Action Of Metformin Research Articles

The use of metformin in the treatment of Intrahepatic cholestasis of pregnancy

Introduction: Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disease. It is characterized by persistent pruritus, usually occurring after 30 weeks of pregnancy, and by elevated levels of bile acids and transaminases, which decrease over the course of 2-3 weeks postpartum. [1,2]The occurrence of ICP in the mother may be associated with significant complications in the fetus, such as: preterm labor, intrauterine asphyxia, or sudden fetal death. Currently, the treatment of choice is ursodeoxycholic acid (UDCA).[2,6] Recently, it was observed that the administration of metformin in cases not responding to standard therapy improved lipid disorders in pregnant women.
 
 The aim of the study: The aim of the study is to present the possibility of using metformin in the treatment of ICP in pregnant women not responding to standard treatment and to present a clinical case..
 Material and methods: The work is a review of the literature on the management of ICP and the use of metformin in the treatment of lipid metabolism disorders, as well as a brief case report of a patient with intrahepatic cholestasis of pregnancy.
 Description of the state of knowledge: Metformin is an oral antidiabetic drug belonging to the group of biguanides. However, the latest observations show that metformin also has a beneficial effect on the liver function and on the lipid metabolism in pregnant women. In these patients, the levels of bile acids and liver enzymes decreased after the use of metformin.
 Summary: The mechanism of action of metformin explaining its beneficial effect on the lipid metabolism in pregnant women with intrahepatic cholestasis is not fully understood.

Metformin and type 2 diabetes in the era of cardiovascular outcome trials; A narrative review

Metformin has been for many years the first-line pharmaceutic treatment for most patients with type 2 diabetes. However, new classes of antidiabetic agents with proven cardiorenal benefits beyond glycemic control challenge metformin’s predominance. The hypoglycemic effect of metformin is mediated in liver by inhibiting gluconeogenesis and improving insulin sensitivity and in intestines by reducing glucose absorption, increasing incretins and altering intestinal microbiome. After decades of use metformin has been proved to be one of the most potent, safe and cost-effective medications for the treatment of type 2 diabetes. Several other pleiotropic actions of metformin in inflammation pathways suggest a potential cardioprotective role. This hypothesis has been tested in a few randomized trials and in more observational studies and metanalyses with controversial results. Given the lack of robust evidence for the cardioprotective effect of metformin compared to the newer antidiabetic agents, current treatment algorithms are under scrutiny. Ongoing randomized clinical trials comparing metformin to placebo are expected to elucidate the effect of metformin on specific cardiovascular and renal outcomes.

From Diabetes to Atherosclerosis: Potential of Metformin for Management of Cardiovascular Disease.

Atherosclerosis is a common cause of cardiovascular disease, which, in turn, is often fatal. Today, we know a lot about the pathogenesis of atherosclerosis. However, the main knowledge is that the disease is extremely complicated. The development of atherosclerosis is associated with more than one molecular mechanism, each making a significant contribution. These mechanisms include endothelial dysfunction, inflammation, mitochondrial dysfunction, oxidative stress, and lipid metabolism disorders. This complexity inevitably leads to difficulties in treatment and prevention. One of the possible therapeutic options for atherosclerosis and its consequences may be metformin, which has already proven itself in the treatment of diabetes. Both diabetes and atherosclerosis are complex metabolic diseases, the pathogenesis of which involves many different mechanisms, including those common to both diseases. This makes metformin a suitable candidate for investigating its efficacy in cardiovascular disease. In this review, we highlight aspects such as the mechanisms of action and targets of metformin, in addition to summarizing the available data from clinical trials on the effective reduction of cardiovascular risks.

Impact of Autophagy Impairment on Experience- and Diet-Related Synaptic Plasticity.

The beneficial effects of diet and exercise on brain function are traditionally attributed to the enhancement of autophagy, which plays a key role in neuroprotection via the degradation of potentially harmful intracellular structures. The molecular machinery of autophagy has also been suggested to influence synaptic signaling via interaction with trafficking and endocytosis of synaptic vesicles and proteins. Still, the role of autophagy in the regulation of synaptic plasticity remains elusive, especially in the mammalian brain. We explored the impact of autophagy on synaptic transmission and homeostatic and acute synaptic plasticity using transgenic mice with induced deletion of the Beclin1 protein. We observed down-regulation of glutamatergic and up-regulation of GABAergic synaptic currents and impairment of long-term plasticity in the neocortex and hippocampus of Beclin1-deficient mice. Beclin1 deficiency also significantly reduced the effects of environmental enrichment, caloric restriction and its pharmacological mimetics (metformin and resveratrol) on synaptic transmission and plasticity. Taken together, our data strongly support the importance of autophagy in the regulation of excitatory and inhibitory synaptic transmission and synaptic plasticity in the neocortex and hippocampus. Our results also strongly suggest that the positive modulatory actions of metformin and resveratrol in acute and homeostatic synaptic plasticity, and therefore their beneficial effects on brain function, occur via the modulation of autophagy.

The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved.

Metformin, a drug widely used in type 2 diabetes (T2D), has been shown to protect human β-cells exposed to gluco- and/or lipotoxic conditions and those in islets from T2D donors. We assessed whether metformin could relieve the human β-cell stress induced by pro-inflammatory cytokines (which mediate β-cells damage in type 1 diabetes, T1D) and investigated the underlying mechanisms using shotgun proteomics. Human islets were exposed to 50 U/mL interleukin-1β plus 1000 U/mL interferon-γ for 48 h, with or without 2.4 µg/mL metformin. Glucose-stimulated insulin secretion (GSIS) and caspase 3/7 activity were studied, and a shotgun label free proteomics analysis was performed. Metformin prevented the reduction of GSIS and the activation of caspase 3/7 induced by cytokines. Proteomics analysis identified more than 3000 proteins in human islets. Cytokines alone altered the expression of 244 proteins (145 up- and 99 down-regulated), while, in the presence of metformin, cytokine-exposure modified the expression of 231 proteins (128 up- and 103 downregulated). Among the proteins inversely regulated in the two conditions, we found proteins involved in vesicle motility, defense against oxidative stress (including peroxiredoxins), metabolism, protein synthesis, glycolysis and its regulation, and cytoskeletal proteins. Metformin inhibited pathways linked to inflammation, immune reactions, mammalian target of rapamycin (mTOR) signaling, and cell senescence. Some of the changes were confirmed by Western blot. Therefore, metformin prevented part of the deleterious actions of pro-inflammatory cytokines in human β-cells, which was accompanied by islet proteome modifications. This suggests that metformin, besides use in T2D, might be considered for β-cell protection in other types of diabetes, possibly including early T1D.

Actions of Metformin in the Brain: A New Perspective of Metformin Treatments in Related Neurological Disorders.

Metformin is a first-line drug for treating type 2 diabetes mellitus (T2DM) and one of the most commonly prescribed drugs in the world. Besides its hypoglycemic effects, metformin also can improve cognitive or mood functions in some T2DM patients; moreover, it has been reported that metformin exerts beneficial effects on many neurological disorders, including major depressive disorder (MDD), Alzheimer’s disease (AD) and Fragile X syndrome (FXS); however, the mechanism underlying metformin in the brain is not fully understood. Neurotransmission between neurons is fundamental for brain functions, and its defects have been implicated in many neurological disorders. Recent studies suggest that metformin appears not only to regulate synaptic transmission or plasticity in pathological conditions but also to regulate the balance of excitation and inhibition (E/I balance) in neural networks. In this review, we focused on and reviewed the roles of metformin in brain functions and related neurological disorders, which would give us a deeper understanding of the actions of metformin in the brain.

Therapeutic vs. Suprapharmacological Metformin Concentrations: Different Effects on Energy Metabolism and Mitochondrial Function in Skeletal Muscle Cells in vitro.

Metformin is an oral antidiabetic agent that has been widely used in clinical practice for over 60 years, and is currently the most prescribed antidiabetic drug worldwide. However, the molecular mechanisms of metformin action in different tissues are still not completely understood. Although metformin-induced inhibition of mitochondrial respiratory chain Complex I and activation of AMP-activated protein kinase have been observed in many studies, published data is inconsistent. Furthermore, metformin concentrations used for in vitro studies and their pharmacological relevance are a common point of debate. The aim of this study was to explore the effects of different metformin concentrations on energy metabolism and activity of relevant signaling pathways in C2C12 muscle cells in vitro. In order to determine if therapeutic metformin concentrations have an effect on skeletal muscle cells, we used micromolar metformin concentrations (50 µM), and compared the effects with those of higher, millimolar concentrations (5 mM), that have already been established to affect mitochondrial function and AMPK activity. We conducted all experiments in conditions of high (25 mM) and low glucose (5.5 mM) concentration, in order to discern the role of glucose availability on metformin action. According to our results, micromolar metformin treatment did not cause Complex I inhibition nor AMPK activation. Also, cells cultured in low glucose medium were more sensitive to Complex I inhibition, mitochondrial membrane depolarization and AMPK activation by millimolar metformin, but cells cultured in high glucose medium were more prone to induction of ROS production. In conclusion, even though suprapharmacological metformin concentrations cause Complex I inhibition and AMPK activation in skeletal muscle cells in vitro, therapeutic concentrations cause no such effect. This raises the question if these mechanisms are relevant for therapeutic effects of metformin in skeletal muscle.

Metabolic Action of Metformin

Metformin, a cheap and safe biguanide derivative, due to its ability to influence metabolism, is widely used as a first-line drug for type 2 diabetes (T2DM) treatment. Therefore, the aim of this review was to present the updated biochemical and molecular effects exerted by the drug. It has been well explored that metformin suppresses hepatic glucose production in both AMPK-independent and AMPK-dependent manners. Substantial scientific evidence also revealed that its action is related to decreased secretion of lipids from intestinal epithelial cells, as well as strengthened oxidation of fatty acids in adipose tissue and muscles. It was recognized that metformin’s supra-therapeutic doses suppress mitochondrial respiration in intestinal epithelial cells, whereas its therapeutic doses elevate cellular respiration in the liver. The drug is also suggested to improve systemic insulin sensitivity as a result of alteration in gut microbiota composition, maintenance of intestinal barrier integrity, and alleviation of low-grade inflammation.

Chlorogenic acid improves anti-lipogenic activity of metformin by positive regulating of AMPK signaling in HepG2 cells.

Metformin improves lipid profile, however, combination therapy is developing to increase its effectiveness and reduce the deleterious effects of metformin. Chlorogenic acid (CGA) has exhibited lipid-lowering effects. This study aimed to investigate the combined effect of metformin and CGA on lipid accumulation, as well as to elucidate the engaged mechanism in HepG2 cells. To find the non-lethal doses of metformin and CGA, MTT assay was performed. High Glucose (HG) at 33 mM was used to induce lipogenesis in HepG2 cells. Following treatment with different concentrations of metformin and CGA, total lipid content (Oil Red O-staining), triglyceride level, the genes expression of SREBP-1c and FAS, and phosphorylation of AMPK and ACC were measured. Both Metformin and CGA decreased HG-induced lipid accumulation individually, by decreasing total lipid content and triglyceride level. The lowest effective doses of metformin and CGA were 0.25 mM and 5 μM, respectively, which significantly reduced SREBP-1c and FAS genes expression. The combination of these concentrations reinforced these effects. The phosphorylation of AMPK and ACC were more increased by metformin in combination with CGA than both individually. Our findings suggest that CGA synergistically enhances metformin lipid reducing action via the regulating of involved factors in fatty acid synthesis. Therefore, co-administration of metformin with CGA may have further medical value in treating lipid metabolism disorders.

Impact of Metformin on the Warburg Effect on Cancer Cells

It is complex to understand all the mechanisms by which tumor cells use for their survival. The aim of the present review is to propose the mechanisms by which metformin would be beneficial in the context of cancer through the inhibition of the Warburg effect. A literature review of the Warburg effect and the mechanism of action of metformin was carried out to determine a theoretical relationship between metformin consumption and inhibition of tumor cell metabolism. There are several mechanisms through which metformin could antagonize tumor cells. As authors, we consider it of vital importance to know these effects in order to extrapolate them to experimental studies and seek the maximum benefit for patients, using the resources we have to date.

Metformin counteracts stimulatory effects induced by insulin in primary breast cancer cells

BackgroundMetabolic disorders are associated with increased incidence, aggressive phenotype and poor outcome of breast cancer (BC) patients. For instance, hyperinsulinemia is an independent risk factor for BC and the insulin/insulin receptor (IR) axis is involved in BC growth and metastasis. Of note, the anti-diabetic metformin may be considered in comprehensive therapeutic approaches in BC on the basis of its antiproliferative effects obtained in diverse pre-clinical and clinical studies.MethodsBioinformatics analysis were performed using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project. The naturally immortalized BC cell line, named BCAHC-1, as well as cancer-associated fibroblasts (CAFs) derived from BC patients were used as model systems. In order to identify further mechanisms that characterize the anticancer action of metformin in BC, we performed gene expression and promoter studies as well as western blotting experiments. Moreover, cell cycle analysis, colony and spheroid formation, actin cytoskeleton reorganization, cell migration and matrigel drops evasion assays were carried out to provide novel insights on the anticancer properties of metformin.ResultsWe first assessed that elevated expression and activation of IR correlate with a worse prognostic outcome in estrogen receptor (ER)-positive BC. Thereafter, we established that metformin inhibits the insulin/IR-mediated activation of transduction pathways, gene changes and proliferative responses in BCAHC-1 cells. Then, we found that metformin interferes with the insulin-induced expression of the metastatic gene CXC chemokine receptor 4 (CXCR4), which we found to be associated with poor disease-free survival in BC patients exhibiting high levels of IR. Next, we ascertained that metformin prevents a motile phenotype of BCAHC-1 cells triggered by the paracrine liaison between tumor cells and CAFs upon insulin activated CXCL12/CXCR4 axis.ConclusionsOur findings provide novel mechanistic insights regarding the anti-proliferative and anti-migratory effects of metformin in both BC cells and important components of the tumor microenvironment like CAFs. Further investigations are warranted to corroborate the anticancer action of metformin on the tumor mass toward the assessment of more comprehensive strategies halting BC progression, in particular in patients exhibiting metabolic disorders and altered insulin/IR functions.

116-LB: Interaction between Iron Stores and Metformin Action

The mechanism of action of MET (MET) remains controversial. MET induces an iron starvation response in yeast, so we hypothesized that tissue iron might influence MET responsiveness in higher organisms. We reviewed electronic health records to correlate MET responsiveness in diabetic humans with serum ferritin, a measure of iron stores. Both higher and subnormal serum ferritin were associated with decreased HbA1c response to MET (N=80, p<0.001) , and MET responsiveness was lost entirely at higher than normal ferritin. Mice were placed on diabetogenic diets with different iron contents, and treated or not with MET. MET responses of fasting glucose values were superior in mice on low-normal and normal iron diets compared to those on high iron: Fasting glucose decreased 60.4 mg/dL on low-normal iron (N=9, p<0.001) , 40.5 mg/dL on normal iron (N=23, p<0.01) and 2.6 mg/dL on high-normal iron (N=27, p=NS) , with significant interaction between iron and MET (p=0.0015, ANOVA) . Other effects of iron (e.g. leptin expression) are known to be mediated by protein modification by O-linked N-acetylglucosamine (O-GlcNAc) . MET increased O-GlcNAc levels 200% in mice on normal iron (p=0.04) but not high-normal iron diets (-8%, p=NS) . In mice with elevated O-GlcNAc resulting from heterozygous deletion of the O-GlcNAcase gene, MET’s ability to decrease fasting glucose levels in mice on high iron was restored, with differences between MET and placebo being 30.3, 61.3, and 56.5 mg/dL on low-normal, normal, and high-normal iron diets (p<0.0001 by ANOVA) ; in contrast to wild type mice, the significant effects of iron and its interaction with MET were lost (p=0.13 and 0.47) . We conclude that tissue iron affects glycemic responses to MET, supporting the hypothesis that MET induces an iron starvation response but that high iron overwhelms that signal. The results on protein O-GlcNAc modification suggest that it mediates the interaction of iron and MET. MET responsiveness in patients with diabetes could be optimized by modulating iron stores. Disclosure D. A. Mcclain: None. C. O. Usoh: None. F. Lorenzo: None. A. V. Harrison: None. Funding VA Research Service 2I01 BX001140; NIH 1P30DK12472

Role of human organic cation transporter-1 (OCT-1/SLC22A1) in modulating the response to metformin in patients with type 2 diabetes

BackgroundOrganic cation transporter 1 primarily governs the action of metformin in the liver. There are considerable inter-individual variations in metformin response. In light of this, it is crucial to obtain a greater understanding of the influence of OCT1 expression or polymorphism in the context of variable responses elicited by metformin treatment.ResultsWe observed that the variable response to metformin in the responders and non-responders is independent of isoform variation and mRNA expression of OCT-1. We also observed an insignificant difference in the serum metformin levels of the patient groups. Further, molecular docking provided us with an insight into the hotspot regions of OCT-1 for metformin binding. Genotyping of these regions revealed SNPs 156T>C and 1222A>G in both the groups, while as 181C>T and 1201G>A were found only in non-responders. The 181T>C and 1222A>G changes were further found to alter OCT-1 structure in silico and affect metformin transport in vitro which was illustrated by their effect on the activation of AMPK, the marker for metformin activity.ConclusionTaken together, our results corroborate the role of OCT-1 in the transport of metformin and also point at OCT1 genetic variations possibly affecting the transport of metformin into the cells and hence its subsequent action in responders and non-responders.

Metformin and Cancer, an Ambiguanidous Relationship.

The deregulation of energetic and cellular metabolism is a signature of cancer cells. Thus, drugs targeting cancer cell metabolism may have promising therapeutic potential. Previous reports demonstrate that the widely used normoglycemic agent, metformin, can decrease the risk of cancer in type 2 diabetics and inhibit cell growth in various cancers, including pancreatic, colon, prostate, ovarian, and breast cancer. While metformin is a known adenosine monophosphate-activated protein kinase (AMPK) agonist and an inhibitor of the electron transport chain complex I, its mechanism of action in cancer cells as well as its effect on cancer metabolism is not clearly established. In this review, we will give an update on the role of metformin as an antitumoral agent and detail relevant evidence on the potential use and mechanisms of action of metformin in cancer. Analyzing antitumoral, signaling, and metabolic impacts of metformin on cancer cells may provide promising new therapeutic strategies in oncology.

Metformin down‐regulates TGF beta signal transduction and production of PAR2 N‐terminus cleaving protease activity in an NR4a1 dependent manner in a PC3 prostate cancer cell line

OBJECTIVEOur aim is to understand the mechanisms of metformin’s antitumor actionsHYPOTHESISMetformin is known to have antitumour effects in cancers like head & neck cancer, that may involve its regulation of TGF‐β signalling, but the metformin receptor mechanisms for this action are not known. We recently discovered that the action of metformin to preserve hypoglycaemia‐impaired endothelial cell function regulated by proteinase‐activated receptor‐2 (PAR2) requires its interaction with the orphan nuclear receptor, NR4A1 (PubMed ID 34452975). PAR2 also plays a role in regulating prostate cancer PC3 cell function whereby autocrine signaling occurs in PC3 cells which secrete a PAR2‐cleaving/activating matrix metalloproteinase, MMP2. We hypothesized that metformin can act in PC3 prostate cancer‐derived cells via NR4A1 to change TGF‐β signalling and to alter the production of PAR‐cleaving proteinases.METHODSThe ability of TGF‐β to upregulate connective tissue growth factor (CTGF) mRNA in PC3 cells was measured for metformin treated cells (</=100 μM) that were transfected with NR4A1, C‐terminally tagged with red‐fluorescent protein (RFP): either wild‐type (WT) or mutant (PPGG) murine NR4A1 that does not interact with metformin. TGF‐β upregulated CTGF mRNA in PC3 cells was monitored after metformin treatment for 20 hours. In similarly transfected WT and mutant PPGG NR4A1‐expressing PC3 cells, treated or not with metformin (</=100 μM), the cleavage status of dually tagged transfected N‐terminal RFP/C‐terminal GFP‐PAR2 was monitored: (confocal imaging: yellow = intact receptor; green = cleaved receptor). Concurrently, the abundance of MMP activity of PC3 cell supernatants was measured by a fluorogenic MMP substrate, Mca‐RPKPVE‐Nval‐WRK(Dnp)‐NH2 (ES002).RESULTSThe expected TGF‐β upregulated CTGF mRNA in PC3 cells was prevented by metformin treatment, but only for cells transfected with the WT and not the mutant PPGG NR4A1. Metformin acted at concentrations (</=100 μM) far lower than those that affect mitochondrial complex I (> mM). We also found that in WT, but not PPGG mutant‐transfected PC3 cells, metformin (</=100 μM) down‐regulated MMP PAR2‐cleaving proteinase activity.CONCLUSIONSOur results show that low concentrations of metformin (</=100 μM), in the presence of wild‐type but not PPGG mutant NR4A1 which does not enable metformin interactions at the NR4A1 alternative ligand binding site, can both block TGF‐ β signaling and reduce cell‐secreted MMP activity that in turn can drive tissue invasion and metastasis via PAR2 activation. Thus, NR4A1 may play a role in the antitumour actions of metformin.

Status and analysis of trends in the metformin -based drug development: formation of the logistic system of scientific research

The aim of the work is analysis of the current state and trends in the metformin-based drug development with the subsequent formation of the logistics system of scientific research.
 Materials and methods. Studies were conducted using databases on the Internet (2015-2022): PubMed; U.S. Food and Drug Administration, European Medicines Agency, the State Expert Center of the Ministry of Health of Ukraine, scientific and metric databases - Scopus, Cochrane Database, US Patent Office. It has used retrospective, logical, graphic research methods, content analysis, modelling.
 Results. The model of the logistic system of metformin scientific research has developed. It represents the set of elements that are interconnected through information communication, its composition and features, which are associated with the pharmacological action of metformin, are determined.
 Logistic system of metformin scientific research allows: to demonstrate the uniqueness of the drug, to reveal its potential and new opportunities for medical use, prospects for the development of new types of dosage forms and new combined drugs; to identify the threat of patent infringement, to identify opportunities for establishing partnerships; to present scientific products in the form of a drug on the pharmaceutical market, optimizing the research time, reducing the development stages due to the available information and documentation, ensuring the synchronization of innovative information flows; to optimize the total costs of scientific research and receive at the expense of the specified profit.
 Logistic system of metformin scientific research is recommended for implementation in scientific organizations and pharmaceutical companies that perform R&D to achieve concentration of information search in solving logistics problems in the field of creating medicines based on metformin.
 Conclusions. Thus, the management of scientific research in pharmacy using the logistic approach ensures the time reduction of the medicine to entry into the market, reduces the cost of its creation, prevents duplication of research, and promotes optimization of solutions. The analysis revealed that the creation of medicines based on metformin should be aimed at the search and development of combined sugar-reducing drugs with mutually complementary mechanisms of action

The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases.

Metformin can suppress gluconeogenesis and reduce blood sugar by activating adenosine monophosphate-activated protein kinase (AMPK) and inducing small heterodimer partner (SHP) expression in the liver cells. The main mechanism of metformin’s action is related to its activation of the AMPK enzyme and regulation of the energy balance. AMPK is a heterothermic serine/threonine kinase made of a catalytic alpha subunit and two subunits of beta and a gamma regulator. This enzyme can measure the intracellular ratio of AMP/ATP. If this ratio is high, the amino acid threonine 172 available in its alpha chain would be activated by the phosphorylated liver kinase B1 (LKB1), leading to AMPK activation. Several studies have indicated that apart from its significant role in the reduction of blood glucose level, metformin activates the AMPK enzyme that in turn has various efficient impacts on the regulation of various processes, including controlling inflammatory conditions, altering the differentiation pathway of immune and non-immune cell pathways, and the amelioration of various cancers, liver diseases, inflammatory bowel disease (IBD), kidney diseases, neurological disorders, etc. Metformin’s activation of AMPK enables it to control inflammatory conditions, improve oxidative status, regulate the differentiation pathways of various cells, change the pathological process in various diseases, and finally have positive therapeutic effects on them. Due to the activation of AMPK and its role in regulating several subcellular signalling pathways, metformin can be effective in altering the cells’ proliferation and differentiation pathways and eventually in the prevention and treatment of certain diseases.Graphical abstract

Biological Properties of Transition Metal Complexes with Metformin and Its Analogues.

Metformin is a widely prescribed medication for the treatment and management of type 2 diabetes. It belongs to a class of biguanides, which are characterized by a wide range of diverse biological properties, including anticancer, antimicrobial, antimalarial, cardioprotective and other activities. It is known that biguanides serve as excellent N-donor bidentate ligands and readily form complexes with virtually all transition metals. Recent evidence suggests that the mechanism of action of metformin and its analogues is linked to their metal-binding properties. These findings prompted us to summarize the existing data on the synthetic strategies and biological properties of various metal complexes with metformin and its analogues. We demonstrated that coordination of biologically active biguanides to various metal centers often resulted in an improved pharmacological profile, including reduced drug resistance as well as a wider spectrum of activity. In addition, coordination to the redox-active metal centers, such as Au(III), allowed for various activatable strategies, leading to the selective activation of the prodrugs and reduced off-target toxicity.

Transcriptome Analysis of Liver Cancer Cell Huh-7 Treated With Metformin.

Metformin is a kind of widely used antidiabetic drug that regulates glucose homeostasis by inhibiting liver glucose production and increasing muscle glucose uptake. Recently, some studies showed that metformin exhibits anticancer properties in a variety of cancers. Although several antitumor mechanisms have been proposed for metformin action, its mode of action in human liver cancer remains not elucidated. In our study, we investigated the underlying molecular mechanisms of metformin's antitumor effect on Huh-7 cells of hepatocellular carcinoma (HCC) in vitro. RNA sequencing was performed to explore the effect of metformin on the transcriptome of Huh-7 cells. The results revealed that 4,518 genes (with log2 fold change > 1 or < −1, adjusted p-value < 0.05) were differentially expressed in Huh-7 cells with treatment of 25-mM metformin compared with 0-mM metformin, including 1,812 upregulated and 2,706 downregulated genes. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses identified 54 classical pathways that were significantly enriched, and 16 pathways are closely associated with cancer, such as cell cycle, DNA replication, extracellular matrix–receptor interaction, and so on. We selected 11 differentially expressed genes, which are closely associated with HCC, to validate their differential expressions through a quantitative real-time reverse transcription-polymerase chain reaction. The result exhibited that the genes of fatty acid synthase, mini-chromosome maintenance complex components 6 and 5, myristoylated alanine-rich C-kinase substrate, fatty acid desaturase 2, C-X-C motif chemokine ligand 1, bone morphogenetic protein 4, S-phase kinase-associated protein 2, kininogen 1, and proliferating cell nuclear antigen were downregulated, and Dual-specificity phosphatase-1 is significantly upregulated in Huh-7 cells with treatment of 25-mM metformin. These differentially expressed genes and pathways might play a crucial part in the antitumor effect of metformin and might be potential targets of metformin treating HCC. Further investigations are required to evaluate the metformin mechanisms of anticancer action in vivo.

Metformin: Sex/Gender Differences in Its Uses and Effects-Narrative Review.

Metformin (MTF) occupies a major and fundamental position in the therapeutic management of type 2 diabetes mellitus (T2DM). Gender differences in some effects and actions of MTF have been reported. Women are usually prescribed lower MTF doses compared to men and report more gastrointestinal side effects. The incidence of cardiovascular events in women on MTF has been found to be lower to that of men on MTF. Despite some promising results with MTF regarding pregnancy rates in women with PCOS, the management of gestational diabetes, cancer prevention or adjunctive cancer treatment and COVID-19, most robust meta-analyses have yet to confirm such beneficial effects.