Myricanol modulates PPARγ/ACSL1/SCD1 metabolic signaling pathway to promote mitochondria biogenesis and fatty acid β-oxidation in high-fat diet-induced obese mice.

Trigonelline regulates glycolysis and energy metabolism during hepatic fibrosis via Glut-1-HIF-1α axis: Focusing the interaction of macrophages and HSCs.

Objectives: The repurposing of existing drugs as anticancer agents has attracted attention in cancer drug discovery. This study aimed to examine the anticancer efficacy of rosiglitazone (RSG) against cholangiocarcinoma (CCA) and its underlying mechanisms. Methods: The effect of RSG on the viability of KKU-100 CCA cells was examined. The possible molecular targets were identified using proteomic analysis and verified by a series of cell-based assays. Furthermore, the expression of PPARγ protein in CCA tissues was also assessed. Results: RSG exhibited a cytotoxic effect against KKU-100 cells. Proteomic analysis demonstrated a significant different expression protein pattern of the 100 μM RSG-treated group compared to the control group. Significant alteration of several proteins was found, including the up-regulation of calcium-binding, cytoskeletal, and metabolic proteins, concomitant with the down-regulation of antioxidant enzymes. Detailed analyses revealed that RSG induced apoptosis in CCA cells, accompanied by increased caspase 3/7 activities, reactive oxygen species (ROS) generation, and disruption of mitochondrial function. RSG altered the expressions of annexin A1 and antioxidant enzymes, according to Western blot analysis. GW9662, a PPARγ antagonist, did not affect the viability and apoptosis of KKU-100 cells caused by RSG. Immunohistochemistry analysis revealed that PPARγ expression in CCA patients was associated with sex, but not with other common clinicopathological parameters. Its expression did not correlate with patients’ overall survival time. Conclusions: RSG induced apoptotic cell death in CCA cells, which was accompanied by increased ROS levels and impaired antioxidant defense. Its apoptosis-inducing effect is independent of PPARγ activation. These findings underscore the therapeutic potential of RSG for CCA treatment.

Alzheimer’s disease (AD) is characterized with impaired brain metabolism, cognitive impairments, neural loss, astrogliosis, and microgliosis. We hypothesized that co-administration of a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, and a histone deacetylase (HDAC) inhibitor would enhance cognitive function in an AD model. Methods: Forty adult male Wistar rats were randomly assigned into five groups (n = 8 per group): (1) Control group receiving saline, (2) AD model group (induced by i.c.v injection of Streptozocin), (3) AD + Rosiglitazone (ROSI) (4) AD+MS-275, and (5) AD + combined ROSI and MS-275 group. Cognitive functions was evaluated using the passive avoidance test and the Morris water maze (MWM). Microglial polarization was assessed by flow cytometry, and protein expression was analyzed by western blotting. Results: Data analyzed by one-way ANOVA and post hoc Tukey for (MWM) showed a significant decrease in latency to the target quadrant both in working and reference memories, and a significant increase in total time spent (TTS) in the target quadrant for reference memory in the group of STZ + ROSI + MS-275 (p < 0.000). Kruskal-Wallis H test revealed a significant increase in the M2/M1 ratio for ROSI + MS-275 + STZ group compared with the STZ + Saline group (p = 0.001). Conclusion: These findings suggest that co-administration of Rosiglitazone and MS-275 improves cognitive function in AD rats, potentially through shifting microglial polarization from the M1 to the M2 phenotype and enhancing synaptic strength via an increased mature brain-derived neurotrophic factor (BDNF)/pro-BDNF ratio.

Valproic acid (VPA), a commonly used treatment for epilepsy and psychiatric disorders, is associated with neurodevelopmental toxicity and an elevated risk of autism spectrum disorder (ASD). This study investigates the protective effects of rosiglitazone (RGZ), a peroxisome proliferator-activated receptor (PPAR) agonist, against VPA-induced neurotoxicity in zebrafish larvae. Zebrafish embryos were exposed to VPA (50, 75, 100 μM) from 0.5-h postfertilization (hpf) to 120 hpf, with or without RGZ cotreatment. VPA exposure significantly reduced locomotor activity, evidenced by decreased swimming distance and velocity, and disrupted neurotransmitter homeostasis, with elevated norepinephrine and L-glutamic acid levels. Transcriptomic analysis and qRT-PCR revealed that VPA downregulated PPAR pathway genes (ppara, pparg, pck1, and fabp1), while RGZ cotreatment partially restored locomotor activity, normalized neurotransmitter levels, and rescued PPAR pathway gene expression. These findings demonstrate that RGZ mitigates VPA-induced neurotoxicity by activating PPAR signaling, restoring metabolic balance, and improving motor function, suggesting PPAR agonists as potential therapeutic agents for VPA-induced neurotoxicity and ASD-related deficits.

Effect of the perfluorooctane sulfonamide on glucose and lipid metabolism in 3T3-L1 adipocytes and zebrafish larvae.

Background/Objectives: Rosiglitazone (RSG), a potent PPARγ agonist for type 2 diabetes mellitus (T2DM), induces adverse adipogenic effects that limit clinical use. We investigated whether emodin (1,3,8-trihydroxy-6-methylanthraquinone, EMO), a natural anthraquinone, mitigates RSG-induced complications while enhancing its insulin-sensitizing benefits in severe obesity. Methods: Male ob/ob mice with established obesity and diabetes were treated for 4 weeks with RSG (10 mg kg−1 day−1), EMO (200 or 400 mg kg−1 day−1) or their combination. Metabolic profiling, organ function, and adipose histology were analyzed. RNA sequencing and mechanistic studies (Western blot, RT-qPCR, luciferase assays) in inguinal subcutaneous adipose tissue (iSAT), epididymal white adipose tissue (eWAT), and 3T3-L1 adipocytes were used to define EMO’s actions. Results: EMO co-treatment dose-dependently reduced RSG-induced weight gain, visceral adiposity (iSAT and eWAT mass, p < 0.05), and ectopic lipid deposition while ameliorating hepatorenal dysfunction. EMO synergistically enhanced RSG’s glucose-lowering effects. Mechanistically, EMO suppressed sterol regulatory element-binding protein 1 (SREBP1)-mediated lipogenesis (Srebp1, Acc, Fasn, Scd1; p < 0.05) and enhanced PPARγ-peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)-driven thermogenesis via enhanced PPARγ transactivation and nuclear translocation. Thermogenic genes (Ucp1, Ppargc1a, Cidea; p < 0.05) were upregulated, with maximal uncoupling protein 1 (UCP1) induction in iSAT at 400 mg/kg EMO. Conclusions: EMO selectively enhances RSG’s glycemic benefits while attenuating its adipogenic effects in severe obesity by dual PPARγ modulation-inhibiting adipogenic pathways while amplifying thermogenesis. This strategy mitigates RSG’s adverse effects while improving insulin sensitivity, supporting the potential of EMO as a PPARγ adjunct therapy.

Small cell lung cancer (SCLC) has a dismal prognosis with a low 2-year survival rate. Chemotherapy for recurrent SCLC fails invariably, and novel tumor targets are needed. Here, the effects of agents targeting the peroxisome proliferator-activated receptors (PPARs) in SCLC are investigated. Initial screening of 96 PPAR-directed agents was performed in two SCLC CTC-derived lines (BHGc10, BHGc16). Compounds showing high cytotoxicity were subsequently tested in two pleural effusion-derived lines (S457, S1392) and the SCLC line NCI-H69. Several PPARs emerged as actionable targets: eight PPARγ ligands and nine ligands for PPARα, PPARα/δ, or PPARβ/δ. For the six most effective compounds, treatment-induced protein changes were further profiled in BHGc16 using protein arrays. Cytotoxicity varied by compound, while the PPARγ agonist pioglitazone and the PPARα agonist fenofibrate were preferentially active in CTC lines, DG172 hydrochloride was selective for pleural effusion-derived lines, while rosiglitazone maleate, cloxiquine, and agrimol B showed no selectivity. Mechanistically, in the CTC-derived cell line BHGc16, these six PPAR-directed agents increased pro-apoptotic proteins (Bax, Bad, caspase-3/9), decreased anti-apoptotic and invasion proteins (Bcl-2, Bcl-XL, c-FLIP-L, ICAM-1, CXCR4), and suppressed Akt/mTOR, MEK/ERK, p38 MAPK, and JAK2/STAT3 signaling. These findings support PPARs as clinically relevant targets in SCLC, with PPAR-directed agents showing cytotoxic effects comparable to those reported in other malignancies. Such agents may aid SCLC treatment and help delineate biological differences between CTCs and resident tumor cells.

Modulation of PM20D1 expression by rosiglitazone confers neuroprotection in tramadol-induced Parkinsonian rats

Two advanced metabolomics-based data processing approaches for comprehensive drug metabolite identification using high-resolution mass spectrometry.

This study aimed to elucidate the role of peroxisome proliferator-activated receptor-γ (PPAR-γ) in regulating macrophage efferocytosis during the pathogenesis of chronic apical periodontitis (CAP). Clinical specimens, rat periapical lesion models, and an in vitro model simulating the CAP inflammatory milieu were employed to examine the contribution of PPAR-γ to efferocytosis throughout disease progression. The expression of PPAR-γ in vivo was assessed by single-cell RNA sequencing and immunohistochemical (IHC) staining. Pearson’s correlation and linear trend tests were conducted to investigate the association between PPAR-γ and macrophage efferocytosis during CAP progression. Pharmacological modulation of PPAR-γ was further conducted using rosiglitazone (RSG) as an agonist and GW9662 as an antagonist, followed by an assessment of efferocytosis-related parameters and inflammatory responses. Both clinical specimens and animal models demonstrated a progressive reduction in PPAR-γ expression and macrophage efferocytosis during CAP. Notably, PPAR-γ attenuated efferocytosis impairment and significantly reduced pathogen-induced inflammatory responses in macrophages. These findings indicate that defective macrophage efferocytosis contributes to the exacerbation of CAP severity, whereas targeting PPAR-γ may represent a promising therapeutic strategy to alleviate inflammation in periapical lesions by restoring efferocytic capacity. Collectively, this study highlights PPAR-γ as a potential therapeutic target warranting further investigation in CAP treatment.

Valproic acid (VPA) is a commonly prescribed antiepileptic drug, with hepatotoxicity being one of its most frequent and severe adverse effects. The underlying mechanisms of VPA-induced hepatotoxicity remain elusive. Thus, this study aimed to investigate the involvement of ferroptosis in VPA-induced hepatotoxicity in vivo and in vitro. C57BL/6 J mice and HepG2 cells were treated with VPA to establish VPA-induced hepatotoxic models. The results demonstrated that VPA not only induced hepatic steatosis but also elevated liver biochemical and oxidative stress indicators, suggesting that VPA-induced hepatotoxicity affects hepatic iron metabolism. Moreover, VPA treatment altered the expression of ferroptosis-related proteins and lipid peroxides, indicating that ferroptosis contributed to VPA-induced hepatotoxicity. To investigate the role of ACSL4, a pivotal enzyme in lipid peroxidation during ferroptosis, in VPA-induced hepatotoxicity, a study was conducted utilizing rosiglitazone (RSG), a specific inhibitor of ACSL4, to interfere with the overexpression of ACSL4 in a model mouse system. Furthermore, an in vitro approach was employed, where ACSL4 siRNA was utilized to knock down ACSL4 expression in a cellular model of VPA-induced hepatotoxicity. This dual-pronged strategy aimed at elucidating the mechanistic contributions of ACSL4 in mediating the deleterious effects of VPA on the liver. In summary, ferroptosis emerges as a novel mechanism underlying VPA-induced hepatotoxicity, and ACSL4 may serve as a crucial target in the process of VPA-induced liver injury. This study has the potential to lay the groundwork for the development of novel therapeutic strategies for treating VPA-induced liver damage.

ABSTRACTPeroxisome proliferator‐activated receptor gamma (PPARγ) is a critical therapeutic target for metabolic disorders like non‐alcoholic fatty liver disease (NAFLD). However, PPARγ full agonists such as rosiglitazone (ROSI) exhibit limited efficacy and off‐target effects. Intriguingly, transcriptomic analyses revealed dynamic PPARγ expression during NAFLD progression—compensatory upregulation in early stages and downregulation in advanced disease—highlighting the need for novel modulators. This study investigates the therapeutic potential of stachyose (STA), a natural bioactive compound, in NAFLD and its mechanism of action via PPARγ modulation. Using structure‐based virtual screening of 4531 natural compounds, STA was identified as a PPARγ‐targeted ligand, validated by surface plasmon resonance and molecular docking. Network pharmacology and functional enrichment analyses elucidated STA's multi‐target effects. In vitro and in vivo models assessed STA's impacts on lipid metabolism, inflammation, and insulin resistance. Molecular dynamics simulations and post‐translational modification studies clarified STA‐PPARγ interactions. STA outperformed ROSI in mitigating hepatic lipid accumulation, inflammation, and insulin resistance in both models. STA bound stably to PPARγ via residues GLU259, GLY284, PHE287, ILE341, and LEU270, with reduced PPARγ acetylation mediated by SIRT1 activation. Unlike ROSI, STA preserved PPARγ activity without inhibiting phosphorylation at Ser273, suggesting a distinct mechanism of action. STA emerges as a partial PPARγ agonist with superior efficacy and safety profiles compared to ROSI. Its dual role in enhancing fatty acid oxidation and suppressing lipogenesis, coupled with SIRT1‐dependent deacetylation of PPARγ, positions STA as a promising candidate for NAFLD therapy. This study provides a mechanistic foundation for developing PPARγ‐targeted interventions with reduced side effects.

PPARγ activation reduces pancreatic beta cell death in type 1 diabetes by decreasing heparanase-dependent insulitis.

Background: Enhancing adipose tissue functionality is a promising cellular-level approach to combating obesity. White adipose tissue (WAT) can acquire beige or brown adipose tissue (BAT)-like properties, characterized by increased thermogenesis and energy dissipation. While the SIRT1-SRSF10–Lipin-1 axis has been identified in hepatocytes, where Lipin-1 regulates triglyceride metabolism, its role in adipocytes remains unclear. This study aimed to investigate the function of Lipin-1 in 3T3-L1 preadipocytes and its interaction with SIRT1, SRSF10, and PPARγ in promoting browning-like transcriptional responses. Methods: Mouse 3T3-L1 preadipocytes were treated during differentiation with either rosiglitazone (RGZ), the SIRT1 activator SRT1720, or the SIRT1 inhibitor EX527. Gene expression was assessed by real-time PCR, and protein levels were measured using the Simple Western blot system. Data were compared with untreated controls and analyzed using GraphPad Prism. Results: Lipin-1 expression was significantly upregulated by RGZ treatment, alongside increased transcription of Sirt1 and Srsf10, supporting the presence of this regulatory axis in adipocytes. Elevated Srsf10 favored the production of the Lipin-1b isoform, whereas SIRT1 inhibition reversed these effects, confirming its upstream role. Pathway activation further enhanced the expression of browning markers, including Ucp1, Pgc1a, PRDM16, and CIDEA. Conclusions: These findings demonstrate that Lipin-1 interacts with the SIRT1–PPARγ–SRSF10 axis in adipocytes and contributes to the acquisition of beige/brown-like characteristics in WAT. This regulatory pathway may represent a potential target for improving lipid metabolism and metabolic health.

Hepatic fibrosis is a progressive liver disease characterized by excessive accumulation of extracellular matrix (ECM) proteins, primarily collagen, in response to chronic liver injury. Despite the availability of treatment options, current therapies face significant challenges, including poor drug targeting and systemic toxicity. In this study, we developed a nanodrug delivery system, Rosiglitazone (RGZ)-loaded perfluoropropane (PFP)-based lipid nanoparticles (LNPs) functionalized with Arg-Gly-Asp (RGD) peptides (RGZ/PFP@LNP-RGD), for ultrasound-assisted targeted therapy of liver fibrosis. RGZ, a selective PPARγ agonist, was encapsulated in LNPs functionalized with RGD peptides, allowing for targeted delivery to activated hepatic stellate cells (aHSCs), the central cells involved in fibrosis progression. PFP, incorporated into the nanoparticle core, serves as an ultrasound-responsive agent, enabling controlled drug release upon ultrasound irradiation. In vitro, RGZ/PFP@LNP-RGD treatment led to a reduction in the expression of key fibrosis markers such as Col Iα1, α-SMA, and TGF-β1 at both the protein and mRNA levels. Ultrasound treatment further enhanced RGZ release from the nanocarriers, improving the inhibition of HSC activation. In vivo, RGZ/PFP@LNP-RGD combined with ultrasound treatment resulted in a marked reduction in liver fibrosis and improved liver function compared to free RGZ treatment. Histological and biochemical assessments confirmed reduced fibrosis marker expression and liver damage. These results suggest that RGZ/PFP@LNP-RGD, especially when combined with ultrasound, offers a promising noninvasive therapeutic strategy for liver fibrosis, with enhanced targeting, controlled drug release, and reduced systemic toxicity.

Placenta-targeting nano-drugs have emerged as a safe and effective treatment option for preeclampsia (PE). Downregulation of peroxisome proliferator-activated receptor γ (PPARγ) induces dysfunctional placental trophoblasts and facilitates placental reactive oxygen species, which weakens the PGC1α/UCP2 oxidative stress pathway, causing PE symptoms. Herein, rosiglitazone (RGZ), as an effective PPARγ agonist, exhibited great potential in PE treatment. However, low solubility and nonspecific effect limit the clinical application. Therefore, this study presents CGKRK-modified and RGZ-loaded lipid nanoparticles (CRNPs), based on the specific binding of CGKRK to calreticulin highly expressed in human and mouse trophoblasts. CRNP alleviates excessive oxidative stress and improves placental development and fetal growth in L-NAME-induced PE mice. However, it does not cause maternal side effects or fetal malformation in pregnant mice injected with a high dose of CRNP through the tail vein. Consequently, the safe and effective delivery of CRNP optimizes the placental-targeting therapeutic strategy.

This research aimed to enhance patient satisfaction by improving the absorption and effectiveness of Rosiglitazone Maleate. Floating tablets were developed using a raft-forming method. Compatibility assessments, including physical observation and FTIR analysis, confirmed minimal drug-polymer interaction. Nine formulations were prepared using varying ratios of HPMC K15M, Guar gum, Chitosan, sodium bicarbonate (effervescent agent), sodium alginate (viscous gel-forming agent), and MCC (diluent). The tablets were evaluated for weight variation (345.09 mg - 352.72 mg), hardness (&lt; 5 kg/cm2), thickness (3.0 - 3.8 mm), friability, drug content uniformity, floating lag time, and in vitro drug release. All formulations exhibited favorable floating properties. Formulation F7 demonstrated 91.68% drug release over twelve hours. Sodium bicarbonate and sodium alginate primarily influenced buoyancy lag time, while HPMC K15M and Guar gum significantly affected drug release. These findings suggest that raft-forming Rosiglitazone Maleate tablets offer a promising approach to improve drug absorption, effectiveness, and patient satisfaction.

Liver regeneration is critical for maintaining whole‐body homeostasis, especially under exposure to deadly chemical toxins. Understanding the molecular mechanisms underlying liver repair is critical for the development of intervention strategies to treat liver diseases. In this study, ubiquitin‐specific Proteases 42 (USP42) is identified as a novel deubiquitinases (DUB) of peroxisome proliferators‐activated receptor γ (PPARγ) in hepatocytes. This DUB interacted, deubiquitinated, and stabilized PPARγ, and increased PPARγ targeted proliferative and antioxidative gene expressions, which protects the liver from carbon tetrachloride (CCL4) induced oxidative injury and promotes liver regeneration. In addition, fibroblast growth factor 2 (FGF2) initiated USP42 expression and enhanced the interaction between USP42 and PPARγ during the liver regeneration process. Moreover, the PPARγ full agonist, rosiglitazone (RSG), possesses the ability to further reinforce the USP42‐PPARγ interplay, which enlightens to construct of an extracellular vesicle‐based targeting strategy to activate the liver USP42‐PPARγ axis and promote liver regeneration. In summary, the work uncovers the importance of USP42‐PPARγ axis‐mediated liver tissue homeostasis and provides a promising regimen to target this protein‐protein interplay for liver regeneration.

BackgroundMicroenvironmental alterations induce significant genetic and epigenetic changes in stem cells. Mitochondria, essential for regenerative capabilities, provide the necessary energy for stem cell function. However, the specific roles of histone modifications and mitochondrial dynamics in human adipose-derived stem cells (ASCs) during morphological transformations remain poorly understood. In this study, we aim to elucidate the mechanisms by which ASC sphere formation enhances mitochondrial function, delivery, and rescue efficiency.MethodsASCs were cultured on chitosan nano-deposited surfaces to form 3D spheres. Mitochondrial activity and ATP production were assessed using MitoTracker staining, Seahorse XF analysis, and ATP luminescence assays. Single-cell RNA sequencing, followed by Ingenuity Pathway Analysis (IPA), was conducted to uncover key regulatory pathways, which were validated through molecular techniques. Pathway involvement was confirmed using epigenetic inhibitors or PPARγ-modulating drugs. Mitochondrial structural integrity and delivery efficiency were evaluated after isolation.ResultsChitosan-induced ASC spheres exhibited unique compact mitochondrial morphology, characterized by condensed cristae, enhanced mitochondrial activity, and increased ATP production through oxidative phosphorylation. High expressions of mitochondrial complex I genes and elevated levels of mitochondrial complex proteins were observed without an increase in reactive oxygen species (ROS). Epigenetic modification of H3K27me3 and PPARγ involvement were discovered and confirmed by inhibiting H3K27me3 with the specific EZH2 inhibitor GSK126 and by adding the PPARγ agonist Rosiglitazone (RSG). Isolated mitochondria from ASC spheres showed improved structural stability and delivery efficiency, suppressed the of inflammatory cytokines in LPS- and TNFα-induced inflamed cells, and rescued cells from damage, thereby enhancing function and promoting recovery.ConclusionEnhancing mitochondrial ATP production via the EZH2-H3K27me3-PPARγ pathway offers an alternative strategy to conventional cell-based therapies. High-functional mitochondria and delivery efficiency show significant potential for regenerative medicine applications.