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1
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Sun ML, Dong JM, Liu C, Li P, Zhang C, Zhen J, Chen W. Metformin-mediated protection against doxorubicin-induced cardiotoxicity. Biomed Pharmacother 2024; 180:117535. [PMID: 39405911 DOI: 10.1016/j.biopha.2024.117535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 10/02/2024] [Accepted: 10/04/2024] [Indexed: 11/14/2024] Open
Abstract
BACKGROUND A phase II clinical trial of metformin (MET) for the treatment of doxorubicin (DOX)-induced cardiotoxicity (NCT02472353) failed. OBJECTIVES The aims of this study were to confirm MET-mediated protection against DOX-induced cardiotoxicity and its mechanism using H9C2 cells, and to establish a Wistar rat model of DOX-induced cardiotoxicity. Subsequently, Wistar rats were utilized to identify clinically relevant indicators for evaluating MET-mediated protection against DOX-induced cardiotoxicity, thereby facilitating early transition towards successful clinical trials. METHODS MET-mediated protection was assessed using cell viability and cytotoxicity experiments. Additionally, intramitochondrial reactive oxygen species (ROS) levels were measured using an ROS fluorescent probe (dihydroethidium) to confirm the oxidative stress mechanism. Eighteen Wistar rats were randomly allocated to the control, DOX, and DOX+MET groups; and the body weight, adverse drug reactions (ADRs), myocardial injury, cardiac function, oxidative stress, and histopathology of heart tissues were compared between groups. RESULTS H9C2 cells treated with MET/Dexrazoxane demonstrated dose-dependent protection against DOX-induced cardiotoxicity. The fluorescence intensity of H9C2 cells suggested DOX-induced cardiomyocyte toxicity and MET-mediated protection against DOX-induced cardiotoxicity. In vivo experiments confirmed that a rat model of DOX-induced cardiotoxicity was successfully established, but MET-mediated protection against DOX-induced cardiotoxicity was not demonstrated. This was attributed to insufficient energy intake because of ADRs, such as vomiting. CONCLUSIONS We confirmed the MET-mediated protection against DOX-induced cardiomyocyte toxicity and its mechanism involving the inhibition of oxidative stress in vitro experiments. It is imperative to investigate the optimal conditions for MET-mediated protection against DOX-induced cardiotoxicity in vivo or clinical trials.
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Affiliation(s)
- Ming-Li Sun
- Phase I Clinical Trial Research Center, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, China.
| | - Jun-Min Dong
- Phase I Clinical Trial Research Center, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, China
| | - Chen Liu
- Phase I Clinical Trial Research Center, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, China
| | - Pu Li
- Phase I Clinical Trial Research Center, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, China
| | - Chao Zhang
- Department of Ultrasonography, Beijing Chaoyang Hospital affiliated to Capital Medical University, Beijing 100020, China
| | - Jie Zhen
- Department of Intensive Care Unit, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, China
| | - Wei Chen
- Department of Intensive Care Unit, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, China.
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2
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Lee HF, Chan YH, Hsu TJ, Chuang C, Li PR, Yeh YH, Su HC, Hsiao FC, See LC. Clinical Outcomes in Type 2 Diabetes Patients After Acute Myocardial Infarction: A Comparison of Sodium-Glucose Cotransporter 2 Inhibitors vs. Non-Users. Clin Pharmacol Ther 2024; 116:426-434. [PMID: 38738997 DOI: 10.1002/cpt.3304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 04/28/2024] [Indexed: 05/14/2024]
Abstract
To compare clinical outcomes in patients with type 2 diabetes (T2D) after acute myocardial infarction (AMI) using sodium-glucose cotransporter-2 inhibitors (SGLT2i) vs. non-use of SGLT2i. A national cohort study based on the Taiwan National Health Insurance Research Database enrolled 944 patients with T2D who had experienced AMI and were treated with SGLT2i and 8,941 patients who did not receive SGLT2i, respectively, from May 1, 2016, to December 31, 2019. We used propensity score matching to balance covariates across study groups. The follow-up period was from the index date to the independent occurrence of the study outcomes, discontinuation of the index drug, or the end of the study period (December 31, 2020), whichever occurred first. The SGLT2i group exhibited a significantly lower incidence of cardiovascular death (0.865% per year vs. 2.048% per year; hazard ratio (HR): 0.42; 95% confidence interval (CI): 0.24-0.76; P = 0.0042), heart failure hospitalization (1.987% per year vs. 3.395% per year; HR: 0.59; 95% CI: 0.39-0.89; P = 0.0126), and all-cause mortality (3.406% per year vs. 4.981% per year, HR: 0.69; 95% CI: 0.50-0.95; P = 0.0225) compared with the non-SGLT2i group. There were no significant differences between the two groups in the incidence of AMI, ischemic stroke, coronary revascularization, major adverse cardiovascular events, composite renal outcomes, or lower limb amputation. These findings suggest that the use of SGLT2i may have favorable effects on clinical outcomes in patients with T2D after AMI.
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Affiliation(s)
- Hsin-Fu Lee
- Division of Cardiology, Department of Internal Medicine, New Taipei City Municipal Tucheng Hospital, New Taipei City, Taiwan
- The Cardiovascular Department, Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Yi-Hsin Chan
- The Cardiovascular Department, Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
- Microscopy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan
| | - Tzyy-Jer Hsu
- The Cardiovascular Department, Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Chi Chuang
- Division of Cardiology, Department of Internal Medicine, New Taipei City Municipal Tucheng Hospital, New Taipei City, Taiwan
- The Cardiovascular Department, Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Pei-Ru Li
- Department of Public Health, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Yung-Hsin Yeh
- The Cardiovascular Department, Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Hung-Chi Su
- Division of Cardiology, Department of Internal Medicine, New Taipei City Municipal Tucheng Hospital, New Taipei City, Taiwan
- The Cardiovascular Department, Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Fu-Chih Hsiao
- The Cardiovascular Department, Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Lai-Chu See
- Department of Public Health, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
- Biostatistics Core Laboratory, Molecular Medicine Research Center, Chang Gung University, Taoyuan City, Taiwan
- Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan
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3
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Kurdi A, Alhussaini W, Alawaji A, Alhudathi A, Alharbi R, Binsaleh F, Alghamidi Y, Al Bekairy A, Alkatheri A, Islam I, Farh I, Ghanem E, Mansour M. Comparative performance of liquid chromatography and spectrophotometry in determining metformin hydrochloride within pharmaceutical formulations. Heliyon 2024; 10:e32551. [PMID: 38988548 PMCID: PMC11233872 DOI: 10.1016/j.heliyon.2024.e32551] [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: 11/30/2023] [Revised: 05/08/2024] [Accepted: 06/05/2024] [Indexed: 07/12/2024] Open
Abstract
The present study compared the performance of Ultra-high performance liquid chromatography (UHPLC) and UV-Vis spectrophotometry for the quantification of metformin hydrochloride in five commercially available metformin hydrochloride products with different strengths. The metformin hydrochloride was measured in the UHPLC with a mobile phase consisting of a mixture of 0.05 M phosphate buffer solution and methanol (35:65, v/v) with a pH of 3.6. Metformin hydrochloride was determined spectrophotometrically at 234 nm using a mixture of methanol and water as a blank. The methods' linearity for metformin hydrochloride was within the concentration range of (2.5-40 μg/ml) in both techniques. The validation process encompassed assessments of specificity, selectivity, linearity, accuracy, precision, the lower limit of quantification (LLOQ), the lower limit of detection (LLOD), robustness, and system suitability. For the UHPLC validation method, the repeatability and reproducibility (expressed as relative standard deviation) were less than 1.578 and 2.718 %, respectively. The LLOQ for metformin hydrochloride was 0.625 μg/ml, and the LLOD was 0.156 μg/ml. For the UV-Vis spectrophotometric validation method, the repeatability and reproducibility (stated as relative standard deviation) were less than 3.773 and 1.988 %, respectively. The percentage recovery results for the five brands of metformin hydrochloride tablets were (98-101 %) and (92-104 %) for the UHPLC and UV-Vis spectrophotometric methods, respectively. In conclusion, the described methodologies were successfully employed for the quantitative analysis of metformin hydrochloride in different pharmaceutical tablet products.
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Affiliation(s)
- Amani Kurdi
- Department of Pharmaceutical Analysis, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
| | - Waleed Alhussaini
- Department of Pharmaceutical Analysis, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
| | - Abdulrahman Alawaji
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
| | - Abdullah Alhudathi
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
| | - Rakan Alharbi
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
| | - Faisal Binsaleh
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
| | - Yazeed Alghamidi
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
| | - Abdulkareem Al Bekairy
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
| | - Abdulmalik Alkatheri
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
| | - Imadul Islam
- Department of Pharmaceutical Analysis, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
| | - Ibrahim Farh
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
| | - Ezzeldeen Ghanem
- Department of Pharmaceutical Analysis, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
| | - Mahmoud Mansour
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia
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4
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Xu M, Li LP, He X, Lu XZ, Bi XY, Li Q, Xue XR. Metformin induction of heat shock factor 1 activation and the mitochondrial unfolded protein response alleviate cardiac remodeling in spontaneously hypertensive rats. FASEB J 2024; 38:e23654. [PMID: 38717442 DOI: 10.1096/fj.202400070r] [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: 01/11/2024] [Revised: 03/30/2024] [Accepted: 04/23/2024] [Indexed: 06/07/2024]
Abstract
Heart failure and cardiac remodeling are both characterized by mitochondrial dysfunction. Healthy mitochondria are required for adequate contractile activity and appropriate regulation of cell survival. In the mammalian heart, enhancement of the mitochondrial unfolded protein response (UPRmt) is cardioprotective under pressure overload conditions. We explored the UPRmt and the underlying regulatory mechanism in terms of hypertension-induced cardiac remodeling and the cardioprotective effect of metformin. Male spontaneously hypertensive rats and angiotensin II-treated neonatal rat cardiomyocytes were used to induce cardiac hypertrophy. The results showed that hypertension induced the formation of aberrant mitochondria, characterized by a reduced mtDNA/nDNA ratio and swelling, as well as lower levels of mitochondrial complexes I to V and inhibition of the expression of one protein subunit of each of complexes I to IV. Such changes eventually enlarged cardiomyocytes and increased cardiac fibrosis. Metformin treatment increased the mtDNA/nDNA ratio and regulated the UPRmt, as indicated by increased expression of activating transcription factor 5, Lon protease 1, and heat shock protein 60, and decreased expression of C/EBP homologous protein. Thus, metformin improved mitochondrial ultrastructure and function in spontaneously hypertensive rats. In vitro analyses revealed that metformin reduced the high levels of angiotensin II-induced mitochondrial reactive oxygen species in such animals and stimulated nuclear translocation of heat shock factor 1 (HSF1). Moreover, HSF1 small-interfering RNA reduced the metformin-mediated improvements in mitochondrial morphology and the UPRmt by suppressing hypertrophic signals and cardiomyocyte apoptosis. These results suggest that HSF1/UPRmt signaling contributes to the beneficial effects of metformin. Metformin-mediated targeting of mitochondrial protein homeostasis and modulation of HSF1 levels have potential therapeutic implications in terms of cardiac remodeling.
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Affiliation(s)
- Man Xu
- Department of Pharmacy, Xi'an People's Hospital (Xi'an Fourth Hospital), Northwest University Affiliated People's Hospital, Xi'an, Shaanxi, China
| | - Li-Peng Li
- Department of Pharmacy, Xi'an People's Hospital (Xi'an Fourth Hospital), Northwest University Affiliated People's Hospital, Xi'an, Shaanxi, China
| | - Xi He
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China
| | - Xing-Zhu Lu
- Department of Pharmacy, Second Affiliated Hospital of Xi'an Jiaotong University Medical School, Xi'an, Shaanxi, China
| | - Xue-Yuan Bi
- Department of Pharmacy, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Qi Li
- Department of Science and Education, Xi'an People's Hospital (Xi'an Fourth Hospital), Northwest University Affiliated People's Hospital, Xi'an, China
| | - Xiao-Rong Xue
- Department of Pharmacy, Xi'an People's Hospital (Xi'an Fourth Hospital), Northwest University Affiliated People's Hospital, Xi'an, Shaanxi, China
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5
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Research progress of metformin in the treatment of liver fibrosis. Int Immunopharmacol 2023; 116:109738. [PMID: 36696857 DOI: 10.1016/j.intimp.2023.109738] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 01/12/2023] [Accepted: 01/12/2023] [Indexed: 01/24/2023]
Abstract
Liver fibrosis is a disease with significant morbidity and mortality. It is a chronic pathological process characterized by an imbalance of extracellular matrix production and degradation in liver tissue. Metformin is a type of hypoglycemic biguanide drug, which can be used in the treatment of liver fibrosis, but its anti-fibrotic effect and mechanism of action are unclear. The purpose of this article is to review the research progress of metformin in the treatment of liver fibrosis and to provide a theoretical basis for its application in the treatment of liver fibrosis.
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6
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Imran M, Sachdeva G, Menon S, Das D, Davuluri S, Acharya K, Chaudhari U. Therapeutic metformin concentrations positively regulate proliferation in endometrial epithelial cells via mTOR activation and augmented mitochondrial strength. Can J Physiol Pharmacol 2023; 101:52-64. [PMID: 36322951 DOI: 10.1139/cjpp-2022-0307] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Metformin, an antidiabetic drug, has recently been repositioned in the treatment of several nondiabetic disorders, including reproductive disorders such as polycystic ovarian syndrome, where it improves endometrial functions. In vitro studies employing supratherapeutic concentrations (5-20 mmol/L) of metformin have reported antiproliferative effects on endometrial epithelial and stromal cells. However, animal and human studies have revealed that therapeutic serum concentrations of metformin range between 20 and 70 µmol/L. In the present study, the effect of therapeutic concentrations of metformin was studied on endometrial epithelial cells (EECs). Therapeutic concentrations of metformin induced proliferation in Ishikawa and HEC-1A cells. The proliferation of EECs was found to be mammalian target of rapamycin (mTOR) dependent. Interestingly, therapeutic metformin concentrations were not able to activate the classical AMP-activated protein kinase (AMPK) signaling. On the contrary, supratherapeutic metformin concentration (10 mmol/L) inhibited mTOR and activated AMPK signaling. Microarray analysis of metformin-treated HEC-1A cells revealed dose-dependent differential effects on biological pathways associated with translation, ribosomal RNA processing, mitochondrial translation, and cell proliferation. Therapeutic concentrations of metformin upregulated mitochondrial number as demonstrated by increased MitoTracker™ Red staining and enhanced succinate dehydrogenase expression; however, higher concentration (10 mmol/L) abrogated the same. Our results suggest that therapeutic concentrations of metformin augment mitochondrial strength and induce mTOR-dependent endometrial cell proliferation.
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Affiliation(s)
- M Imran
- Cell Physiology and Pathology Laboratory, ICMR-National Institute for Research in Reproductive and Child Health, Mumbai, Maharashtra, India
| | - Geetanjali Sachdeva
- Cell Physiology and Pathology Laboratory, ICMR-National Institute for Research in Reproductive and Child Health, Mumbai, Maharashtra, India
| | - Shyla Menon
- Stem Cell Biology Laboratory, ICMR-National Institute for Research in Reproductive and Child Health, Mumbai, Maharashtra, India
| | - Dhanjit Das
- Stem Cell Biology Laboratory, ICMR-National Institute for Research in Reproductive and Child Health, Mumbai, Maharashtra, India
| | | | - Kshitish Acharya
- Shodhaka Life Sciences Pvt. Ltd., Bengaluru, Karnataka, India.,Institute of Bioinformatics and Applied Biotechnology (IBAB), Bengaluru, Karnataka, India
| | - Uddhav Chaudhari
- Cell Physiology and Pathology Laboratory, ICMR-National Institute for Research in Reproductive and Child Health, Mumbai, Maharashtra, India
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7
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Lazzeroni D, Villatore A, Souryal G, Pili G, Peretto G. The Aging Heart: A Molecular and Clinical Challenge. Int J Mol Sci 2022; 23:16033. [PMID: 36555671 PMCID: PMC9783309 DOI: 10.3390/ijms232416033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 12/05/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022] Open
Abstract
Aging is associated with an increasing burden of morbidity, especially for cardiovascular diseases (CVDs). General cardiovascular risk factors, ischemic heart diseases, heart failure, arrhythmias, and cardiomyopathies present a significant prevalence in older people, and are characterized by peculiar clinical manifestations that have distinct features compared with the same conditions in a younger population. Remarkably, the aging heart phenotype in both healthy individuals and patients with CVD reflects modifications at the cellular level. An improvement in the knowledge of the physiological and pathological molecular mechanisms underlying cardiac aging could improve clinical management of older patients and offer new therapeutic targets.
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Affiliation(s)
| | - Andrea Villatore
- School of Medicine, Università Vita-Salute San Raffaele, 20132 Milan, Italy
- Department of Arrhythmology and Cardiac Electrophysiology, Ospedale San Raffaele, 20132 Milan, Italy
| | - Gaia Souryal
- School of Medicine, Università Vita-Salute San Raffaele, 20132 Milan, Italy
| | - Gianluca Pili
- School of Medicine, Università Vita-Salute San Raffaele, 20132 Milan, Italy
| | - Giovanni Peretto
- School of Medicine, Università Vita-Salute San Raffaele, 20132 Milan, Italy
- Department of Arrhythmology and Cardiac Electrophysiology, Ospedale San Raffaele, 20132 Milan, Italy
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Cai Y, Song W, Li J, Jing Y, Liang C, Zhang L, Zhang X, Zhang W, Liu B, An Y, Li J, Tang B, Pei S, Wu X, Liu Y, Zhuang CL, Ying Y, Dou X, Chen Y, Xiao FH, Li D, Yang R, Zhao Y, Wang Y, Wang L, Li Y, Ma S, Wang S, Song X, Ren J, Zhang L, Wang J, Zhang W, Xie Z, Qu J, Wang J, Xiao Y, Tian Y, Wang G, Hu P, Ye J, Sun Y, Mao Z, Kong QP, Liu Q, Zou W, Tian XL, Xiao ZX, Liu Y, Liu JP, Song M, Han JDJ, Liu GH. The landscape of aging. SCIENCE CHINA. LIFE SCIENCES 2022; 65:2354-2454. [PMID: 36066811 PMCID: PMC9446657 DOI: 10.1007/s11427-022-2161-3] [Citation(s) in RCA: 190] [Impact Index Per Article: 63.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 07/05/2022] [Indexed: 02/07/2023]
Abstract
Aging is characterized by a progressive deterioration of physiological integrity, leading to impaired functional ability and ultimately increased susceptibility to death. It is a major risk factor for chronic human diseases, including cardiovascular disease, diabetes, neurological degeneration, and cancer. Therefore, the growing emphasis on "healthy aging" raises a series of important questions in life and social sciences. In recent years, there has been unprecedented progress in aging research, particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes. In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases, we review the descriptive, conceptual, and interventive aspects of the landscape of aging composed of a number of layers at the cellular, tissue, organ, organ system, and organismal levels.
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Affiliation(s)
- Yusheng Cai
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Wei Song
- Frontier Science Center for Immunology and Metabolism, Medical Research Institute, College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Jiaming Li
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ying Jing
- University of Chinese Academy of Sciences, Beijing, 100049, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Chuqian Liang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Liyuan Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
| | - Xia Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Wenhui Zhang
- University of Chinese Academy of Sciences, Beijing, 100049, China
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Beibei Liu
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
| | - Yongpan An
- Peking University International Cancer Institute, Peking University Health Science Center, Peking University, Beijing, 100191, China
| | - Jingyi Li
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Baixue Tang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Siyu Pei
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xueying Wu
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Yuxuan Liu
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, 100084, China
| | - Cheng-Le Zhuang
- Colorectal Cancer Center/Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, 200072, China
| | - Yilin Ying
- Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- International Laboratory in Hematology and Cancer, Shanghai Jiaotong University School of Medicine/Ruijin Hospital, Shanghai, 200025, China
| | - Xuefeng Dou
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yu Chen
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Fu-Hui Xiao
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China
| | - Dingfeng Li
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
| | - Ruici Yang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Ya Zhao
- Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, 330031, China
| | - Yang Wang
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Lihui Wang
- Institute of Ageing Research, Hangzhou Normal University, School of Basic Medical Sciences, Hangzhou, 311121, China
| | - Yujing Li
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Shuai Ma
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
- The Fifth People's Hospital of Chongqing, Chongqing, 400062, China.
| | - Xiaoyuan Song
- MOE Key Laboratory of Cellular Dynamics, Hefei National Research Center for Physical Sciences at the Microscale, CAS Key Laboratory of Brain Function and Disease, Neurodegenerative Disorder Research Center, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.
| | - Jie Ren
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Liang Zhang
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Jun Wang
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Weiqi Zhang
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
| | - Zhengwei Xie
- Peking University International Cancer Institute, Peking University Health Science Center, Peking University, Beijing, 100191, China.
| | - Jing Qu
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Jianwei Wang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
| | - Yichuan Xiao
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Ye Tian
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Gelin Wang
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, 100084, China.
| | - Ping Hu
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Colorectal Cancer Center/Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, 200072, China.
- Guangzhou Laboratory, Guangzhou International Bio Island, Guangzhou, 510005, China.
| | - Jing Ye
- Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
- International Laboratory in Hematology and Cancer, Shanghai Jiaotong University School of Medicine/Ruijin Hospital, Shanghai, 200025, China.
| | - Yu Sun
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
- Department of Medicine and VAPSHCS, University of Washington, Seattle, 98195, USA.
| | - Zhiyong Mao
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
| | - Qing-Peng Kong
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China.
| | - Qiang Liu
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China.
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
| | - Weiguo Zou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Xiao-Li Tian
- Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, 330031, China.
| | - Zhi-Xiong Xiao
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China.
| | - Yong Liu
- Frontier Science Center for Immunology and Metabolism, Medical Research Institute, College of Life Sciences, Wuhan University, Wuhan, 430071, China.
| | - Jun-Ping Liu
- Institute of Ageing Research, Hangzhou Normal University, School of Basic Medical Sciences, Hangzhou, 311121, China.
- Department of Immunology and Pathology, Monash University Faculty of Medicine, Prahran, Victoria, 3181, Australia.
- Hudson Institute of Medical Research, and Monash University Department of Molecular and Translational Science, Clayton, Victoria, 3168, Australia.
| | - Moshi Song
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Jing-Dong J Han
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology, Peking University, Beijing, 100871, China.
| | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
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9
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Dludla PV, Nkambule BB, Nyambuya TM, Ziqubu K, Mabhida SE, Mxinwa V, Mokgalaboni K, Ndevahoma F, Hanser S, Mazibuko-Mbeje SE, Basson AK, Sabbatinelli J, Tiano L. Vitamin C intake potentially lowers total cholesterol to improve endothelial function in diabetic patients at increased risk of cardiovascular disease: A systematic review of randomized controlled trials. Front Nutr 2022; 9:1011002. [PMID: 36386907 PMCID: PMC9659906 DOI: 10.3389/fnut.2022.1011002] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/29/2022] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Vitamin C is one of the most consumed dietary compounds and contains abundant antioxidant properties that could be essential in improving metabolic function. Thus, the current systematic review analyzed evidence on the beneficial effects of vitamin C intake on cardiovascular disease (CVD)-related outcomes in patients with diabetes or metabolic syndrome. METHODS To identify relevant randomized control trials (RCTs), a systematic search was run using prominent search engines like PubMed and Google Scholar, from beginning up to March 2022. The modified Black and Downs checklist was used to assess the quality of evidence. RESULTS Findings summarized in the current review favor the beneficial effects of vitamin C intake on improving basic metabolic parameters and lowering total cholesterol levels to reduce CVD-risk in subjects with type 2 diabetes or related metabolic diseases. Moreover, vitamin C intake could also reduce the predominant markers of inflammation and oxidative stress like C-reactive protein, interleukin-6, and malondialdehyde. Importantly, these positive outcomes were consistent with improved endothelial function or increased blood flow in these subjects. Predominantly effective doses were 1,000 mg/daily for 4 weeks up to 12 months. The included RCTs presented with the high quality of evidence. CONCLUSION Clinical evidence on the beneficial effects of vitamin C intake or its impact on improving prominent markers of inflammation and oxidative stress in patients with diabetes is still limited. Thus, more RCTs are required to solidify these findings, which is essential to better manage diabetic patients at increased risk of developing CVD.
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Affiliation(s)
- Phiwayinkosi V. Dludla
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, South Africa
| | - Bongani B. Nkambule
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Tawanda M. Nyambuya
- Department of Health Sciences, Namibia University of Science and Technology, Windhoek, Namibia
| | - Khanyisani Ziqubu
- Department of Biochemistry, North-West University, Mmabatho, South Africa
| | - Sihle E. Mabhida
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa
| | - Vuyolwethu Mxinwa
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Kabelo Mokgalaboni
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
- Department of Life and Consumer Sciences, University of South Africa, Florida Campus, Roodepoort, South Africa
| | - Fransina Ndevahoma
- Department of Health Sciences, Namibia University of Science and Technology, Windhoek, Namibia
| | - Sidney Hanser
- Department of Physiology and Environmental Health, University of Limpopo, Sovenga, South Africa
| | | | - Albertus K. Basson
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, South Africa
| | - Jacopo Sabbatinelli
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Luca Tiano
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
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10
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Metformin and alpha lipoic acid ameliorate hypothyroidism and its complications in adult male rats. J Diabetes Metab Disord 2022. [DOI: 10.1007/s40200-022-01063-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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11
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Heidary Moghaddam R, Samimi Z, Asgary S, Mohammadi P, Hozeifi S, Hoseinzadeh-Chahkandak F, Xu S, Farzaei MH. Natural AMPK Activators in Cardiovascular Disease Prevention. Front Pharmacol 2022; 12:738420. [PMID: 35046800 PMCID: PMC8762275 DOI: 10.3389/fphar.2021.738420] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 11/03/2021] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular diseases (CVD), as a life-threatening global disease, is receiving worldwide attention. Seeking novel therapeutic strategies and agents is of utmost importance to curb CVD. AMP-activated protein kinase (AMPK) activators derived from natural products are promising agents for cardiovascular drug development owning to regulatory effects on physiological processes and diverse cardiometabolic disorders. In the past decade, different therapeutic agents from natural products and herbal medicines have been explored as good templates of AMPK activators. Hereby, we overviewed the role of AMPK signaling in the cardiovascular system, as well as evidence implicating AMPK activators as potential therapeutic tools. In the present review, efforts have been made to compile and update relevant information from both preclinical and clinical studies, which investigated the role of natural products as AMPK activators in cardiovascular therapeutics.
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Affiliation(s)
- Reza Heidary Moghaddam
- Clinical Research Development Center, Imam Ali and Taleghani Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zeinab Samimi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sedigheh Asgary
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute,.Isfahan University of Medical Sciences, Isfahan, Iran
| | - Pantea Mohammadi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Soroush Hozeifi
- School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | | | - Suowen Xu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Medical Technology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
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12
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Newsholme P, Rowlands J, Rose’Meyer R, Cruzat V. Metabolic Adaptions/Reprogramming in Islet Beta-Cells in Response to Physiological Stimulators—What Are the Consequences. Antioxidants (Basel) 2022; 11:antiox11010108. [PMID: 35052612 PMCID: PMC8773416 DOI: 10.3390/antiox11010108] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/30/2021] [Accepted: 12/31/2021] [Indexed: 12/25/2022] Open
Abstract
Irreversible pancreatic β-cell damage may be a result of chronic exposure to supraphysiological glucose or lipid concentrations or chronic exposure to therapeutic anti-diabetic drugs. The β-cells are able to respond to blood glucose in a narrow concentration range and release insulin in response, following activation of metabolic pathways such as glycolysis and the TCA cycle. The β-cell cannot protect itself from glucose toxicity by blocking glucose uptake, but indeed relies on alternative metabolic protection mechanisms to avoid dysfunction and death. Alteration of normal metabolic pathway function occurs as a counter regulatory response to high nutrient, inflammatory factor, hormone or therapeutic drug concentrations. Metabolic reprogramming is a term widely used to describe a change in regulation of various metabolic enzymes and transporters, usually associated with cell growth and proliferation and may involve reshaping epigenetic responses, in particular the acetylation and methylation of histone proteins and DNA. Other metabolic modifications such as Malonylation, Succinylation, Hydroxybutyrylation, ADP-ribosylation, and Lactylation, may impact regulatory processes, many of which need to be investigated in detail to contribute to current advances in metabolism. By describing multiple mechanisms of metabolic adaption that are available to the β-cell across its lifespan, we hope to identify sites for metabolic reprogramming mechanisms, most of which are incompletely described or understood. Many of these mechanisms are related to prominent antioxidant responses. Here, we have attempted to describe the key β-cell metabolic adaptions and changes which are required for survival and function in various physiological, pathological and pharmacological conditions.
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Affiliation(s)
- Philip Newsholme
- Curtin Medical School and CHIRI, Curtin University, Perth, WA 6845, Australia
- Correspondence: (P.N.); (J.R.)
| | - Jordan Rowlands
- Curtin Medical School and CHIRI, Curtin University, Perth, WA 6845, Australia
- Correspondence: (P.N.); (J.R.)
| | - Roselyn Rose’Meyer
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, QLD 4222, Australia;
| | - Vinicius Cruzat
- Faculty of Health, Torrens University Australia, Brisbane, QLD 4006, Australia;
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13
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Ibrahim WS, Ahmed HMS, Mahmoud AAA, Mahmoud MF, Ibrahim IAAEH. Propranolol and low-dose isoproterenol ameliorate insulin resistance, enhance β-arrestin2 signaling, and reduce cardiac remodeling in high-fructose, high-fat diet-fed mice: Comparative study with metformin. Life Sci 2021; 286:120055. [PMID: 34662551 DOI: 10.1016/j.lfs.2021.120055] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 10/09/2021] [Accepted: 10/11/2021] [Indexed: 01/14/2023]
Abstract
AIMS β-Arrestin2 signaling has emerged as a promising therapeutic target for the management of insulin resistance and related complications. Moreover, recent studies have shown that certain G protein-coupled receptor (GPCR) ligands can modulate β-arrestin2 signaling. The current study examined the effects of the β-blocker propranolol and a low dose of the agonist isoproterenol (L-D-ISOPROT) on β-arrestin2 signaling, insulin resistance, and cardiac remodeling in high-fructose, high-fat diet (HFrHFD)-fed mice. In addition, the effects of these agents were compared to those of the clinical antidiabetic agent, metformin. MATERIALS AND METHODS Insulin resistance was induced by HFrHFD feeding for 16 weeks. Mice were then randomly allocated to groups receiving propranolol, L-D-ISOPROT, metformin, or vehicle (control) for 4 weeks starting on week 13 of HFrHFD feeding. Survival rate, body weight, visceral fat weight, blood glucose, serum insulin, insulin resistance index, hepatic β-arrestin2 signaling, heart weight, left and right ventricular thicknesses, cardiac fibrosis severity, serum endothelin-1, cardiac cardiotrophin-1, and cardiac β-arrestin2 signaling were then compared among groups. KEY FINDINGS HFrHFD for 16 weeks significantly increased insulin resistance index, cardiac fibrosis area, and serum endothelin-1, and reduced hepatic β-arrestin2 signaling, cardiac cardiotrophin-1, and cardiac β-arrestin2 signaling without significant changes in survival rate, body weight, visceral fat weight, heart weight, or left and right ventricular thicknesses. All three drugs reduced insulin resistance and cardiac remodeling parameters and enhanced β-arrestin2 signaling with variable efficacies. SIGNIFICANCE Propranolol and L-D-ISOPROT, like metformin, can reduce insulin-resistance and cardiac remodeling in HFrHFD-fed mice, possibly by upregulating β-arrestin2 signaling activity. Therefore, β-arrestin2-signaling modulation might be a promising strategy for insulin-resistance treatment.
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Affiliation(s)
- Wael S Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt; Department of Pharmacology, School of Pharmacy, Badr University in Cairo, Cairo, Egypt
| | - Hoda M S Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt; Medical Supply Chain, Abo-Hammad Health Administration, Ministry of Health, Egypt
| | - Amr A A Mahmoud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt
| | - Mona F Mahmoud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt
| | - Islam A A E-H Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt.
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14
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Koss-Mikołajczyk I, Todorovic V, Sobajic S, Mahajna J, Gerić M, Tur JA, Bartoszek A. Natural Products Counteracting Cardiotoxicity during Cancer Chemotherapy: The Special Case of Doxorubicin, a Comprehensive Review. Int J Mol Sci 2021; 22:10037. [PMID: 34576204 PMCID: PMC8467966 DOI: 10.3390/ijms221810037] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 12/14/2022] Open
Abstract
Cardiotoxicity is a frequent undesirable phenomenon observed during oncological treatment that limits the therapeutic dose of antitumor drugs and thus may decrease the effectiveness of cancer eradication. Almost all antitumor drugs exhibit toxic properties towards cardiac muscle. One of the underlying causes of cardiotoxicity is the stimulation of oxidative stress by chemotherapy. This suggests that an appropriately designed diet or dietary supplements based on edible plants rich in antioxidants could decrease the toxicity of antitumor drugs and diminish the risk of cardiac failure. This comprehensive review compares the cardioprotective efficacy of edible plant extracts and foodborne phytochemicals whose beneficial activity was demonstrated in various models in vivo and in vitro. The studies selected for this review concentrated on a therapy frequently applied in cancer, anthracycline antibiotic-doxorubicin-as the oxidative stress- and cardiotoxicity-inducing agent.
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Affiliation(s)
- Izabela Koss-Mikołajczyk
- Department of Food Chemistry, Technology and Biotechnology, Gdańsk University of Technology, 11/12 Narutowicza St., 80-233 Gdańsk, Poland;
| | - Vanja Todorovic
- Department of Bromatology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia; (V.T.); (S.S.)
| | - Sladjana Sobajic
- Department of Bromatology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia; (V.T.); (S.S.)
| | - Jamal Mahajna
- Department of Nutrition and Natural Products, Migal-Galilee Research Institute, Kiryat Shmona 11016, Israel;
- Department of Nutritional Sciences, Tel-Hai College, Qiryat Shemona 1220800, Israel
| | - Marko Gerić
- Mutagenesis Unit, Institute for Medical Research and Occupational Health, 10000 Zagreb, Croatia;
| | - Josep A. Tur
- Research Group on Community Nutrition & Oxidative Stress, University of Balearic Islands—IUNICS, IDISBA & CIBEROBN (Physiopathology of Obesity and Nutrition), 07122 Palma de Mallorca, Spain;
| | - Agnieszka Bartoszek
- Department of Food Chemistry, Technology and Biotechnology, Gdańsk University of Technology, 11/12 Narutowicza St., 80-233 Gdańsk, Poland;
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15
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Yan Y, Li T, Li Z, He M, Wang D, Xu Y, Yang X, Bai Y, Lao Y, Zhang Z, Wu W. Metformin Suppresses the Progress of Diabetes-Accelerated Atherosclerosis by Inhibition of Vascular Smooth Muscle Cell Migration Through AMPK-Pdlim5 Pathway. Front Cardiovasc Med 2021; 8:690627. [PMID: 34368251 PMCID: PMC8342753 DOI: 10.3389/fcvm.2021.690627] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 06/21/2021] [Indexed: 12/15/2022] Open
Abstract
Backgrounds: Our previous work revealed that AMP-activated protein kinase (AMPK) activation inhibits vascular smooth muscle cell migration in vitro by phosphorylating PDZ and LIM domain 5 (Pdlim5). As metformin is an AMPK activator, we used a mouse vascular smooth muscle cell (VSMC) line and a Myh11-cre-EGFP mice to investigate whether metformin could inhibit the migration of VSMCs in vitro and in a wire-injury model in vivo. It is recognized that VSMCs contribute to the major composition of atherosclerotic plaques. In order to investigate whether the AMPK–Pdlim5 pathway is involved in the protective function of metformin against atherosclerosis, we utilized ApoE−/− male mice to investigate whether metformin could suppress diabetes-accelerated atherosclerosis by inhibition of VSMC migration via the AMPK–Pdlim5 pathway. Methods: The mouse VSMC cell line was exogenously transfected wild type, phosphomimetic, or unphosphorylatable Pdlim5 mutant before metformin exposure. Myh11-cre-EGFP mice were treated with saline solution or metformin after these were subjected to wire injury in the carotid artery to study whether metformin could inhibit the migration of medial VSMCs into the neo-intima. In order to investigate whether the AMPK–Pdlim5 pathway is involved in the protective function of metformin against atherosclerosis, ApoE−/− male mice were divided randomly into control, streptozocin (STZ), and high-fat diet (HFD)-induced diabetes mellitus; STZ+HFD together with metformin or Pdlim5 mutant carried the adenovirus treatment groups. Results: It was found that metformin could induce the phosphorylation of Pdlim5 and inhibit cell migration as a result. The exogenous expression of phosphomimetic S177D-Pdlim5 inhibits lamellipodia formation and migration in VSMCs. It was also demonstrated that VSMCs contribute to the major composition of injury-induced neointimal lesions, while metformin could alleviate the occlusion of the carotid artery. The data of ApoE−/− mice showed that increased plasma lipids and aggravated vascular smooth muscle cell infiltration into the atherosclerotic lesion in diabetic mice were observed Metformin alleviated diabetes-induced metabolic disorders and atherosclerosis and also reduced VSMC infiltration in atherosclerotic plaques, while the Pdlim5 phospho-abolished mutant that carried adenovirus S177A-Pdlim5 undermines the protective function of metformin. Conclusions: The activation of the AMPK–Pdlim5 pathway by metformin could interrupt the migratory machine of VSMCs and inhibit cell migration in vitro and in vivo. The maintenance of AMPK activity by metformin is beneficial for suppressing diabetes-accelerated atherosclerosis.
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Affiliation(s)
- Yi Yan
- Department of Cardiology, Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Ting Li
- Department of Cardiology, Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Zhonghao Li
- Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong, Southern Medical University, Guangzhou, China
| | - Mingyuan He
- Department of Cardiology, Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Dejiang Wang
- Department of Cardiology, Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yingyi Xu
- Department of Cardiology, Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xuewen Yang
- Department of Cardiology, Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yuanyuan Bai
- Guangzhou First People's Hospital, Guangzhou, China
| | - Yi Lao
- Department of Cardiology, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, China
| | - Zhiyong Zhang
- Department of Cardiology, Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wei Wu
- Department of Cardiology, Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong, Southern Medical University, Guangzhou, China
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16
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Song XM, Li BJ, Zhang YY, Ge WJ, Zhang SF, Cui WF, Li GS, Liang RF. Rutaecarpine enhances the anti-diabetic activity and hepatic distribution of metformin via up-regulation of Oct1 in diabetic rats. Xenobiotica 2021; 51:818-830. [PMID: 33952086 DOI: 10.1080/00498254.2021.1926573] [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
Diabetes mellitus is a chronic metabolic disorder with multiple complications, patients who receive metformin may have a simultaneous intake of herbal medicine containing rutaecarpine due to cardiovascular protection and hypolipidemic effects of rutaecarpine. There might be drug interactions between metformin and rutaecarpine. This study aimed to investigate the effects of rutaecarpine on the pharmacodynamics and pharmacokinetics of metformin in diabetic rats.The diabetic rat model was induced with high-fat diet and low dose streptozotocin. Metformin with or without rutaecarpine was administered by oral gavage for 42 days. Pharmacodynamics and pharmacokinetics parameters were evaluated.The pharmacodynamics results revealed that co-administration of rutaecarpine with metformin resulted in a remarkable reduction of serum glucose and lipid profiles in diabetic rats compared to metformin treated alone. The pharmacokinetics results showed that co-treatments of rutaecarpine with metformin did not affect the systemic exposure and renal distribution of metformin, but increased metformin concentration in liver. Furthermore, rutaecarpine increased Oct1-mediated metformin uptake into hepatocytes by upregulation of Oct1 expression in the liver.The above data indicate that rutaecarpine enhanced the anti-diabetic effect of metformin, which may be associated with the increased hepatic distribution of metformin through up-regulation of Oct1 in response to rutaecarpine.
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Affiliation(s)
- Xian-Mei Song
- Department of Pharmacology, Henan Medical College, Zhengzhou, China
| | - Bing-Jie Li
- Institute of Chinese Materia Medica, Henan Provincial Academy of Traditional Chinese Medicine, Zhengzhou, China.,School of Pharmacology, Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Yan-Yan Zhang
- Department of Pharmacology, Henan Medical College, Zhengzhou, China
| | - Wen-Jing Ge
- Institute of Chinese Materia Medica, Henan Provincial Academy of Traditional Chinese Medicine, Zhengzhou, China.,School of Pharmacology, Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - She-Feng Zhang
- Institute of Chinese Materia Medica, Henan Provincial Academy of Traditional Chinese Medicine, Zhengzhou, China
| | - Wei-Feng Cui
- Institute of Chinese Materia Medica, Henan Provincial Academy of Traditional Chinese Medicine, Zhengzhou, China
| | - Geng-Sheng Li
- Institute of Chinese Materia Medica, Henan Provincial Academy of Traditional Chinese Medicine, Zhengzhou, China
| | - Rui-Feng Liang
- Institute of Chinese Materia Medica, Henan Provincial Academy of Traditional Chinese Medicine, Zhengzhou, China.,School of Pharmacology, Henan University of Traditional Chinese Medicine, Zhengzhou, China
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17
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Karwi QG, Ho KL, Pherwani S, Ketema EB, Sun QY, Lopaschuk GD. Concurrent diabetes and heart failure: interplay and novel therapeutic approaches. Cardiovasc Res 2021; 118:686-715. [PMID: 33783483 DOI: 10.1093/cvr/cvab120] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus increases the risk of developing heart failure, and the co-existence of both diseases worsens cardiovascular outcomes, hospitalization and the progression of heart failure. Despite current advancements on therapeutic strategies to manage hyperglycemia, the likelihood of developing diabetes-induced heart failure is still significant, especially with the accelerating global prevalence of diabetes and an ageing population. This raises the likelihood of other contributing mechanisms beyond hyperglycemia in predisposing diabetic patients to cardiovascular disease risk. There has been considerable interest in understanding the alterations in cardiac structure and function in the diabetic patients, collectively termed as "diabetic cardiomyopathy". However, the factors that contribute to the development of diabetic cardiomyopathies is not fully understood. This review summarizes the main characteristics of diabetic cardiomyopathies, and the basic mechanisms that contribute to its occurrence. This includes perturbations in insulin resistance, fuel preference, reactive oxygen species generation, inflammation, cell death pathways, neurohormonal mechanisms, advanced glycated end-products accumulation, lipotoxicity, glucotoxicity, and posttranslational modifications in the heart of the diabetic. This review also discusses the impact of antihyperglycemic therapies on the development of heart failure, as well as how current heart failure therapies influence glycemic control in diabetic patients. We also highlight the current knowledge gaps in understanding how diabetes induces heart failure.
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Affiliation(s)
- Qutuba G Karwi
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Kim L Ho
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Simran Pherwani
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Ezra B Ketema
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Qiu Yu Sun
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Gary D Lopaschuk
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
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18
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Emelyanova L, Bai X, Yan Y, Bosnjak ZJ, Kress D, Warner C, Kroboth S, Rudic T, Kaushik S, Stoeckl E, Ross GR, Rizvi F, Tajik AJ, Jahangir A. Biphasic effect of metformin on human cardiac energetics. Transl Res 2021; 229:5-23. [PMID: 33045408 PMCID: PMC10655614 DOI: 10.1016/j.trsl.2020.10.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 09/30/2020] [Accepted: 10/05/2020] [Indexed: 02/01/2023]
Abstract
Metformin is the first-line medication for treatment of type 2 diabetes and has been shown to reduce heart damage and death. However, mechanisms by which metformin protects human heart remain debated. The aim of the study was to evaluate the cardioprotective effect of metformin on cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) and mitochondria isolated from human cardiac tissue. At concentrations ≤2.5 mM, metformin significantly increased oxygen consumption rate (OCR) in the hiPSC-CMs by activating adenosine monophosphate activated protein kinase (AMPK)-dependent signaling and enhancing mitochondrial biogenesis. This effect was abrogated by compound C, an inhibitor of AMPK. At concentrations >5 mM, metformin inhibited the cellular OCR and triggered metabolic reprogramming by enhancing glycolysis and glutaminolysis in the cardiomyocytes. In isolated cardiac mitochondria, metformin did not increase the OCR at any concentrations but inhibited the OCR starting at 1 mM through direct inhibition of electron-transport chain complex I. This was associated with reduction of superoxide production and attenuation of Ca2+-induced mitochondrial permeability transition pore (mPTP) opening in the mitochondria. Thus, in human heart, metformin might improve cardioprotection due to its biphasic effect on mitochondria: at low concentrations, it activates mitochondrial biogenesis via AMPK signaling and increases the OCR; at high concentrations, it inhibits the respiration by directly affecting the activity of complex I, reduces oxidative stress and delays mPTP formation. Moreover, metformin at high concentrations causes metabolic reprogramming by enhancing glycolysis and glutaminolysis. These effects can be a beneficial adjunct to patients with impaired endogenous cardioprotective responses.
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Affiliation(s)
- Larisa Emelyanova
- Center for Integrative Research on Cardiovascular Aging, Advocate Aurora Research Institute, Milwaukee, Wisconsin.
| | - Xiaowen Bai
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Yasheng Yan
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Zeljko J Bosnjak
- Departments of Medicine and Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - David Kress
- Aurora Cardiovascular and Thoracic Services, St. Luke's Medical Center, Advocate Aurora Health Care, Milwaukee, Wisconsin
| | - Catherine Warner
- Center for Integrative Research on Cardiovascular Aging, Advocate Aurora Research Institute, Milwaukee, Wisconsin
| | - Stacie Kroboth
- Aurora Cardiovascular and Thoracic Services, St. Luke's Medical Center, Advocate Aurora Health Care, Milwaukee, Wisconsin
| | - Teodore Rudic
- Center for Integrative Research on Cardiovascular Aging, Advocate Aurora Research Institute, Milwaukee, Wisconsin
| | - Sirisha Kaushik
- Center for Integrative Research on Cardiovascular Aging, Advocate Aurora Research Institute, Milwaukee, Wisconsin
| | - Elizabeth Stoeckl
- Center for Integrative Research on Cardiovascular Aging, Advocate Aurora Research Institute, Milwaukee, Wisconsin
| | - Gracious R Ross
- Center for Integrative Research on Cardiovascular Aging, Advocate Aurora Research Institute, Milwaukee, Wisconsin
| | - Farhan Rizvi
- Center for Integrative Research on Cardiovascular Aging, Advocate Aurora Research Institute, Milwaukee, Wisconsin
| | - A Jamil Tajik
- Aurora Cardiovascular and Thoracic Services, St. Luke's Medical Center, Advocate Aurora Health Care, Milwaukee, Wisconsin
| | - Arshad Jahangir
- Aurora Cardiovascular and Thoracic Services, St. Luke's Medical Center, Advocate Aurora Health Care, Milwaukee, Wisconsin
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19
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The relationship between coronary artery disease and SIRT1 protein. North Clin Istanb 2021; 7:631-635. [PMID: 33381707 PMCID: PMC7754863 DOI: 10.14744/nci.2020.31391] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 02/06/2020] [Indexed: 01/07/2023] Open
Abstract
Endothelial cell dysfunction proceeding with increased inflammation and monocyte increase is one of the main causes of vessel injury in CAD. SIRT1 (Sirtuin 1) protein plays an important role in the regulation of cellular physiological mechanisms. SIRT1 has roles in regulating angiogenesis and preventing endothelial dysfunction and reperfusion injury due to ischemia. Suppression of SIRT1 causes monocyte affinity due to endothelial dysfunction. Sirtuins activators are involved in pathologies of many diseases with promising treatments. The objective of this review is to summarize the current progress and future directions of sirtuin protein in the field of CAD.
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20
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Nantsupawat T, Wongcharoen W, Chattipakorn SC, Chattipakorn N. Effects of metformin on atrial and ventricular arrhythmias: evidence from cell to patient. Cardiovasc Diabetol 2020; 19:198. [PMID: 33234131 PMCID: PMC7687769 DOI: 10.1186/s12933-020-01176-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 11/15/2020] [Indexed: 12/23/2022] Open
Abstract
Metformin has been shown to have various cardiovascular benefits beyond its antihyperglycemic effects, including a reduction in stroke, heart failure, myocardial infarction, cardiovascular death, and all-cause mortality. However, the roles of metformin in cardiac arrhythmias are still unclear. It has been shown that metformin was associated with decreased incidence of atrial fibrillation in diabetic patients with and without myocardial infarction. This could be due to the effects of metformin on preventing the structural and electrical remodeling of left atrium via attenuating intracellular reactive oxygen species, activating 5′ adenosine monophosphate-activated protein kinase, improving calcium homeostasis, attenuating inflammation, increasing connexin-43 gap junction expression, and restoring small conductance calcium-activated potassium channels current. For ventricular arrhythmias, in vivo reports demonstrated that activation of 5′ adenosine monophosphate-activated protein kinase and phosphorylated connexin-43 by metformin played a key role in ischemic ventricular arrhythmias reduction. However, metformin failed to show anti-ventricular arrhythmia benefits in clinical trials. In this review, in vitro and in vivo reports regarding the effects of metformin on both atrial arrhythmias and ventricular arrhythmias are comprehensively summarized and presented. Consistent and controversial findings from clinical trials are also summarized and discussed. Due to limited numbers of reports, further studies are needed to elucidate the mechanisms and effects of metformin on cardiac arrhythmias. Furthermore, randomized controlled trials are needed to clarify effects of metformin on cardiac arrhythmias in human.
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Affiliation(s)
- Teerapat Nantsupawat
- Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Chiang Mai, 50200, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Wanwarang Wongcharoen
- Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Chiang Mai, 50200, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Chiang Mai, 50200, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Chiang Mai, 50200, Thailand. .,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand. .,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
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21
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Dludla PV, Nkambule BB, Mazibuko-Mbeje SE, Nyambuya TM, Mxinwa V, Mokgalaboni K, Ziqubu K, Cirilli I, Marcheggiani F, Louw J, Tiano L. Adipokines as a therapeutic target by metformin to improve metabolic function: A systematic review of randomized controlled trials. Pharmacol Res 2020; 163:105219. [PMID: 33017649 DOI: 10.1016/j.phrs.2020.105219] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/27/2020] [Accepted: 09/17/2020] [Indexed: 12/16/2022]
Abstract
Metformin is a widely used glucose-lowering drug, although its impact on adipose tissue function remains elusive. Adipose tissue-derived molecules regulate diverse physiological mechanisms, including energy metabolism, insulin sensitization, and inflammatory response. Alternatively, it has remained relevant to understand the therapeutic regulation of adipokines in efforts to alleviate inflammation in conditions associated with the metabolic syndrome. The current qualitative analysis of available literature focused on randomized clinical trials (RCTs) assessing the association between administration of metformin and adipokine regulation in individuals with metabolic syndrome. The major electronic databases such as MEDLINE, Cochrane Library, Scopus, and EMBASE were searched for eligible RCTs. Overall, 13 RCTs met the inclusion criteria, with a total of 4605 participants. Patients with metabolic syndrome were characterized by a state of obesity, impaired glucose tolerance, insulin resistance, and type 2 diabetes. Cumulative evidence from these RCTs supported the blood glucose lowering effects of metformin, in addition to promoting weight loss, ameliorating insulin resistance, and reducing pro-inflammatory markers such as interleukin-6 and tumor necrosis factor-α in patients with metabolic syndrome. Importantly, these therapeutic effects are associated with the upregulation of adiponectin and suppression of leptin and resistin.
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Affiliation(s)
- Phiwayinkosi V Dludla
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, 7505, South Africa; Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, 60131, Italy.
| | - Bongani B Nkambule
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa
| | | | - Tawanda M Nyambuya
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa; Department of Health Sciences, Faculty of Health and Applied Sciences, Namibia University of Science and Technology, Windhoek, 9000, Namibia
| | - Vuyolwethu Mxinwa
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa
| | - Kabelo Mokgalaboni
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa
| | - Khanyisani Ziqubu
- Department of Biochemistry, North-West University, Mmabatho, 2745, South Africa
| | - Ilenia Cirilli
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, 60131, Italy; School of Pharmacy, University of Camerino, Camerino, 62032, Italy
| | - Fabio Marcheggiani
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, 60131, Italy
| | - Johan Louw
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, 7505, South Africa; Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, 3880, South Africa
| | - Luca Tiano
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, 60131, Italy
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22
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Li J, Wei Q, Li WX, McCowen KC, Xiong W, Liu J, Jiang W, Marin T, Thomas RL, He M, Gongol B, Hepokoski M, Yuan JXJ, Shyy JYJ, Xiong N, Malhotra A. Metformin Use in Diabetes Prior to Hospitalization: Effects on Mortality in Covid-19. Endocr Pract 2020; 26:1166-1172. [PMID: 33471718 PMCID: PMC7834011 DOI: 10.4158/ep-2020-0466] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 09/15/2020] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Although type 2 diabetes mellitus (T2DM) has been reported as a risk factor for coronavirus disease 2019 (COVID-19), the effect of pharmacologic agents used to treat T2DM, such as metformin, on COVID-19 outcomes remains unclear. Metformin increases the expression of angiotensin converting enzyme 2, a known receptor for severe acute respiratory syndrome coronavirus 2. Data from people with T2DM hospitalized for COVID-19 were used to test the hypothesis that metformin use is associated with improved survival in this population. METHODS Retrospective analyses were performed on de-identified clinical data from a major hospital in Wuhan, China, that included patients with T2DM hospitalized for COVID-19 during the recent epidemic. One hundred and thirty-one patients diagnosed with COVID-19 and T2DM were used in this study. The primary outcome was mortality. Demographic, clinical characteristics, laboratory data, diabetes medications, and respiratory therapy data were also included in the analysis. RESULTS Of these 131 patients, 37 used metformin with or without other antidiabetes medications. Among the 37 metformin-taking patients, 35 (94.6%) survived and 2 (5.4%) did not survive. The mortality rates in the metformin-taking group versus the non-metformin group were 5.4% (2/37) versus 22.3% (21/94). Using multivariate analysis, metformin was found to be an independent predictor of survival in this cohort (P = .02). CONCLUSION This study reveals a significant association between metformin use and survival in people with T2DM diagnosed with COVID-19. These clinical data are consistent with potential benefits of the use of metformin for COVID-19 patients with T2DM.
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Affiliation(s)
- Jinghong Li
- From the Department of Medicine, University of California, San Diego, La Jolla, California
| | - Qi Wei
- the Department of Endocrinology, Wuhan Red Cross Hospital, Wuhan, Hubei, China
| | - Willis X Li
- From the Department of Medicine, University of California, San Diego, La Jolla, California
| | - Karen C McCowen
- From the Department of Medicine, University of California, San Diego, La Jolla, California
| | - Wei Xiong
- the Department of Endocrinology, Wuhan Red Cross Hospital, Wuhan, Hubei, China
| | - Jiao Liu
- the Department of Endocrinology, Wuhan Red Cross Hospital, Wuhan, Hubei, China
| | - Wenlijun Jiang
- the Department of Endocrinology, Wuhan Red Cross Hospital, Wuhan, Hubei, China
| | - Traci Marin
- the Department of Health Sciences, Victor Valley College, Victorville, California
| | - Robert L Thomas
- From the Department of Medicine, University of California, San Diego, La Jolla, California
| | - Ming He
- From the Department of Medicine, University of California, San Diego, La Jolla, California
| | - Brendan Gongol
- From the Department of Medicine, University of California, San Diego, La Jolla, California
| | - Mark Hepokoski
- From the Department of Medicine, University of California, San Diego, La Jolla, California
| | - Jason X-J Yuan
- From the Department of Medicine, University of California, San Diego, La Jolla, California
| | - John Y-J Shyy
- From the Department of Medicine, University of California, San Diego, La Jolla, California.
| | - Nian Xiong
- the Department of Endocrinology, Wuhan Red Cross Hospital, Wuhan, Hubei, China; the Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China..
| | - Atul Malhotra
- From the Department of Medicine, University of California, San Diego, La Jolla, California
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23
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Huijink TM, Venema LH, Posma RA, de Vries NJ, Westerkamp AC, Ottens PJ, Touw DJ, Nijsten MW, Leuvenink HGD. Metformin Preconditioning and Postconditioning to Reduce Ischemia Reperfusion Injury in an Isolated Ex Vivo Rat and Porcine Kidney Normothermic Machine Perfusion Model. Clin Transl Sci 2020; 14:222-230. [PMID: 32702185 PMCID: PMC7877823 DOI: 10.1111/cts.12846] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 06/03/2020] [Indexed: 12/16/2022] Open
Abstract
Metformin may act renoprotective prior to kidney transplantation by reducing ischemia-reperfusion injury (IRI). This study examined whether metformin preconditioning and postconditioning during ex vivo normothermic machine perfusion (NMP) of rat and porcine kidneys affect IRI. In the rat study, saline or 300 mg/kg metformin was administered orally twice on the day before nephrectomy. After 15 minutes of warm ischemia, kidneys were preserved with static cold storage for 24 hours. Thereafter, 90 minutes of NMP was performed with the addition of saline or metformin (30 or 300 mg/L). In the porcine study, after 30 minutes of warm ischemia, kidneys were preserved for 3 hours with oxygenated hypothermic machine perfusion. Subsequently, increasing doses of metformin were added during 4 hours of NMP. Metformin preconditioning of rat kidneys led to decreased injury perfusate biomarkers and reduced proteinuria. Postconditioning of rat kidneys resulted, dose-dependently, in less tubular cell necrosis and vacuolation. Heat shock protein 70 expression was increased in metformin-treated porcine kidneys. In all studies, creatinine clearance was not affected. In conclusion, both metformin preconditioning and postconditioning can be done safely and improved rat and porcine kidney quality. Because the effects are minor, it is unknown which strategy might result in improved organ quality after transplantation.
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Affiliation(s)
- Tobias M Huijink
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Leonie H Venema
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Rene A Posma
- Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Nynke J de Vries
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Andrie C Westerkamp
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Petra J Ottens
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Daan J Touw
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Maarten W Nijsten
- Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Henri G D Leuvenink
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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24
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Zhang M, Sun W, Du J, Gou Y, Liu L, Wang R, Xu X. Protective Effect of Metformin on Sepsis Myocarditis in Zebrafish. Dose Response 2020; 18:1559325820938543. [PMID: 32694962 PMCID: PMC7350400 DOI: 10.1177/1559325820938543] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/11/2020] [Accepted: 05/27/2020] [Indexed: 12/11/2022] Open
Abstract
Purpose: We found in previous study that metformin could treat sepsis myocarditis in a mouse model. We employed the zebrafish model organism to investigate the effect of metformin on sepsis myocarditis. Methods and Results: Wild-type zebrafish was used to establish a sepsis myocarditis model and combined with image software analysis and cytokine detection, the protective dose of metformin was determined. The results showed that immersion with Escherichia coli could cause 75% mortality in zebrafish and make larvae appear as characteristics of severe sepsis myocarditis. Pretreatment with 10 mM metformin for 3 hours could effectively reduce heart congestion and swelling in zebrafish with sepsis myocarditis and increased the heart rate. It could reduce the mortality and prolong the survival time of zebrafish with sepsis myocarditis; Tg(mpx: EGFP) transgenic zebrafish were adopted to explore the number of neutrophils in zebrafish heart before and after metformin protection, and metformin could maintain the number of neutrophils in zebrafish heart; quantitative real-time reverse transcription–polymerase chain reaction showed that metformin could reduce the expression of pro-inflammatory factors, tumor necrosis factor-α and interleukin (IL)-6, and could promote the anti-inflammatory factor, transforming growth factor-β and IL-10 expression. Conclusion: We established a zebrafish sepsis myocarditis model and applied metformin in advance to provide a protective effect on the zebrafish heart.
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Affiliation(s)
- Mingming Zhang
- China-Japan Union Hospital, Jilin University, Jilin, China.,Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, China.,Contributed equally to this work
| | - Wei Sun
- Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, China.,Contributed equally to this work
| | - Jianan Du
- Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yawei Gou
- Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Lingling Liu
- Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Ruonan Wang
- Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xuesong Xu
- China-Japan Union Hospital, Jilin University, Jilin, China
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25
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Shi Y, Batibawa JW, Maiga M, Sun B, Li Y, Duan J, Sun Z. Identification and validation of metformin protects against PM 2.5-induced macrophages cytotoxicity by targeting toll like receptor pathway. CHEMOSPHERE 2020; 251:126526. [PMID: 32443237 DOI: 10.1016/j.chemosphere.2020.126526] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 03/12/2020] [Accepted: 03/15/2020] [Indexed: 06/11/2023]
Abstract
Fine particle matter (PM2.5) has been extensively reported to contribute to the pathogenesis of pulmonary diseases. Recently, metformin has been reported to attenuate PM2.5 associated respiratory and cardiovascular injury, but the underling mechanism has not been discovered. Here, we performed comprehensively bioinformatics analysis and fully validation experiment to investigate the protection role of metformin and underling mechanism with RNAseq profile in GEO database. A combination of various bioinformatics tools including edgeR, principal component analysis (PCA), K-Means clustering, Gene Set Enrichment Analysis (GSEA), GO and KEGG enrichment were performed to identify the TLRs/MyD88/NF-κB axis functional as the key signaling transduction during PM2.5 associated toxicity. PM2.5 activated TLRs/MyD88/NF-κB pathway and resulted in significantly generation of IL-6, TNF-α, mitochondrial damage, decreasing of cell viability and increased LDH activity in RAW264.7 cells. Metformin significantly attenuated the production of IL-6, mitochondrial damage, cell viability and LDH activity by limiting TLRs/MyD88/NF-κB pathway. The siRNA against AMPKα2 or negative control were transfected to RAW264.7 cells to identify whether metformin protects PM2.5-induced cytotoxicity in an AMPKα2-dependent manner. Pretreatment with metformin significantly attenuated PM2.5 induced decreasing of cell viability and increased LDH activity, as well as inhibited the TLRs/MyD88/NF-κB pathway in both siControl or siAMPKα2 cells. Taken together, our results indicate that metformin protects against PM2.5-induced mitochondrial damage and cell cytotoxicity by inhibiting TLRs/MyD88/NF-κB signaling pathway in an AMPKα2 independent manner.
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Affiliation(s)
- Yanfeng Shi
- Department of Toxicology and Sanitary Chemistry, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Josevata Werelagi Batibawa
- Department of Toxicology and Sanitary Chemistry, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Modibo Maiga
- Department of Toxicology and Sanitary Chemistry, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Baiyang Sun
- Department of Toxicology and Sanitary Chemistry, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Yang Li
- Department of Toxicology and Sanitary Chemistry, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Junchao Duan
- Department of Toxicology and Sanitary Chemistry, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China.
| | - Zhiwei Sun
- Department of Toxicology and Sanitary Chemistry, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China.
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26
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Hesperidin ameliorates signs of the metabolic syndrome and cardiac dysfunction via IRS/Akt/GLUT4 signaling pathway in a rat model of diet-induced metabolic syndrome. Eur J Nutr 2020; 60:833-848. [PMID: 32462317 DOI: 10.1007/s00394-020-02291-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 05/18/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hesperidin has been reported to have biological activities such as antihypertensive, hypoglycemic, and antioxidant effects. This study investigated whether hesperidin could improve signs of the metabolic syndrome and cardiac function in a high-fat diet (HFD) induced metabolic syndrome (MS) in rats. METHODS Male Sprague-Dawley rats were fed HFD and 15% fructose for 16 weeks and treated with hesperidin (15 or 30 mg/kg, based on signs of MS from a preliminary study) or metformin, a positive control agent, (100 mg/kg) for the final four weeks. Cardiac function, blood pressure, fasting blood glucose, oral glucose tolerance, serum insulin, and lipid profiles were measured. Histomorphometrics of left ventricles, epidydimal fat pads and liver were evaluated. Expressions of phosphorylate insulin receptor substrate1(p-IRS1), p-Akt and GLUT4 in cardiac tissue were determined. RESULTS Hesperidin and metformin attenuated MS in HFD rats (p < 0.05). The accumulation of visceral fat pads and fatty liver associated with increases in liver lipid contents and liver enzymes were found in MS rats that were alleviated in hesperidin or metformin-treated groups (p < 0.05). Hesperidin and metformin improved cardiac dysfunction and hypertrophy observed in MS rats (p < 0.05). Restoration of the insulin signaling pathway, IRS/Akt/GLUT4 protein expression, was demonstrated in hesperidin and metformin-treated groups (p < 0.05). Hesperidin (30 mg/kg) was more effective than the lower dose. CONCLUSION Hesperidin was effective in reducing signs of MS and alterations of LV hypertrophy and function. These beneficial effects on the heart were associated with the restoration of the cardiac insulin signaling pathway in MS rats.
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Dludla PV, Muller CJF, Louw J, Mazibuko-Mbeje SE, Tiano L, Silvestri S, Orlando P, Marcheggiani F, Cirilli I, Chellan N, Ghoor S, Nkambule BB, Essop MF, Huisamen B, Johnson R. The Combination Effect of Aspalathin and Phenylpyruvic Acid-2- O-β-D-glucoside from Rooibos against Hyperglycemia-Induced Cardiac Damage: An In Vitro Study. Nutrients 2020; 12:nu12041151. [PMID: 32325968 PMCID: PMC7231041 DOI: 10.3390/nu12041151] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 04/14/2020] [Accepted: 04/16/2020] [Indexed: 02/08/2023] Open
Abstract
Recent evidence shows that rooibos compounds, aspalathin and phenylpyruvic acid-2-O-β-d-glucoside (PPAG), can independently protect cardiomyocytes from hyperglycemia-related reactive oxygen species (ROS). While aspalathin shows more potency by enhancing intracellular antioxidant defenses, PPAG acts more as an anti-apoptotic agent. Thus, to further understand the protective capabilities of these compounds against hyperglycemia-induced cardiac damage, their combinatory effect was investigated and compared to metformin. An in vitro model of H9c2 cardiomyocytes exposed to chronic glucose concentrations was employed to study the impact of such compounds on hyperglycemia-induced damage. Here, high glucose exposure impaired myocardial substrate utilization by abnormally enhancing free fatty acid oxidation while concomitantly suppressing glucose oxidation. This was paralleled by altered expression of genes involved in energy metabolism including acetyl-CoA carboxylase (ACC), 5′ AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor-alpha (PPARα). The combination treatment improved myocardial substrate metabolism, maintained mitochondrial membrane potential, and attenuated various markers for oxidative stress including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and glutathione content. It also showed a much-improved effect by ameliorating DNA damage when compared to metformin. The current study demonstrates that rooibos compounds offer unique cardioprotective properties against hyperglycemia-induced and potentially against diabetes-induced cardiac damage. These data also support further exploration of rooibos compounds to better assess the cardioprotective effects of different bioactive compound combinations.
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Affiliation(s)
- Phiwayinkosi V. Dludla
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa; (C.J.F.M.); (J.L.); (S.E.M.-M.); (N.C.); (S.G.); (B.H.); (R.J.)
- Department of Life and Environmental Sciences, Polytechnic University of Marche, 60131 Ancona, Italy; (L.T.); (S.S.); (P.O.); (F.M.); (I.C.)
- Correspondence: ; Tel.: +27-21-938-0333
| | - Christo J. F. Muller
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa; (C.J.F.M.); (J.L.); (S.E.M.-M.); (N.C.); (S.G.); (B.H.); (R.J.)
- Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Private Bag X1, Tygerberg 7505, South Africa
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3880, South Africa
| | - Johan Louw
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa; (C.J.F.M.); (J.L.); (S.E.M.-M.); (N.C.); (S.G.); (B.H.); (R.J.)
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3880, South Africa
| | - Sithandiwe E. Mazibuko-Mbeje
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa; (C.J.F.M.); (J.L.); (S.E.M.-M.); (N.C.); (S.G.); (B.H.); (R.J.)
- Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Private Bag X1, Tygerberg 7505, South Africa
| | - Luca Tiano
- Department of Life and Environmental Sciences, Polytechnic University of Marche, 60131 Ancona, Italy; (L.T.); (S.S.); (P.O.); (F.M.); (I.C.)
| | - Sonia Silvestri
- Department of Life and Environmental Sciences, Polytechnic University of Marche, 60131 Ancona, Italy; (L.T.); (S.S.); (P.O.); (F.M.); (I.C.)
| | - Patrick Orlando
- Department of Life and Environmental Sciences, Polytechnic University of Marche, 60131 Ancona, Italy; (L.T.); (S.S.); (P.O.); (F.M.); (I.C.)
| | - Fabio Marcheggiani
- Department of Life and Environmental Sciences, Polytechnic University of Marche, 60131 Ancona, Italy; (L.T.); (S.S.); (P.O.); (F.M.); (I.C.)
| | - Ilenia Cirilli
- Department of Life and Environmental Sciences, Polytechnic University of Marche, 60131 Ancona, Italy; (L.T.); (S.S.); (P.O.); (F.M.); (I.C.)
- School of Pharmacy, University of Camerino, 62032 Camerino, Italy
| | - Nireshni Chellan
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa; (C.J.F.M.); (J.L.); (S.E.M.-M.); (N.C.); (S.G.); (B.H.); (R.J.)
- Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Private Bag X1, Tygerberg 7505, South Africa
| | - Samira Ghoor
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa; (C.J.F.M.); (J.L.); (S.E.M.-M.); (N.C.); (S.G.); (B.H.); (R.J.)
| | - Bongani B. Nkambule
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa;
| | - M. Faadiel Essop
- Centre for Cardio-metabolic Research in Africa, Department of Physiological Sciences, Stellenbosch University, Stellenbosch 7600, South Africa;
| | - Barbara Huisamen
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa; (C.J.F.M.); (J.L.); (S.E.M.-M.); (N.C.); (S.G.); (B.H.); (R.J.)
- Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Private Bag X1, Tygerberg 7505, South Africa
| | - Rabia Johnson
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa; (C.J.F.M.); (J.L.); (S.E.M.-M.); (N.C.); (S.G.); (B.H.); (R.J.)
- Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Private Bag X1, Tygerberg 7505, South Africa
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Metformin and heart failure-related outcomes in patients with or without diabetes: a systematic review of randomized controlled trials. Heart Fail Rev 2020; 26:1437-1445. [PMID: 32157481 DOI: 10.1007/s10741-020-09942-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Metformin is considered a safe anti-hyperglycemic drug for patients with type 2 diabetes (T2D); however, information on its impact on heart failure-related outcomes remains inconclusive. The current systematic review explored evidence from randomized clinical trials (RCTs) reporting on the impact of metformin in modulating heart failure-related markers in patients with or without T2D. Electronic databases such as MEDLINE, Cochrane Library, and EMBASE were searched for eligible studies. Included studies were those assessing the use of metformin as an intervention, and also containing the comparison group on placebo, and all articles had to report on measurable heart failure-related indices in individuals with or without T2D. The modified Downs and Black checklist was used to evaluate the risk of bias. Overall, nine studies met the inclusion criteria, enrolling a total of 2486 patients. Although summarized evidence showed that metformin did not affect left ventricular function, this antidiabetic drug could improve myocardial oxygen consumption concomitant to reducing prominent markers of heart failure such as n-terminal pro-brain natriuretic peptide and low-density lipoprotein levels, inconsistently between diabetic and nondiabetic patients. Effective modulation of some heart failure-related outcomes with metformin treatment was related to its beneficial effects in ameliorating insulin resistance and blocking pro-inflammatory markers such as the aging-associated cytokine CCL11 (C-C motif chemokine ligand 11). Overall, although such beneficial effects were observed with metformin treatment, additional RCTs are necessary to improve our understanding on its modulatory effects on heart failure-related outcomes especially in diabetic patients.
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29
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Bal Altuntaş D. Development of All‐solid‐state Antidiabetic Drug Metformin‐selective Microsensor and its Electrochemical Applications. ELECTROANAL 2020. [DOI: 10.1002/elan.201900773] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Derya Bal Altuntaş
- Department of Bioengineering, Faculty of EngineeringRecep Tayyip Erdogan University Turkey
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30
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Yandrapalli S, Jolly G, Horblitt A, Pemmasani G, Sanaani A, Aronow WS, Frishman WH. Cardiovascular Safety and Benefits of Noninsulin Antihyperglycemic Drugs for the Treatment of Type 2 Diabetes Mellitus-Part 1. Cardiol Rev 2020; 28:177-189. [PMID: 32282393 DOI: 10.1097/crd.0000000000000308] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cardiovascular disease (CVD) is a major contributor to the morbidity and mortality associated with type 2 diabetes mellitus (T2DM). With T2DM growing in pandemic proportions, there will be profound healthcare implications of CVD in person with diabetes. The ideal drugs to improve outcomes in T2DM are those having antiglycemic efficacy in addition to cardiovascular (CV) safety, which has to be determined in appropriately designed CV outcome trials as mandated by regulatory agencies. Available evidence is largely supportive of metformin's CV safety and potential CVD risk reduction effects, whereas sulfonylureas are either CV risk neutral or are associated with variable CVD risk. Pioglitazone was also associated with improved CVD risk in patients with diabetes. The more recent antihyperglycemic medications have shown promise with regards to CVD risk reduction in T2DM patients at a high CV risk. Glucagon-like peptide-1 receptor agonists, a type of incretin-based therapy, were associated with better CV outcomes and mortality in T2DM patients, leading to the Food and Drug Administration approval of liraglutide to reduce CVD risk in high-risk T2DM patients. Ongoing and planned randomized controlled trials of the newer drugs should clarify the possibility of class effects, and of CVD risk reduction benefits in low-moderate CV risk patients. While metformin remains the first-line antiglycemic therapy in T2DM, glucagon-like peptide-1 receptor agonists should be appropriately prescribed in T2DM patients with baseline CVD or in those at a high CVD risk to improve CV outcomes. Dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter-2 inhibitors are discussed in the second part of this review.
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Affiliation(s)
- Srikanth Yandrapalli
- From the Department of Medicine, Division of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY
| | - George Jolly
- Division of Cardiology, Loma Linda University Medical Center, Loma Linda, CA
| | - Adam Horblitt
- Division of Cardiology, Tulane Medical Center, New Orleans, LA
| | - Gayatri Pemmasani
- From the Department of Medicine, Division of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY
| | - Abdallah Sanaani
- From the Department of Medicine, Division of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY
| | - Wilbert S Aronow
- From the Department of Medicine, Division of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY
| | - William H Frishman
- From the Department of Medicine, Division of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY
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31
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Saewanee N, Praputpittaya T, Malaiwong N, Chalorak P, Meemon K. Neuroprotective effect of metformin on dopaminergic neurodegeneration and α-synuclein aggregation in C. elegans model of Parkinson's disease. Neurosci Res 2019; 162:13-21. [PMID: 31881233 DOI: 10.1016/j.neures.2019.12.017] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 12/07/2019] [Accepted: 12/23/2019] [Indexed: 02/07/2023]
Affiliation(s)
- Nada Saewanee
- Mahidol University International College, 999 Phutthamonthon 4 Road, Salaya, Nakhon Pathom, 73170, Thailand
| | - Theethawat Praputpittaya
- Mahidol University International College, 999 Phutthamonthon 4 Road, Salaya, Nakhon Pathom, 73170, Thailand
| | - Nawaphat Malaiwong
- Department of Anatomy, Faculty of Science, Mahidol University, Rama VI Road, Bangkok, 10400, Thailand
| | - Pawanrat Chalorak
- Department of Anatomy, Faculty of Science, Mahidol University, Rama VI Road, Bangkok, 10400, Thailand
| | - Krai Meemon
- Department of Anatomy, Faculty of Science, Mahidol University, Rama VI Road, Bangkok, 10400, Thailand.
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Abstract
Patients with diabetes mellitus have >2× the risk for developing heart failure (HF; HF with reduced ejection fraction and HF with preserved ejection fraction). Cardiovascular outcomes, hospitalization, and prognosis are worse for patients with diabetes mellitus relative to those without. Beyond the structural and functional changes that characterize diabetic cardiomyopathy, a complex underlying, and interrelated pathophysiology exists. Despite the success of many commonly used antihyperglycemic therapies to lower hyperglycemia in type 2 diabetes mellitus the high prevalence of HF persists. This, therefore, raises the possibility that additional factors beyond glycemia might contribute to the increased HF risk in diabetes mellitus. This review summarizes the state of knowledge about the impact of existing antihyperglycemic therapies on HF and discusses potential mechanisms for beneficial or deleterious effects. Second, we review currently approved pharmacological therapies for HF and review evidence that addresses their efficacy in the context of diabetes mellitus. Dysregulation of many cellular mechanisms in multiple models of diabetic cardiomyopathy and in human hearts have been described. These include oxidative stress, inflammation, endoplasmic reticulum stress, aberrant insulin signaling, accumulation of advanced glycated end-products, altered autophagy, changes in myocardial substrate metabolism and mitochondrial bioenergetics, lipotoxicity, and altered signal transduction such as GRK (g-protein receptor kinase) signaling, renin angiotensin aldosterone signaling and β-2 adrenergic receptor signaling. These pathophysiological pathways might be amenable to pharmacological therapy to reduce the risk of HF in the context of type 2 diabetes mellitus. Successful targeting of these pathways could alter the prognosis and risk of HF beyond what is currently achieved using existing antihyperglycemic and HF therapeutics.
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Affiliation(s)
- Helena C Kenny
- From the Fraternal Order of Eagles Diabetes Research Center, and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City
| | - E Dale Abel
- From the Fraternal Order of Eagles Diabetes Research Center, and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City
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Wang L, Quan N, Sun W, Chen X, Cates C, Rousselle T, Zhou X, Zhao X, Li J. Cardiomyocyte-specific deletion of Sirt1 gene sensitizes myocardium to ischaemia and reperfusion injury. Cardiovasc Res 2019; 114:805-821. [PMID: 29409011 DOI: 10.1093/cvr/cvy033] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 02/01/2018] [Indexed: 12/12/2022] Open
Abstract
Aims A longevity gene, Sirtuin 1 (SIRT1) and energy sensor AMP-activated protein kinase (AMPK) have common activators such as caloric restriction, oxidative stress, and exercise. The objective of this study is to characterize the role of cardiomyocyte SIRT1 in age-related impaired ischemic AMPK activation and increased susceptibility to ischemic insults. Methods and results Mice were subjected to ligation of left anterior descending coronary artery for in vivo ischemic models. The glucose and fatty acid oxidation were measured in a working heart perfusion system. The cardiac functions by echocardiography show no difference in young wild-type C57BL/6 J (WT, 4-6 months), aged WT C57BL/6 J (24-26 months), and young inducible cardiomyocyte-specific SIRT1 knockout (icSIRT1 KO) (4-6 months) mice under physiological conditions. However, after 45 mins ischaemia and 24-h reperfusion, the ejection fraction of aged WT and icSIRT1 KO mice was impaired. The aged WT and icSIRT1 KO hearts vs. young WT hearts also show an impaired post-ischemic contractile function in a Langendorff perfusion system. The infarct size of aged WT and icSIRT1 KO hearts was larger than that of young WT hearts. The immunoblotting data demonstrated that aged WT and icSIRT1 KO hearts vs. young WT hearts had impaired phosphorylation of AMPK and downstream acetyl-CoA carboxylase during ischaemia. Intriguingly, AMPK upstream LKB1 is hyper-acetylated in both aged WT and icSIRT1 KO hearts; this could blunt activation of LKB1, leading to an impaired AMPK activation. The working heart perfusion results demonstrated that SIRT1 deficiency significantly impaired substrate metabolism in the hearts; fatty acid oxidation is augmented and glucose oxidation is blunted during ischaemia and reperfusion. Adeno-associated virus (AAV9)-Sirt1 was delivered into the aged hearts via a coronary delivery approach, which significantly rescued the protein level of SIRT1 and the ischemic tolerance of aged hearts. Furthermore, AMPK agonist can rescue the tolerance of aged heart and icSIRT1 KO heart to ischemic insults. Conclusions Cardiac SIRT1 mediates AMPK activation via LKB1 deacetylation, and AMPK modulates SIRT1 activity via regulation of NAD+ level during ischaemia. SIRT1 and AMPK agonists have therapeutic potential for treatment of aging-related ischemic heart disease.
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Affiliation(s)
- Lin Wang
- Department of Cardiovascular Center, The First Hospital of Jilin University, Xinmin Street, Changchun 130021, China.,Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, USA
| | - Nanhu Quan
- Department of Cardiovascular Center, The First Hospital of Jilin University, Xinmin Street, Changchun 130021, China.,Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, USA
| | - Wanqing Sun
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, USA
| | - Xu Chen
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, USA
| | - Courtney Cates
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, USA
| | - Thomas Rousselle
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, USA
| | - Xinchun Zhou
- Department of Pathology, Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Xuezhong Zhao
- Department of Cardiovascular Center, The First Hospital of Jilin University, Xinmin Street, Changchun 130021, China
| | - Ji Li
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, USA
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Abstract
With the increasing age of the general population, medical conditions necessitating a surgical intervention will increase. Concomitant with advanced age, the prevalence of type 2 diabetes mellitus will also increase. These patients have a two- to three-fold higher risk of occurrence of cardiovascular events and are at higher risk of perioperative myocardial ischemia. This review will discuss recent advances in the field of perioperative cardioprotection and focus specifically on strategies that have aimed to protect the diabetic and the aged myocardium. This review will not deal with potential putative cardioprotective effects of opioids and anesthetic agents, as this is a very broad area that would necessitate a dedicated overview.
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Affiliation(s)
- Mona Momeni
- Department of Anesthesiology & Acute Medicine, Cliniques universitaires Saint Luc, Université Catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Avenue Hippocrate, Brussels, 1200, Belgium
| | - Stefan De Hert
- Department of Anesthesiology & Perioperative Medicine, Ghent University Hospital, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium
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Borges KA, Dai J, Parikh ND, Schwartz M, Nguyen MH, Roberts LR, Befeler AS, Srivastava S, Rinaudo JA, Feng Z, Marrero JA, Reddy KR. Rationale and design of the Hepatocellular carcinoma Early Detection Strategy study: A multi-center longitudinal initiative of the National Cancer Institute's Early Detection Research Network. Contemp Clin Trials 2019; 76:49-54. [PMID: 30439517 PMCID: PMC7086481 DOI: 10.1016/j.cct.2018.11.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 11/06/2018] [Accepted: 11/08/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common malignancy with a steadily rising incidence and associated morbidity and mortality. Cirrhosis of the liver is presently the leading risk factor for developing HCC. Abdominal imaging, with or without alpha-fetoprotein (AFP) testing, every 6 months is the current surveillance strategy for patients at risk. The available biomarkers for detecting this cancer at an early stage have inadequate sensitivity and specificity. METHODS The Hepatocellular carcinoma Early Detection Strategy (HEDS) study, a multi-center initiative of the National Cancer Institutes' (NCI) Early Detection Research Network (EDRN), launched an effort to establish what has become the nation's largest comprehensive biorepository and database on patients at high risk of developing HCC. The cohort has been developed in seven clinical centers across the USA. Subjects are enrolled for a five-year period involving data and specimen collection every six months in accordance with standard surveillance for HCC. Extensive clinical data are collected and specimens are stored at a central repository. RESULTS The database and biorepository contain longitudinally collected clinical data and serum and plasma samples from 1482 participants with cirrhosis and without evidence of HCC at baseline. Fifty-six percent are male, 85% Caucasian, 30% have a history of chronic HCV and 71% have compensated cirrhosis. CONCLUSIONS The HEDS cohort provides opportunities for the continued study of the incidence and course of HCC in a comprehensively followed population of patients at high risk for this malignancy. Further, the EDRN biorepository provides a distinct opportunity for the development of novel biomarkers. Trial registry URL: https://edrn.nci.nih.gov/protocols/316-hepatocellular-carcinoma-early-detection-strategy.
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Affiliation(s)
- Kelly A Borges
- Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd 7S, Philadelphia, PA, 19104, USA.
| | - Jianliang Dai
- Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109, USA.
| | - Neehar D Parikh
- University of Michigan, 1500 E Medical Center Dr. Taubman Center SPC 3912, Ann Arbor, MI 48109, USA.
| | - Myron Schwartz
- Mount Sinai Hospital, 1468 Madison Ave, New York, NY 10029, USA.
| | - Mindie H Nguyen
- Stanford University, Stanford, 750 Welch Road, #210, Palo Alto, CA 94304, USA.
| | | | - Alex S Befeler
- Saint Louis University, 1 N Grand Blvd, St. Louis, MO 63103, USA.
| | - Sudhir Srivastava
- National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
| | - Jo Ann Rinaudo
- National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
| | - Ziding Feng
- Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109, USA.
| | - Jorge A Marrero
- University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
| | - K Rajender Reddy
- Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd 7S, Philadelphia, PA, 19104, USA.
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Maack C, Lehrke M, Backs J, Heinzel FR, Hulot JS, Marx N, Paulus WJ, Rossignol P, Taegtmeyer H, Bauersachs J, Bayes-Genis A, Brutsaert D, Bugger H, Clarke K, Cosentino F, De Keulenaer G, Dei Cas A, González A, Huelsmann M, Iaccarino G, Lunde IG, Lyon AR, Pollesello P, Rena G, Riksen NP, Rosano G, Staels B, van Laake LW, Wanner C, Farmakis D, Filippatos G, Ruschitzka F, Seferovic P, de Boer RA, Heymans S. Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology. Eur Heart J 2018; 39:4243-4254. [PMID: 30295797 PMCID: PMC6302261 DOI: 10.1093/eurheartj/ehy596] [Citation(s) in RCA: 178] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 06/21/2018] [Accepted: 09/07/2018] [Indexed: 12/22/2022] Open
Affiliation(s)
- Christoph Maack
- Comprehensive Heart Failure Center, University Clinic Würzburg, Würzburg, Germany
| | - Michael Lehrke
- Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany
| | - Johannes Backs
- Department of Molecular Cardiology and Epigenetics, University of Heidelberg, Heidelberg, Germany
| | - Frank R Heinzel
- Department of Cardiology, Charité—Universitätsmedizin, Berlin, Germany
| | - Jean-Sebastien Hulot
- Paris Cardiovascular Research Center PARCC, INSERM UMR970, CIC 1418, and F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Paris, France
- AP-HP, Hôpital Européen Georges-Pompidou, Paris, France
| | - Nikolaus Marx
- Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany
| | - Walter J Paulus
- Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands
| | - Patrick Rossignol
- Inserm, Centre d’Investigations Cliniques—Plurithématique 14-33, Inserm U1116, CHRU Nancy, Université de Lorraine, and F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France
| | - Heinrich Taegtmeyer
- Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Johann Bauersachs
- Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
| | - Antoni Bayes-Genis
- Heart Failure Unit and Cardiology Service, Hospital Universitari Germans Trias i Pujol, CIBERCV, Badalona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | - Heiko Bugger
- Cardiology and Angiology, Heart Center, University of Freiburg, Freiburg, Germany
| | - Kieran Clarke
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
| | - Francesco Cosentino
- Department of Medicine Solna, Cardiology Unit, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden
| | | | - Alessandra Dei Cas
- Department of Medicine and Surgery, Endocrinology and Metabolism, University of Parma, Parma, Italy
- Division of Endocrinology and Metabolic Diseases, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Arantxa González
- Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona and CIBERCV, Carlos III Institute of Health, Madrid, Spain
| | - Martin Huelsmann
- Division of Cardiology, Department of Medicine II, Medical University of Vienna, Vienna, Austria
| | - Guido Iaccarino
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy
| | - Ida Gjervold Lunde
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Alexander R Lyon
- Cardiovascular Research Centre, Royal Brompton Hospital; National Heart and Lung Institute, Imperial College London, London, UK
| | | | - Graham Rena
- Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
| | - Niels P Riksen
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Giuseppe Rosano
- Cardiovascular Clinical Academic Group, St George's Hospitals NHS Trust University of London, London, UK
- IRCCS San Raffaele Roma, Rome, Italy
| | - Bart Staels
- University of Lille—EGID, Lille, France
- Inserm, U1011, Lille, France
- Institut Pasteur de Lille, Lille, France
- University Hospital CHU Lille, Lille, France
| | - Linda W van Laake
- Department of Cardiology, Heart and Lungs Division, and Regenerative Medicine Centre, University Medical Centre Utrecht, Utrecht, the Netherlands
| | | | - Dimitrios Farmakis
- Heart Failure Unit, Athens University Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece
| | - Gerasimos Filippatos
- Heart Failure Unit, Athens University Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece
| | - Frank Ruschitzka
- University Heart Centre, University Hospital Zurich, Zurich, Switzerland
| | - Petar Seferovic
- Department of Cardiology, Belgrade University Medical Centre, Belgrade, Serbia
| | - Rudolf A de Boer
- Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Stephane Heymans
- Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands
- Netherlands Heart Institute, Utrecht, The Netherlands
- Department of Cardiovascular Sciences, Leuven University, Belgium
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37
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Curcumin-mediated effects on anti-diabetic drug-induced cardiotoxicity. 3 Biotech 2018; 8:399. [PMID: 30221112 DOI: 10.1007/s13205-018-1425-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 09/01/2018] [Indexed: 01/02/2023] Open
Abstract
The present study was designed to compare the cardiotoxicity of two very commonly used anti-diabetic drugs namely pioglitazone (Pio) and metformin (Met); and to study the effects of curcumin (Curc) against these drug-induced cardiotoxicity. Curc, being an anti-oxidant molecule and having cardio-protective potential, can have promising synergistic effects in reducing the cardiac stress induced by anti-diabetic therapies. Various dose and time-dependent cell viability and oxidative stress assays were conducted to study cardiotoxic side-effects and Curc-mediated effects in cardiomyoblasts. Effects of Curc were also studied in hyperglycaemia induced cardiac stress in the presence of drugs. Quantitative assays for cell growth, reactive oxygen species (ROS) generation, lipid peroxidation and mitochondrial permeability followed by anti-oxidant enzymes and caspases activity assays were done to study the mechanism of action of the induced cardiotoxicity. Significant dose and time mediated deleterious effects of Pio and Met were witnessed. Oxidative stress studies showed a remarkable increase in ROS with increasing dose of anti-diabetic drugs. Increased caspase activity and altered mitochondrial integrity were also witnessed in presence of Met and Pio in cardiomyoblasts. These alterations were found to be significantly reduced when treated with Curc simultaneously. The study confirms that Met and Pio exert toxic effects on cardiac cells by generating oxidative stress. Curc, being an anti-oxidative molecule, can suppress this effect and, therefore, can be used as a supplement with anti-diabetic drugs to suppress the induced cardiac stress.
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38
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Yandrapalli S, Jolly G, Horblitt A, Sanaani A, Aronow WS. Cardiovascular benefits and safety of non-insulin medications used in the treatment of type 2 diabetes mellitus. Postgrad Med 2017; 129:811-821. [PMID: 28749197 DOI: 10.1080/00325481.2017.1358064] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 07/18/2017] [Indexed: 02/06/2023]
Abstract
Diabetes mellitus is a growing in exponential proportions. If the current growth trend continues, it may result in every third adult in the United States having diabetes mellitus by 2050, and every 10th adult worldwide. Type 2 diabetes mellitus (T2DM) confers a 2- to 3-fold increased risk of cardiovascular (CV) events compared with non-diabetic patients, and CV mortality is responsible for around 80% mortality in this population. Patients with T2DM can have other features of insulin resistance-metabolic syndrome like hypertension, lipid abnormalities, and obesity which are all associated with increased CV disease and stroke risk even in the absence of T2DM. The management of a T2DM calls for employing a holistic risk factor control approach. Metformin is the first line therapy for T2DM and has been shown to have cardiovascular beneficial effects. Intense debate regarding the risk of myocardial infarction with rosiglitazone led to regulatory agencies necessitating cardiovascular outcome trials with upcoming anti-diabetic medications. Glucagon like peptide-1 agonists and sodium glucose co-transporter-2 inhibitors have shown promising CV safety and additional CV benefit in recent clinical trials. These drugs have favorable effects on traditional CV risk factors. The findings from these studies further support that fact that CV risk factor control plays an important role in reducing morbidity and mortality in T2DM patients. This review article will discuss briefly the cardiovascular safety and benefits of the oral medications which are currently being used for T2DM and will then discuss in detail about the newer medications being investigated for the treatment of T2DM.
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Affiliation(s)
- Srikanth Yandrapalli
- a Cardiology Division, Department of Medicine , Westchester Medical Center /New York Medical College , Valhalla , NY , USA
| | - George Jolly
- a Cardiology Division, Department of Medicine , Westchester Medical Center /New York Medical College , Valhalla , NY , USA
| | - Adam Horblitt
- a Cardiology Division, Department of Medicine , Westchester Medical Center /New York Medical College , Valhalla , NY , USA
| | - Abdallah Sanaani
- a Cardiology Division, Department of Medicine , Westchester Medical Center /New York Medical College , Valhalla , NY , USA
| | - Wilbert S Aronow
- a Cardiology Division, Department of Medicine , Westchester Medical Center /New York Medical College , Valhalla , NY , USA
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39
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Ramachandran R, Saraswathi M. Postconditioning with metformin attenuates apoptotic events in cardiomyoblasts associated with ischemic reperfusion injury. Cardiovasc Ther 2017. [DOI: 10.1111/1755-5922.12279] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Affiliation(s)
- Rajesh Ramachandran
- Department of Biochemistry; Kerala University; Thiruvananthapuram Kerala India
| | - Mini Saraswathi
- Department of Biochemistry; Kerala University; Thiruvananthapuram Kerala India
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40
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Ahn MJ, Cho GW. Metformin promotes neuronal differentiation and neurite outgrowth through AMPK activation in human bone marrow-mesenchymal stem cells. Biotechnol Appl Biochem 2017; 64:836-842. [PMID: 28791738 DOI: 10.1002/bab.1584] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 08/02/2017] [Indexed: 12/16/2022]
Abstract
Metformin is an AMP-activated kinase (AMPK) activator that plays a role in glucose energy metabolism and cell protection. It is widely used to treat several diseases, including type 2 diabetes, cardiovascular diseases, cancer, and metabolic diseases. In this study, we investigated whether AMPK activation upon treatment with metformin may promote neurite outgrowth during the progression of neuronal differentiation in human bone marrow-mesenchymal stem cells (hBM-MSCs). Differentiation of metformin-treated MSCs (Met-MSCs to Met-diMSCs) in the neuronal induction media resulted in an increase in the number of differentiated cells in a metformin concentration dependent manner. The differentiation rate reached its maximum at 3 H after the initial treatment with neuronal induction media. At 3 H of induction, the neurite length increased significantly in Met-diMSCs as compared with control cells without metformin treatment (diMSCs). diMSCs showed a significant increase in the expression of neuronal-specific marker genes; however, the expression of dendrite-specific markers MAP-2 and Tuj-1 was significantly increased in Met-diMSCs as compared to diMSCs, as confirmed by immunoblotting. This effect was abolished upon treatment with the AMPK inhibitor, compound C, as evident by quantitative PCR, immunoblotting, and immunocytochemical staining. Thus, metformin treatment promotes neuronal differentiation and neurite outgrowth in hBM-MSCs through AMPK activation.
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Affiliation(s)
- Min-Ji Ahn
- Department of Biology, College of Natural Science, Chosun University, Gwangju, Korea.,Department of Life Science, BK21-Plus Research Team for Bioactive Control Technology, Chosun University, Gwangju, Korea
| | - Goang-Won Cho
- Department of Biology, College of Natural Science, Chosun University, Gwangju, Korea.,Department of Life Science, BK21-Plus Research Team for Bioactive Control Technology, Chosun University, Gwangju, Korea
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41
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Dludla PV, Joubert E, Muller CJF, Louw J, Johnson R. Hyperglycemia-induced oxidative stress and heart disease-cardioprotective effects of rooibos flavonoids and phenylpyruvic acid-2- O-β-D-glucoside. Nutr Metab (Lond) 2017; 14:45. [PMID: 28702068 PMCID: PMC5504778 DOI: 10.1186/s12986-017-0200-8] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 06/23/2017] [Indexed: 12/15/2022] Open
Abstract
Diabetic patients are at an increased risk of developing heart failure when compared to their non-diabetic counter parts. Accumulative evidence suggests chronic hyperglycemia to be central in the development of myocardial infarction in these patients. At present, there are limited therapies aimed at specifically protecting the diabetic heart at risk from hyperglycemia-induced injury. Oxidative stress, through over production of free radical species, has been hypothesized to alter mitochondrial function and abnormally augment the activity of the NADPH oxidase enzyme system resulting in accelerated myocardial injury within a diabetic state. This has led to a dramatic increase in the exploration of plant-derived materials known to possess antioxidative properties. Several edible plants contain various natural constituents, including polyphenols that may counteract oxidative-induced tissue damage through their modulatory effects of intracellular signaling pathways. Rooibos, an indigenous South African plant, well-known for its use as herbal tea, is increasingly studied for its metabolic benefits. Prospective studies linking diet rich in polyphenols from rooibos to reduced diabetes associated cardiovascular complications have not been extensively assessed. Aspalathin, a flavonoid, and phenylpyruvic acid-2-O-β-D-glucoside, a phenolic precursor, are some of the major compounds found in rooibos that can ameliorate hyperglycemia-induced cardiomyocyte damage in vitro. While the latter has demonstrated potential to protect against cell apoptosis, the proposed mechanism of action of aspalathin is linked to its capacity to enhance the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression, an intracellular antioxidant response element. Thus, here we review literature on the potential cardioprotective properties of flavonoids and a phenylpropenoic acid found in rooibos against diabetes-induced oxidative injury.
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Affiliation(s)
- Phiwayinkosi V Dludla
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council, P.O. Box 19070, Tygerberg, 7505 South Africa.,Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa
| | - Elizabeth Joubert
- Plant Bioactives Group, Post-Harvest and Wine Technology Division, Agricultural Research Council (ARC) Infruitec- Nietvoorbij, Stellenbosch, South Africa.,Department of Food Science, Stellenbosch University, Stellenbosch, South Africa
| | - Christo J F Muller
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council, P.O. Box 19070, Tygerberg, 7505 South Africa.,Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa.,Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, South Africa
| | - Johan Louw
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council, P.O. Box 19070, Tygerberg, 7505 South Africa.,Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, South Africa
| | - Rabia Johnson
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council, P.O. Box 19070, Tygerberg, 7505 South Africa.,Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa
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Lee KT, Yeh YH, Chang SH, See LC, Lee CH, Wu LS, Liu JR, Kuo CT, Wen MS. Metformin is associated with fewer major adverse cardiac events among patients with a new diagnosis of type 2 diabetes mellitus: A propensity score-matched nationwide study. Medicine (Baltimore) 2017; 96:e7507. [PMID: 28700501 PMCID: PMC5515773 DOI: 10.1097/md.0000000000007507] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 06/15/2017] [Accepted: 06/23/2017] [Indexed: 01/05/2023] Open
Abstract
Early type 2 diabetes mellitus (DM) may only require lifestyle modifications for glycemic control without the need for oral hypoglycemic agents (OHAs). Metformin is believed to improve cardiovascular outcomes in patients with DM, and it is considered to be a first-line therapy. However, it is unclear whether metformin is beneficial for patients with a new diagnosis of DM compared to those who do not need OHAs for glycemic control.Data were obtained from a population-based health care database in Taiwan. Patients with a new diagnosis of DM were enrolled if they received metformin monotherapy only between 1999 and 2010. A 4:1 propensity score-matched cohort of patients with a new diagnosis of DM who did not take OHAs or insulin during follow-up was also enrolled. The primary study endpoint was the occurrence of major adverse cardiovascular events (MACEs). The time to the endpoints was compared between groups using Cox proportional hazards models.A total of 474,410 patients with DM were enrolled. During a mean 5.8 years of follow-up, the incidence of MACEs was 1.072% (1072 per 100,000 person-years) in the metformin monotherapy group versus 1.165% in the lifestyle modification group (those who did not take OHAs) (P < .001). After adjusting for confounders, metformin independently protected the DM patients from MACEs (hazard ratio: 0.83, P < .001). The metformin group also had an improved MACE-free survival profile from year 1 to year 12 (P < .001).In addition to lifestyle modifications, the patients with a new diagnosis of DM treated with metformin monotherapy had a lower MACE rate than those who did not take OHAs. Our findings suggest that metformin may be given early to patients with a new diagnosis of DM, even when they do not need OHAs for glycemic control.
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Affiliation(s)
- Kuang-Tso Lee
- Chang Gung University and Department of Cardiology, Chang Gung Memorial Hospital, Taipei
| | - Yung-Hsin Yeh
- Chang Gung University and Department of Cardiology, Chang Gung Memorial Hospital, Taipei
| | - Shang-Hung Chang
- Chang Gung University and Department of Cardiology, Chang Gung Memorial Hospital, Taipei
| | - Lai-Chu See
- Department of Public Health, College of Medicine, Chang Gung University
- Biostatistics Core Laboratory, Molecular Medicine Research Center, Chang Gung University, Taiwan
| | - Cheng-Hung Lee
- Chang Gung University and Department of Cardiology, Chang Gung Memorial Hospital, Taipei
| | - Lung-Sheng Wu
- Chang Gung University and Department of Cardiology, Chang Gung Memorial Hospital, Taipei
| | - Jia-Rou Liu
- Department of Public Health, College of Medicine, Chang Gung University
| | - Chi-Tai Kuo
- Chang Gung University and Department of Cardiology, Chang Gung Memorial Hospital, Taipei
| | - Ming-Shien Wen
- Chang Gung University and Department of Cardiology, Chang Gung Memorial Hospital, Taipei
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43
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Nazer RI, Alburikan KA. Metformin is not associated with lactic acidosis in patients with diabetes undergoing coronary artery bypass graft surgery: a case control study. BMC Pharmacol Toxicol 2017; 18:38. [PMID: 28558845 PMCID: PMC5450408 DOI: 10.1186/s40360-017-0145-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 05/16/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Metformin associated lactic acidosis (MALA) is a rare but lethal complication. There is no consensus regarding when to stop and resume metformin in patients who undergo coronary artery bypass grafting (CABG). This study aimed to determine if uninterrupted metformin administration in patients with diabetes undergoing CABG increases the risk of lactic acidosis. METHODS Over a span of 12 months (2015-2016), 127 patients with type 2 diabetes underwent isolated CABG. Of those, 41 patients (32%) continued taking metformin and 86 patients (68%) took other antidiabetic agents. Patients taking metformin took the drug until the day of surgery and resumed taking it 3 h after extubation. RESULTS There were no differences in clinical outcomes or complications between groups. Serial measurement of cardiac, liver, and kidney biomarkers were similar between groups. The mean peak lactic acid level was significantly higher in the non-metformin users (5.4 ± 2.6 vs. 7.4 ± 4.1 mmol/l; P = 0.001). Multivariable logistic regression analysis identified the need for vasopressor administration as an independent predictor of lactic acidosis (odds ratio: 7.3, 95% confidence interval: 2.5-20.6; P < 0.001). CONCLUSION In the absence of risk factors associated with persistent lactic acidosis, such as shock or acute kidney or liver injury, continued peri-operative metformin administration was not associated with the occurrence of lactic acidosis in patients undergoing CABG. Elevated lactic acid levels seem to be directly related to tissue anoxia caused by escalating vasopressor support after surgery.
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Affiliation(s)
- Rakan I. Nazer
- Department of Cardiac Science, King Fahad Cardiac Center, College of Medicine, King Saud University, KSU 3642, Riyadh, 12372-7143 Kingdom of Saudi Arabia
| | - Khalid A. Alburikan
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia
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44
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Kim Y, Lee IS, Kim KH, Park J, Lee JH, Bang E, Jang HJ, Na YC. Metabolic Profiling of Liver Tissue in Diabetic Mice Treated with Artemisia Capillaris and Alisma Rhizome Using LC-MS and CE-MS. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2016; 44:1639-1661. [PMID: 27852124 DOI: 10.1142/s0192415x16500920] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Artemisia Capillaris (AC) and Alisma Rhizome (AR) are natural products for the treatment of liver disorders in oriental medicine clinics. Here, we report metabolomic changes in the evaluation of the treatment effects of AC and AR on fatty livers in diabetic mice, along with a proposition of the underlying metabolic pathway. Hydrophobic and hydrophilic metabolites extracted from mouse livers were analyzed using HPLC-QTOF and CE-QTOF, respectively, to generate metabolic profiles. Statistical analysis of the metabolites by PLS-DA and OPLA-DA fairly discriminated between the diabetic, and the AC- and AR-treated mice groups. Various PEs mostly contributed to the discrimination of the diabetic mice from the normal mice, and besides, DG (18:1/16:0), TG (16:1/16:1/20:1), PE (21:0/20:5), and PA (18:0/21:0) were also associated with discrimination by s-plot. Nevertheless, the effects of AC and AR treatment were indistinct with respect to lipid metabolites. Of the 97 polar metabolites extracted from the CE-MS data, 40 compounds related to amino acid, central carbon, lipid, purine, and pyrimidine metabolism, with [Formula: see text] values less than 0.05, were shown to contribute to liver dysregulation. Following treatment with AC and AR, the metabolites belonging to purine metabolism preferentially recovered to the metabolic state of the normal mice. The AMP/ATP ratio of cellular energy homeostasis in AR-treated mice was more apparently increased ([Formula: see text]) than that of AC-treated mice. On the other hand, amino acids, which showed the main alterations in diabetic mice, did not return to the normal levels upon treatment with AR or AC. In terms of metabolomics, AR was a more effective natural product in the treatment of liver dysfunction than AC. These results may provide putative biomarkers for the prognosis of fatty liver disorder following treatment with AC and AR extracts.
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Affiliation(s)
- Yumi Kim
- * Western Seoul Center, Korea Basic Science Institute, 150 Bugahyeon-ro, Seodaemun-gu, Seoul 03759, Republic of Korea.,† Department of Biochemistry, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdemun-gu, Seoul 02447, Republic of Korea
| | - In-Seung Lee
- † Department of Biochemistry, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdemun-gu, Seoul 02447, Republic of Korea
| | - Kang-Hoon Kim
- † Department of Biochemistry, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdemun-gu, Seoul 02447, Republic of Korea
| | - Jiyoung Park
- † Department of Biochemistry, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdemun-gu, Seoul 02447, Republic of Korea
| | - Ji-Hyun Lee
- * Western Seoul Center, Korea Basic Science Institute, 150 Bugahyeon-ro, Seodaemun-gu, Seoul 03759, Republic of Korea.,‡ Department of Chemistry and Nano Science, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Republic of Korea
| | - Eunjung Bang
- * Western Seoul Center, Korea Basic Science Institute, 150 Bugahyeon-ro, Seodaemun-gu, Seoul 03759, Republic of Korea
| | - Hyeung-Jin Jang
- † Department of Biochemistry, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdemun-gu, Seoul 02447, Republic of Korea
| | - Yun-Cheol Na
- * Western Seoul Center, Korea Basic Science Institute, 150 Bugahyeon-ro, Seodaemun-gu, Seoul 03759, Republic of Korea.,‡ Department of Chemistry and Nano Science, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Republic of Korea
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45
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Yang X, Xu Z, Zhang C, Cai Z, Zhang J. Metformin, beyond an insulin sensitizer, targeting heart and pancreatic β cells. Biochim Biophys Acta Mol Basis Dis 2016; 1863:1984-1990. [PMID: 27702625 DOI: 10.1016/j.bbadis.2016.09.019] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 09/17/2016] [Accepted: 09/27/2016] [Indexed: 12/22/2022]
Abstract
Metformin, a biguanide derivate, is known as the first-line antidiabetic agent for type 2 diabetes mellitus (T2DM) treatment. It reduces insulin resistance and decreases blood glucose concentration by inhibiting gluconeogenesis and suppressing hepatic glucose production with improved peripheral tissue insulin sensitivity. As an insulin sensitizer, metformin takes pleiotropic actions and exerts protective effects on multiple organs mainly in insulin-targeted tissues such as liver, muscle, and adipose tissues. Recent studies discover that metformin also plays essential roles in heart and pancreatic β cells - two important organs in metabolic regulation. Metformin not only protects T2DM patients from cardiovascular diseases and heart failure, but also restores insulin secretion activities and protects pancreatic β cells from lipotoxicity or glucotoxicity. Although accumulated evidence shed light on the metformin action, the precise mechanism of metformin is still under investigation. Further laboratory investigations and clinical trials are needed to pinpoint a map of metformin action. Based on recent findings, this review characterizes the beneficial role of metformin in cardiovascular diseases and pancreatic β cells.
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Affiliation(s)
- Xin Yang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Central South University, Changsha, Hunan 410011, China
| | - Zhipeng Xu
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Central South University, Changsha, Hunan 410011, China
| | - Chunlan Zhang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Central South University, Changsha, Hunan 410011, China
| | - Zixin Cai
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Central South University, Changsha, Hunan 410011, China
| | - Jingjing Zhang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Central South University, Changsha, Hunan 410011, China.
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46
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Spectroscopic and molecular modelling studies of binding mechanism of metformin with bovine serum albumin. J Mol Struct 2016. [DOI: 10.1016/j.molstruc.2016.04.030] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Bayliss JA, Lemus MB, Santos VV, Deo M, Davies JS, Kemp BE, Elsworth JD, Andrews ZB. Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons. PLoS One 2016; 11:e0159381. [PMID: 27467571 PMCID: PMC4965122 DOI: 10.1371/journal.pone.0159381] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 07/03/2016] [Indexed: 12/25/2022] Open
Abstract
Metformin is a widely prescribed drug used to treat type-2 diabetes, although recent studies show it has wide ranging effects to treat other diseases. Animal and retrospective human studies indicate that Metformin treatment is neuroprotective in Parkinson's Disease (PD), although the neuroprotective mechanism is unknown, numerous studies suggest the beneficial effects on glucose homeostasis may be through AMPK activation. In this study we tested whether or not AMPK activation in dopamine neurons was required for the neuroprotective effects of Metformin in PD. We generated transgenic mice in which AMPK activity in dopamine neurons was ablated by removing AMPK beta 1 and beta 2 subunits from dopamine transporter expressing neurons. These AMPK WT and KO mice were then chronically exposed to Metformin in the drinking water then exposed to MPTP, the mouse model of PD. Chronic Metformin treatment significantly attenuated the MPTP-induced loss of Tyrosine Hydroxylase (TH) neuronal number and volume and TH protein concentration in the nigrostriatal pathway. Additionally, Metformin treatment prevented the MPTP-induced elevation of the DOPAC:DA ratio regardless of genotype. Metformin also prevented MPTP induced gliosis in the Substantia Nigra. These neuroprotective actions were independent of genotype and occurred in both AMPK WT and AMPK KO mice. Overall, our studies suggest that Metformin's neuroprotective effects are not due to AMPK activation in dopaminergic neurons and that more research is required to determine how metformin acts to restrict the development of PD.
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Affiliation(s)
- Jacqueline A. Bayliss
- Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Clayton, Melbourne, Vic., 3800, Australia
| | - Moyra B. Lemus
- Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Clayton, Melbourne, Vic., 3800, Australia
| | - Vanessa V. Santos
- Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Clayton, Melbourne, Vic., 3800, Australia
| | - Minh Deo
- Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Clayton, Melbourne, Vic., 3800, Australia
| | - Jeffrey S. Davies
- Molecular Neurobiology, Institute of Life Science, Swansea University, Swansea, SA28PP, United Kingdom
| | - Bruce E. Kemp
- St Vincent’s Institute & Department of Medicine, The University of Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia
| | - John D. Elsworth
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520, United States of America
| | - Zane B. Andrews
- Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Clayton, Melbourne, Vic., 3800, Australia
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Sheta A, Elsakkar M, Hamza M, Solaiman A. Effect of metformin and sitagliptin on doxorubicin-induced cardiotoxicity in adult male albino rats. Hum Exp Toxicol 2016; 35:1227-1239. [PMID: 26818447 DOI: 10.1177/0960327115627685] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The use of doxorubicin (DOX) as an antitumor therapeutic agent is limited due to its cardiotoxic effects. Metformin (Met) and sitagliptin (Sitg) are suggested to improve cardiac function. The present study aimed to determine the potential protective effects of Met and Sitg on DOX-induced cardiotoxicity. Rats were divided into six groups: groups I, II, and III received normal saline, Met, and Sitg, respectively. Groups IV, V, and VI received DOX only, Met + DOX, and Sitg + DOX, respectively. Heart tissue was used for biochemical assays which measured cardiac reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS), and tumor necrosis factor α (TNF-α). Serum creatinine kinase (CK) and lactate dehydrogenase (LDH) were also measured. The heart apex was prepared for histological (hematoxylin and eosin) and immunohistochemical examination. Intoxication of DOX was associated with a significant elevation in serum CK-MB and LDH, reduction in cardiac GSH, and increased TBARS and TNF-α compared to the controls. Administration of Met or Sitg to DOX-intoxicated rats suppressed serum CK-MB and LDH. Moreover, cardiac GSH was elevated with decreased TBARS and TNF-α. These results were confirmed by histological study. Met and Sitg caused inhibition of caspase 3 and upregulation of B-cell lymphoma 2 (Bcl-2) expression in DOX-intoxicated animals. Sitg was found to exert a significantly better protective effect compared to that of Met. It was concluded that Sitg might be more effective than Met in reducing myocardial injury in DOX-induced cardiotoxicity in rats.
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Affiliation(s)
- A Sheta
- 1 Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - M Elsakkar
- 2 Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - M Hamza
- 2 Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - A Solaiman
- 3 Department of Histology and Cell Biology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
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Abualsuod A, Rutland JJ, Watts TE, Pandat S, Delongchamp R, Mehta JL. The Effect of Metformin Use on Left Ventricular Ejection Fraction and Mortality Post-Myocardial Infarction. Cardiovasc Drugs Ther 2016; 29:265-75. [PMID: 26068409 DOI: 10.1007/s10557-015-6601-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Animal studies showed that the use of metformin after myocardial infarction (MI) resulted in a protective effect on cardiac myocytes. In this study, we examined the effect of metformin in patients with diabetes mellitus (DM) on left ventricular ejection fraction (LVEF) and post-MI mortality. METHODS We reviewed charts of patients with MI admitted to the UAMS medical center. Baseline characteristics and 12-month follow up data were collected. Patients were classified into three groups: Control group- no DM (n = 464), Metformin group- DM + MI (n = 88) and No-Metformin group- DM + MI (n = 168). First, we compared Metformin and No-Metformin groups to the Control group. Second, we performed propensity-score matching in patients with DM, and compared Metformin to No-Metformin groups. RESULTS All-cause 30-day and 12-month mortality was significantly higher in the No-Metformin group compared to controls (13.5 vs 9.3% p = 0.03 at 30 days, 23.7 vs 15.9 % p = 0.03 at 12 months). However, all-cause 30-day and 12-month mortality were similar in the Controls and Metformin group (9.3 vs 6.8 % p = 0.93 at 30 days, 15.9 vs 11.4 % p = 0.97 at 12 months). Mean LVEF on presentation (45 % in the three groups) and at follow up (47.84, 46.38 and 43.62 % in Control, Metformin, and No-Metformin groups, respectively) were not statistically different. There were no significant differences in regard to re-hospitalization, re-intervention, new stroke, CHF development, new MI, or identifiable arrhythmias. Metformin was an independent predictor of lower 30-day and 12-month all-cause mortality in patients with DM (HR 0.25, p = 0.02 and HR 0.32, p = 0.01, respectively). In the matched analysis, 30-day all-cause mortality was significantly higher in the No-Metformin compared to the Metformin group (21.1 vs 8.8 %, p = 0.05). However the difference in 12-month all-cause mortality did not reach statistical significance (24.6 vs 15.8 %, p = 0.15). CONCLUSION This proof-of-concept study shows that use of metformin in patients with DM is associated with lower 30-day all-cause mortality and tendency for a lower 12-month all-cause mortality following MI without discernible improvement in LVEF.
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Affiliation(s)
- Amjad Abualsuod
- Division of General Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA,
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Heidari F, Abbas Zade S, Mir Hosseini SH, Ghadian A. Metformin for the Prevention of Bladder Cancer Recurrence: Is it Effective? Nephrourol Mon 2016; 8:e30261. [PMID: 27570750 PMCID: PMC4983155 DOI: 10.5812/numonthly.30261] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 12/27/2015] [Accepted: 02/24/2016] [Indexed: 12/30/2022] Open
Abstract
Background Many methods have been used for preventing and reducing recurrences of bladder cancers. In recent years, some investigators have examined the use of metformin for this purpose. First lines of evidence have shown that metformin inhibits cancer cell growth and prevents cancer occurrence in patients with type 2 diabetes. Objectives This study is designed to assess metformin usage in the prevention of bladder cancer recurrence after the trans-urethral resection of a bladder tumor (TUR-T). Patients and Methods In the present study, metformin was administered in the treatment of 32 patients with a history of bladder cancer, and their results were compared with those of 33 patients with bladder cancer recurrence (placebo group). Patients in the metformin group received 1000 mg metformin (2 tablets 500 mg) for 1 year. Frequency of tumor recurrence was calculated and compared with the placebo group. Results There was no statistical difference between the 2 groups with respect to the recurrence rate (P > 0.05). Although the recurrence interval was longer for the metformin group, this increase was not statistical significant (P > 0.05). Furthermore, tumor recurrence had no correlation with sex or the grade of the tumors. Conclusions According to our findings, it seems that metformin has no considerable inhibitory effect on the recurrence rate of bladder cancer, but that it can delay tumor recurrence.
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Affiliation(s)
- Fatemeh Heidari
- Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Shahin Abbas Zade
- Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Seyed Hassan Mir Hosseini
- Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Alireza Ghadian
- Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Corresponding author: Alireza Ghadian, Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran. Tel: +98-2181262073, E-mail:
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