Hormonal regulation of endometriosis and clinical significance

Worldwide almost 10% of reproductive-aged women are affected by endometriosis and suffer from dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility. Endometriosis is a gynecological condition in which endometrial cells are deposited outside the uterine cavity and eventually develop into functional endometrial glands and stroma. It is an estrogen-dependent disease and is critically modulated by other hormones of the reproductive system. Estrogen promotes the cell survival and pro-inflammatory roles for both endometrial epithelial and stromal cells. Overexpression of ER-β promotes invasion of endometriotic lesions as well as epithelial-mesenchymal transition. Moreover, estrogen stimulates the production of prostaglandin E2 (PGE2), which supports angiogenesis in the ectopic lesions. Progesterone counteracts estrogen and inhibits the growth of the endometrial glandular cells. Progesterone resistant endometrial cells confer apoptotic-resistance and aggravate disease condition. Oxytocin stimulates the contraction of uterine muscles by upregulating PGF2α secretion via calcium-mediated pathways leading to dysmenorrhea in endometriosis. On the contrary, gonadotropin and its receptor produce amenorrhea by inducing mitochondrial apoptosis and reducing angiogenesis. Scientists are now exploring these hormone-dependent pathologies of endometriosis to develop anti-endometriotic drugs, which mostly include androgen-based drugs and/or potential estrogen inhibitors. This review highlights the role of some important hormones e.g. estrogen, progesterone, prostaglandin, oxytocin, gonadotropin and melatonin in endometriosis progression and their pharmaceutical potentials.

Importance of Neem Leaf: An insight into its role in combating diseases.

The neem (Azadirachta indica A. Juss) is a tropical evergreen tree (Fam. Meliacae; Subfam. Melioideae) traditionally well known for its medicinal value. Beneficialt effects of different parts of neem are attributed to its biologically active principle ‘Azadirachtin’. Apart from Indian subcontinent, neem is widely used in African countries as therapeutics, preservatives and insecticides. Neem leaves, natural source of flavonoids, polyphenols, isoprenoids, sulphurous and polysaccharides, play important role in scavenging the free radical and subsequently arresting disease pathogenesis. Considerable research has gone into neem for developing cost effective and non-toxic products. The present review has compiled different phytochemicals isolated from neem leaves, methods of extraction and their therapeutic use in preventing several diseases. Here, we highlighted the mechanism of anti-inflammatory and antioxidant activity of neem leaf that underscores the disease through regulation of physiological responses. Also, multiple roles of neem leaf and commercial use of neem formulation as an alternative in paving a frontier in the field of drug discovery are discussed.

Inflammation and MMPs in alcohol-induced liver diseases and protective action of antioxidants.

The consumption of alcohol causes several liver-associated diseases all over the world. Alcoholic liver diseases (ALD) include hepatic inflammation, fatty liver, hepatitis, liver cirrhosis and fibrosis and finally hepatocellular carcinoma. Although the cellular, metabolic and biochemical mechanisms for these diseases are quite explicable, the roles of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) are still under investigation. The present review describes the roles and regulation of MMPs and TIMPs in different ALDs along with the involvement of other pathways. This review also summarizes the present knowledge on clinical and experimental trials with different antioxidants that help against alcohol associated liver diseases.

Curcumin delays endometriosis development by inhibiting MMP-2 activity.

Endometriosis is a common reproductive disorder believed to be associated with matrix metalloproteinases (MMPs) activities for invasion and remodeling of endometrial tissues. Ectopic endometrium has higher capacity to produce proMMP-2 than eutopic tissues; however, the role of MMP-2 during early phase of endometriosis development is still unclear. In the present study, we investigated the role of MMP-2 in establishment and development of endometriosis in mouse model. The effect of curcumin on regression of endometriosis through protease/antiprotease balance between MMP-2 and TIMP-2 was also examined. After endometrial inoculation into peritoneum, we observed a significant elevation of proMMP-2 activity from day 2 onwards. This increased MMP-2 activity was associated with decreased expression of tissue inhibitor of MMP (TIMP)-2, while a significant up-regulation of active MMP-2 activity was observed from day 3 onwards. The activation of proMMP-2 to active MMP-2 was associated with increased expression of membrane type 1 matrix metalloproteinase (MT1MMP). Curcumin at a dose of 48 mg/kg b.w. repressed the MMP-2 activity via up-regulation of bound TIMP-2 expression, thus delayed endometriosis development. In addition, curcumin inhibited production of active MMP-2 by down-regulating MT1MMP expression. Moreover, endometriotic progression was directly linked with increased MMP-2/TIMP-2 ratio which was delayed by curcumin pretreatment. In summary, our study documents the regulation of MMP-2 activity by TIMP-2 during the early phase of endometriosis development and inhibitory action of curcumin thereon.

Curcumin arrests endometriosis by downregulation of matrix metalloproteinase-9 activity.

Curcumin, a polyphenol derived from turmeric (Curcuma longa) possesses diverse pharmacological properties including antioxidant, anti-inflammatory and antiproliferative activities. Endometriosis is a gyneocological disorder characterized by growth of endometrial tissues outside uterus that involves aberrant matrix remodeling. In this study the effect of curcumin was studied on surgically developed endometriosis in mice. Endometriosis with varying severity was developed in mice by peritoneal implantation of uterine fragments. The changes in matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloprotease (TIMP)-1 were investigated in endometriotic tissues following curcumin pre- and posttreatment. Results showed that MMP-9 activity increased gradually in endometriotic tissues with severity and curcumin treatment reversed the MMP-9 activity near to control value. Curcumin administered either post- or pre-endometriosis arrested endometriosis in a dose-dependent manner. It inhibited both MMP-9 activity and its expression at the level of secretion, during regression of endometriotic lesion. In addition, the attenuated activity of MMP-9 was associated with decreased expression of tumor necrosis factor-alpha (TNF-alpha) during healing, suggesting the anti-inflammatory property of curcumin. Moreover, curcumin pretreatment prevented lipid peroxidation and protein oxidation in endometriotic tissues. We reported here for the first time the anti-endometriotic property of curcumin via MMP-9 dependent pathway that may lead to new therapeutic intervention.