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Fang XY, Zhang J, Qian TT, Gao P, Wu Q, Fang Q, Ke SS, Huang RG, Zhang HC, Qiao NN, Fan YG, Ye DQ. Metabolomic profiles, polygenic risk scores and risk of rheumatoid arthritis: a population-based cohort study in the UK Biobank. RMD Open 2023; 9:e003560. [PMID: 38035758 PMCID: PMC10689387 DOI: 10.1136/rmdopen-2023-003560] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 10/16/2023] [Indexed: 12/02/2023] Open
Abstract
OBJECTIVE To investigate the relationship between metabolomic profiles, genome-wide polygenic risk scores (PRSs) and risk of rheumatoid arthritis (RA). METHODS 143 nuclear magnetic resonance-based plasma metabolic biomarkers were measured among 93 800 participants in the UK Biobank. The Cox regression model was used to assess the associations between these metabolic biomarkers and RA risk, and genetic correlation and Mendelian randomisation analyses were performed to reveal their causal relationships. Subsequently, a metabolic risk score (MRS) comprised of the weighted sum of 17 clinically validated metabolic markers was constructed. A PRS was derived by assigning weights to genetic variants that exhibited significant associations with RA at a genome-wide level. RESULTS A total of 620 incident RA cases were recorded during a median follow-up time of 8.2 years. We determined that 30 metabolic biomarkers were potentially associated with RA, while no further significant causal associations were found. Individuals in the top decile of MRS had an increased risk of RA (HR 3.52, 95% CI: 2.80 to 4.43) compared with those below the median of MRS. Further, significant gradient associations between MRS and RA risk were observed across genetic risk strata. Specifically, compared with the low genetic risk and favourable MRS group, the risk of incident RA in the high genetic risk and unfavourable MRS group has almost elevated by fivefold (HR 6.10, 95% CI: 4.06 to 9.14). CONCLUSION Our findings suggested the metabolic profiles comprising multiple metabolic biomarkers contribute to capturing an elevated risk of RA, and the integration of genome-wide PRSs further improved risk stratification.
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Affiliation(s)
- Xin-Yu Fang
- Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Jie Zhang
- School of Public Health, Anhui University of Science and Technology, Hefei, Anhui, China
- Anhui Institute of Occupational Safety and Health, Anhui University of Science and Technology, Hefei, China
| | - Ting-Ting Qian
- Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Peng Gao
- Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Qing Wu
- Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Quan Fang
- Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Su-Su Ke
- Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Rong-Gui Huang
- Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Heng-Chuan Zhang
- Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Ni-Ni Qiao
- Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Yin-Guang Fan
- Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Dong-Qing Ye
- Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
- School of Public Health, Anhui University of Science and Technology, Hefei, Anhui, China
- Anhui Institute of Occupational Safety and Health, Anhui University of Science and Technology, Hefei, China
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Zhang J, Fang XY, Leng R, Chen HF, Qian TT, Cai YY, Zhang XH, Wang YY, Mu M, Tao XR, Leng RX, Ye DQ. Metabolic signature of healthy lifestyle and risk of rheumatoid arthritis: observational and Mendelian randomization study. Am J Clin Nutr 2023:S0002-9165(23)48892-2. [PMID: 37127109 DOI: 10.1016/j.ajcnut.2023.04.034] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 04/10/2023] [Accepted: 04/26/2023] [Indexed: 05/03/2023] Open
Abstract
BACKGROUND While substantial evidence reveals that healthy lifestyle behaviors are associated with a lower risk of rheumatoid arthritis (RA), the underlying metabolic mechanisms remain unclear. OBJECTIVES This study aimed to identify the metabolic signature reflecting a healthy lifestyle and investigate its observational and genetic linkage with RA risk. METHODS This study included 87,258 UK Biobank participants (557 cases of incident RA) aged 37 to 73 years with complete lifestyle, genotyping and nuclear magnetic resonance (NMR) metabolomics data. A healthy lifestyle was assessed based on five factors: healthy diet, regular exercise, not smoking, moderate alcohol consumption, and normal body mass index. The metabolic signature was developed by summing selected metabolites' concentrations weighted by the coefficients using elastic net regression. We used multivariate Cox model to assess the associations between metabolic signatures and RA risk, and examined the mediating role of the metabolic signature in the impact of a healthy lifestyle on RA. We performed genome-wide association analysis (GWAS) to obtain genetic variants associated with the metabolic signature, then conducted Mendelian randomization (MR) analyses to detect causality. RESULTS The metabolic signature comprised of 81 metabolites, robustly correlated with healthy lifestyle ( r = 0.45, P = 4.2 × 10-15). The metabolic signature was inversely associated with RA risk (HR per SD increment: 0.76, 95% CI: 0.70-0.83), and largely explained protective effects of healthy lifestyle on RA with 64% (95%CI: 50.4-83.3) mediation proportion. One and two-sample MR analyses also consistently showed the associations of genetically inferred per SD increment in metabolic signature with a reduction in RA risk (HR: 0.84, 95% CI: 0.75-0.94, P = 0.002 and OR: 0.84, 95% CI: 0.73-0.97, P = 0.02 respectively). CONCLUSION Our findings implicate the metabolic signature reflecting healthy lifestyle as a potential causal mediator in the development of RA, highlighting the importance of early lifestyle intervention and metabolic tracking for precise prevention of RA.
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Affiliation(s)
- Jie Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, 230032, China
| | - Xin-Yu Fang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, 230032, China
| | - Rui Leng
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, 230032, China
| | - Hai-Feng Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, 230032, China
| | - Ting-Ting Qian
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, 230032, China
| | - Yu-Yu Cai
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, 230032, China
| | - Xin-Hong Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, 230032, China
| | - Yi-Yu Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, 230032, China
| | - Min Mu
- School of Public Health, Anhui University of Science and Technology, Huainan, Anhui, 232001, China
| | - Xin-Rong Tao
- School of Public Health, Anhui University of Science and Technology, Huainan, Anhui, 232001, China
| | - Rui-Xue Leng
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, 230032, China.
| | - Dong-Qing Ye
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, 230032, China; School of Public Health, Anhui University of Science and Technology, Huainan, Anhui, 232001, China.
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Świątkowska-Stodulska R, Berlińska A, Stefańska K, Zieliński M, Kwiatkowski S, Połom J, Andrysiak-Mamos E, Wydra P, Sworczak K. Endocrine Autoimmunity in Pregnancy. Front Immunol 2022; 13:907561. [PMID: 35844617 PMCID: PMC9277138 DOI: 10.3389/fimmu.2022.907561] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/06/2022] [Indexed: 11/20/2022] Open
Abstract
Human gestation leads to a number of physiological alterations which peak at the development of placentta known for, among many other functions, being a transient but highly potent endocrine organ. Hormonal activity of placenta is marked by its ability to continuously produce and secrete high levels of progesterone. Progesterone guards the well-being of the fetoplacental unit throughout the gestation and one of the proposed mechanisms of this principle involves the development of local and systemic immune tolerance mainly due to impediment of CD4+ lymphocyte activation. However, though these alterations are present and well-established, autoimmunity is not entirely rare and a wide spectrum of diseases can continue, or develop de novo, throughout the gestation or even after the delivery. Up-to-date data supports the existence of a relationship between the clinical course of chosen autoimmune diseases and levels of circulating sex steroids. The most common autoimmune endocrinopathies in pregnant women are Hashimoto’s disease, Graves’ disease, and, more rarely, primary adrenal insufficiency in the form of Addison’s disease. Gestation can influence the clinical course of these endocrinopathies in patients who were diagnosed before conception. Multiple particles, like TSH-receptor stimulating antibodies, thyroid hormones, glucocorticoids, and anti-thyroid medications, can cross the placental barrier and evoke biological action in fetal tissues. Thyroid pathology in the form of postpartum thyroiditis is particularly prevalent in patients with positive anti-thyroperoxidase and anti-thyroglobulin antibodies. Certain populations are more at risk of developing numerous gestational complications and require regular follow-up. In our paper, we would like to address physiological, physiopathological, and clinical aspects of endocrine autoimmunity throughout human gestation, as well as special circumstances to consider in pregnant women.
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Affiliation(s)
- Renata Świątkowska-Stodulska
- Department of Endocrinology and Internal Medicine, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Agata Berlińska
- Department of Endocrinology and Internal Medicine, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Katarzyna Stefańska
- Division of Gynecology and Obstetrics, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Maciej Zieliński
- Department of Medical Immunology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Sebastian Kwiatkowski
- Department of Obstetrics and Gynecology, Pomeranian Medical University of Szczecin, Szczecin, Poland
| | - Joanna Połom
- Department of Internal Medicine, Connective Tissue Diseases and Geriatrics, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Elżbieta Andrysiak-Mamos
- Department of Endocrinology, Metabolic Diseases and Internal Diseases Pomeranian Medical University, Szczecin, Poland
| | - Piotr Wydra
- Department of Medical Immunology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Krzysztof Sworczak
- Department of Endocrinology and Internal Medicine, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
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Malbeteau L, Pham HT, Eve L, Stallcup MR, Poulard C, Le Romancer M. How Protein Methylation Regulates Steroid Receptor Function. Endocr Rev 2022; 43:160-197. [PMID: 33955470 PMCID: PMC8755998 DOI: 10.1210/endrev/bnab014] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Indexed: 02/06/2023]
Abstract
Steroid receptors (SRs) are members of the nuclear hormonal receptor family, many of which are transcription factors regulated by ligand binding. SRs regulate various human physiological functions essential for maintenance of vital biological pathways, including development, reproduction, and metabolic homeostasis. In addition, aberrant expression of SRs or dysregulation of their signaling has been observed in a wide variety of pathologies. SR activity is tightly and finely controlled by post-translational modifications (PTMs) targeting the receptors and/or their coregulators. Whereas major attention has been focused on phosphorylation, growing evidence shows that methylation is also an important regulator of SRs. Interestingly, the protein methyltransferases depositing methyl marks are involved in many functions, from development to adult life. They have also been associated with pathologies such as inflammation, as well as cardiovascular and neuronal disorders, and cancer. This article provides an overview of SR methylation/demethylation events, along with their functional effects and biological consequences. An in-depth understanding of the landscape of these methylation events could provide new information on SR regulation in physiology, as well as promising perspectives for the development of new therapeutic strategies, illustrated by the specific inhibitors of protein methyltransferases that are currently available.
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Affiliation(s)
- Lucie Malbeteau
- Université de Lyon, F-69000 Lyon, France.,Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.,CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France
| | - Ha Thuy Pham
- Université de Lyon, F-69000 Lyon, France.,Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.,CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France
| | - Louisane Eve
- Université de Lyon, F-69000 Lyon, France.,Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.,CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France
| | - Michael R Stallcup
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Center, University of Southern California, Los Angeles, CA 90089, USA
| | - Coralie Poulard
- Université de Lyon, F-69000 Lyon, France.,Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.,CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France
| | - Muriel Le Romancer
- Université de Lyon, F-69000 Lyon, France.,Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.,CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France
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Kültür T, Zengin M. Patients with rheumatoid arthritis and osteoarthritis in terms of sex hormone receptors and histopathological comparison of features. Arch Rheumatol 2021; 36:192-200. [PMID: 34527923 PMCID: PMC8418768 DOI: 10.46497/archrheumatol.2021.8242] [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: 07/12/2020] [Accepted: 07/29/2020] [Indexed: 11/21/2022] Open
Abstract
Objectives
This study aims to investigate the relationship between estrogen receptors (ERs) and progesterone receptors (PRs) and histopathological findings in synovial tissue in rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Patients and methods
Synovial tissue samples obtained from synovial surgery from 30 RA (10 males, 20 females) and 92 OA (27 males, 65 females) patients with median age of 59 (range, 50 to 67) years were analyzed retrospectively between January 2010 and January 2019. The relationship between histopathological features and hormone receptor presence was analyzed. Results
There was a meaningful relationship between histopathological parameters and RA and OA (p=0.01). The sex hormone receptor's presence was significantly higher in females with RA (p=0.01). Additionally, in the RA group, there was a remarkable relationship between ER and focal aggregates of lymphocytes (p=0.01), perivascular infiltrates of lymphocytes (p=0.03), and diffuse infiltrates of lymphocytes (p=0.01). In the OA group, a significant relationship was observed between PR and subchondral inflammation (p=0.01). In multivariate analysis, it was observed that ER was an independent risk factor for focal aggregates of lymphocytes in RA group (odds ratio [OR]=1.51 [1.02-2.25], p=0.04). Besides, PR was found to be an independent risk factor for subchondral inflammation in OA group (OR=3.90 [1.28-11.80], p=0.02). Conclusion The presence of the sex hormone receptor in the synovium may change histopathological features and affect the clinical course.
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Affiliation(s)
- Turgut Kültür
- Department of Physical Medicine and Rehabilitation, Kırıkkale University Faculty of Medicine, Kırıkkale, Turkey
| | - Mehmet Zengin
- Department of Pathology, Kırıkkale University Faculty of Medicine, Kırıkkale, Turkey
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Aryanpour R, Zibara K, Pasbakhsh P, Jame'ei SB, Namjoo Z, Ghanbari A, Mahmoudi R, Amani S, Kashani IR. 17β-Estradiol Reduces Demyelination in Cuprizone-fed Mice by Promoting M2 Microglia Polarity and Regulating NLRP3 Inflammasome. Neuroscience 2021; 463:116-127. [PMID: 33794337 DOI: 10.1016/j.neuroscience.2021.03.025] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 03/18/2021] [Accepted: 03/21/2021] [Indexed: 11/26/2022]
Abstract
Estrogen produces a beneficial role in animal models of multiple sclerosis (MS). The effect of 17β-estradiol therapy on microglia polarization and neuroinflammation in the corpus callosum of the cuprizone-induced demyelination model has not been elucidated. In this study, mice were given 0.2% cuprizone (CPZ) for 5 weeks to induce demyelination during which they received 50 ng of 17β-estradiol (EST), injected subcutaneously in the neck region, twice weekly. Data revealed that treatment with 17β-estradiol therapy (CPZ+EST) improved neurological behavioral deficits, displayed by a significant reduction in escape latencies, in comparison to untreated CPZ mice. Also, administration of 17β-estradiol caused a decrease in demyelination levels and axonal injury, as demonstrated by staining with Luxol fast blue, immunofluorescence to myelin basic protein, and transmission electron microscopy analysis. In addition, at the transcriptional level in the brain, mice treated with 17β-estradiol (CPZ+EST) showed a decrease in the levels of M1-assosicted microglia markers (CD86, iNOS and MHC-II) whereas M2-associated genes (Arg-1, CD206 and Trem-2) were increased, compared to CPZ mice. Moreover, administration of 17β-estradiol resulted in a significant reduction (∼3-fold) in transcript levels of NLRP3 inflammasome and its downstream product IL-18, compared to controls. In summary, this study demonstrated for the first time that exogenous 17β-estradiol therapy robustly leads to the reduction of M1 phenotype, stimulation of polarized M2 microglia, and repression of NLRP3 inflammasome in the corpus callosum of CPZ demyelination model of MS. The positive effects of 17β-estradiol on microglia and inflammasome seems to facilitate and accelerate the remyelination process.
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Affiliation(s)
- Roya Aryanpour
- Department of Anatomy, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Kazem Zibara
- PRASE and Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon.
| | - Parichehr Pasbakhsh
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Zeinab Namjoo
- Department of Anatomical Science, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Amir Ghanbari
- Cell and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Reza Mahmoudi
- Cell and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Showan Amani
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Iraj Ragerdi Kashani
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Lourenço DMR, Araújo DB, Aikawa NE, Yamakami LYS, Borba EF, Maciel GAR, Soares-Junior JM, Baracat EC, Pereira RMR, Bonfa E, Silva CA. Adrenal steroidogenesis and ovarian reserve in adult childhood-onset systemic lupus erytematosus patients. Clin Rheumatol 2021; 40:3651-3658. [PMID: 33712890 DOI: 10.1007/s10067-021-05677-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 02/12/2021] [Accepted: 03/01/2021] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To assess overall adrenal mineralocorticoid/glucocorticoid/androgen steroidogenesis in childhood-onset systemic lupus erythematosus (cSLE) patients and the possible effect of prednisone on adrenal hormones and ovarian reserve. METHODS Fifty-one adult cSLE (ACR criteria) patients and 23 healthy controls were evaluated for adrenal steroidogenesis including mineralocorticoid (progesterone, deoxycorticosterone, aldosterone), glucocorticoid (17-OHprogesterone, 11-desoxycortisol, cortisol), and androgen (dehydroepiandrosterone-sulfate, androstenedione, total testosterone, and dihydrotestosterone) hormones. Ovarian reserve assessment included follicle-stimulating hormone (FSH), estradiol, anti-Müllerian hormone, ovarian volumes, and antral follicle count. RESULTS The median of current age [29.11 (19-39.8) vs. 30.8 (19.6-42.1) years, p = 0.502] was similar in adult cSLE and controls. Regarding mineralocorticoid/glucocorticoid, the median of progesterone (p = 0.003), 17-OH progesterone (p < 0.001), and 11-desoxycortisol (p = 0.036) were significantly lower in patients compared to controls. All androgen steroidogenesis hormones were reduced in the former group [dehydroepiandrosterone-sulfate (p < 0.001), androstenedione (p = 0.001), total testosterone (p = 0.005), and dihydrotestosterone (p < 0.001)]. Further comparison of patients with and without current use of prednisone and controls revealed a predominant impact on adrenal glucocorticoid and androgen steroidogenesis with reduced levels of 17-OH progesterone [0.17 (0-0.5) vs. 0.27 (0.1-2.9) vs. 0.33 (0.1-0.8) ng/mL, p < 0.001], dehydroepiandrosterone-sulfate [0.155 (0-0.6) vs. 0.49 (0.1-1.6) vs. 1.11 (0.1-2.6) μg/mL, p < 0.001], androstenedione [0.56 (0.2-4.4) vs. 1.7 (0.5-4.5) vs. 2.33 (0.3-3.8) ng/mL, p < 0.001], total testosterone [12 (12-167) vs. 16 (12-28) vs. (16.5 (0-50) ng/d, p = 0.002], and dihydrotestosterone [92.68 (11.8-198.5) vs. 160.62 (37.9-842.1) vs. 188.3 (71.3-543.9) pg/ml, p < 0.001] in patients under this drug. In addition, patients with this therapy had reduced median ovarian volumes [4.14 (2-12) vs. 7.13 (2-25.7) vs. 5.18 (2.4-17.3) cm3, p = 0.028) that was not associated with cyclophosphamide cumulative dose (p > 0.05). The median prednisone dose was 15/mg/day (2.5-40). CONCLUSIONS We provided novel evidence that cSLE patients have an overall androgen/glucocorticoid/mineralocorticoid adrenal suppression. Furthermore, low/moderate prednisone use seems to underlie these abnormalities and may also adversely affect ovarian reserve, independently of immunosuppressants. Key Points • cSLE patients have an overall androgen/glucocorticoid/mineralocorticoid adrenal suppression. • Low/moderate prednisone use may affect ovarian reserve, independently of immunosuppressants.
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Affiliation(s)
- Daniela M R Lourenço
- Pediatric Rheumatology Unit, Children's Institute, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, Sao Paulo, SP, 05403-000, Brazil
| | - Daniel B Araújo
- Pediatric Rheumatology Unit, Children's Institute, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, Sao Paulo, SP, 05403-000, Brazil.,Internal Medicine Department, Faculdade de Medicina, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Nadia E Aikawa
- Pediatric Rheumatology Unit, Children's Institute, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, Sao Paulo, SP, 05403-000, Brazil.,Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Lucas Y S Yamakami
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.,Discipline of Gynecology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Eduardo F Borba
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Gustavo A R Maciel
- Discipline of Gynecology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Jose M Soares-Junior
- Discipline of Gynecology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Edmund C Baracat
- Discipline of Gynecology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Rosa M R Pereira
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Eloisa Bonfa
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Clovis A Silva
- Pediatric Rheumatology Unit, Children's Institute, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, Sao Paulo, SP, 05403-000, Brazil. .,Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
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Tu Y, Wang K, Tan L, Han B, Hu Y, Ding H, He C. Dolichosin A, a coumestan isolated from Glycine tabacina, inhibits IL-1β-induced inflammation in SW982 human synovial cells and suppresses RANKL-induced osteoclastogenesis: From network pharmacology to experimental pharmacology. JOURNAL OF ETHNOPHARMACOLOGY 2020; 258:112855. [PMID: 32376366 DOI: 10.1016/j.jep.2020.112855] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/05/2020] [Accepted: 04/05/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Glycine tabacina (Labill.) Benth has been used as a traditional Chinese herbal medicine for the treatment of rheumatoid arthritis (RA) and joint infection. It is also one of the sources of the renowned native herbal medicine 'I-Tiao-Gung' in Taiwan. AIM OF THE STUDY This study aimed to investigate anti-arthritic effects and underlying mechanisms of dolichosin A (DoA), a coumestan compound isolated from G. tabacina, by the integration of network pharmacology and experimental pharmacology. MATERIALS AND METHODS Putative therapeutic targets and potential pharmacological mechanisms of DoA for RA treatment were predicted by network pharmacology approach. The regulated network of DoA acting on RA was constructed using Cytoscape 3.7.1. Anti-arthritic effects of DoA and predicted mechanisms were further validated using IL-1β-induced SW982 human synovial cell model and RANKL-induced osteoclastogenesis model. RESULTS A regulatory network of DoA-targets-pathways-RA was successfully constructed using network pharmacology approach. In this network, 65 candidate targets of DoA related to its therapeutic effect on RA were identified and the functional enrichment analysis revealed that these candidate targets were significantly involved in 12 central signaling pathways such as PI3K/AKT pathway, MAPK pathway and osteoclast differentiation. Furthermore, we found that DoA could significantly inhibit IL-1β-induced inflammation in SW982 human synovial cells, as evidenced by the decreased levels of pro-inflammatory mediators (TNF-α, IL-6 and COX-2) and MMP-3. DoA also suppressed RANKL-induced osteoclastogenesis in vitro, as evidenced by decreased number of TRAP-positive multinucleated osteoclasts and reduced TRAP activity. Further experimental mechanism evidence confirmed the predicted results of network pharmacology that the blockade of PI3K/AKT and MAPK pathways activation was closely associated with these regulated processes of DoA. CONCLUSIONS Our results demonstrated that DoA exhibited strong anti-arthritic activity through suppressing PI3K/AKT and MAPK pathways activation in activated synovial cells and osteoclasts, suggesting its potential as a hopeful candidate for the development of novel agents for the prevention and treatment of RA.
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Affiliation(s)
- Yanbei Tu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, SAR, 999078, China
| | - Kai Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, SAR, 999078, China
| | - Lihua Tan
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, SAR, 999078, China
| | - Bing Han
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, SAR, 999078, China
| | - Yuanjia Hu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, SAR, 999078, China
| | - Hang Ding
- Department of Biochemistry and Molecular Biology, Guangdong Medical University, Dongguan, Guangdong, 523808, China.
| | - Chengwei He
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, SAR, 999078, China.
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Itaborahy RMR, de Medeiros SF. Influence of estrogen therapy on immune markers in postmenopausal women. Climacteric 2016; 19:496-500. [PMID: 27593223 DOI: 10.1080/13697137.2016.1212828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
OBJECTIVE To evaluate the impact of estrogen therapy on cellular and humoral immune markers in postmenopausal women. METHODS This prospective, controlled cohort study included 30 patients who used oral estradiol (1 mg) for 14-17 weeks and 28 patients who served as controls. Total leukocytes and leukocyte subtypes were counted and immunophenotyped by flow cytometry. The concentrations of immunoglobulins and pro- and anti-inflammatory cytokines were also measured in the peripheral blood before and after estrogen therapy. Immunoglobulin E level was measured by electrochemiluminescence, and levels of immunoglobulins A, G, and M were measured by nephelometry. Simultaneous quantification of multiple cytokines was performed by chemiluminescence to measure the serum concentrations of interferon gamma, interleukin (IL)-4, IL-6, IL-10, and IL-17. RESULTS Hematological cellular components were not significantly different before and after the use of estradiol (p = 0.332-0.984). Serum concentrations of immunoglobulins G, M, E, and A also remained stable (p = 0.248-0.845). Finally, cytokines were not modified throughout the 14-17 weeks of follow-up (p = 0.407-0.873). CONCLUSION Isolated estrogen therapy with 1 mg of estradiol for 14-17 weeks in postmenopausal women did not modify any of the cellular or humoral immune markers analyzed in this study.
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Affiliation(s)
- R M Ribeiro Itaborahy
- a Federal University of Mato Grosso, School of Medicine , Department of Obstetrics and Gynecology , Cuiabá , Brazil
| | - S Freitas de Medeiros
- a Federal University of Mato Grosso, School of Medicine , Department of Obstetrics and Gynecology , Cuiabá , Brazil
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10
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Rolf L, Damoiseaux J, Hupperts R, Huitinga I, Smolders J. Network of nuclear receptor ligands in multiple sclerosis: Common pathways and interactions of sex-steroids, corticosteroids and vitamin D3-derived molecules. Autoimmun Rev 2016; 15:900-10. [DOI: 10.1016/j.autrev.2016.07.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 06/08/2016] [Indexed: 01/12/2023]
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da Silva LHA, Panazzolo DG, Marques MF, Souza MGC, Paredes BD, Nogueira Neto JF, Leão LMCSM, Morandi V, Bouskela E, Kraemer-Aguiar LG. Low-dose estradiol and endothelial and inflammatory biomarkers in menopausal overweight/obese women. Climacteric 2016; 19:337-43. [PMID: 27170466 DOI: 10.1080/13697137.2016.1180676] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
OBJECTIVE We aimed to investigate the effects of low-dose transdermal estrogen on endothelial and inflammatory biomarkers in menopausal overweight/obese women. METHODS We recruited 44 menopausal women (47-55 years; body mass index 27.5-34.9 kg/m(2)) and divided them into estradiol (1 mg/day; n = 22) or placebo groups (n = 22). They were double-blinded, followed and treated for 3 months. At baseline and post-intervention, inflammatory biomarkers (hs-CRP, IL-1β, IL-6, MCP-1 and TNF-α) and of vascular injury (activated circulating endothelial cells, CEC-a) and repair (endothelial progenitor cells, EPC) were quantified. Resting CECs (CEC-r) were also assessed. Microvascular reactivity and vasomotion were analyzed by laser-Doppler flowmetry. RESULTS Volunteers (51.8 ± 2.3 years; mean body mass index 31.5 ± 2.5 kg/m(2)) had been menopausal for 3 (range 2-5) years. After treatment, no changes were observed in the placebo group, while levels of CEC-r and EPC increased in the estradiol group. In this group, no changes in inflammatory biomarkers were observed but it required a lower cumulative dose of acetylcholine to achieve peak velocity during endothelial-dependent vasodilatation and there was increased endothelial-independent vasodilatation. CONCLUSIONS The short-term use of low-dose transdermal estradiol therapy in overweight/obese menopausal women increased markers of vascular repair and improved microvascular reactivity without changing the inflammatory biomarkers. CLINICAL TRIAL REGISTRATION NCT01295892 at www.clinicaltrials.gov .
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Affiliation(s)
- L H A da Silva
- a Clinical and Experimental Research Laboratory on Vascular Biology , Biomedical Center, State University of Rio de Janeiro , Rio de Janeiro , Brazil
| | - D G Panazzolo
- a Clinical and Experimental Research Laboratory on Vascular Biology , Biomedical Center, State University of Rio de Janeiro , Rio de Janeiro , Brazil
| | - M Ferreira Marques
- b Angiogenesis and Endothelial Cell Biology Laboratory, Department of Cell Biology , Institute of Biology Roberto Alcântara Gomes, State University of Rio de Janeiro , Rio de Janeiro , Brazil
| | - M G C Souza
- a Clinical and Experimental Research Laboratory on Vascular Biology , Biomedical Center, State University of Rio de Janeiro , Rio de Janeiro , Brazil
| | - B Dias Paredes
- c Molecular and Cellular Cardiology Laboratory , Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro , Rio de Janeiro , Brazil
| | - J F Nogueira Neto
- d Lipids Laboratory , Policlínica Piquet Carneiro, State University of Rio de Janeiro , Rio de Janeiro , Brazil
| | - L M C S M Leão
- e Endocrinology, Department of Internal Medicine, Medical Sciences Faculty , State University of Rio de Janeiro , Rio de Janeiro , Brazil
| | - V Morandi
- b Angiogenesis and Endothelial Cell Biology Laboratory, Department of Cell Biology , Institute of Biology Roberto Alcântara Gomes, State University of Rio de Janeiro , Rio de Janeiro , Brazil
| | - E Bouskela
- a Clinical and Experimental Research Laboratory on Vascular Biology , Biomedical Center, State University of Rio de Janeiro , Rio de Janeiro , Brazil
| | - L G Kraemer-Aguiar
- a Clinical and Experimental Research Laboratory on Vascular Biology , Biomedical Center, State University of Rio de Janeiro , Rio de Janeiro , Brazil ;,e Endocrinology, Department of Internal Medicine, Medical Sciences Faculty , State University of Rio de Janeiro , Rio de Janeiro , Brazil
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Pastore F, Martocchia A, Stefanelli M, Prunas P, Giordano S, Toussan L, Devito A, Falaschi P. Hepatitis C virus infection and thyroid autoimmune disorders: A model of interactions between the host and the environment. World J Hepatol 2016; 8:83-91. [PMID: 26807204 PMCID: PMC4716530 DOI: 10.4254/wjh.v8.i2.83] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 10/28/2015] [Accepted: 12/04/2015] [Indexed: 02/06/2023] Open
Abstract
The hepatitis C virus (HCV) infection is an important public health problem and it is associated with hepatic and extrahepatic manifestations. Autoimmune thyroid diseases are common in HCV infected patients and the standard interferon-based treatment is associated with an increase of the immune-mediated thyroid damage. Recent evidence in the literature analyzed critical points of the mechanisms of thyroid damage, focusing on the balance between the two sides of the interaction: The environment (virus infection with potential cross-reaction) and the host (susceptibility genes with consistent immune response). The spectrum of antiviral treatment for chronic HCV infection is rapidly expanding for the development of dual o triple therapy. The availability of interferon-free combined treatment with direct antiviral agents for HCV is very promising, in order to ameliorate the patient compliance and to reduce the development of thyroid autoimmunity.
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Haghmorad D, Amini AA, Mahmoudi MB, Rastin M, Hosseini M, Mahmoudi M. Pregnancy level of estrogen attenuates experimental autoimmune encephalomyelitis in both ovariectomized and pregnant C57BL/6 mice through expansion of Treg and Th2 cells. J Neuroimmunol 2014; 277:85-95. [PMID: 25457839 DOI: 10.1016/j.jneuroim.2014.10.004] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2014] [Revised: 10/07/2014] [Accepted: 10/09/2014] [Indexed: 12/17/2022]
Abstract
Pregnancy suppressive effect on autoimmune diseases including Multiple Sclerosis and Rheumatoid Arthritis may result from high levels of sex steroids such as estrogen and estriol. This study was designed to reveal the molecular and cellular mechanisms underlying the effect of estrogen on MS alleviation. Female C57BL/6 mice were immunized with MOG35-55. Clinical scores and other relevant parameters were monitored daily. Brain and spinal cord histology was performed to measure lymphocyte infiltration and central nervous system demyelination. Th1/Th2/Th17 and Treg cell profiles were determined through ELISA, flow cytometry, and real-time PCR. Transcription factor expression levels in the CNS were assessed by real-time PCR and T cell differentiation was explored through flow cytometry examination. Pregnancy and pregnancy level of estrogen alleviated clinical manifestations in EAE induced mice, reduced CNS demyelination and cell infiltration, suppressed spleen T cell proliferation, enhanced production of anti-inflammatory cytokines in splenocytes and increased the percentage of Th2 and Treg cells. Furthermore, the results of real-time PCR for transcription factors and related cytokines of Th1/Th2/Th17 and Treg cells in CNS showed reduced expression levels of Th1 and Th17 transcription factors, including T-bet and ROR-γt, and decreased Th1 and Th17 cytokines including IFN-γ, TNF-α, IL-17 and IL-23. These results are the first to indicate that pregnancy and pregnancy level of estrogen ameliorate the EAE condition by favoring Treg and Th2 differentiation through induced expression of Foxp3 and GATA3 in the CNS. Moreover, pregnancy and pregnancy level of estrogen decreased mRNA levels of T-bet and ROR-γt in the CNS.
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Affiliation(s)
- Dariush Haghmorad
- Immunology Research Center, BuAli Research Institute, Department of Immunology and Allergy, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abbas Ali Amini
- Inflammation and Inflammatory Diseases Research Center, Department of Immunology and Allergy, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Maryam Rastin
- Immunology Research Center, BuAli Research Institute, Department of Immunology and Allergy, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Hosseini
- Neurocognitive Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Mahmoudi
- Immunology Research Center, BuAli Research Institute, Department of Immunology and Allergy, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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14
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Multiple sclerosis at menopause: Potential neuroprotective effects of estrogen. Maturitas 2014; 80:133-9. [PMID: 25544310 DOI: 10.1016/j.maturitas.2014.11.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 11/19/2014] [Accepted: 11/20/2014] [Indexed: 12/17/2022]
Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating and neurodegenerative condition of the central nervous system that preferentially afflicts women more than men. Low estrogen states such as menopause and the postpartum period favor exacerbations of multiple sclerosis in women with the disease. Existing and emerging evidence suggests a role for estrogen in the alleviation of symptoms and reversal of pathology associated with MS. While clinical evidence is sparse regarding the benefit of estrogen therapy for women at risk for MS exacerbations, scientific data demonstrates that estrogen potentiates numerous neuroprotective effects on the central nervous system (CNS). Estrogens play a wide range of roles involved in MS disease pathophysiology, including increasing antiinflammatory cytokines, decreasing demyelination, and enhancing oxidative and energy producing processes in CNS cells.
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Liu L, Zhao Y, Xie K, Sun X, Jiang L, Gao Y, Wang Z. Estrogen inhibits LPS-induced IL-6 production in macrophages partially via the nongenomic pathway. Immunol Invest 2014; 43:693-704. [PMID: 24960169 DOI: 10.3109/08820139.2014.917095] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
17β-estradiol (E2)-signaling is widely considered to be mediated through the transcription-regulating intracellular estrogen receptor (iER). In this study, using the cell-impermeable E2-BSA, we investigated the nongenomic effects of E2 on the IL-6 production, MAPK and transcription factor activation following LPS stimulation in mouse bone marrow-derived macrophages (BMMs). It was found that E2 normalized LPS-induced IL-6 production in BMMs. Although the increase in IL-6 production induced by LPS was also attenuated by E2-BSA treatment, the capacity of BMMs to produce the IL-6 cytokine remained higher than the control. In addition, the iER blocker, ICI 182780, did not abolish the total effects of E2 on LPS-stimulated IL-6 production capacity in BMMs. Furthermore, E2 and E2-BSA attenuated the LPS activation of p38 but not that of ERK1/2 and JNK. The p38 inhibitor, SB 203580, significantly reduced the LPS-induced IL-6 production. Moreover, E2 and E2-BSA inhibited LPS-induced activation of NF-κB. This inhibitory effect was associated with decreases in nuclear p65 protein levels. Taken together, these results indicate that E2 has an inhibitory effect on LPS-induced IL-6 production in BMMs through inhibition of p38 MAPK phosphorylation, and blockade of NF-κB activation. These effects are mediated at least in part via a nongenomic pathway.
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Affiliation(s)
- Limin Liu
- Departments of Pathology and Pathophysiology, Medical College of Soochow University , Suzhou, Jiangsu , China , and
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Vejrazkova D, Vcelak J, Vankova M, Lukasova P, Bradnova O, Halkova T, Kancheva R, Bendlova B. Steroids and insulin resistance in pregnancy. J Steroid Biochem Mol Biol 2014. [PMID: 23202146 DOI: 10.1016/j.jsbmb.2012.11.007] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Metabolism of glucose during pregnancy reflects the equilibrium between lactogenic hormones stimulating insulin production and counterregulatory hormones inducing insulin resistance. In physiological pregnancies, insulin-mediated glucose uptake is substantially decreased and insulin secretion increased to maintain euglycemia. This common state of peripheral insulin resistance arises also due to steroid spectra changes. In this review article, we have focused on the role of steroid hormones (androgens, estrogens, gestagens, mineralocorticoids, glucocorticoids, as well as secosteroid vitamin D) in the impairment of glucose tolerance in pregnancy and in the pathogenesis of gestational diabetes mellitus. This article is part of a Special Issue entitled 'Pregnancy and Steroids'.
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Liu L, Zhao Y, Xie K, Sun X, Gao Y, Wang Z. Estrogen-induced nongenomic calcium signaling inhibits lipopolysaccharide-stimulated tumor necrosis factor α production in macrophages. PLoS One 2013; 8:e83072. [PMID: 24376635 PMCID: PMC3871562 DOI: 10.1371/journal.pone.0083072] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Accepted: 11/07/2013] [Indexed: 12/21/2022] Open
Abstract
Estrogen is traditionally thought to exert genomic actions through members of the nuclear receptor family. Here, we investigated the rapid nongenomic effects of 17β-estradiol (E2) on tumor necrosis factor α (TNF-α) production following lipopolysaccharide (LPS) stimulation in mouse bone marrow-derived macrophages (BMMs). We found that LPS induced TNF-α production in BMMs via phosphorylation of p38 mitogen-activated protein kinase (MAPK). E2 itself did not affect the MAPK pathway, although it attenuated LPS-induced TNF-α production through suppression of p38 MAPK activation. Recently, G protein-coupled receptor 30 (GPR30) was suggested to be a membrane estrogen receptor (mER) that can mediate nongenomic estradiol signaling. We found that BMMs expressed both intracellular estrogen receptors (iER) and mER GPR30. The specific GPR30 antagonist G-15 significantly blocked effects of estradiol on LPS-induced TNF-α production, whereas an iER antagonist did not. Moreover, E2 induced a rapid rise in intracellular free Ca2+ that was due to the influx of extracellular Ca2+ and was not inhibited by an iER antagonist or silencing of iER. Ca2+ influx was also induced by an impermeable E2 conjugated to BSA (E2-BSA), which has been used to investigate the nongenomic effects of estrogen. Consequently, Ca2+, a pivotal factor in E2-stimulated nongenomic action, was identified as the key mediator. The inhibitory effects of E2 on LPS-induced TNF-α production and p38 MAPK phosphorylation were dependent on E2-triggered Ca2+ influx because BAPTA, an intracellular Ca2+ chelator, prevented these effects. Taken together, these data indicate that E2 can down-regulate LPS-induced TNF-α production via blockade of p38 MAPK phosphorylation through the mER-mediated nongenomic Ca2+ signaling pathway in BMMs.
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Affiliation(s)
- Limin Liu
- Department of Pathology and Pathophysiology, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Ying Zhao
- Department of Pathology and Pathophysiology, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Keming Xie
- Department of Pathology and Pathophysiology, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Xiaodong Sun
- Department of Pathology and Pathophysiology, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Yuzhen Gao
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, Jiangsu, China
- * E-mail: (YZG); (ZFW)
| | - Zufeng Wang
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, Jiangsu, China
- * E-mail: (YZG); (ZFW)
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18
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Liu L, Wang Z. Estrogen attenuates lipopolysaccharide-induced nitric oxide production in macrophages partially via the nongenomic pathway. Cell Immunol 2013; 286:53-8. [PMID: 24321566 DOI: 10.1016/j.cellimm.2013.11.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Revised: 10/29/2013] [Accepted: 11/13/2013] [Indexed: 01/13/2023]
Abstract
Steroid hormones exert genotropic effects through members of the nuclear hormone receptor family. In the present study, we examined the effects of 17β-estradiol (E2) on nitric oxide (NO) production following lipopolysaccharide (LPS) stimulation and investigated the mechanisms in mouse bone marrow-derived macrophages (BMMs). E2 alone did not affect NO production. In contrast, E2 inhibited LPS-induced production of NO in BMMs. Using a cell-impermeable E2 conjugated to BSA (E2-BSA), which has been used to investigate the nongenomic effects of estrogen, we found that the increase in NO production induced by LPS was also attenuated. In addition, the intracellular estrogen receptor blocker, ICI 182780, only partially antagonized the total effects of E2 on LPS-stimulated NO production capacity. E2 also attenuated the LPS activation of p38 mitogen-activated protein kinase (MAPK) but not that of extracellular-regulated protein kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase (JNK). This attenuation was not abrogated by ICI 182780. Moreover, the p38 inhibitor, SB 203580, greatly reduced the LPS-induced NO production, and the remaining NO levels were no longer regulated by E2. Additionally, E2-BSA inhibited LPS-mediated changes in p38 MAPK activation to the same extent as E2. Moreover, E2 and E2-BSA inhibited LPS-induced activation of nuclear factor-kappa B (NF-κB) and activator protein 1 (AP-1). This inhibitory effect of E2 was only partially antagonized by ICI 182780. Taken together, these results suggest that E2 has an inhibitory effect on LPS-induced NO production in BMMs through inhibition of p38 MAPK phosphorylation, and blockade of NF-κB and AP-1 activation. These effects are mediated at least in part via a nongenomic pathway.
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Affiliation(s)
- Limin Liu
- Departments of Pathology and Pathophysiology, Medical College of Soochow University, Suzhou 215123, Jiangsu, China
| | - Zufeng Wang
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou 215123, Jiangsu, China.
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Ritz SA, Antle DM, Côté J, Deroy K, Fraleigh N, Messing K, Parent L, St-Pierre J, Vaillancourt C, Mergler D. First steps for integrating sex and gender considerations into basic experimental biomedical research. FASEB J 2013; 28:4-13. [PMID: 24056086 DOI: 10.1096/fj.13-233395] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
In recent decades there has been an increasing recognition of the need to account for sex and gender in biology and medicine, in order to develop a more comprehensive understanding of biological phenomena and to address gaps in medical knowledge that have arisen due to a generally masculine bias in research. We have noted that as basic experimental biomedical researchers, we face unique challenges to the incorporation of sex and gender in our work, and that these have remained largely unarticulated, misunderstood, and unaddressed in the literature. Here, we describe some of the specific challenges to the incorporation of sex and gender considerations in research involving cell cultures and laboratory animals. In our view, the mainstreaming of sex and gender considerations in basic biomedical research depends on an approach that will allow scientists to address these issues in ways that do not undermine our ability to pursue our fundamental scientific interests. To that end, we suggest a number of strategies that allow basic experimental researchers to feasibly and meaningfully take sex and gender into account in their work.
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Affiliation(s)
- Stacey A Ritz
- 1Northern Ontario School of Medicine, East Campus-Laurentian University, 935 Ramsey Lake Rd., Sudbury, ON P3E 2C6, Canada.
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Goddard LM, Ton AN, Org T, Mikkola HKA, Iruela-Arispe ML. Selective suppression of endothelial cytokine production by progesterone receptor. Vascul Pharmacol 2013; 59:36-43. [PMID: 23747964 DOI: 10.1016/j.vph.2013.06.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Accepted: 06/01/2013] [Indexed: 01/01/2023]
Abstract
Steroid hormones are well-recognized suppressors of the inflammatory response, however, their cell- and tissue-specific effects in the regulation of inflammation are far less understood, particularly for the sex-related steroids. To determine the contribution of progesterone in the endothelium, we have characterized and validated an in vitro culture system in which human umbilical vein endothelial cells constitutively express human progesterone receptor (PR). Using next generation RNA-sequencing, we identified a selective group of cytokines that are suppressed by progesterone both under physiological conditions and during pathological activation by lipopolysaccharide. In particular, IL-6, IL-8, CXCL2/3, and CXCL1 were found to be direct targets of PR, as determined by ChIP-sequencing. Regulation of these cytokines by progesterone was also confirmed by bead-based multiplex cytokine assays and quantitative PCR. These findings provide a novel role for PR in the direct regulation of cytokine levels secreted by the endothelium. They also suggest that progesterone-PR signaling in the endothelium directly impacts leukocyte trafficking in PR-expressing tissues.
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Affiliation(s)
- Lauren M Goddard
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA
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Spence RD, Voskuhl RR. Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration. Front Neuroendocrinol 2012; 33:105-15. [PMID: 22209870 PMCID: PMC3616506 DOI: 10.1016/j.yfrne.2011.12.001] [Citation(s) in RCA: 191] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Revised: 12/12/2011] [Accepted: 12/15/2011] [Indexed: 12/16/2022]
Abstract
Multiple sclerosis (MS) is a disease characterized by inflammation and demyelination. Currently, the cause of MS is unknown. Experimental autoimmune encephalomyelitis (EAE) is the most common mouse model of MS. Treatments with the sex hormones, estrogens and androgens, are capable of offering disease protection during EAE and are currently being used in clinical trials of MS. Beyond endogenous estrogens and androgens, treatments with selective estrogen receptor modulators (SERMs) for estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) are also capable of providing disease protection. This protection includes, but is not limited to, prevention of clinical disease, reduction of CNS inflammation, protection against demyelination, and protection against axonal loss. In EAE, current efforts are focused on using conditional cell specific knockouts of sex hormone receptors to identify the in vivo targets of these estrogens and androgens as well as downstream molecules responsible for disease protection.
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Affiliation(s)
- Rory D Spence
- University of California, Los Angeles, Department of Neurology, UCLA Multiple Sclerosis Program, 635 Charles E Young Drive South, Neuroscience Research Building 1, Room 479, Los Angeles, CA 90095, United States.
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Abstract
Sexual dimorphism in human immune systems is most apparent in the female predominance of certain autoimmune diseases (ADs) like systemic lupus erythematosus (SLE). Epidemiologic, observational and experimental evidence strongly suggest sex steroids are important modulators of genetic risk in human AD. In this regard, the roles of progesterone (Pg), an immunomodulatory female sex steroid, are poorly understood. Several lines of investigation indicate Pg and synthetic progestins impact risk of AD and immune-mediated injury in different ways depending on their concentrations and their engagement of various Pg receptors expressed in immune organs, immune cells or tissues targeted by immune attack. At low physiologic levels, Pg may enhance interferon-alpha (IFN-α) pathways important in SLE pathogenesis. Commonly used synthetic progestins may have the opposite effect. At pregnancy levels, Pg may suppress disease activity in rheumatoid arthritis (RA) and multiple sclerosis (MS) via inhibition of T helper type 1 (Th1) and Th17 pathways and induction of anti-inflammatory molecules. Importantly, Pg's immunomodulatory effects differ from those of estrogens and androgens. An additional layer of complexity arises from apparent interdependence of sex hormone signaling pathways. Identifying mechanisms by which Pg and other sex steroids modulate risk of AD and immune-mediated injury will require clarification of their cellular and molecular targets in vivo. These future studies should be informed by recent genetic discoveries in human AD, particularly those revealing their sex-specific genetic associations.
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Affiliation(s)
- Grant C Hughes
- University of Washington, 1959 NE Pacific St., Box 356428, Seattle, WA 98195–6428, USA.
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