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Aim: Despite advancements in treatment modalities, myocardial infarction (MI) remains a significant global cause of mortality and morbidity. Metformin (MET), a commonly used antidiabetic medication, has demonstrated potential in various cardioprotective mechanisms. This study investigated whether MET could alleviate the histopathological, electrocardiographic, and molecular consequences of MI in rats., Materials and Methods: The study hypothesis was tested using an isoprenaline (ISOP)-induced MI model, where male Wistar rats were injected with ISOP (85 mg/kg/day, s.c., for 2 days) and treated with MET at the doses of 500 and 1000 mg/kg/day for 18 days or left untreated., Key Findings: ISOP-treated rats exhibited several indicators of MI, including significant ST-segment depression and prolonged QT-intervals on ECGs, worsened left ventricular histopathology with increased inflammatory cell infiltration, reduced expression of cardiac CHRM2, a cardioprotective cholinergic receptor, adaptive increases in AMPK and α7nAchR levels, and elevated levels of iNOS, NO, STAT3, JAK2, IL-6, TNF-α, and NF-κB. These effects were attenuated in rats treated with either low or high doses of MET. MET administration restored normal ECG recordings, diminished oxidative stress and inflammatory mediators, and downregulated NF-κB expression. Moreover, MET improved CHRM2 expression and normalized α7nAchR levels. Additionally, MET influenced the expression of key signaling molecules such as Akt, STAT3, and JAK2., Significance: These findings might suggest that MET exerts cardioprotective effects in ISOP-induced MI in rats by mitigating critical inflammatory signaling pathways and regulating protective cholinergic mechanisms in the heart., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Metformin is an attractive candidate drug among all the repurposed drugs for cancer. Extensive preclinical and clinical research has evaluated its efficacy in cancer therapy, revealing a mixed outcome in clinical settings. To fully exploit metformin's therapeutic potential, understanding cellular factors relevant to its transport and accumulation in cancer cells needs to be understood. This review highlights the relevance of metformin transporter status towards its anti-cancer potential. Metformin transporters are regulated at pre-transcriptional, transcriptional, and post-translational levels. Moreover, the tumour microenvironment can also influence metformin accumulation in cancer cells. Also, Metformin treatment can regulate its transporters by altering global DNA methylation, protein acetylation, and transcription factors. Importantly, metformin transporters not only influence chemotherapeutic drug toxicity but are also associated with the prognosis and survival of individuals having cancer. Strategic decisions based on the expression and regulation of metformin transporters holds promise for its therapeutic implications and relevance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

White matter injury (WMI) is a major form of brain injury that occurs in preterm infants and develops into lifelong disabilities, including cerebral palsy, impaired cognitive function, and psychiatric disorders. Metformin (MET) has been reported to have neuroprotective effects. However, whether MET is responsible for neuroprotection against WMI remains unclear. In this study, we established a WMI model in neonatal mice to explore the neuroprotective effects of MET and attempted to elucidate its potential mechanisms. Our results showed that MET increased the expression of myelin basic protein (MBP), oligodendrocyte transcription factor 2 (Olig2), and CC1, improved the thickness and density of the myelin sheath, and reduced oxidative stress and microglial infiltration after chronic hypoxia induction. Moreover, MET improved memory, learning, and motor abilities as well as relieved anxiety-like behaviors in mice with WMI. These protective effects of MET may involve the upregulation of the nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1(HO-1)/NF-κB pathway related protein expressions. In addition, the NRF2 inhibitor ML385 could significantly reverse the effects of MET. In conclusion, this study suggested that MET attenuated chronic hypoxia-induced WMI through activating the NRF2/HO-1/NF-κB pathway, indicating that MET might be a promising therapeutic option for WMI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objective: Metformin is a medication that is widely used for lowering blood sugar in patients with type 2 diabetes. Metformin was shown to have significant antidepressant effects; however, it is not clear whether metformin treatment improves outcomes in patients with type 2 diabetes who have concomitant depressive symptoms., Methods: A total of 475 patients with type 2 diabetes mellitus with depressive symptoms were included in this study and divided into metformin and nonmetformin groups according to whether they were taking metformin. The DASS-21 was used to assess patients' depression and anxiety scores before and after a 24-week intervention. In addition, general information about whether the patients had developed complications from diabetes and whether they had been diagnosed with other diseases was assessed., Results: (1) After 24 weeks, anxiety and depression scores were significantly lower in the metformin group than in the nonmetformin group. (2) The prevalence of depressive symptoms was significantly greater in female type 2 diabetic patients than in male patients (OR = 2.039, 95 % CI = 1.160-3.568). (3) People with type 2 diabetes who develop complications from diabetes (OR = 1.794, 95 % CI = 1.015-3.171) and those diagnosed with other conditions are more likely to experience depressive symptoms., Conclusion: Metformin has an ameliorative effect on type 2 diabetes. However, women, those with diabetes complications, and those with type 2 diabetes who are also diagnosed with other conditions are more likely to experience depressive symptoms., Competing Interests: Declaration of competing interest There were no conflicts of interest from the beginning to the end of this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diabetes, considered one of the main causes of death in the Mexican population, is a chronic disease caused by alterations in the synthesis of pancreatic insulin or because it is not used effectively by the body. Insufficient action of insulin causes hyperglycemia, which, if not controlled, causes damage to blood capillaries and nerve endings over time, affecting the functioning of various organs and systems. As mentioned above, controlling glucose levels in the population suffering from chronic diseases becomes an essential part of their treatment. The aim of this study was to evaluate the hypoglycemic effect of a hydroalcoholic extract of the aerial parts of Porophyllum ruderale (HEPr). A glucose tolerance curve was developed by monitoring at different times (0-120 min) glucose levels in blood samples taken from an apical tail slice of CD1 mice. HEPr showed a significant effect from baseline on basal glucose levels (114.33 ± 14.74 mg/dL) compared with the control group (60.33 ± 4.16 mg/dL) and the metformin-treated group (129 ± 13 mg/dL). In addition, the values at the end of the tolerance curve (120 min) showed a significant decrease in the study group (66 ± 10.39 mg/dL) compared with the metformin-treated group (108.67 ± 4.50 mg/dL). This effect can be attributed to the presence of chlorogenic acid, cryptochlorogenic acid, ferulic acid, quercetin, and kaempferol 3- O -glucosides in HEPr. In conclusion, P. ruderale constitutes an important source of compounds for use as an adjuvant treatment for the control of hypoglycemia in different chronic diseases.

This study evaluated the effect of green tea extract and metformin and its interaction on markers of oxidative stress and inflammation in overweight women with insulin resistance. After screening, 120 women were randomly allocated in 4 groups: Placebo (PC): 1g of microcrystalline cellulose/day; Green tea (GT): 1 g (558 mg polyphenols) of standardized dry extract of green tea/day and 1 g of placebo/day; Metformin (MF): 1 g of metformin/day and 1 g of placebo/day; Green Tea and Metformin (GTMF): 1 g (558 mg polyphenols) and 1 g of metformin/day. All groups were followed-up for 12 weeks with assessment of oxidative damage to lipids and proteins, specific activity of antioxidant enzymes and inflammatory cytokine serum levels. The association of green tea with metformin significantly reduced IL-6 (GTMF: -29.7((-62.6)-20.2))( p = 0.004). Green tea and metformin isolated reduced TNF-α (GT: -12.1((-18.0)-(-3.5)); MF: -24.5((-38.60)-(-4.4)) compared to placebo (PB: 13.8 (1.2-29.2))( P < 0.001). Also, isolated metformin reduced TGF-β (MF: -25.1((-64.4)-0.04)) in comparison to placebo (PB: 6.3((-1.0)-16.3))( p = 0.038). However, when combined, their effects were nullified either for TNF-α (GTMF: 6.0((-5.7)-23.9) and for TGF-β (GTMF: -1.8((-32.1)-8.5). This study showed that there is a drug-nutrient interaction between green tea and metformin that is dependent on the cytokine analyzed.

Introduction: Metformin has been part of treatment algorithms for type 2 diabetes mellitus (T2DM) for decades. While it has formal approval in the U.S.A. for treatment of T2DM, it is used off-label in gestational diabetes mellitus (GDM), polycystic ovarian syndrome (PCOS), and ovarian hyperstimulation prevention. Its role as an insulin sensitizer has made it an attractive therapeutic to address the insulin resistance seen in these syndromes. In 2022, the European Union approved metformin as the only oral antidiabetic medication for diabetes in pregnancy. While its safety and benefits for the mother are well documented, it does cross the placenta with plasma concentrations comparable between mother and child at delivery., Areas Covered: This special report will focus on major randomized control trials investigating metformin use in pregnancies impacted by PCOS, GDM, T2DM, and obesity and their offspring follow-up trials., Expert Opinion: For the mother, metformin can be beneficial, with reduction in insulin therapeutic burden, weight gain, hypoglycemia and in certain situations, pre-eclampsia. For the neonate, benefits may include reduction in hypoglycemia and no increased risk of congenital anomalies. It is the long-term data in the offspring that remains unknown with some areas of concerns (SGA, altered anthropometrics) requiring continued research.

We present a case of insatiable appetite and harmful overeating in a hospice patient that showcases the burden of hypothalamic hyperphagia, a rare complication of brain cancer. While confounders exist such as progression of disease and prior tapering of dexamethasone, in this case the initiation of metformin was associated with substantial appetite reduction and resolution of our patient's debilitating food-seeking behaviors. We will explore metformin as a potential cost-effective option for palliation in a hospice setting and explore some of the physiologic mechanisms involved., Competing Interests: Conflicts of Interest The authors have no conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier Inc.)

The development of effective therapeutic strategies for triple-negative breast cancer (TNBC), an aggressive subtype with limited treatment options, remains a critical challenge. This study aimed to design and evaluate a combination therapy using chitosan nanoparticles (Cs NPs) loaded with metformin (Met) and methotrexate (MTX) as a promising approach for TNBC management. The Cs NPs exhibited an average size of 78.8 ± 25.84 nm for blank Cs NPs, 84.50 ± 22.54 nm for Met-Cs NPs, and 86.70 ± 30.90 nm for MTX-Cs NPs, with positive surface charges of 26.40 ± 1.40 mV, 28.20 ± 1.60 mV, and 14.30 ± 2.40 mV, respectively. The drug encapsulation efficiency was 88.56 ± 2.26 % for Met-Cs NPs and 97.03 ± 0.52 % for MTX-Cs NPs. The cellular uptake studies demonstrated a time-dependent increase in the accumulation of Shikonin-labeled Cs NPs in 4T1 cells. The cytotoxicity assays revealed that Met-Cs NPs and MTX-Cs NPs exhibited significantly lower IC50 values (19.85 μg/mL and 103.2 ng/mL, respectively) compared to the plain drugs at 48 h. The combination of Met-/MTX-Cs NPs showed a synergistic cytotoxic effect, inducing 50 % cell death at 15.233 μg/mL of Met and 0.166 μg/mL of MTX. In vivo studies using a 4T1 xenograft mouse model demonstrated that the combination of Met-/MTX-Cs NPs resulted in a 100 % reduction in initial tumor volume, compared to a 40 % decrease with the free drug combination. The tumor growth inhibition was 70.45 % for the Met-/MTX-Cs NPs group, significantly higher than the 33.86 % observed in the free drug combination group. The findings of this study highlight the potential of the Met-/MTX-Cs NPs combination as a novel and effective therapeutic approach for TNBC management. The enhanced therapeutic efficacy, improved safety profile, and the ability to modulate key signaling pathways make this nanoparticle-based combination therapy a promising candidate for further clinical investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: This study was aimed to compare the efficacy of two combination tablets of dipeptidyl peptidase-4 (DPP-4) inhibitors and metformin with different dosages, alogliptin/metformin (AM) and vildagliptin/metformin (VM), on glycemic control in patients with type 2 diabetes (T2D). Methods: This was a prospective, multicenter, open-label, randomized, parallel group, comparative trial. After a run-in period of treatment with metformin alone, a total of 59 Japanese outpatients with T2D, aged 20-79 years with glycated hemoglobin (HbA1c) levels of 6.5%-10% were randomly assigned to 12-week AM treatment, alogliptin 25 mg/metformin 500 mg combination tablet orally once a day, or VM treatment, vildagliptin 50 mg/metformin 250 mg combination tablet orally twice a day. The primary endpoints were the changes in HbA1c and fasting plasma glucose (FPG) levels from baseline to week 12 between the two groups. Blinded intermittently scanned continuous glucose monitoring (isCGM) was performed between weeks 10 and 12. The incidence of adverse events during the study was also evaluated. Results: In all, 52 participants were analyzed. Significant decreases in HbA1c and FPG levels from baseline to week 12 were observed in both treatment groups. However, there were no significant differences between the AM and VM groups in the change in HbA1c level (-0.3% and -0.4%, P = 0.309) or the FPG level (-9.0 and -15.0 mg/dL, P = 0.789). The isCGM revealed that both treatments achieved the recommended glycemic target range. No adverse events, such as severe hypoglycemia, were observed in either group. Conclusions: We concluded that there were no significant differences in the efficacy of two combination tablets of DPP-4 inhibitors and metformin with different dosages on glycemic control in patients with T2D.

Introduction: We aim to evaluate the efficacy and safety of pioglitazone/metformin fixed-dose combination (FDC) versus uptitrated metformin in patients with type 2 diabetes mellitus (T2DM) without adequate glycemic control., Methods: A total of 304 patients were recruited from 15 hospitals in China and randomly assigned (1:1) to the test group (pioglitazone/metformin FDC, 15/500 mg) or the control group (uptitrated metformin, 2000-2500 mg/day). The primary endpoint was the proportion of patients with glycated hemoglobin A1c (HbA1c) ≤ 6.5% and ≤ 7.0% at week 16. The secondary outcomes included the change from baseline in glucose, serum lipids, and liver function. Full analysis set (FAS) and per-protocol set (PPS) were used for analyses., Results: In the test group, 103 (69.59%) patients reached HbA1c ≤ 7.0% (FAS, P = 0.009), with 68 (45.95%) patients achieved HbA1c ≤ 6.5 (FAS, P = 0.043). More reduction in HbA1c, homeostatic model assessment for insulin resistance, and diastolic pressure was found. Bodyweight, body mass index, and high-density lipoprotein cholesterol increased markedly. The changes of triglycerides, alanine transaminase, aspartate aminotransferase, and high-sensitivity C-reactive protein decreased noticeably. There were no significant differences in rates of adverse events between the two groups., Conclusions: Pioglitazone/metformin FDC was superior to uptitrated metformin among patients with T2DM without adequate glycemic control., Trial Registration Number: This trial is registered with the Chinese Clinical Trial Registry (ChiCTR1900028606)., (© 2024. The Author(s).)

Background: Emerging evidence suggests a potential association between certain anti-diabetic drugs and a reduced risk of Parkinson's disease (PD). Limited population-based studies have investigated users of newer anti-diabetic drugs such as GLP-1 agonists or SGLT2 inhibitors., Objective: The aim of this study was to assess the risk of PD among individuals with type 2 diabetes mellitus (T2DM) who were treated with various types of anti-diabetic drugs over time., Methods: A population-based cohort comprising T2DM patients aged over 30 who used metformin, GLP-1 agonists, thiazolidinediones, sulfonylureas, DPP4 inhibitors, SGLT2 inhibitors, or meglitinides between January 1, 1999 and December 31, 2018. Data were obtained between the diabetes registration and drug purchase databases of Maccabi Healthcare Services. Time-dependent Cox regression models, adjusted for sex, age, and comorbidities were employed to calculate the adjusted hazard ratios (HRs) for the PD risk associated with different anti-diabetic drugs over time., Results: The study population comprised 86,229 T2DM patients, with 53.9 % males. The mean age at the first anti-diabetic drug purchase was 59.0 ± 11.0 and 62.0 ± 11.0 years for men and women respectively. Compared to metformin, several drug types were associated with a significantly lower PD risk: thiazolidinediones (HR = 0.91, 95 % CI:0.074-1.14); DPP4 inhibitors (HR = 0.60, 95 % CI:0.53-0.67); meglitinides (HR = 0.63, 95 % CI:0.53-0.74); GLP-1 agonists (HR = 0.54, 95 % CI:0.39-0.73); and SGLT2 inhibitors (HR = 0.15, 95 % CI:0.10-0.21)., Conclusions: Our results suggest a reduced risk of PD with certain anti-diabetic drugs, particularly SGLT2 inhibitors and GLP-1 agonists. Validation through extensive big-data studies is essential to confirm these results and to optimize PD prevention and management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aims: Metformin has been attributed to cardiovascular protection even in the absence of diabetes. Recent observations suggest that metformin influences the gut microbiome. We aimed to investigate the influence of metformin on the gut microbiota and hypertensive target organ damage in hypertensive rats., Methods: Male double transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR), a model of angiotensin II-dependent hypertension, were treated with metformin (300 mg/kg/day) or vehicle from 4 to 7 weeks of age. We assessed gut microbiome composition and function using shotgun metagenomic sequencing and measured blood pressure via radiotelemetry. Cardiac and renal organ damage and inflammation were evaluated by echocardiography, histology, and flow cytometry., Results: Metformin treatment increased the production of short-chain fatty acids (SCFA) acetate and propionate in feces without altering microbial composition and diversity. It significantly reduced systolic and diastolic blood pressure and improved cardiac function, as measured by end-diastolic volume, E/A, and stroke volume despite increased cardiac hypertrophy. Metformin reduced cardiac inflammation by lowering macrophage infiltration and shifting macrophage subpopulations towards a less inflammatory phenotype. The observed improvements in blood pressure, cardiac function, and inflammation correlated with fecal SCFA levels in dTGR. In vitro, acetate and propionate altered M1-like gene expression in macrophages, reinforcing anti-inflammatory effects. Metformin did not affect hypertensive renal damage or microvascular structure., Conclusion: Metformin modulated the gut microbiome, increased SCFA production, and ameliorated blood pressure and cardiac remodeling in dTGR. Our findings confirm the protective effects of metformin in the absence of diabetes, highlighting SCFA as a potential mediators., (© 2024 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Background: We performed an exploratory analysis of the SPARTAN trial to determine whether concomitant exposure to several classes of commonly prescribed medications influenced the effect of apalutamide on overall survival (OS) and metastasis-free survival (MFS) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC)., Patients and Methods: SPARTAN was a phase III randomized controlled trial in which nmCRPC patients were randomly assigned in a 2:1 ratio to receive androgen deprivation therapy with or without apalutamide. We focused on 5 commonly prescribed classes of medications: metformin, statins, angiotensin converting enzyme inhibitors (ACEI), acetylsalicylic acid (ASA), and proton pump inhibitors (PPI) based on a plausible biological and clinical rationale. To determine the potential effect modification, we applied multivariable Cox regression models for OS and MFS separately with additional interaction terms. To determine the independent association of concomitant medications with OS and MFS, we used IPTW-based log-rank test. A 2-sided p < 0.01 was considered statistically significant., Results: We did not find statistically significant differences in effect from apalutamide on OS across subgroups stratified by concomitant exposure to any of the medication classes. While there was some difference in the treatment effect from apalutamide on MFS between patients with concomitant statins (adjusted hazard ratio [aHR]: 0.20; 95 % CI: 0.15-0.28) versus without concomitant statins (aHR: 0.31 [0.24-0.39]), this did not reach the pre-specified threshold of statistical significance (p = 0.011). On IPTW-based analysis, patients treated concomitantly with metformin (median: not reached versus 31 months; p = 0.002), or ACEI (median: 37 versus 29 months, p = 0.006) had significantly improved MFS., Conclusions: In this post-hoc exploratory analysis of SPARTAN, effects of apalutamide on MFS and OS were consistent across subgroups stratified by exposure to concomitant medications. Exposure to concomitant metformin and ACEI was independently associated with a significant improvement in MFS., Competing Interests: Declaration of Competing Interest Dr. Roy reports Young Investigator Award from the Prostate Cancer Foundation which funded this research. In addition, Dr. Roy reports research grant from Swim Across America and honorarium from Varian. Dr. Spratt reports personal fees from Blue Earth, personal fees from Janssen, personal fees from AstraZeneca, Gammatile, Varian, and Boston Scientific, outside the submitted work. Dr. Kishan reported receiving personal fees from ViewRay, Inc, Varian Medical Systems, and Boston Scientific; receiving speaking honoraria, consulting fees, and research support from Varian Medical Systems, ViewRay, Inc, and Intelligent Automation; receiving grants from Janssen and Point Biopharma; and receiving research funding from ViewRay, Inc, outside the submitted work. Dr. Agarwal reports consulting or advisory roles for Pfizer, Medivation/Astellas, Bristol Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, Merck, Novartis, Eisai, Seagen, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, Gilead Sciences and research funding from Bayer, Bristol Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas. Dr. Chowdhury, receiving honoraria, fees for serving on a speaker’s bureau, consulting fees, and travel support from Johnson and Johnson, Astellas Pharma, and Sanofi and grant support, honoraria, fees for serving on a speaker’s bureau, consulting fees, and travel support from Clovis Oncology. Dr. Jia reports personal fees from Blue Earth, and Myovant. Dr. Ong reports personal fees from Janssen, Bayer, AstraZeneca, and Pfizer. Dr. Morgan reports personal fees from Astellas, Bayer, Janssen, and TerSera and a research grant (institutional) from Knight Therapeutics, outside the submitted work. Dr. Swami reports consultancy to Astellas, Exelixis, Seattle Genetics, Imvax, Sanofi, Pfizer, AstraZeneca and Gilead and research funding to institute from Janssen, Exelixis and Astellas/Seattle Genetics. Dr. Saad reports grants, personal fees, and non-financial support from Janssen, during the conduct of the study; grants, personal fees, and non-financial support from Astellas, grants, personal fees, and non-financial support from Bayer, outside the submitted work. Dr. Wallis has received honoraria from AbbVie, Astellas, Astra Zeneca, Bayer, EMD Serono, Knight Therapeutics, Merck, Haymarket Media, Science & Medicine Canada, TerSera Canada, and Tolmar Pharmaceuticals Canada; reports consulting fees from Janssen Oncology, SESEN Bio, and Precision Point Specialty LLC; and has received research funding from Knight Therapeutics and Tolmar Pharmaceuticals, outside the submitted work. Dr. Malone has received honoraria from Astellas, Bayer, Janssen, and Sanofi; and travel and accommodations support from TerSera and Sanofi. There are no other conflicts of interest among the other authors., (Copyright © 2024. Published by Elsevier Ltd.)

Aim: To evaluate the efficacy and safety of dapagliflozin versus placebo as an add-on in patients with type 2 diabetes who did not achieve adequate glycaemic control with evogliptin and metformin combination., Patients and Methods: In this multicentre, randomized, double-blind, placebo-controlled Phase 3 trial, patients with glycated haemoglobin (HbA1c) levels ≥7.0% (≥53 mmol/mol) and ≤10.5% (≤91 mmol/mol) who had received stable-dose metformin (≥1000 mg) and evogliptin (5 mg) for at least 8 weeks were randomized to receive dapagliflozin 10 mg or placebo once daily for 24 weeks. Participants continued treatment with metformin and evogliptin. The primary endpoint was change in HbA1c level after 24 weeks of treatment from baseline level., Results: In total, 198 patients were randomized, and 195 patients were included in the efficacy analyses (dapagliflozin: 96, placebo: 99). At Week 24, dapagliflozin significantly reduced HbA1c levels. The least squares mean difference in HbA1c level change from baseline after 24 weeks of treatment was -0.70% (-7.7 mmol/mol) (p < 0.0001). The proportion of participants achieving HbA1c <7.0% (≥53 mmol/mol) was higher in the dapagliflozin group than in the placebo group. Compared to placebo, dapagliflozin significantly reduced fasting plasma glucose, mean daily glucose, 2-h postprandial plasma glucose, fasting insulin, uric acid and gamma-glutamyl transferase levels, homeostatic model assessment for insulin resistance index, body weight, hepatic steatosis index, and albuminuria. Adiponectin level significantly increased from baseline level after 24 weeks of dapagliflozin treatment. Adverse event rates were similar in the two groups., Conclusion: Dapagliflozin add-on to evogliptin plus metformin improved glycaemic control and was well tolerated by the target patients., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Patients with diabetes face a 2-4-fold greater cardiovascular risk compared to those without diabetes. Both metformin and acetylsalicylic acid (aspirin) treatment have demonstrated a significant reduction in this risk. This single-center, open-label, sequence randomized, 2 × 2 crossover, single-dose clinical trial evaluated the pharmacokinetics profile and comparative bioavailability of a novel oral fixed-dose combination (FDC) of metformin/acetylsalicylic acid (500/100 mg tablet) versus the reference mono-drugs administered concomitantly, metformin 500 mg tablet and acetylsalicylic acid 100 mg tablet, in 22 healthy Mexican adult volunteers under fasting conditions. Blood samples were collected predose and at specified intervals across a 24-hour period following administration and were analyzed for metformin and salicylic acid using high-performance liquid chromatography coupled with tandem mass spectrometry. Test products were considered to have comparative bioavailability if confidence intervals of natural log-transformed (maximum plasma drug concentration (C max ), (area under the plasma drug concentration-time curve form 0 up to last sampling time (AUC 0 -t ), and (area under the plasma drug concentration-time cruve from 0 up to infinity (AUC 0 ∞ ) data were within the range of 80%-125%. The results obtained from the present clinical study demonstrate the comparative bioavailability of the FDC when compared with the coadministration of reference mono-drugs. There were no adverse events or adverse reactions reported throughout the study., (© 2024 Laboratorios Silanes. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Objective: Metformin is clinically effective in treating polycystic ovary syndrome (PCOS) with insulin resistance (IR), while its efficacy varies among individuals. This study aims to develop a machine learning model to predict the efficacy of metformin in improving insulin sensitivity among women with PCOS and IR., Methods: This is a retrospective analysis of a multicenter, randomized controlled trial involving 114 women diagnosed with PCOS and IR. All women received metformin treatment for 4 months. We incorporated 27 baseline clinical variables of the women into the construction of our machine learning model. We firstly compared 4 commonly used feature selection methods to screen valuable clinical variables. Then we used the valuable variables as inputs to evaluate the performance of 5 machine learning models, including k-Nearest Neighbors, Support Vector Machine, Logistic Regression, Random Forest, and Extreme Gradient Boosting, in predicting the efficacy of metformin., Results: Among the 5 machine learning models, Support Vector Machine performed the best with an area under the receiver operating characteristic curve of 0.781 (95% confidence interval [CI]: 0.772-0.791). The key predictive variables identified were homeostasis model assessment of insulin resistance, body mass index, and low-density lipoprotein cholesterol., Conclusion: The developed machine learning model could be applied to predict the efficacy of metformin in improving insulin sensitivity among women with PCOS and IR. The result could help doctors evaluate the efficacy of metformin in advance, optimize treatment plans, and thereby enhance overall clinical outcomes., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Aim: To highlight oversimplified quality-adjusted life year (QALY) calculations and incremental cost-effectiveness ratios (ICERs) regarding lifestyle metformin and placebo as flaws in the trial-based (Diabetes Prevention Program) cost-effectiveness analysis., Materials and Methods: We revised the QALY calculations to conform to convention and calculated appropriate ICERs using both original and revised QALYs results. We used several additional health economics tools to present results, showing the consistency of each method and the added value of each. We presented net monetary benefits, assessed decision uncertainty and calculated net losses. We also used graphics, making correct interpretation clearer and allowing illustration and calculation of technical and economic inefficiencies of treatments that were not cost-effective., Results: ICERs with either QALY calculation indicated that metformin was technically and economically inefficient and not cost-effective. There was virtually no decision uncertainty. All methods employed pointed to an identical conclusion., Conclusions: In contrast to original claims, although lifestyle was cost-effective in diabetes prevention, metformin was not, and acting otherwise imposes significant monetary and health costs. Various available tools of economic evaluation would probably have prevented the original misinterpretation by the authors had they been used. The varied tools implemented here illustrate with a common example their consistency and value to the field, showing how to depict the results in various ways., (© 2024 John Wiley & Sons Ltd.)

The harmful effects of PM 2.5 on human health, including an increased risk of chronic kidney disease (CKD), have raised a lot of attention, but the underlying mechanisms are unclear. We used the Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS) to simulate the inhalation of PM 2.5 in the real environment and established an animal model by exposing C57BL/6 mice to filtered air (FA) and Particulate Matter (PM 2.5 ) for 8 weeks. PM 2.5 impaired the renal function of the mice, and the renal tubules underwent destructive changes. Analysis of NHANES data showed a correlation between reduced kidney function and higher blood levels of PM 2.5 components, polychlorinated biphenyls (PCBs) and dioxins, which are Aryl hydrocarbon Receptor (AhR) ligands. PM 2.5 exposure induced higher levels of AhR and CYP1A1 and oxidative stress as evidenced by the higher levels of ROS, MDA, and GSSG in kidneys of mice. PM 2.5 exposure led to AhR overexpression and nuclear translocation in proximal renal tubular epithelial cells. Inhibition of AhR reduced CYP1A1 expression and PM 2.5 -increased levels of ROS, MDA and GSSG. Our study suggested metformin can mitigate PM 2.5 -induced oxidative stress by inhibiting the AhR/CYP1A1 pathway. These findings illuminated the role of AhR/CYP1A1 pathway in PM 2.5 -induced kidney injury and the protective effect of metformin on PM 2.5 -induced cellular damage, offering new insights for air pollution-related renal diseases.

The effect of sitagliptin and empagliflozin on serum levels of asprosin and metabolic parameters in patients with type 2 diabetes mellitus (T2DM) was assessed in a non-randomized, prospective observational study. Seventy-nine T2DM patients, without adequate glycemic control with metformin monotherapy, were included in the study. In addition to the ongoing metformin treatment, patients received sitagliptin 100 mg and empagliflozin 10 mg once daily for 12 weeks. Anthropometric parameters, lipid and glycemic profile, insulin resistance (homeostasis model assessment of insulin resistance index [HOMA-IR]), and asprosin serum levels were assessed at baseline and after 12 weeks of therapy. Both empagliflozin and sitagliptin treatments led to similar, significant improvement in fasting blood glucose (FBG) and hemoglobin A1C (HbA1C). Compared to baseline, triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) were improved with both treatments, but empagliflozin led to the more improvement. No significant change of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were observed in either group. Insulin resistance was significantly attenuated in both groups, but to a greater degree with empagliflozin treatment. The reduction in serum asprosin levels from baseline was significantly higher in patients taking empagliflozin compared to those receiving sitagliptin. Additionally, individuals on empagliflozin exhibited a more decrease in body mass index (BMI) and body weight compared to those on sitagliptin. According to our findings, the addition of empagliflozin to metformin appeared to offer greater benefits compared to the addition of sitagliptin in terms of decreasing asprosin levels and improving certain metabolic parameters in T2DM patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Diabetes currently affects approximately 500 million people worldwide and is one of the most common causes of mortality in the United States. To diagnose and monitor diabetes, finger-prick blood glucose testing has long been used as the clinical gold standard. For diabetes treatment, insulin is typically delivered subcutaneously through cannula-based syringes, pens, or pumps in almost all type 1 diabetic (T1D) patients and some type 2 diabetic (T2D) patients. These painful, invasive approaches can cause non-adherence to glucose testing and insulin therapy. To address these problems, researchers have developed miniaturized blood glucose testing devices as well as microfluidic platforms for non-invasive glucose testing through other body fluids. In addition, glycated hemoglobin (HbA1c), insulin levels, and cellular biomechanics-related metrics have also been considered for microfluidic-based diabetes diagnosis. For the treatment of diabetes, insulin has been delivered transdermally through microdevices, mostly through microneedle array-based, minimally invasive injections. Researchers have also developed microfluidic platforms for oral, intraperitoneal, and inhalation-based delivery of insulin. For T2D patients, metformin, glucagon-like peptide 1 (GLP-1), and GLP-1 receptor agonists have also been delivered using microfluidic technologies. Thus far, clinical studies have been widely performed on microfluidic-based diabetes monitoring, especially glucose sensing, yet technologies for the delivery of insulin and other drugs to diabetic patients with microfluidics are still mostly in the preclinical stage. This article provides a concise review of the role of microfluidic devices in the diagnosis and monitoring of diabetes, as well as the delivery of pharmaceuticals to treat diabetes using microfluidic technologies in the recent literature., (© 2024. The Author(s).)

Ovarian cancer (OC) is the deadliest malignancy of the female reproductive system. The standard first-line therapy for OC involves cytoreductive surgical debulking followed by chemotherapy based on platinum and paclitaxel. Despite these treatments, there remains a high rate of tumor recurrence and resistance to platinum. Recent studies have highlighted the potential anti-tumor properties of metformin (met), a traditional diabetes drug. In our study, we investigated the impact of met on the anticancer activities of cisplatin (cDDP) both in vitro and in vivo. Our findings revealed that combining met with cisplatin significantly reduced apoptosis in OC cells, decreased DNA damage, and induced resistance to cDDP. Furthermore, our mechanistic study indicated that the resistance induced by met is primarily driven by the inhibition of the ATM/CHK2 pathway and the upregulation of the Rad51 protein. Using an ATM inhibitor, KU55933, effectively reversed the cisplatin resistance phenotype. In conclusion, our results suggest that met can antagonize the effects of cDDP in specific types of OC cells, leading to a reduction in the chemotherapeutic efficacy of cDDP., Competing Interests: Declaration of competing interest We declare the manuscript is an original work which has not been previously published in whole or in part and is not under consideration for publication in any other journals. Its publication has been approved by all co-authors. All authors have contributed to this work and state no existing competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Diffuse large B cell lymphoma (DLBCL) is classified into Germinal Center B-cell (GCB) and activated B-cell (ABC) subgroups originating from different stages of lymphoid differentiation. Cell of origin dictates the behavior and therapeutic response of DLBCL. This study aimed to evaluate single and combinatorial effects of metformin and thymoquinone (TQ) in two DLBCL cell lines belonging to GCB and ABC subtypes. Metformin and TQ caused dose-dependent responses in both ABC and GCB DLBCL subtypes. Metformin had a greater impact on the ABC subtype while TQ demonstrated more pronounced effects on the GCB subtype. Synergistic effects were observed in the DHL4 (GCB subtype) but not in the HBL1 (ABC subtype) cell line. This is the first study to compare the effects of metformin and TQ in ABC versus GCB subtype of DLBCL. It brings valuable results that could be utilized in further research aimed at reshaping treatments for subtype-specific lymphomas., (© 2024 Wiley‐VCH GmbH.)

In a rigorous 40-month study, we evaluated the geroprotective effects of metformin on adult male cynomolgus monkeys, addressing a gap in primate aging research. The study encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations, substantiating metformin's influence on delaying age-related phenotypes at the organismal level. Specifically, we leveraged pan-tissue transcriptomics, DNA methylomics, plasma proteomics, and metabolomics to develop innovative monkey aging clocks and applied these to gauge metformin's effects on aging. The results highlighted a significant slowing of aging indicators, notably a roughly 6-year regression in brain aging. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability. The geroprotective effects on primate neurons were partially mediated by the activation of Nrf2, a transcription factor with anti-oxidative capabilities. Our research pioneers the systemic reduction of multi-dimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging., Competing Interests: Declaration of interests J.C.I.B., S.H., C.R.E., P.R., and A.H. are employees of Altos Labs. S.H. is a founder of the non-profit Epigenetic Clock Development Foundation, which has licensed several of his patents from UC Regents and distributes the mammalian methylation array., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Lung cancer is a leading cause of death globally with high mortality and morbidity. Patients are often diagnosed at an advanced stage. Metformin has become a primary medication used in the clinical management of type 2 diabetes mellitus (T2DM) due to its relative safety, low cost, and effectiveness, mainly exerting its hypoglycemic effect by inhibiting hepatic gluconeogenesis and insulin resistance. Research data indicate that metformin extends the distant metastasis-free survival (DMFS) and progression-free survival (PFS) of diabetic patients with lung cancer, improving overall survival rates. Metformin lowers the risk of tumour development through various mechanisms, including the adenosine 5'-monophosphate-activated protein kinase/liver kinase B1/mechanistic target of rapamycin (AMPK/LKB1/mTOR) pathway, insulin-like growth factor-1 receptor pathway, apoptosis, and autophagy. However, research findings are not entirely consistent. This article reviews the research progress of metformin in terms of lung cancer treatment within the past few years, aiming to provide a more comprehensive understanding of how metformin exerts its anti-cancer impact and how it can be clinically applied, as well as provide new insights for lung cancer treatment.

The rising soil-groundwater quality issues due to pharmaceuticals and personal care products (PPCPs) have spurred significant concern. To understand the sorption characteristics of metformin (MTN) and erythromycin (ETM) in sandy and sandy loam soils with varying organic matter and particle composition, sorption kinetics (single and competitive), isotherms, and thermodynamics were studied. The effects of pH and soil moisture content (SMC) were also investigated at environmentally relevant concentrations. The equilibrium time of MTN and ETM sorption by the three soils in a competitive solute system was about 4 h, and the sorption process was in line with a pseudo-second-order model. The rate-determining step in the process involved both intraparticle diffusion and liquid film diffusion mechanisms for the two PPCPs. The highest pollutant uptake occurred in soils with higher organic matter, driven by enhanced H-bonding, electrostatic interactions, and π-π and n-π interactions facilitated by the organic matter. The equilibrium data in the three soils was well described by the Freundlich model and confirmed favourable adsorption (1/n f = 1.01 - 1.90). The sorption coefficient (K d ) on the three soils ranged from 2.1 to 332 L/kg for MTN and from 6.25 to 845 L/kg for ETM. The adsorption process was feasible at 293 K and 303 K (ΔG° = - 0.16 to -10.24 kJ/mol), physical and exothermic in nature (ΔH° = -75.21 to -10.30 kJ/mol) for both the contaminants. Observed alterations in Q e with pH confirmed the participation of electrostatic interactions. A low SMC favoured both MTN and ETM sorption onto the sandy soil. Overall, ETM exhibits higher expected sorption, whereas MTN has a greater tendency for migration in the soils and is thus liable to contaminate the groundwater. The study accentuates novel insights into the transport and fate of MTN and ETM in soil-groundwater systems at environmentally relevant concentrations., Competing Interests: Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Breast cancer is a leading cause of cancer-related deaths among women worldwide. The presence and function of CD8 + T cells in the tumor microenvironment have been associated with better patient outcomes. Drug toxicity has posed a significant challenge to the clinical implementation of chemotherapy-based strategies in cancer treatment., Methods: In this study, we employed flow cytometry to investigate the potential synergistic immunomodulatory effects on CD8 + T cells in a mouse model of breast cancer by combining metformin, an anti-diabetic medication, with doxorubicin., Results: Through flow cytometry analysis, we observed that the combination of the two drugs led to an increased percentage of CD8 + T cells compared to either drug alone. The modulation of HIF-1α and  STAT3 gene expression in the combination group further confirmed the efficacy of this approach., Conclusions: Our findings suggest that combining metformin with doxorubicin can enhance the anticancer activity of doxorubicin and decrease its cytotoxicity in a 4T1 breast cancer mouse model., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Metformin is commonly used to lower blood glucose levels and is one of the most widely used pharmaceuticals worldwide. Typical doses are high (0.5-2.0 g day -1 ) and the majority travels through the digestive system unabsorbed and enters the wastewater system. Metformin isn't removed by standard wastewater treatments and eventually enters freshwater systems, where it can form N-chloro-derivatives that are toxic to fish and human cells. Thus, metformin is one of the most prevalent anthropogenic pollutants worldwide and there has been considerable interest in finding ways to remove it. We recently isolated Pseudomonads capable of growing on metformin as the sole nitrogen source. We identified candidate genes involved in metformin breakdown through genomic analyses informed by feeding studies. One candidate, a pair of genes that are located on ∼80kb extra-genomic plasmids, was shown to encode a heteromeric Ni-dependent hydrolase that converts metformin to guanylurea and dimethylamine. Metforminase activity of these gene products is now well established as our results confirm three recently published independent studies. Our isolated Pseudomonads also grow on biguanide, suggesting the existence of an additional breakdown enzyme. Another candidate gene located on the ∼80kb plasmids was shown to encode an aminohydrolase that converts biguanide to guanylurea. Biguanide may arise through successive N-demethylations of metformin or come from other sources. Our results suggest that the recent evolution of metforminase and biguanide hydrolase enzymes allow Pseudomonads to convert either metformin or biguanide to guanylurea, which can be assimilated by existing pathways., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Ototoxicity is an important side effect of cisplatin. Recent animal and in vitro studies suggest metformin may protect hearing, though human studies are lacking. We report the first retrospective clinical study exploring the effects of metformin on cisplatin-induced ototoxicity., Study Design: Retrospective case-control., Setting: Tertiary-care center., Methods: We reviewed all diabetic patients treated with cisplatin who were enrolled in an auditory monitoring program between January 1, 2000 and December 31, 2018. Patients were grouped according to their use of metformin at the time of chemotherapy. Demographics, oncologic diagnosis and treatment, and prior noise exposure were recorded. Audiometric thresholds were compared before and after chemotherapy. The primary outcome measure was a change in hearing as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Secondary measures of ototoxicity included changes in hearing using the American Speech-Language-Hearing Association (ASHA) and TUNE criteria., Results: Seventy-two diabetic patients met the inclusion criteria. Forty-six patients had taken metformin while on chemotherapy and 26 had not. The proportion of hearing loss as defined by both, CTCAE and ASHA criteria, was more than double in the metformin group relative to the nonmetformin group (CTCAE: 54.4% vs 19.2%, P = .004; ASHA: 62.2% vs 28.0%, P = .003). None of the potential covariates believed to be confounders were significantly associated with the outcome of multivariable analysis., Conclusion: Contrary to expectations from preclinical data, metformin did not reduce the incidence of hearing loss in patients receiving cisplatin and may, in fact, be associated with an increased risk., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Objective Our previous study indicated that the efficacy of metformin in lowering glycated hemoglobin (HbA1c) levels may be influenced by the pretreatment frequency of defecation (FD) in patients with type 2 diabetes mellitus (T2DM). This study aimed to further examine how FD and the metformin dose may affect HbA1c changes (ΔHbA1c) in T2DM patients. Methods A retrospective analysis was conducted on inpatients who received antidiabetic treatment without altering dosages for six months post-discharge, except for minor insulin adjustments. For new patients, FD was assessed before (pretreatment FD) and after the initiation of antidiabetic therapy (posttreatment FD). For patients already on treatment, FD was evaluated during hospitalization (posttreatment FD). Patients were categorized based on their metformin use, and the relationship between FD and ΔHbA1c was assessed 1.5-6 months post-discharge. The impact of the metformin dose and posttreatment FD on the ΔHbA1c level was analyzed, along with other factors affecting posttreatment FD. Results The analysis included 89 patients (41 on metformin, 21 newly treated; 48 not on metformin, 17 newly treated). Both pre- and posttreatment FD were linked to ΔHbA1c levels in the metformin group. The metformin dose correlated with posttreatment FD but not with pretreatment FD. A significant relationship was observed between ΔHbA1c and the metformin dose. A multiple regression analysis identified posttreatment FD and metformin dose as significant independent factors influencing ΔHbA1c levels. Additionally, diabetic peripheral neuropathy and diabetes duration were found to diminish the effectiveness of metformin, likely due to decreased posttreatment FD. Conclusion FD may independently contribute to the dose-dependent HbA1c-lowering effects of metformin.

Background: Metabolism reprogramming is a crucial hallmark of malignant tumors. Tumor cells demonstrate enhanced metabolic efficiency, converting nutrient inputs into glucose, amino acids, and lipids essential for their malignant proliferation and progression. Metformin, a commonly prescribed medication for type 2 diabetes mellitus, has garnered attention for its potential anticancer effects beyond its established hypoglycemic benefits., Methods: This review adopts a comprehensive approach to delineate the mechanisms underlying metabolite abnormalities within the primary metabolic processes of malignant tumors., Results: This review examines the abnormal activation of G protein-coupled receptors (GPCRs) in these metabolic pathways, encompassing aerobic glycolysis with increased lactate production in glucose metabolism, heightened lipid synthesis and cholesterol accumulation in lipid metabolism, and glutamine activation alongside abnormal protein post-translational modifications in amino acid and protein metabolism. Furthermore, the intricate metabolic pathways and molecular mechanisms through which metformin exerts its anticancer effects are synthesized and analyzed, particularly its impacts on AMP-activated protein kinase activation and the mTOR pathway. The analysis reveals a multifaceted understanding of how metformin can modulate tumor metabolism, targeting key nodes in metabolic reprogramming essential for tumor growth and progression. The review compiles evidence that supports metformin's potential as an adjuvant therapy for malignant tumors, highlighting its capacity to interfere with critical metabolic pathways., Conclusion: In conclusion, this review offers a comprehensive overview of the plausible mechanisms mediating metformin's influence on tumor metabolism, fostering a deeper comprehension of its anticancer mechanisms. By expanding the clinical horizons of metformin and providing insight into metabolism-targeted tumor therapies, this review lays the groundwork for future research endeavors aimed at refining and advancing metabolic intervention strategies for cancer treatment., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Diabetes is a public health problem with an estimated worldwide prevalence of 10% and a prevalence of 12% in Mexico. The costs resulting from this chronic-degenerative disease are significant. Treatment for diabetes involves different medication groups, some of which can cause significant gastrointestinal adverse effects, such as dyspepsia, nausea, vomiting, bloating, diarrhea, and constipation. The medications most frequently associated with said adverse effects are metformin, acarbose, and GLP-1 agonists. Gastrointestinal adverse effects negatively impact the quality of life and management of patients with diabetes. The factors of visceral neuropathy, acute dysglycemia, dysbiosis, and intestinal bacterial overgrowth contribute to the gastrointestinal symptoms in patients with diabetes, making it necessary to consider multiple etiologic factors in the presence of gastrointestinal symptoms, and not exclusively attribute them to the use of antidiabetics. Personalized treatment, considering gastrointestinal comorbidity and the type of drug utilized, is essential for mitigating the adverse effects and improving the quality of life in patients with diabetes. The aim of the present narrative review was to describe the gastrointestinal adverse effects of the antidiabetic drugs, their pathophysiologic mechanisms, and the corresponding therapeutic measures., Competing Interests: Declaration of competing interest Barrientos Ávalos has been a speaker for Eli Lilly laboratories and for Silanes. The rest of the authors declare they have no conflict of interest., (Copyright © 2024 Asociación Mexicana de Gastroenterología. Published by Masson Doyma México S.A. All rights reserved.)

Context: Insulin resistance and a disturbed lipid profile are common associations with type 2 diabetes mellitus (T2DM) and different skin diseases, particularly psoriasis (PsO)., Objectives: We investigated potential therapeutic mechanisms of metformin in a murine animal model of psoriasiform lesions in T2DM., Materials and Methods: Forty-two rats were randomly divided into control, PsO, and type II DM (T2DM) groups. After confirmation of DM, the type II diabetic rats were allocated into T2DM+ PsO, T2DM+ PsO+ systemic metformin (S. met), T2DM+ PsO+ topical metformin (T. met)), and T2DM+ PsO + combined metformin (C. met). PsO was induced by topical imiquimod., Results: Systemic administration of the cornerstone antidiabetic drug, metformin, was able to improve insulin resistance and lipid profile. At molecular levels, both topical and systemic metformin significantly increased AMP-activated protein kinase (AMPK), and lowered keratinocyte growth factor (KGF) / "Signal transducer and activator of transcription" (STAT)3 protein levels, and the IL-17RA and IL-17RC gene expression., Conclusion: Although its glucose-controlling effect was not optimum, T.met gel served anti-psoriatic and anti-inflammatory effects.

Many complications associated with type 2 diabetes mellitus (T2DM) are closely linked with the generation of reactive species or free radicals leading to oxidative/nitrosative stress. The aim of this study was to investigate the effect of combined administration of metformin with propionate on the degree of oxidative/nitrosative damage in the brain of rats with an experimental model of T2DM. Male Wistar rats were divided into control (healthy rats); rats with T2DM and no further therapy; rats with T2DM that received: metformin, propionate, propionate + metformin. Ventromedial hypothalamus samples were analyzed by transmission electron microscopy, gas-liquid chromatography, Western blotting, RT-PCR and electron paramagnetic resonance. Combined treatment resulted in normalization of the neuronal NOS levels and reduction of mRNA level of induced nitric oxide synthase (NOS) and superoxide radicals compared to untreated T2DM rats. A decrease was also observed in the level of 8-oxyguanine with normalization of fatty acids distribution. The combined treatment partially mitigated ultrastructural alterations resulting from oxidative/nitrosative damage in neurons' mitochondria in T2DM. Thus, we demonstrated a positive effect of the combined use of metformin and propionate on all indicators of oxidative/nitrosative stress in T2DM., (© 2024. The Author(s).)

Vocal fold fibrosis is a challenging condition with no clear consensus on effective treatment methods. Given the demonstrated efficacy of metformin in treating various fibrotic diseases, we hypothesized that metformin could reduce vocal fold fibrosis via the AMPK signaling pathway. In our study, we induced vocal fold injury in rabbits and administered metformin intraperitoneally at a dose of 250 mg/kg two weeks post-injury. Four weeks after the injury, vocal folds were excised and analyzed for fibrosis using Masson's trichrome staining, immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR), and Western blotting. In vitro, vocal fold fibroblasts treated with metformin (10 μM) ± TGF-β1 (10 ng/mL) were utilized to assess metformin's antifibrotic effects, with Compound C (10 μM) employed to inhibit AMPK signaling. Our results demonstrate that metformin significantly improved the structural integrity of the vocal fold lamina, reduced collagen deposition, and decreased the expression levels of COL1A1 and α-SMA. Furthermore, metformin activated the AMPK signaling pathway in vocal fold fibroblasts, resulting in decreased expression of COL1A1, α-SMA, TGF-β, Smad2, and Smad3. These findings suggest that metformin attenuates vocal fold fibrosis by modulating the AMPK signaling pathway, providing a foundation for developing new therapeutic options for vocal fold fibrosis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background Metformin is frequently prescribed as a first-line oral hypoglycemic drug to treat insulin resistance-causing type 2 diabetes mellitus (T2DM). Long-term metformin use results in vitamin B12 deficiency, which is frequently overlooked and undiagnosed. A severe deficit may cause severe anemia and gastrointestinal, or neurological issues. Studies are scarce on this issue in Pakistani patients with T2DM. The current study aimed to estimate the prevalence of metformin-induced vitamin B12 deficiency in T2DM patients and to explore how it relates to metformin dosage or duration of therapy. Methodology A descriptive cross-sectional study was conducted on 260 T2DM patients using metformin therapy for more than a year and attending the outpatient diabetes clinic and the medicine department of Sheikh Zayed Hospital, Rahim Yar Khan, Pakistan, from August 2022 to October 2023. All socio-demographic, clinical, and general characteristics were collected. Blood samples were taken to measure the serum vitamin B12 levels, and based on these levels, deficient and normal group characteristics were compared. Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 23 (Released 2015; IBM Corp., Armonk, New York, United States). Results Based on the serum levels of vitamin B12 of the studied T2DM on the metformin regimen, the overall prevalence of vitamin B12 deficiency was found to be 36.54% (95). The B12 deficiency was higher among the age group of 41-50 years (109, 41.9%), female gender (150, 57.7%, p-value=0.0035), urban residents (194, 74.6%), non-smokers (197, 75.8%), and with a history of chronic disease (131, 50.4%). There was a statistically significant difference in vitamin B12 levels based on T2DM duration (p=0.012), with a higher prevalence in patients with a longer diabetes history of more than two years. There was no discernible statistical relationship between patients receiving different dosages of metformin (odds ratio (OR)=0.8627; 95% confidence interval (CI) (0.5195, 1.4326); p-value=0.568), durations of metformin (OR=0.7400; 95% CI (0.442, 1.2325); p-value=0.247), or intake of vitamin B12 (OR=0.8532; 95% CI (0.5073, 1.4351); p-value=0.549). Conclusion The prevalence of vitamin B12 deficiency impacted more than one-third of T2DM patients using metformin (36.54%). The risk of vitamin B12 deficiency may increase in females with higher metformin dosages and longer durations of treatment. Furthermore, a statistically significant correlation exists between vitamin B12 deficiency and the longer duration of T2DM. These findings highlight the relevance of routinely monitoring serum levels of vitamin B12 among those with T2DM, especially when metformin is being given for over a year or at doses greater than 1000 mg per day. These preventive strategies will aid in the early detection of vitamin B12 deficiency, allowing patients to be treated with supplementation before problems such as anemia or neuropathies arise, resulting in improved quality of life and a lower socioeconomic burden., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Sheikh Zayed Medical College and Hospital, Rahim Yar Khan issued approval 502/IRB/SZMC/SZH. Your research study titled "Prevalence of Vitamin B12 Deficiency and Its Relationship With Metformin Therapy Among Type 2 Diabetes Mellitus Patients" has been approved in the expedited review. You are allowed to conduct the study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Asghar et al.)

The neurotoxicant trimethyltin (TMT) triggers cognitive impairment and hippocampal neurodegeneration. TMT is a useful research tool for the study of Alzheimer's disease (AD) pathogenesis and treatment. Although the antidiabetic agent metformin has shown promising neuroprotective effects, however, its precise modes of action in neurodegenerative disorders need to be further elucidated. In this study, we investigated whether metformin can mitigate TMT cognition impairment and hippocampal neurodegeneration. To induce an AD-like phenotype, TMT was injected i.p. (8 mg/kg) and metformin was administered daily p.o. for 3 weeks at 200 mg/kg. Our results showed that metformin administration to the TMT group mitigated learning and memory impairment in Barnes maze, novel object recognition (NOR) task, and Y maze, attenuated hippocampal oxidative, inflammatory, and cell death/pyroptotic factors, and also reversed neurodegeneration-related proteins such as presenilin 1 and p-Tau. Hippocampal level of AMP-activated protein kinase (AMPK) as a key regulator of energy homeostasis was also improved following metformin treatment. Additionally, metformin reduced hippocampal acetylcholinesterase (AChE) activity, glial fibrillary acidic protein (GFAP)-positive reactivity, and prevented the loss of CA1 pyramidal neurons. This study showed that metformin mitigated TMT-induced neurodegeneration and this may pave the way to develop new therapeutics to combat against cognitive deficits under neurotoxic conditions., (© 2024. The Author(s).)

Excessive generation of reactive oxygen species (ROS) poses a huge obstacle to the healing process of diabetic wounds, resulting in chronic, non-healing wounds. While numerous anti-ROS therapeutics have been developed, satisfied intra- and extra- cellular ROS homeostasis is hard to be established in diabetic wounds. To address this issue, a nanoparticle via loading metformin and CeO 2 into mesoporous silica (MSN@Met-CeO 2 ) is designed and synthesized, which is then encapsulated within ROS-responsive hydrogel and shaped as microneedles (MNs) for better application in diabetic wounds. Interestingly, a unique metformin-cerium chelate (Ce· 3Metformin) is formed during the synthesis of MSN@Met-CeO 2 MN, which significantly strengthened the inhibitory effect of metformin on mitochondrial complex I. With the presence of Ce· 3Metformin, MSN@Met-CeO 2 MN performed a remarkable effect on intracellular mtROS reduction as well as extracellular ROS elimination, the latter is primarily accomplished through the dissociative CeO 2 in MSN@Met-CeO 2 MN. In the mouse diabetic wound model, MSN@Met-CeO 2 MN exhibited a superior pro-healing effect with accelerated inflammation resolution and enhanced angiogenesis, thus highlighting its significant potential for clinical application., (© 2024 Wiley‐VCH GmbH.)

Posterior capsular opacification (PCO) is a common complication following cataract surgery, which can lead to a significant vision loss. This study introduces a facile method for developing a metformin-derived hydrogel (HCM 6 ) stabilized by dynamic covalent bonds among natural polymers. This hydrogel demonstrates antifibrotic properties, on-demand drug release, pH responsiveness, injectability, and self-healing capabilities. Our in vitro experiments confirmed that the HCM 6 hydrogel exhibits excellent biocompatibility, inhibiting lens epithelial cell migration, and transforming growth factor-2β (TGFβ2)-induced α-smooth muscle actin (α-SMA) expression in lens epithelial cells. In vivo studies conducted in a rat extracapsular lens extraction (ECLE) model revealed that HCM 6 significantly suppressed PCO after 21 days of implantation with no observed pathological effects on surrounding tissues or the optic nerve. According to our experimental results, the inhibitory mechanism of PCO may be attributed to metformin's suppressive effect on lens cell migration, epithelial-mesenchymal transition (EMT), and lens fiber formation. In summary, the long-acting, controllable, and on-demand release characteristics of the HCM 6 hydrogel not only provide an effective strategy for preventing PCO but also offer new avenues for treating undesirable proliferative conditions in ophthalmology and beyond.

Background/objectives: Metformin (Met), an oral drug used to treat type II diabetes, is known to control blood glucose levels. Metformin carbon quantum dots (MetCQDs) were prepared to enhance the bioavailability and effectiveness of metformin. Several studies have shown that carbon quantum dots (CQDs) have attractive properties like small particle size, high penetrability, low cytotoxicity, and ease of synthesis. CQDs are made from a carbon source, namely, citric acid, and a heteroatom, such as nitrogen. The active molecule can be a carbon source or a heteroatom, as reported here., Methods: This study aims to produce MetCQDs from an active molecule. MetCQDs were successfully produced by microwave-based production methods and characterized. The effect of the MetCQDs was tested in Wistar albino rats following a Streptozocin-induced diabetic model., Results: The results show that the products have a particle size of 9.02 ± 0.04 nm, a zeta potential of -10.4 ± 0.214 mV, and a quantum yield of 15.1 ± 0.045%. Stability studies and spectrophotometric analyses were carried out and the effectiveness of MetCQDs evaluated in diabetic rats. The results show a significant reduction in blood sugar levels (34.1-51.1%) compared to the group receiving only metformin (37.1-55.3%) over a period of 30 to 360 min. Histopathological examinations of the liver tissue indicate improvement in the liver health indicators of the group treated with MetCQDs., Conclusions: Based on these results, the products have potential therapeutic advantages in diabetes management through their increased efficacy and may have reduced side effects compared to the control group.

Osteoarthritis (OA) is a degenerative disease that affects the quality of life in elderly and young populations. Current therapies using corticosteroids and non-steroidal anti-inflammatory drugs via parenteral or oral routes show limited ability to retard progression of the disease and achieve long term effectiveness and safety. Herein, the potential of MT-Cur combinatorial nano-formulations in OA management was explored for the first time. MT-Cur loaded nanohyaluosomes (MT-Cur-HL 1 ) were designed for topical administration of the combined therapy in OA. The optimized MT-Cur-HL 1 showed particle size 247.7 ± 3.7 nm, zeta potential -37.3 ± 0.4 mV; and entrapment efficiency (%EE) 70.22 %±0.303 and 76.7 %±0.077 for MT and Cur, respectively. MT-Cur-HL 1 exhibited sustained drug release over 24 h and were stable over 3 months at 4 °C in terms of P.S., ZP and %EE. A detailed preclinical study, using MIA-induced osteoarthritis rat model, revealed the most significant anti-arthritic effect and halted OA progression of MT-Cur-HL 1. This was proved to be mainly through the potentiation of p-AMPK signaling that ultimately led to suppression of its downstream TLR4/ NF-κB signaling pathway with subsequent reduction in MMP13 and ADAMTS5 induced chondrocytes degeneration. This study proved that this trajectory effectively promotes a significant improvement in the articular cartilage structure and reinforcement of joint mobility with an efficient antinociceptive effect. In conclusion, the novel MT-Cur coloaded nanohyaluosomes offer a promising non-invasive approach for the local management of OA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Metformin is known for its antioxidant properties and ability to ameliorate metabolic dysfunction-associated fatty liver disease (MAFLD) and is the focus of this study. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is linked to MAFLD risk. This study investigated the effects of metformin on ferroptosis in free fatty acid (FFA)-treated Huh7 hepatoma cells and its association with MAFLD risk. Using Western blot, immunofluorescence, and ELISA, this study revealed that FFA treatment led to increased intracellular fat and iron accumulation, heightened Lp-PLA2 expression, reduced levels of the cysteine transporter SLC7A11 and glutathione peroxidase 4 (GPX4), altered glutathione (GSH)/oxidized glutathione (GSSG) ratios, generation of reactive oxygen species (ROS), and initiation of lipid peroxidation, which ultimately resulted in cell ferroptosis. Importantly, metformin reversed FFA-induced iron accumulation, and this effect was attenuated by ferrostatin-1 but enhanced by erastin, RSL3, and si-GPX4. Additionally, metformin activated antioxidant and antiapoptotic mechanisms, which reduced lipid peroxidation and suppressed Lp-PLA2 expression in FFA-treated Huh7 cells. In conclusion, our findings indicate that metformin may protect against MAFLD by inhibiting iron accumulation and Lp-PLA2 expression through the ROS, ferroptosis, and apoptosis signaling pathways. This study highlights potential therapeutic strategies for managing MAFLD-related risks and emphasizes the diverse roles of metformin in maintaining hepatocyte balance.

Aims/hypothesis: Metformin is an important first-line treatment for type 2 diabetes and acts by increasing the body's ability to dispose of glucose. Metformin's efficacy can be affected by genetic variants in the transporters that regulate its uptake into cells. The SLC22A3 gene (also known as EMT; EMTH; OCT3) codes for organic cation transporter 3 (OCT3), which is a broad-specificity cation transporter that also transports metformin. Most SLC22A3 variants reduce the rate of metformin transport but the rs8187715 variant (p.Thr44Met) is reported to increase uptake of metformin in vitro. However, the impact of this on in vivo metformin transport and efficacy is unknown. Very few carriers of this variant have been reported globally, but, notably, all were of Pacific Island descent. Therefore, this study aims to understand the prevalence of this variant in Polynesian peoples (Māori and Pacific peoples) and to understand its impact on metformin transport and efficacy in vivo., Methods: rs8187715 was genotyped in 310 individuals with Māori and Pacific ancestry recruited in Aotearoa New Zealand. To study this variant in a physiological context, an orthologous knockin mouse model with C57BL/6J background was used. Pharmacokinetic analysis compared uptake rate of metformin into tissues. Plasma growth/differentiation factor 15 (GDF-15) was also measured as a marker of metformin efficacy. Glucose and insulin tolerance was assessed after acute or sustained metformin treatment in knockin and wild-type control mice to examine the impact of the variant on metformin's glycaemic control., Results: The minor allele frequency of this variant in the Māori and Pacific participants was 15.4%. There was no association of the variant with common metabolic parameters including diabetes status, BMI, blood pressure, lipids, or blood glucose and HbA 1c . However, in the orthologous knockin mouse model, the rate of metformin uptake into the blood and tissues was increased. Acute metformin dosing increased insulin sensitivity in variant knockin mice but this effect was lost after longer-term metformin treatment. Metformin's effects on GDF-15 levels were also lost in variant knockin mice with longer-term metformin treatment., Conclusions/interpretation: These data provide evidence that the SLC22A3 rs8187715 variant accelerates metformin uptake rate in vivo. While this acutely improves insulin sensitivity, there was no increased effect of metformin with longer-term dosing. Thus, our finding of a high prevalence of this variant specifically in Māori and Pacific peoples identifies it as a potential population-specific pharmacogenetic marker with potential to guide metformin therapy in these peoples., (© 2024. The Author(s).)

Metformin was developed from an offshoot of Guanidine. It is known to be the first-line medication for type 2 diabetes mellitus, polycystic ovarian syndrome, and weight reduction. Metformin has also been shown to have effectiveness in the management of non-alcoholic fatty liver disease (NAFLD), liver cirrhosis, and various carcinomas like hepatocellular, colorectal, prostate, breast, urinary bladder, blood, melanoma, bone, skin, lung and so on. This narrative review focuses on the effect of metformin on non-alcoholic fatty liver disease, liver cirrhosis, and hepatocellular carcinoma. The search platforms for the topic were PubMed, Scopus, and Google search engine. Critical words for searching included 'Metformin,' AND 'Indications of Metformin,' AND 'Non-Alcoholic Fatty Liver Disease,' AND 'Metformin mechanism of action,' AND 'NAFLD management,' AND 'NAFLD and inflammation,' AND 'Metformin and insulin,' AND 'Metformin and inflammation,' AND 'Liver cirrhosis,' AND 'Hepatocellular carcinoma.' Lifestyle modification and the use of hypoglycemic agents can help improve liver conditions. Metformin has several mechanisms that enhance liver health, including reducing reactive oxygen species, nuclear factor kappa beta (NF-κB), liver enzymes, improving insulin sensitivity, and improving hepatic cell lipophagy. Long-term use of metformin may cause some adverse effects like lactic acidosis and gastrointestinal disturbance. Metformin long-term overdose may lead to a rise in hydrogen sulfide in liver cells, which calls for pharmacovigilance. Drug regulating authorities should provide approval for further research, and national and international guidelines need to be developed for liver diseases, perhaps with the inclusion of metformin as part of the management regime., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Ahmad et al.)

Background: Propionic acid (PA) is an intermediate product of metabolism of intestinal bacteria and may protect the intestinal barrier from disruption. The aim of the study was to investigate the apoptotic and proliferative processes in the small intestine (SI) of rats with type 2 diabetes mellitus (T2DM) on the background of metformin monotherapy and its combination with PA., Methods: Male Wistar rats were divided: 1) control; 2) T2DM (3-month high-fat diet followed by streptozotocin injection of 25 mg/kg of body weight); 3) T2DM + metformin (60 mg/kg, 14 days, orally); 4) T2DM + PA (60 mg/kg, 14 days, orally); 5) T2DM + PA + metformin. Western blotting, RT-PCR, and scanning electron microscopy were performed., Results: We observed profound changes in the SI of diabetic rats suggesting the disturbed intestinal homeostasis: impaired mitochondrial ultrastructure, increased cristae volume, and decreased content of proliferative marker Ki67 with almost unchanged proapoptotic caspase-3 and its p17 subunit levels. Metformin and PA monotherapies also led to an increased cristae volume, however, after their combination, a tendency to normalization of ultrastructure of mitochondria was observed. While there was a significant inhibition of proliferation in T2DM and, in greater extent, after metformin and PA monotherapies, differential influence on apoptosis in the SI was observed. While metformin inhibited apoptosis via Bax declining, PA mainly acted via caspase-3-dependent mechanism elevating its active p17 subunit., Conclusion: PA supplementation for the improvement of diabetes-induced gastrointestinal complications concurrently with metformin may be consider as a perspective supportive therapy. Data related to PA action on SI may be valuable during the development of new treatment strategies for diabetes-induced intestinal disturbances raised after metformin treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Natrus, Lisakovska, Smirnov, Osadchuk and Klys.)

Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women, associated with dyslipidemia, insulin resistance, and hormonal imbalances. Metformin and curcumin have shown promise in improving these metabolic and hormonal parameters individually, but their combined effects in PCOS remain unclear., Methods: We conducted a randomized, double-blind, placebo-controlled, 12-week factorial trial involving 200 women with PCOS. Participants were randomly assigned in a 1:1:1:1 ratio to receive metformin (500-mg/8 h) + placebo, nanocurcumin soft gel capsule (80-mg/8 h) + placebo, metformin (500-mg/8 h) + nanocurcumin (80-mg/8 h), or double placebo. Lipid profiles, glucose metabolism markers, hormonal parameters, body weight, and body mass index (BMI) were assessed at baseline and week 12., Results: The combination of metformin and curcumin demonstrated significant improvements in lipid profiles, glucose metabolism, hormonal parameters, body weight, and BMI compared to individual agents or placebo. Greater reductions in low-density lipoproteins (LDL) cholesterol, total cholesterol (TC), and triglyceride (TG) levels were observed with the combination therapy, along with increased high-density lipoproteins (HDL) cholesterol. Additionally, the combination therapy significantly improved markers of glucose metabolism and showed synergistic effects in reducing body weight and BMI. Reductions in testosterone and improvements in Follicle-stimulating hormone (FSH) and Luteinizing hormone (LH) levels were also observed with combination therapy., Conclusion: The combination of metformin and curcumin demonstrates superior efficacy in improving lipid profiles, glucose metabolism, hormonal parameters, body weight, and BMI in women with PCOS compared to individual agents or placebo. This highlights the potential synergistic effects of combining these agents for the management of PCOS., Competing Interests: Declaration of competing interest We declare that there is no conflict of interest in this study., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Clinical and experimental evidence has linked Benign Prostatic Hyperplasia (BPH) with dyslipidemic and hypercholesterolemic conditions, though the underlying cellular mechanisms remain unclear. This study investigates the impact of dyslipidemia, specifically oxidized LDL (OxLDL), on prostatic stromal cell proliferation and the release of extracellular vesicles (EVs)., Methods: Mice were fed a high-fat diet, and human prostatic stromal cells (HPSCs) were treated with OxLDL. Proliferation assays and EV characterization were performed to assess the role of EVs in BPH progression., Results: Pro-atherogenic conditions significantly increased cell proliferation in both murine prostatic cells and HPSCs. Treatment with metformin effectively inhibited OxLDL-induced proliferation. Additionally, OxLDL stimulated the production and release of pro-proliferative EVs by HPSCs, which further promoted cellular proliferation., Conclusions: The findings suggest that dyslipidemia drives prostatic stromal cell proliferation and EV secretion, contributing to BPH progression. Metformin demonstrates potential as a therapeutic agent to mitigate these effects, offering insight into novel strategies for BPH management. This study highlights the complex interaction between dyslipidemia, cell proliferation, and extracellular communication in the context of BPH pathogenesis.

This study investigates the anticancer effects of SPION-based silica nanoparticles carrying 5-fluorouracil (5-FU) or oxaliplatin (OX), and metformin (MET) on colorectal cancer cells. Nanocarriers were equipped with pH-responsive gold gatekeepers for controlled release, PEGylation for longer circulation, and folic acid (FA) for targeted delivery. The effects were evaluated by investigating cell viability, cellular uptake, flow cytometry, and clonogenic assay in vitro. The efficacy of the system was also tested in vivo on C57BL/6 mice bearing HT-29 tumors, and potential side effects were evaluated. Nanocarriers were synthesized with hydrodynamic diameters of 79.8 nm for 5-FU and 85.2 nm for OX; zeta potentials of -21 and -22 mV, respectively, and remained stable after 72 h. Encapsulation efficiencies were 85 % for 5-FU, 80 % for OX, and 83 % for MET, with loading capacities of 44 %, 38 %, and 41 %, respectively. Drug release in acidic buffer was 38.7 % for 5-FU, 32.8 % for OX, and 43.5 % for MET. MTT assay showed increased toxicity due to FA conjugation, while PEGylation reduced the hemolysis activity. Targeted nanocarriers demonstrated superior cellular uptake and tumor localization compared to non-targeted variants. The combination of 5-FU-MET and OX-MET nanocarriers with radiation therapy (RT) demonstrated the greatest effect on their antitumor activity, accompanied by minimal side effects indicating effective tumor targeting in vivo. MRI and CT imaging further supported these findings. This study underscores the synergistic impact of MET alongside RT on the inhibition of cancer cells and tumor growth for both targeted 5-FU and OX nanocarriers reflecting the significant radiosensitizing properties of MET., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Polycystic ovary syndrome (PCOS) affects 6-20% of women worldwide, with insulin resistance and hyperinsulinemia occurring in 50-70% of patients. Hyperinsulinemia exacerbates oxidative stress, contributing to PCOS pathogenesis. N-acetylcysteine (NAC) is an antioxidant and insulin sensitizer that shows promise as a therapeutic for PCOS. Our current study aimed to investigate the effects of NAC supplementation on endocrine-metabolic parameters in PCOS mice and its effect on ovulation induction (OI) efficacy in women with PCOS., Methods: Female C57BL/6 mice were orally administered letrozole (LE) to induce PCOS and then randomly divided into groups receiving daily oral administration of 160 mg/kg NAC (PCOS + NAC group), 200 mg/kg metformin (PCOS + Met group), or 0.5% carboxymethyl cellulose (drug solvent) (pure PCOS group) for 12 days. Healthy female mice served as pure controls. Estrous cycles were monitored during the intervention. Metabolic and hormone levels, ovarian phenotypes, antioxidant activity in ovarian tissues, and oxidative stress levels in oocytes were assessed post-intervention. Furthermore, a pragmatic, randomized, controlled clinical study was conducted with 230 PCOS women, randomly assigned to the NAC group (1.8 g/day oral NAC, n = 115) or the control group (n = 115). Patients in both groups underwent ≤ 3 cycles of OI with sequential LE and urinary follicle-stimulating hormone (uFSH). Cycle characteristics and pregnancy outcomes were compared between groups., Results: Similar to metformin, NAC supplementation significantly improved the estrous cycles and ovarian phenotypes of PCOS mice; reduced the LH concentration, LH/FSH ratio, and T level; and increased glucose clearance and insulin sensitivity. Notably, NAC significantly reduced oocyte ROS levels and increased the mitochondrial membrane potential in PCOS mice. Additionally, NAC significantly enhanced enzymatic and nonenzymatic antioxidant activities in PCOS mouse ovaries, whereas metformin had no such effect. In the clinical trial, compared to women in the control group, women receiving NAC had significantly lower average uFSH dosage and duration (p < 0.005) and significantly greater clinical pregnancy rates per OI cycle and cumulative clinical pregnancy rates per patient (p < 0.005)., Conclusion: NAC supplementation improved endocrine-metabolic parameters in PCOS mice and significantly enhanced OI efficacy with sequential LE and uFSH in women with PCOS. Therefore, NAC could be a valuable adjuvant in OI for women with PCOS., (© 2024. The Author(s).)