The effects of PPARγ agonists on long­termpotentiation and apoptosis in the hippocampusarea of juvenile hypothyroid rats.

The aim of the present study was to evaluate the effect of rosiglitazone (RSG) or pioglitazone (POG) on the synaptic plasticity, neuronal apoptosis, brain-derived neurotrophic factor (BDNF), and nitric oxide (NO) metabolites in the hippocampus of juvenile hypothyroid rats. The animals were divided into four groups: control; propylthiouracil (PTU), 0.05% dose in drinking water for 42 days; PTU-POG; and PTU-RSG. The POG (20 mg/kg) and the RSG (4 mg/kg) were administered by IP injection. We conducted long­term potentiation (LTP) in the cornu ammonis 1 area of the hippocampus using high­frequency stimulation of the Schaffer collateral pathway. Then, the hippocampal tissues were collected to determine BDNF and NO levels and the degree of apoptosis. PTU administration decreased the slope (10-90%) and amplitude of the fEPSPs compared to control. Injection of RSG or POG increased the slope, slope (10-90%), and amplitude of the fEPSP in the PTU­POG or PTU­RSG groups compared to the PTU group. TUNEL­positive neurons and NO metabolites in the hippocampus of the PTU group were higher than those of the control group. RSG or POG increased BDNF content in PTU-POG or PTU-RSG groups. Treatment of the rats with POG or RSG decreased apoptotic neurons and NO metabolites in the hippocampus of PTU-POG or PTU-RSG groups, respectively, compared to the PTU group. This study's results revealed that POG or RSG normalized LTP impairment, neuronal apoptosis, and improved BDNF content in the hippocampal tissue of juvenile hypothyroid rats.

Rosiglitazone and trametinib exhibit potent anti-tumor activity in a mouse model of muscle invasive bladder cancer.

Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients.

Evaluation of the protective effect of Curcuma longa and PPARγ agonist, pioglitazone on paraquat-induced lung injury in rats.

BACKGROUND: The inhalation of paraquat (PQ), one of the most widely used herbicides in the world, can result in lung injury. Curcuma longa (Cl) has long history in traditional and folk medicine for the treatment of a wide range of disorders including respiratory diseases. AIM: The aim of the present work was to evaluate the preventive effect of Cl on inhaled PQ-induced lung injury in rats. METHODS: Male Wistar rats were divided into 8 groups (n = 7), one group exposed to saline (control) and other groups exposed to PQ aerosol. Saline (PQ), Cl extract, (two doses), curcumin (Cu), pioglitazone (Pio), and the combination of Cl-L + Pio and dexamethasone (Dex) were administered during the exposure period to PQ. Total and differential white blood cell (WBC) counts, oxidant and antioxidant indicators in the bronchoalveolar lavage (BALF), interleukin (IL)-10, and tumor necrosis alpha (TNF-α) levels in the lung tissues, lung histologic lesions score, and air way responsiveness to methacholine were evaluated. RESULTS: WBC counts (Total and differential), malondialdehyde level, tracheal responsiveness (TR), IL-10, TNF-α and histopathological changes of the lung were markedly elevated but total thiol content and the activities of catalase and superoxide dismutase were decreased in the BALF in the PQ group. Both doses of Cl, Cu, Pio, Cl-L + Pio, and Dex markedly improved all measured variables in comparison with the PQ group. CONCLUSION: CI, Pio, and Cl-L + Pio improved PQ-induced lung inflammation and oxidative damage comparable with the effects of Dex.

Physiologically based pharmacokinetic modeling of CYP2C8 substrate rosiglitazone and its metabolite to predict metabolic drug-drug interaction.

Rosiglitazone is an activator of nuclear peroxisome proliferator-activated (PPAR) receptor gamma used in the treatment of type 2 diabetes mellitus. The elimination of rosiglitazone occurs mainly via metabolism, with major contribution by enzyme cytochrome P450 (CYP) 2C8. Primary routes of rosiglitazone metabolism are N-demethylation and hydroxylation. Modulation of CYP2C8 activity by co-administered drugs lead to prominent changes in the exposure of rosiglitazone and its metabolites. Here, we attempt to develop mechanistic parent-metabolite physiologically based pharmacokinetic (PBPK) model for rosiglitazone. Our goal is to predict potential drug-drug interaction (DDI) and consequent changes in metabolite N-desmethyl rosiglitazone exposure. The PBPK modeling was performed in the PKSim® software using clinical pharmacokinetics data from literature. The contribution to N-desmethyl rosiglitazone formation by CYP2C8 was delineated using vitro metabolite formation rates from recombinant enzyme system. Developed model was verified for prediction of rosiglitazone DDI potential and its metabolite exposure based on observed clinical DDI studies. Developed model exhibited good predictive performance both for rosiglitazone and N-desmethyl rosiglitazone respectively, evaluated based on commonly acceptable criteria. In conclusion, developed model helps with prediction of CYP2C8 DDI using rosiglitazone as a substrate, as well as changes in metabolite exposure. In vitro data for metabolite formation can be successfully utilized to translate to in vivo conditions.

Design, Synthesis, and Characterization of Novel Thiazolidine-2,4-Dione-Acridine Hybrids as Antitumor Agents.

This study focuses on the synthesis and structural characterization of new compounds that integrate thiazolidine-2,4-dione, acridine moiety, and an acetamide linker, aiming to leverage the synergistic effects of these pharmacophores for enhanced therapeutic potential. The newly designed molecules were efficiently synthesized through a multi-step process and subsequently transformed into their hydrochloride salts. Comprehensive spectroscopic techniques, including nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), infrared (IR) spectroscopy, and elemental analysis, were employed to determine the molecular structures of the synthesized compounds. Biological evaluations were conducted to assess the therapeutic potential of the new compounds. The influence of these derivatives on the metabolic activity of various cancer cell lines was assessed, with IC50 values determined via MTT assays. An in-depth analysis of the structure-activity relationship (SAR) revealed intriguing insights into their cytotoxic profiles. Compounds with electron-withdrawing groups generally exhibited lower IC50 values, indicating higher potency. The presence of the methoxy group at the linking phenyl ring modulated both the potency and selectivity of the compounds. The variation in the acridine core at the nitrogen atom of the thiazolidine-2,4-dione core significantly affects the activity against cancer cell lines, with the acridin-9-yl substituent enhancing the compounds' antiproliferative activity. Furthermore, compounds in their hydrochloride salt forms demonstrated better activity against cancer cell lines compared to their free base forms. Compounds 12c·2HCl (IC50 = 5.4 ± 2.4 µM), 13d (IC50 = 4.9 ± 2.9 µM), and 12f·2HCl (IC50 = 4.98 ± 2.9 µM) demonstrated excellent activity against the HCT116 cancer cell line, and compound 7d·2HCl (IC50 = 4.55 ± 0.35 µM) demonstrated excellent activity against the HeLa cancer cell line. Notably, only a few tested compounds, including 7e·2HCl (IC50 = 11.00 ± 2.2 µM), 7f (IC50 = 11.54 ± 2.06 µM), and 7f·2HCl (IC50 = 9.82 ± 1.92 µM), showed activity against pancreatic PATU cells. This type of cancer has a very high mortality due to asymptomatic early stages, the occurrence of metastases, and frequent resistance to chemotherapy. Four derivatives, namely, 7e·2HCl, 12d·2HCl, 13c·HCl, and 13d, were tested for their interaction properties with BSA using fluorescence spectroscopic studies. The values for the quenching constant (Ksv) ranged from 9.59 × 104 to 10.74 × 104 M-1, indicating a good affinity to the BSA protein.

Suppression of Ventilation-Induced Diaphragm Fibrosis through the Phosphoinositide 3-Kinase-γ in a Murine Bleomycin-Induced Acute Lung Injury Model.

Mechanical ventilation (MV), used in patients with acute lung injury (ALI), induces diaphragmatic myofiber atrophy and contractile inactivity, termed ventilator-induced diaphragm dysfunction. Phosphoinositide 3-kinase-γ (PI3K-γ) is crucial in modulating fibrogenesis during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, myofiber fibrosis, and PI3K-γ remain unclear. We hypothesized that MV with or without bleomycin treatment would increase diaphragm muscle fibrosis through the PI3K-γ pathway. Five days after receiving a single bolus of 0.075 units of bleomycin intratracheally, C57BL/6 mice were exposed to 6 or 10 mL/kg of MV for 8 h after receiving 5 mg/kg of AS605240 intraperitoneally. In wild-type mice, bleomycin exposure followed by MV 10 mL/kg prompted significant increases in disruptions of diaphragmatic myofibrillar organization, transforming growth factor-ß1, oxidative loads, Masson's trichrome staining, extracellular collagen levels, positive staining of α-smooth muscle actin, PI3K-γ expression, and myonuclear apoptosis (p < 0.05). Decreased diaphragm contractility and peroxisome proliferator-activated receptor-γ coactivator-1α levels were also observed (p < 0.05). MV-augmented bleomycin-induced diaphragm fibrosis and myonuclear apoptosis were attenuated in PI3K-γ-deficient mice and through AS605240-induced inhibition of PI3K-γ activity (p < 0.05). MV-augmented diaphragm fibrosis after bleomycin-induced ALI is partially mediated by PI3K-γ. Therapy targeting PI3K-γ may ameliorate MV-associated diaphragm fibrosis.

Effects of pioglitazone and metformin on abdominal adhesion formation in an experimental model.

BACKGROUND: This study evaluated the use of metformin or pioglitazone in preventing or reducing the development of post-operative intra-abdominal adhesion (PIAA) by employing histopathological, immunohistochemical, and biochemical analyses in an experimental adhesion model. METHODS: Fifty Wistar-Albino rats were divided into five groups: Group I (Control), Group II (Sham Treatment), Group III (Hy-aluronic Acid), Group IV (Metformin), and Group V (Pioglitazone). Adhesions were induced in the experimental groups, except for the sham group, using the scraping method. After 10 days, rats were euthanized for evaluation. Macroscopic adhesion degrees were assessed using Nair's scoring system. Immunohistochemical and enzyme-linked immunosorbent assay (ELISA) methods were utilized to assess serum, peritoneal lavage, and intestinal tissue samples. Fructosamine, interleukin-6 (IL-6), transforming growth factor-beta (TGF-ß), and fibronectin levels were measured in serum and peritoneal lavage samples. RESULTS: The groups exhibited similar Nair scores and Type I or Type III Collagen staining scores (all, p>0.05). Pioglitazone significantly reduced serum IL-6 and TGF-ß levels compared to controls (p=0.002 and p=0.008, respectively). Both metformin and pioglitazone groups showed elevated IL-6 in peritoneal lavage relative to controls, while fibronectin levels in the lavage were lower in pioglitazone-treated rats compared to the sham group (all, p<0.005). CONCLUSION: Pioglitazone, but not metformin, demonstrated a positive biochemical impact on preventing PIAA formation in an experimental rat model, although histological impacts were not observed. Further experimental studies employing different dose/duration regimens of pioglitazone are needed to enhance our understanding of its effect on PIAA formation.

Development of chromone-thiazolidine-2,4-dione Knoevenagel conjugates as apoptosis inducing agents.

Overexpression of Bcl-2 protein is a predominant hallmark of disturbed apoptotic pathway in most of the cancers. Herein, chromone-linked thiazolidinediones were designed and synthesized to target Bcl-2 for regulating anti-apoptotic proteins. The study on in vitro cancer cell lines revealed the presence of compounds 8a, 8k, 8l, and 8n, which were found to have good to moderate anti-proliferative activity (with an IC50 concentration less than 10 µM). Among them, 8l depicted the highest cytotoxicity on the A549 cell line with an IC50 of 6.1 ± 0.02 µM. Aberrantly, the compounds displayed less toxicity towards human embryonic kidney HEK cells underlining its selectivity. The DCFDA study revealed a gradual increase in the ROS generation of 8l, followed by its quantification by flow analysis. Similarly, the studies including DAPI, AO/EtBr and Annexin-V binding clearly elucidated the DNA damage, membrane integrity prospects, and insights for early and late apoptotic phases. Markedly, the Bcl-2-FITC anti-body study revealed that compound 8l reduced the expression of anti-apoptotic proteins by 79.1 % compared to the control at 9 µM concentration. In addition, the molecular docking study provided the impending scope of these hybrids, showing promising interaction with the Mcl-1 target (member of the Bcl-2 family) with comparable binding affinities.

Synthesis of thiazolidine-2,4-dione tethered 1,2,3-triazoles as α-amylase inhibitors: In vitro approach coupled with QSAR, molecular docking, molecular dynamics and ADMET studies.

A new series of thiazolidine-2,4-dione tethered 1,2,3-triazole derivatives were designed, synthesized and screened for their α-amylase inhibitory potential employing in vitro and in silico approaches. The target compounds were synthesized with the help of Cu (I) catalyzed [3 + 2] cycloaddition of terminal alkyne with numerous azides, followed by unambiguously characterizing the structure by employing various spectroscopic approaches. The synthesized derivatives were assessed for their in vitro α-amylase inhibition and it was found that thiazolidine-2,4-dione derivatives 6e, 6j, 6o, 6u and 6x exhibited comparable inhibition with the standard drug acarbose. The compound 6e with a 7-chloroquinolinyl substituent on the triazole ring exhibited significant inhibition potential with IC50 value of 0.040 µmol mL-1 whereas compound 6c (IC50 = 0.099 µmol mL-1) and 6h (IC50 = 0.098 µmol mL-1) were poor inhibitors. QSAR studies revealed the positively correlating descriptors that aid in the design of novel compounds. Molecular docking was performed to investigate the binding interactions with the active site of the biological receptor and the stability of the complex over a period of 100 ns was examined using molecular dynamics studies. The physiochemical properties and drug-likeliness behavior of the potent derivatives were investigated by carrying out the ADMET studies.

Randomized, Double-blind, Phase III Trial of Lobeglitazone Add-on to Metformin in Type 2 Diabetes (SENSITIZE INDIA).

BACKGROUND: The efficacy and safety of lobeglitazone sulfate has been reported only in the Korean population, and no study has been conducted in India. MATERIALS AND METHODS: In this 16-week randomized, double-blind, and multicenter study, the efficacy and safety of lobeglitazone sulfate 0.5 mg were evaluated with pioglitazone 15 mg. Type 2 diabetes mellitus (T2DM) patients with ≥7.5% glycated hemoglobin (HbA1c) ≤10.5% and on stable metformin dose were assigned to both treatment arms. The primary outcome was a mean change in HbA1c. Safety assessments included adverse events (AE), home-based glucose monitoring, vital parameters, electrocardiogram (ECG), and laboratory assessments. RESULTS: A total of 328 subjects were randomized equally in two groups. A statistically significant reduction in HbA1c at week 16 in the lobeglitazone group with the least square (LS) mean change: 1.01 [standard error (SE): 0.09] (p < 0.0001) was seen. The LS mean difference between the two groups was 0.05 (SE: 0.12) [95% confidence interval (CI): -0.18, 0.27], which was statistically significant (p = 0.0013). Statistically significant reductions were also observed in fasting and postprandial glucose. Treatment-emergent Aes (TEAE) were comparable between both groups. CONCLUSION: Lobeglitazone 0.5 mg once daily was found to be efficacious and safe in the treatment of T2DM in the Indian population. Lobeglitazone significantly improved glycemic parameters and was noninferior to pioglitazone; hence, it could be a promising insulin sensitizer in T2DM management in India.

Restoring adiponectin via rosiglitazone ameliorates tissue wasting in mice with lung cancer.

AIM: To investigate systemic regulators of the cancer-associated cachexia syndrome (CACS) in a pre-clinical model for lung cancer with the goal to identify therapeutic targets for tissue wasting. METHODS: Using the Kras/Lkb1 (KL) mouse model, we found that CACS is associated with white adipose tissue (WAT) dysfunction that directly affects skeletal muscle homeostasis. WAT transcriptomes showed evidence of reduced adipogenesis, and, in agreement, we found low levels of circulating adiponectin. To preserve adipogenesis and restore adiponectin levels, we treated mice with the PPAR-γ agonist, rosiglitazone. RESULTS: Rosiglitazone treatment increased serum adiponectin levels, delayed weight loss, and preserved skeletal muscle and adipose tissue mass, as compared to vehicle-treated mice. The preservation of muscle mass with rosiglitazone was associated with increases in AMPK and AKT activity. Similarly, activation of the adiponectin receptors in muscle cells increased AMPK activity, anabolic signaling, and protein synthesis. CONCLUSION: Our data suggest that PPAR-γ agonists may be a useful adjuvant therapy to preserve tissue mass in lung cancer.

Pioglitazone reduces serum ketone bodies in sodium-glucose cotransporter-2 inhibitor-treated non-obese type 2 diabetes: A single-centre, randomized, crossover trial.

AIM: To examine the effects of the thiazolidinedione (TZD) pioglitazone on reducing ketone bodies in non-obese patients with T2DM treated with the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin. METHODS: Crossover trials with two periods, each treatment period lasting 4 weeks, with a 4-week washout period, were conducted. Participants were randomly assigned in a 1:1 ratio to receive pioglitazone combined with canagliflozin (PIOG + CANA group) versus canagliflozin monotherapy (CANA group). The primary outcome was change (Δ) in ß-hydroxybutyric acid (ß-HBA) before and after the CANA or PIOG + CANA treatments. The secondary outcomes were Δchanges in serum acetoacetate and acetone, the rate of conversion into urinary ketones, and Δchanges in factors related to SGLT2 inhibitor-induced ketone body production including non-esterified fatty acids (NEFAs), glucagon, glucagon to insulin ratio, and noradrenaline (NA). Analyses were performed in accordance with the intention-to-treat principle. RESULTS: Twenty-five patients with a mean age of 49 ± 7.97 years and a body mass index of 25.35 ± 2.22 kg/m2 were included. One patient discontinued the study during the washout period. Analyses revealed a significant increase in the levels of serum ketone bodies and an elevation in the rate of conversion into urinary ketones after both interventions. However, differernces in levels of ketone bodies (except for acetoacetate) in the PIOG + CANA group were significantly smaller than in the CANA group (219.84 ± 80.21 µmol/L vs. 317.69 ± 83.07 µmol/L, p < 0.001 in ß-HBA; 8.98 ± 4.17 µmol/L vs. 12.29 ± 5.27 µmol/L, p = 0.018 in acetone). NEFA, glucagon, glucagon to insulin ratio, and NA were also significantly increased after both CANA and PIOG + CANA treatments; while only NEFAs demonstrated a significant difference between the two groups. Correlation analyses revealed a significant association between the difference in Δchanges in serum NEFA levels with the differences in Δchanges in ketones of ß-HBA and acetoacetate. CONCLUSION: Supplementation of pioglitazone could alleviate canagliflozin-induced ketone bodies. This benefit may be closely associated with decreased substrate NEFAs rather than other factors including glucagon, fasting insulin and NA.

Identification of 1,3,4-Thiadiazolyl-Containing Thiazolidine-2,4-dione Derivatives as Novel PTP1B Inhibitors with Antidiabetic Activity.

Forty-one 1,3,4-thiadiazolyl-containing thiazolidine-2,4-dione derivatives (MY1-41) were designed and synthesized as protein tyrosine phosphatase 1B (PTP1B) inhibitors with activity against diabetes mellitus (DM). All synthesized compounds (MY1-41) presented potential PTP1B inhibitory activities, with half-maximal inhibitory concentration (IC50) values ranging from 0.41 ± 0.05 to 4.68 ± 0.61 µM, compared with that of the positive control lithocholic acid (IC50 = 9.62 ± 0.14 µM). The most potent compound, MY17 (IC50 = 0.41 ± 0.05 µM), was a reversible, noncompetitive inhibitor of PTP1B. Circular dichroism spectroscopy and molecular docking were employed to analyze the binding interaction between MY17 and PTP1B. In HepG2 cells, MY17 treatment could alleviate palmitic acid (PA)-induced insulin resistance by upregulating the expression of phosphorylated insulin receptor substrate and protein kinase B. In vivo, oral administration of MY17 could reduce the fasting blood glucose level and improve glucose tolerance and dyslipidemia in mice suffering from DM.

FIB-4 as a screening and disease monitoring method in pre-fibrotic stages of metabolic dysfunction-associated fatty liver disease (MASLD).

AIMS: Guidelines emphasize screening high-risk patients for metabolic dysfunction-associated steatotic liver disease (MASLD) with a calculated FIB-4 score for therapy to reverse fibrosis. We aimed to determine whether FIB-4 can effectively screen and monitor changes in steatohepatitis (MASH). METHODS: Data were retrieved from the NIDDK-CR R4R central repository, of the CRN/PIVENS (pioglitazone vs vitamin E vs placebo) trial of adult patients without diabetes mellitus and with MASLD. RESULTS: 220 patients with MASLD had alanine transaminase (ALT), aspartate aminotransferase (AST) and platelet count, to calculate FIB-4, and repeat liver biopsies for histological MASLD activity scores (NAS). Compared to NAS score of 2, Fib-4 was higher at NAS 5) (p = 0.03), and NAS score of 6 (p = 0.02). FIB-4 correlated with cellular ballooning (r = 0.309, p < 0.001). Levels of ALT (ANOVA, p = 0.016) and AST (ANOVA p = 0.0008) were associated with NAS. NAS improved with pioglitazone by 39 %, p < 0.001 and with vitamin E by 36 %, p < 0.001. Pioglitazone and vitamin E both improved histological sub-scores for steatosis, and inflammation, without statistical changes in fibrosis grade. Changes in FIB-4 correlated with changes in NAS (r = 0.237, p < 0.001). CONCLUSIONS: In this post hoc analysis, changes in FIB-4 were associated with changes of steatohepatitis. Medication known to treat steatohepatitis, may be considered, before the onset of advanced fibrosis.

Pioglitazone-induced alterations of purine metabolism in healthy male subjects.

Pioglitazone is class of thiazolidinediones that activates peroxisome proliferator-activated receptors (PPARs) in adipocytes to improve glucose metabolism and insulin sensitivity and has been used as a treatment for type 2 diabetes. However, the underlying mechanisms of associated pioglitazone-induced effects remain unclear. Our study aimed to investigate endogenous metabolite alterations associated with pioglitazone administration in healthy male subjects using an untargeted metabolomics approach. All subjects received 30 mg of pioglitazone once daily in the assigned sequence and period. Urine samples were collected before pioglitazone administration and for 24 h after 7 days of administration. A total of 1465 compounds were detected and filtered using a coefficient of variance below 30% and 108 metabolites were significantly altered upon pioglitazone administration via multivariate statistical analysis. Fourteen significant metabolites were identified using authentic standards and public libraries. Additionally, pathway analysis revealed that metabolites from purine and beta-alanine metabolisms were significantly altered after pioglitazone administration. Further analysis of quantification of metabolites from purine metabolism, revealed that the xanthine/hypoxanthine and uric acid/xanthine ratios were significantly decreased at post-dose. Pioglitazone-dependent endogenous metabolites and metabolic ratio indicated the potential effect of pioglitazone on the activation of PPAR and fatty acid synthesis. Additional studies involving patients are required to validate these findings.

Cytotoxicity and toxicoproteomics analysis of thiazolidinedione exposure in human-derived cardiomyocytes.

Thiazolidinediones (TZDs) (e.g. pioglitazone and rosiglitazone), known insulin sensitiser agents for type II diabetes mellitus, exhibit controversial effects on cardiac tissue. Despite consensus on their association with increased heart failure risk, limiting TZD use in diabetes management, the underlying mechanisms remain uncharacterised. Herein, we report a comprehensive in vitro investigation utilising a novel toxicoproteomics pipeline coupled with cytotoxicity assays in human adult cardiomyocytes to elucidate mechanistic insights into TZD cardiotoxicity. The cytotoxicity assay findings showed a significant loss of mitochondrial adenosine triphosphate production upon exposure to either TZD agents, which may underpin TZD cardiotoxicity. Our toxicoproteomics analysis revealed that mitochondrial dysfunction primarily stems from oxidative phosphorylation impairment, with distinct signalling mechanisms observed for both agents. The type of cell death differed strikingly between the two agents, with rosiglitazone exhibiting features of caspase-dependent apoptosis and pioglitazone implicating mitochondrial-mediated necroptosis, as evidenced by the protein upregulation in the phosphoglycerate mutase family 5-dynamin-related protein 1 axis. Furthermore, our analysis revealed additional mechanistic aspects of cardiotoxicity, showcasing drug specificity. The downregulation of various proteins involved in protein machinery and protein processing in the endoplasmic reticulum was observed in rosiglitazone-treated cells, implicating proteostasis in the rosiglitazone cardiotoxicity. Regarding pioglitazone, the findings suggested the potential activation of the interplay between the complement and coagulation systems and the disruption of the cytoskeletal architecture, which was primarily mediated through the integrin-signalling pathways responsible for pioglitazone-induced myocardial contractile failure. Collectively, this study unlocks substantial mechanistic insight into TZD cardiotoxicity, providing the rationale for future optimisation of antidiabetic therapies.

Efficacy of pharmacologic interventions on magnetic resonance imaging biomarkers in patients with nonalcoholic fatty liver disease: systematic review and network meta-analysis.

BACKGROUND AND AIM: Several agents are under investigation for nonalcoholic fatty liver disease (NAFLD). We assessed the comparative efficacy of pharmacologic interventions for patients with NAFLD focusing on magnetic resonance imaging (MRI) biomarkers. METHODS: We searched Medline, Embase, and CENTRAL. We included randomized controlled trials of more than 12 weeks of intervention that recruited patients with biopsy-confirmed or MRI-confirmed NAFLD and assessed the efficacy of interventions on liver fat content (LFC) and fibrosis by means of MRI. We performed random-effects frequentist network meta-analyses and assessed confidence in our estimates using the CINeMA (Confidence in Network Meta-Analysis) approach. RESULTS: We included 47 trials (8583 patients). Versus placebo, thiazolidinediones were the most efficacious for the absolute change in LFC, followed by vitamin E, fibroblast growth factor (FGF) analogs, and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with mean differences ranging from -7.46% (95% confidence interval [-11.0, -3.9]) to -4.36% (-7.2, -1.5). No differences between drug classes were evident. Patients receiving GLP-1 RAs or glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs were more likely to achieve ≥30% relative reduction in LFC. Among agents, efruxifermin produced the largest reduction in LFC compared to placebo [-13.5% (-18.5, -8.5)], followed by pioglitazone, while being superior to most interventions. The effect of interventions on magnetic resonance elastography assessed fibrosis was small and insignificant. The confidence in our estimates was low to very low. CONCLUSIONS: Several drug classes may reduce LFC in patients with NAFLD without a significant effect on fibrosis; nevertheless, trial duration was small, and confidence in the effect estimates was low.

Insulin interacts with PPARγ agonists to promote bovine adipocyte differentiation.

Insulin is a potent adipogenic hormone that triggers a series of transcription factors that regulate the differentiation of preadipocytes into mature adipocytes. Ciglitazone specifically binds to peroxisome proliferator-activated receptor-γ (PPARγ), thereby promoting adipocyte differentiation. As a natural ligand of PPARγ, oleic acid (OA) can promote the translocation of PPARγ into the nucleus, regulate the expression of downstream genes, and promote adipocyte differentiation. We hypothesized that ciglitazone and oleic acid interact with insulin to enhance bovine preadipocyte differentiation. Preadipocytes were cultured 96 h in differentiation medium containing 10 mg/L insulin (I), 10 mg/L insulin + 10 µM cycloglitazone (IC), 10 mg/L insulin + 100 µM oleic acid (IO), or 10 mg/L insulin + 10 µM cycloglitazone+100 µM oleic acid (ICO). Control preadipocytes (CON) were cultured in differentiation medium (containing 5% fetal calf serum). The effects on the differentiation of Yanbian cattle preadipocytes were examined using molecular and transcriptomic techniques, including differentially expressed genes (DEGs) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis. I, IC, IO, and ICO treatments produced higher concentrations of triglycerides (TAG) and lipid droplet accumulation in preadipocytes compared with CON treatment (P < 0.05). Co-treatment of insulin and PPARγ agonists significantly increased the expression of genes involved in regulating adipogenesis and fatty acid synthesis. (P < 0.05). Differential expression analysis identified 1488, 1764, 1974 and 1368 DEGs in the I, IC, IO and ICO groups, respectively. KEGG pathway analysis revealed DEGs mainly enriched in PPAR signalling, FOXO signaling pathway and fatty acid metabolism. These results indicate that OA, as PPARγ agonist, can more effectively promote the expression of bovine lipogenesis genes and the content of TAG and adiponectin when working together with insulin, and stimulate the differentiation of bovine preadipocytes. These findings provide a basis for further screening of relevant genes and transcription factors in intramuscular fat deposition and meat quality to enhance breeding programs.

Management of Type 2 Diabetes Mellitus With Noninsulin Pharmacotherapy.

Type 2 diabetes mellitus is a chronic disease that is increasing in global prevalence. An individualized approach to pharmacotherapy should consider costs, benefits beyond glucose control, and adverse events. Metformin is the first-line therapy due to its low cost and effectiveness. Sulfonylureas and thiazolidinediones are additional low-cost oral hypoglycemic classes available in the United States; however, evidence shows variability in weight gain and hypoglycemia. Thiazolidinediones increase fluid retention and are not recommended in patients with New York Heart Association class III or IV heart failure. Newer medications, including glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors, have demonstrated weight loss, reduced cardiovascular events, decreased renal disease, and improved all-cause morbidity and mortality. Sodium-glucose cotransporter-2 inhibitors are recommended for people with known cardiovascular disease, heart failure, and chronic kidney disease but carry an increased risk of urinary tract and mycotic infections. Glucagon-like peptide-1 receptor agonists are contraindicated in patients with active multiple endocrine neoplasia type 2 or a personal or family history of medullary thyroid carcinoma; adverse effects include gastrointestinal upset and pancreatitis. Dipeptidyl-peptidase-4 inhibitors have a low risk of hypoglycemia but may increase the risk of pancreatitis and require a renal dose adjustment. Public and private programs to increase access to newer hypoglycemic medications are increasing; however, there are limitations to access, particularly for uninsured and underinsured people.

Factors associated with treatment responses to pioglitazone in patients with steatotic liver disease: A 3-year prospective cohort study.

AIM: The response rate to pioglitazone and the predictive factors for its effects on improving liver biochemistry in patients with steatotic liver disease (SLD) remain elusive, so we aimed to investigate these issues. METHODS: A 3-year prospective cohort study of 126 Taiwanese patients with SLD treated with pioglitazone (15-30 mg/day) was conducted. Phospholipase domain-containing protein 3 I148M rs738409, methylenetetrahydrofolate reductase rs1801133, aldehyde dehydrogenase 2 (ALDH2) rs671 and lipoprotein lipase rs10099160 single nucleotide polymorphisms were assessed in the patients. RESULTS: Of 126 patients, 78 (61.9%) were men, and the mean and median ages were 54.3 and 56.5 years, respectively. Pioglitazone responders were defined as those with decreased alanine aminotransferase (ALT) levels at 6 months post-treatment, and 105 (83.3%) patients were responders. Compared with non-responders, responders were more frequently women and had higher baseline ALT levels. The proportion of patients with the ALDH2 rs671 GG genotype was lower among responders (38.6% vs. 66.6%, p = .028). Female sex [odds ratio (OR): 4.514, p = .023] and baseline ALT level (OR: 1.015, p = .046; cut-off level: ≥82 U/L) were associated with pioglitazone response. Among responders, the liver biochemistry and homeostasis model assessment of insulin resistance improved from 6 to 24 months post-treatment. The total cholesterol levels decreased within 6 months, while increases in high-density lipoprotein cholesterol levels and decreases in triglyceride levels and fibrosis-4 scores were noted only at 24 months post-treatment. The 2-year cumulative incidences of cardiovascular events, cancers and hepatic events were similar between responders and non-responders. CONCLUSIONS: Regarding liver biochemistry, over 80% of Taiwanese patients with SLD had a pioglitazone response, which was positively associated with female sex and baseline ALT levels. Insulin resistance improved as early as 6 months post-treatment, while liver fibrosis improvement was not observed until 24 months post-treatment. The link between the pioglitazone response and the ALDH2 genotype warrants further investigation.