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Moawad MHED, Serag I, Alkhawaldeh IM, Abbas A, Sharaf A, Alsalah S, Sadeq MA, Shalaby MMM, Hefnawy MT, Abouzid M, Meshref M. Exploring the Mechanisms and Therapeutic Approaches of Mitochondrial Dysfunction in Alzheimer's Disease: An Educational Literature Review. Mol Neurobiol 2025; 62:6785-6810. [PMID: 39254911 PMCID: PMC12078384 DOI: 10.1007/s12035-024-04468-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 08/30/2024] [Indexed: 09/11/2024]
Abstract
Alzheimer's disease (AD) presents a significant challenge to global health. It is characterized by progressive cognitive deterioration and increased rates of morbidity and mortality among older adults. Among the various pathophysiologies of AD, mitochondrial dysfunction, encompassing conditions such as increased reactive oxygen production, dysregulated calcium homeostasis, and impaired mitochondrial dynamics, plays a pivotal role. This review comprehensively investigates the mechanisms of mitochondrial dysfunction in AD, focusing on aspects such as glucose metabolism impairment, mitochondrial bioenergetics, calcium signaling, protein tau and amyloid-beta-associated synapse dysfunction, mitophagy, aging, inflammation, mitochondrial DNA, mitochondria-localized microRNAs, genetics, hormones, and the electron transport chain and Krebs cycle. While lecanemab is the only FDA-approved medication to treat AD, we explore various therapeutic modalities for mitigating mitochondrial dysfunction in AD, including antioxidant drugs, antidiabetic agents, acetylcholinesterase inhibitors (FDA-approved to manage symptoms), nutritional supplements, natural products, phenylpropanoids, vaccines, exercise, and other potential treatments.
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Affiliation(s)
- Mostafa Hossam El Din Moawad
- Faculty of Pharmacy, Clinical Department, Alexandria Main University Hospital, Alexandria, Egypt
- Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Ibrahim Serag
- Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | | | - Abdallah Abbas
- Faculty of Medicine, Al-Azhar University, Damietta, Egypt
| | - Abdulrahman Sharaf
- Department of Clinical Pharmacy, Salmaniya Medical Complex, Government Hospital, Manama, Bahrain
| | - Sumaya Alsalah
- Ministry of Health, Primary Care, Governmental Health Centers, Manama, Bahrain
| | | | | | | | - Mohamed Abouzid
- Department of Physical Pharmacy and Pharmacokinetics, Faculty of Pharmacy, Poznan University of Medical Sciences, Rokietnicka 3 St., 60-806, Poznan, Poland.
- Doctoral School, Poznan University of Medical Sciences, 60-812, Poznan, Poland.
| | - Mostafa Meshref
- Department of Neurology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
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2
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Melnik BC, Weiskirchen R, John SM, Stremmel W, Leitzmann C, Weiskirchen S, Schmitz G. White Adipocyte Stem Cell Expansion Through Infant Formula Feeding: New Insights into Epigenetic Programming Explaining the Early Protein Hypothesis of Obesity. Int J Mol Sci 2025; 26:4493. [PMID: 40429638 PMCID: PMC12110815 DOI: 10.3390/ijms26104493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 05/03/2025] [Accepted: 05/06/2025] [Indexed: 05/29/2025] Open
Abstract
Prolonged breastfeeding (BF), as opposed to artificial infant formula feeding (FF), has been shown to prevent the development of obesity later in life. The aim of our narrative review is to investigate the missing molecular link between postnatal protein overfeeding-often referred to as the "early protein hypothesis"-and the subsequent transcriptional and epigenetic changes that accelerate the expansion of adipocyte stem cells (ASCs) in the adipose vascular niche during postnatal white adipose tissue (WAT) development. To achieve this, we conducted a search on the Web of Science, Google Scholar, and PubMed databases from 2000 to 2025 and reviewed 750 papers. Our findings revealed that the overactivation of mechanistic target of rapamycin complex 1 (mTORC1) and S6 kinase 1 (S6K1), which inhibits wingless (Wnt) signaling due to protein overfeeding, serves as the primary pathway promoting ASC commitment and increasing preadipocyte numbers. Moreover, excessive protein intake, combined with the upregulation of the fat mass and obesity-associated gene (FTO) and a deficiency of breast milk-derived microRNAs from lactation, disrupts the proper regulation of FTO and Wnt pathway components. This disruption enhances ASC expansion in WAT while inhibiting brown adipose tissue development. While BF has been shown to have protective effects against obesity, the postnatal transcriptional and epigenetic changes induced by excessive protein intake from FF may predispose infants to early and excessive ASC commitment in WAT, thereby increasing the risk of obesity later in life.
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Affiliation(s)
- Bodo C. Melnik
- Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, D-49076 Osnabrück, Germany;
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany;
| | - Swen Malte John
- Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, D-49076 Osnabrück, Germany;
- Institute for Interdisciplinary Dermatological Prevention and Rehabilitation (iDerm), University of Osnabrück, D-49076 Osnabrück, Germany
| | | | - Claus Leitzmann
- Institut für Ernährungswissenschaft, Universität Gießen, D-35392 Gießen, Germany;
| | - Sabine Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany;
| | - Gerd Schmitz
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital of Regensburg, D-93053 Regensburg, Germany;
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3
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Ganguly S, Chattopadhyay T, Kazi R, Das S, Malik B, Ml U, Iyer PS, Kashiv M, Singh A, Ghadge A, Nair SD, Sonawane MS, Kolthur-Seetharam U. Consumption of sucrose-water rewires macronutrient uptake and utilization mechanisms in a tissue specific manner. J Nutr Biochem 2025; 139:109850. [PMID: 39889860 DOI: 10.1016/j.jnutbio.2025.109850] [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: 06/23/2024] [Revised: 10/31/2024] [Accepted: 01/25/2025] [Indexed: 02/03/2025]
Abstract
Consumption of sugar-sweetened beverages (SSBs) have been linked to metabolic dysfunction, obesity, diabetes and enhanced risk of cardiovascular diseases across all age-groups globally. Decades of work that have provided insights into pathophysiological manifestations of sucrose overfeeding have employed paradigms that rarely mimic human consumption of SSBs. Thus, our understanding of multiorgan cross-talk and molecular and/or cellular mechanisms, which operate across scales and drive physiological derangement is still poor. By employing a paradigm of sucrose water feeding in mice that closely resembles chronic SSB consumption in humans (10% sucrose in water), we have unraveled hitherto unknown tissue-specific mechanistic underpinnings, which contribute towards perturbed physiology. Our findings illustrate that systemic impaired glucose homeostasis, mediated by hepatic gluconeogenesis and insulin resistance, does not involve altered gene expression programs in the liver. We have discovered the pivotal role of the small intestine, which in conjunction with liver and muscles, drives dyshomeostasis. Importantly, we have uncovered rewiring of molecular mechanisms in the proximal intestine that is either causal or consequential to systemic ill-effects of chronic sucrose water consumption including dysfunction of liver and muscle mitochondria. Tissue-specific molecular signatures, which we have unveiled as the primary outcome, clearly indicate that inefficient utilization of glucose is exacerbated by enhanced uptake by the gut. Besides providing systems-wide mechanistic insights, we propose that consumption of SSBs causes intestinal 'molecular addiction' for deregulated absorption of hexose-sugars, and drives diseases such as diabetes and obesity.
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Affiliation(s)
- Saptarnab Ganguly
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India
| | - Tandrika Chattopadhyay
- Centre for innovation in molecular and pharmaceutical sciences, Dr. Reddy's Institute of Life Sciences, Hyderabad, Telangana, India
| | - Rubina Kazi
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Souparno Das
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Bhavisha Malik
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Uthpala Ml
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India
| | - Padmapriya S Iyer
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India
| | - Mohit Kashiv
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India
| | - Anshit Singh
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Amita Ghadge
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Shyam D Nair
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India
| | - Mahendra S Sonawane
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India; Development and Aging (ARUMDA), Advanced Research Unit on Metabolism, Tata Institute of Fundamental Research, Hyderabad, Telangana, India.
| | - Ullas Kolthur-Seetharam
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India; Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India; Development and Aging (ARUMDA), Advanced Research Unit on Metabolism, Tata Institute of Fundamental Research, Hyderabad, Telangana, India; Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
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4
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Mustafa AM, El-Shiekh RA, Esmail MM, Hassan E, Senna MM, Ebid N, Elgindy AM. Surveying the Therapeutic Potentials of Isoliquiritigenin (ISL): A Comprehensive Review. Chem Biodivers 2025:e202500456. [PMID: 40274535 DOI: 10.1002/cbdv.202500456] [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: 02/06/2025] [Revised: 04/22/2025] [Accepted: 04/23/2025] [Indexed: 04/26/2025]
Abstract
Isoliquiritigenin (ISL), a major chalcone-type flavonoid produced predominantly from liquorice roots (Glycyrrhiza species), has exceptional therapeutic potential across a wide range of pharmacological activities. ISL has numerous benefits including antioxidant, anti-inflammatory, antidiabetic, cardioprotective, hepatoprotective, neuroprotective, and anticancer activities. This review gathers the pharmacological effects of ISL remarking into its mechanism of actions such as how it modulates oxidative stress, inflammatory pathways, glucose metabolism, and cancer growth, demonstrating its pharmacological versatility. The review emphasizes new advances in the field, allowing for more rational development and clinical use of ISL in medicine. However, further research is required to confirm the target-organ toxicity or side-effect investigations.
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Affiliation(s)
- Aya M Mustafa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Riham A El-Shiekh
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Manar M Esmail
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Eslam Hassan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Mohamed Magdy Senna
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Nouran Ebid
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Ali M Elgindy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
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5
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Ryytty S, Nurminen K, Mäkinen P, Suomalainen A, Hämäläinen RH. Heightened sensitivity to adverse effects of metformin in mtDNA mutant patient cells. Life Sci 2025; 366-367:123486. [PMID: 39978587 DOI: 10.1016/j.lfs.2025.123486] [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: 11/04/2024] [Revised: 01/23/2025] [Accepted: 02/16/2025] [Indexed: 02/22/2025]
Abstract
AIMS Metformin (Met) is a widely used, cost-effective, and relatively safe drug, primarily prescribed for diabetes, that also exhibits beneficial effects in other conditions, such as in cardiovascular diseases, neurological disorders, and cancer. Despite its common use, the safety of Met in patients with primary mitochondrial disease remains uncertain, as both Met and mitochondrial dysfunction increase the risk of lactic acidosis. Here we have examined the effects of Met in patient cells with m.3243A>G mitochondrial DNA mutation. MATERIALS AND METHODS We utilized induced pluripotent stem cells (iPSCs) derived from two m.3243A>G patients, alongside cardiomyocytes differentiated from these iPSCs (iPSC-CMs). The cells were exposed to 10, 100, and 1000 μM Met for 24 h, and the effects on cellular metabolism and mitochondrial function were evaluated. KEY FINDINGS While low concentrations, relative to common therapeutic plasma levels, increased mitochondrial respiration, higher concentrations decreased respiration in both patient and control cells. Furthermore, cells with high level of the m.3243A>G mutation were more sensitive to Met than control cells. Additionally, we observed a clear patient-specific response to Met in cardiomyocytes. SIGNIFICANCE The findings emphasize the critical importance of selecting appropriate Met concentrations in cellular experiments and demonstrate the variability in Met's effects between individuals. Moreover, the results highlight the need for caution when considering Met use in patients with primary mitochondrial disorders.
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Affiliation(s)
- Sanna Ryytty
- A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland
| | - Katriina Nurminen
- A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland
| | - Petri Mäkinen
- A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland
| | - Anu Suomalainen
- Stem Cell and Metabolism Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland; HUSLab, Helsinki University Hospital, Helsinki, Finland
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Bar-Tana J. mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS. J Transl Med 2025; 23:297. [PMID: 40059164 PMCID: PMC11892318 DOI: 10.1186/s12967-025-06220-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 02/10/2025] [Indexed: 05/13/2025] Open
Abstract
Post-acute SarS-Cov2 (PASC), Myalgia encephalomyelitis/Chronic fatigue syndrome (ME/CFS) and Post-acute infection syndrome (PAIS) consist of chronic post-acute infectious syndromes, sharing exhaustive fatigue, post exertional malaise, intermittent pain, postural tachycardia and neuro-cognitive-psychiatric dysfunction. However, the concerned shared pathophysiology is still unresolved in terms of upstream drivers and transducers. Also, risk factors which may determine vulnerability/progression to the chronic phase still remain to be defined. In lack of drivers and a cohesive pathophysiology, the concerned syndromes still remain unmet therapeutic needs. 'mTORC1 Syndrome' (TorS) implies an exhaustive disease entity driven by sustained hyper-activation of the mammalian target of rapamycin C1 (mTORC1), and resulting in a variety of disease aspects of the Metabolic Syndrome (MetS), non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, some cancers, neurodegeneration and other [Bar-Tana in Trends Endocrinol Metab 34:135-145, 2023]. TorS may offer a cohesive insight of PASC, ME/CFS and PAIS drivers, pathophysiology, vulnerability and treatment options.
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Affiliation(s)
- Jacob Bar-Tana
- Hebrew University Medical School, 91120, Jerusalem, Israel.
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7
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Witham MD, McDonald C, Wilson N, Rennie KJ, Bardgett M, Bradley P, Clegg AP, Connolly S, Hancock H, Hiu S, Nicholson K, Robertson L, Simms L, Steel AJ, Steves CJ, Storey B, Wason J, von Zglinicki T, Sayer AA. Metformin and physical performance in older people with probable sarcopenia and physical prefrailty or frailty in England (MET-PREVENT): a double-blind, randomised, placebo-controlled trial. THE LANCET. HEALTHY LONGEVITY 2025; 6:100695. [PMID: 40147475 DOI: 10.1016/j.lanhl.2025.100695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/28/2025] [Accepted: 01/31/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Metformin has effects on multiple biological systems relevant to ageing and has been posited as a candidate therapy for sarcopenia and physical frailty. We aimed to test the efficacy and safety of metformin, a candidate geroprotector, to improve physical performance in older people with probable sarcopenia and physical prefrailty or frailty. METHODS In this double-blind, randomised, parallel-group, placebo-controlled trial (MET-PREVENT), participants aged 65 years and older with a 4-m walk speed of less than 0·8 m/s and probable sarcopenia, characterised by low handgrip strength (<16 kg for women and <27 kg for men) or five times sit-to-stand time of longer than 15 s (or inability to complete five sit-to-stands) were recruited from primary care and hospital clinics in Gateshead and Newcastle, UK. Participants were randomly assigned (1:1), via a web-based system with minimisation to ensure balance by sex and baseline 4-m walk speed, to receive either 500 mg oral metformin or matching placebo three times a day for 4 months. The primary outcome was the adjusted between-group difference in 4-m walk speed at 4 months. The primary outcome was analysed in the intention-to-treat population (ie, all participants randomly assigned to treatment) who had complete data, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with the ISRCTN registry, ISRCTN29932357, and is now complete. FINDINGS Between Aug 1, 2021, and Sept 30, 2022, 268 individuals were screened for inclusion in the trial, and 72 participants were randomly assigned to either metformin (n=36) or placebo (n=36; intention-to-treat population). Mean age was 80·4 years (SD 5·7), 42 (58%) of 72 participants were female, 30 (42%) were male, and 70 (97%) were White British. 70 (97%) of 72 participants had complete follow-up data (n=34 in the metformin group and n=36 in the placebo group). Mean 4-m walk speed at 4 months was 0·57 m/s (SD 0·19) in the metformin group and 0·58 m/s (0·24) in the placebo group (adjusted treatment effect 0·001 m/s [95% CI -0·06 to 0·06]; p=0·96). 108 adverse events occurred in 35 (100%) of 35 participants who received metformin and 77 adverse events occurred in 33 (92%) of 36 participants who received placebo, and 12 (34%) of 35 participants had hospital admissions in the metformin group versus three (8%) of 36 participants in the placebo group. One death occurred, in the metformin group (one [3%] of 35), and was judged to be unrelated to study treatment. INTERPRETATION Metformin did not improve 4-m walk speed and was poorly tolerated in this population. FUNDING National Institute for Health and Care Research Newcastle Biomedical Research Centre.
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Affiliation(s)
- Miles D Witham
- AGE Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust and Newcastle University, Newcastle upon Tyne, UK.
| | - Claire McDonald
- AGE Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust and Newcastle University, Newcastle upon Tyne, UK; Queen Elizabeth Hospital, Gateshead Health NHS Trust, Gateshead, UK
| | - Nina Wilson
- Biostatistics Research Group, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Katherine J Rennie
- Newcastle Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK
| | - Michelle Bardgett
- Newcastle Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK
| | - Penny Bradley
- Pharmacy Directorate, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Andrew P Clegg
- Academic Unit for Ageing and Stroke Research, University of Leeds, Bradford Royal Infirmary, Bradford, UK
| | - Stephen Connolly
- NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust and Newcastle University, Newcastle upon Tyne, UK
| | - Helen Hancock
- Newcastle Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK
| | - Shaun Hiu
- Biostatistics Research Group, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Karen Nicholson
- Newcastle Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK
| | - Laura Robertson
- Newcastle Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK
| | - Laura Simms
- Newcastle Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK
| | - Alison J Steel
- Newcastle Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK
| | | | - Bryony Storey
- Queen Elizabeth Hospital, Gateshead Health NHS Trust, Gateshead, UK
| | - James Wason
- Biostatistics Research Group, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Thomas von Zglinicki
- Ageing Research Laboratories, Newcastle University Biosciences Institute, Newcastle upon Tyne, UK
| | - Avan A Sayer
- AGE Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust and Newcastle University, Newcastle upon Tyne, UK
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8
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Zhang T, Zhou L, Makarczyk MJ, Feng P, Zhang J. The Anti-Aging Mechanism of Metformin: From Molecular Insights to Clinical Applications. Molecules 2025; 30:816. [PMID: 40005128 PMCID: PMC11858480 DOI: 10.3390/molecules30040816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 01/31/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
Aging represents a complex biological phenomenon marked by the progressive deterioration of physiological functions over time, reduced resilience, and increased vulnerability to age-related diseases, ultimately culminating in mortality. Recent research has uncovered diverse molecular mechanisms through which metformin extends its benefits beyond glycemic control, presenting it as a promising intervention against aging. This review delves into the anti-aging properties of metformin, highlighting its role in mitochondrial energy modulation, activation of the AMPK-mTOR signaling pathway, stimulation of autophagy, and mitigation of inflammation linked to cellular aging. Furthermore, we discuss its influence on epigenetic modifications that underpin genomic stability and cellular homeostasis. Metformin's potential in addressing age-associated disorders including metabolic, cardiovascular, and neurodegenerative diseases is also explored. The Targeting Aging with Metformin (TAME) trial aims to provide key evidence on its efficacy in delaying aging in humans. Despite these promising insights, significant challenges persist in gaining a more comprehensive understanding into its underlying mechanisms, determining optimal dosing strategies, and evaluating long-term safety in non-diabetic populations. Addressing these challenges is crucial to fully realizing metformin's potential as an anti-aging therapeutic.
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Affiliation(s)
- Ting Zhang
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Lijun Zhou
- School of Public Health, Xinjiang Medical University, Urumqi 830011, China
| | - Meagan J. Makarczyk
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Peng Feng
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
- School of Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Jianying Zhang
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
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Schooling CM, Yang G, Soliman GA, Leung GM. A Hypothesis That Glucagon-like Peptide-1 Receptor Agonists Exert Immediate and Multifaceted Effects by Activating Adenosine Monophosphate-Activate Protein Kinase (AMPK). Life (Basel) 2025; 15:253. [PMID: 40003662 PMCID: PMC11857512 DOI: 10.3390/life15020253] [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: 12/09/2024] [Revised: 01/20/2025] [Accepted: 01/31/2025] [Indexed: 02/27/2025] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce bodyweight and blood glucose. Extensive evidence from randomized controlled trials has indicated that GLP-1RAs have benefits well beyond weight loss and glucose control, extending from reductions in cardiovascular mortality to reductions in prostate cancer risk. Notably, some benefits of GLP-1RAs for the cardiovascular-kidney-metabolic (CKM) system arise before weight loss occurs for reasons that are not entirely clear but are key to patient care and drug development. Here, we hypothesize that GLP-1RAs act by inducing calorie restriction and by activating adenosine monophosphate-activated protein kinase (AMPK), which not only provides an explanation for the unique effectiveness of GLP-1RAs but also indicates a common mechanism shared by effective CKM therapies, including salicylates, metformin, statins, healthy diet, and physical activity. Whether AMPK activation is obligatory for effective CKM therapies should be considered. As such, we propose a mechanism of action for GLP-1RAs and explain how it provides an overarching framework for identifying means of preventing and treating cardiovascular, kidney, metabolic and related diseases, as well as informing the complementary question as to the components of a healthy lifestyle.
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Affiliation(s)
- C. Mary Schooling
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; (G.Y.)
- School of Public Health and Health Policy, City University of New York, Graduate School of Public Health and Health Policy, 55 W 125th St, New York, NY 10027, USA;
| | - Guoyi Yang
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; (G.Y.)
| | - Ghada A. Soliman
- School of Public Health and Health Policy, City University of New York, Graduate School of Public Health and Health Policy, 55 W 125th St, New York, NY 10027, USA;
| | - Gabriel M. Leung
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; (G.Y.)
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10
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Martin-Quesada AI, Hennessy MA, Gutiérrez AC. Charting cancer's course: revealing the role of diet, exercise, and the microbiome in cancer evolution and immunotherapy response. Clin Transl Oncol 2025; 27:473-485. [PMID: 39095683 PMCID: PMC11782318 DOI: 10.1007/s12094-024-03595-1] [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: 04/08/2024] [Accepted: 07/03/2024] [Indexed: 08/04/2024]
Abstract
A variety of pathophysiological mechanisms exist by which physical exercise, nutrition, and the microbiome can impact the development of cancer and the response of tumor cells to systemic anti-cancer therapy. Physical exercise positively impacts the different stages of oncological disease and may improve overall survival and quality of life, reduce treatment-associated toxicity, and improve response to immunotherapy. Nutrition impacts quality of life, and novel nutritional regimens and their role in cancer treatment and outcomes are under active investigation. Finally, the microbiome may act as a predictor of response and resistance to immunotherapy. This comprehensive review delves into the interplay between these elements and their impact on oncological outcomes, emphasizing their role in modulating the immune system and enhancing the response to immunotherapy.The data that support the findings of this study are openly available and referenced in the bibliography section.
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Affiliation(s)
- Ana Isabel Martin-Quesada
- Cell Therapy and Early Drug Development Unit, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
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11
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Shivaprakash P, Beeraka NM, Madhunapantula SRV, Nikolenko VN, Basalingappa KM. Metformin Effects on SHIP2, AMPKs and Gut Microbiota: Recent Updates on Pharmacology. Curr Med Chem 2025; 32:1732-1754. [PMID: 38409699 DOI: 10.2174/0109298673289342240213040144] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 01/25/2024] [Accepted: 01/29/2024] [Indexed: 02/28/2024]
Abstract
INTRODUCTION Metformin, a biguanide on the WHO's list of essential medicines has a long history of 50 years or more in treating hyperglycemia, and its therapeutic saga continues beyond diabetes treatment. Glucoregulatory actions are central to the physiological effects of metformin; surprisingly, the precise mechanism with which metformin regulates glucose metabolism is not thoroughly understood yet. METHODS The main aim of this review is to explore the recent implications of metformin in hepatic gluconeogenesis, AMPKs, and SHIP2 and subsequently to elucidate the metformin action across intestine and gut microbiota. We have searched PubMed, Google scholar, Medline, eMedicine, National Library of Medicine (NLM), clinicaltrials.gov (registry), and ReleMed for the implications of metformin with its updated role in AMPKs, SHIP2, and hepatic gluoconeogenesis, and gut microbiota. In this review, we have described the efficacy of metformin as a drug repurposing strategy in modulating the role of AMPKs lysosomal-AMPKs, and also, the controversies associated with metformin. RESULTS Research suggests that biguanide exhibits hormetic effects depending on the concentrations used (micromolar to millimolar). The primary mechanism attributed to metformin action is the inhibition of mitochondrial complex I, and subsequent reduction of cellular energy state, as observed with increased AMP or ADP ratio, thereby metformin can also activate the cellular energy sensor AMPK to inhibit hepatic gluconeogenesis. However, new mechanistic models have been proposed lately to explain the pleiotropic actions of metformin; at low dose, metformin can activate lysosomal-AMPK via the AXIN-LKB1 pathway. Conversely, in an AMPK-independent mechanism, metformin-induced elevation of AMP suppresses adenylate cyclase and glucagon-activated cAMP production to inhibit hepatic glucose output by glucagon. Metformin inhibits mitochondrial glycerophosphate dehydrogenase; mGPDH, and increases the cytosolic NADH/NAD+, affecting the availability of lactate and glycerol for gluconeogenesis. Metformin can inhibit Src homology 2 domain-containing inositol 5-phosphatase 2; SHIP2 to increase the insulin sensitivity and glucose uptake by peripheral tissues. In addition, new exciting mechanisms suggest the role of metformin in promoting beneficial gut microbiome and gut health. Metformin regulates duodenal AMPK activation, incretin harmone secretion and bile acid homeostasis to improve intestinal glucose absorption and utilization. CONCLUSION The proper understanding of the key regulators of metformin actions is of utmost importance to enhance its pleotropic benefits on diabetes and beyond.
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Affiliation(s)
- Priyanka Shivaprakash
- Division of Molecular Biology, School of Life Sciences, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India
| | - Narasimha Murthy Beeraka
- Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapuramu, Andhra Pradesh, India
- Department of Human Anatomy, Sechenov First Moscow State Medical University, 8-2 Trubetskaya St., Moscow, 119991, Russia
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Subba Rao V Madhunapantula
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center), Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research, Mysore, Karnataka, India
| | - Vladimir N Nikolenko
- Department of Human Anatomy, Sechenov First Moscow State Medical University, 8-2 Trubetskaya St., Moscow, 119991, Russia
| | - Kanthesh M Basalingappa
- Division of Molecular Biology, School of Life Sciences, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India
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12
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Shimizu K, Inuzuka H, Tokunaga F. The interplay between cell death and senescence in cancer. Semin Cancer Biol 2025; 108:1-16. [PMID: 39557316 DOI: 10.1016/j.semcancer.2024.11.001] [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: 08/15/2024] [Revised: 11/10/2024] [Accepted: 11/12/2024] [Indexed: 11/20/2024]
Abstract
Cellular senescence is a state of permanent proliferative arrest that occurs in response to DNA damage-inducing endogenous and exogenous stresses, and is often accompanied by dynamic molecular changes such as a senescence-associated secretory phenotype (SASP). Accumulating evidence indicates that age-associated increases in the upstream and downstream signals of regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, are closely related to the induction of cellular senescence and its phenotype. Furthermore, elevated levels of pro-inflammatory SASP factors with aging can be both a cause and consequence of several cell death modes, suggesting the reciprocal effects of cellular senescence and cells undergoing regulated cell death. Here, we review the critical molecular pathways of the regulated cell death forms and describe the crosstalk between aging-related signals and cancer. In addition, we discuss how targeting regulated cell death could be harnessed in therapeutic interventions for cancer. ABBREVIATIONS: Abbreviations that are not standard in this field are defined at their first occurrence in the article and are used consistently throughout the article.
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Affiliation(s)
- Kouhei Shimizu
- Department of Medical Biochemistry, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan.
| | - Hiroyuki Inuzuka
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA02215, USA
| | - Fuminori Tokunaga
- Department of Medical Biochemistry, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
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13
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Chim SM, Howell K, Dronzek J, Wu W, Van Hout C, Ferreira MAR, Ye B, Li A, Brydges S, Arunachalam V, Marcketta A, Locke AE, Bovijn J, Verweij N, De T, Lotta L, Mitnaul L, LeBlanc M, Center RG, Carey DJ, Melander O, Shuldiner A, Karalis K, Economides AN, Nistala H. Genetic inactivation of zinc transporter SLC39A5 improves liver function and hyperglycemia in obesogenic settings. eLife 2024; 12:RP90419. [PMID: 39671241 DOI: 10.7554/elife.90419] [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: 12/14/2024] Open
Abstract
Recent studies have revealed a role for zinc in insulin secretion and glucose homeostasis. Randomized placebo-controlled zinc supplementation trials have demonstrated improved glycemic traits in patients with type II diabetes (T2D). Moreover, rare loss-of-function variants in the zinc efflux transporter SLC30A8 reduce T2D risk. Despite this accumulated evidence, a mechanistic understanding of how zinc influences systemic glucose homeostasis and consequently T2D risk remains unclear. To further explore the relationship between zinc and metabolic traits, we searched the exome database of the Regeneron Genetics Center-Geisinger Health System DiscovEHR cohort for genes that regulate zinc levels and associate with changes in metabolic traits. We then explored our main finding using in vitro and in vivo models. We identified rare loss-of-function (LOF) variants (MAF <1%) in Solute Carrier Family 39, Member 5 (SLC39A5) associated with increased circulating zinc (p=4.9 × 10-4). Trans-ancestry meta-analysis across four studies exhibited a nominal association of SLC39A5 LOF variants with decreased T2D risk. To explore the mechanisms underlying these associations, we generated mice lacking Slc39a5. Slc39a5-/- mice display improved liver function and reduced hyperglycemia when challenged with congenital or diet-induced obesity. These improvements result from elevated hepatic zinc levels and concomitant activation of hepatic AMPK and AKT signaling, in part due to zinc-mediated inhibition of hepatic protein phosphatase activity. Furthermore, under conditions of diet-induced non-alcoholic steatohepatitis (NASH), Slc39a5-/- mice display significantly attenuated fibrosis and inflammation. Taken together, these results suggest SLC39A5 as a potential therapeutic target for non-alcoholic fatty liver disease (NAFLD) due to metabolic derangements including T2D.
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Affiliation(s)
| | | | - John Dronzek
- Regeneron Genetics Center, New York, United States
| | - Weizhen Wu
- Regeneron Genetics Center, New York, United States
| | | | | | - Bin Ye
- Regeneron Genetics Center, New York, United States
| | - Alexander Li
- Regeneron Genetics Center, New York, United States
| | | | | | | | - Adam E Locke
- Regeneron Genetics Center, New York, United States
| | - Jonas Bovijn
- Regeneron Genetics Center, New York, United States
| | - Niek Verweij
- Regeneron Genetics Center, New York, United States
| | - Tanima De
- Regeneron Genetics Center, New York, United States
| | - Luca Lotta
- Regeneron Genetics Center, New York, United States
| | | | | | | | | | | | | | | | - Aris N Economides
- Regeneron Genetics Center, New York, United States
- Regeneron Pharmaceuticals, New York, United States
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14
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Khalili-Hezarjaribi H, Bahrami AR, Sh Saljooghi A, Matin MM. Modified mesoporous silica nanocarriers containing superparamagnetic iron oxide nanoparticle, 5-fluorouracil or oxaliplatin, and metformin as a radiosensitizer, significantly impact colorectal cancer radiation therapy. Int J Pharm 2024; 666:124838. [PMID: 39419365 DOI: 10.1016/j.ijpharm.2024.124838] [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: 06/21/2024] [Revised: 09/25/2024] [Accepted: 10/13/2024] [Indexed: 10/19/2024]
Abstract
This study investigates the anticancer effects of SPION-based silica nanoparticles carrying 5-fluorouracil (5-FU) or oxaliplatin (OX), and metformin (MET) on colorectal cancer cells. Nanocarriers were equipped with pH-responsive gold gatekeepers for controlled release, PEGylation for longer circulation, and folic acid (FA) for targeted delivery. The effects were evaluated by investigating cell viability, cellular uptake, flow cytometry, and clonogenic assay in vitro. The efficacy of the system was also tested in vivo on C57BL/6 mice bearing HT-29 tumors, and potential side effects were evaluated. Nanocarriers were synthesized with hydrodynamic diameters of 79.8 nm for 5-FU and 85.2 nm for OX; zeta potentials of -21 and -22 mV, respectively, and remained stable after 72 h. Encapsulation efficiencies were 85 % for 5-FU, 80 % for OX, and 83 % for MET, with loading capacities of 44 %, 38 %, and 41 %, respectively. Drug release in acidic buffer was 38.7 % for 5-FU, 32.8 % for OX, and 43.5 % for MET. MTT assay showed increased toxicity due to FA conjugation, while PEGylation reduced the hemolysis activity. Targeted nanocarriers demonstrated superior cellular uptake and tumor localization compared to non-targeted variants. The combination of 5-FU-MET and OX-MET nanocarriers with radiation therapy (RT) demonstrated the greatest effect on their antitumor activity, accompanied by minimal side effects indicating effective tumor targeting in vivo. MRI and CT imaging further supported these findings. This study underscores the synergistic impact of MET alongside RT on the inhibition of cancer cells and tumor growth for both targeted 5-FU and OX nanocarriers reflecting the significant radiosensitizing properties of MET.
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Affiliation(s)
| | - Ahmad Reza Bahrami
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran; Industrial Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Amir Sh Saljooghi
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran; Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Maryam M Matin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran; Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran.
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15
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Soraya S, Arfianti A, Adikusuma W, Irham LM, Hamidy MY, Winarto W, Rangkuti IF, Darmawi D. Unveiling the impacts of metformin on hepatocellular carcinoma: A bioinformatic exploration in cell lines. NARRA J 2024; 4:e968. [PMID: 39816125 PMCID: PMC11731935 DOI: 10.52225/narra.v4i3.968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 08/12/2024] [Indexed: 01/18/2025]
Abstract
The most common type of liver cancer is hepatocellular carcinoma (HCC), accounting for 75-85% of cases. Despite its associated side effects, sorafenib remains the standard treatment for HCC. Given the critical need to improve therapeutic efficacy while minimizing adverse effects, alternative drugs must be thoroughly investigated. Numerous studies indicate that combining sorafenib with metformin results in a more favorable treatment profile. The aim of this study was to employ bioinformatics methodologies to elucidate the molecular pathways and genetic underpinnings of metformin's efficacy in HCC treatment. Genes associated with metformin and its action against HCC (Huh-7 and HepG2 cells) were acquired from the NCBI-GEO data collection by utilizing pre-determined keywords. Subsequently, pathways implicated in metformin-mediated HCC treatment were analyzed through the Kyoto Encyclopedia of Genes and Genomes (KEGG). Our analysis revealed the involvement of multiple pathways, with metabolic pathways implicated in 80% of the total cases. Neurodegenerative pathways were involved in only around 60% of the total cases. These findings align with the multifaceted mechanisms of metformin's action, encompassing adenosine monophosphate-activated protein kinase activation, apoptosis induction, insulin regulation, anti-inflammatory responses, and modulation of cell proliferation. This comprehensive investigation sheds light on the intricate molecular landscape underpinning metformin's therapeutic efficacy in HCC, thereby informing potential avenues for optimizing treatment strategies.
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Affiliation(s)
- Soraya Soraya
- Master Program in Biomedical Sciences, Faculty of Medicine, Universitas Riau, Pekanbaru, Indonesia
- Department of Biochemistry, Faculty of Medicine, Universitas Awal Bros, Pekanbaru, Indonesia
| | - Arfianti Arfianti
- Department of Medical Biology, Faculty of Medicine, Universitas Riau, Pekanbaru, Indonesia
| | - Wirawan Adikusuma
- Department of Pharmacy, Universitas Muhammadiyah Mataram, Mataram, Indonesia
- Research Center for Computing, Research Organization for Electronics and Informatics, National Research and Innovation Agency, Cibinong Science Center, Cibinong, Indonesia
| | - Lalu M. Irham
- Faculty of Pharmacy, Universitas Ahmad Dahlan, Yogyakarta, Indonesia
| | - Muhammad Y. Hamidy
- Department of Pharmacology, Faculty of Medicine, Universitas Riau, Pekanbaru, Indonesia
| | - Winarto Winarto
- Department of Histology, Faculty of Medicine, Universitas Riau, Pekanbaru, Indonesia
| | - Ina F. Rangkuti
- Department of Pathological Anatomy, Faculty of Medicine, Universitas Riau, Pekanbaru, Indonesia
| | - Darmawi Darmawi
- Department of Histology, Faculty of Medicine, Universitas Riau, Pekanbaru, Indonesia
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16
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Arden C, Park SH, Yasasilka XR, Lee EY, Lee MS. Autophagy and lysosomal dysfunction in diabetes and its complications. Trends Endocrinol Metab 2024; 35:1078-1090. [PMID: 39054224 DOI: 10.1016/j.tem.2024.06.010] [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: 03/26/2024] [Revised: 06/03/2024] [Accepted: 06/14/2024] [Indexed: 07/27/2024]
Abstract
Autophagy is critical for energy homeostasis and the function of organelles such as endoplasmic reticulum (ER) and mitochondria. Dysregulated autophagy due to aging, environmental factors, or genetic predisposition can be an underlying cause of not only diabetes through β-cell dysfunction and metabolic inflammation, but also diabetic complications such as diabetic kidney diseases (DKDs). Dysfunction of lysosomes, effector organelles of autophagic degradation, due to metabolic stress or nutrients/metabolites accumulating in metabolic diseases is also emerging as a cause or aggravating element in diabetes and its complications. Here, we discuss the etiological role of dysregulated autophagy and lysosomal dysfunction in diabetes and a potential role of autophagy or lysosomal modulation as a new avenue for treatment of diabetes and its complications.
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Affiliation(s)
- Catherine Arden
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
| | - Seo H Park
- Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan, Republic of Korea
| | - Xaviera Riani Yasasilka
- Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan, Republic of Korea
| | - Eun Y Lee
- Division of Nephrology, Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea
| | - Myung-Shik Lee
- Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan, Republic of Korea; Division of Endocrinology, Department of Internal Medicine and Department of Microbiology and Immunology, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea.
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17
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Liu Y, Dong X, Wu B, Cheng Z, Zhang J, Wang J. Promising Pharmacological Interventions for Posterior Capsule Opacification: A Review. GLOBAL CHALLENGES (HOBOKEN, NJ) 2024; 8:2400181. [PMID: 39679290 PMCID: PMC11637782 DOI: 10.1002/gch2.202400181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 10/18/2024] [Indexed: 12/17/2024]
Abstract
Phacoemulsification combined with intraocular lens implantation is the primary treatment for cataract. Although this treatment strategy benefits patients with cataracts, posterior capsule opacification (PCO) remains a common complication that impairs vision and affects treatment outcomes. The pathogenesis of PCO is associated with the proliferation, migration, and fibrogenesis activity of residual lens epithelial cells, with epithelial-mesenchymal transition (EMT) serving as a key mechanism underlying the condition. Transforming growth factor-beta 2 (TGF-β2) is a major promotor of EMT, thereby driving PCO development. Most studies have shown that drugs and miRNAs mitigate EMT by inhibiting, clearing, or eliminating LECs. In addition, targeting EMT-related signaling pathways in TGF-β2-stimulated LECs has garnered attention as a research focus. This review highlights potential treatments for PCO and details the mechanisms by which drugs and miRNAs counter EMT.
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Affiliation(s)
- Yuxuan Liu
- AIER Cataract InstituteShenyangLiaoning Province110000China
- Shenyang Aier Ophthalmology Institute of Precision MedicineShenyangLiaoning Province110000China
- Liaoning Aier Eye HospitalShenyangLiaoning Province110000China
| | - Xiaoming Dong
- AIER Cataract InstituteShenyangLiaoning Province110000China
- Shenyang Aier Ophthalmology Institute of Precision MedicineShenyangLiaoning Province110000China
- Liaoning Aier Eye HospitalShenyangLiaoning Province110000China
| | - Bin Wu
- AIER Cataract InstituteShenyangLiaoning Province110000China
- Shenyang Aier Ophthalmology Institute of Precision MedicineShenyangLiaoning Province110000China
- Shenyang Aier Excellent Eye HospitalShenyangLiaoning Province110000China
| | - Zhigang Cheng
- AIER Cataract InstituteShenyangLiaoning Province110000China
- Shenyang Aier Ophthalmology Institute of Precision MedicineShenyangLiaoning Province110000China
- Chaoyang Aier Eye HospitalChaoyangLiaoning Province122000China
| | - Jinsong Zhang
- AIER Cataract InstituteShenyangLiaoning Province110000China
- Shenyang Aier Ophthalmology Institute of Precision MedicineShenyangLiaoning Province110000China
- Liaoning Aier Eye HospitalShenyangLiaoning Province110000China
- Shenyang Aier Excellent Eye HospitalShenyangLiaoning Province110000China
| | - Jing Wang
- AIER Cataract InstituteShenyangLiaoning Province110000China
- Shenyang Aier Ophthalmology Institute of Precision MedicineShenyangLiaoning Province110000China
- Liaoning Aier Eye HospitalShenyangLiaoning Province110000China
- Shenyang Aier Excellent Eye HospitalShenyangLiaoning Province110000China
- Aier Academy of OphthalmologyCentral South UniversityNo. 188, Furong South Road, Tianxin DistrictChangshaHunan410004P. R. China
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18
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Jindal J, Hill J, Harte J, Dunachie SJ, Kronsteiner B. Starvation and infection: The role of sickness-associated anorexia in metabolic adaptation during acute infection. Metabolism 2024; 161:156035. [PMID: 39326837 DOI: 10.1016/j.metabol.2024.156035] [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: 05/17/2024] [Revised: 09/13/2024] [Accepted: 09/17/2024] [Indexed: 09/28/2024]
Abstract
Sickness-associated anorexia, the reduction in appetite seen during infection, is a widely conserved and well-recognized symptom of acute infection, yet there is very little understanding of its functional role in recovery. Anorexic sickness behaviours can be understood as an evolutionary strategy to increase tolerance to pathogen-mediated illness. In this review we explore the evidence for mechanisms and potential metabolic benefits of sickness-associated anorexia. Energy intake can impact on the immune response, control of inflammation and tissue stress, and on pathogen fitness. Fasting mediators including hormone-sensitive lipase, peroxisome proliferator-activated receptor-alpha (PPAR-α) and ketone bodies are potential facilitators of infection recovery through multiple pathways including suppression of inflammation, adaptation to lipid utilising pathways, and resistance to pathogen-induced cellular stress. However, the effect and benefit of calorie restriction is highly heterogeneous depending on both the infection and the metabolic status of the host, which has implications regarding clinical recommendations for feeding during different infections.
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Affiliation(s)
- Jessy Jindal
- The Medical School, Medical Sciences Division, University of Oxford, Oxford, UK
| | - Jennifer Hill
- NDM Centre for Global Health Research, Nuffield Dept. of Clinical Medicine, University of Oxford, Oxford, UK
| | - Jodie Harte
- NDM Centre for Global Health Research, Nuffield Dept. of Clinical Medicine, University of Oxford, Oxford, UK
| | - Susanna J Dunachie
- NDM Centre for Global Health Research, Nuffield Dept. of Clinical Medicine, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand.
| | - Barbara Kronsteiner
- NDM Centre for Global Health Research, Nuffield Dept. of Clinical Medicine, University of Oxford, Oxford, UK.
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Roberts CT, Raabe N, Wiegand L, Kadar Shahib A, Rastegar M. Diverse Applications of the Anti-Diabetic Drug Metformin in Treating Human Disease. Pharmaceuticals (Basel) 2024; 17:1601. [PMID: 39770443 PMCID: PMC11677501 DOI: 10.3390/ph17121601] [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: 10/13/2024] [Revised: 11/21/2024] [Accepted: 11/25/2024] [Indexed: 01/11/2025] Open
Abstract
Metformin is a commonly used drug for treating type 2 diabetes. Metformin is an inexpensive drug with low/no side effects and is well tolerated in human patients of different ages. Recent therapeutic strategies for human disease have considered the benefits of drug repurposing. This includes the use of the anti-diabetic drug metformin. Accordingly, the anti-inflammatory, anti-cancer, anti-viral, neuroprotective, and cardioprotective potentials of metformin have deemed it a suitable candidate for treating a plethora of human diseases. As results from preclinical studies using cellular and animal model systems appear promising, clinical trials with metformin in the context of non-diabetes-related illnesses have been started. Here, we aim to provide a comprehensive overview of the therapeutic potential of metformin in different animal models of human disease and its suggested relationship to epigenetics and ailments with epigenetic components.
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Affiliation(s)
| | | | | | | | - Mojgan Rastegar
- Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
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Xiang J, Leary SC, Wu Z, Yu M. Molecular basis and pathways of the Yin-Yang theory in T cell immunity. Front Immunol 2024; 15:1463399. [PMID: 39611157 PMCID: PMC11602496 DOI: 10.3389/fimmu.2024.1463399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 11/04/2024] [Indexed: 11/30/2024] Open
Affiliation(s)
- Jim Xiang
- Cancer Research Cluster, Saskatchewan Cancer Agency, Saskatoon, SK, Canada
- Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Scot C. Leary
- Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Zhaojia Wu
- Cancer Research Cluster, Saskatchewan Cancer Agency, Saskatoon, SK, Canada
- Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Michelle Yu
- Cancer Research Cluster, Saskatchewan Cancer Agency, Saskatoon, SK, Canada
- Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
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21
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Johnson SG, Abedian S, Stürmer T, Huling JD, Lewis V C, Buse JB, Brosnahan SB, Mudumbi PC, Erlandson KM, McComsey GA, Arnold J, Wiggen TD, Wong R, Murphy S, Rosen C, Kaushal R, Weiner MG, Bramante C, RECOVER PCORnet EHR Cohort and the N3C Consortium. Prevalent Metformin Use in Adults With Diabetes and the Incidence of Long COVID: An EHR-Based Cohort Study From the RECOVER Program. Diabetes Care 2024; 47:1930-1940. [PMID: 39287394 PMCID: PMC11502533 DOI: 10.2337/dca24-0032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/05/2024] [Indexed: 09/19/2024]
Abstract
OBJECTIVE Studies show metformin use before and during SARS-CoV-2 infection reduces severe COVID-19 and postacute sequelae of SARS-CoV-2 (PASC) in adults. Our objective was to describe the incidence of PASC and possible associations with prevalent metformin use in adults with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS This is a retrospective cohort analysis using the National COVID Cohort Collaborative (N3C) and Patient-Centered Clinical Research Network (PCORnet) electronic health record (EHR) databases with an active comparator design that examined metformin-exposed individuals versus nonmetformin-exposed individuals who were taking other diabetes medications. T2DM was defined by HbA1c ≥6.5 or T2DM EHR diagnosis code. The outcome was death or PASC within 6 months, defined by EHR code or computable phenotype. RESULTS In the N3C, the hazard ratio (HR) for death or PASC with a U09.9 diagnosis code (PASC-U09.0) was 0.79 (95% CI 0.71-0.88; P < 0.001), and for death or N3C computable phenotype PASC (PASC-N3C) was 0.85 (95% CI 0.78-0.92; P < 0.001). In PCORnet, the HR for death or PASC-U09.9 was 0.87 (95% CI 0.66-1.14; P = 0.08), and for death or PCORnet computable phenotype PASC (PASC-PCORnet) was 1.04 (95% CI 0.97-1.11; P = 0.58). Incident PASC by diagnosis code was 1.6% metformin vs. 2.0% comparator in the N3C, and 2.1% metformin vs. 2.5% comparator in PCORnet. By computable phenotype, incidence was 4.8% metformin and 5.2% comparator in the N3C and 24.7% metformin vs. 26.1% comparator in PCORnet. CONCLUSIONS Prevalent metformin use is associated with a slightly lower incidence of death or PASC after SARS-CoV-2 infection. PASC incidence by computable phenotype is higher than by EHR code, especially in PCORnet. These data are consistent with other observational analyses showing prevalent metformin is associated with favorable outcomes after SARS-CoV-2 infection in adults with T2DM.
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Affiliation(s)
- Steven G. Johnson
- Institute for Health Informatics, University of Minnesota, Minneapolis, MN
| | - Sajjad Abedian
- Information Technologies and Services Department, Weill Cornell Medicine, New York, NY
| | - Til Stürmer
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Jared D. Huling
- Division of Biostatistics and Health Data Science, University of Minnesota School of Public Health, Minneapolis, MN
| | - Colby Lewis V
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY
| | - John B. Buse
- Division of Endocrinology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC
| | - Shari B. Brosnahan
- Department of Medicine, New York University Grossman School of Medicine, New York, NY
| | - Praveen C. Mudumbi
- Department of Population Health, New York University Grossman School of Medicine, New York, NY
| | | | | | - Jonathan Arnold
- Division of General Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Talia D. Wiggen
- Institute for Health Informatics, University of Minnesota, Minneapolis, MN
| | - Rachel Wong
- Department of Biomedical Informatics and the Department of Internal Medicine, Stony Brook University, Stony Brook, NY
| | | | | | - Rainu Kaushal
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY
| | - Mark G. Weiner
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY
| | - Carolyn Bramante
- Division of General Internal Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN
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22
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Flores K, Almeida C, Arriaza K, Pena E, El Alam S. mTOR in the Development of Hypoxic Pulmonary Hypertension Associated with Cardiometabolic Risk Factors. Int J Mol Sci 2024; 25:11023. [PMID: 39456805 PMCID: PMC11508063 DOI: 10.3390/ijms252011023] [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: 09/12/2024] [Revised: 10/08/2024] [Accepted: 10/10/2024] [Indexed: 10/28/2024] Open
Abstract
The pathophysiology of pulmonary hypertension is complex and multifactorial. It is a disease characterized by increased pulmonary vascular resistance at the level due to sustained vasoconstriction and remodeling of the pulmonary arteries, which triggers an increase in the mean pulmonary artery pressure and subsequent right ventricular hypertrophy, which in some cases can cause right heart failure. Hypoxic pulmonary hypertension (HPH) is currently classified into Group 3 of the five different groups of pulmonary hypertensions, which are determined according to the cause of the disease. HPH mainly develops as a product of lung diseases, among the most prevalent causes of obstructive sleep apnea (OSA), chronic obstructive pulmonary disease (COPD), or hypobaric hypoxia due to exposure to high altitudes. Additionally, cardiometabolic risk factors converge on molecular mechanisms involving overactivation of the mammalian target of rapamycin (mTOR), which correspond to a central axis in the development of HPH. The aim of this review is to summarize the role of mTOR in the development of HPH associated with metabolic risk factors and its therapeutic alternatives, which will be discussed in this review.
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Affiliation(s)
| | | | - Karem Arriaza
- High Altitude Medicine Research Center (CEIMA), Arturo Prat University, Iquique 1110939, Chile; (K.F.); (C.A.); (E.P.); (S.E.A.)
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23
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Ahmad R, Haque M. Metformin: Beyond Type 2 Diabetes Mellitus. Cureus 2024; 16:e71730. [PMID: 39421288 PMCID: PMC11486535 DOI: 10.7759/cureus.71730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 10/17/2024] [Indexed: 10/19/2024] Open
Abstract
Metformin was developed from an offshoot of Guanidine. It is known to be the first-line medication for type 2 diabetes mellitus, polycystic ovarian syndrome, and weight reduction. Metformin has also been shown to have effectiveness in the management of non-alcoholic fatty liver disease (NAFLD), liver cirrhosis, and various carcinomas like hepatocellular, colorectal, prostate, breast, urinary bladder, blood, melanoma, bone, skin, lung and so on. This narrative review focuses on the effect of metformin on non-alcoholic fatty liver disease, liver cirrhosis, and hepatocellular carcinoma. The search platforms for the topic were PubMed, Scopus, and Google search engine. Critical words for searching included 'Metformin,' AND 'Indications of Metformin,' AND 'Non-Alcoholic Fatty Liver Disease,' AND 'Metformin mechanism of action,' AND 'NAFLD management,' AND 'NAFLD and inflammation,' AND 'Metformin and insulin,' AND 'Metformin and inflammation,' AND 'Liver cirrhosis,' AND 'Hepatocellular carcinoma.' Lifestyle modification and the use of hypoglycemic agents can help improve liver conditions. Metformin has several mechanisms that enhance liver health, including reducing reactive oxygen species, nuclear factor kappa beta (NF-κB), liver enzymes, improving insulin sensitivity, and improving hepatic cell lipophagy. Long-term use of metformin may cause some adverse effects like lactic acidosis and gastrointestinal disturbance. Metformin long-term overdose may lead to a rise in hydrogen sulfide in liver cells, which calls for pharmacovigilance. Drug regulating authorities should provide approval for further research, and national and international guidelines need to be developed for liver diseases, perhaps with the inclusion of metformin as part of the management regime.
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Affiliation(s)
- Rahnuma Ahmad
- Department of Physiology, Medical College for Women and Hospital, Dhaka, BGD
| | - Mainul Haque
- Department of Pharmacology and Therapeutics, National Defence University of Malaysia, Kuala Lumpur, MYS
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24
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Maltaneri RE, Chamorro ME, Gionco SE, Nesse AB, Vittori DC. Erythropoietin enhances iron bioavailability in HepG2 cells by downregulating hepcidin through mTOR, C/EBPα and HIF-1α. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119800. [PMID: 39047915 DOI: 10.1016/j.bbamcr.2024.119800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 06/26/2024] [Accepted: 07/12/2024] [Indexed: 07/27/2024]
Abstract
The regulation of iron (Fe) levels is essential to maintain an adequate supply for erythropoiesis, among other processes, and to avoid possible toxicity. The liver-produced peptide hepcidin is regarded as the main regulator of Fe absorption in enterocytes and release from hepatocytes and macrophages, as it impairs Fe export through ferroportin. The glycoprotein erythropoietin (Epo) drives erythroid progenitor survival and differentiation in the bone marrow, and has been linked to the mobilization of Fe reserves necessary for hemoglobin production. Herein we show that Epo inhibits hepcidin expression directly in the HepG2 hepatic cell line, thus leading to a decrease in intracellular Fe levels. Such inhibition was dependent on the Epo receptor-associated kinase JAK2, as well as on the PI3K/AKT/mTOR pathway, which regulates nutrient homeostasis. Epo was also found to decrease binding of the C/EBP-α transcription factor to the hepcidin promoter, which could be attributed to an increased expression of its inhibitor CHOP. Epo did not only hinder the stimulating effect of C/EBP-α on hepcidin transcription, but also favored hepcidin inhibition by HIF-1α, by increasing is nuclear translocation as well as its protein levels. Moreover, in assays with the inhibitor genistein, this transcription factor was found necessary for Epo-induced hepcidin suppression. Our findings support the involvement of the PI3K/AKT/mTOR pathway in the regulation of Fe levels by Epo, and highlight the contrasting roles of the C/EBP-α and HIF-1α transcription factors as downstream effectors of the cytokine in this process.
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Affiliation(s)
- Romina Eugenia Maltaneri
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto del Departamento de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina.
| | - María Eugenia Chamorro
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto del Departamento de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
| | - Silvana Estela Gionco
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto del Departamento de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
| | - Alcira Beatriz Nesse
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto del Departamento de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
| | - Daniela Cecilia Vittori
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto del Departamento de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
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25
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Zhao S, Hao S, Zhou J, Chen X, Zhang T, Qi Z, Zhang T, Jalal S, Zhai C, Yin L, Bo Y, Teng H, Wang Y, Gao D, Zhang H, Huang L. mTOR/miR-142-3p/PRAS40 signaling cascade is critical for tuberous sclerosis complex-associated renal cystogenesis. Cell Mol Biol Lett 2024; 29:125. [PMID: 39333852 PMCID: PMC11429883 DOI: 10.1186/s11658-024-00638-x] [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: 05/30/2024] [Accepted: 08/22/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Patients with tuberous sclerosis complex (TSC) develop renal cysts and/or angiomyolipomas (AMLs) due to inactive mutations of either TSC1 or TSC2 and consequential mTOR hyperactivation. The molecular events between activated mTOR and renal cysts/AMLs are still largely unknown. METHODS The mouse model of TSC-associated renal cysts were constructed by knocking out Tsc2 specifically in renal tubules (Tsc2f/f; ksp-Cre). We further globally deleted PRAS40 in these mice to investigate the role of PRAS40. Tsc2-/- cells were used as mTOR activation model cells. Inhibition of DNA methylation was used to increase miR-142-3p expression to examine the effects of miR-142-3p on PRAS40 expression and TSC-associated renal cysts. RESULTS PRAS40, a component of mTOR complex 1, was overexpressed in Tsc2-deleted cell lines and mouse kidneys (Tsc2f/f; ksp-Cre), which was decreased by mTOR inhibition. mTOR stimulated PRAS40 expression through suppression of miR-142-3p expression. Unleashed PRAS40 was critical to the proliferation of Tsc2-/- cells and the renal cystogenesis of Tsc2f/f; ksp-Cre mice. In contrast, inhibition of DNA methylation increased miR-142-3p expression, decreased PRAS40 expression, and hindered cell proliferation and renal cystogenesis. CONCLUSIONS Our data suggest that mTOR activation caused by TSC2 deletion increases PRAS40 expression through miR-142-3p repression. PRAS40 depletion or the pharmacological induction of miR-142-3p expression impaired TSC2 deficiency-associated renal cystogenesis. Therefore, harnessing mTOR/miR-142-3p/PRAS40 signaling cascade may mitigate hyperactivated mTOR-related diseases.
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Affiliation(s)
- Shuyun Zhao
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Shuai Hao
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Jiasheng Zhou
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Xinran Chen
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Tianhua Zhang
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
- Liaoning Provincial Key Laboratory of Medical Cellular and Molecular Biology, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Zhaolai Qi
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Ting Zhang
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
- Liaoning Provincial Key Laboratory of Medical Cellular and Molecular Biology, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Sajid Jalal
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Chuanxin Zhai
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Lu Yin
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Yufei Bo
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Hongming Teng
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
- Liaoning Provincial Key Laboratory of Medical Cellular and Molecular Biology, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Yue Wang
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
- Liaoning Provincial Key Laboratory of Medical Cellular and Molecular Biology, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Dongyan Gao
- Department of Pharmacology, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Hongbing Zhang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, People's Republic of China
| | - Lin Huang
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China.
- Liaoning Provincial Key Laboratory of Medical Cellular and Molecular Biology, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China.
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26
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Fert A, Richard J, Raymond Marchand L, Planas D, Routy JP, Chomont N, Finzi A, Ancuta P. Metformin facilitates viral reservoir reactivation and their recognition by anti-HIV-1 envelope antibodies. iScience 2024; 27:110670. [PMID: 39252967 PMCID: PMC11381840 DOI: 10.1016/j.isci.2024.110670] [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: 02/13/2024] [Revised: 05/27/2024] [Accepted: 08/01/2024] [Indexed: 09/11/2024] Open
Abstract
The mechanistic target of rapamycin (mTOR) positively regulates multiple steps of the HIV-1 replication cycle. We previously reported that a 12-week supplementation of antiretroviral therapy (ART) with metformin, an indirect mTOR inhibitor used in type-2 diabetes treatment, reduced mTOR activation and HIV transcription in colon-infiltrating CD4+ T cells, together with systemic inflammation in nondiabetic people with HIV-1 (PWH). Herein, we investigated the antiviral mechanisms of metformin. In a viral outgrowth assay performed with CD4+ T cells from ART-treated PWH, and upon infection in vitro with replication-competent and VSV-G-pseudotyped HIV-1, metformin decreased virion release, but increased the frequency of productively infected CD4lowHIV-p24+ T cells. These observations coincided with increased BST2/tetherin (HIV release inhibitor) and Bcl-2 (pro-survival factor) expression, and improved recognition of productively infected T cells by HIV-1 envelope antibodies. Thus, metformin exerts pleiotropic effects on post-integration steps of the HIV-1 replication cycle and may be used to accelerate viral reservoir decay in ART-treated PWH.
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Affiliation(s)
- Augustine Fert
- Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, QC H2X 0A9, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - Jonathan Richard
- Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, QC H2X 0A9, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | | | - Delphine Planas
- Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, QC H2X 0A9, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - Jean-Pierre Routy
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Division of Hematology, McGill University Health Centre, Montreal, QC, Canada
| | - Nicolas Chomont
- Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, QC H2X 0A9, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - Andrés Finzi
- Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, QC H2X 0A9, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - Petronela Ancuta
- Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, QC H2X 0A9, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada
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27
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Qi L, Groeger M, Sharma A, Goswami I, Chen E, Zhong F, Ram A, Healy K, Hsiao EC, Willenbring H, Stahl A. Adipocyte inflammation is the primary driver of hepatic insulin resistance in a human iPSC-based microphysiological system. Nat Commun 2024; 15:7991. [PMID: 39266553 PMCID: PMC11393072 DOI: 10.1038/s41467-024-52258-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 08/28/2024] [Indexed: 09/14/2024] Open
Abstract
Interactions between adipose tissue, liver and immune system are at the center of metabolic dysfunction-associated steatotic liver disease and type 2 diabetes. To address the need for an accurate in vitro model, we establish an interconnected microphysiological system (MPS) containing white adipocytes, hepatocytes and proinflammatory macrophages derived from isogenic human induced pluripotent stem cells. Using this MPS, we find that increasing the adipocyte-to-hepatocyte ratio moderately affects hepatocyte function, whereas macrophage-induced adipocyte inflammation causes lipid accumulation in hepatocytes and MPS-wide insulin resistance, corresponding to initiation of metabolic dysfunction-associated steatotic liver disease. We also use our MPS to identify and characterize pharmacological intervention strategies for hepatic steatosis and systemic insulin resistance and find that the glucagon-like peptide-1 receptor agonist semaglutide improves hepatocyte function by acting specifically on adipocytes. These results establish our MPS modeling the adipose tissue-liver axis as an alternative to animal models for mechanistic studies or drug discovery in metabolic diseases.
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Affiliation(s)
- Lin Qi
- Department of Nutritional Science and Toxicology, College of Natural Resources, University of California Berkeley, Berkeley, CA, 94720, USA
| | - Marko Groeger
- Division of Transplant Surgery, Department of Surgery, University of California San Francisco, San Francisco, CA, 94143, USA
- Eli and Edythe Broad Center for Regeneration Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Aditi Sharma
- Eli and Edythe Broad Center for Regeneration Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Ishan Goswami
- Department of Bioengineering, College of Engineering, University of California Berkeley, Berkeley, CA, 94720, USA
| | - Erzhen Chen
- Department of Nutritional Science and Toxicology, College of Natural Resources, University of California Berkeley, Berkeley, CA, 94720, USA
| | - Fenmiao Zhong
- Department of Nutritional Science and Toxicology, College of Natural Resources, University of California Berkeley, Berkeley, CA, 94720, USA
| | - Apsara Ram
- Eli and Edythe Broad Center for Regeneration Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Kevin Healy
- Department of Bioengineering, College of Engineering, University of California Berkeley, Berkeley, CA, 94720, USA
- Department of Materials Science and Engineering, College of Engineering, University of California Berkeley, Berkeley, CA, 94720, USA
| | - Edward C Hsiao
- Eli and Edythe Broad Center for Regeneration Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Holger Willenbring
- Division of Transplant Surgery, Department of Surgery, University of California San Francisco, San Francisco, CA, 94143, USA.
- Eli and Edythe Broad Center for Regeneration Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.
- Liver Center, University of California San Francisco, San Francisco, CA, 94143, USA.
| | - Andreas Stahl
- Department of Nutritional Science and Toxicology, College of Natural Resources, University of California Berkeley, Berkeley, CA, 94720, USA.
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28
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Hu D, Sheeja Prabhakaran H, Zhang YY, Luo G, He W, Liou YC. Mitochondrial dysfunction in sepsis: mechanisms and therapeutic perspectives. Crit Care 2024; 28:292. [PMID: 39227925 PMCID: PMC11373266 DOI: 10.1186/s13054-024-05069-w] [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: 05/14/2024] [Accepted: 08/17/2024] [Indexed: 09/05/2024] Open
Abstract
Sepsis is a severe medical condition characterized by a systemic inflammatory response, often culminating in multiple organ dysfunction and high mortality rates. In recent years, there has been a growing recognition of the pivotal role played by mitochondrial damage in driving the progression of sepsis. Various factors contribute to mitochondrial impairment during sepsis, encompassing mechanisms such as reactive nitrogen/oxygen species generation, mitophagy inhibition, mitochondrial dynamics change, and mitochondrial membrane permeabilization. Damaged mitochondria actively participate in shaping the inflammatory milieu by triggering key signaling pathways, including those mediated by Toll-like receptors, NOD-like receptors, and cyclic GMP-AMP synthase. Consequently, there has been a surge of interest in developing therapeutic strategies targeting mitochondria to mitigate septic pathogenesis. This review aims to delve into the intricate mechanisms underpinning mitochondrial dysfunction during sepsis and its significant impact on immune dysregulation. Moreover, we spotlight promising mitochondria-targeted interventions that have demonstrated therapeutic efficacy in preclinical sepsis models.
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Affiliation(s)
- Dongxue Hu
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543, Singapore
| | - Harshini Sheeja Prabhakaran
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543, Singapore
| | - Yuan-Yuan Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Gaoxing Luo
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Chongqing Key Laboratory for Disease Proteomics, Chongqing, 400038, China
| | - Weifeng He
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Chongqing Key Laboratory for Disease Proteomics, Chongqing, 400038, China.
| | - Yih-Cherng Liou
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543, Singapore.
- Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore, 119077, Singapore.
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29
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Bramante CT, Beckman KB, Mehta T, Karger AB, Odde DJ, Tignanelli CJ, Buse JB, Johnson DM, Watson RHB, Daniel JJ, Liebovitz DM, Nicklas JM, Cohen K, Puskarich MA, Belani HK, Siegel LK, Klatt NR, Anderson B, Hartman KM, Rao V, Hagen AA, Patel B, Fenno SL, Avula N, Reddy NV, Erickson SM, Fricton RD, Lee S, Griffiths G, Pullen MF, Thompson JL, Sherwood NE, Murray TA, Rose MR, Boulware DR, Huling JD. Favorable Antiviral Effect of Metformin on SARS-CoV-2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of COVID-19. Clin Infect Dis 2024; 79:354-363. [PMID: 38690892 PMCID: PMC11327787 DOI: 10.1093/cid/ciae159] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Indexed: 05/03/2024] Open
Abstract
BACKGROUND Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. METHODS COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. RESULTS The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95% confidence interval [CI], -1.05 to -.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. CONCLUSIONS In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. CLINICAL TRIALS REGISTRATION NCT04510194.
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Affiliation(s)
- Carolyn T Bramante
- General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Kenneth B Beckman
- Genomics Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Tanvi Mehta
- Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA
| | - Amy B Karger
- Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - David J Odde
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA
| | | | - John B Buse
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Darrell M Johnson
- Genomics Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Ray H B Watson
- Genomics Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Jerry J Daniel
- Genomics Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - David M Liebovitz
- General Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Jacinda M Nicklas
- General Internal Medicine, University of Colorado, School of Medicine, Aurora, Colorado, USA
| | - Ken Cohen
- UnitedHealth Group, Optum Labs, Minnetonka, Minnesota, USA
| | - Michael A Puskarich
- Emergency Medicine, Hennepin County Medical Center, Minneapolis, Minnesota, USA
| | - Hrishikesh K Belani
- Department of Medicine, Olive View—University of California, Los Angeles, California, USA
| | - Lianne K Siegel
- Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA
| | - Nichole R Klatt
- Department of Surgery, Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - Blake Anderson
- Atlanta Veterans Affairs Medical Center, Atlanta, Georgia, USA
- Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Katrina M Hartman
- General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Via Rao
- General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Aubrey A Hagen
- General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Barkha Patel
- General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Sarah L Fenno
- General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Nandini Avula
- General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Neha V Reddy
- General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Spencer M Erickson
- General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Regina D Fricton
- General Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Samuel Lee
- General Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Gwendolyn Griffiths
- General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Matthew F Pullen
- Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Jennifer L Thompson
- Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Nancy E Sherwood
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA
| | - Thomas A Murray
- Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA
| | - Michael R Rose
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - David R Boulware
- Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Jared D Huling
- Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA
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Siedner MJ, Sax PE. Repurposing Revisited: Exploring the Role of Metformin for Treatment of COVID-19. Clin Infect Dis 2024; 79:292-294. [PMID: 38690870 DOI: 10.1093/cid/ciae154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Indexed: 05/03/2024] Open
Affiliation(s)
- Mark J Siedner
- Medical Practice Evaluation Center and Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
- Clinical Research Department, Africa Health Research Institute, KwaZulu-Natal, South Africa
| | - Paul E Sax
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
- Division of Infectious Diseases and Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
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31
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Liu X, Guo B, Li Q, Nie J. mTOR in metabolic homeostasis and disease. Exp Cell Res 2024; 441:114173. [PMID: 39047807 DOI: 10.1016/j.yexcr.2024.114173] [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: 10/07/2023] [Revised: 07/20/2024] [Accepted: 07/21/2024] [Indexed: 07/27/2024]
Abstract
The ability to maintain cellular metabolic homeostasis is critical to life, in which mTOR plays an important role. This kinase integrates upstream nutrient signals and performs essential functions in physiology and metabolism by increasing metabolism and suppressing autophagy. Thus, dysregulation of mTOR activity leads to diseases, especially metabolic diseases such as cancer, type 2 diabetes and neurological disorders. Therefore, inhibition of overactivated mTOR becomes a rational approach to treat a variety of metabolic diseases. In this review, we discuss how mTOR responds to upstream signals and how mTOR regulates metabolic processes, including protein, nucleic acid, and lipid metabolism. Furthermore, we discuss the possible causes and consequences of dysregulated mTOR signaling activity, and summarize relevant applications, such as inhibition of mTOR activity to treat these diseases. This review will advance our comprehensive knowledge of the association between mTOR and metabolic homeostasis, which has significant ramifications for human health.
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Affiliation(s)
- Xuejia Liu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
| | - Bin Guo
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
| | - Qiye Li
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
| | - Jing Nie
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China.
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32
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Ashraf N, Van Nostrand JL. Fine-tuning AMPK in physiology and disease using point-mutant mouse models. Dis Model Mech 2024; 17:dmm050798. [PMID: 39136185 PMCID: PMC11340815 DOI: 10.1242/dmm.050798] [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] [Indexed: 08/17/2024] Open
Abstract
AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that monitors the cellular energy status to adapt it to the fluctuating nutritional and environmental conditions in an organism. AMPK plays an integral part in a wide array of physiological processes, such as cell growth, autophagy and mitochondrial function, and is implicated in diverse diseases, including cancer, metabolic disorders, cardiovascular diseases and neurodegenerative diseases. AMPK orchestrates many different physiological outcomes by phosphorylating a broad range of downstream substrates. However, the importance of AMPK-mediated regulation of these substrates in vivo remains an ongoing area of investigation to better understand its precise role in cellular and metabolic homeostasis. Here, we provide a comprehensive overview of our understanding of the kinase function of AMPK in vivo, as uncovered from mouse models that harbor phosphorylation mutations in AMPK substrates. We discuss some of the inherent limitations of these mouse models, highlight the broader implications of these studies for understanding human health and disease, and explore the valuable insights gained that could inform future therapeutic strategies for the treatment of metabolic and non-metabolic disorders.
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Affiliation(s)
- Naghmana Ashraf
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jeanine L. Van Nostrand
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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Rajeev D, MacIver NJ. Metformin as a Therapeutic Agent for Obesity-Associated Immune Dysfunction. J Nutr 2024; 154:2534-2542. [PMID: 38972391 DOI: 10.1016/j.tjnut.2024.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 05/16/2024] [Accepted: 07/02/2024] [Indexed: 07/09/2024] Open
Abstract
Obesity is associated with impaired immune function, characterized by inflammation, and leading to poor response to infection, impaired vaccine response, increased susceptibility to autoimmune disease, and increased risk of cancer and cancer mortality. Worse, there is evidence that weight loss alone may be insufficient to reverse the immune dysfunction caused by obesity. It is therefore critically important to identify alternative therapeutic approaches to decrease the negative effects of obesity-associated inflammation. In this article, we will review evidence that the antidiabetic drug metformin may be considered as a therapeutic agent for obesity-associated immune dysfunction. Metformin has immunomodulatory effects, stimulating or suppressing the immune response in both a cell-specific and disease-specific manner. Although the mechanism of action of metformin on the immune system remains to be fully elucidated, there is strong evidence that metformin enters select immune cells and disrupts electron transport, leading to both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent effects on immune cell differentiation and cytokine production. These effects of metformin on immune cells have been shown to improve immune responses to infection, autoimmunity, and cancer.
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Affiliation(s)
- Devika Rajeev
- Department of Nutrition, University of North Carolina at Chapel Hill, NC, United States
| | - Nancie J MacIver
- Department of Nutrition, University of North Carolina at Chapel Hill, NC, United States; Department of Pediatrics, University of North Carolina at Chapel Hill, NC, United States; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, NC, United States.
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De la Cruz-López KG, Alvarado-Ortiz E, Valencia-González HA, Beltrán-Anaya FO, Zamora-Fuentes JM, Hidalgo-Miranda A, Ortiz-Sánchez E, Espinal-Enríquez J, García-Carrancá A. Metformin induces ZFP36 by mTORC1 inhibition in cervical cancer-derived cell lines. BMC Cancer 2024; 24:853. [PMID: 39026155 PMCID: PMC11256429 DOI: 10.1186/s12885-024-12555-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Accepted: 06/24/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND Metformin, a widely prescribed antidiabetic drug, has shown several promising effects for cancer treatment. These effects have been shown to be mediated by dual modulation of the AMPK-mTORC1 axis, where AMPK acts upstream of mTORC1 to decrease its activity. Nevertheless, alternative pathways have been recently discovered suggesting that metformin can act through of different targets regulation. METHODS We performed a transcriptome screening analysis using HeLa xenograft tumors generated in NOD-SCID mice treated with or without metformin to examine genes regulated by metformin. Western Blot analysis, Immunohistochemical staining, and RT-qPCR were used to confirm alterations in gene expression. The TNMplot and GEPIA2 platform were used for in silico analysis of genes found up-regulated by metformin, in cervical cancer patients. We performed an AMPK knock-down using AMPK-targeted siRNAs and mTOR inhibition with rapamycin to investigate the molecular mechanisms underlying the effect of metformin in cervical cancer cell lines. RESULTS We shown that metformin decreases tumor growth and increased the expression of a group of antitumoral genes involved in DNA-binding transcription activator activity, hormonal response, and Dcp1-Dcp2 mRNA-decapping complex. We demonstrated that ZFP36 could act as a new molecular target increased by metformin. mTORC1 inhibition using rapamycin induces ZFP36 expression, which could suggest that metformin increases ZFP36 expression and requires mTORC1 inhibition for such effect. Surprisingly, in HeLa cells AMPK inhibition did not affect ZFP36 expression, suggesting that additional signal transducers related to suppressing mTORC1 activity, could be involved. CONCLUSIONS These results highlight the importance of ZFP36 activation in response to metformin treatment involving mTORC1 inhibition.
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Affiliation(s)
- Karen Griselda De la Cruz-López
- Programa de Doctorado en Ciencias Biomédicas, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer. Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México & Instituto Nacional de Cancerología., Av. San Fernando No. 22 Colonia Sección XVI, Tlalpan, Mexico City, 14080, Mexico
| | - Eduardo Alvarado-Ortiz
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Heriberto A Valencia-González
- Laboratorio de Células Troncales y Desarrollo Terapéutico Antineoplásico, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico
| | - Fredy Omar Beltrán-Anaya
- Laboratorio de Diagnóstico e Investigación en Salud, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo de los Bravo, Gro, Mexico
| | - José María Zamora-Fuentes
- Laboratorio de Oncología Teórica, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
- Centro de Ciencias de La Complejidad, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Alfredo Hidalgo-Miranda
- Laboratorio de Genómica de Cáncer, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Elizabeth Ortiz-Sánchez
- Laboratorio de Células Troncales y Desarrollo Terapéutico Antineoplásico, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico
| | - Jesús Espinal-Enríquez
- Laboratorio de Oncología Teórica, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
- Centro de Ciencias de La Complejidad, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Alejandro García-Carrancá
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer. Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México & Instituto Nacional de Cancerología., Av. San Fernando No. 22 Colonia Sección XVI, Tlalpan, Mexico City, 14080, Mexico.
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Huang Q, Ren Y, Yuan P, Huang M, Liu G, Shi Y, Jia G, Chen M. Targeting the AMPK/Nrf2 Pathway: A Novel Therapeutic Approach for Acute Lung Injury. J Inflamm Res 2024; 17:4683-4700. [PMID: 39051049 PMCID: PMC11268519 DOI: 10.2147/jir.s467882] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 07/09/2024] [Indexed: 07/27/2024] Open
Abstract
ALI(acute lung injury) is a severe respiratory dysfunction caused by various intrapulmonary and extrapulmonary factors. It is primarily characterized by oxidative stress and affects the integrity of the pulmonary barrier. In severe cases, ALI can progress to ARDS(acute respiratory distress syndrome), a condition that poses a serious threat to the lives of affected patients. To date, the etiological mechanisms underlying ALI remain elusive, and available therapeutic options are quite limited. AMPK(AMP-activated protein kinase), an essential serine/threonine protein kinase, performs a pivotal function in the regulation of cellular energy levels and cellular regulatory mechanisms, including the detection of redox signals and mitigating oxidative stress. Meanwhile, Nrf2(nuclear factor erythroid 2-related factor 2), a critical transcription factor, alleviates inflammation and oxidative responses by interacting with multiple signaling pathways and contributing to the modulation of oxidative enzymes associated with inflammation and programmed cell death. Indeed, AMPK induces the dissociation of Nrf2 from Keap1(kelch-like ECH-associated protein-1) and facilitates its translocation into the nucleus to trigger the transcription of downstream antioxidant genes, ultimately suppressing the expression of inflammatory cells in the lungs. Given their roles, AMPK and Nrf2 hold promise as novel treatment targets for ALI. This study aimed to summarise the current status of research on the AMPK/Nrf2 signaling pathway in ALI, encompassing recently reported natural compounds and drugs that can activate the AMPK/Nrf2 signaling pathway to alleviate lung injury, and provide a theoretical reference for early intervention in lung injury and future research on lung protection.
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Affiliation(s)
- Qianxia Huang
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi City, Gui Zhou, People’s Republic of China
| | - Yingcong Ren
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi City, Gui Zhou, People’s Republic of China
| | - Ping Yuan
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi City, Gui Zhou, People’s Republic of China
| | - Ma Huang
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi City, Gui Zhou, People’s Republic of China
| | - Guoyue Liu
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi City, Gui Zhou, People’s Republic of China
| | - Yuanzhi Shi
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi City, Gui Zhou, People’s Republic of China
| | - Guiyang Jia
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi City, Gui Zhou, People’s Republic of China
| | - Miao Chen
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi City, Gui Zhou, People’s Republic of China
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36
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Shan M, Cheng Q, Parris AB, Kong L, Yang X, Shi Y. Metformin reduces basal subpopulation and attenuates mammary epithelial cell stemness in FVB/N mice. Front Cell Dev Biol 2024; 12:1427395. [PMID: 39055652 PMCID: PMC11269140 DOI: 10.3389/fcell.2024.1427395] [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: 05/03/2024] [Accepted: 06/17/2024] [Indexed: 07/27/2024] Open
Abstract
Metformin shows promise in breast cancer prevention, but its underlying mechanisms remain unclear. This study investigated the impact of metformin on the repopulation dynamics of mammary epithelial cells (MECs) and the signaling pathways in non-tumorigenic FVB/N mice. This study aimed to enhance our understanding of the role of metformin in reducing the susceptibility of MECs in premalignant tissues to oncogenic factors. In this study, female mice were administered 200 mg/kg/day of metformin via intraperitoneal (i.p.) injection from 8 to 18 weeks of age. After this treatment period, morphogenesis, flow cytometry, analyses of MEC stemness, and RNA sequencing were performed. The study findings indicated that metformin treatment in adult mice reduced mammary gland proliferation, as demonstrated by decreased Ki67+ cells and lateral bud formation. Additionally, metformin significantly reduced both basal and mammary repopulating unit subpopulations, indicating an impact on mammary epithelial cell repopulation. Mammosphere, colony-forming cell, and 3D culture assays revealed that metformin adversely affected mammary epithelial cell stemness. Furthermore, metformin downregulated signaling in key pathways including AMPK/mTOR, MAPK/Erk, PI3K/Akt, and ER, which contribute to its inhibitory effects on mammary proliferation and stemness. Transcriptome analysis with RNA sequencing indicated that metformin induced significant downregulation of genes involved in multiple critical pathways. KEGG-based pathway analysis indicated that genes in PI3K/Akt, focal adhesion, ECM-receptor, small cell lung cancer and immune-modulation pathways were among the top groups of differentially regulated genes. In summary, our research demonstrates that metformin inhibits MEC proliferation and stemness, accompanied by the downregulation of intrinsic signaling. These insights suggest that the regulatory effects of metformin on premalignant mammary tissues could potentially delay or prevent the onset of breast cancer, offering a promising avenue for developing new preventive strategies.
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Affiliation(s)
- Minghui Shan
- Department of Pathology, People’s Hospital of Zhengzhou University, Zhengzhou, Hena, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Qiong Cheng
- Department of Pathology, People’s Hospital of Zhengzhou University, Zhengzhou, Hena, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Amanda B. Parris
- Biomedical/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Research Campus, North Carolina Central University, Kannapolis, NC, United States
| | - Lingfei Kong
- Department of Pathology, People’s Hospital of Zhengzhou University, Zhengzhou, Hena, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Xiaohe Yang
- Department of Pathology, People’s Hospital of Zhengzhou University, Zhengzhou, Hena, China
- Biomedical/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Research Campus, North Carolina Central University, Kannapolis, NC, United States
| | - Yujie Shi
- Department of Pathology, People’s Hospital of Zhengzhou University, Zhengzhou, Hena, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
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Chmielewski PP, Data K, Strzelec B, Farzaneh M, Anbiyaiee A, Zaheer U, Uddin S, Sheykhi-Sabzehpoush M, Mozdziak P, Zabel M, Dzięgiel P, Kempisty B. Human Aging and Age-Related Diseases: From Underlying Mechanisms to Pro-Longevity Interventions. Aging Dis 2024:AD.2024.0280. [PMID: 38913049 DOI: 10.14336/ad.2024.0280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 06/02/2024] [Indexed: 06/25/2024] Open
Abstract
As human life expectancy continues to rise, becoming a pressing global concern, it brings into focus the underlying mechanisms of aging. The increasing lifespan has led to a growing elderly population grappling with age-related diseases (ARDs), which strains healthcare systems and economies worldwide. While human senescence was once regarded as an immutable and inexorable phenomenon, impervious to interventions, the emerging field of geroscience now offers innovative approaches to aging, holding the promise of extending the period of healthspan in humans. Understanding the intricate links between aging and pathologies is essential in addressing the challenges presented by aging populations. A substantial body of evidence indicates shared mechanisms and pathways contributing to the development and progression of various ARDs. Consequently, novel interventions targeting the intrinsic mechanisms of aging have the potential to delay the onset of diverse pathological conditions, thereby extending healthspan. In this narrative review, we discuss the most promising methods and interventions aimed at modulating aging, which harbor the potential to mitigate ARDs in the future. We also outline the complexity of senescence and review recent empirical evidence to identify rational strategies for promoting healthy aging.
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Affiliation(s)
- Piotr Pawel Chmielewski
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Krzysztof Data
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Bartłomiej Strzelec
- 2nd Department of General Surgery and Surgical Oncology, Medical University Hospital, Wroclaw, Poland
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Amir Anbiyaiee
- Department of Surgery, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Uzma Zaheer
- School of Biosciences, Faculty of Health Sciences and Medicine, The University of Surrey, United Kingdom
| | - Shahab Uddin
- Translational Institute and Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, India
| | | | - Paul Mozdziak
- Graduate Physiology Program, North Carolina State University, Raleigh, NC 27695, USA
| | - Maciej Zabel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, Wroclaw, Poland
- Division of Anatomy and Histology, The University of Zielona Góra, Poland
| | - Piotr Dzięgiel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, Wroclaw, Poland
| | - Bartosz Kempisty
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, Torun, Poland
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC 27695, USA
- Center of Assisted Reproduction, Department of Obstetrics and Gynecology, University Hospital and Masaryk University, Brno, Czech Republic
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Yasasilka XR, Lee M. Role of β-cell autophagy in β-cell physiology and the development of diabetes. J Diabetes Investig 2024; 15:656-668. [PMID: 38470018 PMCID: PMC11143416 DOI: 10.1111/jdi.14184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 02/14/2024] [Accepted: 02/28/2024] [Indexed: 03/13/2024] Open
Abstract
Elucidating the molecular mechanism of autophagy was a landmark in understanding not only the physiology of cells and tissues, but also the pathogenesis of diverse diseases, including diabetes and metabolic disorders. Autophagy of pancreatic β-cells plays a pivotal role in the maintenance of the mass, structure and function of β-cells, whose dysregulation can lead to abnormal metabolic profiles or diabetes. Modulators of autophagy are being developed to improve metabolic profile and β-cell function through the removal of harmful materials and rejuvenation of organelles, such as mitochondria and endoplasmic reticulum. Among the known antidiabetic drugs, glucagon-like peptide-1 receptor agonists enhance the autophagic activity of β-cells, which might contribute to the profound effects of glucagon-like peptide-1 receptor agonists on systemic metabolism. In this review, the results from studies on the role of autophagy in β-cells and their implication in the development of diabetes are discussed. In addition to non-selective (macro)autophagy, the role and mechanisms of selective autophagy and other minor forms of autophagy that might occur in β-cells are discussed. As β-cell failure is the ultimate cause of diabetes and unresponsiveness to conventional therapy, modulation of β-cell autophagy might represent a future antidiabetic treatment approach, particularly in patients who are not well managed with current antidiabetic therapy.
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Affiliation(s)
- Xaviera Riani Yasasilka
- Soonchunhyang Institute of Medi‐bio Science and Division of Endocrinology, Department of Internal MedicineSoonchunhyang University College of MedicineCheonanKorea
| | - Myung‐Shik Lee
- Soonchunhyang Institute of Medi‐bio Science and Division of Endocrinology, Department of Internal MedicineSoonchunhyang University College of MedicineCheonanKorea
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39
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Zamanian MY, Golmohammadi M, Yumashev A, Hjazi A, Toama MA, AbdRabou MA, Gehlot A, Alwaily ER, Shirsalimi N, Yadav PK, Moriasi G. Effects of metformin on cancers in experimental and clinical studies: Focusing on autophagy and AMPK/mTOR signaling pathways. Cell Biochem Funct 2024; 42:e4071. [PMID: 38863255 DOI: 10.1002/cbf.4071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 05/25/2024] [Accepted: 06/02/2024] [Indexed: 06/13/2024]
Abstract
Metformin (MET) is a preferred drug for the treatment of type 2 diabetes mellitus. Recent studies show that apart from its blood glucose-lowering effects, it also inhibits the development of various tumours, by inducing autophagy. Various studies have confirmed the inhibitory effects of MET on cancer cell lines' propagation, migration, and invasion. The objective of the study was to comprehensively review the potential of MET as an anticancer agent, particularly focusing on its ability to induce autophagy and inhibit the development and progression of various tumors. The study aimed to explore the inhibitory effects of MET on cancer cell proliferation, migration, and invasion, and its impact on key signaling pathways such as adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and PI3K. This review noted that MET exerts its anticancer effects by regulating key signalling pathways such as phosphoinositide 3-kinase (PI3K), LC3-I and LC3-II, Beclin-1, p53, and the autophagy-related gene (ATG), inhibiting the mTOR protein, downregulating the expression of p62/SQSTM1, and blockage of the cell cycle at the G0/G1. Moreover, MET can stimulate autophagy through pathways associated with the 5' AMPK, thereby inhibiting he development and progression of various human cancers, including hepatocellular carcinoma, prostate cancer, pancreatic cancer, osteosarcoma, myeloma, and non-small cell lung cancer. In summary, this detailed review provides a framework for further investigations that may appraise the autophagy-induced anticancer potential of MET and its repurposing for cancer treatment.
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Affiliation(s)
- Mohammad Yasin Zamanian
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Maryam Golmohammadi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alexey Yumashev
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Mariam Alaa Toama
- College of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | | | - Anita Gehlot
- Department of Electronics & Communication Engineering, Uttaranchal Institute of Technology, Uttaranchal University, Dehradun, India
| | - Enas R Alwaily
- Microbiology Research Group, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Niyousha Shirsalimi
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Pankaj Kumar Yadav
- Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, India
| | - Gervason Moriasi
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Mount Kenya University, Thika, Kenya
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40
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Kumar V, Stewart Iv JH. Pattern-Recognition Receptors and Immunometabolic Reprogramming: What We Know and What to Explore. J Innate Immun 2024; 16:295-323. [PMID: 38740018 PMCID: PMC11250681 DOI: 10.1159/000539278] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 05/07/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Evolutionarily, immune response is a complex mechanism that protects the host from internal and external threats. Pattern-recognition receptors (PRRs) recognize MAMPs, PAMPs, and DAMPs to initiate a protective pro-inflammatory immune response. PRRs are expressed on the cell membranes by TLR1, 2, 4, and 6 and in the cytosolic organelles by TLR3, 7, 8, and 9, NLRs, ALRs, and cGLRs. We know their downstream signaling pathways controlling immunoregulatory and pro-inflammatory immune response. However, the impact of PRRs on metabolic control of immune cells to control their pro- and anti-inflammatory activity has not been discussed extensively. SUMMARY Immune cell metabolism or immunometabolism critically determines immune cells' pro-inflammatory phenotype and function. The current article discusses immunometabolic reprogramming (IR) upon activation of different PRRs, such as TLRs, NLRs, cGLRs, and RLRs. The duration and type of PRR activated, species studied, and location of immune cells to specific organ are critical factors to determine the IR-induced immune response. KEY MESSAGE The work herein describes IR upon TLR, NLR, cGLR, and RLR activation. Understanding IR upon activating different PRRs is critical for designing better immune cell-specific immunotherapeutics and immunomodulators targeting inflammation and inflammatory diseases.
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Affiliation(s)
- Vijay Kumar
- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Medical Education Building-C, Morehouse School of Medicine, Atlanta, Georgia, USA
| | - John H Stewart Iv
- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Medical Education Building-C, Morehouse School of Medicine, Atlanta, Georgia, USA
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Plowman TJ, Christensen H, Aiges M, Fernandez E, Shah MH, Ramana KV. Anti-Inflammatory Potential of the Anti-Diabetic Drug Metformin in the Prevention of Inflammatory Complications and Infectious Diseases Including COVID-19: A Narrative Review. Int J Mol Sci 2024; 25:5190. [PMID: 38791227 PMCID: PMC11121530 DOI: 10.3390/ijms25105190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 05/03/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
Metformin, a widely used first-line anti-diabetic therapy for the treatment of type-2 diabetes, has been shown to lower hyperglycemia levels in the blood by enhancing insulin actions. For several decades this drug has been used globally to successfully control hyperglycemia. Lactic acidosis has been shown to be a major adverse effect of metformin in some type-2 diabetic patients, but several studies suggest that it is a typically well-tolerated and safe drug in most patients. Further, recent studies also indicate its potential to reduce the symptoms associated with various inflammatory complications and infectious diseases including coronavirus disease 2019 (COVID-19). These studies suggest that besides diabetes, metformin could be used as an adjuvant drug to control inflammatory and infectious diseases. In this article, we discuss the current understanding of the role of the anti-diabetic drug metformin in the prevention of various inflammatory complications and infectious diseases in both diabetics and non-diabetics.
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Affiliation(s)
| | | | | | | | | | - Kota V. Ramana
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, UT 84606, USA
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42
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Rindone GM, Dasso ME, Centola CL, Sobarzo CM, Galardo MN, Meroni SB, Riera MF. Effect of Metformin on Sertoli Cell Fatty Acid Metabolism and Blood-Testis Barrier Formation. BIOLOGY 2024; 13:330. [PMID: 38785812 PMCID: PMC11117697 DOI: 10.3390/biology13050330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 05/06/2024] [Accepted: 05/08/2024] [Indexed: 05/25/2024]
Abstract
Sertoli cells (SCs) are essential to maintaining germ cell development. Metformin, the main pharmacologic treatment for pediatric type 2 diabetes, is administered to children during SC maturation. The present study aimed to analyze whether metformin affects SC energy metabolism and blood-testis barrier (BTB) integrity. Primary SC cultures were used for the in vitro studies. In vivo effects were studied in Sprague-Dawley rats treated with 200 mg/kg metformin from Pnd14 to Pnd30. Metformin decreased fatty acid oxidation and increased 3-hydroxybutyrate production in vitro. Moreover, it decreased the transepithelial electrical resistance across the monolayer and induced ZO-1 redistribution, suggesting an alteration of cell junctions. In vivo, a mild but significant increase in BTB permeability and ZO-1 expression was observed in the metformin group, without changes in testicular histology and meiosis progression. Additionally, adult rats that received metformin treatment during the juvenile period showed no alteration in BTB permeability or daily sperm production. In conclusion, metformin exposure may affect BTB permeability in juvenile rats, but this seems not to influence spermatogenesis progression. Considering the results obtained in adult animals, it is possible to speculate that metformin treatment during the juvenile period does not affect testicular function in adulthood.
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Affiliation(s)
- Gustavo Marcelo Rindone
- Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), FEI–División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires C1425EFD, Argentina; (G.M.R.); (M.E.D.); (C.L.C.); (M.N.G.); (S.B.M.)
| | - Marina Ercilia Dasso
- Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), FEI–División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires C1425EFD, Argentina; (G.M.R.); (M.E.D.); (C.L.C.); (M.N.G.); (S.B.M.)
| | - Cecilia Lucia Centola
- Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), FEI–División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires C1425EFD, Argentina; (G.M.R.); (M.E.D.); (C.L.C.); (M.N.G.); (S.B.M.)
| | - Cristian Marcelo Sobarzo
- Instituto de Investigaciones Biomédicas (INBIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires C1121ABG, Argentina;
| | - María Noel Galardo
- Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), FEI–División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires C1425EFD, Argentina; (G.M.R.); (M.E.D.); (C.L.C.); (M.N.G.); (S.B.M.)
| | - Silvina Beatriz Meroni
- Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), FEI–División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires C1425EFD, Argentina; (G.M.R.); (M.E.D.); (C.L.C.); (M.N.G.); (S.B.M.)
| | - María Fernanda Riera
- Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), FEI–División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires C1425EFD, Argentina; (G.M.R.); (M.E.D.); (C.L.C.); (M.N.G.); (S.B.M.)
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Yagasaki R, Morita A, Mori A, Sakamoto K, Nakahara T. The Anti-Diabetic Drug Metformin Suppresses Pathological Retinal Angiogenesis via Blocking the mTORC1 Signaling Pathway in Mice (Metformin Suppresses Pathological Angiogenesis). Curr Eye Res 2024; 49:505-512. [PMID: 38251680 DOI: 10.1080/02713683.2024.2302865] [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: 05/20/2023] [Accepted: 01/03/2024] [Indexed: 01/23/2024]
Abstract
PURPOSE Metformin, a biguanide antihyperglycemic drug, can exert various beneficial effects in addition to its glucose-lowering effect. The effects of metformin are mainly mediated by AMP-activated protein kinase (AMPK)-dependent pathway. AMPK activation interferes with the action of the mammalian target of rapamycin complex 1 (mTORC1), and blockade of mTORC1 pathway suppresses pathological retinal angiogenesis. Therefore, in this study, we examined the effects of metformin on pathological angiogenesis and mTORC1 activity in the retinas of mice with oxygen-induced retinopathy (OIR). METHODS OIR was induced by exposing the mice to 80% oxygen from postnatal day (P) 7 to P10. The OIR mice were treated with metformin, rapamycin (an inhibitor of mTORC1), or the vehicle from P10 to P12 or P14. The formation of neovascular tufts, revascularization in the central avascular areas, expression of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) 2, and phosphorylated ribosomal protein S6 (pS6), a downstream indicator of mTORC1 activity, were evaluated at P10, P13, or P15. RESULTS Neovascular tufts and vascular growth in the central avascular areas were observed in the retinas of P15 OIR mice. The formation of neovascular tufts, but not the revascularization in the central avascular areas, was attenuated by metformin administration from P10 to P14. Metformin had no significant inhibitory effect on the expression of VEGF and VEGFR2, but it reduced the pS6 immunoreactivity in vascular cells at the sites of angiogenesis. Rapamycin completely blocked the phosphorylation of ribosomal protein S6 and markedly reduced the formation of neovascular tufts. CONCLUSIONS These results suggest that metformin partially suppresses the formation of neovascular tufts on the retinal surface by blocking the mTORC1 signaling pathway. Metformin may exert beneficial effects against the progression of ocular diseases in which abnormal angiogenesis is associated with the pathogenesis.
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Affiliation(s)
- Rina Yagasaki
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
| | - Akane Morita
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
| | - Asami Mori
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
| | - Kenji Sakamoto
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
| | - Tsutomu Nakahara
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
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44
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Yew MJ, Heywood SE, Ng J, West OM, Pal M, Kueh A, Lancaster GI, Myers S, Yang C, Liu Y, Reibe S, Mellett NA, Meikle PJ, Febbraio MA, Greening DW, Drew BG, Henstridge DC. ACAD10 is not required for metformin's metabolic actions or for maintenance of whole-body metabolism in C57BL/6J mice. Diabetes Obes Metab 2024; 26:1731-1745. [PMID: 38351663 DOI: 10.1111/dom.15484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 01/08/2024] [Accepted: 01/18/2024] [Indexed: 04/09/2024]
Abstract
AIM Acyl-coenzyme A dehydrogenase family member 10 (ACAD10) is a mitochondrial protein purported to be involved in the fatty acid oxidation pathway. Metformin is the most prescribed therapy for type 2 diabetes; however, its precise mechanisms of action(s) are still being uncovered. Upregulation of ACAD10 is a requirement for metformin's ability to inhibit growth in cancer cells and extend lifespan in Caenorhabditis elegans. However, it is unknown whether ACAD10 plays a role in metformin's metabolic actions. MATERIALS AND METHODS We assessed the role for ACAD10 on whole-body metabolism and metformin action by generating ACAD10KO mice on a C57BL/6J background via CRISPR-Cas9 technology. In-depth metabolic phenotyping was conducted in both sexes on a normal chow and high fat-high sucrose diet. RESULTS Compared with wildtype mice, we detected no difference in body composition, energy expenditure or glucose tolerance in male or female ACAD10KO mice, on a chow diet or high-fat, high-sucrose diet (p ≥ .05). Hepatic mitochondrial function and insulin signalling was not different between genotypes under basal or insulin-stimulated conditions (p ≥ .05). Glucose excursions following acute administration of metformin before a glucose tolerance test were not different between genotypes nor was body composition or energy expenditure altered after 4 weeks of daily metformin treatment (p ≥ .05). Despite the lack of a metabolic phenotype, liver lipidomic analysis suggests ACAD10 depletion influences the abundance of specific ceramide species containing very long chain fatty acids, while metformin treatment altered clusters of cholesterol ester, plasmalogen, phosphatidylcholine and ceramide species. CONCLUSIONS Loss of ACAD10 does not alter whole-body metabolism or impact the acute or chronic metabolic actions of metformin in this model.
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Affiliation(s)
- Michael J Yew
- School of Health Sciences, The University of Tasmania, Launceston, Tasmania, Australia
| | - Sarah E Heywood
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Joe Ng
- School of Health Sciences, The University of Tasmania, Launceston, Tasmania, Australia
| | - Olivia M West
- School of Health Sciences, The University of Tasmania, Launceston, Tasmania, Australia
| | - Martin Pal
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- School of Dentistry and Medical Sciences, Charles Sturt University, Wagga Wagga, New South Wales, Australia
| | - Andrew Kueh
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | | | - Stephen Myers
- School of Health Sciences, The University of Tasmania, Launceston, Tasmania, Australia
| | - Christine Yang
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Yingying Liu
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Saskia Reibe
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- University of Oxford, Oxford, UK
| | | | - Peter J Meikle
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Baker Department of Cardiovascular Research, Translation and Implementation, Melbourne, Victoria, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Victoria, Australia
| | - Mark A Febbraio
- Monash Institute of Pharmaceutical Sciences, Melbourne, Victoria, Australia
| | - David W Greening
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Baker Department of Cardiovascular Research, Translation and Implementation, Melbourne, Victoria, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Victoria, Australia
| | - Brian G Drew
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Darren C Henstridge
- School of Health Sciences, The University of Tasmania, Launceston, Tasmania, Australia
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
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45
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Arezoumand KS, Roberts CT, Rastegar M. Metformin Induces MeCP2 in the Hippocampus of Male Mice with Sex-Specific and Brain-Region-Dependent Molecular Impact. Biomolecules 2024; 14:505. [PMID: 38672521 PMCID: PMC11048179 DOI: 10.3390/biom14040505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/29/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Rett Syndrome (RTT) is a progressive X-linked neurodevelopmental disorder with no cure. RTT patients show disease-associated symptoms within 18 months of age that include developmental regression, progressive loss of useful hand movements, and breathing difficulties, along with neurological impairments, seizures, tremor, and mental disability. Rett Syndrome is also associated with metabolic abnormalities, and the anti-diabetic drug metformin is suggested to be a potential drug of choice with low or no side-effects. Previously, we showed that in vitro exposure of metformin in a human brain cell line induces MECP2E1 transcripts, the dominant isoform of the MECP2 gene in the brain, mutations in which causes RTT. Here, we report the molecular impact of metformin in mice. Protein analysis of specific brain regions in the male and female mice by immunoblotting indicated that metformin induces MeCP2 in the hippocampus, in a sex-dependent manner. Additional experiments confirm that the regulatory role of metformin on the MeCP2 target "BDNF" is brain region-dependent and sex-specific. Measurement of the ribosomal protein S6 (in both phosphorylated and unphosphorylated forms) confirms the sex-dependent role of metformin in the liver. Our results can help foster a better understanding of the molecular impact of metformin in different brain regions of male and female adult mice, while providing some insight towards its potential in therapeutic strategies for the treatment of Rett Syndrome.
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Affiliation(s)
| | | | - Mojgan Rastegar
- Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
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Sekar AP, Nurmala S, Matsuura E, Tan XW, Rahmasari R, Sauriasari R. Estrogen Receptor Is Required for Metformin-Induced Apoptosis in Breast Cancer Cells Under Hyperglycemic Conditions. Breast Cancer (Auckl) 2024; 18:11782234241240173. [PMID: 38779416 PMCID: PMC11110926 DOI: 10.1177/11782234241240173] [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: 07/11/2023] [Accepted: 02/29/2024] [Indexed: 05/25/2024] Open
Abstract
Backgrounds About 25% to 30% of estrogen receptor (ER)-positive breast cancer patients develop resistance to endocrine therapy. Human epidermal growth factor receptor 2 (HER2) has been shown to cooperate with several growth factors that regulate cellular energy metabolism, including the insulin-like growth factor 1 receptor (IGF-1R). Objective As the first-line therapy for type 2 diabetes mellitus (T2DM) patients, metformin is widely known to inhibit the metabolic reprogramming of cancer cells. This study aims to investigate metformin's efficacy in inhibiting endocrine resistance related to genes regulating energy metabolism in both ER-positive and ER-negative breast cancer cell lines under hyperglycemic conditions. Design and methods MDA-MB-361 (ER-positive, HER2-positive) and SKBR3 (ER-negative, HER2-positive) cancer cell lines were used to represent ER status. Cell viability and cell survival rate were measured using the colorimetric assay of Cell Counting Kit-8. All mRNA levels were quantified using real-time quantitative polymerase chain reaction preceded by reverse transcription. A P value of <.05 was considered statistically significant. Results Unlike MDA-MB-361, SKBR3 were found to acquire resistance upon metformin treatment in hyperglycemic conditions. Moreover, the mRNA expression of IGF-1R and its downstream signaling, such as the mammalian target of rapamycin (mTOR), was not affected by metformin. Meanwhile, the mRNA expression level of ribosomal S6 kinase 1 (S6K1) was upregulated, whereas forkhead box O1 (FOXO1) was downregulated after metformin treatment in hyperglycemic conditions. Conclusions This preliminary study suggests that an alternative pathway of metformin resistance may exist in the absence of ERα. Therefore, relying solely on metformin may be inadequate to inhibit the aggressiveness of breast cancer cells.
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Affiliation(s)
- Andisyah Putri Sekar
- Pharmacology and Clinical Pharmacy Laboratory, Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia
| | - Septia Nurmala
- Pharmacology and Clinical Pharmacy Laboratory, Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia
| | - Eiji Matsuura
- Graduate School of Interdiscplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan
| | - Xian Wen Tan
- Collaborative Research Center for Okayama Medical Innovation Center & Department of Cell Chemistry, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Ratika Rahmasari
- Microbiology and Biotechnology Laboratory, Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia
| | - Rani Sauriasari
- Pharmacology and Clinical Pharmacy Laboratory, Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia
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Lee JY, Bhandare RR, Boddu SHS, Shaik AB, Saktivel LP, Gupta G, Negi P, Barakat M, Singh SK, Dua K, Chellappan DK. Molecular mechanisms underlying the regulation of tumour suppressor genes in lung cancer. Biomed Pharmacother 2024; 173:116275. [PMID: 38394846 DOI: 10.1016/j.biopha.2024.116275] [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: 11/24/2023] [Revised: 01/30/2024] [Accepted: 02/13/2024] [Indexed: 02/25/2024] Open
Abstract
Tumour suppressor genes play a cardinal role in the development of a large array of human cancers, including lung cancer, which is one of the most frequently diagnosed cancers worldwide. Therefore, extensive studies have been committed to deciphering the underlying mechanisms of alterations of tumour suppressor genes in governing tumourigenesis, as well as resistance to cancer therapies. In spite of the encouraging clinical outcomes demonstrated by lung cancer patients on initial treatment, the subsequent unresponsiveness to first-line treatments manifested by virtually all the patients is inherently a contentious issue. In light of the aforementioned concerns, this review compiles the current knowledge on the molecular mechanisms of some of the tumour suppressor genes implicated in lung cancer that are either frequently mutated and/or are located on the chromosomal arms having high LOH rates (1p, 3p, 9p, 10q, 13q, and 17p). Our study identifies specific genomic loci prone to LOH, revealing a recurrent pattern in lung cancer cases. These loci, including 3p14.2 (FHIT), 9p21.3 (p16INK4a), 10q23 (PTEN), 17p13 (TP53), exhibit a higher susceptibility to LOH due to environmental factors such as exposure to DNA-damaging agents (carcinogens in cigarette smoke) and genetic factors such as chromosomal instability, genetic mutations, DNA replication errors, and genetic predisposition. Furthermore, this review summarizes the current treatment landscape and advancements for lung cancers, including the challenges and endeavours to overcome it. This review envisages inspired researchers to embark on a journey of discovery to add to the list of what was known in hopes of prompting the development of effective therapeutic strategies for lung cancer.
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Affiliation(s)
- Jia Yee Lee
- School of Health Sciences, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Richie R Bhandare
- Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, Ajman University, Al-Jurf, P.O. Box 346, Ajman, United Arab Emirates; Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Al-Jurf, P.O. Box 346, Ajman, United Arab Emirates.
| | - Sai H S Boddu
- Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, Ajman University, Al-Jurf, P.O. Box 346, Ajman, United Arab Emirates; Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Al-Jurf, P.O. Box 346, Ajman, United Arab Emirates
| | - Afzal B Shaik
- St. Mary's College of Pharmacy, St. Mary's Group of Institutions Guntur, Affiliated to Jawaharlal Nehru Technological University Kakinada, Chebrolu, Guntur, Andhra Pradesh 522212, India; Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, India
| | - Lakshmana Prabu Saktivel
- Department of Pharmaceutical Technology, University College of Engineering (BIT Campus), Anna University, Tiruchirappalli 620024, India
| | - Gaurav Gupta
- Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Al-Jurf, P.O. Box 346, Ajman, United Arab Emirates; School of Pharmacy, Suresh Gyan Vihar University, Jaipur, Rajasthan 302017, India
| | - Poonam Negi
- School of Pharmaceutical Sciences, Shoolini University, PO Box 9, Solan, Himachal Pradesh 173229, India
| | - Muna Barakat
- Department of Clinical Pharmacy & Therapeutics, Applied Science Private University, Amman-11937, Jordan
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T Road, Phagwara 144411, India; Australian Research Centre in Complementary and Integrative Medicine, Faculty of Health, University of Technology Sydney, Sydney 2007, Australia
| | - Kamal Dua
- Australian Research Centre in Complementary and Integrative Medicine, Faculty of Health, University of Technology Sydney, Sydney 2007, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney 2007, Australia
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia.
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48
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Xiao S, Li VL, Lyu X, Chen X, Wei W, Abbasi F, Knowles JW, Tung ASH, Deng S, Tiwari G, Shi X, Zheng S, Farrell L, Chen ZZ, Taylor KD, Guo X, Goodarzi MO, Wood AC, Chen YDI, Lange LA, Rich SS, Rotter JI, Clish CB, Tahir UA, Gerszten RE, Benson MD, Long JZ. Lac-Phe mediates the effects of metformin on food intake and body weight. Nat Metab 2024; 6:659-669. [PMID: 38499766 PMCID: PMC11062621 DOI: 10.1038/s42255-024-00999-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 01/30/2024] [Indexed: 03/20/2024]
Abstract
Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. There is ongoing debate about the mechanisms that mediate metformin's effects on energy balance. Here, we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) in cells, in mice and two independent human cohorts. Metformin drives Lac-Phe biosynthesis through the inhibition of complex I, increased glycolytic flux and intracellular lactate mass action. Intestinal epithelial CNDP2+ cells, not macrophages, are the principal in vivo source of basal and metformin-inducible Lac-Phe. Genetic ablation of Lac-Phe biosynthesis in male mice renders animals resistant to the effects of metformin on food intake and body weight. Lastly, mediation analyses support a role for Lac-Phe as a downstream effector of metformin's effects on body mass index in participants of a large population-based observational cohort, the Multi-Ethnic Study of Atherosclerosis. Together, these data establish Lac-Phe as a critical mediator of the body weight-lowering effects of metformin.
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Affiliation(s)
- Shuke Xiao
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA
| | - Veronica L Li
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA
- Department of Chemistry, Stanford University, Stanford, CA, USA
- Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA
| | - Xuchao Lyu
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA
- Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA
| | - Xudong Chen
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA
- Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
| | - Wei Wei
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA
| | - Fahim Abbasi
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Joshua W Knowles
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, USA
| | - Alan Sheng-Hwa Tung
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA
| | - Shuliang Deng
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Gaurav Tiwari
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Xu Shi
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Shuning Zheng
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Laurie Farrell
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Zsu-Zsu Chen
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Kent D Taylor
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Mark O Goodarzi
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Alexis C Wood
- USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA
| | - Yii-Der Ida Chen
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Leslie A Lange
- Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Stephen S Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Jerome I Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Clary B Clish
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Usman A Tahir
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Robert E Gerszten
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Mark D Benson
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Jonathan Z Long
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
- Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
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49
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Cheng M, Ren L, Jia X, Wang J, Cong B. Understanding the action mechanisms of metformin in the gastrointestinal tract. Front Pharmacol 2024; 15:1347047. [PMID: 38617792 PMCID: PMC11010946 DOI: 10.3389/fphar.2024.1347047] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 03/15/2024] [Indexed: 04/16/2024] Open
Abstract
Metformin is the initial medication recommended for the treatment of type 2 diabetes mellitus (T2DM). In addition to diabetes treatment, the function of metformin also can be anti-aging, antiviral, and anti-inflammatory. Nevertheless, further exploration is required to fully understand its mode of operation. Historically, the liver has been acknowledged as the main location where metformin reduces glucose levels, however, there is increasing evidence suggesting that the gastrointestinal tract also plays a significant role in its action. In the gastrointestinal tract, metformin effects glucose uptake and absorption, increases glucagon-like peptide-1 (GLP-1) secretion, alters the composition and structure of the gut microbiota, and modulates the immune response. However, the side effects of it cannot be ignored such as gastrointestinal distress in patients. This review outlines the impact of metformin on the digestive system and explores potential explanations for variations in metformin effectiveness and adverse effects like gastrointestinal discomfort.
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Affiliation(s)
- Meihui Cheng
- Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- College of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, China
- NHC Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lili Ren
- Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- NHC Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xianxian Jia
- Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Pathogen Biology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Jianwei Wang
- Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- NHC Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bin Cong
- Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- College of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, China
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50
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Goglia U, Hasballa I, Teti C, Boschetti M, Ferone D, Albertelli M. Ianus Bifrons: The Two Faces of Metformin. Cancers (Basel) 2024; 16:1287. [PMID: 38610965 PMCID: PMC11011026 DOI: 10.3390/cancers16071287] [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: 01/18/2024] [Revised: 03/10/2024] [Accepted: 03/20/2024] [Indexed: 04/14/2024] Open
Abstract
The ancient Roman god Ianus was a mysterious divinity with two opposite faces, one looking at the past and the other looking to the future. Likewise, metformin is an "old" drug, with one side looking at the metabolic role and the other looking at the anti-proliferative mechanism; therefore, it represents a typical and ideal bridge between diabetes and cancer. Metformin (1,1-dimethylbiguanidine hydrochloride) is a drug that has long been in use for the treatment of type 2 diabetes mellitus, but recently evidence is growing about its potential use in other metabolic conditions and in proliferative-associated diseases. The aim of this paper is to retrace, from a historical perspective, the knowledge of this molecule, shedding light on the subcellular mechanisms of action involved in metabolism as well as cellular and tissue growth. The intra-tumoral pharmacodynamic effects of metformin and its possible role in the management of different neoplasms are evaluated and debated. The etymology of the name Ianus is probably from the Latin term ianua, which means door. How many new doors will this old drug be able to open?
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Affiliation(s)
- Umberto Goglia
- Endocrinology and Diabetology Unit, Local Health Authority CN1, 12100 Cuneo, Italy
| | - Iderina Hasballa
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy (M.B.); (D.F.); (M.A.)
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, 16132 Genoa, Italy
| | - Claudia Teti
- Endocrinology and Diabetology Unit, Local Health Autorithy Imperia 1, 18100 Imperia, Italy;
| | - Mara Boschetti
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy (M.B.); (D.F.); (M.A.)
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, 16132 Genoa, Italy
| | - Diego Ferone
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy (M.B.); (D.F.); (M.A.)
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, 16132 Genoa, Italy
| | - Manuela Albertelli
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy (M.B.); (D.F.); (M.A.)
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, 16132 Genoa, Italy
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