Metabolic dysfunction-associated steatotic liver disease (MASLD) is clinically heterogeneous. Patients with similar body mass index, waist circumference, or noninvasive fibrosis stratum may differ markedly in histologic activity, fibrosis trajectory, and progression risk. Adipose tissue dysfunction helps explain this variation. Adipose dysfunction has been characterized by direct depot quantification, measurement of subcutaneous adipose tissue fibrogenesis, adipose tissue insulin resistance, and circulating adipokine profiles. These measures capture different features of adipose biology and have each been linked to liver injury or fibrosis severity. Clinically recognizable body-composition phenotypes-lean MASLD, sarcopenic visceral obesity, myosteatosis, and the hypertriglyceridemic waist-differ in accessibility, mechanistic specificity, and prognostic value. Recent therapeutic developments in metabolic dysfunction-associated steatohepatitis (MASH), including resmetirom, semaglutide, tirzepatide, fibroblast growth factor 21 (FGF21) analogs, and older adipose-directed agents such as pioglitazone, illustrate the importance of distinguishing adipose-mediated, weight-mediated, and liver-directed mechanisms. This review summarizes the literature on adipose tissue dysfunction in MASLD, the body-composition phenotypes associated with it, and recent therapeutic data in the context of adipose-liver-muscle biology.

Objective The study assessed the bioequivalence of a fixed-dose combination (FDC) of dapagliflozin 10 mg/pioglitazone 15 mg co-administered with the reference products Forxiga® 10 mg: AstraZeneca Pharmaceuticals LP, Indiana, USA and Pioglit® 15 mg: Sun Pharma Laboratories Ltd., Assam, India in healthy adult participants under fasting conditions. Materials and methods A randomized, open-label, single-dose, two-period, crossover design was used in the study. Eligible participants were randomly assigned to receive either the test FDC or the respective reference products during the first period, followed by the administration of the alternate treatment after a 7-day washout interval. The primary pharmacokinetic parameters included maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to last measurable concentration (AUC0-t), while secondary parameters were area under the curve extrapolated to infinity (AUC0-∞), time to reach maximum plasma concentration (Tmax), and elimination half-life (t½). Results Forty-two healthy male volunteers were randomized; 39 completed both study periods. For dapagliflozin, the geometric mean of the test-to-reference ratios were 94.22% for Cmax (90% CI: 86.54%-102.58%) and 98.04% for AUC0-t (90% CI: 96.01%-100.11%). For pioglitazone, the corresponding values were 102.35% for Cmax (90% CI: 88.12%-118.87%) and 107.39% for AUC0-t (90% CI: 92.97%-124.05%). All results were within the acceptable bioequivalence range of 80.00-125.00%. Two mild adverse events were observed, with no serious or clinically significant safety issues reported. Conclusion The FDC of dapagliflozin and pioglitazone was bioequivalent to the individual reference products in fasting, healthy male subjects and was well-tolerated.

Diabetes mellitus (DM) remains a major global health challenge, highlighting the need for safer and more effective antidiabetic therapies. In the present study, a series of acetyl pyrrolidine-2-carbonitrile-based benzylidene-thiazolidine-2,4-dione hybrids (5a-5i) were designed, synthesized and structurally characterized using standard spectroscopic techniques. The synthesized compounds were evaluated for their in vitro antidiabetic potential through α-amylase and α-glucosidase inhibition assays. Among the series, compounds 5c and 5i demonstrated the most promising inhibitory activity with IC50 values of 32.62 ± 1.72 and 34.35 ± 1.63 μg mL[-1] against α-amylase and 23.79 ± 1.76 and 24.87 ± 1.09 μg mL[-1] against α-glucosidase, respectively. In addition, both compounds showed significant dose-dependent activation of PPAR-γ suggesting their potential to improve insulin sensitivity. Molecular docking studies revealed favourable binding interactions of 5c and 5i with key active-site residues of PPAR-γ, including TYR473, HIS323 and SER289, which was further supported by molecular dynamics simulations demonstrating stable protein-ligand complexes throughout the simulation period. DFT studies also indicated lower HOMO-LUMO energy gaps for the active compounds compared to pioglitazone, suggesting enhanced electronic reactivity and interaction potential. The in vivo antidiabetic activity was further confirmed in streptozotocin-induced diabetic Wistar rats, where compound 5c significantly improved glucose tolerance and reduced blood glucose levels from 256.3 mg dL[-1] in the diabetic control group to 142 mg dL[-1] at 120 min. Furthermore, treatment improved lipid profiles, antioxidant status and preserved pancreatic architecture. Together, these findings provide a strong basis for further optimization of thiazolidinedione-based hybrids as potential next-generation antidiabetic agents.

Neurodegenerative diseases' treatments still represent one of the major unmet medical needs, and their related clinical trials are characterized by one of the highest failure rates. Despite the promising preclinical premises, pioglitazone lies among those drugs that failed clinical translation. It is an antidiabetic drug acting as a PPARγ agonist and later repurposed as a competitive and selective MAO-B inhibitor featuring polyhedral neuroprotective properties. In pursuing our efforts to broaden the therapeutic potential of pioglitazone toward the neurodegenerative context, we herein developed and preliminarily characterized a new series of glitazone derivatives. Particularly, by means of different connectors, a disulfide covalent warhead was attached to the 5-benzylthiazolidine-2,4-dione head to potentially engage cysteines located in MAO-B and PPARγ binding sites and turn pioglitazone into a prolonged-acting modulator. Interestingly, compound 5 emerged as a selective competitive MAO-B inhibitor and a PPARγ agonist with a very slow dissociation rate, revealing long-lasting target engagement, albeit exhibiting lower potencies with respect to pioglitazone. This peculiar biological profile resulted in promising antioxidant and anti-inflammatory properties, laying the ground for future development of covalent pioglitazone derivatives.

Aortic dissection (AD) is a catastrophic cardiovascular syndrome with an in-hospital mortality of more than 90%. We previously identified oxidative inactivation of sarcoplasmic/endoplasmic reticulum Ca[2+]-ATPase 2 (SERCA2) at cysteine 674 (C674) as a driver of aortic smooth muscle cell (ASMC) phenotypic switching. However, its causal impact on autophagic flux and AD remains unresolved. SERCA2 C674S mutant knock-in (SKI) mice, human AD specimens, and primary ASMCs were subjected to quantitative proteomics, histopathology, and autophagy flux assays. Interventions included Ca[2+] chelation (BAPTA-AM), endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyrate, mammalian target of rapamycin (mTOR) inhibitor rapamycin, redox modulator Tempol, calcineurin inhibitor cyclosporine A, peroxisome-proliferator-activated receptor γ (PPARγ) agonist pioglitazone, and SERCA2 agonist [6]-gingerol. Therapeutic efficacy was evaluated in β-aminopropionitrile (BAPN)-induced AD. Human AD specimens and SKI aortas displayed suppressed autophagy within the tunica media. SERCA2 dysfunction activated PI3K-AKT-mTOR signaling pathway, reduced TFEB and Rab7, and impaired autophagosome-lysosome fusion in ASMCs. These defects were rescued by BAPTA-AM, 4-phenylbutyrate, rapamycin, Tempol, or [6]-gingerol, but not by calcineurin or pioglitazone. In vivo, rapamycin and [6]-gingerol restored medial autophagy, suppressed ASMC synthetic phenotype, lowered AD incidence and severity, and preserved medial integrity in BAPN-treated SKI mice. In conclusion, oxidative SERCA2 inactivation evokes cytosolic Ca[2+] overload, couples ER/oxidative stress to mTOR hyper-activation, and blunts autophagic flux, thereby establishing a self-amplifying loop that precipitates AD. We define a previously unrecognized SERCA2-Ca[2+]-mTOR-autophagy axis as a guardian of aortic wall homeostasis and establish autophagy rebalancing and SERCA2 activation as mechanistically grounded therapeutic strategies against AD.