Abstract
Endometriosis is defined as endometrial tissues found outside the uterine cavity. ProEGCG is a prodrug of Epigallocatechin gallate (EGCG), a potent polyphenol found in green tea. It inhibits the development of endometriotic lesions of mouse model in vivo, with higher efficacy and more remarkable anti-oxidative ability than EGCG. Our study aims to identify the molecular binding targets and pharmacological actions of ProEGCG in treating endometriosis. Protein target interaction study is essential to fully characterize the mechanism of actions, related therapeutic effects, and side effects. We employed a combined approach, starting with an in silico reverse screening of protein targets and molecular docking, followed by in vitro cellular thermal shift assay (CESTA) to assess the stability of protein-small molecule complexes. Then microarray and immunostaining of endometriotic lesions in mice in vivo confirmed the molecular interaction of the selected targets after treatment. Our study identified enzymes nicotinamide nucleotide adenylyltransferase (NMNAT)1 and NMNAT3 as protein targets of ProEGCG in silico and in vitro and were overexpressed after ProEGCG treatment in vivo. These findings suggested that participation in nicotinate and nicotinamide metabolism potentially regulated the redox status of endometriosis via its antioxidative capacities through binding to the potential therapeutic targets of ProEGCG.
Highlights
IntroductionIt is a benign condition defined as endometrial tissues found outside the uterine cavity, usually in ovaries or fallopian tubes (Burney and Giudice, 2012; Zondervan et al, 2020)
Prodrug of EGCG (ProEGCG) differentially participated in RNA polymerase II transcription factor activity and regulation of gene expression, angiogenesis, responses to hypoxia, and steroid hormone-mediated signaling pathway; and was involved in renin-angiotensin system, as well as a range of metabolic pathways that included: pyruvate metabolism, nicotinate and nicotinamide metabolism, drug metabolism in cytochrome P450, arginine and proline metabolism; and glutathione and arachidonic acid metabolism
Bioavailability, oxygen radical absorbance capacity in plasma, and apoptosis in endometriotic lesions were significantly higher in ProEGCG, while level of VEGF concentration in plasma was significantly lower after ProEGCG treatment parameters were compared with control and Epigallocatechin gallate (EGCG) groups (Wang et al, 2013)
Summary
It is a benign condition defined as endometrial tissues found outside the uterine cavity, usually in ovaries or fallopian tubes (Burney and Giudice, 2012; Zondervan et al, 2020). Etiology of endometriosis includes Sampson’s theory of retrograde menstruation, which describes the dissemination of endometrium into the peritoneal cavity through fallopian tubes during menstruation (Sampson, 1927). Endometriosis is a progressive disease of oxidative stress and chronic inflammation (Gordts et al, 2017). The choice of current treatment for endometriosis depends on patients’ medical history, fertility plan and severity of symptoms. Ideal new treatment and novel drug discovery are needed to help women alleviate the symptoms and cure the disease. In preclinical research of a new drug, it is imperative to understand the mechanism of the drugs’ actions
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