|
1
|
Zhu BT, Liao QQ, Tian HY, Yu DJ, Xie T, Sun XL, Zhou XM, Han YX, Zhao YJ, El-Kassas M, Liu XX, Sun XD, Zhang YY. Estrogen: the forgotten player in metaflammation. Front Pharmacol 2024; 15:1478819. [PMID: 39575382 PMCID: PMC11578702 DOI: 10.3389/fphar.2024.1478819] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 10/21/2024] [Indexed: 11/24/2024] Open
Abstract
Metaflammation is low-grade inflammation triggered by chronic metabolic imbalance and caused by dysregulated metabolites in metabolic inflammatory syndrome (MIS), which includes four diseases: obesity, type 2 diabetes mellitus (T2DM), atherosclerosis (AS), and nonalcoholic fatty liver diseases (NAFLD, recently proposed to be replaced by metabolic dysfunction-associated steatotic liver disease, MASLD). These diseases exhibit apparent sex dimorphism as regards MIS. Estrogen not only plays a crucial role in gender differences in adults but also possesses an anti-inflammatory effect on many metabolic diseases. In this study, we present a prediction of the differential proteins and signal transduction of estrogen in MIS through network pharmacology and review the validated studies on obesity, T2DM, AS, and NAFLD. Subsequently, we compared them to obtain valuable targets, identify current gaps, and provide perspectives for future research on the mechanisms of estrogen in metaflammation.
Collapse
Affiliation(s)
- Bao-Ting Zhu
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Qing-Qing Liao
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Hai-Ying Tian
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Dao-Jiang Yu
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China
| | - Teng Xie
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Xi-Lu Sun
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Xin-Meng Zhou
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Ying-Xuan Han
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Yu-Jie Zhao
- Medical College, Tibet University, Lasa, China
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
- Liver Disease Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Steatotic Liver Disease Study Foundation in Middle East and North Africa (SLMENA), Cairo, Egypt
| | - Xiu-Xiu Liu
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Xiao-Dong Sun
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- Medical College, Tibet University, Lasa, China
| | - Yuan-Yuan Zhang
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China
| |
Collapse
|
|
2
|
Boye A, Osei SA, Brah AS. Therapeutic prospects of sex hormone receptor signaling in hormone-responsive cancers. Biomed Pharmacother 2024; 180:117473. [PMID: 39326105 DOI: 10.1016/j.biopha.2024.117473] [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: 07/18/2024] [Revised: 09/11/2024] [Accepted: 09/19/2024] [Indexed: 09/28/2024] Open
Abstract
Globally, hormone-responsive cancers afflict millions of people contributing to cancer-related morbidity and mortality. While hormone-responsive cancers overburden patients, their close families, and even health budgets at the local levels, knowledge of these cancers particularly their biology and possible avenues for therapy remains poorly exploited. Herewith, this review highlights the role of sex hormones (estrogens and androgens) in the pathophysiology of hormone-responsive cancers and the exploration of therapeutic targets. Major scientific databases including but not limited to Scopus, PubMed, Science Direct, Web of Science core collections, and Google Scholar were perused using a string of search terms: Hormone-responsive cancers, androgens and cancers, estrogens and cancer, androgen receptor signalling, estrogen receptor signalling, etc.
Collapse
Affiliation(s)
- Alex Boye
- Department of Medical Laboratory Science, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana.
| | - Silas Acheampong Osei
- Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Augustine Suurinobah Brah
- Department of Biomedical Sciences, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| |
Collapse
|
|
3
|
Sex Differences in Cardiovascular Diseases: A Matter of Estrogens, Ceramides, and Sphingosine 1-Phosphate. Int J Mol Sci 2022; 23:ijms23074009. [PMID: 35409368 PMCID: PMC8999971 DOI: 10.3390/ijms23074009] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/01/2022] [Accepted: 04/04/2022] [Indexed: 12/30/2022] Open
Abstract
The medical community recognizes sex-related differences in pathophysiology and cardiovascular disease outcomes (CVD), culminating with heart failure. In general, pre-menopausal women tend to have a better prognosis than men. Explaining why this occurs is not a simple matter. For decades, sex hormones like estrogens (Es) have been identified as one of the leading factors driving these sex differences. Indeed, Es seem protective in women as their decline, during and after menopause, coincides with an increased CV risk and HF development. However, clinical trials demonstrated that E replacement in post-menopause women results in adverse cardiac events and increased risk of breast cancer. Thus, a deeper understanding of E-related mechanisms is needed to provide a vital gateway toward better CVD prevention and treatment in women. Of note, sphingolipids (SLs) and their metabolism are strictly related to E activities. Among the SLs, ceramide and sphingosine 1-phosphate play essential roles in mammalian physiology, particularly in the CV system, and appear differently modulated in males and females. In keeping with this view, here we explore the most recent experimental and clinical observations about the role of E and SL metabolism, emphasizing how these factors impact the CV system.
Collapse
|
|
4
|
Nasser SA, Afify EA, Kobeissy F, Hamam B, Eid AH, El-Mas MM. Inflammatory Basis of Atherosclerosis: Modulation by Sex Hormones. Curr Pharm Des 2021; 27:2099-2111. [PMID: 33480335 DOI: 10.2174/1381612827666210122142811] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 12/17/2020] [Indexed: 11/22/2022]
Abstract
Atherosclerosis-related cardiovascular diseases (CVDs) are the leading cause of death globally. Several lines of evidence are supportive of the contributory role of vascular inflammation in atherosclerosis. Diverse immune cell types, including monocytes/macrophages, T-cells and neutrophils, as well as specialized proresolving lipid mediators, have been successfully characterized as key players in vascular inflammation. The increased prevalence of atherosclerotic CVD in men in comparison to age-matched premenopausal women and the abolition of sex differences in prevalence during menopause strongly suggest a pivotal role of sex hormones in the development of CVD. Indeed, many animal and human studies conclusively implicate sex hormones as a crucial component in driving the immune response. This is further corroborated by the effective identification of sex hormone receptors in vascular endothelial cells, vascular smooth muscle cells and immune cells. Collectively, these findings suggest a cellular communication between sex hormones and vascular or immune cells underlying the vascular inflammation in atherosclerosis. The aim of this review is to provide an overview of vascular inflammation as a causal cue underlying atherosclerotic CVDs within the context of the modulatory effects of sex hormones. Moreover, the cellular and molecular signaling pathways underlying the sex hormones- immune system interactions as potential culprits for vascular inflammation are highlighted with detailed and critical discussion. Finally, the review concludes by speculations on the potential sex-related efficacy of currently available immunotherapies in mitigating vascular inflammation. Conceivably, a deeper understanding of the immunoregulatory influence of sex hormones on vascular inflammation-mediated atherosclerosis permits sex-based management of atherosclerosis-related CVDs.
Collapse
Affiliation(s)
- Suzanne A Nasser
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Beirut Arab University, P.O. Box 11-5020, Beirut, Lebanon
| | - Elham A Afify
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Firas Kobeissy
- Department of Biochemistry and Molecular Genetics, American University of Beirut, P.O. Box 11-0236, Beirut, Lebanon
| | - Bassam Hamam
- Department of Biological and Chemical Sciences, School of Arts and Sciences, Lebanese International University, P.O. Box 146404, Beirut, Lebanon
| | - Ali H Eid
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Mahmoud M El-Mas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| |
Collapse
|
|
5
|
Okechukwu CC, Pirro NT, Chappell MC. Evidence that angiotensin II does not directly stimulate the MD2-TLR4 innate inflammatory pathway. Peptides 2021; 136:170436. [PMID: 33181267 PMCID: PMC7855779 DOI: 10.1016/j.peptides.2020.170436] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/22/2020] [Accepted: 10/27/2020] [Indexed: 12/11/2022]
Abstract
The renin-angiotensin system (RAS) plays a critical role in the regulation of blood pressure. Inappropriate activation of the RAS, particularly stimulation of the ACE-Ang II-AT1 receptor axis is a key factor in hypertension and AT1R antagonists (ARBs) are first line therapies in the treatment of cardiovascular disease (CVD). Accumulating evidence suggests that the Ang II-AT1R axis may stimulate both innate and adaptive immune systems. Indeed, recent studies suggest that Ang II stimulates inflammatory events in an AT1R-independent manner by binding the MD2 accessory protein of the TLR4 complex in renal NRK-52E cells. Direct Ang II stimulation of the TLR4 complex is clinically relevant as ARBs increase circulating Ang II levels. Thus, the current study further investigated Ang II stimulation of the TLR4 pathway to release of the pro-inflammatory cytokine CCL2 under identical conditions to the TLR4 ligands LPS and palmitate in the NRK-52E cells. Although LPS (1 ng/mL) and palmitate (100 μM) stimulated CCL2 release 20-fold, Ang II (0.1-10 μM) failed to induce CCL2 release. Both the LPS and palmitate CCL2 responses were abolished by the TLR4 inhibitor Tak242 and significantly reduced by the MD2 inhibitor L48H37. Ang II (1 μM) had no additive effects on LPS (1 ng/mL) or palmitate (100 μM), and the ARB candesartan failed to attenuate CCL2 release to either agent alone. Ang II also failed to induce the release of the putative TLR4 ligand HMBG1. These studies failed to confirm that Ang II directly stimulates the MD2-TLR4 complex to induce cytokine release in NRK-52E cells.
Collapse
Affiliation(s)
- Charles C Okechukwu
- Hypertension & Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Nancy T Pirro
- Hypertension & Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Mark C Chappell
- Hypertension & Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
| |
Collapse
|
|
6
|
Xu X, Yan Q, Liu X, Li P, Li X, Chen Y, Simoncini T, Liu J, Zhu D, Fu X. 17β-Estradiol nongenomically induces vascular endothelial H 2S release by promoting phosphorylation of cystathionine γ-lyase. J Biol Chem 2019; 294:15577-15592. [PMID: 31439665 DOI: 10.1074/jbc.ra119.008597] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 08/13/2019] [Indexed: 12/12/2022] Open
Abstract
Estrogen exerts its cardiovascular protective role at least in part by regulating endothelial hydrogen sulfide (H2S) release, but the underlying mechanisms remain to be fully elucidated. Estrogen exerts genomic effects, i.e. those involving direct binding of the estrogen receptor (ER) to gene promoters in the nucleus, and nongenomic effects, mediated by interactions of the ER with other proteins. Here, using human umbilical vein endothelial cells (HUVECs), immunological detection, MS-based analyses, and cGMP and H2S assays, we show that 17β-estradiol (E2) rapidly enhances endothelial H2S release in a nongenomic manner. We found that E2 induces phosphorylation of cystathionine γ-lyase (CSE), the key enzyme in vascular endothelial H2S generation. Mechanistically, E2 enhanced the interaction of membrane ERα with the Gα subunit Gαi-2/3, which then transactivated particulate guanylate cyclase-A (pGC-A) to produce cGMP, thereby activating protein kinase G type I (PKG-I). We also found that PKG-Iβ, but not PKG-Iα, interacts with CSE, leading to its phosphorylation, and rapidly induces endothelial H2S release. Furthermore, we report that silencing of either CSE or pGC-A in mice attenuates E2-induced aorta vasodilation. These results provide detailed mechanistic insights into estrogen's nongenomic effects on vascular endothelial H2S release and advance our current understanding of the protective activities of estrogen in the cardiovascular system.
Collapse
Affiliation(s)
- Xingyan Xu
- Department of Gynecology and Obstetrics, The Sixth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China.,State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Qing Yan
- Department of Gynecology and Obstetrics, The Sixth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China.,State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Xiaoyun Liu
- Department of Gynecology and Obstetrics, The Sixth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China.,State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Ping Li
- Department of Gynecology and Obstetrics, The Sixth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China.,State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Xiaosa Li
- Department of Gynecology and Obstetrics, The Sixth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China.,State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Yiwen Chen
- Department of Gynecology and Obstetrics, The Sixth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China.,State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Tommaso Simoncini
- Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa 56100, Italy
| | - Junxiu Liu
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Dongxing Zhu
- Department of Gynecology and Obstetrics, The Sixth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China .,State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Xiaodong Fu
- Department of Gynecology and Obstetrics, The Sixth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China .,State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| |
Collapse
|
|
7
|
Ramesh SS, Christopher R, Indira Devi B, Bhat DI. The vascular protective role of oestradiol: a focus on postmenopausal oestradiol deficiency and aneurysmal subarachnoid haemorrhage. Biol Rev Camb Philos Soc 2019; 94:1897-1917. [DOI: 10.1111/brv.12541] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 06/04/2019] [Accepted: 06/10/2019] [Indexed: 12/24/2022]
Affiliation(s)
- Shruthi S. Ramesh
- Department of NeurochemistryNational Institute of Mental Health and Neuro Sciences Bengaluru‐560029 Karnataka India
| | - Rita Christopher
- Department of NeurochemistryNational Institute of Mental Health and Neuro Sciences Bengaluru‐560029 Karnataka India
| | - Bhagavatula Indira Devi
- Department of NeurosurgeryNational Institute of Mental Health and Neuro Sciences Bengaluru‐560029 Karnataka India
| | - Dhananjaya I. Bhat
- Department of NeurosurgeryNational Institute of Mental Health and Neuro Sciences Bengaluru‐560029 Karnataka India
| |
Collapse
|
|
8
|
Pollow DP, Uhlorn JA, Sylvester MA, Romero-Aleshire MJ, Uhrlaub JL, Lindsey ML, Nikolich-Zugich J, Brooks HL. Menopause and FOXP3 + Treg cell depletion eliminate female protection against T cell-mediated angiotensin II hypertension. Am J Physiol Heart Circ Physiol 2019; 317:H415-H423. [PMID: 31099612 DOI: 10.1152/ajpheart.00792.2018] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Although it is known that the prevalence and severity of hypertension increases in women after menopause, the contribution of T cells to this process has not been explored. Although the immune system is both necessary and required for the development of angiotensin II (ANG II) hypertension in men, we have demonstrated that premenopausal women are protected from T cell-mediated hypertension. The goal of the current study was to test the hypotheses that 1) female protection against T cell-mediated ANG II hypertension is eliminated following progression into menopause and 2) T regulatory cells (Tregs) provide premenopausal protection against ANG II-induced hypertension. Menopause was induced in Rag-1-/- mice (via 4-vinylcyclohexene diepoxide), and all mice received a 14-day ANG II infusion. Donor CD3+ T cells were adoptively transferred 3 wk before ANG II infusion. In the absence of T cells, systolic blood pressure responses to ANG II were similar to those seen in premenopausal mice (Δ12 mmHg). After adoptive transfer of T cells, ANG II significantly increased systolic blood pressure in postmenopausal females (Δ28 mmHg). A significant increase in F4/80 positive renal macrophages, an increase in renal inflammatory gene expression, along with a reduction in renal expression of mannose receptor C-type 1, a marker for M2 macrophages, accompanied the increase in systolic blood pressure (SBP). Flow cytometric analysis identified that Tregs were significantly decreased in the spleen and kidneys of Rag-1-/- menopausal mice versus premenopausal females, following ANG II infusion. In a validation study, an anti-CD25 antibody was used to deplete Tregs in premenopausal mice, which induced a significant increase in SBP. These results demonstrate that premenopausal protection against T cell-mediated ANG II hypertension is eliminated once females enter menopause, suggesting that a change in hormonal status upregulates macrophage-induced proinflammatory and T cell-dependent responses. Furthermore, we are the first to report that the presence of Tregs are required to suppress ANG II hypertension in premenopausal females.NEW & NOTEWORTHY Whether progression into menopause eliminated female protection against T cell-mediated hypertension was examined. Menopausal mice without T cells remained protected against angiotensin II (ANG II) hypertension; however, in the presence of T cells, blood pressure responses to ANG II increased significantly in menopause. Underlying mechanisms examined were anti-inflammatory protection provided by T regulatory cells in premenopausal females and renal inflammatory processes involving macrophage infiltration and cytokine activation.
Collapse
Affiliation(s)
- Dennis P Pollow
- Department of Physiology, University of Arizona, Tucson, Arizona
| | - Joshua A Uhlorn
- Department of Physiology, University of Arizona, Tucson, Arizona
| | | | | | - Jennifer L Uhrlaub
- Department of Immunobiology, University of Arizona, Tucson, Arizona.,University of Arizona Center on Aging, University of Arizona, Tucson, Arizona
| | - Merry L Lindsey
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.,Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, Mississippi
| | - Janko Nikolich-Zugich
- Department of Immunobiology, University of Arizona, Tucson, Arizona.,University of Arizona Center on Aging, University of Arizona, Tucson, Arizona
| | - Heddwen L Brooks
- Department of Physiology, University of Arizona, Tucson, Arizona.,University of Arizona Center on Aging, University of Arizona, Tucson, Arizona.,Department of Pharmacology, University of Arizona, Tucson, Arizona.,Sarver Heart Center, University of Arizona, Tucson, Arizona
| |
Collapse
|
|
9
|
Chen SQ, Ding LN, Zeng NX, Liu HM, Zheng SH, Xu JW, Li RM. Icariin induces irisin/FNDC5 expression in C2C12 cells via the AMPK pathway. Biomed Pharmacother 2019; 115:108930. [PMID: 31055234 DOI: 10.1016/j.biopha.2019.108930] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 04/22/2019] [Accepted: 04/26/2019] [Indexed: 01/09/2023] Open
Abstract
Backgroud Icariin, a major bioactive pharmaceutical component of the Chinese herbal medicine Epimedii Herba, has demonstrated lipid-lowering and anti-obesity effects. Irisin/ fibronectin type III domain-containing 5 (FNDC5) protects against obesity by inducing browning in white adipose tissue. Objectives This study investigated the effects of icariin on irisin/FNDC5 expression in C2C12 myotubes. Method Cultured murine C2C12 myocytes were used to study the effects of icariin on irisin/FNDC5 expressions by Western-blot, qPCR, Elisa and Immunofluorescence. We also investigated FNDC5 expression in icariin-treated intact mice. Results Icariin increased irisin/FNDC5 protein levels. mRNA levels of irisin/FNDC5 were also increased in C2C12 myocytes after treatment with icariin. Icariin increased peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1α) protein and mRNA levels. Additionally, icariin exposure resulted in phosphorylation of AMP-activated protein kinase (AMPK) in a dose-dependent manner. The regulatory effect of icariin on FNDC5 protein expression was blocked by the AMPK antagonist compound C or silencing of AMPK, suggesting that icariin increased FNDC5 protein expression via the AMPK pathway. In vivo, icariin decreased body weight gain in C57BL/6 mice and increased FNDC5, PGC-1α, and p-AMPK expression levels in skeletal muscle. Conclusions Taken together, our results indicated that icariin induces irisin/FNDC5 expression via the AMPK pathway, indicating that icariin may be promising as an anti-obesity drug.
Collapse
Affiliation(s)
- Sui-Qing Chen
- The research center of basic integrative medicine, Basic Medical College, Guangzhou University of Chinese Medicine, University Town, Guangzhou 510006, China
| | - Li-Na Ding
- The research center of basic integrative medicine, Basic Medical College, Guangzhou University of Chinese Medicine, University Town, Guangzhou 510006, China
| | - Ning-Xi Zeng
- The research center of basic integrative medicine, Basic Medical College, Guangzhou University of Chinese Medicine, University Town, Guangzhou 510006, China
| | - Hai-Mei Liu
- The research center of basic integrative medicine, Basic Medical College, Guangzhou University of Chinese Medicine, University Town, Guangzhou 510006, China
| | - Shu-Hui Zheng
- Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong Province, China
| | - Jin-Wen Xu
- The research center of basic integrative medicine, Basic Medical College, Guangzhou University of Chinese Medicine, University Town, Guangzhou 510006, China.
| | - Run-Mei Li
- The research center of basic integrative medicine, Basic Medical College, Guangzhou University of Chinese Medicine, University Town, Guangzhou 510006, China.
| |
Collapse
|
|
10
|
Qiu L, Xu C, Jiang H, Li W, Tong S, Xia H. Cantharidin Attenuates the Proliferation and Migration of Vascular Smooth Muscle Cells through Suppressing Inflammatory Response. Biol Pharm Bull 2019; 42:34-42. [DOI: 10.1248/bpb.b18-00462] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Liqiang Qiu
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University
| | - Changwu Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University
| | - Hong Jiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University
| | - Wenjing Li
- Department of Oncology and Hematology, Affiliated Hospital of Changchun University of Chinese Medicine
| | - Suiyang Tong
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University
| | - Hao Xia
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University
| |
Collapse
|
|
11
|
Wang C, Li J, Ye S, Zhang Y, Li P, Wang L, Wang TH. Oestrogen Inhibits VEGF Expression And Angiogenesis In Triple-Negative Breast Cancer By Activating GPER-1. J Cancer 2018; 9:3802-3811. [PMID: 30405852 PMCID: PMC6216003 DOI: 10.7150/jca.29233] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 08/18/2018] [Indexed: 12/31/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is the most malignant type of breast cancer with ample vascularisation and high vascular endothelial growth factor (VEGF) expression. The sex steroid hormone oestrogen is involved in several cellular activities associated with TNBC regulation. However, the role of oestrogen in VEGF expression and angiogenesis in TNBC remains unclear. In this study, we found that treatment with 17β-oestradiol (E2) inhibited VEGF mRNA and protein expression in the TNBC cell lines MDA-MB-468 and MDA-MB-436. To further elaborate on the phenomenon of E2-regulated angiogenesis, we showed that conditioned medium from the TNBC cell line MDA-MB-468 treated with E2 inhibits the tube formation ability of human umbilical vein endothelial cells (HUVECs). Additionally, the G-protein-coupled oestrogen receptor-1 (GPER-1)-specific agonist G-1 has a function similar to that of E2. While G-15, the selective antagonist of GPER-1, notably reversed the inhibitory effects of E2 and G-1 on VEGF expression and tube formation, suggesting that GPER-1 is involved in the E2-induced angiogenesis suppression in TNBC cells. Moreover, E2 inhibited in vivo tumour growth and angiogenesis and reduced the expression levels of VEGF, NF-κB/p65, STAT3, and the endothelial marker CD34 in MDA-MB-468 xenograft tumours. Our findings provide important evidence that E2 can inhibit VEGF expression and angiogenesis in TNBC by activating GPER-1, offering additional insight into tumour angiogenesis and targets for drug intervention in TNBC.
Collapse
Affiliation(s)
- Chen Wang
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jiehao Li
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Shuang Ye
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Yaxing Zhang
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Ping Li
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Ling Wang
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Ting-Huai Wang
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
| |
Collapse
|
|
12
|
Zheng S, Sun P, Liu H, Li R, Long L, Xu Y, Chen S, Xu J. 17β-estradiol upregulates striatin protein levels via Akt pathway in human umbilical vein endothelial cells. PLoS One 2018; 13:e0202500. [PMID: 30138337 PMCID: PMC6107185 DOI: 10.1371/journal.pone.0202500] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 08/04/2018] [Indexed: 11/19/2022] Open
Abstract
17β-estradiol (E2) has been shown to have beneficial effects on the cardiovascular system. We previously demonstrated that E2 increases striatin levels and inhibits migration in vascular smooth muscle cells. The objective of the present study was to investigate the effects of E2 on the regulation of striatin expression in human umbilical vein endothelial cells (HUVECs). We demonstrated that E2 increased striatin protein expression in a dose- and time-dependent manner in HUVECs. Pretreatment with ICI 182780 or the phosphatidylinositol-3 kinase inhibitor, wortmannin, abolished E2-mediated upregulation of striatin protein expression. Treatment with E2 resulted in Akt phosphorylation in a time-dependent manner. Moreover, silencing striatin significantly inhibited HUVEC migration, while striatin overexpression significantly promoted HUVEC migration. Finally, E2 enhanced HUVEC migration, which was inhibited by silencing striatin. In conclusion, our results demonstrated that E2-mediated upregulation of striatin promotes cell migration in HUVECs.
Collapse
Affiliation(s)
- Shuhui Zheng
- Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Peng Sun
- Department of Pathology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative innovation Center for Cancer Medicine, Guangzhou, China
| | - Haimei Liu
- Department of Physiology, Basic Medical College, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| | - Runmei Li
- School of Chinese Pharmaceutical Science, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| | - Lingli Long
- Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Yuxia Xu
- Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Suiqing Chen
- Department of Physiology, Basic Medical College, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| | - Jinwen Xu
- Department of Physiology, Basic Medical College, Guangzhou University of Chinese Medicine, University Town, Guangzhou, China
| |
Collapse
|
|
13
|
Boese AC, Chang L, Yin KJ, Chen YE, Lee JP, Hamblin MH. Sex differences in abdominal aortic aneurysms. Am J Physiol Heart Circ Physiol 2018; 314:H1137-H1152. [PMID: 29350999 DOI: 10.1152/ajpheart.00519.2017] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Abdominal aortic aneurysm (AAA) is a vascular disorder with a high case fatality rate in the instance of rupture. AAA is a multifactorial disease, and the etiology is still not fully understood. AAA is more likely to occur in men, but women have a greater risk of rupture and worse prognosis. Women are reportedly protected against AAA possibly by premenopausal levels of estrogen and are, on average, diagnosed at older ages than men. Here, we review the present body of research on AAA pathophysiology in humans, animal models, and cultured cells, with an emphasis on sex differences and sex steroid hormone signaling.
Collapse
Affiliation(s)
- Austin C Boese
- Department of Pharmacology, Tulane University School of Medicine , New Orleans, Louisiana
| | - Lin Chang
- Center for Advanced Models for Translational Sciences and Therapeutics, Department of Internal Medicine, University of Michigan , Ann Arbor, Michigan
| | - Ke-Jie Yin
- Department of Neurology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
| | - Y Eugene Chen
- Center for Advanced Models for Translational Sciences and Therapeutics, Department of Internal Medicine, University of Michigan , Ann Arbor, Michigan
| | - Jean-Pyo Lee
- Department of Physiology, Tulane University School of Medicine , New Orleans, Louisiana.,Center for Stem Cell Research and Regenerative Medicine , New Orleans, Louisiana
| | - Milton H Hamblin
- Department of Pharmacology, Tulane University School of Medicine , New Orleans, Louisiana
| |
Collapse
|
|
14
|
Sukocheva OA. Estrogen, estrogen receptors, and hepatocellular carcinoma: Are we there yet? World J Gastroenterol 2018; 24:1-4. [PMID: 29358876 PMCID: PMC5757114 DOI: 10.3748/wjg.v24.i1.1] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 12/06/2017] [Accepted: 12/12/2017] [Indexed: 02/06/2023] Open
Abstract
A protective role of the sex steroid hormone estrogen in hepatocellular carcinoma (HCC) was suggested a few decades ago according to clinical data showing higher HCC morbidity and mortality among males. Several recent studies further confirmed the anti-cancer effects of estrogen in the liver. However, it remains to be identified how to exploit estrogen signalling within clinical settings for HCC treatment. There are several unresolved issues related to the estrogen pathway in liver cells. The main problems include the absence of a clear understanding of which estrogen receptor (ER) isoform is predominantly expressed in normal and malignant liver cells, the ER isoform expression difference between males and females, and which ER isoform should be targeted when designing HCC therapy. Some of those questions were recently addressed by Iyer and co-authors. The current editorial review critically analyses the study by Iyer et al (WJG, 2017) that investigated the expression of ER subtypes in liver samples collected from patients with a healthy liver, hepatitis C virus cirrhosis, and HCC. ER presence was evaluated in association with gender, intracellular localization, inflammation marker NF-κB, and proliferation-related effector cyclin D1. The study limitations and advantages are discussed in light of recent advances in the HCC and estrogen signalling areas.
Collapse
Affiliation(s)
- Olga A Sukocheva
- School of Health Sciences, Flinders University of South Australia, Flinders Drive, Bedford Park 5042, Australia
| |
Collapse
|
|
15
|
Zhou LJ, Chen XY, Liu SP, Zhang LL, Xu YN, Mu PW, Geng DF, Tan Z. Downregulation of Cavin-1 Expression via Increasing Caveolin-1 Degradation Prompts the Proliferation and Migration of Vascular Smooth Muscle Cells in Balloon Injury-Induced Neointimal Hyperplasia. J Am Heart Assoc 2017; 6:e005754. [PMID: 28751541 PMCID: PMC5586430 DOI: 10.1161/jaha.117.005754] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 06/08/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND Percutaneous coronary intervention has been widely used in the treatment of ischemic heart disease, but vascular restenosis is a main limitation of percutaneous coronary intervention. Our previous work reported that caveolin-1 had a key functional role in intimal hyperplasia, whereas whether Cavin-1 (another important caveolae-related protein) was involved is still unknown. Therefore, we will investigate the effect of Cavin-1 on neointimal formation. METHODS AND RESULTS Balloon injury markedly reduced Cavin-1 protein and enhanced ubiquitin protein expression accompanied with neointimal hyperplasia in injured carotid arteries, whereas Cavin-1 mRNA had no change. In cultured vascular smooth muscle cells (VSMCs), Cavin-1 was downregulated after inhibition of protein synthesis by cycloheximide, which was distinctly prevented by pretreatment with proteasome inhibitor MG132 but not by lysosomal inhibitor chloroquine, suggesting that proteasomal degradation resulted in Cavin-1 downregulation. Knockdown of Cavin-1 by local injection of Cavin-1 short hairpin RNA (shRNA) into balloon-injured carotid arteries in vivo promoted neointimal formation. In addition, inhibition or overexpression of Cavin-1 in cultured VSMCs in vitro prompted or suppressed VSMC proliferation and migration via increasing or decreasing extracellular signal-regulated kinase phosphorylation and matrix-degrading metalloproteinases-9 activity, respectively. However, under basic conditions, the effect of Cavin-1 on VSMC migration was stronger than on proliferation. Moreover, our results indicated that Cavin-1 regulated caveolin-1 expression via lysosomal degradation pathway. CONCLUSIONS Our study revealed the role and the mechanisms of Cavin-1 downregulation in neointimal formation by promoting VSMC proliferation, migration, and synchronously enhancing caveolin-1 lysosomal degradation. Cavin-1 may be a potential therapeutic target for the treatment of postinjury vascular remodeling.
Collapse
MESH Headings
- Angioplasty, Balloon/adverse effects
- Animals
- Carotid Artery Injuries/etiology
- Carotid Artery Injuries/genetics
- Carotid Artery Injuries/metabolism
- Carotid Artery Injuries/pathology
- Carotid Artery, External/metabolism
- Carotid Artery, External/pathology
- Caveolin 1/metabolism
- Cell Movement
- Cell Proliferation
- Cells, Cultured
- Disease Models, Animal
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Lysosomes/metabolism
- Matrix Metalloproteinase 9/metabolism
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Muscle, Smooth, Vascular/injuries
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Neointima
- Proteasome Endopeptidase Complex/metabolism
- Proteolysis
- RNA Interference
- RNA, Small Interfering/administration & dosage
- RNA-Binding Proteins/genetics
- RNA-Binding Proteins/metabolism
- Rats, Sprague-Dawley
- Signal Transduction
- Time Factors
- Transfection
- Vascular Remodeling
Collapse
Affiliation(s)
- Li-Jun Zhou
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xue-Ying Chen
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Shui-Ping Liu
- Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Lin-Lin Zhang
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ya-Nan Xu
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Pan-Wei Mu
- Department of Endocrinology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Deng-Feng Geng
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhi Tan
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
16
|
Associations of estradiol levels and genetic polymorphisms of inflammatory genes with the risk of ischemic stroke. J Biomed Sci 2017; 24:25. [PMID: 28351426 PMCID: PMC5371181 DOI: 10.1186/s12929-017-0332-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 03/22/2017] [Indexed: 02/05/2023] Open
Abstract
Background Estrogen plays an important role as an anti-inflammatory and neuroprotective agent in ischemic stroke. In this study, we analyzed the effect of a polygenic risk score (PRS) constructed using inflammatory genes and estradiol levels on the risk of ischemic stroke. Methods This case-control study was conducted with 624 ischemic stroke patients and 624 age- and gender-matched controls. The PRS estimated the polygenic contribution of inflammatory genes from ischemic stroke susceptibility loci. Estradiol levels were measured using a radioimmunoassay. High and low estradiol levels were defined according to the log-transformed median estradiol levels in female and male controls. Results Subjects in the fourth quartile of the PRS had a significant 1.57-fold risk of ischemic stroke (95% confidence interval [CI], 1.12 ~ 2.19), after adjusting for covariates compared to individuals in the lowest quartile. Compared to individuals with high estradiol levels and a low PRS as the reference group, those exposed to low estradiol levels and a high PRS had an increased risk of ischemic stroke (odds ratio, 3.35; 95% CI, 1.79 ~ 6.28). Similar results were also observed in males when the analysis was stratified by gender. Conclusions Our data suggest that the PRS can be useful in evaluating a high risk of ischemic stroke among patients, especially those exposed to low estradiol levels.
Collapse
|
|
17
|
Li P, Wei J, Li X, Cheng Y, Chen W, Cui Y, Simoncini T, Gu Z, Yang J, Fu X. 17β-Estradiol Enhances Vascular Endothelial Ets-1/miR-126-3p Expression: The Possible Mechanism for Attenuation of Atherosclerosis. J Clin Endocrinol Metab 2017; 102:594-603. [PMID: 27870587 DOI: 10.1210/jc.2016-2974] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Accepted: 11/17/2016] [Indexed: 01/30/2023]
Abstract
CONTEXT Endothelial microRNA 126 (miR-126) attenuates the development of atherosclerosis (AS). However, there is no evidence showing the role of miR-126 in estrogen's antiatherogenic effects. OBJECTIVE We hypothesized that 17β-estradiol (E2) modulates miR-126 expression and thus may improve endothelial function and retard AS development. DESIGN/SETTING/PARTICIPANTS This was a prospective cohort study of 12 healthy regularly menstruating female volunteers. ApoE-/- mice were used as the atherosclerosis model and human umbilical vascular endothelial cells (HUVECs) were cultured as the cell model. MAIN OUTCOME MEASURES Serum hormones and miR-126-3p levels were measured up to 3 times for 1 cycle. Real-time polymerase chain reaction, histology for atherosclerotic lesions, immunofluorescence, luciferase assay, transfection experiments, cell proliferation, migration and tube formation assay, and western blot were performed. RESULTS Serum concentrations of miR-126-3p in cycling women were higher at the ovulatory and luteal phases than in the follicular phase, and they were positively correlated with E2 values. Administration of miR-126-3p mimics to ApoE-/- mice-attenuated atherogenesis, and antagomir-126-3p partially reversed the protective effect of E2 on atherogenesis. In HUVECs, E2 increased miR-126-3p expression via upregulation of Ets-1 (a transcription factor for miR-126). c-Src/Akt signaling was important for E2-mediated expression of Ets-1/miR-126. E2 decreased expression of miR-126-3p target Spred1 (a protein that inhibits mitogenic signaling). Overexpression of Spred1 partially blocked enhancement of endothelial cell proliferation, migration, and tube formation by E2. Additionally, E2 regulates miR-126-3p-mediated expression of vascular cell adhesion molecule-1 to inhibit monocyte adhesion into HUVECs. CONCLUSIONS E2 protection against atherogenesis is possibly mediated by Ets-1/miR-126.
Collapse
Affiliation(s)
- Ping Li
- Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, People's Republic of China
| | - Jinzhi Wei
- Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, People's Republic of China
| | - Xiaosa Li
- Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, People's Republic of China
| | - Yang Cheng
- Department of Gynecology and Obstetrics, Municipal First People's Hospital of Guangzhou, Guangzhou 510180, People's Republic of China
| | - Weiyu Chen
- School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2052, Australia; and
| | - Yuhong Cui
- Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, People's Republic of China
| | - Tommaso Simoncini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56100, Italy
| | - Zhengtian Gu
- Department of Gynecology and Obstetrics, Municipal First People's Hospital of Guangzhou, Guangzhou 510180, People's Republic of China
| | - Jun Yang
- Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, People's Republic of China
| | - Xiaodong Fu
- Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, People's Republic of China
| |
Collapse
|
|
18
|
Glassberg MK, Catanuto P, Shahzeidi S, Aliniazee M, Lilo S, Rubio GA, Elliot SJ. Estrogen deficiency promotes cigarette smoke-induced changes in the extracellular matrix in the lungs of aging female mice. Transl Res 2016; 178:107-117. [PMID: 27519148 DOI: 10.1016/j.trsl.2016.07.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 07/12/2016] [Accepted: 07/17/2016] [Indexed: 02/07/2023]
Abstract
Female smokers have a faster decline in lung function with increasing age and overall develop a greater loss of lung function than male smokers. This raises the question of whether estrogen status in women affects susceptibility to cigarette smoke (CS)-induced lung disease. Mouse models suggest that female mice are more susceptible than males to CS-induced lung disease. Moreover, young CS-exposed female mice develop emphysema earlier than male mice. The purpose of this study was to characterize the relationship of estrogen status on the pattern and severity of CS-induced lung disease. In this study, 15-month-old female C57BL/6J mice were ovariectomized and administered either placebo (pla) or 17β-estradiol (E2, 0.025 mg) 2 weeks after ovariectomy. They were further divided into those that were exposed to CS and no-smoke controls (NSC). Mice were exposed to CS in stainless steel inhalation chambers 3 hours a day, 5 days a week for 6 months, and sacrificed after 24 weeks of CS exposure. Blood and urine were collected at sacrifice to measure estrogen and cotinine levels, a metabolite of nicotine. Uterine weight was recorded as an indicator of estrogen status. Results showed that CS in the absence of E2 induced a decrease in hydroxyproline content, macrophage number, and respiratory chain complex-1 protein. CS without E2 also resulted in an increase in matrix metalloproteinase-2 activity and apoptosis and a change in the ratio of estrogen receptor subtype. These findings were abrogated with administration of E2, suggesting that estrogen deficiency increases susceptibility to CS-induced lung disease.
Collapse
Affiliation(s)
- Marilyn K Glassberg
- Department of Medicine, Miller School of Medicine, University of Miami, Miami, Fla; Department of Surgery, Miller School of Medicine, University of Miami, Miami, Fla.
| | - Paola Catanuto
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Fla
| | - Shahriar Shahzeidi
- Division of Pediatric Pulmonology, Department of Pediatrics, Miller School of Medicine, University of Miami, Miami, Fla
| | | | - Sarit Lilo
- Department of Medicine, Miller School of Medicine, University of Miami, Miami, Fla
| | - Gustavo A Rubio
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Fla
| | - Sharon J Elliot
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Fla
| |
Collapse
|
|
19
|
Oestrogen exerts anti-inflammation via p38 MAPK/NF-κB cascade in adipocytes. Obes Res Clin Pract 2016; 10:633-641. [PMID: 27004692 DOI: 10.1016/j.orcp.2016.02.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 02/24/2016] [Accepted: 02/29/2016] [Indexed: 01/09/2023]
Abstract
BACKGROUND Oestrogen has anti-inflammatory property in obesity. However, the mechanism is still not defined. OBJECTIVE To investigate the effect of oestrogen on LPS-induced monocyte chemoattractant protein-1 (MCP-1) production in adipocytes. METHODS Lipopolysaccharides (LPS) was used to imitate inflammatory responses and monocyte chemotactic protein-1 (MCP-1) was selected as an inflammatory marker to observe. 17β-Estradiol (E2), SB203580 (SB), pyrrolidine dithiocarbamate (PDTC), pertussis toxin (PTX), wortmannin (WM), p65 siRNA and p38 MAPK siRNA were pre-treated respectively or together in LPS-induced MCP-1. Then p38 MAPK and NF-κB cascade were silenced successively to observe the change of each other. Lastly, oestrogen receptor (ER) α agonist, ERβ agonist and ER antagonist were utilised. RESULTS LPS-induced MCP-1 largely impaired by pre-treatment with E2, SB, PDTC or silencing NF-κB subunit. E2 inhibited LPS-induced MCP-1 in a time- and dose-dependent manner, which was related to the suppression of p65 translocation to nucleus. Furthermore, LPS rapidly activated p38 MAPK, while E2 markedly inhibited this activation. It markedly attenuated LPS-stimulated p65 translocation to nucleus and MCP-1 production by transfecting with p38 MAPK siRNA or using p38 MAPK inhibitor. The oestrogen's inhibitory effect was mimicked by the ERα agonist, but not by the ERβ agonist. The inhibition of E2 on p38 MAPK phosphorylation was prevented by ER antagonist. CONCLUSIONS E2 inhibits LPS-stimulated MCP-1 in adipocytes. This effect is related to the inhibition of p38 MAPK/NF-κB cascade, and ERα appears to be the dominant ER subtype in these events.
Collapse
|
|
20
|
Liu Q, Li J, Liang Q, Wang D, Luo Y, Yu F, Janicki JS, Fan D. Sparstolonin B suppresses rat vascular smooth muscle cell proliferation, migration, inflammatory response and lipid accumulation. Vascul Pharmacol 2015; 67-69:59-66. [PMID: 25869499 DOI: 10.1016/j.vph.2015.03.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 03/06/2015] [Accepted: 03/30/2015] [Indexed: 01/04/2023]
Abstract
Vascular smooth muscle cells (VSMCs) play a crucial role in atherosclerotic lesion formation. Sparstolonin B (SsnB) is a TLR2/TLR4 antagonist that inhibits inflammatory responses in multiple cell types. Herein, we investigated if SsnB inhibited VSMC proliferation, migration, inflammatory response and lipid accumulation. We found that SsnB suppressed VSMC proliferation and migration induced by PDGF. SsnB significantly suppressed the expression of MCP-1, TNFα and IL-6 in VSMCs stimulated by either lipopolysaccharide (LPS) or PDGF. Erk1/2 and Akt signaling pathways, which are responsible for the VSMC inflammatory response, were activated by LPS or PDGF stimulation, and SsnB significantly inhibited their activation. SsnB also substantially suppressed the intracellular cholesterol accumulation in VSMCs loaded with acetylated LDL. Mechanistically, SsnB remarkably repressed LPS-induced up-regulation of CD36, which is responsible for lipid uptake, and dramatically reversed LPS-induced inhibition of ABCA1, which promotes the efflux of intracellular free cholesterol. In conclusion, our results indicate that SsnB significantly inhibits VSMC proliferation, migration, inflammatory responses and lipid accumulation. Along with the previously reported anti-inflammatory activities of SsnB on macrophages and vascular endothelial cells, our data strongly suggest that SsnB may be developed as a new anti-atherogenic therapy.
Collapse
Affiliation(s)
- Qing Liu
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, United States; Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Jianping Li
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, United States
| | - Qiaoli Liang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Dawei Wang
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Yi Luo
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Fang Yu
- Department of Nutrition and Food Hygiene, Fourth Military Medical University, Xi'an 710032, China
| | - Joseph S Janicki
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, United States
| | - Daping Fan
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, United States.
| |
Collapse
|
|
21
|
Zheng S, Chen X, Hong S, Long L, Xu Y, Simoncini T, Fu X. 17β-Estradiol inhibits vascular smooth muscle cell migration via up-regulation of striatin protein. Gynecol Endocrinol 2015. [PMID: 26220767 DOI: 10.3109/09513590.2015.1021325] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Striatin, an estrogen receptor (ER)-interacting protein, plays an important role in estrogen's nongenomic actions in vascular endothelial cells. However, the role of striatin in VSMCs is unknown. Here, we investigated the role of striatin in estrogen-regulated VSMCs migration. 17β-Estradiol (E2) at 10 nM largely inhibited VSMCs migration, which was reversed by the silencing of striatin expression. E2 increased striatin protein expression in a dose- and time-dependent manner. ERα agonist PPT, but not ERβ agonist DPN, mimicked the regulatory effect of E2. The regulatory effect of E2 on striatin protein expression was blocked by the pure ER antagonist ICI 182,780 or the mitogen-activated protein kinase inhibitor PD98059, but not by the phosphatidylinositol-3 kinase inhibitor wortmannin or Src inhibitor PP2, suggesting that E2 increased striatin protein expression via extracellular-signal regulated kinase 1/2 (ERK1/2). E2 resulted in phosphorylation of ERK1/2 in a time-dependent manner. The silencing of ERK1/2 largely abolished E2-enhanced striatin expression. Finally, the inhibitory effect of E2 on VSMC migration was reversed by ICI 182,780 or PD98059. Taken together, our results indicate that E2 inhibits VSMC migration by increasing striatin expression via ERα to ERK1/2 pathway, which maybe helpful to understand estrogen's anti-atherogenic effect in VSMCs.
Collapse
Affiliation(s)
- Shuhui Zheng
- a Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-Sen University , Guangzhou , Guangdong Province , China
| | - Xi Chen
- b Department of Rehabilitation Medicine , the Third Affiliated Hospital, Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Shubin Hong
- c Department of Endocrinology , the First Affiliated Hospital, Sun Yat-Sen University , Guangzhou , Guangdong Province , China
| | - Lingli Long
- a Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-Sen University , Guangzhou , Guangdong Province , China
| | - Yuxia Xu
- a Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-Sen University , Guangzhou , Guangdong Province , China
| | - Tommaso Simoncini
- d Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development , University of Pisa , Pisa , Italy , and
| | - Xiaodong Fu
- e School of Basic Sciences, Guangzhou Medical University , Guangzhou , Guangdong Province , China
| |
Collapse
|
|
22
|
WANG HUAN, LIU YAN, ZHU LING, WANG WENJING, WAN ZHAOFEI, CHEN FANGYUAN, WU YAN, ZHOU JUAN, YUAN ZUYI. 17β-estradiol promotes cholesterol efflux from vascular smooth muscle cells through a liver X receptor α-dependent pathway. Int J Mol Med 2014; 33:550-8. [DOI: 10.3892/ijmm.2014.1619] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Accepted: 12/23/2013] [Indexed: 11/05/2022] Open
|
|
23
|
Curcumin inhibits LPS-induced inflammation in rat vascular smooth muscle cells in vitro via ROS-relative TLR4-MAPK/NF-κB pathways. Acta Pharmacol Sin 2013; 34:901-11. [PMID: 23645013 DOI: 10.1038/aps.2013.24] [Citation(s) in RCA: 149] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Accepted: 02/27/2013] [Indexed: 12/17/2022]
Abstract
AIM To investigate whether curcumin (Cur) suppressed lipopolysaccharide (LPS)-induced inflammation in vascular smooth muscle cells (VSMCs) of rats, and to determine its molecular mechanisms. METHODS Primary rat VSMCs were treated with LPS (1 μg/L) and Cur (5, 10, or 30 μmol/L) for 24 h. The levels of MCP-1, TNF-α, and iNOS were measured using ELISA and real-time RT-PCR. NO level was analyzed with the Griess reaction. Western-blotting was used to detect the activation of TLR4, MAPKs, IκBα, NF-κB p65, and the p47(phox) subunit of NADPH oxidase in the cells. RESULTS Treatment of VSMCs with LPS dramatically increased expression of inflammatory cytokines MCP-1 and TNF-α, expression of TLR4 and iNOS, and NO production. LPS also significantly increased phosphorylation of IκBα, nuclear translocation of NF-κB (p65) and phosphorylation of MAPKs in VSMCs. Furthermore, LPS significantly increased production of intracellular ROS, and decreased expression of p47(phox) subunit of NADPH oxidase. Pretreatment with Cur concentration-dependently attenuated all the aberrant changes in LPS-treated VSMCs. The LPS-induced overexpression of MCP-1 and TNF-α, and NO production were attenuated by pretreatment with the ERK inhibitor PD98059, the p38 MAPK inhibitor SB203580, the NF-κB inhibitor PDTC or anti-TLR4 antibody, but not with the JNK inhibitor SP600125. CONCLUSION Cur suppresses LPS-induced overexpression of inflammatory mediators in VSMCs in vitro via inhibiting the TLR4-MAPK/NF-κB pathways, partly due to block of NADPH-mediated intracellular ROS production.
Collapse
|
|
24
|
Abstract
Coronary heart disease is a leading cause of premature death in men. Epidemiological studies have shown a high prevalence of low serum testosterone levels in men with cardiovascular disease (CVD). Furthermore, a low testosterone level is associated in some but not in all observational studies with an increase in cardiovascular events and mortality. Testosterone has beneficial effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation: key mediators of atherosclerosis. A bidirectional relationship between low endogenous testosterone levels and concurrent illness complicates attempts to validate causality in this association and potential mechanistic actions are complex. Testosterone is a vasoactive hormone that predominantly has vasodilatory actions on several vascular beds, although some studies have reported conflicting effects. In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart failure. Although the mechanism of the action of testosterone on vascular tone in vivo is not understood, laboratory research has found that testosterone is an L-calcium channel blocker and induces potassium channel activation in vascular smooth muscle cells. Animal studies have consistently demonstrated that testosterone is atheroprotective, whereas testosterone deficiency promotes the early stages of atherogenesis. The translational effects of testosterone between in vitro animal and human studies, some of which have conflicting effects, will be discussed in this review. We review the evidence for a role of testosterone in vascular health, its therapeutic potential and safety in hypogonadal men with CVD, and some of the possible underlying mechanisms.
Collapse
Affiliation(s)
- Daniel M Kelly
- Department of Human Metabolism, Medical School, The University of Sheffield, Sheffield S10 2RX, UK
| | | |
Collapse
|
|
25
|
Peptide inhibitor of NF-κB translocation ameliorates experimental atherosclerosis. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 182:1910-21. [PMID: 23597852 DOI: 10.1016/j.ajpath.2013.01.022] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Revised: 12/17/2012] [Accepted: 01/10/2013] [Indexed: 11/22/2022]
Abstract
Atherosclerosis is a chronic inflammatory disease of the arterial wall. NF-κB is a major regulator of inflammation that controls the expression of many genes involved in atherogenesis. Activated NF-κB was detected in human atherosclerotic plaques, and modulation of NF-κB inflammatory activity limits disease progression in mice. Herein, we investigate the anti-inflammatory and atheroprotective effects of a cell-permeable peptide containing the NF-κB nuclear localization sequence (NLS). In vascular smooth muscle cells and macrophages, NLS peptide specifically blocked the importin α-mediated nuclear import of NF-κB and prevented lipopolysaccharide-induced pro-inflammatory gene expression, cell migration, and oxidative stress. In experimental atherosclerosis (apolipoprotein E-knockout mice fed a high-fat diet), i.p., 0.13 μmol/day NLS peptide administration for 5 weeks attenuated NF-κB activation in atherosclerotic plaques. NLS peptide significantly inhibited lesion development at both early (age 10 weeks) and advanced (age 28 weeks) stages of atherosclerosis in mice, without affecting serum lipid levels. Plaques from NLS-treated mice contained fewer macrophages of pro-inflammatory M1 subtype than those from respective untreated controls. By contrast, the relative smooth muscle cell and collagen content was increased, indicating a more stable plaque phenotype. NLS peptide also attenuated pro-inflammatory gene expression and oxidative stress in aortic lesions. Our study demonstrates that targeting NF-κB nuclear translocation hampers inflammation and atherosclerosis development and identifies cell-permeable NLS peptide as a potential anti-atherosclerotic agent.
Collapse
|
|
26
|
Tani A, Yasui T, Matsui S, Kato T, Kunimi K, Tsuchiya N, Yuzurihara M, Kase Y, Irahara M. Different circulating levels of monocyte chemoattractant protein-1 and interleukin-8 during the menopausal transition. Cytokine 2013; 62:86-90. [DOI: 10.1016/j.cyto.2013.02.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Revised: 01/30/2013] [Accepted: 02/08/2013] [Indexed: 10/27/2022]
|
|
27
|
High-mobility group box-1 induces proinflammatory cytokines production of Kupffer cells through TLRs-dependent signaling pathway after burn injury. PLoS One 2012. [PMID: 23209806 DOI: 10.1371/journal.] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Kupffer cells (KCs) were a significant source of cytokine release during the early stage of severe burns. High mobility group box protein 1 (HMGB1) was recently identified as a new type of proinflammatory cytokine. The ability of HMGB1 to generate inflammatory responses after burn trauma has not been well characterized. KCs were isolated from sham animals and rats with a 30% full-thickness burn, and then were stimulated with increasing concentrations of HMGB1. The levels of Tumor necrosis factor (TNF)-α and interleukin (IL)-1β in culture supernatant were measured by enzyme-linked immunosorbent assay. Northern blot analysis was performed to detect the expressions of TNF-α and IL-1β mRNAs. The activities of p38 MAPK and JNK (by Western blot analysis) as well as NF-κB (by EMSA) in KCs were also examined. As a result, HMGB1 in vitro upregulated expressions of TNF-α and IL-1β of KCs in a dose-dependent manner, and HMGB1 promoted KCs from burn rats to produce significantly more TNF-α and IL-1β proteins than those from sham animals. After harvested from burn rats, KCs were pre-incubated with anti-TLR2 or anti-TLR4 antibody prior to HMGB1 administration. HMGB1 exposure not only significantly increased expressions of TNF-α and IL-1β mRNAs in KCs from burn rats, but also enhanced activities of p38 MAPK, JNK and NF-κB. However, these upregulation events were all reduced by pre-incubation with anti-TLR2 or anti-TLR4 antibody. These results indicate that HMGB1 induces proinflammatory cytokines production of KCs after sever burn injury, and this process might be largely dependent on TLRs-dependent MAPKs/NF-κB signal pathway.
Collapse
|
|
28
|
Chen XL, Sun L, Guo F, Wang F, Liu S, Liang X, Wang RS, Wang YJ, Sun YX. High-mobility group box-1 induces proinflammatory cytokines production of Kupffer cells through TLRs-dependent signaling pathway after burn injury. PLoS One 2012; 7:e50668. [PMID: 23209806 PMCID: PMC3507775 DOI: 10.1371/journal.pone.0050668] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2012] [Accepted: 10/25/2012] [Indexed: 11/19/2022] Open
Abstract
Kupffer cells (KCs) were a significant source of cytokine release during the early stage of severe burns. High mobility group box protein 1 (HMGB1) was recently identified as a new type of proinflammatory cytokine. The ability of HMGB1 to generate inflammatory responses after burn trauma has not been well characterized. KCs were isolated from sham animals and rats with a 30% full-thickness burn, and then were stimulated with increasing concentrations of HMGB1. The levels of Tumor necrosis factor (TNF)-α and interleukin (IL)-1β in culture supernatant were measured by enzyme-linked immunosorbent assay. Northern blot analysis was performed to detect the expressions of TNF-α and IL-1β mRNAs. The activities of p38 MAPK and JNK (by Western blot analysis) as well as NF-κB (by EMSA) in KCs were also examined. As a result, HMGB1 in vitro upregulated expressions of TNF-α and IL-1β of KCs in a dose-dependent manner, and HMGB1 promoted KCs from burn rats to produce significantly more TNF-α and IL-1β proteins than those from sham animals. After harvested from burn rats, KCs were pre-incubated with anti-TLR2 or anti-TLR4 antibody prior to HMGB1 administration. HMGB1 exposure not only significantly increased expressions of TNF-α and IL-1β mRNAs in KCs from burn rats, but also enhanced activities of p38 MAPK, JNK and NF-κB. However, these upregulation events were all reduced by pre-incubation with anti-TLR2 or anti-TLR4 antibody. These results indicate that HMGB1 induces proinflammatory cytokines production of KCs after sever burn injury, and this process might be largely dependent on TLRs-dependent MAPKs/NF-κB signal pathway.
Collapse
Affiliation(s)
- Xu-Lin Chen
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, PR China.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Abstract
Estrogens not only play a pivotal role in sexual development but are also involved in several physiological processes in various tissues including vasculature. While several epidemiological studies documented an inverse relationship between plasma estrogen levels and the incidence of cardiovascular disease and related it to the inhibition of atherosclerosis, an interventional trial showed an increase in cardiovascular events among postmenopausal women on estrogen treatment. The development of atherosclerotic lesions involves complex interplay between various pro- or anti-atherogenic processes that can be effectively studied only in vivo in appropriate animal models. With the advent of genetic engineering, transgenic mouse models of atherosclerosis have supplemented classical dietary cholesterol-induced disease models such as the cholesterol-fed rabbit. In the last two decades, these models were widely applied along with in vitro cell systems to specifically investigate the influence of estrogens on the development of early and advanced atherosclerotic lesions. The present review summarizes the results of these studies and assesses their contribution toward better understanding of molecular mechanisms underlying anti- and/or pro-atherogenic effects of estrogens in humans.
Collapse
Affiliation(s)
- Jerzy-Roch Nofer
- Center for Laboratory Medicine, University Hospital Münster, Albert Schweizer Campus 1, Gebäude A1, 48129 Münster, Germany.
| |
Collapse
|
|
30
|
Fu XD, Garibaldi S, Gopal S, Polak K, Palla G, Spina S, Mannella P, Genazzani AR, Genazzani AD, Simoncini T. Dydrogesterone exerts endothelial anti-inflammatory actions decreasing expression of leukocyte adhesion molecules. Mol Hum Reprod 2011; 18:44-51. [DOI: 10.1093/molehr/gar062] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
|