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Aminbakhsh AP, Théberge ET, Burden E, Adejumo CK, Gravely AK, Lehman A, Sedlak TL. Exploring associations between estrogen and gene candidates identified by coronary artery disease genome-wide association studies. Front Cardiovasc Med 2025; 12:1502985. [PMID: 40182431 PMCID: PMC11965610 DOI: 10.3389/fcvm.2025.1502985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 03/04/2025] [Indexed: 04/05/2025] Open
Abstract
Introduction Coronary artery disease (CAD) is the leading cause of death around the world, with epidemiological sex and gender differences in prevalence, pathophysiology and outcomes. It has been hypothesized that sex steroids, like estrogen, may contribute to these sex differences. There is a relatively large genetic component to developing CAD, with heritability estimates ranging between 40%-60%. In the last two decades, genome-wide association studies (GWAS) have contributed substantially to advancing the understanding of genetic candidates contributing to CAD. The aim of this study was to determine if genes discovered in CAD GWASs are affected by estrogen via direct modulation or indirect down-stream targets. Methods A scoping review was conducted using MEDLINE and EMBASE for studies of atherosclerotic coronary artery disease and a genome-wide association study (GWAS) design. Analysis was limited to candidate genes with corresponding single nucleotide polymorphisms (SNPs) surpassing genome-wide significance and had been mapped to genes by study authors. The number of studies that conducted sex-stratified analyses with significant genes were quantified. A literature search of the final gene lists was done to examine any evidence suggesting estrogen may modulate the genes and/or gene products. Results There were 60 eligible CAD GWASs meeting inclusion criteria for data extraction. Of these 60, only 36 had genome-wide significant SNPs reported, and only 3 of these had significant SNPs from sex-stratified analyses mapped to genes. From these 36 studies, a total of 61 genes were curated, of which 26 genes (43%) were found to have modulation by estrogen. All 26 were discovered in studies that adjusted for sex. 12/26 genes were also discovered in studies that conducted sex-stratified analyses. 12/26 genes were classified as having a role in lipid synthesis, metabolism and/or lipoprotein mechanisms, while 11/26 were classified as having a role in vascular integrity, and 3/26 were classified as having a role in thrombosis. Discussion This study provides further evidence of the relationship between estrogen, genetic risk and the development of CAD. More sex-stratified research will need to be conducted to further characterize estrogen's relation to sex differences in the pathology and progression of CAD.
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Affiliation(s)
- Ava P. Aminbakhsh
- Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Emilie T. Théberge
- Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Elizabeth Burden
- Division of Internal Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
- Vancouver Coastal Health, Vancouver, BC, Canada
| | - Cindy Kalenga Adejumo
- Division of Internal Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
- Vancouver Coastal Health, Vancouver, BC, Canada
| | - Annabel K. Gravely
- Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Anna Lehman
- Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
- Vancouver Coastal Health, Vancouver, BC, Canada
| | - Tara L. Sedlak
- Vancouver Coastal Health, Vancouver, BC, Canada
- Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
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Zhang L, Li M, Fan L, Liu F, Zhang P, Huang Q, Mai G, Shentu J. Pharmacokinetics and Safety of Estradiol Valerate Tablet and Its Generic: A Phase 1 Bioequivalence Study in Healthy Chinese Postmenopausal Female Subjects. Drug Des Devel Ther 2024; 18:2891-2904. [PMID: 39006193 PMCID: PMC11246651 DOI: 10.2147/dddt.s460681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 07/03/2024] [Indexed: 07/16/2024] Open
Abstract
Purpose Estradiol valerate (Progynova®) is used as hormone therapy to supplement estrogen deficiency. This study aimed to assess the bioequivalence of an estradiol valerate tablet and its generic form, under fasting and fed conditions. Methods A randomized, open-label, single-dose, 2-period crossover study was conducted on healthy postmenopausal Chinese female volunteers under fasting and fed conditions. For each period, the subjects received either a 1 mg tablet of estradiol valerate or its generic. Blood samples were collected before dosing and up to 72 hours after administration. Plasma levels of total estrone, estradiol, and unconjugated estrone were quantified using a validated liquid chromatography-tandem mass spectrometry method. Results A total of 54 volunteers were enrolled in this study. The primary pharmacokinetic parameters, including Cmax, AUC0-t, and AUC0-∞, were similar for the two drugs under both fasting and fed conditions, with 90% confidence intervals for the geometric mean ratios of these parameters, all meeting the bioequivalence criterion of 80-125%. A total of 48 adverse events (AEs) were reported in the fed study compared with 24 AEs in the fasting study. Conclusion Estradiol valerate and its generic form were bioequivalent and well tolerated under both fasting and fed conditions.
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Affiliation(s)
- Li Zhang
- Phase 1 Clinical Trial Center, Deyang People′s Hospital, Deyang, Sichuan, People’s Republic of China
| | - Mupeng Li
- Phase 1 Clinical Trial Center, Deyang People′s Hospital, Deyang, Sichuan, People’s Republic of China
| | - Lianlian Fan
- Phase 1 Clinical Trial Center, Deyang People′s Hospital, Deyang, Sichuan, People’s Republic of China
| | - Fangfang Liu
- Phase 1 Clinical Trial Center, Deyang People′s Hospital, Deyang, Sichuan, People’s Republic of China
| | - Peiwen Zhang
- Phase 1 Clinical Trial Center, Deyang People′s Hospital, Deyang, Sichuan, People’s Republic of China
| | - Qian Huang
- Phase 1 Clinical Trial Center, Deyang People′s Hospital, Deyang, Sichuan, People’s Republic of China
| | - Gang Mai
- Phase 1 Clinical Trial Center, Deyang People′s Hospital, Deyang, Sichuan, People’s Republic of China
| | - Jianzhong Shentu
- Phase 1 Clinical Trial Center, Deyang People′s Hospital, Deyang, Sichuan, People’s Republic of China
- Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China
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Yao H, Hu Y, Tong H, Shi S. Dimethylglycine Alleviates Metabolic Dysfunction-Associated Fatty Liver Disease by Improving the Circulating Estrogen Level via Gut Staphylococcus. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:2708-2717. [PMID: 38131116 DOI: 10.1021/acs.jafc.3c07075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2023]
Abstract
Our previous study screened out dietary 0.1% dimethylglycine (DMG), which had beneficial effects on egg production and fat deposition in laying hens during the late laying period. In this paper, it was further found that dietary DMG alleviated fatty liver disease and enhanced lipid deposited into the yolk while promoting hepatic lipid transport. There are intestinal estrogen-metabolizing bacteria (EBM) having β-glucuronase (GUS) activity that regulates the content of circulating estrogen (E2) in mammals. There were 39 related bacteria found in laying hens, and DMG increased E2 in blood, Staphylococcus abundance among EBM and GUS activity in cecum chyme. Interfered in situ, Staphylococcus with GUS activity was proved the target bacteria for DMG. Furthermore, E2 could modify hepatic lipid deposition through promoting lipid transport by the steatosis LMH model. These perspectives confirm that DMG, mediated by Staphylococcus, alleviates the restriction of hepatic lipid transport due to reduced levels of E2 in laying hens.
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Affiliation(s)
- Hong Yao
- Jiangsu Institute of Poultry Science, Yangzhou, Jiangsu 225125, China
| | - Yan Hu
- Jiangsu Institute of Poultry Science, Yangzhou, Jiangsu 225125, China
| | - Haibing Tong
- Jiangsu Institute of Poultry Science, Yangzhou, Jiangsu 225125, China
| | - Shourong Shi
- Jiangsu Institute of Poultry Science, Yangzhou, Jiangsu 225125, China
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Zhao Y, Gan YH. Combination of hyperlipidemia and 17β-Estradiol induces TMJOA-like pathological changes in rats. Oral Dis 2023; 29:3640-3653. [PMID: 35765240 DOI: 10.1111/odi.14294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 06/12/2022] [Accepted: 06/20/2022] [Indexed: 11/28/2022]
Abstract
OBJECTIVE We explored whether hyperlipidemia or combination of hyperlipidemia and E2 could induce TMJOA. MATERIALS AND METHODS Four groups of female rats were treated with normal diet, normal diet with E2, high-fat diet, and high-fat diet with E2 (HFD/E2), respectively, to induce TMJOA till 8 weeks. Another three groups were then used for COX2 inhibitor celecoxib to block the induction of TMJOA. Primary condylar chondrocytes were treated with combination of E2, ox-LDL, and corresponding inhibitors for evaluating expressions of related molecules. RESULTS Condylar cartilage proliferation with plenty of chondrocyte apoptosis and increased staining for LOX1, nuclear NF-κB, IL-1β, and COX2 at 4 weeks and decreased condylar cartilage and increased subchondral bone density at 8 weeks were observed only in the HFD/E2 group. Celecoxib significantly alleviated the cartilage proliferation and apoptosis in the HFD/E2 group. Serum ox-LDL increased in both high-fat diet groups, while serum IL-1β increased only in the HFD/E2 group. Combination of E2 and ox-LDL synergistically induced expressions of LOX1, phosphorylated NF-κB, IL-1β, and COX2, while LOX1 inhibitor blocked the induction of phosphorylated NF-κB, and NF-κB inhibitor the induction of IL-1β, and IL-1β inhibitor the induction of COX2. CONCLUSION Combination of hyperlipidemia and E2-induced TMJOA-like pathological changes through LOX1/NF-κB/IL-1β/COX2-signaling pathway.
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Affiliation(s)
- Yan Zhao
- Central laboratory, Peking University School and Hospital of Stomatology, Beijing, China
- Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China
| | - Ye-Hua Gan
- Central laboratory, Peking University School and Hospital of Stomatology, Beijing, China
- Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China
- Center for Temporomandibular Disorders & Orofacial Pain, Peking University School and Hospital of Stomatology, Beijing, China
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Chen Y, Wang A, Zhang X, Xia F, Zhao X. Effect of age at menopause and menopause itself on high sensitivity C-reactive protein, pulse wave velocity, and carotid intima-media thickness in a Chinese population. Medicine (Baltimore) 2023; 102:e35629. [PMID: 37861482 PMCID: PMC10589532 DOI: 10.1097/md.0000000000035629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 09/22/2023] [Indexed: 10/21/2023] Open
Abstract
Potential associations between menopause, age at menopause, and clinical indicators related to cardiovascular disease (CVD) have not been elucidated. To identify the risk of CVD early and contribute to its prevention and intervention, the present study used relevant biomarkers to evaluate the risk of CVD among pre- and postmenopausal women. An overall population of 816 women (aged 40-60 y) was evaluated as premenopause, natural early menopause, or natural late menopause (ages ≤ 48 and ≥52 y), with ages 49-51 years as reference (natural menopause). High-sensitivity C-reactive protein, carotid intima-media thickness, and brachial-ankle pulse wave velocity were measured. Triglycerides (TG), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol (LDL-C) of the postmenopausal group were each significantly higher than that of the premenopausal. However, the 3 menopausal groups were similar regarding hypertension, diabetes, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. In the logistic regression model, the CRP, brachial-ankle pulse wave velocity, and carotid intima-media thickness levels were similar among the premenopause and early and late menopause groups. These results were unchanged after further adjustment for multiple confounders including age, smoking, drinking, salt intake habits, presence of hypertension, or diabetes mellitus. Menopause itself is a more important risk factor for CVD compared with menopause that begins at early or late age.
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Affiliation(s)
- Ying Chen
- Department of Obstetrics and Gynecology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Anxin Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Xiaoli Zhang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Fengqin Xia
- Department of Obstetrics and Gynecology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xingquan Zhao
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
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Association between the Triglyceride-Glucose Index and Vitamin D Status in Type 2 Diabetes Mellitus. Nutrients 2023; 15:nu15030639. [PMID: 36771345 PMCID: PMC9919416 DOI: 10.3390/nu15030639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/20/2023] [Accepted: 01/23/2023] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Vitamin D deficiency (VDD) increases the risk for type 2 diabetes mellitus (T2DM), which might be related to insulin resistance (IR). We aimed to explore the association between the triglyceride-glucose (TyG) index, a reliable indicator of IR, and VDD in patients with T2DM. METHODS There were 1034 participants with T2DM enrolled in the Second Xiangya Hospital of Central South University. The TyG index was calculated as ln (fasting triglyceride (TG, mg/dL) × fasting blood glucose (mg/dL)/2). VDD was defined as 25-hydroxyvitamin D [25(OH)D] level <50 nmol/L. RESULTS Correlation analysis showed a negative association between the TyG index and 25(OH)D level. After adjustments for clinical and laboratory parameters, it was revealed that when taking the Q1 quartile of TyG index as a reference, an increasing trend of VDD prevalence was presented in the other three groups divided by TyG index quartiles, where the OR (95% CI) was 1.708 (1.132-2.576) for Q2, 2.041 (1.315-3.169) for Q3, and 2.543 (1.520-4.253) for Q4 (all p < 0.05). CONCLUSIONS Patients with higher TyG index were more likely to have an increased risk of VDD in T2DM population, which may be related to IR.
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Alam N, Najnin H, Islam M, Shakya S, Khan IM, Zaidi R. Biochemical and histopathological analysis after sub-chronic administration of oxyresveratrol in Wistar rats. Drug Chem Toxicol 2023; 46:166-175. [PMID: 34913788 DOI: 10.1080/01480545.2021.2015243] [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: 02/02/2023]
Abstract
Oxyresveratrol (OXY) is a naturally occurring phenolic compound; however, there are no toxicity studies reported on its long term use. The aim of our work was to demonstrate the evaluation of acute and sub-chronic toxicity of oxyresveratrol in rats to assess its safety profile. To evaluate the LD50 value, 2000 mg/kg of oxyresveratrol was administered to Wistar rats by oral gavage. For sub-chronic toxicity assessment, 80 Wistar rats were randomly divided into four groups (10 animal/sex/group) and oxyresveratrol administered at a dose of 50, 100, 150 mg/kg/day by oral gavage. Bodyweight, food, and water consumption were monitored every week. At the end of the experiments, biochemical and hematological parameters were analyzed. Gross and microscopic organ analyses were also carried out. LD50 of oxyresveratrol was greater than 2000 mg/kg sub-chronic administration of oxyresveratrol did not influence any mortality. Doses of 50 and 100 mg/kg of oxyresveratrol did not produce any sign of toxicity. However, the 150 mg/kg oxyresveratrol group depicted changes in multiple biochemical and hematological parameters with changes in the pathology of cardiac, hepatic, and renal tissues when compared with control. Therefore, no observed adverse effect level (NOAEL) of oxyresveratrol was observed to be 100 mg/kg per day for both male and female rats.
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Affiliation(s)
- Nisat Alam
- Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
| | - Hasina Najnin
- Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
| | - Maidul Islam
- Department of Chemistry, Faculty of Science, Aligarh Muslim University, Aligarh, India
| | - Sonam Shakya
- Department of Chemistry, Faculty of Science, Aligarh Muslim University, Aligarh, India
| | - Ishaat M Khan
- Department of Chemistry, Faculty of Science, Aligarh Muslim University, Aligarh, India
| | - Rana Zaidi
- Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
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Thapa S, Nandy A, Rendina-Ruedy E. Endocrinal metabolic regulation on the skeletal system in post-menopausal women. Front Physiol 2022; 13:1052429. [PMID: 36439254 PMCID: PMC9691779 DOI: 10.3389/fphys.2022.1052429] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 10/27/2022] [Indexed: 08/13/2023] Open
Abstract
Osteoporosis is a common endocrinologic disorder characterized as a chronic bone loss condition. Sexual dimorphism is ubiquitous in the incidence of osteoporosis with post-menopausal women being acutely affected. Gonadal sex hormones including estrogen act as crucial regulators of bone mass; therefore, loss of such hormones leads to an imbalance in skeletal turnover leading to osteoporosis. Estrogen can influence both bone formation as well as resorption by reducing osteoblast activity and enhancing osteoclastogenesis. Additionally, estrogen is a potent regulator of systemic metabolism. Recent studies have provided clues that estrogenic effect on bone might also involve alterations in bone cell metabolism and bioenergetic potential. While direct effects of gonadal hormones ability to alter intracellular metabolism of bone cells has not been studied, there is precedence within the literature that this is occurring and contributing to post-menopausal bone loss. This review aims to serve as a perspective piece detailing the prospective role of gonadal hormones regulating bone cell metabolic potential.
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Affiliation(s)
- Santosh Thapa
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Ananya Nandy
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Elizabeth Rendina-Ruedy
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, United States
- Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, United States
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Xu L, Yuan Y, Che Z, Tan X, Wu B, Wang C, Xu C, Xiao J. The Hepatoprotective and Hepatotoxic Roles of Sex and Sex-Related Hormones. Front Immunol 2022; 13:939631. [PMID: 35860276 PMCID: PMC9289199 DOI: 10.3389/fimmu.2022.939631] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 06/13/2022] [Indexed: 12/18/2022] Open
Abstract
Most liver diseases, including acute liver injury, drug-induced liver injury, viral hepatitis, metabolic liver diseases, and end-stage liver diseases, are strongly linked with hormonal influences. Thus, delineating the clinical manifestation and underlying mechanisms of the "sexual dimorphism" is critical for providing hints for the prevention, management, and treatment of those diseases. Whether the sex hormones (androgen, estrogen, and progesterone) and sex-related hormones (gonadotrophin-releasing hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin) play protective or toxic roles in the liver depends on the biological sex, disease stage, precipitating factor, and even the psychiatric status. Lifestyle factors, such as obesity, alcohol drinking, and smoking, also drastically affect the involving mechanisms of those hormones in liver diseases. Hormones deliver their hepatic regulatory signals primarily via classical and non-classical receptors in different liver cell types. Exogenous sex/sex-related hormone therapy may serve as a novel strategy for metabolic liver disease, cirrhosis, and liver cancer. However, the undesired hormone-induced liver injury should be carefully studied in pre-clinical models and monitored in clinical applications. This issue is particularly important for menopause females with hormone replacement therapy (HRT) and transgender populations who want to receive gender-affirming hormone therapy (GAHT). In conclusion, basic and clinical studies are warranted to depict the detailed hepatoprotective and hepatotoxic mechanisms of sex/sex-related hormones in liver disease. Prolactin holds a promising perspective in treating metabolic and advanced liver diseases.
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Affiliation(s)
- Linlin Xu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuan Yuan
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zhaodi Che
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xiaozhi Tan
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bin Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Cunchuan Wang
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Chengfang Xu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jia Xiao
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
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Kurmanbekova BT, Noruizbaeva AM. Cardiovascular Effects of Metformin. RATIONAL PHARMACOTHERAPY IN CARDIOLOGY 2022. [DOI: 10.20996/1819-6446-2022-02-12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Type 2 diabetes mellitus is one of the most important independent risk factors for the development, progression and mortality from cardiovascular diseases (CVD). The world communities are faced with the question of developing the optimal management tactics for such comorbidity patients. Thus, the prescribed drug should not only have an adequate hypoglycemic effect, but also have a number of cardioprotective properties, be safe in patients with CVD, and possibly even improve the prognosis and reduce mortality rates. This review is devoted to a representative of the biguanide class - metformin, which is one of the earliest and most effective antihyperglycemic drugs, both as monotherapy and in combination with other antihyperglycemic drugs and insulin; while the evidence base for its cardiovascular profile is only gaining momentum. Thus, the purpose of this review is to highlight the cardiovascular effects of metformin in the context of recent research.
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Affiliation(s)
- B. T. Kurmanbekova
- National Center of cardiology and internal medicine named after academician M.Mirrakhimov
| | - A. M. Noruizbaeva
- National Center of cardiology and internal medicine named after academician M.Mirrakhimov
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Circulating oestradiol determines liver lipid deposition in rats fed standard diets partially unbalanced with higher lipid or protein proportions. Br J Nutr 2021; 128:1499-1508. [PMID: 34776031 PMCID: PMC9557166 DOI: 10.1017/s0007114521004505] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
The ingestion of excess lipids often produces the accumulation of liver fat. The modulation of diet energy partition affects this process and other metabolic responses, and oestrogens and androgens are implied in this process. Ten-week-old male and female rats were fed with either standard rat chow (SD), SD enriched with coconut oil (high-fat diet, HF), SD enriched with protein (high-protein diet, HP) or a ‘cafeteria’ diet (CAF) for 1 month. HF and CAF diets provided the same lipid-derived percentage of energy (40 %), HP diet protein energy derived was twice (40 %) that of the SD. Animals were killed under anaesthesia and samples of blood and liver were obtained. Hepatic lipid content showed sex-related differences: TAG accumulation tended to increase in HF and CAF fed males. Cholesterol content was higher only in the CAF males. Plasma oestradiol in HF and HP males was higher than in CAF. Circulating cholesterol was inversely correlated with plasma oestradiol. These changes agreed with the differences in the expression of some enzymes related to lipid and energy metabolism, such as fatty acid synthetase or phosphoglycolate phosphatase. Oestrogen protective effects extend to males with ‘normal’ diets, that is, not unbalanced by either lipid or protein, but this protection was not enough against the CAF diet. Oestradiol seems to actively modulate the liver core of 2C-3C partition of energy substrates, regulating cholesterol deposition and lactate production.
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Alemany M. Estrogens and the regulation of glucose metabolism. World J Diabetes 2021; 12:1622-1654. [PMID: 34754368 PMCID: PMC8554369 DOI: 10.4239/wjd.v12.i10.1622] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/10/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
The main estrogens: estradiol, estrone, and their acyl-esters have been studied essentially related to their classical estrogenic and pharmacologic functions. However, their main effect in the body is probably the sustained control of core energy metabolism. Estrogen nuclear and membrane receptors show an extraordinary flexibility in the modulation of metabolic responses, and largely explain gender and age differences in energy metabolism: part of these mechanisms is already sufficiently known to justify both. With regard to energy, the estrogen molecular species act essentially through four key functions: (1) Facilitation of insulin secretion and control of glucose availability; (2) Modulation of energy partition, favoring the use of lipid as the main energy substrate when more available than carbohydrates; (3) Functional protection through antioxidant mechanisms; and (4) Central effects (largely through neural modulation) on whole body energy management. Analyzing the different actions of estrone, estradiol and their acyl esters, a tentative classification based on structure/effects has been postulated. Either separately or as a group, estrogens provide a comprehensive explanation that not all their quite diverse actions are related solely to specific molecules. As a group, they constitute a powerful synergic action complex. In consequence, estrogens may be considered wardens of energy homeostasis.
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Affiliation(s)
- Marià Alemany
- Faculty of Biology, University of Barcelona, Barcelona 08028, Catalonia, Spain
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Miyamura K, Nawa N, Isumi A, Doi S, Ochi M, Fujiwara T. The Association of Passive Smoking and Dyslipidemia Among Adolescence in Japan: Results From A-CHILD Study. J Clin Endocrinol Metab 2021; 106:e2738-e2748. [PMID: 33595668 DOI: 10.1210/clinem/dgab094] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Indexed: 01/19/2023]
Abstract
CONTEXT Passive smoking in childhood has been reported to be associated with dyslipidemia in Western countries. However, this association in Asian countries remains unclear. Further, no study has investigated the sex difference of the association. OBJECTIVE This study aimed to elucidate the association between passive smoking and dyslipidemia in adolescent boys and girls in Japan. METHODS We used a cross-sectional data of junior high school students in the Adachi Child Health Impact of Living Difficulty (A-CHILD) study in Adachi City, Tokyo, Japan in 2016 and 2018. Of the 1431 available students, 1166 students and their parents responded to the survey, including frequency of passive smoking (response rate 81.5%). We assessed dyslipidemia using total cholesterol (TC) levels, low-density lipoprotein cholesterol (LDL-C) levels and high-density lipoprotein cholesterol (HDL-C) levels. The association between passive smoking and dyslipidemia was evaluated by using multivariate regression analyses adjusted for socioeconomic status and lifestyle factors stratified by boys (N = 564) and girls (N = 602). RESULTS Among boys, HDL-C levels were significantly lower if exposed to passive smoking frequently, compared with those not exposed (β = -3.19; 95% CI, -5.84 to -0.55). However, this trend does not hold true among girls. Passive smoking was not associated with TC levels and LDL-C levels in either boys or girls. CONCLUSION We found that exposure to passive smoking was associated with HDL-C level among boys in Japan, but not in girls. Further longitudinal study is needed to confirm the association between passive smoking and dyslipidemia among boys in Japan.
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Affiliation(s)
- Keitaro Miyamura
- Department of Global Health Promotion, Tokyo Medical and Dental University, Tokyo, Japan
| | - Nobutoshi Nawa
- Department of Global Health Promotion, Tokyo Medical and Dental University, Tokyo, Japan
| | - Aya Isumi
- Department of Global Health Promotion, Tokyo Medical and Dental University, Tokyo, Japan
| | - Satomi Doi
- Department of Global Health Promotion, Tokyo Medical and Dental University, Tokyo, Japan
| | - Manami Ochi
- Department of Global Health Promotion, Tokyo Medical and Dental University, Tokyo, Japan
- National Institute of Public Health, Department of Health and Welfare Services, Saitama, Japan
| | - Takeo Fujiwara
- Department of Global Health Promotion, Tokyo Medical and Dental University, Tokyo, Japan
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Luo F, Das A, Chen J, Wu P, Li X, Fang Z. Metformin in patients with and without diabetes: a paradigm shift in cardiovascular disease management. Cardiovasc Diabetol 2019; 18:54. [PMID: 31029144 PMCID: PMC6486984 DOI: 10.1186/s12933-019-0860-y] [Citation(s) in RCA: 113] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 04/18/2019] [Indexed: 02/06/2023] Open
Abstract
With an increasing global burden of coronary artery disease (CAD), early detection and timely management of risk factors are crucial to reduce morbidity and mortality in such patients. Diabetes mellitus (DM) is considered an independent risk factor for the development of CAD. Metformin, an anti-diabetic drug, has been shown in pre-clinical and clinical studies, to lower the cardiovascular events in the DM patients. Growing evidence suggests that metformin has a protective effect on coronary artery beyond its hypoglycemic effects. Given its global availability, route of administration and cost, metformin provides an alternate/additional therapeutic option for primary and secondary prevention of CAD in DM and non-diabetics alike. Future prospective cohort-based studies and randomized clinical trials are needed to identify 'at-risk' population who may potentially benefit from metformin.
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Affiliation(s)
- Fei Luo
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011 Hunan China
| | - Avash Das
- Departments of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
| | - Jingfei Chen
- Department of Obstetrics and Gynecology, Xiangya Hospital, Central South University, Changsha, 410011 Hunan China
| | - Panyun Wu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011 Hunan China
| | - Xiangping Li
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011 Hunan China
| | - Zhenfei Fang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011 Hunan China
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Luo J, Xu L, Li J, Zhao S. Effects and mechanisms of apolipoprotein A-V on the regulation of lipid accumulation in cardiomyocytes. Lipids Health Dis 2018. [PMID: 29530023 PMCID: PMC5848552 DOI: 10.1186/s12944-018-0692-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background Apolipoprotein (apo) A-V is a key regulator of triglyceride (TG) metabolism. We investigated effects of apoA-V on lipid metabolism in cardiomyocytes in this study. Methods We first examined whether apoA-V can be taken up by cardiomyocytes and whether low density lipoprotein receptor family members participate in this process. Next, triglyceride (TG) content and lipid droplet changes were detected at different concentrations of apoA-V in normal and lipid-accumulation cells in normal and obese animals. Finally, we tested the levels of fatty acids (FAs) taken up into cardiomyocytes and lipid secretion through [14C]-oleic acid. Results Our results show that heart tissue has apoA-V protein, and apoA-V is taken up by cardiomyocytes. When HL-1 cells were transfected with low density lipoprotein receptor (LDLR)-related protein 1(LRP1) siRNA, apoA-V intake decreased by 53% (P<0.05), while a 37% lipid accumulation in HL-1 cells remain unchanged. ApoA-V localized to the cytoplasm and was associated with lipid droplets in HL-1 cells. A 1200 and 1800 ng/mL apoA-V intervention decreased TG content by 28% and 45% in HL-1 cells, respectively and decreased TG content by 39% in mouse heart tissue (P<0.05). However, apoA-V had no effects on TG content in either normal HL-1 cells or mice. The levels of FAs taken up into cardiomyocytes decreased by 43% (P < 0.05), and the levels of TG and cholesterol ester secretion increased by 1.2-fold and 1.6-fold, respectively (P < 0.05). Conclusion ApoA-V is a novel regulator of lipid metabolism in cardiomyocytes.
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Affiliation(s)
- Jun Luo
- Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Li Xu
- Department of The Second Chest Medicine, The Affiliated Cancer Hospital of Xiangya School of medicine, Central South University, Changsha, Hunan, 410013, China
| | - Jiang Li
- Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
| | - Shuiping Zhao
- Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
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Luo F, Huang WY, Guo Y, Ruan GY, Peng R, Li XP. 17β-estradiol lowers triglycerides in adipocytes via estrogen receptor α and it may be attenuated by inflammation. Lipids Health Dis 2017; 16:182. [PMID: 28946914 PMCID: PMC5613454 DOI: 10.1186/s12944-017-0575-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 09/20/2017] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Estrogen was reported to protect against obesity, however the mechanism remains unclear. We aimed to investigate the impact of 17β-estradiol (17β-E2) on triglyceride metabolism in adipocytes with or without lipopolysacchride (LPS) stimulating, providing novel potential mechanism for estrogen action. METHODS 3T3-L1 adipocytes were cultured and differentiated into mature adipocytes in vitro. The differentiated 3T3-L1 cells were divided into six groups: (i) control group, treated with 0.1% DMSO alone; (ii) 17β-E2 group, treated with 1, 0.1, or 0.001 μM 17β-E2 for 48 h; (iii) 17β-E2 plus MPP group, pre-treated with 10 μM MPP (a selective ERα receptor inhibitor) for 1 h, then incubated with 1 μM 17β-E2 for 48 h; (iv) 17β-E2 plus PHTPP group, pre-treated with 10 μM PHTPP (a selective ERβ receptor inhibitor), then incubated with 1 μM 17β-E2 for 48 h; (v) LPS group, pre-treated with 100 ng/mL LPS for 24 h, then cells were washed by PBS for 3 times and incubated with 0.1% DMSO alone for 48 h; (vi) 17β-E2 plus LPS group, pre-treated with 100 ng/mL LPS for 24 h, then cells were washed by PBS for 3 times and incubated with 1 μM 17β-E2 for 48 h. The levels of triglyceride and adipose triglyceride lipase (ATGL) in differentiated 3T3-L1 cells and the concentrations of interleukin-6 (IL-6) in culture medium were measured. RESULTS Comparing with control group, 1 μM and 0.1 μM 17β-E2 decreased the intracellular TG levels by about 20% and 10% respectively (all P < 0.05). The triglyceride-lowing effect of 17β-E2 in differentiated 3T3-L1 cells was abolished by ERα antagonist MPP but not ERβ antagonist PHTPP. Comparing with control group, the IL-6 levels were significantly higher in the culture medium of the cultured differentiated 3T3-L1 cells in LPS group and 17β-E2 + LPS group (all P < 0.05). And, the IL-6 levels were similar in LPS group and 17β-E2 + LPS group (P > 0.05). There was no significant difference in the triglyceride contents of differentiated 3T3-L1 cells among control group, LPS group and 17β-E2 + LPS group (all P > 0.05). ATGL expression in 17β-E2 group was significantly higher than control group (P < 0.05), which was abolished by ERα antagonist MPP or LPS. CONCLUSIONS 17β-E2 increased ATGL expression and lowered triglycerides in adipocytes but not in LPS stimulated adipocytes via estrogen ERα.
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Affiliation(s)
- Fei Luo
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011 Hunan People’s Republic of China
| | - Wen-yu Huang
- Department of Emergency Medicine, Yantai Yuhuangding Hospital, Qingdao University Medical College, Yantai, Shangdong 264000 People’s Republic of China
| | - Yuan Guo
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011 Hunan People’s Republic of China
| | - Gui-yun Ruan
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011 Hunan People’s Republic of China
| | - Ran Peng
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011 Hunan People’s Republic of China
| | - Xiang-ping Li
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011 Hunan People’s Republic of China
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