Synthesis, biological evaluation and molecular docking study of pyrimidine linked thiazolidinedione derivatives as potential antimicrobial and antitubercular agents.

The design and development of novel antimicrobial agents are highly desired to combat the emergence of medication resistance against microorganisms that cause infections. A series of new pyrimidine-linked thiazolidinedione derivatives (5a-j) were synthesized, characterized, and their antimicrobial properties assessed in the current investigation. Here, novel pyrimidine-linked thiazolidinedione compounds were designed using the molecular hybridization approach. Elemental and spectral techniques were used to determine the structures of the synthesized hybrids. The majority of compounds showed encouraging antibacterial properties. Among the active compounds, 5g, 5i, and 5j showed 1.85, 1.15, and 1.38 times the activity of streptomycin against S. aureus, respectively, with MIC values of 6.4, 10.3, and 8.6 µM. With MIC values of 10.8, 21.9, and 15.4 µM, respectively, the compounds 5g, 5i, and 5j showed 2.14, 1.05, and 1.50 times the activity of linezolid against the methicillin-resistant S. aureus (MRSA) strain. Furthermore, when compared to the reference medications, compounds 5g, 5i, and 5j demonstrated broad-range antimicrobial efficacy against all tested strains of bacteria and fungus. Out of all the compounds that were investigated, compounds 5g, 5i, and 5j showed noteworthy anti-tubercular activity. 5g is the most effective, 1.59 times more effective than reference drug isoniazid. To anticipate the binding manner, the synthesized potent compounds were subjected to molecular docking into the active binding site of MRSA and the mycobacterial membrane protein large 3 (MmpL3) protein. The compounds 5g, 5i, and 5j may eventually serve as lead compounds in the search for antimicrobial and anti-TB therapeutic agents.

Effect of Drugs Used in Pharmacotherapy of Type 2 Diabetes on Bone Density and Risk of Bone Fractures.

This review summarizes the complex relationship between medications used to treat type 2 diabetes and bone health. T2DM patients face an increased fracture risk despite higher bone mineral density; thus, we analyzed the impact of key drug classes, including Metformin, Sulphonylureas, SGLT-2 inhibitors, DPP-4 inhibitors, GLP-1 agonists, and Thiazolidinediones. Metformin, despite promising preclinical results, lacks a clear consensus on its role in reducing fracture risk. Sulphonylureas present conflicting data, with potential neutral effects on bone. SGLT-2 inhibitors seem to have a transient impact on serum calcium and phosphorus, but evidence on their fracture association is inconclusive. DPP-4 inhibitors emerge as promising contributors to bone health, and GLP-1 agonists exhibit positive effects on bone metabolism, reducing fracture risk. Thiazolidinediones, however, demonstrate adverse impacts on bone, inducing loss through mesenchymal stem cell effects. Insulin presents a complex relationship with bone health. While it has an anabolic effect on bone mineral density, its role in fracture risk remains inconsistent. In conclusion, a comprehensive understanding of diabetes medications' impact on bone health is crucial. Further research is needed to formulate clear guidelines for managing bone health in diabetic patients, considering individual profiles, glycemic control, and potential medication-related effects on bone.

Time-dependent risk of fracture in adults with type 2 diabetes receiving anti-diabetic drug: A one-stage network meta-analysis.

AIMS: To assess the time-dependent risk of fracture in adults with type 2 diabetes receiving anti-diabetic drugs. MATERIALS AND METHODS: We searched MEDLINE, EMBASE, and Cochrane Library up to 18 November 2021, for randomized controlled trials (RCTs) and propensity-score-matched non-randomized studies (NRSs) comparing all anti-diabetic drugs with standard treatment or with each other on fracture in adults with type 2 diabetes. The study performed a one-stage network meta-analysis using discrete-time hazard regression with reconstructed individual time-to-event data. RESULTS: This network meta-analysis involved seven RCTs (65,051 adults with type 2 diabetes) with a median follow-up of 36 months and three propensity-score-based NRSs (17,954 participants) with a median follow-up of 27.3 months. Among anti-diabetic drugs, thiazolidinediones increased the overall hazard of fracture by 42% (95% credible interval [CrI], 3%-97%) and almost tripled the risk after 4 years (hazard ratio [HR], 2.74; 95% CrI, 1.53-4.80). Credible subgroup analysis suggested that thiazolidinediones increased the hazard of fracture only in females (HR, 2.19; 95% CrI, 1.26-3.74) but not among males (HR, 0.81; 95% CrI, 0.45-1.40). Moderate certainty evidence established that thiazolidinediones increase 92 fractures in five years per 1000 female patients. We did not find the risk of fractures with other anti-diabetic drugs including metformin, sulfonylureas, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors. CONCLUSIONS: Long-term use of thiazolidinediones elevates the risk of fracture among females with type 2 diabetes. There is no evidence eliciting fracture risk associated with other anti-diabetic drugs.

Thiazolidine-2,4-dione derivatives as potential α-glucosidase inhibitors: Synthesis, inhibitory activity, binding interaction and hypoglycemic activity.

In order to find effective α-glucosidase inhibitors, a series of thiazolidine-2,4-dione derivatives (C1 âˆ¼ 36) were synthesized and evaluated for α-glucosidase inhibitory activity. Compared to positive control acarbose (IC50 = 654.35 ± 65.81 µM), all compounds (C1 âˆ¼ 36) showed stronger α-glucosidase inhibitory activity with IC50 values of 0.52 ± 0.06 âˆ¼ 9.31 ± 0.96 µM. Among them, C23 with the best anti-α-glucosidase activity was a reversible mixed-type inhibitor. Fluorescence quenching suggested the binding process of C23 with α-glucosidase in a static process. Fluorescence quenching, CD spectra, and 3D fluorescence spectra results also implied that the binding of C23 with α-glucosidase caused the conformational change of α-glucosidase to inhibit the activity. Molecular docking displayed the binding interaction of C23 with α-glucosidase. Compound C23 (8 âˆ¼ 64 µM) showed no cytotoxicity against LO2 and 293 cells. Moreover, oral administration of C23 (50 mg/kg) could reduce blood glucose and improve glucose tolerance in mice.

The risk of common hypoglycemic and antihypertensive medications and COVID-19: A 2-sample Mendelian randomization study.

BACKGROUND: It has been reported that diabetes and hypertension increase the adverse outcomes of coronavirus disease 2019 (COVID-19). Aside from the inherent factors of diabetes and hypertension, it remains unclear whether antidiabetic or antihypertensive medications contribute to the increased adverse outcomes of COVID-19. The effect of commonly used antidiabetic and antihypertensive medications on COVID-19 outcomes has been inconsistently concluded in existing observational studies. Conducting a systematic study on the causal relationship between these medications and COVID-19 would be beneficial in guiding their use during the COVID-19 pandemic. METHODS: We employed the 2-sample Mendelian randomization approach to assess the causal relationship between 5 commonly used antidiabetic medications (SGLT-2 inhibitors, Sulfonylureas, Insulin analogues, Thiazolidinediones, GLP-1 analogues) and 3 commonly used antihypertensive medications (calcium channel blockers [CCB], ACE inhibitors, ß-receptor blockers [BB]), and COVID-19 susceptibility, hospitalization, and severe outcomes. The genetic variations in the drug targets of the 5 antidiabetic medications and 3 antihypertensive medications were utilized as instrumental variables. European population-specific genome-wide association analysis (GWAS) data on COVID-19 from the Host Genetics Initiative meta-analyses were obtained, including COVID-19 susceptibility (n = 2597,856), COVID-19 hospitalization (n = 2095,324), and COVID-19 severity (n = 1086,211). The random-effects inverse variance-weighted estimation method was employed as the primary assessment technique, with various sensitivity analyses conducted to evaluate heterogeneity and pleiotropy. RESULTS: There were no potential associations between the genetic variations in the drug targets of the 5 commonly used antidiabetic medications (SGLT-2 inhibitors, Sulfonylureas, Insulin analogues, Thiazolidinediones, GLP-1 analogues) and the 3 commonly used antihypertensive medications (CCBs, ACE inhibitors, BBs) with COVID-19 susceptibility, hospitalization, and severity (all P > .016). CONCLUSION: The findings from this comprehensive Mendelian randomization analysis suggest that there may be no causal relationship between the 5 commonly used antidiabetic medications (SGLT-2 inhibitors, Sulfonylureas, Insulin analogues, Thiazolidinediones, GLP-1 analogues) and the 3 commonly used antihypertensive medications (CCBs, ACE inhibitors, BBs) with COVID-19 susceptibility, hospitalization, and severity.

Uncovering PPAR-γ agonists: An integrated computational approach driven by machine learning.

Peroxisome proliferator-activated receptor gamma (PPAR-γ) serves as a nuclear receptor with a pivotal function in governing diverse facets of metabolic processes. In diabetes, the prime physiological role of PPAR-γ is to enhance insulin sensitivity and regulate glucose metabolism. Although PPAR-γ agonists such as Thiazolidinediones are effective in addressing diabetes complications, it is vital to be mindful that they are associated with substantial side effects that could potentially give rise to health challenges. The recent surge in the discovery of selective modulators of PPAR-γ inspired us to formulate an integrated computational strategy by leveraging the promising capabilities of both machine learning and in silico drug design approaches. In pursuit of our objectives, the initial stage of our work involved constructing an advanced machine learning classification model, which was trained utilizing chemical information and physicochemical descriptors obtained from known PPAR-γ modulators. The subsequent application of machine learning-based virtual screening, using a library of 31,750 compounds, allowed us to identify 68 compounds having suitable characteristics for further investigation. A total of four compounds were identified and the most favorable configurations were complemented with docking scores ranging from -8.0 to -9.1 kcal/mol. Additionally, the compounds engaged in hydrogen bond interactions with essential conserved residues including His323, Leu330, Phe363, His449 and Tyr473 that describe the ligand binding site. The stability indices investigated herein for instance root-mean-square fluctuations in the backbone atoms indicated higher mobility in the region of orthosteric site in the presence of agonist with the deviation peaks in the range of 0.07-0.69 nm, signifying moderate conformational changes. The deviations at global level revealed that the average values lie in the range of 0.25-0.32 nm. In conclusion, our identified hits particularly, CHEMBL-3185642 and CHEMBL-3554847 presented outstanding results and highlighted the stable conformation within the orthosteric site of PPAR-γ to positively modulate the activity.

Assessment of anti-hyperglycemic and anti-hyperlipidemic effects of thiazolidine-2,4-dione derivatives in HFD-STZ diabetic animal model.

Type 2 diabetes mellitus (T2DM) is a chronic endocrine/metabolic disorder characterized by elevated postprandial and fasting glycemic levels that result in disturbances in primary metabolism. In this study, we evaluated the metabolic effects of thiazolidine-2,4-dione derivatives in Wistar rats and Swiss mice that were fed a high-fat diet (HFD) for 4 weeks and received 90 mg/kg of streptozotocin (STZ) intraperitoneally as a T2DM model. The HFD consisted of 17% carbohydrate, 58% fat, and 25% protein, as a percentage of total kcal. The thiazolidine-2,4-dione derivatives treatments reduced fasting blood glucose (FBG) levels by an average of 23.98%-50.84%, which were also improved during the oral starch tolerance test (OSTT). Treatment with thiazolidine-2,4-dione derivatives also improved triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), and total cholesterol levels (P < 0.05). The treatment intake has also shown a significant effect to modulate the altered hepatic and renal biomarkers. Further treatment with thiazolidine-2,4-dione derivatives for 28 days significantly ameliorated changes in appearance and metabolic risk factors, including favorable changes in histopathology of the liver, kidney, and pancreas compared with the HFD/STZ-treated group, suggesting its potential role in the management of diabetes. Thiazolidine-2,4-dione derivatives are a class of drugs that act as insulin sensitizers by activating peroxisome proliferator-activated receptor-gamma (PPAR-γ), a nuclear receptor that regulates glucose and lipid metabolism. The results of this study suggest that thiazolidine-2,4-dione derivatives may be a promising treatment option for T2DM by improving glycemic control, lipid metabolism, and renal and hepatic function.

Outcomes of Various Classes of Oral Antidiabetic Drugs on Nonalcoholic Fatty Liver Disease.

Importance: Several oral antidiabetic drug (OAD) classes can potentially improve patient outcomes in nonalcoholic fatty liver disease (NAFLD) to varying degrees, but clinical data on which class is favored are lacking. Objective: To investigate which OAD is associated with the best patient outcomes in NAFLD and type 2 diabetes (T2D). Design, Setting, and Participants: This retrospective nonrandomized interventional cohort study used the National Health Information Database, which provided population-level data for Korea. This study involved patients with T2D and concomitant NAFLD. Exposures: Receiving either sodium-glucose cotransporter 2 (SGLT2) inhibitors, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, or sulfonylureas, each combined with metformin for 80% or more of 90 consecutive days. Main Outcomes and Measures: The main outcomes were NAFLD regression assessed by the fatty liver index and composite liver-related outcome (defined as liver-related hospitalization, liver-related mortality, liver transplant, and hepatocellular carcinoma) using the Fine-Gray model regarding competing risks. Results: In total, 80 178 patients (mean [SD] age, 58.5 [11.9] years; 43 007 [53.6%] male) were followed up for 219 941 person-years, with 4102 patients experiencing NAFLD regression. When compared with sulfonylureas, SGLT2 inhibitors (adjusted subdistribution hazard ratio [ASHR], 1.99 [95% CI, 1.75-2.27]), thiazolidinediones (ASHR, 1.70 [95% CI, 1.41-2.05]), and DPP-4 inhibitors (ASHR, 1.45 [95% CI, 1.31-1.59]) were associated with NAFLD regression. SGLT2 inhibitors were associated with a higher likelihood of NAFLD regression when compared with thiazolidinediones (ASHR, 1.40 [95% CI, 1.12-1.75]) and DPP-4 inhibitors (ASHR, 1.45 [95% CI, 1.30-1.62]). Only SGLT2 inhibitors (ASHR, 0.37 [95% CI, 0.17-0.82]), not thiazolidinediones or DPP-4 inhibitors, were significantly associated with lower incidence rates of adverse liver-related outcomes when compared with sulfonylureas. Conclusions and Relevance: The results of this cohort study suggest that physicians may lean towards prescribing SGLT2 inhibitors as the preferred OAD for individuals with NAFLD and T2D, considering their potential benefits in NAFLD regression and lower incidences of adverse liver-related outcomes. This observational study should prompt future research to determine whether prescribing practices might merit reexamination.

Toxicometabolomics-based cardiotoxicity evaluation of Thiazolidinedione exposure in human-derived cardiomyocytes.

INTRODUCTION: Thiazolidinediones (TZDs), represented by pioglitazone and rosiglitazone, are a class of cost-effective oral antidiabetic agents posing a marginal hypoglycaemia risk. Nevertheless, observations of heart failure have hindered the clinical use of both therapies. OBJECTIVE: Since the mechanism of TZD-induced heart failure remains largely uncharacterised, this study aimed to explore the as-yet-unidentified mechanisms underpinning TZD cardiotoxicity using a toxicometabolomics approach. METHODS: The present investigation included an untargeted liquid chromatography-mass spectrometry-based toxicometabolomics pipeline, followed by multivariate statistics and pathway analyses to elucidate the mechanism(s)of TZD-induced cardiotoxicity using AC16 human cardiomyocytes as a model, and to identify the prognostic features associated with such effects. RESULTS: Acute administration of either TZD agent resulted in a significant modulation in carnitine content, reflecting potential disruption of the mitochondrial carnitine shuttle. Furthermore, perturbations were noted in purine metabolism and amino acid fingerprints, strongly conveying aberrations in cardiac energetics associated with TZD usage. Analysis of our findings also highlighted alterations in polyamine (spermine and spermidine) and amino acid (L-tyrosine and valine) metabolism, known modulators of cardiac hypertrophy, suggesting a potential link to TZD cardiotoxicity that necessitates further research. In addition, this comprehensive study identified two groupings - (i) valine and creatine, and (ii) L-tryptophan and L-methionine - that were significantly enriched in the above-mentioned mechanisms, emerging as potential fingerprint biomarkers for pioglitazone and rosiglitazone cardiotoxicity, respectively. CONCLUSION: These findings demonstrate the utility of toxicometabolomics in elaborating on mechanisms of drug toxicity and identifying potential biomarkers, thus encouraging its application in the toxicological sciences. (245 words).

Use of drugs for hyperlipidaemia and diabetes and risk of primary and secondary brain tumours: nested case-control studies using the UK Clinical Practice Research Datalink (CPRD).

OBJECTIVES: Previous studies have suggested that fibrates and glitazones may have a role in brain tumour prevention. We examined if there is support for these observations using primary care records from the UK Clinical Practice Research Datalink (CPRD). DESIGN: We conducted two nested case-control studies using primary and secondary brain tumours identified within CPRD between 2000 and 2016. We selected cases and controls among the population of individuals who had been treated with any anti-diabetic or anti-hyperlipidaemic medication to reduce confounding by indication. SETTING: Adults older than 18 years registered with a general practitioner in the UK contributing data to CPRD. RESULTS: We identified 7496 individuals with any brain tumour (4471 primary; 3025 secondary) in total. After restricting cases and controls to those prescribed any anti-diabetic or anti-hyperlipidaemic medication, there were 1950 cases and 7791 controls in the fibrate and 480 cases with 1920 controls in the glitazone analyses. Longer use of glitazones compared with all other anti-diabetic medications was associated with a reduced risk of primary (adjusted OR (aOR) 0.89 per year, 95% CI 0.80 to 0.98), secondary (aOR 0.87 per year, 95% CI 0.77 to 0.99) or combined brain tumours (aOR 0.88 per year, 95% CI 0.81 to 0.95). There was little evidence that fibrate exposure was associated with risk of either primary or secondary brain tumours. CONCLUSIONS: Longer exposure to glitazones was associated with reduced primary and secondary brain tumour risk. Further basic science and population-based research should explore this finding in greater detail, in terms of replication and mechanistic studies.

Gastroprotective effect of rhodanine and 2,4-thiazolidinediones scaffolds in rat stomachs by contribution of anti-apoptotic (BCL-2) and tumor suppressor (P53) proteins.

In recent times, the methods used to evaluate gastric ulcer healing worldwide have been based on visual examinations and estimating ulcer dimensions in experimental animals. In this study, the protective effect of rhodanine and 2,4-thiazolidinediones scaffolds compared to esomeprazole was investigated in an ethanol model of stomach ulcers in rats. Pretreatment with experimental treatments or esomeprazole prevented the development of ethanol-induced gastric ulcers. The severity of the lesions and injuries was significantly lower than that of vehicle (10% Tween 80) treated rats. Significant and excellent results were obtained with the compound 6 group, with inhibition percentage and ulcer area values of 97.8% and 12.8 ± 1.1 mm2, respectively. Synthesized compounds 2, 7 and 8 exhibited inhibition percentages and ulcer areas of 94.3% and 31.2 ± 1.1 mm2, 91. 3% and 48.1 ± 0. 8 mm2, 89. 5% and 57. 6 ± 1. 2 mm2, and 89. 1% and 60.3 ± 0. 8 mm2, respectively. These biological outcomes are consistent with the docking studies in which Compounds 7 and 8 showed remarkable binding site affinities toward human H+/K+-ATPase α protein (ID: P20648), rat H+/K+-ATPase α protein (ID: P09626), and Na+/K+-ATPase crystal structure (PDB ID:2ZXE) with binding site energies of - 10.7, - 9.0, and - 10.4 (kcal/mol) and - 8.7, - 8.5, and - 8.0 (kcal/mol), respectively. These results indicate that these test samples were as effective as esomeprazole. Likewise, immunohistochemical staining of antiapoptotic (BCL2) and tumor suppressor (P53) proteins showed strong positive marks in the10% Tween 80- treated group, opposing the mild staining results for the esomeprazole-treated group. Similarly, the staining intensity of the group treated with Compounds 2-8 was variable for both proteins.

3,5-Disubstituted-thiazolidine-2,4-dione hybrids as antidiabetic agents: Design, synthesis, in-vitro and In vivo evaluation.

Diabetes is one of the fastest-growing metabolic disorders, nearly doubling the number of patients each year. There are different treatment approaches available for the management of diabetes, which lacks due to their side effects. The inhibition of enzymes involved in the metabolism of complex polysaccharides to monosaccharides has proven beneficial in patients with type 2 diabetes mellitus. Two enzymes, α-amylase and α-glucosidase, have emerged as potential drug targets and are widely explored for drug development against type 2 diabetes mellitus. In this context, thiazolidine-2,4-diones (TZDs) have emerged as potential drug candidates for developing newer molecules against α-amylase and α-glucosidase. Nineteen TZD-hybrids were synthesized and evaluated in vitro α-amylase and α-glucosidase inhibitory activity. The compounds 7i, 7k, and 7p have emerged as the best dual inhibitors with IC50 of 10.33 ± 0.11-20.94 ± 0.76 µM and 10.19 ± 0.25-24.07 ± 1.56 µM against α-glucosidase and α-amylase, respectively. The derivatives had good anti-oxidant activity, displaying IC50 = 14.95 ± 0.65-23.27 ± 0.99 µM. The compounds 7k and 7p showed the best inhibition of reactive oxygen species in the PNAC-1 cells. The molecules exhibit good binding within the active site of α-amylase (PDB id: 1B2Y) and α-glucosidase (PDB id: 3W37), displaying binding energies of -7.5 to -10.7 kcal/mol and -7.4 to -10.3 kcal/mol, respectively. Further, the compounds were nontoxic (LD50 = 500-1311 mg/kg) and possessed good GI absorption. The compounds 7i, 7k, and 7p were evaluated in vivo antidiabetic activity in an STZ-induced diabetic model in Wistar rats. The compound 7p emerged as the best compound in the in vivo studies; however, the activity was lesser than that of the standard drug pioglitazone.

Indole clubbed 2,4-thiazolidinedione linked 1,2,3-triazole as a potent antimalarial and antibacterial agent against drug-resistant strain and molecular modeling studies.

In the face of escalating challenges of microbial resistance strains, this study describes the design and synthesis of 5-({1-[(1H-1,2,3-triazol-4-yl)methyl]-1H-indol-3-yl}methylene)thiazolidine-2,4-dione derivatives, which have demonstrated significant antimicrobial properties. Compared with the minimum inhibitory concentrations (MIC) values of ciprofloxacin on the respective strains, compounds 5a, 5d, 5g, 5l, and 5m exhibited potent antibacterial activity with MIC values ranging from 16 to 25 µM. Almost all the synthesized compounds showed lower MIC compared to standards against vancomycin-resistant enterococcus and methicillin-resistant Staphylococcus aureus strains. Additionally, the majority of the synthesized compounds demonstrated remarkable antifungal activity, against Candida albicans and Aspergillus niger, as compared to nystatin, griseofulvin, and fluconazole. Furthermore, the majority of compounds exhibited notable inhibitory effects against the Plasmodium falciparum strain, having IC50 values ranging from 1.31 to 2.79 µM as compared to standard quinine (2.71 µM). Cytotoxicity evaluation of compounds 5a-q on SHSY-5Y cells at up to 100 µg/mL showed no adverse effects. Comparison with control groups highlights their noncytotoxic characteristics. Molecular docking confirmed compound binding to target active sites, with stable protein-ligand complexes displaying drug-like molecules. Molecular dynamics simulations revealed dynamic stability and interactions. Rigorous tests and molecular modeling unveil the effectiveness of the compounds against drug-resistant microbes, providing hope for new antimicrobial compounds with potential safety.

Factors and economic burden of non-severe hypoglycemia among insulin-treated type 2 diabetes patients: a cross-sectional study.

OBJECTIVE: This cross-sectional survey was performed to assess the prevalence, factors, and economic burden of non-severe hypoglycemia among insulin-treated type 2 diabetes (T2D) patients in northern Thailand. METHODS: Between April 2021 and August 2022, 600 participants were evaluated via structured questionnaires containing sociodemographic and clinical characteristics, medications, and economic burden. Patients were divided into two groups (having and not having non-severe hypoglycemia). Variables with a p value <.05 in the univariate model were included in the multivariate model. RESULTS: The percentage of non-severe hypoglycemia was 50.3% (302/600). Of all participants, the average age was 61.4 ± 26.0 years, 55.7% were female, 53.5% used premix insulin, and the average duration of diabetes was 16.1 ± 10.0 years. Multivariate logistic regression analysis indicated that age (OR = .96; p <.001), duration of diabetes (OR = 1.04; p <.001), BMI (OR = .95; p = .002), thiazolidinedione (OR = 1.56; p = .012) and insulin regimens were associated with having non-severe hypoglycemia. Compared to basal insulin, basal bolus (OR = 6.93; p = .001), basal plus (OR = 3.58; p <.001), and premix insulin (OR = 1.83; p =.003) were associated with hypoglycemia. Greater numbers of sick leave were found in the hypoglycemia group (14 vs 4 patients, p = .029). CONCLUSIONS: These findings help to individuate those patients who are at higher risk of non-severe hypoglycemia in insulin-treated T2D patients. Compared to the non-hypoglycemia group, patients with hypoglycemia were younger, had longer diabetes duration, lower BMI, received thiazolidinedione and insulin regimens such as premix, basal plus, or basal bolus insulins, and more productivity loss.

Thiazolidinedione enhances the efficacy of anti-PD-1 monoclonal antibody in murine melanoma.

Several clinical studies observed a surprising beneficial effect of obesity on enhancing immunotherapy responsiveness in patients with melanoma, highlighting an as-yet insufficiently understood relationship between metabolism and immunogenicity. Here, we demonstrate that the thiazolidinedione (TZD) rosiglitazone, a drug commonly used to treat diabetes by sequestering fatty acids in metabolically inert subcutaneous adipose tissue, improved sensitivity to anti-programmed cell death protein 1 (PD-1) treatment in YUMMER1.7 tumor-bearing mice, an initially immunotherapy-sensitive murine melanoma model. We observed a transition from high to intermediate PD-1 expression in tumor-infiltrating CD8+ T cells. Moreover, TZD inhibited PD-1 expression in mouse and human T cells treated in vitro. In addition to its direct impact on immune cells, TZD also decreased circulating insulin concentrations, while insulin induced T cell exhaustion in culture. In TZD-treated mice, we observed higher fatty acid concentrations in the tumor microenvironment, with fatty acids protecting against exhaustion in culture. Together, these data are consistent with an indirect mechanism of TZD inhibiting T cell exhaustion. Finally, we analyzed imaging data from patients with melanoma before and after anti-PD-1 treatment, confirming the beneficial effect of increased subcutaneous fat on anti-PD-1 responsiveness in patients. We also found that the expression of peroxisome proliferator-activated receptor gamma (PPARγ), the canonical activator of lipid uptake and adipogenesis activated by TZD, correlated with overall survival time. Taken together, these data identify a new adjuvant to enhance immunotherapy efficacy in YUMMER1.7 melanoma mice, and discover a new metabolism-based prognostic marker in human melanoma.NEW & NOTEWORTHY Zhang et al. demonstrate that the diabetes drug rosiglitazone improves the efficacy of immunotherapy in mouse melanoma. This effect is both direct and indirect: TZD directly reduces PD-1 expression in CD8+ T cells (i.e., reduces exhaustion), and indirectly reduces exhaustion by lowering insulin levels and increasing local fat. Finally, they demonstrate that hallmarks of TZD action (such as PPARγ expression and subcutaneous fat content) correlate with improved immunotherapy efficacy in humans with melanoma.

Diabetes, antidiabetic medications and risk of dementia: A systematic umbrella review and meta-analysis.

AIMS: The objective of this umbrella review and meta-analysis was to evaluate the effect of diabetes on risk of dementia, as well as the mitigating effect of antidiabetic treatments. MATERIALS AND METHODS: We conducted a systematic umbrella review on diabetes and its treatment, and a meta-analysis focusing on treatment. We searched MEDLINE/PubMed, Embase, PsycINFO, CINAHL and the Cochrane Library for systematic reviews and meta-analyses assessing the risk of cognitive decline/dementia in individuals with diabetes until 2 July 2023. We conducted random-effects meta-analyses to obtain risk ratios and 95% confidence intervals estimating the association of metformin, thiazolidinediones, pioglitazone, dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors, meglitinides, insulin, sulphonylureas, glucagon-like peptide-1 receptor agonists (GLP1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) with risk of dementia from cohort/case-control studies. The subgroups analysed included country and world region. Risk of bias was assessed with the AMSTAR tool and Newcastle-Ottawa Scale. RESULTS: We included 100 reviews and 27 cohort/case-control studies (N = 3 046 661). Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with significant reduction in risk of dementia. When studies examining metformin were divided by country, the only significant effect was for the United States. Moreover, the effect of metformin was significant in Western but not Eastern populations. No significant effect was observed for dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors, or insulin, while meglitinides and sulphonylureas were associated with increased risk. CONCLUSIONS: Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with reduced risk of dementia. More longitudinal studies aimed at determining their relative benefit in different populations should be conducted.

New thiophene-1,3,4-oxadiazole-thiazolidine-2,4-dione hybrids: Synthesis, MCF-7 inhibition and binding studies.

Two synthetic methods were proposed for the preparation of a new series of thiophene-1,3,4-oxadiazole-thiazolidine-2,4-dione hybrids (TOT-1 to 15) and their structures were elucidated based on spectral data. Studies on cytotoxicity, ROS, cellular uptake and interactions of TOT-14 with calf thymus DNA were carried out. Anticancer activity of compounds, TOT-1 to 15 on breast cancer (MCF-7) cell lines was investigated. The IC50 values for the standard, epirubicin hydrochloride and TOT-12, 13, 14 and 15 were found to be 6.78, 5.52, 6.53, 4.83 and 5.57 µg/mL, respectively. Notably, TOT-14 exhibited a remarkable antiproliferative activity with a strikingly selective inhibitory effect compared to standard. This specific selectivity could be attributed to the synergistic effect of increased cellular uptake and generation of higher ROS in cancer cells after irradiation. The binding constant of 4.25 x 103 M-1 indicated the moderate interaction between TOT-14 and ct-DNA. The docking score of TOT derivativeswas substantially identical to the docking score of epirubicin hydrochloride. The designed molecules complied with the requirements for drug-likeness and ADME.

New chromone derivatives bearing thiazolidine-2,4-dione moiety as potent PTP1B inhibitors: Synthesis and biological activity evaluation.

A series of chromone derivatives bearing thiazolidine-2,4-dione moiety (5 âˆ¼ 37) were synthesized and evaluated for their PTP1B inhibitory activity, interaction analysis and effects on insulin pathway in palmitic acid (PA)-induced HepG2 cells. The results showed that all derivatives presented potential PTP1B inhibitory activity with IC50 values of 1.40 ± 0.04 âˆ¼ 16.83 ± 0.54 µM comparing to that of positive control lithocholic acid (IC50: 9.62 ± 0.14 µM). Among them, compound 9 had the strongest PTP1B inhibitory activity with the IC50 value of 1.40 ± 0.04 µM. Inhibition kinetic study revealed that compound 9 was a reversible mixed-type inhibitor against PTP1B. CD spectra results confirmed that compound 9 changed the secondary structure of PTP1B by their interaction. Molecular docking explained the detailed binding between compound 9 and PTP1B. Compound 9 also showed 19-fold of selectivity for PTP1B over TCPTP. Moreover compound 9 could recovery PA-induced insulin resistance by increasing the phosphorylation of IRSI and AKT. CETSA results showed that compound 9 significantly increased the thermal stability of PTP1B.

Effects of different insulin sensitisers in the management of polycystic ovary syndrome: A systematic review and meta-analysis.

OBJECTIVE: Characteristic features of polycystic ovary syndrome (PCOS) include insulin resistance and an increased risk for type 2 diabetes. To promote improved insulin sensitivity, insulin sensitisers have been used in PCOS. However, direct comparisons across these agents are limited. This study compared the effects of metformin, rosiglitazone and pioglitazone in the management of PCOS to inform the 2023 International Evidence-based PCOS Guideline. DESIGN: Systematic review and meta-analysis of the literature. PATIENTS: Women with PCOS and treatment with insulin sensitisers. MEASUREMENTS: Hormonal and clinical outcomes, as well as side effects. RESULTS: Of 1660 publications identified, 13 randomised controlled trials were included. Metformin was superior in lowering weight (mean difference [MD]: -4.39, 95% confidence interval [CI]: -7.69 to -1.08 kg), body mass index (MD: -0.95, 95% CI: -1.41 to -0.49 kg/m2 ) and testosterone (MD: -0.10, 95% CI: -0.18 to -0.03 nmol/L) versus rosiglitazone, whereas there was no difference when comparing metformin to pioglitazone. Adding rosiglitazone or pioglitazone to metformin did not improve metabolic outcomes. However, rosiglitazone seemed superior to metformin in lowering lipid concentrations. CONCLUSIONS: Metformin should remain the first-line insulin sensitising treatment in adults with PCOS for the prevention and management of weight and metabolic features. The addition of thiazolidinediones appears to offer little benefit.

GIPR Agonism Enhances TZD-Induced Insulin Sensitivity in Obese IR Mice.

Recent studies have found that glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism can enhance the metabolic efficacy of glucagon-like peptide-1 receptor agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings have prompted new investigations aimed at better understanding the broad metabolic benefit of GIPR activation. Herein, we determined whether GIPR agonism favorably influenced the pharmacologic efficacy of the insulin-sensitizing thiazolidinedione (TZD) rosiglitazone in obese insulin-resistant (IR) mice. Genetic and pharmacological approaches were used to examine the role of GIPR signaling on rosiglitazone-induced weight gain, hyperphagia, and glycemic control. RNA sequencing was conducted to uncover potential mechanisms by which GIPR activation influences energy balance and insulin sensitivity. In line with previous findings, treatment with rosiglitazone induced the mRNA expression of the GIPR in white and brown fat. However, obese GIPR-null mice dosed with rosiglitazone had equivalent weight gain to that of wild-type (WT) animals. Strikingly, chronic treatment of obese IR WT animals with a long-acting GIPR agonist prevented rosiglitazone-induced weight-gain and hyperphagia, and it enhanced the insulin-sensitivity effect of this TZD. The systemic insulin sensitization was accompanied by increased glucose disposal in brown adipose tissue, which was underlined by the recruitment of metabolic and thermogenic genes. These findings suggest that GIPR agonism can counter the negative consequences of rosiglitazone treatment on body weight and adiposity, while improving its insulin-sensitizing efficacy at the same time.