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      Abnormal expression of Nrf2 may play an important role in the pathogenesis and development of adenomyosis

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          Abstract

          Objective

          To explore the expression level of Nrf2 in adenomyosis and study the mechanism of abnormal expression of Nrf2 in the pathogenesis of adenomyosis.

          Methods

          Western blot, immunohistochemistry(IHC) and real time PCR were used to measure Nrf2 expression levels in tissue and cell samples. Knockdown and overexpression of Nrf2 were used to investigate the variation of migration ability of endometrial glandular cells as well as the regulatory mechanism.

          Results

          Nrf2 protein levels were significantly higher in the eutopic and ectopic endometrial glands when compared with control cases using IHC and western blot methods. (p< 0.05). However, there was no statistical difference in Nrf2 mRNA expression levels between the adenomyosis and control groups. Using an agonist and Nrf2 siRNA, we regulated the Nrf2 protein levels of primary cultured endometrial glandular cells. With increased expression of Nrf2, cell scratch assay showed that the agonist-treated group migrated significantly faster than the control group, with MMP9 protein level markedly elevated. In contrast, Nrf2 siRNA-treated group migrated slower than the control group, with decreased expression of MMP9 protein. All of the scratching healing spaces and protein levels between the treated and control groups were statistically significant ( p< 0.05).

          Conclusions

          Abnormal expression of Nrf2 may play an important role in the pathogenesis and development of adenomyosis. Specified reduction of Nrf2 expression could prove to be a new therapeutic target in the clinical treatment of adenomyosis.

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          Most cited references17

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          High levels of Nrf2 determine chemoresistance in type II endometrial cancer.

          Type II endometrial cancer, which mainly presents as serous and clear cell types, has proved to be the most malignant and recurrent carcinoma among various female genital malignancies. The transcription factor Nrf2 was first described as having chemopreventive activity. Activation of the Nrf2-mediated cellular defense response protects cells against the toxic and carcinogenic effects of environmental insults by upregulating an array of genes that detoxify reactive oxygen species and restore cellular redox homeostasis. However, the cancer-promoting role of Nrf2 has recently been revealed. Nrf2 is constitutively upregulated in several types of human cancer tissues and cancer cell lines. Furthermore, inhibition of Nrf2 expression sensitizes cancer cells to chemotherapeutic drugs. In this study, the constitutive level of Nrf2 was compared in different types of human endometrial tumors. It was found that Nrf2 was highly expressed in endometrial serous carcinoma (ESC), whereas complex hyperplasia and endometrial endometrioid carcinoma (EEC) had no or marginal expression of Nrf2. Likewise, the ESC-derived SPEC-2 cell line had a higher level of Nrf2 expression and was more resistant to the toxic effects of cisplatin and paclitaxel than the Ishikawa cell line, which was generated from EEC. Silencing of Nrf2 rendered SPEC-2 cells more susceptible to chemotherapeutic drugs, whereas it had a limited effect on Ishikawa cells. Inhibition of Nrf2 expression by overexpressing Keap1 sensitized SPEC-2 cells or SPEC-2-derived xenografts to chemotherapeutic treatments using both cell culture and severe combined immunodeficient mouse models. Collectively, we provide a molecular basis for the use of Nrf2 inhibitors to increase the efficacy of chemotherapeutic drugs and to combat chemoresistance, the biggest obstacle in chemotherapy. Copyright 2010 AACR.
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            Multifaceted role of matrix metalloproteinases (MMPs)

            Matrix metalloproteinases (MMPs), a large family of calcium-dependent zinc-containing endopeptidases, are involved in the tissue remodeling and degradation of the extracellular matrix. MMPs are widely distributed in the brain and regulate various processes including microglial activation, inflammation, dopaminergic apoptosis, blood-brain barrier disruption, and modulation of α-synuclein pathology. High expression of MMPs is well documented in various neurological disorders including Parkinson's disease (PD), Alzheimer's disease (AD), Japanese encephalitis (JE), and Glaucoma. Although potentially critical, the role of MMPs in neuronal disorders is under-investigated. The present review summarizes the role of MMPs in neurodegeneration with a particular emphasis on PD, AD, JE, and Glaucoma.
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              Adenomyosis: A Clinical Review of a Challenging Gynecologic Condition.

              Adenomyosis is a heterogenous gynecologic condition. Patients with adenomyosis can have a range of clinical presentations. The most common presentation of adenomyosis is heavy menstrual bleeding and dysmenorrhea; however, patients can also be asymptomatic. Currently, there are no standard diagnostic imaging criteria, and choosing the optimal treatment for patients is challenging. Women with adenomyosis often have other associated gynecologic conditions such as endometriosis or leiomyomas, therefore making the diagnosis and evaluating response to treatment challenging. The objective of this review was to highlight current clinical information regarding the epidemiology, risk factors, pathogenesis, clinical manifestations, diagnosis, imaging findings, and treatment of adenomyosis. Several studies support the theory that adenomyosis results from invasion of the endometrium into the myometrium, causing alterations in the junctional zone. These changes are commonly seen on imaging studies such as transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI). The second most common theory is that adenomyosis results from embryologic-misplaced pluripotent mullerian remnants. Traditionally, adenomyosis was only diagnosed after hysterectomy; however, studies have shown that a diagnosis can be made with biopsies at hysteroscopy and laparoscopy. Noninvasive imaging can be used to help guide the differential diagnosis. The most common findings on 2-dimensional/3-dimensional TVUS and MRI are reviewed. Two-dimensional TVUS and MRI have a respectable sensitivity and specificity; however, recent studies indicate that 3-dimensional TVUS is superior to 2-dimensional TVUS for the diagnosis of adenomyosis and may allow for the diagnosis of early-stage disease. Management options for adenomyosis, both medical and surgical, are reviewed. Currently, the only definitive management option for patients is hysterectomy.
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                Author and article information

                Contributors
                Role: Formal analysisRole: Funding acquisitionRole: MethodologyRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: Writing – original draft
                Role: InvestigationRole: ResourcesRole: Software
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Validation
                Role: InvestigationRole: ResourcesRole: Visualization
                Role: Funding acquisitionRole: Project administrationRole: SupervisionRole: Validation
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                17 August 2017
                2017
                : 12
                : 8
                : e0182773
                Affiliations
                [1 ] Department of Gynecology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
                [2 ] School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
                West China Second Hospital, Sichuan University, CHINA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-17-03560
                10.1371/journal.pone.0182773
                5560740
                28817677
                aa1ab807-0421-47aa-8f85-904515aec0d8
                © 2017 Chen et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 February 2017
                : 24 July 2017
                Page count
                Figures: 4, Tables: 1, Pages: 10
                Funding
                This study was supported by grants from the Zhejiang Provincial Natural Science Foundation (NO. LY16H040006), National Natural Science Foundation of China (NO.81302247), and Science Foundation of Education Department of Zhejiang Province(NO.Y201328871). The content is solely the responsibility of the authors and does not necessarily represent the official views of the grant-awarding bodies.
                Categories
                Research Article
                Biology and life sciences
                Genetics
                Gene expression
                Gene regulation
                Small interfering RNAs
                Biology and life sciences
                Biochemistry
                Nucleic acids
                RNA
                Non-coding RNA
                Small interfering RNAs
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogenesis
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and Life Sciences
                Anatomy
                Reproductive System
                Uterus
                Endometrium
                Medicine and Health Sciences
                Anatomy
                Reproductive System
                Uterus
                Endometrium
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Protein Expression
                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Protein Expression
                Biology and Life Sciences
                Anatomy
                Reproductive System
                Uterus
                Myometrium
                Medicine and Health Sciences
                Anatomy
                Reproductive System
                Uterus
                Myometrium
                Biology and Life Sciences
                Cell Biology
                Cell Motility
                Cell Migration
                Biology and Life Sciences
                Developmental Biology
                Cell Migration
                Research and Analysis Methods
                Histochemistry and Cytochemistry Techniques
                Immunohistochemistry Techniques
                Research and Analysis Methods
                Immunologic Techniques
                Immunohistochemistry Techniques
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                All relevant data are within the paper and its Supporting Information files.

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