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Bushi A, Ma Y, Adu-Amankwaah J, Wang R, Cui F, Xiao R, Zhao J, Yuan J, Tan R. G protein-coupled estrogen receptor biased signaling in health and disease. Pharmacol Ther 2025; 269:108822. [PMID: 39978643 DOI: 10.1016/j.pharmthera.2025.108822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 02/03/2025] [Accepted: 02/12/2025] [Indexed: 02/22/2025]
Abstract
G protein-coupled estrogen receptor (GPER) is now recognized for its pivotal role in cellular signaling, influencing diverse physiological processes and disease states. Unlike classical estrogen receptors, GPER exhibits biased signaling, wherein ligand binding triggers selective pathways over others, significantly impacting cellular responses. This review explores the nuanced mechanisms of biased signaling mediated by GPER, underscoring its relevance in cardiovascular health, neurological function, immune modulation, and oncogenic processes. Despite its critical implications, biased signaling through GPER remains underexplored compared to traditional signaling paradigms. We explore recent progress in understanding GPER signaling specificity and its potential therapeutic implications across various diseases. Future research directions aim to uncover the molecular basis of biased signaling, develop selective ligands, and translate these insights into personalized therapeutic approaches. Exploiting the therapeutic potential of GPER biased signaling represents a promising frontier in precision medicine, offering innovative strategies to address unmet medical needs.
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Affiliation(s)
- Aisha Bushi
- School international education, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Yixuan Ma
- First Clinical Medical School, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Joseph Adu-Amankwaah
- Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Rong Wang
- The second clinical college, China Medical University, Shenyang, Liaoning 110122, China
| | - Fen Cui
- Research Institution of Behavioral Medicine Education, Jining Medical University, Jining 272067, China
| | - Rui Xiao
- Second Clinical Medical School, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Jinming Zhao
- Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang 110122, China; Department of Pathology, The First Hospital of China Medical University, Shenyang 110001, China.
| | - Jinxiang Yuan
- Lin He's Academician Workstation of New Medicine and Clinical Translation, Jining Medical University, Jining, Shandong, China.
| | - Rubin Tan
- Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
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Zhang J, Liu T, Xue T, Jia Z. Paricalcitol alleviates intestinal ischemia-reperfusion injury via inhibition of the ATF4-CHOP pathway. Front Pharmacol 2025; 16:1529343. [PMID: 40248101 PMCID: PMC12003279 DOI: 10.3389/fphar.2025.1529343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Accepted: 03/24/2025] [Indexed: 04/19/2025] Open
Abstract
Introduction Intestinal ischemia reperfusion (I/R) injury is a severe condition characterized by inflammation, oxidative stress, and compromised intestinal barrier function, which can lead to death. This study investigated the effects of paricalcitol, a synthetic vitamin D receptor (VDR) agonist, on intestinal I/R injury, focusing on the activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP) signaling pathway and the modulation of endoplasmic reticulum stress (ERS). Methods This study consists of both in vivo and in vitro experiments. In vivo experiment, a mouse model of intestinal I/R injury was established by clamping the superior mesenteric artery, and followed by 24 or 72 h of reperfusion. 6-week-old male C57BL/6 J mice were randomly assigned to six groups: sham, I/R 24h, I/R 72 h, and their respective paricalcitol-treated counterparts. VDR knockout mice and wild-type mice were assigned to WT, VDR-KO, WT + I/R and VDR-KO + I/R groups. The paricalcitol-treated groups received oral gavage of paricalcitol (0.3 μg/kg) once daily for 5 days before I/R. In vitro, IEC-6 cells were incubated in a microaerophilic system (5% CO2, 1% O2, 94% N2) for 6 h to induce hypoxia. The cells were then transferred to complete medium with or without paricalcitol (200 nM) and cultured under normoxic conditions for 24 h to establish the hypoxia/re-oxygenation (H/R) model and investigate the protective effects of paricalcitol on H/R-induced injury in cells. We further utilized VDR- and ATF4-silenced cells to examine how paricalcitol regulates the expression of VDR, ATF4, and CHOP. Results We demonstrated that protective paricalcitol treatment reduces ERS and apoptosis by activating VDR and inhibiting the ATF4-CHOP pathway, thereby alleviating intestinal I/R injury in vivo and H/R injury in vitro. Furthermore, experiments with VDR knockout mice demonstrated that the absence of VDR exacerbated I/R injury, underscoring the protective role of VDR in intestinal epithelial cells. Discussion These findings suggest that the protective effects of paricalcitol may offer a promising therapeutic strategy for managing intestinal I/R injury.
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Affiliation(s)
- Jiawei Zhang
- Department of Interventional and Vascular Surgery, The Third Affiliated Hospital of Nanjing Medical University (Changzhou Second People’s Hospital), Changzhou, China
| | - Tingting Liu
- Graduate College of Dalian Medical University, Dalian, China
| | - Tongqing Xue
- Department of Interventional Radiology, Huaian Hospital of Huai’an City (Huaian Cancer Hospital), Huai’an, China
| | - Zhongzhi Jia
- Department of Interventional and Vascular Surgery, The Third Affiliated Hospital of Nanjing Medical University (Changzhou Second People’s Hospital), Changzhou, China
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Wang Y, Jia Z, Zheng M, Wang P, Gao J, Zhang X, Zhou T, Zu G. Inhibition of miR-142-3p promotes intestinal epithelial proliferation and barrier function after ischemia/reperfusion injury by targeting FoxM1. Mol Cell Biochem 2025; 480:1121-1135. [PMID: 38819598 DOI: 10.1007/s11010-024-05038-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 05/14/2024] [Indexed: 06/01/2024]
Abstract
Damage of intestinal barrier function (BF) after ischemia/reperfusion (I/R) injury can induce serious complications and high mortality. MicroRNAs (miRNAs) are involved in intestinal mucosal BF and epithelial proliferation after I/R injury have been reported. We aimed to investigate the role and regulatory mechanism of miR-142-3p (miR-142) in intestinal epithelial proliferation and BF after I/R injury. We detected the proliferation, barrier function and miR-142 expression in clinical ischemic intestinal tissues. Furthermore, we induced an in vivo intestinal I/R injury mouse model and in vitro IEC-6 cells hypoxia/reoxygenation (H/R) injury model. After increasing and decreasing expression of miR-142, we detected the proliferation and barrier function of intestinal epithelial cells after I/R or H/R injury. We found that miR-142 expression was significantly increased in clinical ischemic intestinal mucosa and mouse intestinal mucosa exposed to I/R injury, and there was an inverse relationship between miR-142 and proliferation/BF. Inhibition of miR-142 significant promoted intestinal epithelial proliferation and BF after I/R injury. Furthermore, inhibition of miR-142 improved overall survival rate of mice after I/R injury. MiR-142 directly targeted FoxM1 which was identified by bioinformatics analysis and luciferase activity assay in IEC-6 cells. Inhibition of miR-142 promotes intestinal epithelial proliferation and BF after I/R injury in a FoxM1-mediated manner.
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Affiliation(s)
- Yuhang Wang
- Department of Gastroenterology Surgery, the Central Hospital of Dalian University of Technology (Dalian Municipal Central Hospital), No. 826 of Southwest Road Shahekou District, Dalian, 116033, People's Republic of China
- Department of Graduate School, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Zirui Jia
- Department of Gastroenterology Surgery, the Central Hospital of Dalian University of Technology (Dalian Municipal Central Hospital), No. 826 of Southwest Road Shahekou District, Dalian, 116033, People's Republic of China
- Department of Graduate School, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Mingcan Zheng
- Department of Gastroenterology Surgery, the Central Hospital of Dalian University of Technology (Dalian Municipal Central Hospital), No. 826 of Southwest Road Shahekou District, Dalian, 116033, People's Republic of China
- Department of Graduate School, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Puxu Wang
- Department of Gastroenterology Surgery, the Central Hospital of Dalian University of Technology (Dalian Municipal Central Hospital), No. 826 of Southwest Road Shahekou District, Dalian, 116033, People's Republic of China
- Department of Graduate School, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Jiacheng Gao
- Department of Gastroenterology Surgery, the Central Hospital of Dalian University of Technology (Dalian Municipal Central Hospital), No. 826 of Southwest Road Shahekou District, Dalian, 116033, People's Republic of China
- Department of Graduate School, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Xiangwen Zhang
- Department of Gastroenterology Surgery, the Central Hospital of Dalian University of Technology (Dalian Municipal Central Hospital), No. 826 of Southwest Road Shahekou District, Dalian, 116033, People's Republic of China
| | - Tingting Zhou
- Department of Neurology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Guo Zu
- Department of Gastroenterology Surgery, the Central Hospital of Dalian University of Technology (Dalian Municipal Central Hospital), No. 826 of Southwest Road Shahekou District, Dalian, 116033, People's Republic of China.
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Huang L, Xu Z, Lei X, Huang Y, Tu S, Xu L, Xia J, Liu D. Paneth cell-derived iNOS is required to maintain homeostasis in the intestinal stem cell niche. J Transl Med 2023; 21:852. [PMID: 38007452 PMCID: PMC10675917 DOI: 10.1186/s12967-023-04744-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 11/20/2023] [Indexed: 11/27/2023] Open
Abstract
BACKGROUND Mammalian intestinal epithelium constantly undergoes rapid self-renewal and regeneration sustained by intestinal stem cells (ISCs) within crypts. Inducible nitric oxide synthase (iNOS) is an important regulator in tissue homeostasis and inflammation. However, the functions of iNOS on ISCs have not been clarified. Here, we aimed to investigate the expression pattern of inducible nitric oxide synthase (iNOS) within crypts and explore its function in the homeostatic maintenance of the ISC niche. METHODS Expression of iNOS was determined by tissue staining and qPCR. iNOS-/- and Lgr5 transgenic mice were used to explore the influence of iNOS ablation on ISC proliferation and differentiation. Enteroids were cultured to study the effect of iNOS on ISCs in vitro. Ileum samples from wild-type and iNOS-/- mice were collected for RNA-Seq to explore the molecular mechanisms by which iNOS regulates ISCs. RESULTS iNOS was physiologically expressed in Paneth cells. Knockout of iNOS led to apparent morphological changes in the intestine, including a decrease in the small intestine length and in the heights of both villi and crypts. Knockout of iNOS decreased the number of Ki67+ or BrdU+ proliferative cells in crypts. Loss of iNOS increased the number of Olfm4+ ISCs but inhibited the differentiation and migration of Lgr5+ ISCs in vivo. iNOS depletion also inhibited enteroid formation and the budding efficiency of crypts in vitro. Moreover, iNOS deficiency altered gluconeogenesis and the adaptive immune response in the ileum transcriptome. CONCLUSION Paneth cell-derived iNOS is required to maintain a healthy ISC niche, and Knockout of iNOS hinders ISC function in mice. Therefore, iNOS represents a potential target for the development of new drugs and other therapeutic interventions for intestinal disorders.
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Affiliation(s)
- Lingxiao Huang
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Experimental Research, Sichuan Cancer Hospital & Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Zhenni Xu
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Experimental Research, Sichuan Cancer Hospital & Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Xudan Lei
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Experimental Research, Sichuan Cancer Hospital & Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Yujun Huang
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Experimental Research, Sichuan Cancer Hospital & Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Siyu Tu
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Experimental Research, Sichuan Cancer Hospital & Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Lu Xu
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Experimental Research, Sichuan Cancer Hospital & Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Jieying Xia
- Animal Experiment Center of Sichuan Academy of Traditional Chinese Medicine Sciences, Chengdu, 610041, China
| | - Dengqun Liu
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Experimental Research, Sichuan Cancer Hospital & Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China.
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Shen X, Shi H, Chen X, Han J, Liu H, Yang J, Shi Y, Ma J. Esculetin Alleviates Inflammation, Oxidative Stress and Apoptosis in Intestinal Ischemia/Reperfusion Injury via Targeting SIRT3/AMPK/mTOR Signaling and Regulating Autophagy. J Inflamm Res 2023; 16:3655-3667. [PMID: 37641705 PMCID: PMC10460583 DOI: 10.2147/jir.s413941] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 07/06/2023] [Indexed: 08/31/2023] Open
Abstract
Aim Intestinal ischemia/reperfusion (I/R) injury is a challenging pathological phenomenon accountable for significant mortality in clinical scenarios. Substantial evidence has supported the protective role of esculetin in myocardial I/R injury. This study is designed to reveal the specific impacts of esculetin on intestinal I/R injury and disclose the underlying mechanism. Methods First, intestinal I/R injury model and intestinal epithelial cell line hypoxia/reoxygenation (H/R) model were established. Pathologic damages to intestinal tissues were observed through H&E staining. Serum diamine oxidase (DAO) levels were examined. RT-qPCR and Western blot examined the expression of inflammatory mediators. Commercial kits were used for detecting the levels of oxidative stress markers. TUNEL assay and caspase 3 activity assay measured cell apoptosis. Immunofluorescence (IF) staining measured autophagy levels. Western blot analyzed the expression of apoptosis-, Sirtuin 3 (SIRT3)/AMP activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling- and autophagy-related proteins. Molecular docking verified the interaction of esculetin with SIRT3. Cell viability was explored via CCK-8 assay. Results The experimental results revealed that esculetin treatment mitigated pathological damage of intestinal tissues, reduced serum DAO level, ameliorated inflammation, oxidative stress and apoptosis and promoted autophagy in intestinal I/R rats. Moreover, esculetin bond to SIRT3 and activated SIRT3/AMPK/mTOR signaling both in vitro and in vivo. Furthermore, esculetin treatment enhanced cell viability and SIRT3 silencing reversed the impacts of esculetin on autophagy, inflammation, oxidative stress and apoptosis in H/R cell model. Conclusion In a word, esculetin activated SIRT3/AMPK/mTOR signaling and autophagy to protect against inflammation, oxidative stress and apoptosis in intestinal I/R injury.
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Affiliation(s)
- Xin Shen
- Department of Gastrointestinal Surgery, Xi’an Daxing Hospital, Xi’an, 710016, People’s Republic of China
| | - Hai Shi
- Department of Gastrointestinal Surgery, Xi’an Daxing Hospital, Xi’an, 710016, People’s Republic of China
| | - Xinli Chen
- Department of Gastrointestinal Surgery, Xi’an Daxing Hospital, Xi’an, 710016, People’s Republic of China
| | - Junwei Han
- Department of Gastrointestinal Surgery, Xi’an Daxing Hospital, Xi’an, 710016, People’s Republic of China
| | - Haiwang Liu
- Department of Gastrointestinal Surgery, Xi’an Daxing Hospital, Xi’an, 710016, People’s Republic of China
| | - Jie Yang
- Department of Gastrointestinal Surgery, Xi’an Daxing Hospital, Xi’an, 710016, People’s Republic of China
| | - Yuan Shi
- Department of Gynecology and Obstetrics, Xijing Hospital, Air Force Military Medical University, Xi’an, 710032, People’s Republic of China
| | - Jiajia Ma
- Department of Gynecology and Obstetrics, Xijing Hospital, Air Force Military Medical University, Xi’an, 710032, People’s Republic of China
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Prossnitz ER, Barton M. The G protein-coupled oestrogen receptor GPER in health and disease: an update. Nat Rev Endocrinol 2023:10.1038/s41574-023-00822-7. [PMID: 37193881 DOI: 10.1038/s41574-023-00822-7] [Citation(s) in RCA: 97] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/28/2023] [Indexed: 05/18/2023]
Abstract
Oestrogens and their receptors contribute broadly to physiology and diseases. In premenopausal women, endogenous oestrogens protect against cardiovascular, metabolic and neurological diseases and are involved in hormone-sensitive cancers such as breast cancer. Oestrogens and oestrogen mimetics mediate their effects via the cytosolic and nuclear receptors oestrogen receptor-α (ERα) and oestrogen receptor-β (ERβ) and membrane subpopulations as well as the 7-transmembrane G protein-coupled oestrogen receptor (GPER). GPER, which dates back more than 450 million years in evolution, mediates both rapid signalling and transcriptional regulation. Oestrogen mimetics (such as phytooestrogens and xenooestrogens including endocrine disruptors) and licensed drugs such as selective oestrogen receptor modulators (SERMs) and downregulators (SERDs) also modulate oestrogen receptor activity in both health and disease. Following up on our previous Review of 2011, we herein summarize the progress made in the field of GPER research over the past decade. We will review molecular, cellular and pharmacological aspects of GPER signalling and function, its contribution to physiology, health and disease, and the potential of GPER to serve as a therapeutic target and prognostic indicator of numerous diseases. We also discuss the first clinical trial evaluating a GPER-selective drug and the opportunity of repurposing licensed drugs for the targeting of GPER in clinical medicine.
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Affiliation(s)
- Eric R Prossnitz
- Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
- Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
- University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
| | - Matthias Barton
- Molecular Internal Medicine, University of Zürich, Zürich, Switzerland.
- Andreas Grüntzig Foundation, Zürich, Switzerland.
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Sun Q, Zhang H, Du HB, Zhao ZA, Li CJ, Chen SJ, Li YM, Zhang SL, Liu JC, Niu CY, Zhao ZG. ESTROGEN ALLEVIATES POSTHEMORRHAGIC SHOCK MESENTERIC LYMPH-MEDIATED LUNG INJURY THROUGH AUTOPHAGY INHIBITION. Shock 2023; 59:754-762. [PMID: 36840514 DOI: 10.1097/shk.0000000000002102] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/26/2023]
Abstract
ABSTRACT Background: Hemorrhagic shock-induced acute lung injury (ALI) is commonly associated with the posthemorrhagic shock mesenteric lymph (PHSML) return. Whether excessive autophagy is involved in PHSML-mediated ALI remains unclear. The relationship between estrogen treatment and PHSML or autophagy needs to verify. The current study will clarify the role of estrogen in reducing PHSML-mediated ALI through inhibition of autophagy. Methods: First, a hemorrhagic shock model in conscious rats was used to observe the effects of 17β-estradiol (E2) on intestinal blood flow, pulmonary function, intestinal and pulmonary morphology, and expression of autophagy marker proteins. Meanwhile, the effect of PHSML and autophagy agonist during E2 treatment was also investigated. Secondly, rat primary pulmonary microvascular endothelial cells were used to observe the effect of PHSML, PHSML plus E2, and E2-PHSML (PHSML obtained from rats treated by E2) on the cell viability. Results: Hemorrhagic shock induced intestinal and pulmonary tissue damage and increased wet/dry ratio, reduced intestinal blood flow, along with pulmonary dysfunction characterized by increased functional residual capacity and lung resistance and decreased inspiratory capacity and peak expiratory flow. Hemorrhagic shock also enhanced the autophagy levels in intestinal and pulmonary tissue, which was characterized by increased expressions of LC3 II/I and Beclin-1 and decreased expression of p62. E2 treatment significantly attenuated these adverse changes after hemorrhagic shock, which was reversed by PHSML or rapamycin administration. Importantly, PHSML incubation decreased the viability of pulmonary microvascular endothelial cells, while E2 coincubation or E2-treated lymph counteracted the adverse roles of PHSML. Conclusions: The role of estrogen reducing PHSML-mediated ALI is associated with the inhibition of autophagy.
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Affiliation(s)
| | | | | | | | | | - Si-Jie Chen
- Institute of Microcirculation and Basic Medical College, Hebei North University, Zhangjiakou, China
| | - Yi-Ming Li
- Institute of Microcirculation and Basic Medical College, Hebei North University, Zhangjiakou, China
| | - Sen-Lu Zhang
- Institute of Microcirculation and Basic Medical College, Hebei North University, Zhangjiakou, China
| | - Jun-Chao Liu
- The First Affiliated Hospital, Hebei North University, Zhangjiakou, China
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Arterburn JB, Prossnitz ER. G Protein-Coupled Estrogen Receptor GPER: Molecular Pharmacology and Therapeutic Applications. Annu Rev Pharmacol Toxicol 2023; 63:295-320. [PMID: 36662583 PMCID: PMC10153636 DOI: 10.1146/annurev-pharmtox-031122-121944] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The actions of estrogens and related estrogenic molecules are complex and multifaceted in both sexes. A wide array of natural, synthetic, and therapeutic molecules target pathways that produce and respond to estrogens. Multiple receptors promulgate these responses, including the classical estrogen receptors of the nuclear hormone receptor family (estrogen receptors α and β), which function largely as ligand-activated transcription factors, and the 7-transmembrane G protein-coupled estrogen receptor, GPER, which activates a diverse array of signaling pathways. The pharmacology and functional roles of GPER in physiology and disease reveal important roles in responses to both natural and synthetic estrogenic compounds in numerous physiological systems. These functions have implications in the treatment of myriad disease states, including cancer, cardiovascular diseases, and metabolic disorders. This review focuses on the complex pharmacology of GPER and summarizes major physiological functions of GPER and the therapeutic implications and ongoing applications of GPER-targeted compounds.
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Affiliation(s)
- Jeffrey B Arterburn
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico, USA
- University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA;
| | - Eric R Prossnitz
- University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA;
- Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, and Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
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Chronic GPER activation prompted the proliferation of ileal stem cell in ovariectomized mice depending on Paneth cell-derived Wnt3. Clin Sci (Lond) 2023; 137:109-127. [PMID: 36503938 DOI: 10.1042/cs20220392] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 12/07/2022] [Accepted: 12/09/2022] [Indexed: 12/14/2022]
Abstract
Menopausal women often face long-term estrogen treatment. G protein-coupled estrogen receptor (GPER) expressed in intestinal crypt was activated by estrogen therapy, but it was unclear whether chronic GPER activation during menopause had an effect on intestinal stem cells (ISCs). We tested the effect of chronic GPER activation on ISCs of ovariectomized (OVX) mice by injection of the selective GPER agonist G-1 for 28 days, or G-1 stimulation of organoids derived from crypts of OVX mice. G-1 up-regulated crypt depth, the number of Ki67+, bromodeoxyuridine+ cells and Olfm4+ ISCs, and the expression of ISCs marker genes (Lgr5, Olfm4 and Axin2). G-1 administration promoted organoid growth, increased the number of EdU+ cells per organoid and protein expression of Cyclin D1 and cyclin B1 in organoids. After G-1 treatment in vivo or in vitro, Paneth cell-derived Wnt3, Wnt3 effector β-catenin and Wnt target genes c-Myc and Cyclin D1 increased in ileum or organoids. Once blocking the secretion of Wnt3 from Paneth cells, the effects of G-1 on organoids growth, ISCs marker genes and Wnt/β-catenin signaling were abolished. G-1 did not affect the number of Paneth cells in ex vivo organoids, while activated Mmp7/cryptdin program in Paneth cells, promoted their maturation, and increased the expression of lysozyme protein. G-1 pretreatment in OVX mice inhibited radiation-induced ISCs proliferation injury and enhanced the resistance of mice to intestinal injury. In conclusion, chronic GPER activation prompted the Wnt3 synthesis in Paneth cells, thus increased the proliferation of ISCs via activation of Wnt3/β-catenin signaling in OVX mice.
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Recombinant Human Annexin A5 Alleviated Traumatic-Brain-Injury Induced Intestinal Injury by Regulating the Nrf2/HO-1/HMGB1 Pathway. Molecules 2022; 27:molecules27185755. [PMID: 36144494 PMCID: PMC9501944 DOI: 10.3390/molecules27185755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 08/26/2022] [Accepted: 09/05/2022] [Indexed: 11/17/2022] Open
Abstract
Aims: Annexin A5 (ANXA5) exhibited potent antithrombotic, antiapoptotic, and anti-inflammatory properties in a previous study. The role of ANXA5 in traumatic brain injury (TBI)-induced intestinal injury is not fully known. Main methods: Recombinant human ANXA5 (50 µg/kg) or vehicle (PBS) was administered to mice via the tail vein 30 min after TBI. Mouse intestine tissue was gathered for hematoxylin and eosin staining 0.5 d, 1 d, 2 d, and 7 d after modeling. Intestinal Western blotting, immunofluorescence, TdT-mediated dUTP nick-end labeling staining, and enzyme-linked immunosorbent assays were performed 2 days after TBI. A series of kits were used to assess lipid peroxide indicators such as malonaldehyde, superoxide dismutase activity, and catalase activity. Key findings: ANXA5 treatment improved the TBI-induced intestinal mucosa injury at different timepoints and significantly increased the body weight. It significantly reduced apoptosis and matrix metalloproteinase-9 and inhibited the degradation of tight-junction-associated protein in the small intestine. ANXA5 treatment improved intestinal inflammation by regulating inflammation-associated factors. It also mitigated the lipid peroxidation products 4-HNE, 8-OHDG, and malonaldehyde, and enhanced the activity of the antioxidant enzymes, superoxide dismutase and catalase. Lastly, ANXA5 significantly enhanced nuclear factor E2-related factor 2 (Nrf2) and hemeoxygenase-1, and decreased high mobility group box 1 (HMGB1). Significance: Collectively, the results suggest that ANXA5 inhibits TBI-induced intestinal injury by restraining oxidative stress and inflammatory responses. The mechanisms involved sparking the Nrf2/hemeoxygenase-1-induced antioxidant system and suppressing the HMGB1 pathway. ANXA5 may be an attractive therapeutic candidate for protecting against TBI-induced intestinal injury.
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Gohar EY, Almutlaq RN, Fan C, Balkawade RS, Butt MK, Curtis LM. Does G Protein-Coupled Estrogen Receptor 1 Contribute to Cisplatin-Induced Acute Kidney Injury in Male Mice? Int J Mol Sci 2022; 23:ijms23158284. [PMID: 35955435 PMCID: PMC9368456 DOI: 10.3390/ijms23158284] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/18/2022] [Accepted: 07/21/2022] [Indexed: 12/04/2022] Open
Abstract
Nephrotoxicity is the dose-limiting side-effect of the chemotherapeutic agent cisplatin (Cp). Recent evidence points to renal protective actions of G protein-coupled estrogen receptor 1 (GPER1). In addition, it has been shown that GPER1 signaling elicits protective actions against acute ischemic injuries that involve multiple organ systems; however, the involvement of GPER1 signaling in Cp-induced acute kidney injury (AKI) remains unclear. This study tested whether genetic deletion of GPER1 exacerbates Cp-induced AKI in male mice. We subjected male mice, homozygous (homo) and heterozygous (het) knockout for the GPER1 gene, and wild-type (WT) littermates to Cp or saline injections and assessed markers for renal injury on the third day after injections. We also determined serum levels of proinflammatory markers in saline and Cp-treated mice. Given the protective role of heme oxygenase-1 (HO-1) in Cp-mediated apoptosis, we also investigated genotypic differences in renal HO-1 abundance, cell death, and proliferation by Western blotting, the TUNEL assay, and Ki67 immunostaining, respectively. Cp increased serum creatinine, urea, and neutrophil gelatinase-associated lipocalin (NGAL) levels, the renal abundance of kidney injury molecule-1, and NGAL in all groups. Cp-induced AKI resulted in comparable histological evidence of injury in all genotypes. WT and homo mice showed greater renal HO-1 abundance in response to Cp. Renal HO-1 abundance was lower in Cp-treated homo, compared to Cp-treated WT mice. Of note, GPER1 deletion elicited a remarkable increase in renal apoptosis; however, no genotypic differences in cell proliferation were observed. Cp augmented kidney Ki67-positive counts, regardless of the genotype. Overall, our data do not support a role for GPER1 in mediating Cp-induced renal injury. GPER1 deletion promotes renal apoptosis and diminishes HO-1 induction in response to Cp, suggesting that GPER1 may play cytoprotective and anti-apoptotic actions in AKI. GPER1-induced regulation of HO-1 and apoptosis may offer novel therapeutic targets for the treatment of AKI.
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Affiliation(s)
- Eman Y. Gohar
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Correspondence: ; Tel.: +1-615-875-0623
| | - Rawan N. Almutlaq
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (R.N.A.); (C.F.); (R.S.B.); (M.K.B.); (L.M.C.)
| | - Chunlan Fan
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (R.N.A.); (C.F.); (R.S.B.); (M.K.B.); (L.M.C.)
| | - Rohan S. Balkawade
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (R.N.A.); (C.F.); (R.S.B.); (M.K.B.); (L.M.C.)
| | - Maryam K. Butt
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (R.N.A.); (C.F.); (R.S.B.); (M.K.B.); (L.M.C.)
| | - Lisa M. Curtis
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (R.N.A.); (C.F.); (R.S.B.); (M.K.B.); (L.M.C.)
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12
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Gao Y, Zhang H, Wang Y, Han T, Jin J, Li J, Tang Y, Liu C. L-Cysteine Alleviates Myenteric Neuron Injury Induced by Intestinal Ischemia/Reperfusion via Inhibitin the Macrophage NLRP3-IL-1β Pathway. Front Pharmacol 2022; 13:899169. [PMID: 35754513 PMCID: PMC9213754 DOI: 10.3389/fphar.2022.899169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 04/26/2022] [Indexed: 11/13/2022] Open
Abstract
Ischemia/reperfusion injury is a common pathophysiological process in the clinic. It causes various injuries, multiple organ dysfunction, and even death. There are several possible mechanisms about ischemia/reperfusion injury, but the influence on intestinal myenteric neurons and the underlying mechanism are still unclear. C57BL6/J mice were used to establish the ischemia/reperfusion model in vivo. Peritoneal macrophages were used for ATP depletion and hypoxia/reoxygenation experiment in vitro. L-cysteine, as the substrate of hydrogen sulfide, is involved in many physiological and pathological processes, including inflammation, metabolism, neuroprotection, and vasodilation. In the current study, we confirmed that intestinal ischemia/reperfusion led to the injury of myenteric neurons. From experiments in vitro and in vivo, we demonstrated that L-cysteine protected myenteric neurons from the injury. AOAA reversed the protective effect of L-cysteine. Also, L-cysteine played a protective role mainly by acting on intestinal macrophages via decreasing the expression of NLRP3, cleaved caspase-1, and mature IL-1β. L-cysteine increased cystathionine beta synthase and H2S produced by intestinal macrophages to protect myenteric mature neurons and enteric neural precursor cells from apoptosis. Moreover, the addition of IL-1β-neutralizing antibody alleviated the injury of myenteric neurons and enteric neural precursor cells caused by intestinal ischemia/reperfusion. Our study provided a new target for the protection of myenteric neurons in clinical intestinal ischemia/reperfusion injury.
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Affiliation(s)
- Yifei Gao
- Department of Physiology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China
| | - Haojie Zhang
- Department of Physiology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China
| | - Yujin Wang
- Department of Physiology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China
| | - Ting Han
- Department of Gastroenterology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
| | - Jing Jin
- Department of TCM Rheumatology, China-Japan Friendship Hospital, Beijing, China
| | - Jingxin Li
- Department of Physiology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China
| | - Yan Tang
- Department of Gastroenterology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
| | - Chuanyong Liu
- Department of Physiology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China.,Provincial Key Lab of Mental Disorders, Shandong University, Jinan, China
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Wang Y, Cao Z, Zhao H, Gu Z. Bisphenol A attenuates the therapeutic effect of the selective G protein-coupled estrogen receptor agonist G-1 on allergic rhinitis inflammation in mice. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 238:113607. [PMID: 35533451 DOI: 10.1016/j.ecoenv.2022.113607] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/29/2022] [Accepted: 05/02/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Bisphenol A (BPA) is found in many plastics widely used in everyday life and affects the immune system. Previous studies found that the selective G protein coupled estrogen receptor (GPER) agonist G-1 can reduce the inflammation associated with asthma and allergic rhinitis (AR). BPA also interferes with the protective effect of estradiol against myocardial ischemia-reperfusion injury. OBJECTIVE We explored whether BPA attenuates the effect of G-1 on inflammation in a mouse AR model. METHODS The AR model was established by sensitizing and stimulating female BALB/c mice with ovalbumin (OVA) and G-1/BPA. Eosinophils, neutrophils, and lymphocyte subsets (including T and B cells) in nasal mucosa and Th2 and Treg cells in the spleen were detected by flow cytometry. Cytokines and transcription factors characteristic of Th2 and Treg cells in nasal mucosa were detected using cytometric bead arrays and quantitative PCR, respectively. RESULTS G-1 reduced OVA-induced nasal mucosal inflammation in mice. The proportions of eosinophils, neutrophils, Siglec-F+ neutrophils, lymphocytes, and T cell subsets were reduced by G-1, and this effect was attenuated by BPA. G-1 significantly decreased the Th2 population and levels of IL-4, IL-5, IL-13 and GATA-3; these effects were attenuated by BPA. The enhanced Treg response (as evidenced by an increased Treg population and higher IL-10 and Foxp3 levels) mediated by G-1 tended to be reduced by BPA. DISCUSSION We found that G-1 reduced OVA-induced nasal mucosal inflammation and significantly decreased the Th2 response, while increasing the Treg response. These effects were attenuated by BPA.
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Affiliation(s)
- Yunxiu Wang
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang City 110004, Liaoning Province, China
| | - Zhiwei Cao
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang City 110004, Liaoning Province, China
| | - He Zhao
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang City 110004, Liaoning Province, China
| | - Zhaowei Gu
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang City 110004, Liaoning Province, China.
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Abstract
Chemotherapy-induced gastrointestinal dysfunction is a common occurrence associated with many different classes of chemotherapeutic agents. Gastrointestinal toxicity includes mucositis, diarrhea, and constipation, and can often be a dose-limiting complication, induce cessation of treatment and could be life threatening. The gastrointestinal epithelium is rich in rapidly dividing cells and hence is a prime target for chemotherapeutic drugs. The incidence of gastrointestinal toxicity, including diarrhea and mucositis, is extremely high for a wide array of chemotherapeutic and radiation regimens. In fact, 60%-100% of patients on high-dose chemotherapy suffer from gastrointestinal side effects. Unfortunately, treatment options are limited, and therapy is often restricted to palliative care. Therefore, there is a great unmet therapeutic need for preventing and treating chemotherapy-induced gastrointestinal toxicities in the clinic. In this review, we discuss our current understanding of the mechanisms underlying chemotherapy-induced diarrhea and mucositis, and emerging mechanisms involving the enteric nervous system, smooth muscle cells and enteric immune cells. Recent evidence has also implicated gut dysbiosis in the pathogenesis of not only chemotherapy-induced mucositis and diarrhea, but also chemotherapy-induced peripheral neuropathy. Oxidative stress induced by chemotherapeutic agents results in post-translational modification of ion channels altering neuronal excitability. Thus, investigating how chemotherapy-induced changes in the gut- microbiome axis may lead to gut-related toxicities will be critical in the discovery of new drug targets for mitigating adverse gastrointestinal effects associated with chemotherapy treatment.
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Affiliation(s)
- Hamid I Akbarali
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States.
| | - Karan H Muchhala
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Donald K Jessup
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Stanley Cheatham
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
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Chen G, Zeng H, Li X, Liu J, Li Z, Xu R, Ma Y, Liu C, Xue B. Activation of G protein coupled estrogen receptor prevents chemotherapy-induced intestinal mucositis by inhibiting the DNA damage in crypt cell in an extracellular signal-regulated kinase 1- and 2- dependent manner. Cell Death Dis 2021; 12:1034. [PMID: 34718327 PMCID: PMC8557214 DOI: 10.1038/s41419-021-04325-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 10/12/2021] [Accepted: 10/14/2021] [Indexed: 12/13/2022]
Abstract
Chemotherapy-induced intestinal mucositis (CIM) is a common adverse reaction to antineoplastic treatment with few appropriate, specific interventions. We aimed to identify the role of the G protein coupled estrogen receptor (GPER) in CIM and its mechanism. Adult male C57BL/6 mice were intraperitoneally injected with 5-fluorouracil to establish the CIM model. The selective GPER agonist G-1 significantly inhibited weight loss and histological damage in CIM mice and restored mucosal barrier dysfunction, including improving the expression of ZO-1, increasing the number of goblet cells, and decreasing mucosal permeability. Moreover, G-1 treatment did not alter the antitumor effect of 5-fluorouracil. In the CIM model, G-1 therapy reduced the expression of proapoptotic protein and cyclin D1 and cyclin B1, reversed the changes in the number of TUNEL+ cells, Ki67+ and bromodeoxyuridine+ cells in crypts. The selective GPER antagonist G15 eliminated all of the above effects caused by G-1 on CIM, and application of G15 alone increased the severity of CIM. GPER was predominantly expressed in ileal crypts, and G-1 inhibited the DNA damage induced by 5-fluorouracil in vivo and vitro, as confirmed by the decrease in the number of γH2AX+ cells in the crypts and the comet assay results. Referring to the data from GEO dataset we verified GPER activation restored ERK1/2 activity in CIM and 5-fluorouracil-treated IEC-6 cells. Once the effects of G-1 on ERK1/2 activity were abolished with the ERK1/2 inhibitor PD0325901, the effects of G-1 on DNA damage both in vivo and in vitro were eliminated. Correspondingly, all of the manifestations of G-1 protection against CIM were inhibited by PD0325901, such as body weight and histological changes, the mucosal barrier, the apoptosis and proliferation of crypt cells. In conclusion, GPER activation prevents CIM by inhibiting crypt cell DNA damage in an ERK1/2-dependent manner, suggesting GPER might be a target preventing CIM.
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Affiliation(s)
- Guanyu Chen
- Department of Physiology and Pathophysiology, School of basic medical science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Honghui Zeng
- Department of Physiology and Pathophysiology, School of basic medical science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xinyun Li
- The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Shandong University, Jinan, China
| | - Jianbo Liu
- Department of Physiology and Pathophysiology, School of basic medical science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zhao Li
- Department of Physiology and Pathophysiology, School of basic medical science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Runze Xu
- Department of Physiology and Pathophysiology, School of basic medical science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yuntao Ma
- Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Chuanyong Liu
- Department of Physiology and Pathophysiology, School of basic medical science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Bing Xue
- Department of Physiology and Pathophysiology, School of basic medical science, Cheeloo College of Medicine, Shandong University, Jinan, China.
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16
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Estrogen alleviates hepatocyte necroptosis depending on GPER in hepatic ischemia reperfusion injury. J Physiol Biochem 2021; 78:125-137. [PMID: 34651286 DOI: 10.1007/s13105-021-00846-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 09/09/2021] [Indexed: 01/28/2023]
Abstract
Hepatic ischemia reperfusion injury (IRI) occurs in liver transplantation, complex liver resection, and hemorrhagic shock, which causes donor organ shortage and hepatic damage. The burst of reactive oxygen species (ROS) during reperfusion leads to cell apoptosis and necroptosis. It has been reported that estrogen could attenuate hepatic IRI. G protein estrogen receptor (GPER) mediates estrogen effects via nonclassic receptor systems. Here, we investigate whether estrogen protecting liver from hepatic IRI depends on GPER and the influence of GPER activation on hepatocyte necroptosis. We proved that estrogen had a protective effect on both hepatocyte hypoxia re-oxygen (H/R) challenge and mouse hepatic ischemia reperfusion model. However, the application of GPER specific antagonist G15 before estrogen inhibited this beneficial effect. The results of mitochondria functional measurement revealed that estrogen improved hepatocyte mitochondria function by activating GPER, which might benefit from the increased expression of connexin 43 (Cx43) in mitochondria. To investigate the relationship between GPER activation and necroptosis, we used caspase-3/7 inhibitor benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-chloromethylketone (Z-DEVD-FMK) to eliminate the interference of apoptosis. Estrogen showed a protective effect on hepatic IRI after using Z-DEVD-FMK, which could be suppressed by G15. GPER activation decreased the level of receptor interacting protein kinase (RIPK) 3, phosphorylated (p-) RIPK1, and p-mixed lineage kinase domain-like (MLKL). The co-immunoprecipitation result indicated that GPER could bind with RIPK3. GPER is indispensable in estrogen protecting liver from IRI. GPER activation attenuates hepatocyte necroptosis by decreasing the level of RIPK3, p-RIPK1, and p-MLKL.
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Remote ischemic conditioning avoids the development of intestinal damage after ischemia reperfusion by reducing intestinal inflammation and increasing intestinal regeneration. Pediatr Surg Int 2021; 37:333-337. [PMID: 33555396 DOI: 10.1007/s00383-020-04831-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/30/2020] [Indexed: 01/02/2023]
Abstract
AIM OF THE STUDY Midgut volvulus is a potentially life-threatening condition which is based on intestinal ischemia and reperfusion (I/R) injury. Remote ischemia conditioning (RIC) applied to a limb can protect distant organs such as heart and kidney. The aims of this study were to investigate the effect of RIC on a model of midgut volvulus and to explore its underlying mechanism of action. METHODS Six-weeks old C57BL/6 mice were studied: (a) sham (n = 4): laparotomy alone. (b) Intestinal I/R injury (n = 5): occlusion of the superior mesenteric artery (SMA) for 45 min followed by reperfusion. (c) Intestinal I/R (as in group above) with RIC immediately after reperfusion (n = 5). RIC consisted of 4 cycles of 5 min hind limb ischemia followed by 5 min reperfusion. 24-h after laparotomy, animals were euthanized, and the small intestine (same distance from cecum) was harvested. The intestine was examined for inflammatory cytokines (TNF-α and IL-6), epithelial proliferation marker Ki67 and stem cell marker Lgr5 expression. MAIN RESULTS Compared to sham, the small intestine of IR mice had more intestinal damage, increased expression of inflammatory cytokines, decreased intestinal proliferation and stem cell activity. RIC significantly counteracted all these changes. CONCLUSIONS Remote ischemia conditioning avoids intestinal damage due to I/R injury. This beneficial effect is associated with decreased intestinal inflammation and enhanced intestinal regeneration. This study implicates that RIC is a novel non-invasive intervention to reduce the intestinal damage occurring in midgut volvulus.
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Wang Q, Li Z, Liu K, Liu J, Chai S, Chen G, Wen S, Ming T, Wang J, Ma Y, Zeng H, Liu C, Xue B. Activation of the G Protein-Coupled Estrogen Receptor Prevented the Development of Acute Colitis by Protecting the Crypt Cell. J Pharmacol Exp Ther 2021; 376:281-293. [PMID: 33318078 DOI: 10.1124/jpet.120.000216] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022] Open
Abstract
G protein-coupled estrogen receptor (GPER) might be involved in ulcerative colitis (UC), but the direct effect of GPER on UC is still unclear. We used male C57BL/6 mice to establish the acute colitis model with administration of dextran sulfate sodium and explored the effect of GPER on acute colitis and its possible mechanism. The selective GPER agonist G-1 inhibited weight loss and colon shortening and decreased the disease activity index for colitis and histologic damage in mice with colitis. All of these effects were prevented by a selective GPER blocker. G-1 administration prevented the dysfunction of tight junction protein expression and goblet cells in colitis model and thus inhibited the increase of mucosal permeability in colitis-suffering mice significantly. GPER activation reduced expression of glucose-regulating peptide-78 and anti-CCAAT/enhancer-binding protein homologous protein and attenuated the three arms of the unfolded protein response in colitis. G-1 therapy inhibited the increase of cleavage caspase-3- and TUNEL-positive cells in colonic crypts in the colitis model, increased the number of Ki67- and bromodeoxyuridine-positive cells in crypts, and reversed the decrease of cyclin D1 and cyclin B1 expression in colitis, indicating its protective effect on crypt cells. In cultured CCD841 cells, G-1 treatment fought against cell injury induced by endoplasmic reticulum stress. These findings demonstrate that GPER activation prevents colitis by protecting the colonic crypt cells, which are associated with inhibition of endoplasmic reticulum stress. SIGNIFICANCE STATEMENT: We demonstrate that G protein-coupled estrogen receptor (GPER) activation prevents dextran sulfate sodium-induced acute colitis by protecting the crypt cells, showing that it inhibited the crypt cell apoptosis and protected proliferation of crypt cells, which resulted in protection of the intestinal mucosal barrier. This protective effect was achieved (at least in part) by inhibiting endoplasmic reticulum stress. Mucosal healing is regarded as a key therapeutic target for colitis, and GPER is expected to become a new therapeutic target for colitis.
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Affiliation(s)
- Qian Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Zhao Li
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Kaixuan Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Jianbo Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Shiquan Chai
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Guanyu Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Shuyu Wen
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Tian Ming
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Jiayi Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Yuntao Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Honghui Zeng
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Chuanyong Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Bing Xue
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
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Wang Y, Liu F, Liu P. 23-Hydroxytormentic acid reduces cerebral ischemia/reperfusion damage in rats through anti-apoptotic, antioxidant, and anti-inflammatory mechanisms. Naunyn Schmiedebergs Arch Pharmacol 2021; 394:1045-1054. [PMID: 33394135 DOI: 10.1007/s00210-020-02038-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 12/08/2020] [Indexed: 11/25/2022]
Abstract
23-Hydroxytormentic acid (23-HTA) is an important herbal medicine purified from immature fruits of African Rubus aceae (Rosaceae). This study was carried out to examine the protection properties and potential mechanisms of 23-HTA against cerebral ischemia/reperfusion (I/R) damage. Rats underwent middle cerebral artery occlusion/reperfusion (MCAO/R) 2/24 h. All animals were euthanized 24 h after reperfusion. Rats were injected with various concentrations of 23-HTA intraperitoneally. Evaluations of infarct volumes, neurological deficit, and brain water contents were carried out to assess the outcome of 23-HTA treatment. The results showed that 23-HTA reduced infarct volumes, brain water content, and neurological deficit in a dosage-dependent manner. 23-HTA can also significantly reduce the numbers of TUNEL-positive cells, the expression levels of Bax, caspase-3, lipid peroxidation, Sod 1, Sod 2, catalase, and pro-inflammatory cytokines TNF and IL-1β and increase the expression levels of Bcl-2 and p-Akt. 23-HTA has a neuroprotective effect due to its anti-apoptotic, antioxidant, and anti-inflammatory effects.
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Affiliation(s)
- Yamin Wang
- Department of Neurology, The 80th Army Hospital of the Chinese People's Liberation Army, No.256 Beigong West Street, Weicheng District, Weifang, 261041, Shandong, China
| | - Fengrong Liu
- Department of Neurology, The 80th Army Hospital of the Chinese People's Liberation Army, No.256 Beigong West Street, Weicheng District, Weifang, 261041, Shandong, China
| | - Peng Liu
- Department of Neurology, The 80th Army Hospital of the Chinese People's Liberation Army, No.256 Beigong West Street, Weicheng District, Weifang, 261041, Shandong, China.
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Huang X, Pan M, Du P, Chen Y, Zhang C, Lu W, Lin J. Maternally expressed 3 protects the intestinal barrier from cardiac arrest-induced ischemia/reperfusion injury via miR-34a-3p/sirtuin 1/nuclear factor kappa B signaling. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:122. [PMID: 33569424 PMCID: PMC7867908 DOI: 10.21037/atm-20-6438] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 12/26/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Cardiac arrest (CA), a common disease with a high mortality rate, is a leading cause of ischemia/reperfusion (I/R)-induced dysfunction of the intestinal barrier. Long non-coding RNAs (lncRNAs) play crucial roles in multiple pathological processes. However, the effect of the lncRNA maternally expressed 3 (MEG3) on intestinal I/R injury and the intestinal barrier has not been fully determined. Therefore, this study aimed to investigate the function of MEG3 in CA-induced intestinal barrier dysfunction. METHODS The oxygen and glucose deprivation (OGD) model in the human colorectal adenocarcinoma Caco-2 cells and in vivo cardiac arrest-induced intestinal barrier dysfunction model in Sprague-Dawley (SD) rats were established. The effect and underlying mechanism of MEG3 on the intestinal barrier from cardiac arrest-induced ischemia/reperfusion injury were analyzed by methyl thiazolyl tetrazolium (MTT) assays, Annexin V-FITC/PI apoptosis detection kit, Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining, quantitative polymerase chain reaction (qPCR) assays, Western blot analysis, luciferase reporter gene assays, transepithelial electrical resistance (TEER) measurements, immunofluorescence analysis, and enzyme-linked immunosorbent assay (ELISA) assays. RESULTS Interestingly, we found that MEG3 could protect Caco-2 cells from oxygen-glucose deprivation (OGD)/reoxygenation-induced I/R injury by modulating cell proliferation and apoptosis. Moreover, MEG3 relieved OGD-induced intestinal barrier dysfunction in vitro, as demonstrated by its significant rescue effect on transepithelial electrical resistance and the expression of tight junction proteins such as occludin and claudin-1 (CLDN1), which were impaired in OGD-treated Caco-2 cells. Mechanistically, MEG3 inhibited the expression of inflammatory factors including interleukin (IL)-1β, tumor necrosis factor (TNF)-α, interferon-gamma (IFN)-γ, inflammatory factors including interleukin (IL)-10, and transforming growth factor beta (TGFb)-1, as well as nuclear factor-kappa B (NF-κB) signaling. In response to OGD treatment in vitro, MEG3 also activated the expression of sirtuin 1 (SIRT1) by Caco-2 cells via sponging miR-34a-3p. Furthermore, MEG3 relieved CA-induced intestinal barrier dysfunction through NF-κB signaling in vivo. CONCLUSIONS LncRNA MEG3 can protect the intestinal barrier from cardiac arrest-induced I/R injury via miR-34a-3p/SIRT1/NF-κB signaling. This finding provides new insight into the mechanism by which MEG3 restores intestinal barrier function following I/R injury, presenting it as a potential therapeutic candidate or strategy in intestinal injury.
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Affiliation(s)
- Xianwei Huang
- Emergency Department, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Mandong Pan
- Emergency Department, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Penghui Du
- Emergency Department, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Yinrong Chen
- Emergency Department, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Caixia Zhang
- Emergency Department, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Wang Lu
- Emergency Department, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Jiyan Lin
- Emergency Department, The First Affiliated Hospital of Xiamen University, Xiamen, China
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Dexmedetomidine Resists Intestinal Ischemia-Reperfusion Injury by Inhibiting TLR4/MyD88/NF-κB Signaling. J Surg Res 2020; 260:350-358. [PMID: 33383282 DOI: 10.1016/j.jss.2020.11.041] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 09/29/2020] [Accepted: 11/01/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND Intestinal ischemia/reperfusion (I/R) is a common clinical problem that occurs during various clinical pathological processes. Dexmedetomidine (DEX), a widely used anesthetic adjuvant agent, can induce protection against intestinal I/R in vivo; however, the underlying mechanism is not fully understood. In the present study, we aimed to investigate the protective effects of DEX and examine whether its mechanism was associated with the TLR4/MyD88/NF-κB signaling pathway. METHODS Sprague-Dawley rats were pretreated with DEX and then subjected to I/R-induced intestinal injury. In vivo, intestinal histopathological examination and scoring were performed, the levels of serum intestinal fatty acid-binding protein (I-FABP), intestinal tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and expression levels of TLR4, MyD88, and NF-κB in the intestine were determined. In in vitro experiments, the human colon carcinoma cell line (Caco-2) was incubated with DEX before deprivation/reoxygenation (OGD/R) treatment. The cell viability of Caco-2 cells, the levels of lactate dehydrogenase (LDH), TNF-α, and IL-1β in the supernatant, as well as protein expression of TLR4, MyD88, and NF-κB in Caco-2 cells, were measured. Statistical analysis was performed using SPSS version 21.0. RESULTS DEX preconditioning significantly reduced the intestinal pathological Chiu's score, serum I-FABP, intestinal TNF-α, IL-1β levels, and the protein expression of TLR4, MyD88, and NF-κB in the rats with intestinal I/R injury. Similarly, in vitro, DEX pretreatment protected against OGD/R-induced Caco-2 cell damage and inhibited TLR4/MyD88/NF-κB signaling, as evidenced by increased cell viability, decreased LDH activity, reduced TNF-α and IL-1β levels, as well as downregulated TLR4, MyD88, and NF-κB protein levels. CONCLUSIONS Our findings suggested that DEX could reduce intestinal I/R injury in rats and OGD/R damage in Caco-2 cells, and this protection might be attributed to antiinflammatory effects and inhibition of the TLR4/MyD88/NF-κB signaling pathway.
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Yang S, Cheng W, Li X, Liang F, Zhou R, Wang H, Feng Y, Wang Y. Use of embryonic stem cell-derived cardiomyocytes to study cardiotoxicity of bisphenol AF via the GPER/CAM/eNOS pathway. Toxicology 2020; 432:152380. [DOI: 10.1016/j.tox.2020.152380] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 11/20/2019] [Accepted: 01/20/2020] [Indexed: 12/16/2022]
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Imam Aliagan A, Madungwe NB, Tombo N, Feng Y, Bopassa JC. Chronic GPER1 Activation Protects Against Oxidative Stress-Induced Cardiomyoblast Death via Preservation of Mitochondrial Integrity and Deactivation of Mammalian Sterile-20-Like Kinase/Yes-Associated Protein Pathway. Front Endocrinol (Lausanne) 2020; 11:579161. [PMID: 33193095 PMCID: PMC7604496 DOI: 10.3389/fendo.2020.579161] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/07/2020] [Indexed: 12/18/2022] Open
Abstract
Introduction: Estrogen (17β-estradiol, E2) is well-known to induce cardioprotective effects against ischemia/reperfusion (I/R) injury. We recently reported that acute application of E2 at the onset of reperfusion in vivo induces cardioprotective effects against I/R injury via activation of its non-steroidal receptor, G protein-coupled estrogen receptor 1 (GPER1). Here, we investigated the impact and mechanism underlying chronic GPER1 activation in cultured H9c2 rat cardiomyoblasts. Methods: H9c2 rat cardiomyoblasts were cultured and pretreated with the cytotoxic agent H2O2 for 24 h and incubated in the presence of vehicle (control), GPER1 agonists E2 and G1, or GPER1 agonists supplemented with G15 (GPER1 antagonist) for 48 or 96 h. After treatment, cells were collected to measure the rate of cell death and viability using flow cytometry and Calcein AM assay or MTT assay, respectively. The resistance to opening of the mitochondrial permeability transition pore (mPTP), the mitochondrial membrane potential, and ATP production was assessed using fluorescence microscopy, and the mitochondrial structural integrity was observed with electron microscopy. The levels of the phosphorylation of mammalian sterile-20-like kinase (MST1) and yes-associated protein (YAP) were assessed by Western blot analysis in whole-cell lysate, while the expression levels of mitochondrial biogenesis genes, YAP target genes, and proapoptotic genes were measured by qRT-PCR. Results: We found that after H2O2 treatment, chronic E2/G1 treatment decreased cell death effect was associated with the prevention of the S phase of the cell cycle arrest compared to control. In the mitochondria, chronic E2/G1 activation treatment preserved the cristae morphology, and increased resistance to opening of mPTP, but with little change to mitochondrial fusion/fission. Additionally, chronic E2/G1 treatment predominantly reduced phosphorylation of MST1 and YAP, as well as increased MST1 and YAP protein levels. E2 treatment also upregulated the expression levels of TGF-β and PGC-1α mRNAs and downregulated PUMA and Bim mRNAs. Except for ATP production, all the E2 or G1 effects were prevented by the cotreatment with the GPER1 antagonist, G15. Conclusion: Together, these results indicate that chronic GPER1 activation with its agonists E2 or G1 treatment protects H9c2 cardiomyoblasts against oxidative stress-induced cell death and increases cell viability by preserving mitochondrial structure and function as well as delaying the opening of mPTP. These chronic GPER1 effects are associated with the deactivation of the non-canonical MST1/YAP mechanism that leads to genetic upregulation of cell growth genes (CTGF, CYR61, PGC-1α, and ANKRD1), and downregulation of proapoptotic genes (PUMA and Bim).
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Affiliation(s)
- Abdulhafiz Imam Aliagan
- Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Ngonidzashe B. Madungwe
- Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
- Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX, United States
| | - Nathalie Tombo
- Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Yansheng Feng
- Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Jean C. Bopassa
- Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
- *Correspondence: Jean C. Bopassa
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Xu S, Yu S, Dong D, Lee LTO. G Protein-Coupled Estrogen Receptor: A Potential Therapeutic Target in Cancer. Front Endocrinol (Lausanne) 2019; 10:725. [PMID: 31708873 PMCID: PMC6823181 DOI: 10.3389/fendo.2019.00725] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 10/09/2019] [Indexed: 12/13/2022] Open
Abstract
The G protein-coupled estrogen receptor (GPER) is a seven-transmembrane-domain receptor that mediates non-genomic estrogen related signaling. After ligand activation, GPER triggers multiple downstream pathways that exert diverse biological effects on the regulation of cell growth, migration and programmed cell death in a variety of tissues. A significant correlation between GPER and the progression of multiple cancers has likewise been reported. Therefore, a better understanding of the role GPER plays in cancer biology may lead to the identification of novel therapeutic targets, especially among estrogen-related cancers. Here, we review cell signaling and detail the functions of GPER in malignancies.
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Affiliation(s)
- Shen Xu
- Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shan Yu
- Faculty of Health Sciences, Centre of Reproduction Development and Aging, University of Macau, Macau, China
- Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China
| | - Daming Dong
- Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Leo Tsz On Lee
- Faculty of Health Sciences, Centre of Reproduction Development and Aging, University of Macau, Macau, China
- Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China
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