Lack of Food and Drug Administration-approved treatments for cocaine use disorder contributes to high rates of treatment attrition, relapse, and overdose. Metformin is a Type 2 diabetes drug being investigated for multiple new therapeutic indications. This study set out to determine whether metformin would impact the conditioned rewarding effects of cocaine in an abbreviated or standard two-chamber conditioned place preference (CPP) assay. Adult male (n = 73) and female (n = 82) Sprague Dawley rats were conditioned in a 7-day (abbreviated: 2 × 30 min sessions daily) or a 12-day timeline (standard: 1 × 30 min sessions daily) alternating control and treatment sessions using an unbiased design. Metformin (175 mg/kg) or saline pretreatment occurred 30 min before conditioning with cocaine (20 mg/kg) or vehicle (saline). Data showed sex differences in physiological responses to cocaine and metformin, as well as variant behavioral patterns with different conditioning paradigms. Metformin pretreatment impaired acquisition of cocaine CPP in abbreviated, but not standard conditioning among male rats only. Cocaine-induced locomotor effects are moderated with metformin pretreatment in both female and male rats in different phases of conditioning, suggesting the potential therapeutic value of symptom alleviation when tapering patients off cocaine use with the goal of abstinence. Sex differences observed highlight the importance in better understanding the unique pharmacological profiles of female and male patients. This study provides evidence supporting the potential repurposing of metformin for disrupting rewarding and psychomotor effects of cocaine, paving the way for safe, low-cost, and accessible treatment. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

The prevalence of prediabetes has more than doubled over the past two decades. Although hormones associated with the menstrual cycle may offer some protection against diabetes by enhancing insulin sensitivity and suppressing gluconeogenesis, the prevalence of diabetes among women remains high at 10.5%. Notably, among the perimenopausal population, the prevalence catches up to-and even surpasses-that of men starting from the 70-74 age group, according to the 2021 International Diabetes Federation (IDF) report. This narrative review examines the benefits and potential risks of metformin across diverse populations, with a particular emphasis on women in the perimenopausal phase. Metformin's interaction with hormonal regulation significantly influences both its therapeutic efficacy and long-term side effect profile, contributing to sex-specific differences in treatment response. Consequently, its effectiveness varies among women at different stages of menopause, potentially due to differential impacts on inflammatory markers and modulation of the hypothalamic-pituitary-ovarian (HPO) and hypothalamic-pituitary-thyroid (HPT) axes. Emerging evidence also highlights metformin's potential in managing conditions such as polycystic ovary syndrome (PCOS), breast tissue inflammation and endometrial disorders within this demographic. Given these potential and multifaceted benefits, this review highlights the need for further randomized controlled trials (RCTs) to investigate metformin's role among perimenopausal and menopausal women and to better understand how menopausal status may influence its efficacy. PLAIN LANGUAGE SUMMARY: The number of people with prediabetes has more than doubled in the last 20 years. By 2021, about 720 million people worldwide were living with this condition, and that number is expected to reach 1 billion by 2045. While hormones that fluctuate with the menstrual cycle might help protect against diabetes, the overall rate of diabetes among women is still concerning, at 10.5%. For women going through menopause, the situation is even more serious. From the age of 70 to 74, the rates of diabetes in women surpass those in men. This may be because menopause reduces levels of protective hormones like estrogen and progesterone, which help guard against type 2 diabetes (T2D). Despite this growing issue, there hasn't been much research focused on prediabetes in women going through menopause and how the changes in hormones might affect treatment guidelines. To address this lack of information, our review focused on the use of metformin for women in the perimenopausal stage with prediabetes, aiming to help prevent them from developing T2D in the future. We gathered insights from recent clinical trials to summarize the benefits and risks of metformin for various groups, particularly perimenopausal women. Our findings indicate that metformin can be effective for managing prediabetes, although opinions vary. It's currently the only diabetes medication recommended for prediabetes by the American Diabetes Association (ADA), supported by significant studies like the Diabetes Prevention Program (DPP) and the Coronary Endothelial Dysfunction Multicentre Prospective Study (CODYCE study). Metformin's effectiveness seems to increase when combined with lifestyle changes, such as diet and exercise. Some challenges exist, though, like concerns that it might only work for those at a high risk of developing T2D, potential side effects, and the availability of other options, such as lifestyle adjustments or a new medication called tirzepatide. Still, many experts argue that metformin remains valuable because it allows for early intervention, particularly when lifestyle changes alone may not be enough. We also found that metformin might work differently for men and women due to variations in hormone interactions, differing gut bacteria, and weight-related factors that can influence its effectiveness. Interestingly, metformin seems to work better for women who have not yet gone through menopause. This might be because it helps with weight loss and reduces inflammation, which are important for postmenopausal health. Moreover, metformin has shown promise in addressing other health issues that postmenopausal women may face, such as inflammation in breast tissue, certain types of cancer, endometrial problems (as an alternative to hormone therapy), and polycystic ovarian syndrome (PCOS). In conclusion, our review stresses the importance of creating specific guidelines for managing prediabetes (e.g., metformin therapy) in the perimenopausal population. Understanding how sex hormones interact with blood sugar control is crucial for developing effective treatments tailored to women at different stages of menopause.

Metformin is widely prescribed for the management of type 2 diabetes mellitus, polycystic ovary syndrome, and gestational diabetes mellitus in pregnancy. Its use is driven by factors including oral administration, lower patient and health system burden and cost, and benefits including lower risk of excess gestational weight gain and hypoglycemia compared with insulin. Metformin use appears safe in pregnancy; however, there remain concerns regarding long-term effects of intrauterine metformin exposure on offspring health. Randomized controlled trial follow-up studies suggest that metformin-exposed offspring may have altered postnatal growth trajectories and increased adiposity in childhood, although data are limited. Whether this is a transient adaptation or a precursor to long-term metabolic dysfunction is unclear, as data on cardiometabolic and neurodevelopmental parameters, including glucose homeostasis, lipid metabolism, and cognitive function, are sparse and inconsistent. Methodological challenges include heterogeneous study designs, high attrition rates, and inadequate control for confounding variables. Given these uncertainties, further well-powered, long-term prospective studies and individual patient data meta-analyses, harmonizing data and adjusting for confounders, are needed to clarify risks and benefits of metformin use in pregnancy. Until such data are available, clinicians must weigh the benefits and advantages of metformin use in pregnancy against the unknowns regarding potential long-term impact on offspring health. PLAIN LANGUAGE SUMMARY: Metformin is a medicine often used during pregnancy to help manage conditions such as type 2 diabetes, gestational diabetes, and polycystic ovary syndrome (PCOS). It is commonly chosen because it is taken as a tablet rather than by injection, has a lower risk of causing low blood sugar, and is generally easier and less expensive to use than insulin. Research has shown that metformin is safe for use during pregnancy in the short term. However, there are still questions about whether it has any lasting effects on children who were exposed to it before birth. This review explores this topic in detail. Some studies have found that children exposed to metformin during pregnancy may have slightly different growth patterns, such as having more body fat or being heavier in early childhood. However, these results are inconsistent and most studies show no clear differences in overall health outcomes, including in heart health, metabolism, or brain development. The results are mixed, and many studies are small or have design limitations, which makes it difficult to draw strong conclusions. At this stage, there is no clear evidence that metformin causes harm to children in the long term. However, because some studies suggest there may be effects on childhood growth and development, researchers emphasize the need for further long-term research. These future studies should follow children into adolescence and adulthood to better understand any lasting impacts. Until more is known, doctors and patients will need to carefully consider the known benefits of metformin in pregnancy alongside the current uncertainties about long-term effects on child health.

Metformin, initially prescribed as an oral hypoglycemic medication for type 2 diabetes, has recently gained attention for its potential anticancer effects. Its history dates to 1918, when guanidine, a component of the traditional European herb Galega officinalis, was found to reduce glycemia. This review precisely examines the mechanisms underlying Metformin's anticancer effects across various neoplastic conditions. This investigation explores the complex interactions between metformin and major signaling pathways associated with carcinogenesis, including AMP-activated protein kinase (AMPK), mTOR, and insulin-like growth factor (IGF) pathways. The review emphasizes Metformin's diverse effects on angiogenesis, inflammation, apoptosis, and cellular metabolism in cancer cells. Additionally, new data on metformin's capacity to alter the tumor microenvironment and enhance immune surveillance systems against cancer are examined. The review underscores Metformin's potential for repurposing in oncology, emphasizing its clinical relevance as an adjuvant therapy for various cancers. The review provides insightful information about the complex anticancer mechanisms of metformin by combining data from preclinical and clinical studies. These findings not only broaden our knowledge of the effects of metformin but also open new avenues for oncology research and treatment developments.

Digestive tract cancers account for a significant proportion of the global cancer burden, and their prevention and treatment pose a worldwide challenge. Metformin, as a first-line treatment for diabetes, offers advantages such as high safety and affordability. Previous research has suggested that the use of metformin may reduce the risk of cancers, but there is still a lack of strong evidence regarding its causal relationship with digestive tract cancers.

We employed Mendelian randomization (MR) analysis to investigate the causal relationships between metformin use and various digestive tract cancers. We selected single nucleotide polymorphisms (SNPs) related to the Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), which is associated with the action of metformin, as instrumental variables. The inverse variance-weighted method (IVW) was the most important method. Cochran's Q was used to detect heterogeneity, and the MR-PRESSO test and MR-Egger regression were used to detect horizontal pleiotropy. Subsequently, we verified the toxicity and proliferation inhibition of metformin on Huh 7 and PLC in hepatocellular carcinoma cells.

IVW results showed that metformin use reduced the risk of liver and bile duct cancers (OR = 0.994, 95% CI 0.990-0.999; P = 0.008), but there were no causal relationships with other digestive tract cancers. Our cell experiments have confirmed this point.

Metformin may be used for the prevention or treatment of liver and bile duct cancers.

Endothelial cell senescence serves as a pivotal driver of vascular dysfunction and cardiovascular pathogenesis. Metformin, a first-line antidiabetic agent, has expanded beyond its traditional role in glycemic control, with accumulating evidence underscoring its anti-aging properties. Endothelial dysfunction constitutes a central pathological basis for the development and progression of cardiovascular disease (CVD), and the restoration of endothelial function has been demonstrated to significantly mitigate cardiovascular event risks. Preclinical and clinical studies indicate that metformin-whether administered as monotherapy or in combination regimens-has demonstrated significant potential in the treatment of CVD by ameliorating endothelial dysfunction. Emerging evidence indicates metformin attenuates endothelial senescence and enhances cellular function via pleiotropic mechanisms, thereby preserving endothelial function and retarding cardiovascular disease (CVD) progression. This review systematically elucidates current understanding of metformin's senescence-inhibitory mechanisms in endothelial cells and evaluates its translational potential for CVD intervention, which may provide novel strategies for next-generation CVD pharmacotherapeutics.

Obesity is a significant health concern, significantly contributing to increased morbidity and mortality by disrupting multiple physiological systems. It is strongly associated with metabolic dysfunctions, including impaired glycemic homeostasis, compromised intestinal barrier integrity, and gut microbiota imbalances, all exacerbating the risk of chronic diseases. The hydroalcoholic extract of açaí seeds (ASE), rich in phenolic compounds, has demonstrated beneficial effects on obesity and hyperglycemia; however, its impacts on gut health and gut-hypothalamus communication remain unclear. This study aimed to investigate the therapeutic effect of ASE in intestinal and hypothalamic alterations associated with obesity and compare it with Metformin. Male C57BL/6 mice were fed a high-fat or standard diet for 14 weeks. The ASE (300 mg/kg/day) and Metformin (300 mg/kg/day) treatments started in the tenth week until the fourteenth week, totaling four weeks of treatment. Our data show that the treatment with ASE and Metformin reduced body weight, ameliorated lipid profile, hyperglycemia, and plasma hyperleptinemia, and decreased the oxidative damage in the gut by reducing immunostaining of 8-isoprostane and NOX-4 expression, and improved the intestinal parameters and hypothalamic gene expression. Obesity-induced dysbiosis in the HF group was marked by reduced Proteobacteria and elevated LPS plasma levels, which were improved by treatments with ASE and Metformin. These findings suggest that ASE and Metformin are promising strategies to counteract the adverse effects of obesity on intestinal health and gut-hypothalamus communication, though they act through distinct mechanisms. Therefore, we can suggest that ASE is a promising natural product for treating the intestinal alterations associated with obesity.

Metformin (MET) and its metabolite guanylurea (GUA) are prevalent in aquatic environments, raising concerns about their potential risks to aquatic organisms. However, the toxicity of these compounds through different exposure routes has not been reported. This study evaluated the effects of MET and GUA on the growth of the green algae Tetradesmus obliquus and on life table parameters of the freshwater rotifer Brachionus calyciflorus through various exposure routes, including waterborne, foodborne, and combined waterborne + foodborne. Our results indicated that both MET and GUA, at concentrations of 1 mg/L and 100 mg/L, inhibited algae growth, with GUA causing greater stress than MET. Additionally, compared to waterborne exposure, foodborne and combined waterborne + foodborne exposures of MET and GUA at these concentrations significantly decreased the net reproductive rate (R0), intrinsic rate of population increase (rm), and life expectancy (e0) of B. calyciflorus. Notably, the impact of exposure routes on the life table parameters of B. calyciflorus was generally greater than the impact of exposure concentrations. Therefore, previous studies focusing solely on waterborne exposure may have underestimated the toxicity of MET and GUA.

Biochemical alterations linked to metabolic syndrome (MetS), type 2 diabetes (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD) may be brought on by the Western diet. Based on research conducted over the past decade, fructose is one of the main culprits. Over 80% of ingested fructose is metabolized by the liver at first pass, where it stimulates de novo lipogenesis (DNL) to drive hepatic triglyceride (TG) synthesis, which contributes to MASLD, hepatic insulin resistance (IR), and dyslipidemia. Fructose reduction produces quick and significant amelioration in these metabolic disturbances. We hereby propose potential overarching processes that can link these pathways to signaling disruption by the critical metabolic sensor AMP-activated protein kinase (AMPK). We proffer that when large amounts of fructose and glucose enter the liver, triose fluxes may be sufficient to produce transient increases in methylglyoxal (MG), allowing steady-state concentrations between its production and catabolism by glyoxalases to be high enough to modify AMPK-sensitive functional amino acid residues. These reactions would transiently interfere with AMPK activation by both AMP and aldolase. Such a sequence of events would boost the well-documented lipogenic impact of fructose. Given that MG adducts are irreversible, modified AMPK molecules would be less effective in metabolite sensing until they were replaced by synthesis. If proven, this mechanism provides another avenue of possibilities to tackle the problem of fructose in our diet. We additionally discuss potential multimodal treatments and future research avenues for this apparent hepatic AMPK malfunction.

Metformin is frequently prescribed to treat type 2 diabetes. Its primarily regulates hepatic and colonic glucose metabolism, but recent studies have suggested an anti-inflammatory effect, especially in colitis. It has been suggested that metformin may enhance immune checkpoint inhibition (ICI) efficacy for cancer treatment. Our study aims to explore the impact of metformin on ICI efficacy and the risk for colitis.

This was a single center, retrospective analysis of consecutive patients at a tertiary cancer center who received ICI between 01/2010-12/2022 and developed immune-mediated colitis (IMC). Patients were screened for colitis based on stool tests, then divided into two groups depending on metformin use prior to colitis onset. We collected data on demographic and colitis clinical information including treatments, and outcomes.

A total of 953 patients were included. The incidence of IMC was higher among metformin users (7.6 %) than non-metformin users (4.9 %; p < 0.01). There were no significant differences in colitis features and outcomes, except for longer hospital stay among metformin users (8 days vs 6 for non-metformin users; p = 0.03). Metformin use was associated with shorter overall survival vs non-metformin users among patients with IMC (p = 0.03).

Our study is among the first to explore the impact of metformin on IMC and overall survival. We found that metformin use may be associated with higher risk of IMC. We also found an association between metformin use and shorter overall survival among patients who developed IMC. Larger studies with risk-stratified analysis are needed to validate our findings.

Vitamin B12 deficiency is a common and neglected adverse effect experienced by type 2 diabetic patients treated with metformin. A lack of vitamin B12 may have severe consequences, such as fatigue, macrocytic anaemia and worsened peripheral diabetic neuropathy. This study aims to identify the rate of vitamin B12 deficiency and the associated factors in type 2 diabetic patients treated with metformin.

Cross-sectional study.

This study involved 145 type 2 diabetic patients treated with metformin in Cho Ray hospital, a tertiary healthcare centre in South Vietnam. The levels of vitamin B12 and associated clinical and paraclinical parameters were measured and collected.

The study population's mean age was 61.5 years, of which 51.7% were women. The median duration of metformin use was 10 years, and the median metformin dose was 1700 mg. The vitamin B12 deficiency rate was 22.1%. HbA1c, duration of metformin use and metformin dose were independent factors statistically associated with vitamin B12 deficiency.

This study identified the rate of vitamin B12 deficiency and associated factors in type 2 diabetic patients treated with metformin. These findings can be helpful in screening patients and replacing vitamin B12 in high-risk populations with vitamin B12 deficiency.

Ethical Committee of Cho Ray Hospital (approval number 1711/CN-HĐĐĐ).

This meta-analysis aimed to evaluate the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) when compared to metformin and placebo in the management of body weight, glucose homeostasis and hormone levels in women polycystic ovary syndrome (PCOS). A systematic search of "PubMed", "EMBASE", "Cochrane Library", "Web of Science" and "Google Scholar" was conducted up to October 2024 for randomized controlled trials involving adult women with PCOS treated with GLP-1RAs compared to metformin or placebo. The primary outcomes were changes in body mass index (BMI), body weight, waist circumference (WC), waist-to-hip ratio (WHR) and abdominal girth (AG). Secondary outcomes included glucose homeostasis (fasting glucose, fasting insulin, OGTT results and HOMA-IR), hormone levels (DHEAS, SHBG, total and free testosterone and FAI), lipid profiles (total cholesterol, HDL, LDL and triglycerides) and safety. GLP-1RAs significantly reduced BMI, body weight, WC, WHR and AG (P < 0.0001 in all cases). For glucose homeostasis, GLP-1RAs significantly reduced fasting insulin, glucose level at 2 h after OGTT, and HOMA-IR. There was also a reduction in HDL. All the other parameters measured were unchanged. In addition, GLP-1RAs increased nausea (P = 0.02), vomiting (0.04) and dizziness (0.03). GLP-1RAs effectively reduced body weight, BMI and insulin resistance in patients with PCOS, although they were accompanied by nausea, vomiting and dizziness. Further studies are needed to explore their long-term effects on glucose homeostasis and lipid profiles.

Metformin is an antidiabetic drug that has shown its benefit in increasing the effect of radiotherapy in the treatment of solid tumors in preclinical studies. The objective of this systematic review is to study the effect of metformin as a radiosensitizer in studies carried out in clinical practice.

Systematic review carried out according to PRISMA criteria of clinical trials, systematic reviews and observational studies focused on the influence of metformin as a radiosensitizer in solid tumors. The studies were published between the years 2010 and 2022. The results of the studies have been analyzed in terms of survival (OS, PFS, DFS, DMFS) and response (ORR) between patients treated with metformin and without it.

A total of 16 studies have been found in the literature (the most frequent tumor was prostate cancer, 5 studies). External radiotherapy was administered in all the studies and in two of them to greater brachytherapy. The use of metformin with radiotherapy showed a consistent benefit in terms of survival and response in tumors of prostate, hepatic and gynecological origin. The benefit in the rest of the tumors analyzed (lung, rectal, and head and neck cancer) is doubtful, and the results are contradictory. The greatest benefits were observed in prostate tumors both in OS and SLE.

The use of metformin in combination with radiotherapy in solid tumors is one of the most promising treatments under development in oncology. The benefit observed in real-life studies makes it necessary to develop clinical trials that specifically evaluate its use in clinical practice in the future.

Schizophrenia (SCZ) represents a considerable health concern, not only due to its impact on cognitive and psychiatric domains, but also because of its association with metabolic abnormalities. Individuals with SCZ face an increased risk of developing metabolic syndrome (MS), which contributes to the increased cardiovascular burden and reduced life expectancy observed in this population. Metabolic alterations are associated with both the SCZ condition itself and extrinsic factors, particularly the use of antipsychotic medications. Additionally, the link between SCZ and MS seems to be guided by distinct genetic parameters. The present narrative review summarizes the relationship between SCZ and MS and emphasizes the various therapeutic approaches for managing its components in patients with these conditions. Recommended therapeutic approaches include lifestyle modifications as the primary strategy, with a focus on behavioral lifestyle programs, addressing dietary patterns and physical activity. Pharmacological interventions include administering common antidiabetic medications and the selection of less metabolically harmful antipsychotics. Alternative interventions with limited clinical application are also discussed. Ultimately, a personalized therapeutic approach encompassing both the psychological and metabolic aspects is essential for the effective management of MS in patients with SCZ.

The global prevalence of obesity is skyrocketing at an alarming rate, with recent data estimating that one-in-eight people are now living with the disease. Obesity is a chronic metabolic disorder that shares underlying pathophysiology with other metabolically-linked diseases such as type 2 diabetes mellitus, cardiovascular disease and diabetic cardiomyopathy. There is a distinct correlation between type 2 diabetes status and the likelihood of heart failure. Of note, there is an apparent sexual dimorphism, with women disproportionately affected with respect to the degree of severity of the cardiac phenotype of diabetic cardiomyopathy that results from diabetes. The current pharmacotherapies available for the attenuation of hyperglycaemia in type 2 diabetes are not always effective, and have varying degrees of efficacy in the setting of heart failure. Insulin can worsen heart failure prognosis whereas metformin, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and more recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs), have demonstrated cardioprotection with their administration. This review will highlight the advancement of incretin therapies for individuals with diabetes and heart failure and explore newly-reported evidence of the clinical usefulness of GLP-1R agonists in this distinct phenotype of heart failure.

Benzimidazoles are the most frequently prescribed therapeutic options for treating trichinellosis in clinical settings; however, they have a lot of disadvantages. Therefore, researchers are focusing on the hunt for substitute chemicals. The goal of the current study was to compare the effectiveness of albendazole and the anti-diabetic medication metformin loaded on chitosan nanoparticles in treating mice infected with various stages of T. spiralis infection. 160 mice were included in the present study and divided into 8 groups: 6 experimentally treated groups, and positive and negative control groups. For studying the intestinal and parenteral phase, each group was broken into two more subgroups (a and b) according to the time of drug administration. The effects of albendazole, albendazole-loaded NPs, metformin, metformin-loaded NPs, combined albendazole and metformin, and metformin and albendazole-loaded NPs were assessed using parasitological studies, histopathological examination, and ultrastructural examination using SEM.Statistically significant differences were detected in all studied subgroups compared to the control infected subgroup both in the intestinal and muscular phases. The greatest decrease in recovered adult worm and muscle larvae numbers was achieved by ABZ & MET/ Cs NPs. These findings were confirmed by histopathological examination. SEM examination of the tegument of T. spirals adult worms and muscle larvae showed destruction with multiple degenerative changes.Our results suggested that metformin and its combination with albendazole especially when loaded on chitosan nanoparticles could be potential therapeutic alternative drugs against trichinellosis.

Diabetic cardiomyopathy (DCM) is a global health concern. However, studies examining the effect of metformin on diabetes-induced cardiac myocyte aging are lacking. This study aimed to investigate the protective effect of metformin against DCM involving modulation of macrophage phenotypes, growth differentiation factor-15 (GDF-15), and the anti-aging protein Klotho. Diabetes was induced in male Wistar rats using streptozotocin. Diabetic and nondiabetic rats were treated with metformin (200 mg/kg/day) and saline (control). DCM, inflammation, adhesion molecules, immunometabolic, and GDF-15 biomarkers were assessed using immunoassays. Western blotting was used to analyze Klotho expression. Macrophage phenotypes, senescence-associated-galactosidase (SA-β-gal), and p16INK4a were examined using immunohistochemistry, whereas the heart sections were histologically examined. The untreated diabetic rats showed increased serum troponin I and creatine kinase-MB levels, reflecting cardiac damage, which was confirmed via morphological changes and senescence. Klotho expression was decreased, indicating cardiac aging. Treatment with metformin reduced the heart weight-body weight ratio and lowered cardiac injury, inflammation, and adhesion molecule biomarker levels. It also reversed the histopathological changes induced by diabetes. It shifted macrophage polarization toward the M2 phenotype, decreased p16INK4a and SA-β-gal expression, and enhanced Klotho and GDF-15 expression. These findings revealed that diabetes induces cardiac aging by increasing senescence markers and decreasing the expression of Klotho. Metformin treatment protects against DCM by modulating macrophage phenotypes, attenuating immunosenescence-related dysregulation, and enhancing GDF-15 and Klotho expressions. Thus, metformin has potential clinical implications in alleviating DCM.

Drug repurposing is the process of using currently approved drugs for a novel treatment or medical condition for which it was not previously indicated. Despite promising preclinical and clinical results, most of the newly designed senotherapeutic agents synthesized have limited clinical utility due to individual and organ-specific variations in aging phenotype and adverse side effects. All these limitations indicate that further clinical research is required to determine the effectiveness of repurposed senotherapeutic drug interventions, such as metformin, for age-related diseases. Metformin exerts diverse senotherapeutic effects on various aging tissues at different metabolic conditions. Although not exhibiting senolytic properties, metformin has effectively suppressed cellular senescence and senescence-associated secretory phenotype (SASP) in age-related diseases (ARDs). Targeting specific SASP-related signaling pathways with metformin may offer new therapeutic benefits to alleviate the detrimental effects of senescent cells accumulated in most common ARDs in the elderly. Metformin was also the first drug evaluated for its senescence-targeting effects in a large clinical trial named "Targeting Aging with Metformin (TAME)". In this review, we critically evaluate the literature to highlight senotherapeutic mechanisms in which metformin can be therapeutically repurposed for the prevention and treatment of ARDs.

Metformin, a widely used antidiabetic drug, modulates the cellular physiology and metabolism of various body tissues, including adipose tissue. Adipogenesis, a complex process in which mesenchymal stem cells (MSC) differentiate into functional adipocytes, plays a key role in metabolic health and represents a potential therapeutic target for diverse metabolic disorders. Notably, recent evidence suggests that metformin modulates adipocyte differentiation. This narrative review explores the effects of metformin on cellular metabolism, with a particular focus on adipogenesis. The findings compiled in this review show that metformin regulates glucose and lipid metabolism in multiple tissues, including skeletal muscle, adipose tissue, liver, and intestine. Furthermore, metformin modulates adipogenesis through AMP-activated protein kinase (AMPK)-dependent and independent mechanisms in 3T3-L1 cells and adipose-derived stem cells. The review also emphasizes that metformin can promote or inhibit adipogenesis and lipid accumulation, depending on its concentration. Additionally, metformin attenuates inflammatory pathways by reducing the production of proinflammatory cytokines such as IL-6, MCP-1, and COX-2. Finally, evidence supports that vitamin D enhances the anti-inflammatory actions of metformin and promotes cell differentiation toward a beige adipocyte phenotype. In summary, this review examines the molecular actions of metformin to propose potential new therapeutic strategies for managing obesity and related metabolic diseases.

Oxidative stress impairs intestinal function and causes poor growth performance in piglets. Carvacrol is a natural essential oil, and its anti-oxidative and anti-inflammatory activities in the intestines of piglets have been reported in many studies. However, the mechanisms underlying these protective effects against oxidative stress remain unclear. This study aimed to investigate the possible pathway of carvacrol in the porcine intestine under oxidative stress using an in vitro model. Porcine intestinal epithelial cells (IPEC-J2) were treated with carvacrol and hydrogen peroxide (H2O2), an oxidative stress inducer, to investigate the protective mechanisms of carvacrol under oxidative stress. We found that carvacrol ameliorated a H2O2-induced loss of cell viability, apoptosis, and reduced intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Carvacrol reduced mitochondrial ROS generation and increased citrate synthase activity during oxidative stress. Furthermore, carvacrol attenuated an increase in the autophagy marker LC3II-to-I ratio and reduced the accumulation of lysosomes and autolysosomes induced by H2O2. The increased protein expression of the mitophagy marker PINK1, induced by H2O2, was also reduced by carvacrol treatment. Metformin-activated autophagy diminished the protective effects of carvacrol on cell viability and MDA levels under H2O2 treatment, indicating that autophagy inhibition is necessary for carvacrol-induced protection in IPEC-J2 cells during oxidative stress. In conclusion, this study demonstrated the underlying mechanism that carvacrol exerted its anti-oxidative effects on porcine intestinal epithelial cells by relieving excessive autophagy during weaning stress.

Humans encounter ionizing radiation (IR) through various ways, such as medical applications, agricultural industry, and potential exposure from radioactive materials or acts of radiological terrorism. Hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) are crucial for maintaining the balance of blood cell lineages. The hematopoietic system, recognized as the most sensitive human tissue, is severely affected by IR, which can result in bone marrow (BM) failure, increased susceptibility to infections, hemorrhagic events, or anemia in affected individuals. Therefore, it is essential to develop radioprotective compounds to protect HSCs/HPCs. This review highlights several radioprotective agents that protect the hematopoietic system from IR-related damage to HSCs and HPCs and provides an overview of the mechanisms involved in damage and protection.

Gestational diabetes mellitus (GDM) is a common pregnancy complication closely associated with maternal oxidative and antioxidant imbalance, known as oxidative stress. Environmental and dietary exposure plays an important role in inducing oxidative stress during pregnancy. This review aims to provide an in-depth analysis of the role of oxidative stress induced by environmental and dietary exposure in GDM while incorporating current research frontiers. Environmental pollution, smoking, excessive nutrition, and unhealthy eating habits such as a high-fat diet and vitamin deficiency, may contribute to the generation and accumulation of reactive oxygen species (ROS), leading to oxidative stress. Within the pathway of oxidative stress in GDM, the production and clearance mechanisms of ROS play a pivotal role. Relevant studies have demonstrated that ROS production is closely linked to insulin resistance, adipose tissue accumulation, inflammation, and other pathological processes. Antioxidant substances like vitamins C and E or glutathione can mitigate oxidative stress damage on pregnant women and fetuses by scavenging ROS. Currently, there remain several cutting-edge issues regarding the involvement of the oxidative stress pathway in GDM pathogenesis as well as its relationship with environmental and dietary factors, for instance: how to reduce maternal oxidative stress levels through dietary adjustments or lifestyle modifications; how antioxidant substances can be utilized for intervention treatment; and accurate assessment methods for maternal oxidative stress status along with its association with GDM risk. In conclusion, environmental and dietary factors exert significant influence on GDM pathogenesis while highlighting increasing attention toward understanding the role played by the oxidative stress pathway within this context. In-depth research endeavors within this field are anticipated to offer novel insights into prevention strategies as well as therapeutic approaches for GDM.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), affecting over 40% of patients with diabetes. DKD progression involves fibrosis and damage to glomerular and tubulointerstitial regions, with mitochondrial dysfunction playing a critical role. Impaired mitochondria lead to reduced adenosine triphosphate (ATP) production, damaged mitochondria accumulation, and increased reactive oxygen species (ROS), contributing to renal deterioration. Maintaining mitochondrial quality control (MQC) is essential for preventing cell death, tissue injury, and kidney failure. Recent clinical trials show that enhancing MQC can alleviate DKD. However, current treatments cannot halt kidney function decline, underscoring the need for new therapeutic strategies. Mitochondrial-targeted drugs show potential; however, challenges remain because of adverse effects and unclear mechanisms. Future research should aim to comprehensively explore therapeutic potential of MQC in DKD. This review highlights the significance of MQC in DKD treatment, emphasizing the need to maintain mitochondrial quality for developing new therapies.

Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing 3 (NLRP3) is a signaling pathway that is involved in inflammatory cascades, cell survival and the immune response. NLRP3 is activated by cellular damage, oxidative stress, and other factors that stimulate the immune system. Stimulation of NLRP3 induces inflammatory reactions and the production of inflammatory cytokines. These inflammatory mediators are implicated in several diseases. Metformin (MET) is an anti-hyperglycemia agent that is extensively used in clinical practice worldwide due to its high efficiency, safety profile, and affordable price. MET is the only member of biguanide class that is used in clinical practice and a potent AMP-activated protein kinase (AMPK) agonist with proven anti-inflammatory characteristics. Due to its anti-inflammatory properties, MET is considered to be effective against diseases that have an inflammatory background, and the NLRP3 pathway is involved in the pathophysiology of these disorders. In this review, we have evaluated the evidence if MET can affect this pathway and its utility for future therapeutic approaches.

Medicinal herbs continue to play an important part in modern drugs and healthcare because customers think that most of them have fewer or milder side effects than traditional modern medicines. Bioactive compounds are typically isolated from plants before being used as a source of therapeutic medicines. As a result, extracting bioactive compounds from medicinal plants is an important step in developing plant-based medications. Orientin is a flavonoid C-glycoside found in many plants, is frequently used in bioactivity studies due to its numerous beneficial properties, which include antioxidants, antiaging, anti-inflammation, vasodilation and cardioprotective, neuroprotective, antidiabetic, hepatoprotective, and adaptogenic effects. In this review, the comprehensive search for the health benefits of orientin was traced. The findings reflected that orientin could be considered one of the important natural candidates as a potential nutraceutical. This underscores its promising attributes and potential applications in health and wellness. Further research may be guaranteed to fully elucidate its benefits and mechanisms of action.

Insufficiency of Akkermansia muciniphila (Akk) has been implicated in the pathogenesis of metabolic diseases, and administration or restoration of Akk has ameliorated these disorders. Recently, Pasteurized Akk (PA-Akk) has been approved as a functional food. However, the impact of Akk on lipid absorption in the proximal intestine, which is directly exposed to orally administered Akk, remains largely unexplored. In this study, we orally administered Akk and PA-Akk to mice and investigated the subsequent lipid absorption. Long-term administration of Akk resulted in reduced lipid deposits in the liver and adipocytes, along with improved glucose metabolism. This was primarily attributed to a reduction in lipid absorption by epithelial cells in the proximal jejunum. Mechanistically, Akk activated AMP-activated protein kinase (AMPK) and directly inhibit lipids absorption in both mouse and human jejunal epithelial cells. Furthermore, we demonstrated that Akk treatment, but not PA-Akk treatment, promotes the abundance of genera that are highly abundant in the normal jejunum and belong to the phylum Firmicutes. Thus, our study concludes that oral administration of Akk provides beneficial effects on metabolism, partially through inhibiting jejunal lipid absorption and promoting the abundance of core jejunal microbes.

Bacteria deep in the wound can cause prolonged inflammation and dysfunctional angiogenesis, impeding healing and potentially leading to chronic conditions, disability, or even death. To address this, we developed a double-layer metal-organic framework (MOF) microneedle (MN) patch system (GCM-MN-CSH), designed to accelerate the healing of infected wounds through programmed therapy. The GCM-MN-CSH system consists of a hydrocaffeic acid-modified chitosan (CSH) hydrogel patch and a metformin (Met)-loaded Ga-Car-MOF (GCM)-based γ-polyglutamic acid matrix MN array (GCM-MN). The GCM nanoparticles were incorporated in the MN tips. The deep, localized penetration of GCM-MN, combined with the multifunctional activity of GCM, enables effective delivery of GCM nanoparticles into the dermis. These nanoparticles acid-response release Ga3+ ions and benzylpenicillin carboxylate, which possess antimicrobial activity, as well as Met, which promotes tissue regeneration. The adhesive CSH patch not only helps create a controlled, moist environment at the wound site but also provides antimicrobial properties on the surface. Together, the components of the GCM-MN-CSH system work synergistically to control infection, reduce inflammation, stimulate tissue proliferation, support tissue remodeling, and ultimately enable programmed wound healing. This advanced system offers a promising therapeutic platform for the management of infected wounds.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects. This comprehensive review discusses the dualistic role of NRF2 in disease pathophysiology, covering its protective and/or destructive roles in autoimmune, respiratory, cardiovascular, and metabolic diseases, as well as diseases of the digestive system and cancer. Additionally, we also review the development of drugs that either activate or inhibit NRF2, discuss main barriers in translating NRF2-based therapies from bench to bedside, and consider the ways to monitor NRF2 activation in vivo.

Radiation induced structural damage of salivary gland including reducing acinar cell and fibrosis. These changes result in hypofunction of salivary gland which has a significant impact on the quality of life of head and neck cancer patients who treated with radiotherapy. Nevertheless, no preventive method has been found. Metformin, a diabetes drug, has recently attracted considerable attention because it can cause tissue regeneration by anti-inflammatory action and influencing stem cells. This study examined the effects of metformin on salivary gland tissue damage caused by radiation therapy. Cultured human parotid epithelial cells are irradiated with 15 Gy of 4MV X-rays. The analysis including DNA damage, inflammatory markers and proliferation, is conducted to confirm the effect of metformin. Similarly, an in vivo mouse model is established. Histologic and functional analyses, such as salivary flow rate and lag time, are performed. The in vitro experiment revealed irradiation increased DNA damage, NF-кB, IL-6, and apoptosis with reduced proliferation. The treatment with metformin decreased the radiation-induced DNA damage and inflammation, and increased proliferation. The in vivo model also shows the same results. The group taking metformin after irradiation has preserved salivary gland parenchyma compared to irradiation only group, and the functional analysis results are comparable to the normal group. Histologic and functional analysis shows that metformin reduced radiation-induced hypofunction of salivary gland. Hence, metformin can be used to prevent radiation-induced salivary gland dysfunction.

Cancer treatment era has been revolutionized by the novel therapeutic methods such as immunotherapy in recent years. Immunotherapy-based approaches are considered effective and reliable methods that has brought hope to eradicate certain cancers. Nonetheless, there are some issues, considered as critical obstacles in successful cancer immunotherapy. Such issues are attributed to the ability of the tumor cells in providing a tolerant microenvironment that impairs the immune responses, and help the cancer cells evade the immunogenic cell death. It has been suggested that the re-activation and maintenance of effector immune cells may become possible by metabolic reprogramming. Several signaling pathways have been noticed with the possibility of metabolic reprogramming of tumor-specific T cells, to overcome the metabolic restrictions in the tumor microenvironment; and among them, AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptors (PPAR) have been investigated the most as the main energy sensors and regulators of mitochondrial biogenesis. The synergic effects of AMPK activators and/or PPAR agonists in cancer immunotherapy have been reported. In this review, we compare the roles of AMPK activators and PPAR agonists, and the efficacy of their combination in metabolic reprogramming of cytotoxic T cells in favoring cancer immunotherapy.

Effective, user-friendly, lifestyle-compatible, and economic treatment for type 2 diabetes (T2D) is urgently needed due to its high incidence and health threats. Here, we remolded Lactococcus lactis through genetic engineering to persistently secrete glucagon-like peptide-1 (L. lactis-GLP-1) and subsequent bioorthogonal arming with dopamine (DA)-based "gripper" and β-glucan (GN)-based "shield" (L. lactis-GLP-1-DA@GN) for treatment of T2D mice via oral administration. With protection by GN-based "shield", L. lactis-GLP-1-DA@GN achieved an impressive enhancement of survival by 20666 times compared with bare L. lactis-GLP-1 after experiencing gastrointestinal conditions and DA-based "gripper" was shielded from interaction with the upper digestive tract. Once prebiotic GN was metabolized by gut microbiota into short-chain fatty acids (SCFAs), underlying DA-based "gripper" was exposed to assist intestinal colonization of L. lactis-GLP-1, achieving synergistic treatment effects through secreted GLP-1 and SCFAs. With all advances, oral administration of L. lactis-GLP-1-DA@GN realized effective T2D treatment through improving glucose/lipid homeostasis, repairing major organs' damages, and positively modulating gut microbiota. Moreover, multi-omics analysis revealed that L. lactis-GLP-1-DA@GN also mainly intervened in liver's signaling pathways regarding lipid metabolism and oxidative regulation to advance anti-T2D process. Our strategy marks reconstruction of probiotics by combining chemical and biological tools, broadening the avenue of manipulating probiotics for disease treatments.

Diabetic cardiomyopathy (DCM), a critical complication of type 2 diabetes mellitus (T2DM), is marked by metabolic dysfunction, oxidative stress, and chronic inflammation, ultimately progressing to heart failure. This study investigated the synergistic therapeutic potential of Hippophae rhamnoides L. (sea buckthorn, SBU) extract and metformin in a mouse model of T2DM-induced DCM. T2DM was induced using a 45% high-fat-AGEs-enriched diet, followed by treatment with SBU, metformin, or their combination. Treatment effects were monitored through bioinformatic analysis, chemoinformatic prediction, behavioral testing, biochemical assays, histopathological evaluations and gene expression profiles. Based on bioinformatic analysis, we identified key hub genes involved in the diabetic cardiomyopathy including SERPINE1, NRG1, MYH11, PTH, NR4A2, NRF2, PGC1α, GPX4, ATF1, ASCL2, NOX1, NLRP3, CCK8, COX2, CCL2, PTGS2, EGFR, and oncostatin, which are pivotal in modulating the ferroptosis pathway. Furthermore, the expression of long non-coding RNAs (lncRNAs) NEAT1 and MALAT1, critical regulators of inflammation and cell death, was effectively downregulated, correlating with decreased levels of the pro-inflammatory marker oncostatin. The combined therapy significantly improved glucose regulation, reduced systemic inflammation and protected the heart from oxidative damage. Histopathological analysis revealed notable reductions in cardiac necrosis and fibrosis. Particularly, the combination therapy of SBU and metformin demonstrated a synergistic effect, surpassing the benefits of individual treatments in preventing cardiac damage. These findings highlight the potential of integrating SBU with metformin as a novel therapeutic strategy for managing DCM by targeting both metabolic and ferroptosis-related pathways. This dual intervention opens promising avenues for future clinical applications in diabetic heart disease management, offering a comprehensive approach to mitigating the progression of DCM.

This comprehensive review examines the therapeutic potential of metformin, a well-established diabetes medication, in treating neurodegenerative disorders. Originally used as a first-line treatment for type 2 diabetes, recent studies have begun investigating metformin's effects beyond metabolic disorders, particularly its neuroprotective capabilities against conditions like Parkinson's disease, Alzheimer's disease, Huntington's disease, and multiple sclerosis. Key findings demonstrate that metformin's neuroprotective effects operate through multiple pathways: AMPK activation enhancing cellular energy metabolism and autophagy; upregulation of antioxidant defenses; suppression of inflammation; inhibition of protein aggregation; and improvement of mitochondrial function. These mechanisms collectively address common pathological features in neurodegeneration and neuroinflammation, including oxidative stress, protein accumulation, and mitochondrial dysfunction. Clinical and preclinical evidence supporting metformin's association with improved cognitive performance, reduced risk of dementia, and modulation of pathological hallmarks of neurodegenerative diseases is critically evaluated. While metformin shows promise as a therapeutic agent, this review emphasizes the need for further investigation to fully understand its mechanisms and optimal therapeutic applications in neurodegenerative diseases.

Gestational diabetes mellitus (GD)-induced gut dysbiosis in pregnant mothers may increase the risk of cognitive impairment and neurological disorders in both the mother and offspring as they age. Restoring gut balance could improve cognitive outcomes for both. Despite advancements in GD treatment, side effects have increased, and long-term neurocognitive impacts on offspring born to GD mothers remain underexplored. This study uses a GD mouse model, inducing pancreatic dysfunction in 3-month-old pregnant C57BL/6J mice with Streptozotocin. The efficacy and mechanism of the prebiotic phytocompound green leaf extract (Allmania nodiflora) were assessed, with metformin as the standard. GD dams exhibited weight and glucose reduction, pancreatic IL-6 elevation, GLUT3 reduction, astroglia changes in the cerebral cortex, gut barrier impairment, cognitive impairment, and heightened anxiety compared to controls. Bacterial 16s rRNA sequencing revealed dysbiosis, with reduced Erysipelotrichales in GD dams compared to controls. Metformin lowered blood glucose levels but failed to rescue functional and behavioral phenotypes in both GD dams and offspring. Phytocompound treatment improved blood glucose, reduced pancreatic inflammation, improved gut barrier integrity, reversed dysbiosis, and enhanced brain health. It rescued behavioral deficits and improved cognitive outcomes in offspring, suggesting the prebiotic phytocompound may be a more effective therapeutic agent for GD in humans.

Background/Objectives: Diabetes mellitus is a growing global health concern, driving the exploration of new therapies like cannabidiol (CBD), which shows potential in improving insulin sensitivity and glycemic control, though its effects on glucose metabolism remain unclear. This study evaluates CBD's dose-dependent effects on glycemia, insulin, and hepatic carbohydrate metabolism in diabetic rats. Methods: The Oral Glucose Tolerance Test (OGTT) was performed in healthy rats to compare intragastric vs. intraperitoneal CBD (0.5, 5, 50 mg/kg). Diabetic rats were treated with intragastric CBD (25, 50, 100 mg/kg) or metformin (70 mg/kg) for 8 days. Blood glucose, insulin, lipid profiles, and key carbohydrate-metabolizing enzymes were analyzed. Results: In the OGTT, intragastric CBD reduced glycemic AUC, with 50 mg/kg showing the strongest effect, while intraperitoneal CBD had no impact. In diabetic rats, metformin and 25 mg/kg CBD lowered blood glucose, but only CBD increased insulin. The 50 mg/kg dose caused the greatest glucose reduction and moderate insulin rise, while 100 mg/kg had no effect. At 25 mg/kg, CBD inhibited glucose-6-phosphatase and increased glucose-6-phosphate. The 50 mg/kg dose further suppressed gluconeogenic enzymes, reduced glycogen phosphorylase and liver glucose, and enhanced glucose-6-phosphate, showing the strongest metabolic effects. The 100 mg/kg dose increased hexokinase but had weaker metabolic effects. Metformin improved glucose utilization and glycogen storage. CBD at 25 and 50 mg/kg reduced triacylglycerols and increased HDL, while 100 mg/kg had no effect. Conclusions: This study provides strong evidence of CBD's antidiabetic potential, especially at 50 mg/kg, particularly through its modulation of glucose metabolism and tendency to regulate insulin levels.

Background and Objectives: Type 2 Diabetes Mellitus (T2DM) is a metabolic disease caused by the failure of the skeletal muscle, liver and adipose tissue to respond to insulin. Metformin is the first choice for the treatment of T2DM. Isthmin 1 (Ism1) is a newly discovered adipokine that affects all carbohydrate, lipid and protein metabolism. This study examines the changes in serum and salivary levels of Ism1 in patients using metformin, considering its potential as a follow-up marker for T2DM if present in the salivary glands. Materials and Methods: The study included 30 newly diagnosed T2DM patients and 30 non-diabetic controls. Ism1 was measured by ELISA in serum and saliva after 3 months and compared with routine biochemical parameters. Immunostaining of Ism1 was performed in salivary glands. Results: Ism1 was immunohistochemically detected in salivary glands for the first time. Serum Ism1 levels increased significantly after 3 months of metformin treatment (p = 0.028). The increase in salivary Ism1 levels did not reach statistical significance. Fasting plasma glucose (FPG) (p < 0.001), HbA1c (p < 0.001) and LDL (p = 0.015) levels decreased with metformin. There was a significant negative correlation between the increase in Ism1 levels and the decrease in LDL levels (rho = -0.362, p = 0.05). Conclusions: Despite its first detection in salivary glands, the hypothesis that Ism1 may be a surveillance marker in T2DM could not be confirmed. The negative correlation of Ism1 with LDL levels suggests that Ism1 may contribute to the ameliorative effect of metformin on serum lipids. Further studies are needed to support this conclusion.

Obesity is a risk factor for poor asthma control. Previous research suggests that patients with asthma and obesity have reduced responsiveness to corticosteroids. Recent studies indicate that body fat percentage may be more strongly associated with obesity-related diseases compared with body mass index. However, the relationship between body fat percentage and asthma, particularly regarding steroid sensitivity, remains unclear.

To investigate the association between body fat percentage and steroid sensitivity in patients with asthma and elucidate the potential mechanisms underlying this association.

Adult patients with asthma were enrolled and categorized into patients with high body fat percentage (HBF) and control groups. Peripheral blood mononuclear cells were isolated from the blood samples. These cells were cultured with dexamethasone followed by stimulation with tumor necrosis factor-α to assess the half-maximal inhibitory concentration of dexamethasone (IC50-Dex). Serum adipocytokines and oxidative stress markers were also measured. The effects of metformin on steroid sensitivity and oxidative stress in peripheral blood mononuclear cells were evaluated ex vivo.

The HBF group exhibited significantly higher IC50-Dex values than the control group. In the HBF group, IC50-Dex correlated with the number of acute exacerbations per year and serum oxidative stress marker levels. Treatment with metformin significantly reduced both IC50-Dex and oxidative stress marker levels in the HBF group.

Oxidative stress associated with increased body fat may contribute to impaired steroid sensitivity in patients with asthma. Metformin may improve steroid sensitivity by reducing oxidative stress, suggesting a potential therapeutic approach in this patient population.

Exposure to heavy metals significantly contributes to insulin resistance, a major factor in type 2 diabetes. This study investigated the antioxidant and therapeutic potential of ethanol leaf extract of Cnidoscolus aconitifolius in mitigating heavy metal-induced insulin resistance, oxidative stress and inflammation in albino rats. Thirty rats were divided into five groups: Groups I and II received normal saline and a lead-mercury mixture, respectively, while Groups III, IV and V were treated with the extract (200, 400 and 600 mg/kg) for four weeks after exposure. The extract, rich in catechin, rutin, gallic acid and kaempferol, exhibited strong antioxidant activity. Heavy metal exposure induced hepatic insulin resistance, dyslipidaemia, oxidative stress and inflammation, as shown by elevated HOMA-IR values. Extract treatment reversed these effects in a dose-dependent manner, restoring insulin sensitivity via oxidative stress and inflammation modulation. This highlights the potential of C. aconitifolius as a nutraceutical for heavy metal-induced metabolic disorders.