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Mahran SE, Salem SE, Sabry NA, Farid SF. The nephroprotective effect of metformin with cisplatin in bladder cancer: randomized clinical trial. Int Urol Nephrol 2025:10.1007/s11255-025-04505-2. [PMID: 40319155 DOI: 10.1007/s11255-025-04505-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 03/31/2025] [Indexed: 05/07/2025]
Abstract
PURPOSE Cisplatin-based combination chemotherapy is the mainstay treatment strategy in various forms of carcinomas and sarcomas. However, its dosage and therapeutic efficacy are significantly limited by its nephrotoxicity. Based on metformin renal benefits in different studies, the study aims to determine safety and the potential nephroprotective effect of metformin when used with cisplatin in patients with bladder cancer. METHODS This was a prospective, randomized, parallel, controlled, open-label study in which 78 chemotherapy naïve bladder cancer patients aged 18-65 years and would receive gemcitabine/cisplatin regimen were selected and randomly assigned to treatment or control group in 1:1 allocation. Both groups were receiving cisplatin standard-of-care regimen, whereas metformin (500 mg, twice daily) was added to the treatment group's regimen only. Patients were prospectively followed up for four cycles of gemcitabine/cisplatin with assessment of renal function tests, serum neutrophil gelatinase-associated lipocalin (NGAL), cystatin-c, and metformin's adverse effects. RESULTS Serum creatinine, serum NGAL, and cystatin-C significantly increased in the control group only (P < 0.001). Estimated glomerular filtration rate (eGFR) significantly declines in the control group only (P < 0.001). On the contrary, serum NGAL significantly improved in the treatment group (P = 0.02) with stable and normal mean value of serum creatinine, eGFR, and cystatin-C without a concomitant significant increase in adverse events, such as hypoglycemia, gastrointestinal symptoms, or weight loss compared to the control group. CONCLUSION Metformin prevented renal damage and deterioration in kidney function in cisplatin-treated patients. Therefore, it is a promising agent in reducing cisplatin-induced nephrotoxicity. The study was registered in ClinicalTrials.gov on December, 16, 2023, Identifier Number NCT06215976.
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Affiliation(s)
- Samah E Mahran
- Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini St, P. O. Box: 11562, Cairo, Egypt.
| | - Salem Eid Salem
- Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Nirmeen A Sabry
- Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini St, P. O. Box: 11562, Cairo, Egypt
| | - Samar F Farid
- Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini St, P. O. Box: 11562, Cairo, Egypt
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Srivastava SP, Kopasz-Gemmen O, Thurman A, Rajendran BK, Selvam MM, Kumar S, Srivastava R, Suresh MX, Kumari R, Goodwin JE, Inoki K. The molecular determinants regulating redox signaling in diabetic endothelial cells. Front Pharmacol 2025; 16:1563047. [PMID: 40290438 PMCID: PMC12023289 DOI: 10.3389/fphar.2025.1563047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 03/14/2025] [Indexed: 04/30/2025] Open
Abstract
Oxidation and reduction are vital for keeping life through several prime mechanisms, including respiration, metabolism, and other energy supplies. Mitochondria are considered the cell's powerhouse and use nutrients to produce redox potential and generate ATP and H2O through the process of oxidative phosphorylation by operating electron transfer and proton pumping. Simultaneously, mitochondria also produce oxygen free radicals, called superoxide (O2 -), non-enzymatically, which interacts with other moieties and generate reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), peroxynitrite (ONOO-), and hydroxyl radical (OH-). These reactive oxygen species modify nucleic acids, proteins, and carbohydrates and ultimately cause damage to organs. The nutrient-sensing kinases, such as AMPK and mTOR, function as a key regulator of cellular ROS levels, as loss of AMPK or aberrant activation of mTOR signaling causes ROS production and compromises the cell's oxidant status, resulting in various cellular injuries. The increased ROS not only directly damages DNA, proteins, and lipids but also alters cellular signaling pathways, such as the activation of MAPK or PI3K, the accumulation of HIF-1α in the nucleus, and NFkB-mediated transcription of pro-inflammatory cytokines. These factors cause mesenchymal activation in renal endothelial cells. Here, we discuss the biology of redox signaling that underlies the pathophysiology of diabetic renal endothelial cells.
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Affiliation(s)
- Swayam Prakash Srivastava
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, United States
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, United States
- Vascular Biology and Therapeutic Program, Yale University School of Medicine, New Haven, CT, United States
| | | | - Aaron Thurman
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, United States
| | - Barani Kumar Rajendran
- Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, United States
| | - M. Masilamani Selvam
- Department of Pharmaceutical Technology, Paavai Engineering College, Namakkal, Tamil Nadu, India
| | - Sandeep Kumar
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, United States
| | - Rohit Srivastava
- Laboratory of Medical Transcriptomics, Department of Endocrinology, Nephrology Services, Hadassah Hebrew-University Medical Center, Jerusalem, Israel
| | - M. Xavier Suresh
- School of Advanced Sciences and Languages, VIT Bhopal University, Sehore, Madhya Pradesh, India
| | - Reena Kumari
- Department of Physiology, Augusta University, Augusta, GA, United States
| | - Julie E. Goodwin
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, United States
- Vascular Biology and Therapeutic Program, Yale University School of Medicine, New Haven, CT, United States
| | - Ken Inoki
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, United States
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
- Department of Internal Medicine, Division of Nephrology, University of Michigan Medical School, Ann Arbor, MI, United States
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Bagheri R, Daneshi SS, Bina S, Haghshenas M, Khoshnoud MJ, Asadi-Yousefabad SL, Khodaei F, Rashedinia M. Metformin Mitigates the Impact of Arsenic Exposure on the Maternal and Offspring Reproductive System of Female Mice. Biol Trace Elem Res 2025:10.1007/s12011-025-04577-2. [PMID: 40119994 DOI: 10.1007/s12011-025-04577-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 03/08/2025] [Indexed: 03/25/2025]
Abstract
Exposure to arsenic causes health problems and is associated with adverse effects on fertility and development. Humans are facing increasing exposure to arsenic from multiple sources, such as drinking water, food products, and industrial processes. The mechanisms behind arsenic-induced reproductive toxicity and its impact on fertility and the development of future generations are investigated by the protective role of metformin (200 mg/kg) against arsenic-induced (20 ppm As2O3) ovarian damage in both maternal and offspring generations. Results showed arsenic exposure caused significant weight loss, increased mortality, reduced serum anti-Mullerian hormone (AMH) levels, and heightened oxidative stress, indicated by increased reactive oxygen species (ROS), malondialdehyde (MDA), and reduced ovarian antioxidant activity. Gene expression changes related to apoptosis and inflammation, such as BAX, Bcl-2, Bcl-2, caspase-3, tumor necrosis factor-alpha (TNF-α), and interleukin-1 (IL-1), were also noted, along with a decrease in HO-1 expression. Arsenic exposure led to a reduction in ovarian follicles and an increase in atretic follicles and uterine thickness. However, metformin significantly reduced ROS and MDA levels, enhanced antioxidant capacity, and protected ovarian tissue by upregulating heme oxygenase-1 (HO-1) and Bcl-2, modulating apoptotic and inflammatory genes, and preserving AMH levels. The possible protective role of metformin against arsenic-induced toxicity and its detrimental effects aims to improve therapeutic approaches to alleviate the harmful consequences of environmental pollutants, especially arsenic.
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Affiliation(s)
- Razieh Bagheri
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyyed Sajad Daneshi
- Department of Anatomy, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Samaneh Bina
- Department of Biology, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran
| | - Marziyeh Haghshenas
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Javad Khoshnoud
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Forouzan Khodaei
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Marzieh Rashedinia
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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Del Valle JS, Van Helden RW, Moustakas I, Wei F, Asseler JD, Metzemaekers J, Pilgram GSK, Mummery CL, van der Westerlaken LAJ, van Mello NM, Chuva de Sousa Lopes SM. Ex vivo removal of pro-fibrotic collagen and rescue of metabolic function in human ovarian fibrosis. iScience 2025; 28:112020. [PMID: 40104066 PMCID: PMC11914289 DOI: 10.1016/j.isci.2025.112020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 10/21/2024] [Accepted: 02/11/2025] [Indexed: 03/20/2025] Open
Abstract
Tissue fibrosis, with the excessive accumulation of extracellular matrix, leads to organ dysfunction. The ovary shows signs of fibrosis from an early age, creating a permissive environment for ovarian cancer. A robust culture-platform to study human ovarian fibrosis would enable screens for antifibrotic drugs to prevent or even reverse this process. Based on previous results showing that androgen therapy can induce ovarian fibrosis, we characterized the fibrotic state of ovaries from transmasculine donors of reproductive age. Anti-inflammatory and antioxidant drugs, such as Pirfenidone, Metformin, and Mitoquinone, could reduce and revert the excess collagen content of the ovarian cortical tissue during culture. We demonstrated that Metformin exerts an antioxidant role and prevents a glycolytic metabolic shift in non-immune ovarian stromal cells in the human ovary, while promoting early folliculogenesis during culture. These results may contribute to develop strategies to manage pro-tumorigenic fibrotic ovarian stroma in advanced age and metabolic disorders.
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Affiliation(s)
- Julieta S Del Valle
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden 2333 ZC, the Netherlands
| | - Ruben W Van Helden
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden 2333 ZC, the Netherlands
| | - Ioannis Moustakas
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden 2333 ZC, the Netherlands
- Sequencing Analysis Support Core, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden 2333 ZC, the Netherlands
| | - Fu Wei
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden 2333 ZC, the Netherlands
| | - Joyce D Asseler
- Department of Obstetrics and Gynecology, Amsterdam University Medical Center, Amsterdam 1105 AZ, the Netherlands
- Amsterdam UMC, Centre of Expertise on Gender Dysphoria, Amsterdam 1081 HV, the Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam 1081 HV, the Netherlands
| | - Jeroen Metzemaekers
- Department of Gynecology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands
| | - Gonneke S K Pilgram
- Department of Gynecology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands
| | - Christine L Mummery
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden 2333 ZC, the Netherlands
| | | | - Norah M van Mello
- Department of Obstetrics and Gynecology, Amsterdam University Medical Center, Amsterdam 1105 AZ, the Netherlands
- Amsterdam UMC, Centre of Expertise on Gender Dysphoria, Amsterdam 1081 HV, the Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam 1081 HV, the Netherlands
| | - Susana M Chuva de Sousa Lopes
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden 2333 ZC, the Netherlands
- Ghent-Fertility and Stem Cell Team (G-FAST), Department of Reproductive Medicine, Ghent University Hospital, 9000 Ghent, Belgium
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To M, Arimoto Y, Honda N, Furusho N, Kinouchi T, Takeshita Y, Haruki K, To Y. Elevated oxidative stress and steroid insensitivity in patients with asthma and high body fat percentage. Ann Allergy Asthma Immunol 2025:S1081-1206(25)00126-7. [PMID: 40097096 DOI: 10.1016/j.anai.2025.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/12/2025] [Accepted: 03/12/2025] [Indexed: 03/19/2025]
Abstract
BACKGROUND Obesity is a risk factor for poor asthma control. Previous research suggests that patients with asthma and obesity have reduced responsiveness to corticosteroids. Recent studies indicate that body fat percentage may be more strongly associated with obesity-related diseases compared with body mass index. However, the relationship between body fat percentage and asthma, particularly regarding steroid sensitivity, remains unclear. OBJECTIVE To investigate the association between body fat percentage and steroid sensitivity in patients with asthma and elucidate the potential mechanisms underlying this association. METHODS Adult patients with asthma were enrolled and categorized into patients with high body fat percentage (HBF) and control groups. Peripheral blood mononuclear cells were isolated from the blood samples. These cells were cultured with dexamethasone followed by stimulation with tumor necrosis factor-α to assess the half-maximal inhibitory concentration of dexamethasone (IC50-Dex). Serum adipocytokines and oxidative stress markers were also measured. The effects of metformin on steroid sensitivity and oxidative stress in peripheral blood mononuclear cells were evaluated ex vivo. RESULTS The HBF group exhibited significantly higher IC50-Dex values than the control group. In the HBF group, IC50-Dex correlated with the number of acute exacerbations per year and serum oxidative stress marker levels. Treatment with metformin significantly reduced both IC50-Dex and oxidative stress marker levels in the HBF group. CONCLUSION Oxidative stress associated with increased body fat may contribute to impaired steroid sensitivity in patients with asthma. Metformin may improve steroid sensitivity by reducing oxidative stress, suggesting a potential therapeutic approach in this patient population.
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Affiliation(s)
- Masako To
- Department of Laboratory Medicine, Dokkyo Medical University, Saitama Medical Center, Saitama, Japan; Department of Respiratory Medicine, The Fraternity Memorial Hospital, Tokyo, Japan.
| | - Yoshihito Arimoto
- Department of Laboratory Medicine, Dokkyo Medical University, Saitama Medical Center, Saitama, Japan
| | - Natsue Honda
- Department of Laboratory Medicine, Dokkyo Medical University, Saitama Medical Center, Saitama, Japan
| | - Naho Furusho
- Department of Pulmonary Medicine, International University of Health and Welfare Narita Hospital, Chiba, Japan
| | - Toru Kinouchi
- Department of Pulmonary Medicine, International University of Health and Welfare Narita Hospital, Chiba, Japan
| | - Yuichiro Takeshita
- Department of Pulmonary Medicine, International University of Health and Welfare Narita Hospital, Chiba, Japan
| | - Kosuke Haruki
- Department of Laboratory Medicine, Dokkyo Medical University, Saitama Medical Center, Saitama, Japan
| | - Yasuo To
- Department of Pulmonary Medicine, International University of Health and Welfare Narita Hospital, Chiba, Japan
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6
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Osman AAM, Seres-Bokor A, Ducza E. Diabetes mellitus therapy in the light of oxidative stress and cardiovascular complications. J Diabetes Complications 2025; 39:108941. [PMID: 39671854 DOI: 10.1016/j.jdiacomp.2024.108941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 11/19/2024] [Accepted: 12/09/2024] [Indexed: 12/15/2024]
Abstract
Type 2 diabetes is a chronic disease requiring comprehensive pharmacological and non-pharmacological interventions to slow its progression and prevent or delay its micro- and macrovascular complications. Oxidative stress contributes to the development and progression of type 2 diabetes as well as to the development of its complications through several mechanisms. Therefore, therapeutic targeting of oxidative stress could aid in managing this disease and its complications. In our study, we have collected information on the most frequently used antidiabetic drugs (metformin, glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors) in the EU and the USA based on their antioxidant effects. Based on our results, we can conclude that the antioxidant effects of the investigated antidiabetics may contribute significantly to the management of the disease and its complications and may open new therapeutic perspectives in their prevention.
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Affiliation(s)
- Alaa A M Osman
- Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, H-6720 Szeged, Hungary
| | - Adrienn Seres-Bokor
- Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, H-6720 Szeged, Hungary
| | - Eszter Ducza
- Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, H-6720 Szeged, Hungary.
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7
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Ahuja T, Begum F, Kumar G, Shenoy S, Kumar N, Shenoy RR. Exploring the protective role of metformin and dehydrozingerone in sodium fluoride-induced neurotoxicity: evidence from prenatal rat models. 3 Biotech 2025; 15:36. [PMID: 39790448 PMCID: PMC11711601 DOI: 10.1007/s13205-024-04175-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 11/22/2024] [Indexed: 01/12/2025] Open
Abstract
This study is aimed at evaluating the neurotoxic effects of chronic exposure of sodium fluoride (NaF) in developmental stages in rat using prenatal models. NaF (100 ppm, orally) dosing via drinking water was given to pregnant rats in disease group. In the treatment groups, Metformin & Dehydrozingerone (DHZ) (200 mg/kg) were administered orally along with NaF, and the dosing was continued throughout the gestation and lactation periods to the pups until the end of experiment. Behavioural studies like Novel Object Recognition Test (NORT), Open Field & Actophotometer test and biochemical estimations like Acetylcholinesterase (AchE), Glutathione (GSH), Malondialdehyde (MDA) were conducted on animals followed by histopathological image analysis. It was observed that NaF exposure significantly decreased learning, memory and locomotor ability (at p < 0.05, p ≤ 0.01) in rat pups and was also able to induce anxiety like behavior. Levels of AchE (p ≤ 0.001) and MDA (p ≤ 0.01, p ≤ 0.001) was found to be significantly elevated and GSH levels were significantly decreased (p ≤ 0.01, p ≤ 0.001) in hippocampus and frontal cortex in the disease group. Histopathological image analysis showed presence of degenerated neurons in hippocampus of disease group. From this study, it was observed that treatment with Metformin and DHZ, was able to significantly ameliorate the cognitive impairments, improve the condition of oxidative stress and decrease neuronal degeneration in NaF fed rat pups. These results established the protective role of Metformin and DHZ in NaF induced neurodevelopmental toxicity with particular emphasis on their antioxidant properties.
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Affiliation(s)
- Tejas Ahuja
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104 India
| | - Farmiza Begum
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104 India
- Department of Pharmacology, Vaagdevi Pharmacy College, Bollikunta, Warangal, Telangana 506005 India
| | - Gautam Kumar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104 India
- School of Pharmacy, Sharda University, Greater Noida-201306, Uttar Pradesh, India
| | - Smita Shenoy
- Department of Pharmacology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka 576104 India
| | - Nitesh Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Vaishali, Hajipur, Bihar, 844102 India
| | - Rekha R. Shenoy
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104 India
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Cekuc MS, Ergul YS, Pius AK, Meagan M, Shinohara I, Murayama M, Susuki Y, Ma C, Morita M, Chow SKH, Bunnell BA, Lin H, Gao Q, Goodman SB. Metformin Modulates Cell Oxidative Stress to Mitigate Corticosteroid-Induced Suppression of Osteogenesis in a 3D Model. J Inflamm Res 2024; 17:10383-10396. [PMID: 39654863 PMCID: PMC11625639 DOI: 10.2147/jir.s498888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 11/26/2024] [Indexed: 12/12/2024] Open
Abstract
Background Corticosteroids provide well-established therapeutic benefits; however, they are also accompanied by adverse effects on bone. Metformin is a widely used medication for managing type 2 diabetes mellitus. Recent studies have highlighted additional therapeutic benefits of metformin, particularly concerning bone health and oxidative stress. Objective This research investigates the effects of prednisolone on cellular metabolic functions and bone formation using a 3D in vitro model. Then, we demonstrate the potential therapeutic effects of metformin on oxidative stress and the formation of calcified matrix due to corticosteroids. Methods Human mesenchymal stem cells (MSCs) and macrophages were cultured in a 3D GelMA scaffold and stimulated with prednisolone, with and without metformin. The adverse effects of prednisolone and metformin's therapeutic effect(s) were assessed by analyzing cell viability, osteogenesis markers, bone mineralization, and inflammatory markers. Oxidative stress was measured by evaluating reactive oxygen species (ROS) levels and ATP production. Results Prednisolone exhibited cytotoxic effects, reducing the viability of MSCs and macrophages. Lower osteogenesis potential was also detected in the MSC group. Metformin positively affected cell functions, including enhanced osteoblast activity and increased bone mineralization. Furthermore, metformin effectively reduced oxidative stress, as evidenced by decreased ROS levels and increased ATP production. These findings indicate that metformin protects against oxidative damage, thus supporting osteogenesis. Conclusion Metformin exhibits promising therapeutic potential beyond its role in diabetes management. The capacity to alleviate oxidative stress highlights the potential of metformin in supporting bone formation in inflammatory environments.
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Affiliation(s)
- Mehmet Sertac Cekuc
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Yasemin Sude Ergul
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Alexa K Pius
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Makarcyzk Meagan
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA
| | - Issei Shinohara
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Masatoshi Murayama
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Yosuke Susuki
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Chao Ma
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Mayu Morita
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Simon Kwoon-Ho Chow
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Bruce A Bunnell
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
| | - Hang Lin
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA
| | - Qi Gao
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Stuart B Goodman
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
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Larry M, Rabizadeh S, Mohammadi F, Yadegar A, Jalalpour A, Mirmiranpour H, Farahmand G, Esteghamati A, Nakhjavani M. Relationship between advanced glycation end-products and advanced oxidation protein products in patients with type 2 diabetes with and without albuminuria: A cross-sectional survey. Health Sci Rep 2024; 7:e70057. [PMID: 39355098 PMCID: PMC11439888 DOI: 10.1002/hsr2.70057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 08/02/2024] [Accepted: 08/16/2024] [Indexed: 10/03/2024] Open
Abstract
Background and Aims Literature suggests that oxidative stress plays a crucial role in the progression of diabetes. Since poor glycemic control enhances the formation of advanced glycation end-products (AGEs) and advanced oxidation protein products (AOPP) in individuals with diabetes, exploring the association between glycation and oxidative states in diabetes could also shed light on potential consequences. This study evaluated the effects of albuminuria on AGEs and AOPP levels and measured their relationship in participants with type 2 diabetes (T2D) with or without albuminuria. Methods A cross-sectional, matched case-control study was designed, including 38 T2D subjects with albuminuria and 38 matched T2D subjects with normoalbuminuria. Patients were matched by their body mass index (BMI), age, and duration of diabetes. The unadjusted and adjusted correlation between AGEs and AOPP in the studied groups were analyzed by multiple logistic regression. Using ggplot2, the ties between these two biochemical factors in cases and controls were plotted. Results This study elucidated a significant association between AGEs and AOPP in participants with normoalbuminuria (r = 0.331, p-value < 0.05), which continued to be significant after controlling for BMI, age, systolic blood pressure (SBP), and diastolic blood pressure (DBP) (r = 0.355, p-value < 0.05). However, there was no significant association between AGEs and AOPP in those with albuminuria in the unadjusted model (r = 0.034, p-value = 0.841) or after controlling for BMI, age, SBP, and DBP (r = 0.076, p-value = 0.685). Conclusion Oxidation and glycation molecular biomarkers were correlated in patients without albuminuria; however, this association was not observed in those with albuminuria.
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Affiliation(s)
- Mehrdad Larry
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| | - Soghra Rabizadeh
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| | - Fatemeh Mohammadi
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| | - Amirhossein Yadegar
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| | - Azadeh Jalalpour
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| | - Hossein Mirmiranpour
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| | - Ghasem Farahmand
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| | - Alireza Esteghamati
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| | - Manouchehr Nakhjavani
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
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10
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Karim A, Waheed A, Ahmad F, Qaisar R. Metformin effects on plasma zonulin levels correlate with enhanced physical performance in osteoarthritis patients with diabetes. Inflammopharmacology 2024; 32:3195-3203. [PMID: 39158775 DOI: 10.1007/s10787-024-01558-0] [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: 08/03/2024] [Accepted: 08/12/2024] [Indexed: 08/20/2024]
Abstract
PURPOSE Metformin (MTF) shows promise in protecting against physical decline in osteoarthritis (OA), but how it works remains unclear. We studied MTF's effects on gut permeability and its link to physical performance in OA patients. METHODS We studied four groups: control (n = 72), OA non-diabetic (n = 58), OA diabetic on MTF (n = 55), and OA diabetic on other anti-diabetics (n = 57). We measured zonulin levels, as intestinal permeability marker, hand-grip strength (HGS), Oxford knee scoring (OKS) to determine OA severity, and short performance physical battery (SPPB) to determine physical functions. RESULTS Patients suffering from OA showed a reduction in HGS and SPPB scores with raised plasma zonulin than controls, irrespective of disease severity. MTF decreased plasma zonulin levels and improved OKS, gait speed, HGS, and SPPB scores in OA patients. However, OA patients taking other anti-diabetic medications demonstrated higher levels of plasma zonulin, reduced HGS, and SPPB scores. Furthermore, a robust correlation of plasma zonulin and HGS, OKS, gait speed, and SPPB scores in OA patients on MTF was observed. Moreover, we found reduced oxidative stress and inflammation associated with these alterations in OA patients treated with MTF. CONCLUSION MTF improves HGS and physical performance by lowering zonulin levels, preserving gut permeability in OA patients.
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Affiliation(s)
- Asima Karim
- Basic Medical Sciences, Department of Basic Sciences, College of Medicine, University of Sharjah, 27272, Sharjah, United Arab Emirates.
- Iron Biology Research Group, Research Institute of Medical and Health Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates.
| | - Abdul Waheed
- Trauma and Orthopaedics, Department of Orthopaedics, Rehman Medical Institute, Peshawar, Pakistan
| | - Firdos Ahmad
- Basic Medical Sciences, Department of Basic Sciences, College of Medicine, University of Sharjah, 27272, Sharjah, United Arab Emirates
- Cardiovascular Research Group, Research Institute of Medical and Health Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates
| | - Rizwan Qaisar
- Basic Medical Sciences, Department of Basic Sciences, College of Medicine, University of Sharjah, 27272, Sharjah, United Arab Emirates
- Cardiovascular Research Group, Research Institute of Medical and Health Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates
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11
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Ahmed SM, Elkhenany HA, Ahmed TA, Ghoneim NI, Elkodous MA, Mohamed RH, Magdeldin S, Osama A, Anwar AM, Gabr MM, El-Badri N. Diabetic microenvironment deteriorates the regenerative capacities of adipose mesenchymal stromal cells. Diabetol Metab Syndr 2024; 16:131. [PMID: 38880916 PMCID: PMC11181634 DOI: 10.1186/s13098-024-01365-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 05/29/2024] [Indexed: 06/18/2024] Open
Abstract
BACKGROUND Type 2 diabetes is an endocrine disorder characterized by compromised insulin sensitivity that eventually leads to overt disease. Adipose stem cells (ASCs) showed promising potency in improving type 2 diabetes and its complications through their immunomodulatory and differentiation capabilities. However, the hyperglycaemia of the diabetic microenvironment may exert a detrimental effect on the functionality of ASCs. Herein, we investigate ASC homeostasis and regenerative potential in the diabetic milieu. METHODS We conducted data collection and functional enrichment analysis to investigate the differential gene expression profile of MSCs in the diabetic microenvironment. Next, ASCs were cultured in a medium containing diabetic serum (DS) or normal non-diabetic serum (NS) for six days and one-month periods. Proteomic analysis was carried out, and ASCs were then evaluated for apoptosis, changes in the expression of surface markers and DNA repair genes, intracellular oxidative stress, and differentiation capacity. The crosstalk between the ASCs and the diabetic microenvironment was determined by the expression of pro and anti-inflammatory cytokines and cytokine receptors. RESULTS The enrichment of MSCs differentially expressed genes in diabetes points to an alteration in oxidative stress regulating pathways in MSCs. Next, proteomic analysis of ASCs in DS revealed differentially expressed proteins that are related to enhanced cellular apoptosis, DNA damage and oxidative stress, altered immunomodulatory and differentiation potential. Our experiments confirmed these data and showed that ASCs cultured in DS suffered apoptosis, intracellular oxidative stress, and defective DNA repair. Under diabetic conditions, ASCs also showed compromised osteogenic, adipogenic, and angiogenic differentiation capacities. Both pro- and anti-inflammatory cytokine expression were significantly altered by culture of ASCs in DS denoting defective immunomodulatory potential. Interestingly, ASCs showed induction of antioxidative stress genes and proteins such as SIRT1, TERF1, Clusterin and PKM2. CONCLUSION We propose that this deterioration in the regenerative function of ASCs is partially mediated by the induced oxidative stress and the diabetic inflammatory milieu. The induction of antioxidative stress factors in ASCs may indicate an adaptation mechanism to the increased oxidative stress in the diabetic microenvironment.
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Affiliation(s)
- Sara M Ahmed
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Sheikh Zayed District, 6th of October City , 12582, Giza, Egypt
| | - Hoda A Elkhenany
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Sheikh Zayed District, 6th of October City , 12582, Giza, Egypt
- Department of surgery, Faculty of Veterinary Medicine, Alexandria University, Alexandria, Egypt
| | - Toka A Ahmed
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Sheikh Zayed District, 6th of October City , 12582, Giza, Egypt
| | - Nehal I Ghoneim
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Sheikh Zayed District, 6th of October City , 12582, Giza, Egypt
| | - Mohamed Abd Elkodous
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Sheikh Zayed District, 6th of October City , 12582, Giza, Egypt
| | - Rania Hassan Mohamed
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Sheikh Zayed District, 6th of October City , 12582, Giza, Egypt
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Sameh Magdeldin
- Proteomic and Metabolomics Research Program, Basic Research Department, Children's Cancer Hospital, Cairo, Egypt
- Department of Physiology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, 41522, Egypt
| | - Aya Osama
- Proteomic and Metabolomics Research Program, Basic Research Department, Children's Cancer Hospital, Cairo, Egypt
| | - Ali Mostafa Anwar
- Proteomic and Metabolomics Research Program, Basic Research Department, Children's Cancer Hospital, Cairo, Egypt
| | - Mahmoud M Gabr
- Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Sheikh Zayed District, 6th of October City , 12582, Giza, Egypt.
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, Sheikh Zayed District, Giza 12588, 6th of October City, Egypt.
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12
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Buczyńska A, Sidorkiewicz I, Krętowski AJ, Adamska A. Examining the clinical relevance of metformin as an antioxidant intervention. Front Pharmacol 2024; 15:1330797. [PMID: 38362157 PMCID: PMC10867198 DOI: 10.3389/fphar.2024.1330797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 01/19/2024] [Indexed: 02/17/2024] Open
Abstract
In physiological concentrations, reactive oxygen species play a vital role in regulating cell signaling and gene expression. Nevertheless, oxidative stress is implicated in the pathogenesis of numerous diseases and can inflict damage on diverse cell types and tissues. Thus, understanding the factors that mitigate the deleterious effects of oxidative stress is imperative for identifying new therapeutic targets. In light of the absence of direct treatment recommendations for reducing oxidative stress, there is a continuing need for fundamental research that utilizes innovative therapeutic approaches. Metformin, known for its multifaceted beneficial properties, is acknowledged for its ability to counteract the adverse effects of increased oxidative stress at both molecular and cellular levels. In this review, we delve into recent insights regarding metformin's antioxidant attributes, aiming to expand its clinical applicability. Our review proposes that metformin holds promise as a potential adjunctive therapy for various diseases, given its modulation of oxidative stress characteristics and regulation of diverse metabolic pathways. These pathways include lipid metabolism, hormone synthesis, and immunological responses, all of which may experience dysregulation in disease states, contributing to increased oxidative stress. Furthermore, our review introduces potential novel metformin-based interventions that may merit consideration in future research. Nevertheless, the necessity for clinical trials involving this drug remains imperative, as they are essential for establishing therapeutic dosages and addressing challenges associated with dose-dependent effects.
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Affiliation(s)
- Angelika Buczyńska
- Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
| | - Iwona Sidorkiewicz
- Clinical Research Support Centre, Medical University of Bialystok, Bialystok, Poland
| | - Adam Jacek Krętowski
- Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Agnieszka Adamska
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
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13
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Kamel AM, Ismail B, Abdel Hafiz G, Sabry N, Farid S. Effect of Metformin on Oxidative Stress and Left Ventricular Geometry in Nondiabetic Heart Failure Patients: A Randomized Controlled Trial. Metab Syndr Relat Disord 2024; 22:49-58. [PMID: 37816240 DOI: 10.1089/met.2023.0164] [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] [Indexed: 10/12/2023] Open
Abstract
Introduction: There is an increasing interest in using metformin in cardiovascular diseases and its potential new roles. Only two randomized controlled trials investigated the effect of metformin in nondiabetic heart failure (HF) patients. However, none of these studies assess the role of metformin in reducing oxidative stress. We hypothesized that metformin might improve oxidative stress and left ventricular remodeling in nondiabetic HF patients with reduced ejection fraction (HFrEF). Methods and Methods: Seventy HFrEF patients (EF 37% ± 8%; median age 66 years) were randomized to metformin (n = 35) or standard of care (SOC) for HF (n = 35) for 6 months in addition to standard therapy. Outcomes included the difference in the change (Δ) in total antioxidant capacity (TAC) and malondialdehyde (MDA), both assessed colorimetrically and left ventricular mass index (LVMI) assessed through transthoracic echocardiography. Results: Compared with the SOC, metformin treatment increased TAC [Δ = 0.12 mmol/L, confidence intervals (95% CIs): 0.03-0.21; P = 0.007]. TAC increased significantly only in the metformin group (0.90 ± 0.08 mmol/L at baseline vs. 1.04 ± 0.99 mmol/L at 6 months, P < 0.05). Metformin therapy preserved LVMI (Δ = -23 g/m2, 95% CI: -42.91 to -4.92; P = 0.014) and reduced fasting plasma glucose (Δ = -6.16, 95% CI: -12.31 to -0.02, P = 0.047) compared with the SOC. Results did not change after adjusting for baseline values. Changes in MDA left ventricular ejection fraction (LVEF) and blood pressure were not significantly different between groups. Conclusion: Metformin treatment in HF patients with reduced LVEF improved TAC and prevented the increase in LVMI compared with the SOC. These effects of metformin warrant further research in HF patients without diabetes to explore the potential benefits of metformin. Trial Registration Number: This protocol was registered in ClinicalTrials.gov under the number NCT05177588.
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Affiliation(s)
- Ahmed M Kamel
- Clinical Pharmacy Department, Faculty of Pharmacy Cairo University, Cairo, Egypt
| | - Batool Ismail
- Ministry of Interior, Agouza Police Hospital, Cairo, Egypt
| | | | - Nirmeen Sabry
- Clinical Pharmacy Department, Faculty of Pharmacy Cairo University, Cairo, Egypt
| | - Samar Farid
- Clinical Pharmacy Department, Faculty of Pharmacy Cairo University, Cairo, Egypt
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14
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Bashghareh A, Rastegar T, Modarresi P, Kazemzadeh S, Salem M, Hedayatpour A. Recovering Spermatogenesis By Protected Cryopreservation Using Metformin and Transplanting Spermatogonial Stem Cells Into Testis in an Azoospermia Mouse Model. Biopreserv Biobank 2024; 22:68-81. [PMID: 37582284 DOI: 10.1089/bio.2022.0178] [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] [Indexed: 08/17/2023] Open
Abstract
Cryopreservation and transplantation of spermatogonial stem cells (SSCs) may serve as a new method to restore male fertility in patients undergoing chemotherapy or radiotherapy. However, SSCs may be damaged during cryopreservation due to the production of reactive oxygen species (ROS). Therefore, different antioxidants have been used as protective agents. Studies have shown that metformin (MET) has antioxidant activity. The aim of this study was to assess the antioxidant and antiapoptotic effects of MET in frozen-thawed SSCs. In addition, the effect of MET on the proliferation and differentiation of SSCs was evaluated. To this end, SSCs were isolated from mouse pups aged 3-6 days old, cultured, identified by flow cytometry (ID4, INTEGRIN β1+), and finally evaluated for survival and ROS rate. SSCs were transplanted after busulfan and cadmium treatment. Cryopreserved SSCs with and without MET were transplanted after 1 month of cryopreservation. Eight weeks after transplantation, the recipient testes were evaluated for the expression of apoptosis (BAX, BCL2), proliferation (PLZF), and differentiation (SCP3, TP1, TP2, PRM1) markers using immunohistochemistry, Western blot, and quantitative real-time polymerase chain reaction. The findings revealed that the survival rate of SSCs was higher in the 500 μm/mL MET group compared to the other groups (50 and 5000 μm/mL). MET significantly decreased the intracellular ROS production. Transplantation of SSCs increased the expression level of proliferation (PLZF) and differentiation (SCP3, TP1, TP2, PRM1) markers compared to azoospermia group, and their levels were significantly higher in the MET group compared to the cryopreservation group containing basic freezing medium (p < 0.05). MET increased the survival rate of SSCs, proliferation, and differentiation and decreased the ROS production and the apoptosis rate. Cryopreservation by MET seems to be effective in treating infertility.
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Affiliation(s)
- Alieh Bashghareh
- Department of Anatomy, School of Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Tayebeh Rastegar
- Department of Anatomy, School of Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Peyman Modarresi
- Department of Veterinary Medicine, Faculty of Veterinary Medicine, Islamic Azad University, Shabestar, Iran
| | - Shokoofeh Kazemzadeh
- Department of Anatomy, Faculty of Medicine, Shoushtar University of Medical Sciences, Shoushtar, Iran
| | - Maryam Salem
- Department of Anatomy, School of Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Azim Hedayatpour
- Department of Anatomy, School of Medicine, Tehran University of Medical Science, Tehran, Iran
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15
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Sutter A, Landis D, Nugent K. Metformin has immunomodulatory effects which support its potential use as adjunctive therapy in tuberculosis. Indian J Tuberc 2024; 71:89-95. [PMID: 38296396 DOI: 10.1016/j.ijtb.2023.05.011] [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: 06/02/2022] [Revised: 08/30/2022] [Accepted: 05/15/2023] [Indexed: 02/08/2024]
Abstract
Metformin is the preferred oral medication for patients with type 2 diabetes mellitus, and this blood glucose-lowering and insulin-sensitizing drug has immunomodulatory effects that could contribute to the management of patients with various other autoimmune and infectious diseases. Tuberculosis is one such infection, and it remains prevalent worldwide, largely due to the successful evasion of the host's immune responses by the infecting pathogen, Mycobacterium tuberculosis. This review focuses on the possible mechanisms relevant to metformin's modulation of innate and adaptive immune responses to Mycobacterium tuberculosis and its potential use as an adjunctive drug in the treatment of tuberculosis. Current data suggest that metformin increases autophagy, phagocytosis, and mitochondrial reactive oxygen species production, while limiting excess inflammation and tissue destruction. This multifaceted drug also augments cell-mediated immune responses by maintaining CD8+ T cell metabolic homeostasis and improving immunological memory. Several murine models have demonstrated that metformin can reduce tuberculosis severity and tissue pathology, and two in vitro human studies confirmed enhanced immune responses in metformin-treated cells. These studies provide convincing evidence supporting the use of metformin to augment immune responses in patients with tuberculosis.
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Affiliation(s)
- Alex Sutter
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Dylan Landis
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Kenneth Nugent
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
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16
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Tarry-Adkins JL, Robinson IG, Pantaleão LC, Armstrong JL, Thackray BD, Holzner LMW, Knapton AE, Virtue S, Jenkins B, Koulman A, Murray AJ, Ozanne SE, Aiken CE. The metabolic response of human trophoblasts derived from term placentas to metformin. Diabetologia 2023; 66:2320-2331. [PMID: 37670017 PMCID: PMC10627909 DOI: 10.1007/s00125-023-05996-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 07/18/2023] [Indexed: 09/07/2023]
Abstract
AIMS/HYPOTHESIS Metformin is increasingly used therapeutically during pregnancy worldwide, particularly in the treatment of gestational diabetes, which affects a substantial proportion of pregnant women globally. However, the impact on placental metabolism remains unclear. In view of the association between metformin use in pregnancy and decreased birthweight, it is essential to understand how metformin modulates the bioenergetic and anabolic functions of the placenta. METHODS A cohort of 55 placentas delivered by elective Caesarean section at term was collected from consenting participants. Trophoblasts were isolated from the placental samples and treated in vitro with clinically relevant doses of metformin (0.01 mmol/l or 0.1 mmol/l) or vehicle. Respiratory function was assayed using high-resolution respirometry to measure oxygen concentration and calculated [Formula: see text]. Glycolytic rate and glycolytic stress assays were performed using Agilent Seahorse XF assays. Fatty acid uptake and oxidation measurements were conducted using radioisotope-labelled assays. Lipidomic analysis was conducted using LC-MS. Gene expression and protein analysis were performed using RT-PCR and western blotting, respectively. RESULTS Complex I-supported oxidative phosphorylation was lower in metformin-treated trophoblasts (0.01 mmol/l metformin, 61.7% of control, p<0.05; 0.1 mmol/l metformin, 43.1% of control, p<0.001). The proton efflux rate arising from glycolysis under physiological conditions was increased following metformin treatment, up to 23±5% above control conditions following treatment with 0.1 mmol/l metformin (p<0.01). There was a significant increase in triglyceride concentrations in trophoblasts treated with 0.1 mmol/l metformin (p<0.05), particularly those of esters of long-chain polyunsaturated fatty acids. Fatty acid oxidation was reduced by ~50% in trophoblasts treated with 0.1 mmol/l metformin compared with controls (p<0.001), with no difference in uptake between treatment groups. CONCLUSIONS/INTERPRETATION In primary trophoblasts derived from term placentas metformin treatment caused a reduction in oxidative phosphorylation through partial inactivation of complex I and potentially by other mechanisms. Metformin-treated trophoblasts accumulate lipids, particularly long- and very-long-chain polyunsaturated fatty acids. Our findings raise clinically important questions about the balance of risk of metformin use during pregnancy, particularly in situations where the benefits are not clear-cut and alternative therapies are available.
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Affiliation(s)
- Jane L Tarry-Adkins
- Department of Obstetrics and Gynaecology, the Rosie Hospital and NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - India G Robinson
- Department of Obstetrics and Gynaecology, the Rosie Hospital and NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Lucas C Pantaleão
- Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Jenna L Armstrong
- Department of Physiology, Neuroscience and Development, University of Cambridge, Cambridge, UK
| | - Benjamin D Thackray
- Department of Physiology, Neuroscience and Development, University of Cambridge, Cambridge, UK
| | - Lorenz M W Holzner
- Department of Physiology, Neuroscience and Development, University of Cambridge, Cambridge, UK
| | - Alice E Knapton
- Department of Physiology, Neuroscience and Development, University of Cambridge, Cambridge, UK
| | - Sam Virtue
- Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Benjamin Jenkins
- Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Albert Koulman
- Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Andrew J Murray
- Department of Physiology, Neuroscience and Development, University of Cambridge, Cambridge, UK
- Centre for Trophoblast Research, University of Cambridge, Cambridge, UK
| | - Susan E Ozanne
- Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
- Centre for Trophoblast Research, University of Cambridge, Cambridge, UK
| | - Catherine E Aiken
- Department of Obstetrics and Gynaecology, the Rosie Hospital and NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
- Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
- Centre for Trophoblast Research, University of Cambridge, Cambridge, UK.
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17
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Salama AM, Elmahy RA, Ibrahim HA, Amer AIM, Eltantawy AF, Elgendy DI. Effects of metformin on parasitological, pathological changes in the brain and liver and immunological aspects during visceral toxocariasis in mice. Parasitol Res 2023; 122:3213-3231. [PMID: 37874393 PMCID: PMC10667394 DOI: 10.1007/s00436-023-08011-1] [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: 06/28/2023] [Accepted: 10/12/2023] [Indexed: 10/25/2023]
Abstract
There are currently insufficient anthelmintic medications available for the treatment of toxocariasis. For instance, Albendazole (ABZ) is the preferred medication, but its effectiveness against tissue-dwelling parasites is limited. In addition, Metformin (MTF) is a widely used oral antidiabetic medication that is considered to be safe for treatment. This study aimed to investigate any potential effects of MTF, alone or in combination with ABZ, on mice infections caused by Toxocara canis (T. canis). The efficacy of the treatment was assessed in the acute and chronic phases of the infection by larval recovery and histopathological, immunohistochemical, and biochemical studies. The results showed that combined therapy significantly reduced larval counts in the liver, brain, and muscles and ameliorated hepatic and brain pathology. It reduced oxidative stress and TGF-β mRNA expression and increased FGF21 levels in the liver. It decreased TNF-α levels and MMP-9 expression in the brain. In addition, it increased serum levels of IL-12 and IFN-γ and decreased serum levels of IL-4 and IL-10. In the acute and chronic phases of the infection, the combined treatment was more effective than ABZ alone. In conclusion, this study highlights the potential role of MTF as an adjuvant in the treatment of experimental T. canis infection when administered with ABZ.
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Affiliation(s)
- Amina M Salama
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Rasha A Elmahy
- Zoology Department, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Hoda A Ibrahim
- Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | - Asmaa Fawzy Eltantawy
- Medical Pharmacology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Dina I Elgendy
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
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18
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Lin H, Ao H, Guo G, Liu M. The Role and Mechanism of Metformin in Inflammatory Diseases. J Inflamm Res 2023; 16:5545-5564. [PMID: 38026260 PMCID: PMC10680465 DOI: 10.2147/jir.s436147] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 11/17/2023] [Indexed: 12/01/2023] Open
Abstract
Metformin is a classical drug used to treat type 2 diabetes. With the development of research on metformin, it has been found that metformin also has several advantages aside from its hypoglycemic effect, such as anti-inflammatory, anti-aging, anti-cancer, improving intestinal flora, and other effects. The prevention of inflammation is critical because chronic inflammation is associated with numerous diseases of considerable public health. Therefore, there has been growing interest in the role of metformin in treating various inflammatory conditions. However, the precise anti-inflammatory mechanisms of metformin were inconsistent in the reported studies. Thus, this review aims to summarize various currently known possible mechanisms of metformin involved in inflammatory diseases and provide references for the clinical application of metformin.
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Affiliation(s)
- Huan Lin
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
| | - Haiyong Ao
- Jiangxi Key Laboratory of Nanobiomaterials & School of Materials Science and Engineering, East China Jiaotong University, Nanchang, Jiangxi, People’s Republic of China
| | - Guanghua Guo
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
| | - Mingzhuo Liu
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
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19
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Malaekeh-Nikouei A, Shokri-Naei S, Karbasforoushan S, Bahari H, Baradaran Rahimi V, Heidari R, Askari VR. Metformin beyond an anti-diabetic agent: A comprehensive and mechanistic review on its effects against natural and chemical toxins. Biomed Pharmacother 2023; 165:115263. [PMID: 37541178 DOI: 10.1016/j.biopha.2023.115263] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 07/24/2023] [Accepted: 07/31/2023] [Indexed: 08/06/2023] Open
Abstract
In addition to the anti-diabetic effect of metformin, a growing number of studies have shown that metformin has some exciting properties, such as anti-oxidative capabilities, anticancer, genomic stability, anti-inflammation, and anti-fibrosis, which have potent, that can treat other disorders other than diabetes mellitus. We aimed to describe and review the protective and antidotal efficacy of metformin against biologicals, chemicals, natural, medications, pesticides, and radiation-induced toxicities. A comprehensive search has been performed from Scopus, Web of Science, PubMed, and Google Scholar databases from inception to March 8, 2023. All in vitro, in vivo, and clinical studies were considered. Many studies suggest that metformin affects diseases other than diabetes. It is a radioprotective and chemoprotective drug that also affects viral and bacterial diseases. It can be used against inflammation-related and apoptosis-related abnormalities and against toxins to lower their effects. Besides lowering blood sugar, metformin can attenuate the effects of toxins on body weight, inflammation, apoptosis, necrosis, caspase-3 activation, cell viability and survival rate, reactive oxygen species (ROS), NF-κB, TNF-α, many interleukins, lipid profile, and many enzymes activity such as catalase and superoxide dismutase. It also can reduce the histopathological damages induced by many toxins on the kidneys, liver, and colon. However, clinical trials and human studies are needed before using metformin as a therapeutic agent against other diseases.
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Affiliation(s)
- Amirhossein Malaekeh-Nikouei
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sina Shokri-Naei
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sobhan Karbasforoushan
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Bahari
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vafa Baradaran Rahimi
- Department of Cardiovascular Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Heidari
- Medical Biotechnology Research Center, AJA University of Medical Sciences, Tehran, Iran; Research Center for Cancer Screening and Epidemiology, AJA University of Medical Sciences, Tehran, Iran
| | - Vahid Reza Askari
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran; Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran.
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20
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Keegan GL, Bhardwaj N, Abdelhafiz AH. The outcome of frailty in older people with diabetes as a function of glycaemic control and hypoglycaemic therapy: a review. Expert Rev Endocrinol Metab 2023; 18:361-375. [PMID: 37489773 DOI: 10.1080/17446651.2023.2239907] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/08/2023] [Accepted: 07/19/2023] [Indexed: 07/26/2023]
Abstract
INTRODUCTION Frailty is an emerging and newly recognized complication of diabetes in older people. However, frailty is not thoroughly investigated in diabetes outcome studies. AREAS COVERED This manuscript reviews the effect of glycemic control and hypoglycemic therapy on the incidence of frailty in older people with diabetes. EXPERT OPINION Current studies show that both low glycemia and high glycemia are associated with frailty. However, most of the studies, especially low glycemia studies, are cross-sectional or retrospective, suggesting association, rather than causation, of frailty. In addition, frail patients in the low glycemia studies are characterized by lower body weight or lower body mass index (BMI), contrary to those in the high glycemia studies, who are either overweight or obese. This may suggest that frailty has a heterogeneous metabolic spectrum, starting with an anorexic malnourished (AM) phenotype at one end, which is associated with low glycemia and a sarcopenic obese (SO) phenotype on the other end, which is associated with high glycemia. The current little evidence suggests that poor glycemic control increases the risk of frailty, but there is a paucity of evidence to suggest that tight glycemic control would reduce the risk of incident frailty. Metformin is the only well-studied hypoglycemic agent, so far, to have a protective effect against frailty independent of glycemic control in the non-frail older people with diabetes. However, once frailty is developed, the choice of the best hypoglycemic agent for these patients will be affected by the metabolic phenotype of frailty. For example, sodium glucose transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) are appropriate in the SO phenotype due to their weight losing properties, while insulin therapy may be considered early in the AM phenotype due to its anabolic and weight gaining benefits. Future studies are still required to further investigate the metabolic effects of frailty on older people with diabetes, determine the most appropriate HbA1c target, and explore the most suitable hypoglycemic agent in each metabolic phenotype of frailty.
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Affiliation(s)
- Grace L Keegan
- Department of Geriatric Medicine, Rotherham General Hospital, Rotherham, UK
| | - Namita Bhardwaj
- Department of Geriatric Medicine, Rotherham General Hospital, Rotherham, UK
| | - Ahmed H Abdelhafiz
- Department of Geriatric Medicine, Rotherham General Hospital, Rotherham, UK
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21
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Bakry HM, Mansour NO, ElKhodary TR, Soliman MM. Efficacy of metformin in prevention of paclitaxel-induced peripheral neuropathy in breast cancer patients: a randomized controlled trial. Front Pharmacol 2023; 14:1181312. [PMID: 37583905 PMCID: PMC10424931 DOI: 10.3389/fphar.2023.1181312] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 07/17/2023] [Indexed: 08/17/2023] Open
Abstract
Background: Paclitaxel-induced peripheral neuropathy (PN) is a serious clinical problem with no approved drug for prevention. This study aimed to examine the neuroprotective effect of metformin against paclitaxel-induced PN in breast cancer patients. Methods: Patients with confirmed breast cancer diagnosis who were planned to receive paclitaxel were randomized to receive either metformin or placebo. Both groups received the standard chemotherapy protocol for breast cancer. Patients started metformin/placebo 1 week before paclitaxel initiation and continued study interventions thereafter for nine consecutive weeks. The primary outcome was the incidence of development of grade two or more paclitaxel-induced sensory PN. The PN was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Patients' quality of life (QoL) was assessed by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACTGOG-Ntx) subscale. Pain severity was measured by the Brief Pain Inventory Short Form (BPI-SF). Serum levels of nerve growth factor (NGF) and neurotensin (NT) were measured at baseline and at the end paclitaxel treatment. Results: A total of 73 patients (36 in the metformin arm and 37 in the control arm) were evaluated. The cumulative incidence of development of grade two or more PN was significantly lower in the metformin arm (14 (38.9%) than the control arm (28 (75.7%); p = 0.001). At the end of paclitaxel treatment, patients' QoL was significantly better in the metformin arm [median (IQR) FACTGOG-Ntx subscale of (24.0 (20.5-26.5)] compared to the control arm (21.0 (18.0-24.0); p = 0.003). The metformin arm showed lower "average" and "worst" pain scores than those detected in the control arm. At the end of the paclitaxel treatment, there was a significant difference in the median serum NGF levels between the two arms, favoring metformin (p < 0.05), while NT serum levels were deemed comparable between the two study arms (p = 0.09). Conclusion: The use of metformin in breast cancer patients offered a marked protection against paclitaxel-induced PN, which translated to better patient QoL. Clinical Trial Registration: https://classic.clinicaltrials.gov/ct2/show/NCT05351021, identifier NCT05351021.
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Affiliation(s)
- Hala M. Bakry
- Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Noha O. Mansour
- Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Tawfik R. ElKhodary
- Oncology Center, Medical Oncology Unit, Mansoura University, Mansoura, Egypt
| | - Moetaza M. Soliman
- Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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22
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Sekar P, Hsiao G, Hsu SH, Huang DY, Lin WW, Chan CM. Metformin inhibits methylglyoxal-induced retinal pigment epithelial cell death and retinopathy via AMPK-dependent mechanisms: Reversing mitochondrial dysfunction and upregulating glyoxalase 1. Redox Biol 2023; 64:102786. [PMID: 37348156 PMCID: PMC10363482 DOI: 10.1016/j.redox.2023.102786] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 06/09/2023] [Accepted: 06/14/2023] [Indexed: 06/24/2023] Open
Abstract
Diabetic retinopathy (DR) is a major cause of blindness in adult, and the accumulation of advanced glycation end products (AGEs) is a major pathologic event in DR. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is a precursor of AGEs. Although the therapeutic potential of metformin for retinopathy disorders has recently been elucidated, possibly through AMPK activation, it remains unknown how metformin directly affects the MGO-induced stress response in retinal pigment epithelial cells. Therefore, in this study, we compared the effects of metformin and the AMPK activator A769662 on MGO-induced DR in mice, as well as evaluated cytotoxicity, mitochondrial dynamic changes and dysfunction in ARPE-19 cells. We found MGO can induce mitochondrial ROS production and mitochondrial membrane potential loss, but reduce cytosolic ROS level in ARPE-19 cells. Although these effects of MGO can be reversed by both metformin and A769662, we demonstrated that reduction of mitochondrial ROS production rather than restoration of cytosolic ROS level contributes to cell protective effects of metformin and A769662. Moreover, MGO inhibits AMPK activity, reduces LC3II accumulation, and suppresses protein and gene expressions of MFN1, PGC-1α and TFAM, leading to mitochondrial fission, inhibition of mitochondrial biogenesis and autophagy. In contrast, these events of MGO were reversed by metformin in an AMPK-dependent manner as evidenced by the effects of compound C and AMPK silencing. In addition, we observed an AMPK-dependent upregulation of glyoxalase 1, a ubiquitous cellular enzyme that participates in the detoxification of MGO. In intravitreal drug-treated mice, we found that AMPK activators can reverse the MGO-induced cotton wool spots, macular edema and retinal damage. Functional, histological and optical coherence tomography analysis support the protective actions of both agents against MGO-elicited retinal damage. Metformin and A769662 via AMPK activation exert a strong protection against MGO-induced retinal pigment epithelial cell death and retinopathy. Therefore, metformin and AMPK activator can be therapeutic agents for DR.
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Affiliation(s)
- Ponarulselvam Sekar
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
| | - George Hsiao
- Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
| | - Shu-Hao Hsu
- Medical Research Center, Cardinal Tien Hospital, New Taipei City, Taiwan
| | - Duen-Yi Huang
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wan-Wan Lin
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan; Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
| | - Chi-Ming Chan
- Department of Ophthalmology, Cardinal Tien Hospital, New Taipei City, Taiwan; School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
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23
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Siddiqa A, Wang Y, Thapa M, Martin DE, Cadar AN, Bartley JM, Li S. A pilot metabolomic study of drug interaction with the immune response to seasonal influenza vaccination. NPJ Vaccines 2023; 8:92. [PMID: 37308481 PMCID: PMC10261085 DOI: 10.1038/s41541-023-00682-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 05/24/2023] [Indexed: 06/14/2023] Open
Abstract
Many human diseases, including metabolic diseases, are intertwined with the immune system. The understanding of how the human immune system interacts with pharmaceutical drugs is still limited, and epidemiological studies only start to emerge. As the metabolomics technology matures, both drug metabolites and biological responses can be measured in the same global profiling data. Therefore, a new opportunity presents itself to study the interactions between pharmaceutical drugs and immune system in the high-resolution mass spectrometry data. We report here a double-blinded pilot study of seasonal influenza vaccination, where half of the participants received daily metformin administration. Global metabolomics was measured in the plasma samples at six timepoints. Metformin signatures were successfully identified in the metabolomics data. Statistically significant metabolite features were found both for the vaccination effect and for the drug-vaccine interactions. This study demonstrates the concept of using metabolomics to investigate drug interaction with the immune response in human samples directly at molecular levels.
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Affiliation(s)
- Amnah Siddiqa
- The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT, 06032, USA
| | - Yating Wang
- The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT, 06032, USA
| | - Maheshwor Thapa
- The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT, 06032, USA
| | - Dominique E Martin
- Department of Immunology and Center on Aging, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT, 06030, USA
| | - Andreia N Cadar
- Department of Immunology and Center on Aging, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT, 06030, USA
| | - Jenna M Bartley
- Department of Immunology and Center on Aging, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT, 06030, USA.
| | - Shuzhao Li
- The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT, 06032, USA.
- Department of Immunology and Center on Aging, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT, 06030, USA.
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24
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Karami F, Jamaati H, Coleman-Fuller N, Zeini MS, Hayes AW, Gholami M, Salehirad M, Darabi M, Motaghinejad M. Is metformin neuroprotective against diabetes mellitus-induced neurodegeneration? An updated graphical review of molecular basis. Pharmacol Rep 2023; 75:511-543. [PMID: 37093496 DOI: 10.1007/s43440-023-00469-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 02/21/2023] [Accepted: 02/23/2023] [Indexed: 04/25/2023]
Abstract
Diabetes mellitus (DM) is a metabolic disease that activates several molecular pathways involved in neurodegenerative disorders. Metformin, an anti-hyperglycemic drug used for treating DM, has the potential to exert a significant neuroprotective role against the detrimental effects of DM. This review discusses recent clinical and laboratory studies investigating the neuroprotective properties of metformin against DM-induced neurodegeneration and the roles of various molecular pathways, including mitochondrial dysfunction, oxidative stress, inflammation, apoptosis, and its related cascades. A literature search was conducted from January 2000 to December 2022 using multiple databases including Web of Science, Wiley, Springer, PubMed, Elsevier Science Direct, Google Scholar, the Core Collection, Scopus, and the Cochrane Library to collect and evaluate peer-reviewed literature regarding the neuroprotective role of metformin against DM-induced neurodegenerative events. The literature search supports the conclusion that metformin is neuroprotective against DM-induced neuronal cell degeneration in both peripheral and central nervous systems, and this effect is likely mediated via modulation of oxidative stress, inflammation, and cell death pathways.
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Affiliation(s)
- Fatemeh Karami
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamidreza Jamaati
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Natalie Coleman-Fuller
- Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN, 55108, USA
| | - Maryam Shokrian Zeini
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - A Wallace Hayes
- University of South Florida College of Public Health and Institute for Integrative Toxicology, Michigan State University, East Lansing, USA
| | - Mina Gholami
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahsa Salehirad
- Cognitive and Neuroscience Research Center (CNRC), Amir-Almomenin Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Darabi
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Motaghinejad
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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25
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Cardoso JDS, Cardoso Teixeira F, De Mello JE, Soares De Aguiar MS, Souto Oliveira P, Torchelsen Saraiva J, Vizzotto M, Borelli Grecco F, Lencina CL, Spanevello RM, Tavares RG, Stefanello FM, Stefanello FM. Psidium cattleianum fruit extract prevents systemic alterations in an animal model of type 2 diabetes mellitus: comparison with metformin effects. Biomarkers 2023; 28:238-248. [PMID: 36576409 DOI: 10.1080/1354750x.2022.2163695] [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: 12/29/2022]
Abstract
Objective: In this study, we aimed to determine the role of Psidium cattleianum extract (PCE) and compare its effects with those of metformin (Met) in an animal model with type 2 diabetes mellitus (T2DM).Methods: T2DM was induced in rats using a high-fat diet (HFD), followed by a single dose of streptozotocin (STZ). Met and PCE were administered intragastrically once a day throughout the experiment, and their effects on biochemical, inflammatory, oxidative, and histological parameters were evaluated.Results: Met and PCE prevented the increase in serum levels of glucose, total cholesterol (TC), triacylglycerol (TG), very low-density lipoprotein (VLDL) and interleukin-6 (IL-6) induced by T2DM, and restored redox homeostasis in the liver and brain. Met increased the serum levels of anti-inflammatory cytokine and interleukin-10 (IL-10). Furthermore, both treatments restored the liver and pancreas from marked cellular disorganisation, vacuolisation, and necrosis, with PCE being more effective than Met in recovering histological changes.Conclusion: PCE is a promising agent for the prevention of T2DM complications.
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Affiliation(s)
- Juliane De Souza Cardoso
- Laboratório de Biomarcadores, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Fernanda Cardoso Teixeira
- Laboratório de Neuroquímica, Inflamação e Câncer, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Julia Eisenhardt De Mello
- Laboratório de Neuroquímica, Inflamação e Câncer, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Mayara Sandrielly Soares De Aguiar
- Laboratório de Neuroquímica, Inflamação e Câncer, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Pelotas, Brazil
| | | | - Juliane Torchelsen Saraiva
- Laboratório de Biomarcadores, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Marcia Vizzotto
- Empresa Brasileira de Pesquisa Agropecuária, Centro de Pesquisa Agropecuária de Clima Temperado, Pelotas, Brazil
| | - Fabiane Borelli Grecco
- Laboratório de Patologia Animal, Programa de Pós-Graduação em Veterinária, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Claiton Leoneti Lencina
- Laboratório de Biomarcadores, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Pelotas, Brazil
| | | | - Rejane Giacomelli Tavares
- Laboratório de Biomarcadores, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Pelotas, Brazil.,Centro de Investigação em Biociências e Tecnologias da Saúde (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, Lisboa, Portugal
| | - Francieli Moro Stefanello
- Laboratório de Biomarcadores, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Francieli Moro Stefanello
- Laboratório de Biomarcadores, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Campus Universitário Capão do Leão s/n, Pelotas, RS, Brazil
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26
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Karmanova E, Chernikov A, Usacheva A, Ivanov V, Bruskov V. Metformin counters oxidative stress and mitigates adverse effects of radiation exposure: An overview. Fundam Clin Pharmacol 2023. [PMID: 36852652 DOI: 10.1111/fcp.12884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 01/19/2023] [Accepted: 02/15/2023] [Indexed: 03/01/2023]
Abstract
Metformin (1,1-dimethylbiguanidine hydrochloride) (MF) is a drug that has long been in use for the treatment of type 2 diabetes mellitus and recently is coming into use in the radiation therapy of cancer and other conditions. Exposure to ionizing radiation disturbs the redox homeostasis of cells and causes damage to proteins, membranes, and mitochondria, destroying a number of biological processes. After irradiation, MF activates cellular antioxidant and repair systems by signaling to eliminate the harmful consequences of disruption of redox homeostasis. The use of MF in the treatment of the negative effects of irradiation has great potential in medical patients after radiotherapy and in victims of nuclear accidents or radiologic terrorism.
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Affiliation(s)
- Ekaterina Karmanova
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia.,Institute of Cell Biophysics, Pushchino Scientific Center for Biological Research, Federal Research Center of the Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia
| | - Anatoly Chernikov
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia
| | - Anna Usacheva
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia
| | - Vladimir Ivanov
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia
| | - Vadim Bruskov
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia
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27
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Kunachowicz D, Ściskalska M, Kepinska M. Modulatory Effect of Lifestyle-Related, Environmental and Genetic Factors on Paraoxonase-1 Activity: A Review. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:2813. [PMID: 36833509 PMCID: PMC9957543 DOI: 10.3390/ijerph20042813] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/02/2023] [Accepted: 02/03/2023] [Indexed: 06/18/2023]
Abstract
Paraoxonase-1 (PON1) is a calcium-dependent, HDL-bound serum hydrolase active toward a wide variety of substrates. PON1 displays three types of activities, among which lactonase, paraoxonase, arylesterase and phosphotriesterase can be distinguished. Not only is this enzyme a major organophosphate compound detoxifier, but it is also an important constituent of the cellular antioxidant system and has anti-inflammatory and antiatherogenic functions. The concentration and activity of PON1 is highly variable among individuals, and these differences can be both of genetic origin and be a subject of epigenetic regulation. Owing to the fact that, in recent decades, the exposure of humans to an increasing number of different xenobiotics has been continuously rising, the issues concerning the role and activity of PON1 shall be reconsidered with particular attention to growing pharmaceuticals intake, dietary habits and environmental awareness. In the following manuscript, the current state of knowledge concerning the influence of certain modifiable and unmodifiable factors, including smoking, alcohol intake, gender, age and genotype variation on PON1 activity, along with pathways through which these could interfere with the enzyme's protective functions, is presented and discussed. Since exposure to certain xenobiotics plays a key role in PON1 activity, the influence of organophosphates, heavy metals and several pharmaceutical agents is also specified.
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Affiliation(s)
| | | | - Marta Kepinska
- Department of Pharmaceutical Biochemistry, Division of Biomedical and Environmental Sciences, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50–556 Wrocław, Poland
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28
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Lambova SN. Pleiotropic Effects of Metformin in Osteoarthritis. Life (Basel) 2023; 13:life13020437. [PMID: 36836794 PMCID: PMC9960992 DOI: 10.3390/life13020437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/15/2023] [Accepted: 01/25/2023] [Indexed: 02/09/2023] Open
Abstract
The involvement of the knee joint is the most common localization of the pathological process in osteoarthritis (OA), which is associated with obesity in over 50% of the patients and is mediated by mechanical, inflammatory, and metabolic mechanisms. Obesity and the associated conditions (hyperglycemia, dyslipidemia, and hypertension) have been found to be risk factors for the development of knee OA, which has led to the emerging concept of the existence of a distinct phenotype, i.e., metabolic knee OA. Combined assessment of markers derived from dysfunctional adipose tissue, markers of bone and cartilage metabolism, as well as high-sensitivity inflammatory markers and imaging, might reveal prognostic signs for metabolic knee OA. Interestingly, it has been suggested that drugs used for the treatment of other components of the metabolic syndrome may also affect the clinical course and retard the progression of metabolic-associated knee OA. In this regard, significant amounts of new data are accumulating about the role of metformin-a drug, commonly used in clinical practice with suggested multiple pleiotropic effects. The aim of the current review is to analyze the current views about the potential pleiotropic effects of metformin in OA. Upon the analysis of the different effects of metformin, major mechanisms that might be involved in OA are the influence of inflammation, oxidative stress, autophagy, adipokine levels, and microbiome modulation. There is an increasing amount of evidence from in vitro studies, animal models, and clinical trials that metformin can slow OA progression by modulating inflammatory and metabolic factors that are summarized in the current up-to-date review. Considering the contemporary concept about the existence of metabolic type knee OA, in which the accompanying obesity and systemic low-grade inflammation are suggested to influence disease course, metformin could be considered as a useful and safe component of the personalized therapeutic approach in knee OA patients with accompanying type II diabetes or obesity.
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Affiliation(s)
- Sevdalina Nikolova Lambova
- Department of Propaedeutics of Internal Diseases “Prof Dr Anton Mitov”, Faculty of Medicine, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
- Department in Rheumatology, MHAT “Sveti Mina”, 4002 Plovdiv, Bulgaria
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29
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The Synergistic Action of Metformin and Glycyrrhiza uralensis Fischer Extract Alleviates Metabolic Disorders in Mice with Diet-Induced Obesity. Int J Mol Sci 2023; 24:ijms24020936. [PMID: 36674447 PMCID: PMC9862386 DOI: 10.3390/ijms24020936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/31/2022] [Accepted: 01/02/2023] [Indexed: 01/06/2023] Open
Abstract
Metformin, an antidiabetic drug, and Glycyrrhiza uralensis Fischer (GU), an oriental medicinal herb, have been reported to exert anti-obesity effects. This study investigated the synergistic action of metformin and GU in improving diet-induced obesity. Mice were fed a normal diet, a high-fat diet (HFD), or HFD + 0.015% GU water extract for 8 weeks. The HFD and GU groups were then randomly divided into two groups and fed the following diets for the next 8 weeks: HFD with 50 mg/kg metformin (HFDM) and GU with 50 mg/kg metformin (GUM). GUM prevented hepatic steatosis and adiposity by suppressing expression of mRNAs and enzyme activities related to lipogenesis in the liver and upregulating the expression of adipocyte mRNAs associated with fatty acid oxidation and lipolysis, and as a result, improved dyslipidemia. Moreover, GUM improved glucose homeostasis by inducing glucose uptake in tissues and upregulating mRNA expressions associated with glycolysis in the liver and muscle through AMP-activated protein kinase activation. GUM also improved inflammation by increasing antioxidant activity in the liver and erythrocytes and decreasing inflammatory cytokine productions. Here, we demonstrate that GU and metformin exert synergistic action in the prevention of obesity and its complications.
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30
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Durrington PN, Bashir B, Soran H. Paraoxonase 1 and atherosclerosis. Front Cardiovasc Med 2023; 10:1065967. [PMID: 36873390 PMCID: PMC9977831 DOI: 10.3389/fcvm.2023.1065967] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/30/2023] [Indexed: 02/18/2023] Open
Abstract
Paraoxonase 1 (PON1), residing almost exclusively on HDL, was discovered because of its hydrolytic activity towards organophosphates. Subsequently, it was also found to hydrolyse a wide range of substrates, including lactones and lipid hydroperoxides. PON1 is critical for the capacity of HDL to protect LDL and outer cell membranes against harmful oxidative modification, but this activity depends on its location within the hydrophobic lipid domains of HDL. It does not prevent conjugated diene formation, but directs lipid peroxidation products derived from these to become harmless carboxylic acids rather than aldehydes which might adduct to apolipoprotein B. Serum PON1 is inversely related to the incidence of new atherosclerotic cardiovascular disease (ASCVD) events, particularly in diabetes and established ASCVD. Its serum activity is frequently discordant with that of HDL cholesterol. PON1 activity is diminished in dyslipidaemia, diabetes, and inflammatory disease. Polymorphisms, most notably Q192R, can affect activity towards some substrates, but not towards phenyl acetate. Gene ablation or over-expression of human PON1 in rodent models is associated with increased and decreased atherosclerosis susceptibility respectively. PON1 antioxidant activity is enhanced by apolipoprotein AI and lecithin:cholesterol acyl transferase and diminished by apolipoprotein AII, serum amyloid A, and myeloperoxidase. PON1 loses this activity when separated from its lipid environment. Information about its structure has been obtained from water soluble mutants created by directed evolution. Such recombinant PON1 may, however, lose the capacity to hydrolyse non-polar substrates. Whilst nutrition and pre-existing lipid modifying drugs can influence PON1 activity there is a cogent need for more specific PON1-raising medication to be developed.
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Affiliation(s)
- Paul N Durrington
- Cardiovascular Research Group, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Bilal Bashir
- Cardiovascular Research Group, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.,Department of Diabetes, Endocrinology and Metabolism, Peter Mount Building, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Handrean Soran
- Cardiovascular Research Group, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.,Department of Diabetes, Endocrinology and Metabolism, Peter Mount Building, Manchester University NHS Foundation Trust, Manchester, United Kingdom
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Choice of Glucose-Lowering Drugs as Initial Monotherapy for Type 2 Diabetes Patients with Contraindications or Intolerance to Metformin: A Systematic Review and Meta-Analysis. J Clin Med 2022; 11:jcm11237094. [PMID: 36498669 PMCID: PMC9740076 DOI: 10.3390/jcm11237094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/24/2022] [Accepted: 11/27/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND There are multiple glucose-lowering drugs available as alternative initial monotherapy for type 2 diabetes patients with contraindications or intolerance to metformin. However, little comparative and systematic data are available for them as initial monotherapy. This study estimated and compared the treatment effects of glucose-lowering drugs as initial monotherapy for type 2 diabetes. METHODS PubMed, Web of Science, Embase, CNKI, Chongqing VIP, and WanFang Data from 1 January 1990 until 31 December 2020 were searched for randomized controlled trials which compared a glucose-lowering drug with placebo/lifestyle-intervention for type 2 diabetes. Drug classes included metformin, sulfonylureas (SUs), thiazolidinediones (TZDs), glinides (NIDEs), α-glucosidase inhibitors (AGIs), dipeptidyl peptidase-4 inhibitors (DPP-4is), sodium-glucose cotransporter-2 inhibitors (SGLT2is), insulins (INSs), and glucagon-like peptide-1 receptor agonists (GLP-1RAs). RESULTS A total of 185 trials were included, identifying 38,376 patients from 56 countries across six continents. When choosing an initial drug monotherapy alternative to metformin, SUs were most efficacious in reducing HbA1c (-1.39%; 95% CI -1.63, -1.16) and FPG (-2.70 mmol/L; 95% CI -3.18, -2.23), but increased hypoglycemia risks (5.44; 95% CI 2.11, 14.02). GLP-1RAs were most efficacious in reducing BMI (-1.05 kg/m2; 95% CI -1.81, -0.29) and TC (-0.42 mmol/L; 95% CI -0.61, -0.22). TZDs were most efficacious in increasing HDL-C (0.12 mmol/L; 95% CI 0.07, 0.17). SGLT2is were most efficacious in lowering SBP (-4.18 mmHg; 95% CI -4.84, -3.53). While AGIs conferred higher risk of AE-induced discontinuations (2.57; 95% CI 1.64, 4.03). Overall, only GLP-1RAs showed an integrated beneficial effect on all outcomes. Our results also confirmed the intraclass differences in treatment effects across drugs. Most trials were short-term, and no significant differences in mortality, total vascular events, myocardial infarction, heart failure, stroke, or diabetic nephropathy were observed across drug classes. CONCLUSIONS Our results suggest a potential treatment hierarchy for decision-makers, with GLP-1RAs being the preferred alternative therapy to metformin regarding their favorable efficacy and safety profiles.
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Frasca D, Diaz A, Romero M, Blomberg BB. Metformin Enhances B Cell Function and Antibody Responses of Elderly Individuals With Type-2 Diabetes Mellitus. FRONTIERS IN AGING 2022; 2:715981. [PMID: 35822013 PMCID: PMC9261392 DOI: 10.3389/fragi.2021.715981] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 07/12/2021] [Indexed: 12/22/2022]
Abstract
Our previous work has shown that young and elderly patients with Type-2 Diabetes Mellitus (T2DM) treated with Metformin have optimal B cell function and serum antibodies specific for the seasonal influenza vaccine. In this paper, we have evaluated B cell function and the metabolic requirements of B cell antibody responses in elderly T2DM patients (ET2DM) taking or not Metformin, and compared to those of healthy elderly (EH) and healthy young (YH) individuals. Results show that Metformin significantly increases in vivo B cell function, measured by influenza vaccine-specific serum antibodies, in ET2DM patients to the levels observed in EH and more importantly in YH individuals. Metformin also decreases the frequencies of pro-inflammatory B cell subsets, as well as intrinsic inflammation and metabolic requirements of peripheral B cells from ET2DM. This hyper-metabolic phenotype of B cells from ET2DM is needed to support intrinsic inflammation, measured by the expression of transcripts for markers of the senescence-associated secretory phenotype (SASP), and the secretion of autoimmune antibodies. Importantly, B cell function in ET2DM patients taking Metformin is not only increased as compared to that in ET2DM patients not taking Metformin, but is comparable to B cell function measured in YH individuals. These results altogether strongly support the anti-aging effects of Metformin on humoral immunity.
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Affiliation(s)
- Daniela Frasca
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States.,Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Alain Diaz
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Maria Romero
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Bonnie B Blomberg
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States.,Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, United States
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33
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Rempuia V, Anima B, Jeremy M, Gurusubramanian G, Pankaj PP, Kharwar RK, Roy VK. Effects of metformin on the uterus of d-galactose-induced aging mice: Histomorphometric, immunohistochemical localization (B-cell lymphoma 2, Bcl2-associated X protein, and active capase3), and oxidative stress study. JOURNAL OF EXPERIMENTAL ZOOLOGY. PART A, ECOLOGICAL AND INTEGRATIVE PHYSIOLOGY 2022; 337:600-611. [PMID: 35286779 DOI: 10.1002/jez.2592] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 02/18/2022] [Accepted: 02/23/2022] [Indexed: 06/14/2023]
Abstract
d-galactose (DG)-induced rodent aging model has widely been used for the study of age-related dysfunctions of various organs, including gonads and uterus. Antidiabetic drug metformin has gained an attention as antiaging drug in model organism and human but its effect on uterus has not been studied in relation to induced aging. Therefore, we investigated the effect of metformin on uterus of DG-induced aging mice model. Mice were randomly divided into three groups, that is, control (CN), DG-induced aging model and aging model treated with metformin. Histomorphometric results showed significantly decreased number of uterine glands, endometrial thickness, and increased luminal epithelium height in aging model. Furthermore, metformin resumed the number of uterine glands, endometrial thickness, and luminal epithelium height up to CN group. Metformin has also significantly decreased the age-associated oxidative stress (malondialdehyde and lipid hydroperoxide). Superoxide dismutase was significantly decreased in both treated groups compared to the CN group. However, catalase and glutathione peroxidase enzymes were significantly increased by metformin compared to the aging model. Immunostaining of active caspase3 and BAX were intense in the endometrium of aging model compare to CN- and metformin-treated groups. Localization of B-cell lymphoma 2 (Bcl2) showed intense immunostaining in the uterus of CN- and metformin-treated groups, with mild immunostaining in aging model. Our observations suggested that metformin treatment might be helpful for management of age-associated uterine dysfunctions. Moreover, it may be concluded that metformin might ameliorate uterine dysfunctions by reducing oxidative stress, suppressing apoptosis, and increasing the survival/antiapoptotic protein Bcl2.
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Affiliation(s)
- Vanlal Rempuia
- Department of Zoology, Mizoram University, Aizawl, Mizoram, India
| | - Borgohain Anima
- Department of Zoology, Mizoram University, Aizawl, Mizoram, India
| | | | | | - Pranay P Pankaj
- Department of Zoology, Nagaland University, Lumami, Nagaland, India
| | - Rajesh K Kharwar
- Department of Zoology, Kutir Post Graduate College, Chakkey, Jaunpur, India
| | - Vikas K Roy
- Department of Zoology, Mizoram University, Aizawl, Mizoram, India
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Association of Metformin Use During Hospitalization and Mortality in Critically Ill Adults With Type 2 Diabetes Mellitus and Sepsis. Crit Care Med 2022; 50:935-944. [PMID: 35120041 DOI: 10.1097/ccm.0000000000005468] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
OBJECTIVES Whether metformin exposure is associated with improved outcomes in patients with type 2 diabetes mellitus and sepsis. DESIGN Retrospective cohort study. SETTING Patients admitted to ICUs in 16 hospitals in Pennsylvania from October 2008 to December 2014. PATIENTS Adult critical ill patients with type 2 diabetes mellitus and sepsis. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We conducted a retrospective cohort study to compare 90-day mortality in diabetic patients with sepsis with and without exposure to metformin during hospitalization. Data were obtained from the electronic health record of a large healthcare system in Pennsylvania from October 2008 to December 2014, on patients admitted to the ICU at any of the 16 hospitals within the system. The primary outcome was mortality at 90 days. The absolute and adjusted odds ratio (OR) with 95% CI were calculated in a propensity score-matched cohort. Among 14,847 patients with type 2 diabetes mellitus and sepsis, 682 patients (4.6%) were exposed to metformin during hospitalization and 14,165 (95.4%) were not. Within a total of 2,691 patients subjected to propensity score-matching at a 1:4 ratio, exposure to metformin (n = 599) was associated with decreased 90-day mortality (71/599, 11.9% vs 475/2,092, 22.7%; OR, 0.46; 95% CI, 0.35-0.60), reduced severe acute kidney injury (50% vs 57%; OR, 0.75; 95% CI, 0.62-0.90), less Major Adverse Kidney Events at 1 year (OR, 0.27; 95% CI, 0.22-0.68), and increased renal recovery (95% vs 86%; OR, 6.43; 95% CI, 3.42-12.1). CONCLUSIONS Metformin exposure during hospitalization is associated with a decrease in 90-day mortality in patients with type 2 diabetes mellitus and sepsis.
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Schmitz K, Turnwald EM, Kretschmer T, Janoschek R, Bae-Gartz I, Voßbrecher K, Kammerer MD, Köninger A, Gellhaus A, Handwerk M, Wohlfarth M, Gründemann D, Hucklenbruch-Rother E, Dötsch J, Appel S. Metformin Prevents Key Mechanisms of Obesity-Related Complications in Visceral White Adipose Tissue of Obese Pregnant Mice. Nutrients 2022; 14:nu14112288. [PMID: 35684088 PMCID: PMC9182976 DOI: 10.3390/nu14112288] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 12/13/2022] Open
Abstract
With the gaining prevalence of obesity, related risks during pregnancy are rising. Inflammation and oxidative stress are considered key mechanisms arising in white adipose tissue (WAT) sparking obesity-associated complications and diseases. The established anti-diabetic drug metformin reduces both on a systemic level, but only little is known about such effects on WAT. Because inhibiting these mechanisms in WAT might prevent obesity-related adverse effects, we investigated metformin treatment during pregnancy using a mouse model of diet-induced maternal obesity. After mating, obese mice were randomised to metformin administration. On gestational day G15.5, phenotypic data were collected and perigonadal WAT (pgWAT) morphology and proteome were examined. Metformin treatment reduced weight gain and visceral fat accumulation. We detected downregulation of perilipin-1 as a correlate and observed indications of recovering respiratory capacity and adipocyte metabolism under metformin treatment. By regulating four newly discovered potential adipokines (alpha-1 antitrypsin, Apoa4, Lrg1 and Selenbp1), metformin could mediate anti-diabetic, anti-inflammatory and oxidative stress-modulating effects on local and systemic levels. Our study provides an insight into obesity-specific proteome alterations and shows novel modulating effects of metformin in pgWAT of obese dams. Accordingly, metformin therapy appears suitable to prevent some of obesity’s key mechanisms in WAT.
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Affiliation(s)
- Katrin Schmitz
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Eva-Maria Turnwald
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Tobias Kretschmer
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
- UFZ-Helmholtz Centre for Environmental Research, Department Environmental Immunology, Permoserstraße 15, 04318 Leipzig, Germany
| | - Ruth Janoschek
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Inga Bae-Gartz
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Kathrin Voßbrecher
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Merlin D. Kammerer
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Angela Köninger
- Department of Obstetrics and Gynecology, University of Regensburg, St. Hedwigs Clinic of the Order of St. John, Steinmetzstrasse 1-3, 93049 Regensburg, Germany;
| | - Alexandra Gellhaus
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany;
| | - Marion Handwerk
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Maria Wohlfarth
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Dirk Gründemann
- Department of Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Gleueler Straße 24, 50931 Cologne, Germany;
| | - Eva Hucklenbruch-Rother
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Jörg Dötsch
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
| | - Sarah Appel
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 16, 50931 Cologne, Germany; (K.S.); (E.-M.T.); (T.K.); (R.J.); (I.B.-G.); (K.V.); (M.D.K.); (M.H.); (M.W.); (E.H.-R.); (J.D.)
- Correspondence: ; Tel.: +49-221-478-96890
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Schernthaner G, Brand K, Bailey CJ. Metformin and the heart: Update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure. Metabolism 2022; 130:155160. [PMID: 35143848 DOI: 10.1016/j.metabol.2022.155160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 01/05/2022] [Accepted: 02/03/2022] [Indexed: 12/15/2022]
Abstract
Metformin has been in clinical use for the management of type 2 diabetes for more than 60 years and is supported by a vast database of clinical experience: this includes evidence for cardioprotection from randomised trials and real-world studies. Recently, the position of metformin as first choice glucose-lowering agent has been supplanted to some extent by the emergence of newer classes of antidiabetic therapy, namely the sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. These agents have benefitted through support from large cardiovascular outcomes trials with more modern trial designs than earlier studies conducted to assess metformin. Nevertheless, clinical research on metformin continues to further assess its many potentially advantageous effects. Here, we review the evidence for improved cardiovascular outcomes with metformin in the context of the current era of diabetes outcomes trials. Focus is directed towards the potentially cardioprotective actions of metformin in patients with type 2 diabetes and heart failure (HF), now recognised as the most common complication of diabetes.
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Jura-Półtorak A, Olczyk P, Chałas-Lipka A, Komosińska-Vassev K, Kuźnik-Trocha K, Winsz-Szczotka K, Ivanova D, Kiselova-Kaneva Y, Krysik K, Telega A, Olczyk K. Urinary sulphated glycosaminoglycans excretion in obese patients with type 2 diabetes mellitus treated with metformin. Arch Physiol Biochem 2022; 128:507-513. [PMID: 31815550 DOI: 10.1080/13813455.2019.1697889] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
OBJECTIVE The pattern of urinary excretion of total sulphated glycosaminoglycans (GAGs) and their particular types: chondroitin sulphate/dermatan sulphate (CS/DS) and heparan sulphate (HS) was analysed in obese patients with type 2 diabetes mellitus (T2DM) treated with metformin in monotherapy for the period of six months. METHODS The urinary sulphated glycosaminoglycans were quantitated using standardised dye (1.9-dimethylmethylene blue)-binding method and normalised to creatinine level. RESULTS Urinary total GAGs, CS/DS and HS levels were significantly higher in untreated diabetic patients in comparison to healthy subjects. Moreover, it was observed that urinary total GAGs, CS/DS and HS levels in diabetic patients after six-month metformin therapy were significantly decreased versus pre-treatment situation. CONCLUSIONS The obtained results suggest that the six-month treatment with metformin in obese patients with T2DM has a regulating influence on the systemic changes in proteoglycans/glycosaminoglycans, resulting in a decrease in the urinary excretion of total GAGs, CS/DS and HS.
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Affiliation(s)
- Agnieszka Jura-Półtorak
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Poland
| | - Paweł Olczyk
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Poland
| | - Aleksandra Chałas-Lipka
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Poland
| | - Katarzyna Komosińska-Vassev
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Poland
| | - Kornelia Kuźnik-Trocha
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Poland
| | - Katarzyna Winsz-Szczotka
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Poland
| | - Diana Ivanova
- Department of Biochemistry, Molecular Medicine and Nutrigenomics, The Faculty of Pharmacy, Medical University Varna, Varna, Bulgaria
| | - Yoana Kiselova-Kaneva
- Department of Biochemistry, Molecular Medicine and Nutrigenomics, The Faculty of Pharmacy, Medical University Varna, Varna, Bulgaria
| | - Katarzyna Krysik
- Department of Ophthalmology with Paediatric Unit, St. Barbara Hospital, Trauma Center, Sosnowiec, Poland
| | - Alicja Telega
- The Diabetes Outpatient Clinic, Non-public Health Care Unit, Jaworzno, Poland
| | - Krystyna Olczyk
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Poland
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Short-Term Treatment of Metformin and Glipizide on Oxidative Stress, Lipid Profile and Renal Function in a Rat Model with Diabetes Mellitus. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12042019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Background: Oxidative stress, lipid profile and renal functions are well-known conventional risk factors for diabetes mellitus (DM). Metformin and gliclazide are popularly used monotherapy drugs for the treatment of DM. Aims: This study aims to assess the short-term treatment of single and dual therapy of glipizide/metformin on oxidative stress, glycemic control, serum lipid profiles and renal function in diabetic rats. Methods: DM was induced in rats with streptozotocin (STZ), then five different treatments were applied, including group I (untreated healthy control), group II (diabetic and untreated), group III (diabetic and treated with metformin), group IVI (diabetic and treated with glipizide) and group V (diabetic and treated with a combination of metformin and glipizide. Lipid peroxidation (LPO), nitric oxide (NO), total antioxidant capacity (TAC), fasting blood glucose (FBG), glycated hemoglobin (HbA1c), total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), creatinine and urea were measured. Results: Compared to the untreated DM group, FBG and HbA1c were significantly reduced in the DM groups (p < 0.01) treated with metformin (159.7 mg/dL & 6.7%), glipizide (184.3 mg/dL & 7.3%) and dual therapy (118 mg/dL & 5.2%), respectively. Treatment with dual therapy and metformin significantly decreased LPO and NO levels but increased TAC in diabetic rats more than glipizide compared to untreated diabetic rats. Furthermore, metformin (19.8 mg/dL, p < 0.001), glipizide (22.7 mg/dL, p < 0.001), and dual therapy (25.7 mg/dL, p < 0.001) significantly decreased urea levels in the treated rats compared to untreated DM rats (32.2 mg/dL). Both drugs and their combination exhibited a substantial effect on total cholesterol, HDL, LDL and atherogenic index. Conclusions: These results suggest that the therapeutic benefits of metformin and glipizide are complementary. Metformin exhibited superior performance in improving glycemic control and decreasing oxidative stress, while glipizide was more effective against dyslipidemia. These findings could be helpful for the treatment of future vascular patients, antilipidemic medicines and antioxidant therapy to improve the quality of life.
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Clark GJ, Pandya K, Lau-Cam CA. Assessment of In Vitro Tests as Predictors of the Antioxidant Effects of Insulin, Metformin, and Taurine in the Brain of Diabetic Rats. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1370:243-256. [DOI: 10.1007/978-3-030-93337-1_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Lin KJ, Wang TJ, Chen SD, Lin KL, Liou CW, Lan MY, Chuang YC, Chuang JH, Wang PW, Lee JJ, Wang FS, Lin HY, Lin TK. Two Birds One Stone: The Neuroprotective Effect of Antidiabetic Agents on Parkinson Disease-Focus on Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors. Antioxidants (Basel) 2021; 10:antiox10121935. [PMID: 34943038 PMCID: PMC8750793 DOI: 10.3390/antiox10121935] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 11/25/2021] [Accepted: 11/29/2021] [Indexed: 12/13/2022] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease affecting more than 1% of the population over 65 years old. The etiology of the disease is unknown and there are only symptomatic managements available with no known disease-modifying treatment. Aging, genes, and environmental factors contribute to PD development and key players involved in the pathophysiology of the disease include oxidative stress, mitochondrial dysfunction, autophagic-lysosomal imbalance, and neuroinflammation. Recent epidemiology studies have shown that type-2 diabetes (T2DM) not only increased the risk for PD, but also is associated with PD clinical severity. A higher rate of insulin resistance has been reported in PD patients and is suggested to be a pathologic driver in this disease. Oral diabetic drugs including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to provide neuroprotective effects in both PD patients and experimental models; additionally, antidiabetic drugs have been demonstrated to lower incidence rates of PD in DM patients. Among these, the most recently developed drugs, SGLT2 inhibitors may provide neuroprotective effects through improving mitochondrial function and antioxidative effects. In this article, we will discuss the involvement of mitochondrial-related oxidative stress in the development of PD and potential benefits provided by antidiabetic agents especially focusing on sglt2 inhibitors.
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Affiliation(s)
- Kai-Jung Lin
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Department of Family Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan
| | - Tzu-Jou Wang
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Department of Pediatric, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Shang-Der Chen
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Kai-Lieh Lin
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Chia-Wei Liou
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Min-Yu Lan
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Yao-Chung Chuang
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Jiin-Haur Chuang
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Department of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Pei-Wen Wang
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Department of Metabolism, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Jong-Jer Lee
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Feng-Sheng Wang
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Hung-Yu Lin
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Research Assistant Center, Show Chwan Memorial Hospital, Changhua 500, Taiwan
| | - Tsu-Kung Lin
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
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Corica D, Pepe G, Currò M, Aversa T, Tropeano A, Ientile R, Wasniewska M. Methods to investigate advanced glycation end-product and their application in clinical practice. Methods 2021; 203:90-102. [DOI: 10.1016/j.ymeth.2021.12.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 12/01/2021] [Accepted: 12/16/2021] [Indexed: 12/15/2022] Open
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NETosis in ischemic/reperfusion injuries: An organ-based review. Life Sci 2021; 290:120158. [PMID: 34822798 DOI: 10.1016/j.lfs.2021.120158] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/11/2021] [Accepted: 11/13/2021] [Indexed: 10/19/2022]
Abstract
Neutrophil extracellular trap (NETosis), the web-like structures induced by neutrophil death, is an important inflammatory mechanism of the immune system leading to reactive oxygen species production/coagulopathy, endothelial dysfunction, atherosclerosis, and ischemia. NETosis exerts its role through different mechanisms such as triggering Toll-like receptors, inflammatory cytokines, platelet aggregation, neutrophil activation/infiltration, and vascular impairment. NETosis plays a key role in the prognosis of coronary artery disease, ischemic injury of kidney, lung, gastrointestinal tract and skeletal muscles. In this review, we explored the molecular mechanisms involved in NETosis, and ischemic/reperfusion injuries in body organs.
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Leisegang K, Roychoudhury S, Slama P, Finelli R. The Mechanisms and Management of Age-Related Oxidative Stress in Male Hypogonadism Associated with Non-communicable Chronic Disease. Antioxidants (Basel) 2021; 10:1834. [PMID: 34829704 PMCID: PMC8615233 DOI: 10.3390/antiox10111834] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 12/24/2022] Open
Abstract
Androgens have diverse functions in muscle physiology, lean body mass, the regulation of adipose tissue, bone density, neurocognitive regulation, and spermatogenesis, the male reproductive and sexual function. Male hypogonadism, characterized by reduced testosterone, is commonly seen in ageing males, and has a complex relationship as a risk factor and a comorbidity in age-related noncommunicable chronic diseases (NCDs), such as obesity, metabolic syndrome, type 2 diabetes, and malignancy. Oxidative stress, as a significant contributor to the ageing process, is a common feature between ageing and NCDs, and the related comorbidities, including hypertension, dyslipidemia, hyperglycemia, hyperinsulinemia, and chronic inflammation. Oxidative stress may also be a mediator of hypogonadism in males. Consequently, the management of oxidative stress may represent a novel therapeutic approach in this context. Therefore, this narrative review aims to discuss the mechanisms of age-related oxidative stress in male hypogonadism associated with NCDs and discusses current and potential approaches for the clinical management of these patients, which may include conventional hormone replacement therapy, nutrition and lifestyle changes, adherence to the optimal body mass index, and dietary antioxidant supplementation and/or phytomedicines.
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Affiliation(s)
- Kristian Leisegang
- School of Natural Medicine, Faculty of Community and Health Sciences, Bellville, Cape Town 7535, South Africa
| | | | - Petr Slama
- Department of Animal Morphology, Physiology and Genetics, Faculty of AgriSciences, Mendel University in Brno, 61300 Brno, Czech Republic
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Mohan M, Dihoum A, Mordi IR, Choy AM, Rena G, Lang CC. Left Ventricular Hypertrophy in Diabetic Cardiomyopathy: A Target for Intervention. Front Cardiovasc Med 2021; 8:746382. [PMID: 34660744 PMCID: PMC8513785 DOI: 10.3389/fcvm.2021.746382] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/02/2021] [Indexed: 12/12/2022] Open
Abstract
Heart failure is an important manifestation of diabetic heart disease. Before the development of symptomatic heart failure, as much as 50% of patients with type 2 diabetes mellitus (T2DM) develop asymptomatic left ventricular dysfunction including left ventricular hypertrophy (LVH). Left ventricular hypertrophy (LVH) is highly prevalent in patients with T2DM and is a strong predictor of adverse cardiovascular outcomes including heart failure. Importantly regression of LVH with antihypertensive treatment especially renin angiotensin system blockers reduces cardiovascular morbidity and mortality. However, this approach is only partially effective since LVH persists in 20% of patients with hypertension who attain target blood pressure, implicating the role of other potential mechanisms in the development of LVH. Moreover, the pathophysiology of LVH in T2DM remains unclear and is not fully explained by the hyperglycemia-associated cellular alterations. There is a growing body of evidence that supports the role of inflammation, oxidative stress, AMP-activated kinase (AMPK) and insulin resistance in mediating the development of LVH. The recognition of asymptomatic LVH may offer an opportune target for intervention with cardio-protective therapy in these at-risk patients. In this article, we provide a review of some of the key clinical studies that evaluated the effects of allopurinol, SGLT2 inhibitor and metformin in regressing LVH in patients with and without T2DM.
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Affiliation(s)
- Mohapradeep Mohan
- Division of Mental Health and Wellbeing, Warwick Medical School, University of Warwick, Coventry, United Kingdom.,Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom
| | - Adel Dihoum
- Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom
| | - Ify R Mordi
- Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom
| | - Anna-Maria Choy
- Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom
| | - Graham Rena
- Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom
| | - Chim C Lang
- Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom.,UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Tu WJ, Zeng Q, Wang K, Wang Y, Sun BL, Zeng X, Liu Q. Prestroke Metformin Use on the 1-Year Prognosis of Intracerebral Hemorrhage Patients with Type 2 Diabetes. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:2027359. [PMID: 34567407 PMCID: PMC8457962 DOI: 10.1155/2021/2027359] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 07/29/2021] [Accepted: 08/16/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Although recent studies have focused on the use of metformin in treating ischemic stroke, there is little literature to support whether it can treat intracerebral hemorrhage (ICH). Therefore, this study is aimed at evaluating the possible effects of prestroke metformin (MET) on ICH patients with type 2 diabetes. METHODS From January 2010 to December 2019, all first-ever ICH patients with type 2 diabetes from our hospitals were included. All discharged patients would receive a one-time follow-up at 1 year after admission. Death, disability, and recurrence events were recorded. RESULTS We included 730 patients for analysis (the median age: 65 [IQR, 56-72] years and 57.7% was men). Of those patients, 281 (38.5%) had received MET before ICH (MET+), whereas 449 (61.5%) had not (MET-). MET (+) patients had a lower median baseline hematoma volume than did MET (-) patients (9.6 ml [IQR, 5.3-22.4 ml] vs. 14.7 ml [IQR, 7.9-28.6 ml]; P < 0.001). The inhospital mortality events were not significantly reduced in the MET (+) group compared with the MET (-) group (6.4% vs 8.9%, respectively; absolute difference, -2.5% [95% CI, -3.9% to -0.7%]; OR, 0.70 [95% CI, 0.39 to 1.27]; P = 0.22). The 1-year mortality events were not significantly reduced in the MET (+) group compared with the MET (-) group (14.1% vs 17.4%, respectively; absolute difference, -3.3% [95% CI, -5.1% to -1.8%]; OR, 0.73 [95% CI, 0.47 to 1.14]; P = 0.16). The 1-year disability events were not significantly reduced in the MET (+) group compared with the MET (-) group (28.4% vs 34.1%, respectively; absolute difference, -5.7% [95% CI, -8.2% to -3.3%]; OR, 0.77 [95% CI, 0.52 to 1.13]; P = 0.18). Finally, the recurrence rates in those two groups were not significantly different (MET [+] vs. MET [-]: 6.4% vs. 5.9%; absolute difference, 0.5% [95% CI, 0.2% to 1.3%]; OR, 1.08 [95% CI, 0.51 to 2.28]; P = 0.84). CONCLUSIONS Pre-ICH metformin use was not associated with inhospital mortality and 1-year prognosis in diabetic ICH patients.
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Affiliation(s)
- Wen-Jun Tu
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Qingjia Zeng
- School of Healthcare Science, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester M156GX, UK
| | - Kai Wang
- Department of Neurology, Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Yu Wang
- Department of Endocrinology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Bao-Liang Sun
- Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Xianwei Zeng
- Rehabilitation Hospital of the National Research Center for Rehabilitation Technical Aids, Beijing, China
- Department of Neurosurgery, Shandong University Qilu Hospital, Jinan, China
- People's Hospital of Ningjin County, Dezhou, China
| | - Qiang Liu
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
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Histological investigation of the protective effect of metformin on testis and sperm parameters in obese rats with type 2 diabetes mellitus. JOURNAL OF SURGERY AND MEDICINE 2021. [DOI: 10.28982/josam.956929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Ommati MM, Mohammadi H, Mousavi K, Azarpira N, Farshad O, Dehghani R, Najibi A, Kamran S, Niknahad H, Heidari R. Metformin alleviates cholestasis-associated nephropathy through regulating oxidative stress and mitochondrial function. LIVER RESEARCH 2021; 5:171-180. [PMID: 39957842 PMCID: PMC11791814 DOI: 10.1016/j.livres.2020.12.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 10/01/2020] [Accepted: 12/07/2020] [Indexed: 12/11/2022]
Abstract
Background and aim Cholestasis-associated renal injury or cholemic nephropathy (CN) is a serious clinical problem. Previous studies mentioned that oxidative stress and mitochondrial impairment play a role in CN. There is no specific pharmacological intervention for CN. Metformin is an anti-diabetic drug administered for decades. On the other hand, novel pharmacological properties have emerged for this drug. The effect of metformin on oxidative stress parameters has been well-recognized in different experimental models. It has also been found that metformin positively affected mitochondrial function. The current study aimed to evaluate the effects of metformin in an animal model of CN. Methods Rats underwent bile duct ligation (BDL) and were treated with metformin (250 and 500 mg/kg) for 14 consecutive days. Two weeks after the BDL operations, urine, serum, and kidney samples were collected and analyzed. Results Markers of oxidative stress, including reactive oxygen species (ROS) formation, lipid peroxidation, protein carbonylation, depleted antioxidant capacity, and decreased glutathione (GSH) levels were detected in BDL animals. Moreover, mitochondrial indices, including adenosine triphosphate (ATP) level, dehydrogenase activity, mitochondrial membrane potential, and mitochondrial permeability, were impaired in the kidney of cholestatic rats. Renal histopathological alterations in cholestatic animals included tubular degeneration and interstitial inflammation, cast formation, and fibrosis. It was found that metformin significantly alleviated oxidative stress and improved mitochondrial indices in the kidney of cholestatic rats. Tissue histopathological alterations were also mitigated in metformin-treated groups. Conclusions Metformin could be a candidate for managing CN. The nephroprotective role of metformin is primarily associated with its effects on oxidative stress parameters and mitochondrial function.
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Affiliation(s)
| | - Hamidreza Mohammadi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Khadijeh Mousavi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Omid Farshad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reyhaneh Dehghani
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Asma Najibi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Chemistry, Payame Noor University, Tehran, Iran
| | - Sedigheh Kamran
- Department of Chemistry, Payame Noor University, Tehran, Iran
| | - Hossein Niknahad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Nelson MAM, Efird JT, Kew KA, Katunga LA, Monroe TB, Doorn JA, Beatty CN, Shi Q, Akhter SA, Alwair H, Robidoux J, Anderson EJ. Enhanced Catecholamine Flux and Impaired Carbonyl Metabolism Disrupt Cardiac Mitochondrial Oxidative Phosphorylation in Diabetes Patients. Antioxid Redox Signal 2021; 35:235-251. [PMID: 33066717 PMCID: PMC8262387 DOI: 10.1089/ars.2020.8122] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Aims: Catecholamine metabolism via monoamine oxidase (MAO) contributes to cardiac injury in models of ischemia and diabetes, but the pathogenic mechanisms involved are unclear. MAO deaminates norepinephrine (NE) and dopamine to produce H2O2 and highly reactive "catecholaldehydes," which may be toxic to mitochondria due to the localization of MAO to the outer mitochondrial membrane. We performed a comprehensive analysis of catecholamine metabolism and its impact on mitochondrial energetics in atrial myocardium obtained from patients with and without type 2 diabetes. Results: Content and maximal activity of MAO-A and MAO-B were higher in the myocardium of patients with diabetes and they were associated with body mass index. Metabolomic analysis of atrial tissue from these patients showed decreased catecholamine levels in the myocardium, supporting an increased flux through MAOs. Catecholaldehyde-modified protein adducts were more abundant in myocardial tissue extracts from patients with diabetes and were confirmed to be MAO dependent. NE treatment suppressed mitochondrial ATP production in permeabilized myofibers from patients with diabetes in an MAO-dependent manner. Aldehyde dehydrogenase (ALDH) activity was substantially decreased in atrial myocardium from these patients, and metabolomics confirmed lower levels of ALDH-catalyzed catecholamine metabolites. Proteomic analysis of catechol-modified proteins in isolated cardiac mitochondria from these patients identified >300 mitochondrial proteins to be potential targets of these unique carbonyls. Innovation and Conclusion: These findings illustrate a unique form of carbonyl toxicity driven by MAO-mediated metabolism of catecholamines, and they reveal pathogenic factors underlying cardiometabolic disease. Importantly, they suggest that pharmacotherapies targeting aldehyde stress and catecholamine metabolism in heart may be beneficial in patients with diabetes and cardiac disease. Antioxid. Redox Signal. 35, 235-251.
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Affiliation(s)
- Margaret-Ann M Nelson
- Department of Pharmacology & Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA
| | - Jimmy T Efird
- Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, Australia
| | - Kimberly A Kew
- Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA
| | - Lalage A Katunga
- Department of Pharmacology & Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA
| | - T Blake Monroe
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa, USA
| | - Jonathan A Doorn
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa, USA
| | - Cherese N Beatty
- Department of Pharmacology & Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA
| | - Qian Shi
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Shahab A Akhter
- Department of Cardiovascular Sciences, Brody School of Medicine, East Carolina Heart Institute, Greenville, North Carolina, USA
| | - Hazaim Alwair
- Department of Cardiovascular Sciences, Brody School of Medicine, East Carolina Heart Institute, Greenville, North Carolina, USA
| | - Jacques Robidoux
- Department of Pharmacology & Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA
| | - Ethan J Anderson
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa, USA.,Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA
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Advanced Glycation End Products: New Clinical and Molecular Perspectives. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18147236. [PMID: 34299683 PMCID: PMC8306599 DOI: 10.3390/ijerph18147236] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/30/2021] [Accepted: 07/03/2021] [Indexed: 12/17/2022]
Abstract
Diabetes mellitus (DM) is considered one of the most massive epidemics of the twenty-first century due to its high mortality rates caused mainly due to its complications; therefore, the early identification of such complications becomes a race against time to establish a prompt diagnosis. The research of complications of DM over the years has allowed the development of numerous alternatives for diagnosis. Among these emerge the quantification of advanced glycation end products (AGEs) given their increased levels due to chronic hyperglycemia, while also being related to the induction of different stress-associated cellular responses and proinflammatory mechanisms involved in the progression of chronic complications of DM. Additionally, the investigation for more valuable and safe techniques has led to developing a newer, noninvasive, and effective tool, termed skin fluorescence (SAF). Hence, this study aimed to establish an update about the molecular mechanisms induced by AGEs during the evolution of chronic complications of DM and describe the newer measurement techniques available, highlighting SAF as a possible tool to measure the risk of developing DM chronic complications.
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Modaghegh MHS, Saberianpour S, Amoueian S, Shahri JJ, Rahimi H. The effect of redox signaling on extracellular matrix changes in diabetic wounds leading to amputation. Biochem Biophys Rep 2021; 26:101025. [PMID: 34095552 PMCID: PMC8166643 DOI: 10.1016/j.bbrep.2021.101025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/30/2021] [Accepted: 05/12/2021] [Indexed: 01/09/2023] Open
Abstract
INTRODUCTION & Objectives: Redox signaling is a critical regulator in the process of wound healing. This signaling pathway can be effective in the development or healing of diabetic ulcers through the ECM.In this study, the structure of extracellular matrix investigated in relation to redox signaling in the tissue of patients with diabetic ulcers that lead to organ amputation. MATERIALS AND METHODS The case-control design on diabetic patients ulcers as case group and non-diabetic limb ischemia as control were used.Hematoxylin-eosin, trichrome, and elastin staining methods were used for pathological evaluations of ECM. MDA, total thiol, and SOD levels were measured using ELISA kits to assess the oxidative stress level. Also, NO level was measured by using ELISA kits in both groups. Expression levels of genes MMP2, MMP9, and HIF were detected using real-time PCR with SYBR-green assay. RESULTS The pathological results showed an increase in the thickness of collagen and elastin fibers. Lipids atrophy was visible in the tissue isolated from the diabetic wound group. The amount of MAD to evaluate the level of lipid oxidation in patients with diabetic Ulcer was significantly higher than the control group(p < 0.01). Thiol level was significantly lower in the diabetic ulcer group than in the control group(p < 0.0001). The expression of metalloproteinases 2 and 9 genes in the tissues isolated from diabetic ulcers was lower than the control group(p < 0.0001). While the expression of the HIF gene in this group was higher than the control group(p < 0.0001). CONCLUTION In the diabetic wound, the HIF secretion due to hypoxic conditions is beneficial for matrix deposition and prevents protease activity, but if the hypoxia persists, it can lead to ECM deposition subsequently increases the tissue pressure, increases of the collagen I-to-collagen III ratio in collagen accumulation that due to more hypoxia , lipidsAtrophy and eventually amputation.
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Affiliation(s)
| | - Shirin Saberianpour
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sakineh Amoueian
- Departement of Pathology, Emam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Jamal Jalili Shahri
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamidreza Rahimi
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Departement of Medical Genetics and Molecular Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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