was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI15C0810 awarded to G.S. and HI17C0929 awarded to W.L.). The authors declare that there are no conflicts of interest.
Infertility affects approximately 15 % of couples worldwide [1]. During normal cellular metabolism, reactive oxygen species (ROS) are generated on a continuous basis, either by endogenous sources (see Chap. 1) or exogenous sources (see Chap. 5). ROS are essential for many processes in the human body, including essential intracellular signaling pathways [2]. Notwithstanding, an elevation in ROS eventually leads to oxidative stress (OS), defined as the imbalance between oxidants and antioxidants [3]. Oxidative stress can result in subfertility by negatively affecting multiple processes in the male and female reproductive systems.
Angiogenesis is likely to be involved in the pathogenesis of endometriosis. According to the transplantation theory, when the exfoliated endometrium is attached to the peritoneal layer, the establishment of a new blood supply is essential for the survival of the endometrial implant and development of endometriosis. From the known angiogenic factors, vascular endothelial growth factor (VEGF) has emerged as a pivotally important regulator of normal angiogenesis and pathological neovascularization. The VEGF protein was evaluated immunohistochemically in the eutopic endometrium of 10 women without endometriosis (group I) at laparoscopy and the eutopic endometrium and peritoneal endometriotic lesions of 43 women with endometriosis (group II). VEGF histological scores were 9.7 +/- 4.3 and 4.0 +/- 2.6 respectively in the epithelium and stroma of the eutopic endometrium of group I women, and 10.3 +/- 2.3 and 3.6 +/- 2.3 respectively in women of group II. In red lesions, the VEGF scores were 11.1 +/- 3.0 in the epithelium and 5.1 +/- 3.0 in the stroma, and in black lesions were 8.6 +/- 2.7 and 1.6 +/- 1.6, respectively. Significantly lower values were observed in black lesions as compared with eutopic endometrium and red lesions, the values of which were similar. Scores were also evaluated according to the phase of the cycle. In eutopic as well as ectopic endometrium, no significant cyclic variations were observed throughout the cycle. However, VEGF content was found to be higher in the eutopic glandular epithelium of women with endometriosis during the late secretory phase, possibly suggesting a more likely tendency to implant. In contrast, significantly higher VEGF content was noted in red lesions as compared with black lesions. During all phases of the cycle, the VEGF content in stromal cells of red lesions was higher than in black lesions. Similarities in VEGF content were observed in the glandular epithelium of the eutopic endometrium of women with endometriosis and red lesions, suggesting that endometriosis probably arises from the peritoneal seeding of viable endometrial cells during retrograde menstruation and that red lesions can be considered as the first stage of implantation. After the attachment phase, the high VEGF levels could provoke an increase in the subperitoneal vascular network and facilitate implantation and viability in the retroperitoneal space. Lower VEGF levels in black lesions explain the decrease in both stromal vascularization, followed by fibrosis and inactivation of the implant.
(+)-Catechin and (-)-epicatechin are known to be biologically effective antioxidants present in the human diet, particularly in wine and tea. We studied the metabolism of these compounds to elucidate the truly active structures in biological fluids by their oral administration to rats. Without any treatment with beta-glucuronidase and sulfatase, a pair of metabolites were detected at much higher concentrations in the plasma, bile, and urine than the originally ingested compounds. Each major metabolite found in the plasma at the highest concentration was excreted in both the bile and urine, and was purified from urine. Their chemical structures were established to be (+)-catechin 5-O-beta-glucuronide and (-)-epicatechin 5-O-beta-glucuronide by MS and NMR analyses. These glucuronide conjugates exhibited high antioxidative activities as superoxide anion radical scavengers like their parent compounds. It is concluded that (+)-catechin 5-O-beta-glucuronide and (-)-epicatechin 5-O-beta-glucuronide are the biologically active in vivo structures of the ingested polyphenolic antioxidants.
The purpose of this study was to validate the suitability of the severe combined immunodeficient (SCID) mouse as an experimental
model for endometriosis, by defining the morphological and histological features of induced endometrial implants, and characterizing
specific biochemical properties of these implants. Human secretory endometrial tissues were injected into the peritoneal cavity
of SCID/SCID CB17 mature female mice. Successful peritoneal implantation was observed in 55 of 57 (96.5%) SCID mice and consisted
of circumscribed elevated nodules. Haematoxylin–eosin staining of implanting lesions demonstrated the presence of endometrial
glandular tissue in a mixed background of stromal and inflammatory cells. When progesterone was administered to mice, epithelial
glands underwent well-defined secretory changes. Immunohistochemical analysis using polyclonal human pan-cytokeratin antibodies
demonstrated selective positive staining in the glandular epithelium of the human implants with none in the surrounding stroma.
In-situ hybridization analysis using complement component 3 cDNA radiolabelled riboprobes yielded significantly more intense
signals in glands compared to stroma. As human endometrial implants in SCID mice were shown to retain specific histological,
functional and biochemical properties, we conclude that the SCID mouse is an attractive animal model for the study of endometriosis.
Catechins are key components of teas that have antiproliferative properties. We investigated the effects of green tea catechins on intracellular signalling and VEGF induction in vitro in serum-deprived HT29 human colon cancer cells and in vivo on the growth of HT29 cells in nude mice. In the in vitro studies, (-)-epigallocatechin gallate (EGCG), the most abundant catechin in green tea extract, inhibited Erk-1 and Erk-2 activation in a dose-dependent manner. However, other tea catechins such as (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epicatechin (EC) did not affect Erk-1 or 2 activation at a concentration of 30 microM. EGCG also inhibited the increase of VEGF expression and promoter activity induced by serum starvation. In the in vivo studies, athymic BALB/c nude mice were inoculated subcutaneously with HT29 cells and treated with daily intraperitoneal injections of EC (negative control) or EGCG at 1.5 mg day(-1)mouse(-1)starting 2 days after tumour cell inoculation. Treatment with EGCG inhibited tumour growth (58%), microvessel density (30%), and tumour cell proliferation (27%) and increased tumour cell apoptosis (1.9-fold) and endothelial cell apoptosis (3-fold) relative to the control condition (P< 0.05 for all comparisons). EGCG may exert at least part of its anticancer effect by inhibiting angiogenesis through blocking the induction of VEGF.
Epidemiological and animal studies have indicated that consumption of green tea and high vitamin E intake are associated with a reduced risk of developing certain forms of cancer. However, the inhibitory mechanism of green tea catechins and vitamin E in angiogenesis, an important process in tumor growth, has not been well established. In the present study, alpha-tocopherol and several major catechins of green tea (catechin, epicatechin, epicatechin gallate, epigallocatechin, and epigallocatechin gallate) were tested for their ability to inhibit tube formation in vitro using a model in which human microvascular endothelial cells were exposed to a constant rate of a physiologically low level of H2O2. In this model, the production of interleukin (IL)-8 by human microvascular endothelial cells at a low level of H2O2 was required for angiogenesis, as assessed by tube formation in three-dimensional gel in culture. Vitamin E (d-alpha-tocopherol, 40 microM) in the culture media significantly reduced IL-8 production and angiogenesis. Among the green tea catechins, epigallocatechin (0.5-1 microM) was the most effective in reducing IL-8 production and inhibiting angiogenesis. These results suggest that consumption of green tea catechins or supplemental intake of vitamin E may have preventive effects on tumor development, mediated, at least in part, through inhibition of angiogenesis via suppression of IL-8 production.
Investigators have shown that green tea and its main catechin epigallocatechin-3 gallate (EGCG) may decrease the risk of cancer. Our previous study showed that green tea extract (GTE) as well as its individual catechin components inhibited MDA-MB231 breast cancer cell and human umbilical vein endothelial cell (HUVEC) proliferation. Further, GTE suppressed breast cancer xenograft size and decreased the tumor vessel density in vivo. In the current study, we investigated the effect of GTE on the major angiogenic factor vascular endothelial growth factor (VEGF) in an in vitro experiment. GTE or EGCG (40 mg/L) significantly decreased the levels of the VEGF peptide secreted into conditioned media. This occurred in both HUVEC and human breast cancer cells and the effect was dose dependent. Furthermore, GTE and EGCG decreased the RNA levels of VEGF in MDA-MB231 cells. This inhibition occurred at the transcriptional regulation level and was accompanied by a significant decrease in VEGF promoter activity. We also showed that GTE decreased c-fos and c-jun RNA transcripts, suggesting that activator protein (AP)-1-responsive regions present in the human VEGF promoter may be involved in the inhibitory effect of GTE. Furthermore, GTE suppressed the expression of protein kinase C, another VEGF transcription modulator, in breast cancer cells. Inhibition of VEGF transcription appeared to be one of the molecular mechanism(s) involved in the antiangiogenic effects of green tea, which may contribute to its potential use for breast cancer treatment and/or prevention.
It is known that angiogenesis is of pivotal importance for the development of endometriosis. However, in the treatment of endometriosis patients, prevention of endometriosis lesion development only will not be sufficient as a therapy. Treatment options, aimed at interfering with established lesions, have to be developed. In this study we evaluated whether inhibition of angiogenesis by angiostatic therapy is also effective in antagonizing the sustentation of endometriosis. We evaluated the effect of the angiostatic compounds antihuman vascular endothelial growth factor, TNP-470, endostatin, and anginex on the growth of established endometriosis lesions in the nude mouse model. We show that human endometrium in the proliferative endometrium is highly angiogenic and that vascular endothelial growth factor-A is the most important angiogenesis promotory factor. The angiostatic compounds significantly decreased microvessel densities and the number of established endometriosis lesions. In the remaining lesions, the number of pericyte-protected vessels is not different in control and treated mice; however, the number of unprotected vessels was significantly reduced in the groups treated with the angiostatic agents. Our data demonstrate that inhibitors of angiogenesis effectively interfere with the maintenance and growth of endometriosis by inhibiting angiogenesis. This suggests that the use of angiostatic agents may be promising as a therapy for endometriosis.
Green tea consumption has been linked to a reduced occurrence of some tumor types. Current data indicate that the principal mediator of this chemopreventive effect is epigallocatechin-3-gallate (EGCG), the most abundant polyphenol found in dried tea leaves. Here, we examined the effects of this compound on the two key cell populations typically involved in tumor growth: tumor cells and endothelial cells.
The effects of green tea and EGCG were tested in a highly vascular Kaposi's sarcoma (KS) tumor model and on endothelial cells in a panel of in vivo and in vitro assays.
EGCG inhibited KS-IMM cell growth and endothelial cell growth, chemotaxis, and invasion over a range of doses; high concentrations also induced tumor cell apoptosis. EGCG inhibited the metalloprotease-mediated gelatinolytic activity produced by endothelial cell supernatants and the formation of new capillary-like structures in vitro. Green tea or purified EGCG when administered to mice in the drinking water inhibited angiogenesis in vivo in the Matrigel sponge model and restrained KS tumor growth. Histological analysis of the tumors were consistent with an anti-angiogenic activity of EGCG and green tea.
These data suggest that the green tea gallate or its derivatives may find use in the prevention and treatment of vascular tumors in a chemoprevention or adjuvant setting.
We earlier demonstrated that oral infusion of green tea polyphenols inhibits development and progression of prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Evidence indicates that elevated levels of IGF-I with concomitant lowering of IGF binding protein (IGFBP)-3 are associated with increased risk for prostate cancer development and progression. In this study, we examined the role of IGF/IGFBP-3 signaling and its downstream and other associated events during chemoprevention of prostate cancer by green tea polyphenols in TRAMP mice. Our data demonstrated an increase in the levels of IGF-I, phosphatidylinositol 3'-kinase, phosphorylated Akt (Thr-308), and extracellular signal-regulated kinase 1/2 with concomitant decrease in IGFBP-3 in dorso-lateral prostate of TRAMP mice during the course of cancer progression, i.e., as a function of age. Continuous green tea polyphenol infusion for 24 weeks to these mice resulted in substantial reduction in the levels of IGF-I and significant increase in the levels of IGFBP-3 in the dorso-lateral prostate. This modulation of IGF/IGFBP-3 was found to be associated with an inhibition of protein expression of phosphatidylinositol 3'-kinase, phosphorylated forms of Akt (Thr-308) and extracellular signal-regulated kinase 1/2. Furthermore, green tea polyphenol infusion resulted in marked inhibition of markers of angiogenesis and metastasis most notably vascular endothelial growth factor, urokinase plasminogen activator, and matrix metalloproteinases 2 and 9. Based on our data, we suggest that IGF-I/IGFBP-3 signaling pathway is a prime pathway for green tea polyphenol-mediated inhibition of prostate cancer that limits the progression of cancer through inhibition of angiogenesis and metastasis.
Vascular endothelial growth factor (VEGF), a major mediator of angiogenesis and vascular permeability, is known to play a key role in the pathophysiology of endometriosis.
The single nucleotide polymorphisms, -460C>T and +405G>C, in the 5'-untranslated region of the VEGF gene were tested for association in a case-control study of 215 affected women and 210 women with no evidence of disease. All the women were of South Indian origin and ascertained from the same infertility clinic. The genotype and allele frequencies of the -460C>T polymorphism did not differ significantly between cases and controls. In contrast, the genotype (P = 0.002) and allele (P = 0.001) frequencies of the +405G>C polymorphism showed a significant difference between cases and controls. The +405 GG genotype was found more often in patients with an endometrioma >3 cm compared to controls. The frequency of the -460T/+405C haplotype (P = 0.016) was significantly lower in affected women compared to controls.
The -460T/+405C haplotype in the VEGF gene, which is associated with lower promoter activity, was significantly less common in women with endometriosis than in controls. These data suggest that the +405G allele may influence the likelihood of a woman developing the disease.
Vascular endothelial growth factor (VEGF) is known to play a pivotal role in the development of endometriosis. This study was performed to investigate whether the VEGF gene 5'-untranslated region polymorphism is associated with susceptibility to advanced stage endometriosis.
This study comprised 215 women with advanced stage endometriosis, 219 control women without endometriosis, and 70 fertile women. Following extraction of genomic DNA, genotyping of the -460 C/T and +405 C/G polymorphisms of the VEGF gene were performed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis.
The distribution of genotypes and allele frequencies of the -460 C/T polymorphism in the endometriosis group did not differ from those in the control group and the fertile women group. However, genotype distribution of the +405 C/G polymorphism was significantly different between patients with and without endometriosis (P = 0.01) and between patients with endometriosis and the fertile women (P = 0.02). Patients with endometriosis showed a higher incidence of the +405 CC genotype compared with the controls and the fertile women (P = 0.007 and 0.016 respectively).
These findings suggest that the VEGF +405 C/G polymorphism may be associated with the risk of advanced stage endometriosis in the Korean population.
Controlled degradation of the extracellular matrix (ECM) is crucial for the growth, invasive capacity, metastasis and angiogenesis of tumours. Matrix metalloproteinases (MMPs), a family of zinc-dependent neutral endopeptidases that are collectively capable of degrading essentially all ECM components, apparently play an important role in all of these aspects of tumour development. In addition, there is recent evidence that MMPs are also important for tumour cell survival. At present, therapeutic intervention on tumour growth and invasion based on the inhibition of MMP activity is under intensive investigation, and several MMP inhibitors are already being used on malignant tumours of various organs in clinical trials. In this review we discuss the role of MMPs and their inhibitors in tumour invasion as a basis for prognostic purposes and for targeted therapeutic intervention in cancer.
Keywords:chemoprotection;antimutagenesis;green tea;antioxidant catechins
Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic-helix-loop-helix-PAS transcription factor consisting of HIF-1 alpha and HIF-1 beta subunits. HIF-1 alpha expression and HIF-1 transcriptional activity increase exponentially as cellular O2 concentration is decreased. Several dozen target genes that are transactivated by HIF-1 have been identified, including those encoding erythropoietin, glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. The products of these genes either increase O2 delivery or allow metabolic adaptation to reduced O2 availability. HIF-1 is required for cardiac and vascular development and embryonic survival. In fetal and postnatal life, HIF-1 is required for a variety of physiological responses to chronic hypoxia. HIF-1 expression is increased in tumor cells by multiple mechanisms and may mediate adaptation to hypoxia that is critical for tumor progression. HIF-1 thus appears to function as a master regulator of O2 homeostasis that plays essential roles in cellular and systemic physiology, development, and pathophysiology.
Following malignant transformation, tumor cells and their surrounding stroma produce a variety of growth factors and proteolytic enzymes to induce new capillary formation (angiogenesis) and matrix degradation to promote tumor development. Two key families of proteases, matrix metalloproteases (MMPs) and urokinase (uPA) are now strongly implicated in this process of angiogenesis and matrix degradation. Both MMPs and uPA are abundantly produced by various tumors where their level of expression can serve as prognostic markers. Using gene transfer techniques, overexpression of these proteases and their receptors enhances the invasive and metastatic potential of tumor cells. Furthermore, blockage of actions of MMPs and uPA by molecular and chemical approaches results in a marked decrease in tumor growth to further validate the significance of these enzymes as targets for anti-cancer therapy.
Metazoan organisms are dependent on a continuous supply of O(2) for survival. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in development, physiology, and disease. HIF-1 activity is induced in response to continuous hypoxia, intermittent hypoxia, growth factor stimulation, and Ca(2+) signaling. HIF-1 mediates adaptive responses to hypoxia, including erythropoiesis, angiogenesis, and metabolic reprogramming. In each case, HIF-1 regulates the expression of multiple genes encoding key components of the response pathway. HIF-1 also mediates maladaptive responses to chronic continuous and intermittent hypoxia, which underlie the development of pulmonary and systemic hypertension, respectively.
Angiogenesis depends on the adhesive interactions of vascular cells. The adhesion receptor integrin alpha v beta 3 was identified
as a marker of angiogenic vascular tissue. Integrin alpha v beta 3 was expressed on blood vessels in human wound granulation
tissue but not in normal skin, and it showed a fourfold increase in expression during angiogenesis on the chick chorioallantoic
membrane. In the latter assay, a monoclonal antibody to alpha v beta 3 blocked angiogenesis induced by basic fibroblast growth
factor, tumor necrosis factor-alpha, and human melanoma fragments but had no effect on preexisting vessels. These findings
suggest that alpha v beta 3 may be a useful therapeutic target for diseases characterized by neovascularization.
Because of its special aroma, green tea is a popular beverage consumed by some human populations worldwide. In recent years, many laboratory studies have shown that in a variety of animal tumor bioassay systems the administration of green tea, specifically the polyphenolic fraction isolated from green tea leaves (green tea polyphenols), affords protection against cancer induction. In mouse skin tumor bioassay systems, topical application of green tea polyphenols to skin has been shown to result in protection against a) 3-methylcholanthrene-induced skin tumorigenicity, b) 7,12-dimethylbenz(a)anthracene (DMBA)-induced skin tumor initiation, c) 12-O-tetradecanoylphorbol-13-acetate and other tumor promoters caused tumor promotion in DMBA-initiated skin, and d) benzoyl peroxide- and 4-nitroquinoline N-oxide caused enhanced malignant progression of nonmalignant lesions. Green tea extract has also been shown to cause partial regression of established skin papillomas in mouse. Similarly, chronic oral feeding of green tea polyphenols or water extract of green tea has also been shown to result in the protection against both chemical carcinogen- and ultraviolet B radiation-induced skin tumorigenicity. Collectively these data suggest that green tea possesses significant chemopreventive effect against each stage of carcinogenesis, and that it may be useful against inflammatory responses associated with the exposure of skin to chemical tumor promoters as well as to solar radiation. Available data regarding the mechanism by which green tea affords these diversified effects is discussed.
To establish an experimental system useful for long-term evaluation of human endometrial tissue by its heterotransplantation to SCID mice.
Human endometrium was transplanted subcutaneously into SCID mice, nude mice, or nude mice given anti-asialo GM1 antibody, a natural killer activity suppressor. The transplant was observed by ultrasonography for up to 10 weeks and then morphologically. To assess the drug susceptibility of the transplant, danazol (10-100 mg/kg/day orally), buserelin (0.01 mg/kg/day subcutaneously), or estradiol (0.5 mg/kg/day intraperitoneally) was administered to the host mice for up to 10 weeks after the transplantation. Multiple-comparison procedures were used for statistical evaluation.
The heterotransplant was accepted 100% in SCID mice and natural killer activity-suppressed nude mice, but was significantly inferior (40%) in nude mice at 10 weeks after the transplantation. The transplant size was volumetrically measurable noninvasively by ultrasonography. Using this SCID mouse model, we could evaluate drug effects on the transplanted endometrium.
This system in SCID mice may be useful for evaluating drug actions on human endometrium and endometriotic tissues.
To evaluate the stromal vascularization of different appearances of peritoneal endometriosis, biopsies were taken from peritoneal areas with endometriosis in a series of 135 infertile women and classified as typical (black), red, or white lesions. The number of capillaries per mm2 of stroma, their mean surface area, and the ratio of capillaries/stroma surface area, and the mitotic activity were analyzed in typical, red, and white lesions. Significant differences were found between the different subgroups. The higher vascularization and mitotic activity observed in red lesions suggested the hypothesis that such lesions are very active and probably the first stage of early implantation of endometrial glands and stroma. The poor vascularization and the absence of mitosis observed in white lesions suggested that these lesions are much less active than red lesions and are a quiescent stage of the disease. Our study proves that the "activity" of peritoneal endometriosis is related to the vascularity. This concept must be considered in the further discussion of American Fertility Society Endometriosis Classification. Typical, red and white lesions are three different stages of the peritoneal disease and their relative relation to infertility is also probably different.
This article summarizes available data on the chemopreventive efficacies of tea polyphenols, curcumin and ellagic acid in various model systems. Emphasis is placed upon the anticarcinogenic activity of these polyphenols and their proposed mechanism(s) of action.
Tea is grown in about 30 countries and, next to water, is the most widely consumed beverage in the world. Tea is manufactured as either green, black, or oolong; black tea represents approximately 80% of tea products. Epidemiological studies, though inconclusive, suggest a protective effect of tea consumption on human cancer. Experimental studies of the antimutagenic and anticarcinogenic effects of tea have been conducted principally with green tea polyphenols (GTPs). GTPs exhibit antimutagenic activity in vitro, and they inhibit carcinogen-induced skin, lung, forestomach, esophagus, duodenum and colon tumors in rodents. In addition, GTPs inhibit TPA-induced skin tumor promotion in mice. Although several GTPs possess anticarcinogenic activity, the most active is (–)-epigallocatechin-3-gallate (EGCG), the major constituent in the GTP fraction. Several mechanisms appear to be responsible for the tumor-inhibitory properties of GTPs, including enhancement of antioxidant (glutathione peroxidase, catalase and quinone reductase) and phase II (glutathione-S-transferase) enzyme activities; inhibition of chemically induced lipid peroxidation; inhibition of irradiation-and TPA-induced epidermal ornithine decarboxylase (ODC) and cyclooxygenase activities; inhibition of protein kinase C and cellular proliferation; antiinflammatory activity; and enhancement of gap junction intercellular communication.
Curcumin is the yellow coloring agent in the spice turmeric. It exhibits antimutagenic activity in the Ames Salmonella test and has anticarcinogenic activity, inhibiting chemically induced preneoplastic lesions in the breast and colon and neoplastic lesions in the skin, forestomach, duodenum and colon of rodents. In addition, curcumin inhibits TPA-induced skin tumor promotion in mice. The mechanisms for the anticarcinogenic effects of curcumin are similar to those of the GTPs. Curcumin enhances glutathione content and glutathione-S-transferase activity in liver; and it inhibits lipid peroxidation and arachidonic acid metabolism in mouse skin, protein kinase C activity in TPA-treated NIH 3T3 cells, chemically induced ODC and tyrosine protein kinase activities in rat colon, and 8-hydroxyguanosine formation in mouse fibroblasts.
Ellagic acid is a polyphenol found abundantly in various fruits, nuts and vegetables. Ellagic acid is active in antimutagenesis assays, and has been shown to inhibit chemically induced cancer in the lung, liver, skin and esophagus of rodents, and TPA-induced tumor promotion in mouse skin. Ellagic acid functions through a variety of mechanisms, including inhibition of microsomal P-450 enzymes, stimulation of glutathione-S-transferase, scavenging the reactive metabolites of carcinogens, and direct binding to DNA, thus potentially masking sites that would normally interact with ultimate carcinogens.
GTP, curcumin and ellagic acid exhibit potent antioxidant effects. This property, coupled with their other effects, make them effective chemopreventives against both the initiation and promotion/progression stages of carcinogenesis.
The human endometrium undergoes a complex process of vascular and glandular proliferation, differentiation, and regeneration with each menstrual cycle in preparation for implantation. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific angiogenic protein that appears to play an important role in both physiological and pathological neovascularization. To investigate whether VEGF may regulate human endometrial angiogenesis, we examined VEGF messenger ribonucleic acid (mRNA) and protein throughout the menstrual cycle and studied the regulation of VEGF by reproductive steroids in isolated human endometrial cells. By ribonuclease protection analysis, VEGF mRNA increased relative to early proliferative phase expression by 1.6-,2.0-, and 3.6-fold in midproliferative, late proliferative, and secretory endometrium, respectively. In histological sections, VEGF mRNA and protein were localized focally in glandular epithelial cells and more diffusely in surrounding stroma, with greatest VEGF expression in s