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Oncotarget 2022
Topics: Humans; Hypoglycemic Agents; Metformin
PubMed: 35028013
DOI: 10.18632/oncotarget.28097 -
International Journal of Molecular... Mar 2022Myotonic dystrophy type 1 (DM1) is a multisystemic disorder of genetic origin. Progressive muscular weakness, atrophy and myotonia are its most prominent neuromuscular... (Review)
Review
Myotonic dystrophy type 1 (DM1) is a multisystemic disorder of genetic origin. Progressive muscular weakness, atrophy and myotonia are its most prominent neuromuscular features, while additional clinical manifestations in multiple organs are also common. Overall, DM1 features resemble accelerated aging. There is currently no cure or specific treatment for myotonic dystrophy patients. However, in recent years a great effort has been made to identify potential new therapeutic strategies for DM1 patients. Metformin is a biguanide antidiabetic drug, with potential to delay aging at cellular and organismal levels. In DM1, different studies revealed that metformin rescues multiple phenotypes of the disease. This review provides an overview of recent findings describing metformin as a novel therapy to combat DM1 and their link with aging.
Topics: Humans; Hypoglycemic Agents; Metformin; Muscle Weakness; Myotonic Dystrophy; Phenotype
PubMed: 35270043
DOI: 10.3390/ijms23052901 -
Advances in Wound Care Jan 2021Biofilms are small densely packed aggregations of microbes that are highly resistant to host immune responses and treatment. They attach to each other and to nearby... (Review)
Review
Biofilms are small densely packed aggregations of microbes that are highly resistant to host immune responses and treatment. They attach to each other and to nearby surfaces. Biofilms are difficult to study and identify in a clinical setting as their quantification necessitates the use of advanced microscopy techniques such as confocal laser scanning microscopy. Nonetheless, it is likely that biofilms contribute to the pathophysiology of chronic skin wounds. Reducing, removing, or preventing biofilms is thus a logical approach to help clinicians heal chronic wounds. Wound care products have demonstrated varying degrees of efficacy in destroying biofilms in and preclinical models, as well as in some clinical studies. Controlled studies exploring the beneficial role of biofilm eradication and its relationship to healing in patients with chronic wounds are limited. This review aims to discuss the mode of action and clinical significance of currently available antibiofilm products, including surfactants, dressings, and others, with a focus on levels of evidence for efficacy in disrupting biofilms and ability to improve wound healing outcomes. Few available products have good evidence to support antibiofilm activity and wound healing benefits. Novel therapeutic strategies are on the horizon. More high-quality clinical studies are needed. The development of noninvasive techniques to quantify biofilms will facilitate increased ease of research about biofilms in wounds and how to combat them.
Topics: Animals; Anti-Infective Agents, Local; Bandages; Benzalkonium Compounds; Biguanides; Biofilms; Disinfectants; Honey; Humans; Hypochlorous Acid; Iodophors; Low-Level Light Therapy; Surface-Active Agents; Ultrasonic Therapy; Wound Healing; Wound Infection
PubMed: 32496980
DOI: 10.1089/wound.2020.1193 -
The Biochemical Journal Sep 2014The biguanide metformin is widely prescribed for Type II diabetes and has anti-neoplastic activity in laboratory models. Despite evidence that inhibition of...
The biguanide metformin is widely prescribed for Type II diabetes and has anti-neoplastic activity in laboratory models. Despite evidence that inhibition of mitochondrial respiratory complex I by metformin is the primary cause of its cell-lineage-specific actions and therapeutic effects, the molecular interaction(s) between metformin and complex I remain uncharacterized. In the present paper, we describe the effects of five pharmacologically relevant biguanides on oxidative phosphorylation in mammalian mitochondria. We report that biguanides inhibit complex I by inhibiting ubiquinone reduction (but not competitively) and, independently, stimulate reactive oxygen species production by the complex I flavin. Biguanides also inhibit mitochondrial ATP synthase, and two of them inhibit only ATP hydrolysis, not synthesis. Thus we identify biguanides as a new class of complex I and ATP synthase inhibitor. By comparing biguanide effects on isolated complex I and cultured cells, we distinguish three anti-diabetic and potentially anti-neoplastic biguanides (metformin, buformin and phenformin) from two anti-malarial biguanides (cycloguanil and proguanil): the former are accumulated into mammalian mitochondria and affect oxidative phosphorylation, whereas the latter are excluded so act only on the parasite. Our mechanistic and pharmacokinetic insights are relevant to understanding and developing the role of biguanides in new and existing therapeutic applications, including cancer, diabetes and malaria.
Topics: Animals; Antimalarials; Antineoplastic Agents; Biguanides; Cattle; Diabetes Mellitus, Type 2; Electron Transport Complex I; Hep G2 Cells; Humans; Metformin; Mitochondria, Heart; Mitochondria, Liver; Mitochondrial Proton-Translocating ATPases; Oxidative Phosphorylation; Plasmodium; Proguanil; Rats; Reperfusion Injury; Triazines
PubMed: 25017630
DOI: 10.1042/BJ20140620 -
Aging Nov 2010Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors in aging. Insulin/insulin-like growth factor 1 (IGF-1)... (Review)
Review
Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors in aging. Insulin/insulin-like growth factor 1 (IGF-1) signaling molecules that have been linked to longevity include daf-2 and InR and their homologues in mammals, and inactivation of the corresponding genes increases life span in nematodes, fruit flies and mice. It is possible that the life-prolonging effect of caloric restriction is due to decreasing IGF-1 levels. Evidence has emerged that antidiabetic drugs are promising candidates for both life span extension and prevention of cancer. Thus, antidiabetic drugs postpone spontaneous carcinogenesis in mice and rats, as well as chemical and radiation carcinogenesis in mice, rats and hamsters. Furthermore metformin seems to decrease cancer risk in diabetic patients.
Topics: Aging; Animals; Antineoplastic Agents; Biguanides; Caloric Restriction; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin-Like Growth Factor I; Life Expectancy; Longevity; Metformin; Neoplasms
PubMed: 21084729
DOI: 10.18632/aging.100230 -
Scientific Reports Jul 2023Diabetes medications may modify the risk of certain cancers. We systematically searched MEDLINE, Embase, Web of Science, and Cochrane CENTRAL from 2011 to March 2021 for... (Meta-Analysis)
Meta-Analysis
Diabetes medications may modify the risk of certain cancers. We systematically searched MEDLINE, Embase, Web of Science, and Cochrane CENTRAL from 2011 to March 2021 for studies evaluating associations between diabetes medications and the risk of breast, lung, colorectal, prostate, liver, and pancreatic cancers. A total of 92 studies (3 randomized controlled trials, 64 cohort studies, and 25 case-control studies) were identified in the systematic review, involving 171 million participants. Inverse relationships with colorectal (n = 18; RR = 0.85; 95% CI = 0.78-0.92) and liver cancers (n = 10; RR = 0.55; 95% CI = 0.46-0.66) were observed in biguanide users. Thiazolidinediones were associated with lower risks of breast (n = 6; RR = 0.87; 95% CI = 0.80-0.95), lung (n = 6; RR = 0.77; 95% CI = 0.61-0.96) and liver (n = 8; RR = 0.83; 95% CI = 0.72-0.95) cancers. Insulins were negatively associated with breast (n = 15; RR = 0.90; 95% CI = 0.82-0.98) and prostate cancer risks (n = 7; RR = 0.74; 95% CI = 0.56-0.98). Positive associations were found between insulin secretagogues and pancreatic cancer (n = 5; RR = 1.26; 95% CI = 1.01-1.57), and between insulins and liver (n = 7; RR = 1.74; 95% CI = 1.08-2.80) and pancreatic cancers (n = 8; RR = 2.41; 95% CI = 1.08-5.36). Overall, biguanide and thiazolidinedione use carried no risk, or potentially lower risk of some cancers, while insulin secretagogue and insulin use were associated with increased pancreatic cancer risk.
Topics: Male; Humans; Diabetes Mellitus; Insulin; Pancreatic Neoplasms; Biguanides; Insulin Secretagogues; Colorectal Neoplasms
PubMed: 37481610
DOI: 10.1038/s41598-023-38431-z -
Biological & Pharmaceutical Bulletin 2022We studied the effect of dietary fibers (DFs) on the levels of free hypoglycemic agents in vitro, i.e., glimepiride and the biguanides buformin and metformin. The levels...
We studied the effect of dietary fibers (DFs) on the levels of free hypoglycemic agents in vitro, i.e., glimepiride and the biguanides buformin and metformin. The levels of free buformin and free metformin were not affected by mixtures of DFs, i.e., cellulose, chitosan, pectin (PE), and glucomannan (GM), in fluids of pH 1.2 and 6.8 (similar to the pH of the stomach and intestines, respectively). However, the free biguanide level was significantly reduced by mixing with PE or sodium alginate (AL), in water. The free glimepiride level was reduced in the mixture of AL, PE, and GM (in a solution with a pH of 6.8). The changes in aqueous AL solution pH seemed to reflect the free metformin levels. Therefore, the effects of DFs on free drug levels were dependent on drug type, hypoglycemic agent, and mixing solution. In this study, the oral regimen concentrations of the drug and DFs were used. Based on these results, it is important to consider the interactions between hypoglycemic agents and DFs.
Topics: Hypoglycemic Agents; Buformin; Metformin; Dietary Fiber
PubMed: 36328507
DOI: 10.1248/bpb.b22-00385 -
Biomolecules Apr 2022Metformin is a synthetic biguanide that improves insulin sensitivity and reduces hepatic gluconeogenesis. Aside being the first-line therapy for Type 2 Diabetes (T2D),... (Review)
Review
Metformin is a synthetic biguanide that improves insulin sensitivity and reduces hepatic gluconeogenesis. Aside being the first-line therapy for Type 2 Diabetes (T2D), many pleiotropic effects have been discovered in recent years, such as its capacity to reduce cancer risk and tumorigenesis. Although widely studied, the effect of metformin on thyroid cancer remains controversial. Potential mechanisms for its growth inhibitory effects have been elucidated in various preclinical studies that involved pathways related to adenosine mono-phosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), mitochondrial glycerophosphate dehydrogenase (mGPDH), and the nuclear factor κB (NF-κB). Hyperinsulinemia increases cell glucose uptake and oxidative stress, and promotes thyroid cell growth, leading to hyperproliferation, carcinogenesis, and the development of malignant tumors. Furthermore, it has also been related to thyroid nodules size in nodular disease, as well as tumoral size in patients with thyroid cancer. Several clinical studies concluded that metformin might have an important role as an adjuvant therapy to reduce the growth of benign and malignant thyroid neoplasms. This suggests that metformin might be useful for patients with differentiated or poorly differentiated thyroid cancer and metabolic diseases such as insulin resistance or diabetes.
Topics: Adenocarcinoma; Cell Cycle; Cell Proliferation; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Metformin; Thyroid Neoplasms
PubMed: 35454163
DOI: 10.3390/biom12040574 -
Scientific Reports May 2021We present the design and synthesis of a small library of substituted biguanidium salts and their capacity to inhibit the growth of pancreatic cancer cells. We first...
We present the design and synthesis of a small library of substituted biguanidium salts and their capacity to inhibit the growth of pancreatic cancer cells. We first present their in vitro and membrane activity, before we address their mechanism of action in living cells and in vivo activity. We show that phenylethynyl biguanidium salts possess higher ability to cross hydrophobic barriers, improve mitochondrial accumulation and anticancer activity. Mechanistically, the most active compound, 1b, like metformin, activated AMPK, decreased the NAD/NADH ratio and mitochondrial respiration, but at 800-fold lower concentration. In vivo studies show that compound 1b significantly inhibits the growth of pancreatic cancer xenografts in mice, while biguanides currently in clinical trials had little activity.
Topics: AMP-Activated Protein Kinases; Animals; Biguanides; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Screening Assays, Antitumor; Electron Transport Complex I; Fibroblasts; Humans; Inhibitory Concentration 50; Mice; Mitochondria; Pancreatic Neoplasms
PubMed: 33972583
DOI: 10.1038/s41598-021-87993-3 -
ELife Aug 2023Biguanides, including the world's most prescribed drug for type 2 diabetes, metformin, not only lower blood sugar, but also promote longevity in preclinical models....
Biguanides, including the world's most prescribed drug for type 2 diabetes, metformin, not only lower blood sugar, but also promote longevity in preclinical models. Epidemiologic studies in humans parallel these findings, indicating favorable effects of metformin on longevity and on reducing the incidence and morbidity associated with aging-related diseases. Despite this promise, the full spectrum of molecular effectors responsible for these health benefits remains elusive. Through unbiased screening in , we uncovered a role for genes necessary for ether lipid biosynthesis in the favorable effects of biguanides. We demonstrate that biguanides prompt lifespan extension by stimulating ether lipid biogenesis. Loss of the ether lipid biosynthetic machinery also mitigates lifespan extension attributable to dietary restriction, target of rapamycin (TOR) inhibition, and mitochondrial electron transport chain inhibition. A possible mechanistic explanation for this finding is that ether lipids are required for activation of longevity-promoting, metabolic stress defenses downstream of the conserved transcription factor /Nrf. In alignment with these findings, overexpression of a single, key, ether lipid biosynthetic enzyme, /FAR1, is sufficient to promote lifespan extension. These findings illuminate the ether lipid biosynthetic machinery as a novel therapeutic target to promote healthy aging.
Topics: Humans; Animals; Caenorhabditis elegans; Longevity; Diabetes Mellitus, Type 2; Ethyl Ethers; Ethers; Metformin; Antimalarials; Lipids
PubMed: 37606250
DOI: 10.7554/eLife.82210