PPARγ Agonist Pioglitazone Prevents Hypoxia-induced Cardiac Dysfunction by Reprogramming Glucose Metabolism.

The heart relies on various defense mechanisms, including metabolic plasticity, to maintain its normal structure and function under high-altitude hypoxia. Pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ), sensitizes insulin, which in turn regulates blood glucose levels. However, its preventive effects against hypoxia-induced cardiac dysfunction at high altitudes have not been reported. In this study, pioglitazone effectively prevented cardiac dysfunction in hypoxic mice for 4 weeks, independent of its effects on insulin sensitivity. In vitro experiments demonstrated that pioglitazone enhanced the contractility of primary cardiomyocytes and reduced the risk of QT interval prolongation under hypoxic conditions. Additionally, pioglitazone promoted cardiac glucose metabolic reprogramming by increasing glycolytic capacity; enhancing glucose oxidation, electron transfer, and oxidative phosphorylation processes; and reducing mitochondrial reactive ROS production, which ultimately maintained mitochondrial membrane potential and ATP production in cardiomyocytes under hypoxic conditions. Notably, as a PPARγ agonist, pioglitazone promoted hypoxia-inducible factor 1α (HIF-1α) expression in hypoxic myocardium. Moreover, KC7F2, a HIF-1α inhibitor, disrupted the reprogramming of cardiac glucose metabolism and reduced cardiac function in pioglitazone-treated mice under hypoxic conditions. In conclusion, pioglitazone effectively prevented high-altitude hypoxia-induced cardiac dysfunction by reprogramming cardiac glucose metabolism.

Structure-based screening, optimization and biological evaluation of novel chrysin-based derivatives as selective PPARγ modulators for the treatment of T2DM and hepatic steatosis.

In consideration of several serious side effects induced by the classical AF-2 involved "lock" mechanism, recently disclosed PPARγ-Ser273 phosphorylation mode of action has become an alternative and mainstream mechanism for currently PPARγ-based drug discovery and development with an improved therapeutic index. In this study, by virtue of structure-based virtual high throughput screening (SB-VHTS), structurally chemical optimization by targeting the inhibition of the PPARγ-Ser273 phosphorylation as well as in vitro biological evaluation, which led to the final identification of a chrysin-based potential hit (YGT-31) as a novel selective PPARγ modulator with potent binding affinity and partial agonism. Further in vivo evaluation demonstrated that YGT-31 possessed potent glucose-lowering and relieved hepatic steatosis effects without involving the TZD-associated side effects. Mechanistically, YGT-31 presented such desired therapeutic index, mainly because it effectively inhibited the CDK5-mediated PPARγ-Ser273 phosphorylation, selectively elevated the level of insulin sensitivity-related Glut4 and adiponectin but decreased the expression of insulin-resistance-associated genes PTP1B and SOCS3 as well as inflammation-linked genes IL-6, IL-1ß and TNFα. Finally, the molecular docking study was also conducted to uncover an interesting hydrogen-bonding network of YGT-31 with PPARγ-Ser273 phosphorylation-related key residues Ser342 and Glu343, which not only gave a clear verification for our targeting modification but also provided a proof of concept for the abovementioned molecular mechanism.

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.

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.

Cheminformatic Read-Across Approach Revealed Ultraviolet Filter Cinoxate as an Obesogenic Peroxisome Proliferator-Activated Receptor γ Agonist.

This study introduces a novel cheminformatic read-across approach designed to identify potential environmental obesogens, substances capable of disrupting metabolism and inducing obesity by mainly influencing nuclear hormone receptors (NRs). Leveraging real-valued two-dimensional features derived from chemical fingerprints of 8435 Tox21 compounds, cluster analysis and subsequent statistical testing revealed 385 clusters enriched with compounds associated with specific NR targets. Notably, one cluster exhibited selective enrichment in peroxisome proliferator-activated receptor γ (PPARγ) agonist activity, prominently featuring methoxy cinnamate ultraviolet (UV) filters and obesogen-related compounds. Experimental validation confirmed that 2-ethoxyethyl 4-methoxycinnamate, an organic UV filter cinoxate, could selectively bind to PPARγ (Ki = 18.0 µM), eliciting an obesogenic phenotype in human bone marrow-derived mesenchymal stem cells during adipogenic differentiation. Molecular docking and further experiments identified cinoxate as a potent PPARγ full agonist, demonstrating a preference for coactivator SRC3 recruitment. Moreover, cinoxate upregulated transcription levels of genes encoding lipid metabolic enzymes in normal human epidermal keratinocytes as primary cells exposed during clinical usage. This study provides compelling evidence for the efficacy of cheminformatic read-across analysis in prioritizing potential obesogens, showcasing its utility in unveiling cinoxate as an obesogenic PPARγ agonist.

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.

Exploring the molecular mechanisms of PPARγ agonists in modulating memory impairment in neurodegenerative disorders.

Neurodegenerative diseases are characterized by progressive memory impairment and cognitive decline. This review aims to unravel the molecular mechanisms involved in the enhancement of memory function and mitigation of memory impairment through the activation of PPARγ agonists in neurodegenerative diseases. The findings suggest that PPARγ agonists modulate various molecular pathways involved in memory formation and maintenance. Activation of PPARγ enhances synaptic plasticity, promotes neuroprotection, suppresses neuroinflammation, attenuates oxidative stress, and regulates amyloid-beta metabolism. The comprehensive understanding of these molecular mechanisms would facilitate the development of novel therapeutic approaches targeting PPARγ to improve memory function and ultimately to alleviate the burden of neurodegenerative diseases. Further research, including clinical trials, is warranted to explore the efficacy, safety, and optimal use of specific PPARγ agonists as potential therapeutic agents in the treatment of memory impairments associated with neurodegenerative diseases.

Pioglitazone ameliorates sepsis-associated encephalopathy through SIRT1 signaling pathway.

Sepsis is a severe immune response to an infection. It is associated with multiple organ dysfunction syndrome (MODs) along with systemic and neuronal inflammatory response. This study focused on the acute neurologic dysfunction associated with sepsis by exploring the role of PPARγ/SIRT1 pathway against sepsis. We studied the role of this axis in ameliorating sepsis-associated encephalopathy (SAE) and its linked neurobehavioral disorders by using pioglitazone (PIO). This PPARγ agonist showed neuroprotective actions in neuroinflammatory disorders. Sepsis was induced in mice by LPS (10 mg/kg). Survival rate and MODs were assessed. Furthermore, behavioral deficits, cerebral oxidative, inflammatory, and apoptotic markers, and the cerebral expression level of SIRT1 were determined. In this study, we observed that PIO attenuated sepsis-induced cerebral injury. PIO significantly enhanced survival rate, attenuated MODs, and systemic inflammatory response in septic mice. PIO also promoted cerebral SIRT1 expression and reduced cerebral activation of microglia, oxidative stress, HMGB, iNOS, NLRP3 and caspase-3 along with an obvious improvement in behavioral deficits and cerebral pathological damage induced by LPS. Most of the neuroprotective effects of PIO were abolished by EX-527, a SIRT1 inhibitor. These results highlight that the neuroprotective effect of PIO in SAE is mainly SIRT1-dependent.

Association between genetically proxied PPARG activation and psoriasis vulgaris: a Mendelian randomization study.

BACKGROUND: Psoriasis is a common autoimmune disease in clinical practice, and previous observational studies have suggested that PPARG agonists such as Pioglitazone may be potential therapeutic agents. However, due to interference from various confounding factors, different observational studies have not reached a unified conclusion. We aim to evaluate the potential use of PPARG agonists for treating psoriasis from a new perspective through drug-targeted Mendelian randomization (MR) analysis. MATERIALS AND METHODS: This study includes data on 8,876 individuals for acute myocardial infarction from GWAS, and LDL cholesterol data from 343,621 Europeans. FinnGen contributed psoriasis vulgaris data for 403,972 individuals. The DrugBank10 databases function to identify genes encoding protein products targeted by active constituents of lipid-modifying targets. A two-sample MR analysis and summary-data-based MR (SMR) analysis estimated the associations between expressions of drug target genes and symptoms of psoriasis vulgaris. A multivariable MR study was further conducted to examine if the observed association was direct association. RESULTS: SMR analysis revealed that enhanced PPARG gene expression in the blood (equivalent to a one standard deviation increase) was a protective factor for psoriasis vulgaris (beta = -0.2017, se = 0.0723, p = 0.0053). Besides, there exists an MR association between LDL mediated by PPARG and psoriasis vulgaris outcomes (beta = -3.9169, se = 0.5676, p = 5.17E-12). These results indicate that PPARG is a therapeutic target for psoriasis, suggesting that psoriasis may be a potential indication for PPARG agonists. CONCLUSION: This study confirms that therapeutic activation of PPARG helps suppress the development of psoriasis. Psoriasis may be a new indication for PPARG agonists, such as Pioglitazone. In the future, new anti-psoriatic drugs could be developed targeting PPARG.

A chemical modification of a peroxisome proliferator-activated receptor pan agonist produced a shift to a new dual alpha/gamma partial agonist endowed with mitochondrial pyruvate carrier inhibition and antidiabetic properties.

New analogs of the PPAR pan agonist AL29-26 encompassed ligand (S)-7 showing potent activation of PPARα and -γ subtypes as a partial agonist. In vitro experiments and docking studies in the presence of PPAR antagonists were performed to help interpretation of biological data and investigate the main interactions at the binding sites. Further in vitro experiments showed that (S)-7 induced anti-steatotic effects and enhancement of the glucose uptake. This latter effect could be partially ascribed to a significant inhibition of the mitochondrial pyruvate carrier demonstrating that (S)-7 also acted through insulin-independent mechanisms. In vivo experiments showed that this compound reduced blood glucose and lipid levels in a diabetic mice model displaying no toxicity on bone, kidney, and liver. To our knowledge, this is the first example of dual PPARα/γ partial agonist showing these combined effects representing, therefore, the potential lead of new drugs for treatment of dyslipidemic type 2 diabetes.

Structural Studies on the Binding Mode of Bisphenols to PPARγ.

Bisphenol A (BPA) and bisphenol B (BPB) are widely used in the production of plastics, and their potential adverse health effects, particularly on endocrine disruption and metabolic health, have raised concern. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a pivotal role in metabolic regulation and adipogenesis, making it a target of interest in understanding the development of obesity and associated health impacts. In this study, we employ X-ray crystallography and molecular dynamics (MD) simulations to study the interaction of PPARγ with BPA and BPB. Crystallographic structures reveal the binding of BPA and BPB to the ligand binding domain of PPARγ, next to C285, where binding of partial agonists as well as antagonists and inverse agonists of PPARγ signaling has been previously observed. However, no interaction of BPA and BPB with Y437 in the activation function 2 site is observed, showing that these ligands cannot stabilize the active conformation of helix 12 directly. Furthermore, free energy analyses of the MD simulations revealed that I341 has a large energetic contribution to the BPA and BPB binding modes characterized in this study.

Weight of evidence evaluation of the metabolism disrupting effects of triphenyl phosphate using an expert knowledge elicitation approach.

Identification of Endocrine-Disrupting Chemicals (EDCs) in a regulatory context requires a high level of evidence. However, lines of evidence (e.g. human, in vivo, in vitro or in silico) are heterogeneous and incomplete for quantifying evidence of the adverse effects and mechanisms involved. To date, for the regulatory appraisal of metabolism-disrupting chemicals (MDCs), no harmonised guidance to assess the weight of evidence has been developed at the EU or international level. To explore how to develop this, we applied a formal Expert Knowledge Elicitation (EKE) approach within the European GOLIATH project. EKE captures expert judgment in a quantitative manner and provides an estimate of uncertainty of the final opinion. As a proof of principle, we selected one suspected MDC -triphenyl phosphate (TPP) - based on its related adverse endpoints (obesity/adipogenicity) relevant to metabolic disruption and a putative Molecular Initiating Event (MIE): activation of peroxisome proliferator activated receptor gamma (PPARγ). We conducted a systematic literature review and assessed the quality of the lines of evidence with two independent groups of experts within GOLIATH, with the objective of categorising the metabolic disruption properties of TPP, by applying an EKE approach. Having followed the entire process separately, both groups arrived at the same conclusion, designating TPP as a "suspected MDC" with an overall quantitative agreement exceeding 85%, indicating robust reproducibility. The EKE method provides to be an important way to bring together scientists with diverse expertise and is recommended for future work in this area.

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.

MASLD/MASH and type 2 diabetes: Two sides of the same coin? From single PPAR to pan-PPAR agonists.

Type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), mainly related to nutrition and lack of physical activity, are both very common conditions, share several disease pathways and clinical manifestations, and increasingly co-occur with disease progression. Insulin resistance is an upstream node in the biology of both conditions and triggers liver parenchymal injury, inflammation and fibrosis. Peroxisome proliferator-activated receptor (PPAR) nuclear transcription factors are master regulators of energy homeostasis - insulin signaling in liver, adipose and skeletal muscle tissue - and affect immune and fibrogenesis pathways. Among distinct yet overlapping effects, PPARα regulates lipid metabolism and energy expenditure, PPARß/δ has anti-inflammatory effects and increases glucose uptake by skeletal muscle, while PPARγ improves insulin sensitivity and exerts direct antifibrotic effects on hepatic stellate cells. Together PPARs thus represent pharmacological targets across the entire biology of MASH. Single PPAR agonists are approved for hypertriglyceridemia (PPARα) and T2D (PPARγ), but these, as well as dual PPAR agonists, have shown mixed results as anti-MASH treatments in clinical trials. Agonists of all three PPAR isoforms have the potential to improve the full disease spectrum from insulin resistance to fibrosis, and correspondingly to improve cardiometabolic and hepatic health, as has been shown (phase II data) with the pan-PPAR agonist lanifibranor.

White adipose tissue, a novel antirheumatic target: Clues from its secretory capability and adipectomy-based therapy.

BACKGROUND AND PURPOSE: White adipose tissue (WAT) is involved in rheumatoid arthritis (RA). This study explored its potential as an antirheumatic target. EXPERIMENTAL APPROACH: WAT status of healthy and adjuvant-induced arthritis (AIA) rats were compared. The contribution of WAT to RA pathology was evaluated by pre-adipocyte transplant experiments and by dissecting perirenal fat pads of AIA rats. The impact of RA on WAT was investigated by culturing pre-adipocytes. Proteins differentially expressed in WAT of healthy and AIA rats were identified by the UPLC/MS2 method. These together with PPARγ siRNA and agonist were used to treat pre-adipocytes in vitro. The medium was used for THP-1 monocyte culture. KEY RESULTS: Compared with healthy controls, AIA WAT was smaller but secreted more leptin, eNAMPT, MCP-1, TNF-α, and IL-6. AIA rat pre-adipocytes increased the levels of these adipokines in healthy recipients. RA patients' serum induced a similar secretion change and impaired differentiation of pre-adipocytes. Adipectomy eased AIA-related immune abnormalities and arthritic manifestations. Hepatokines PON1, IGFBP4, and GPIHBP1 were among the differential proteins in high levels in RA blood, and induced inflammatory secretions by pre-adipocytes. GPIHBP1 inhibited PPARγ expression and caused differentiation impairment and inflammatory secretion by pre-adipocytes, a similar outcome to PPARγ-silencing. This endowed the cells with an ability to activate monocytes, which can be abrogated by rosiglitazone. CONCLUSION AND IMPLICATIONS: Certain hepatokines potentiate inflammatory secretions by pre-adipocytes and expedite RA progression by inhibiting PPARγ. Targeting this signalling or abnormal WAT secretion by various approaches may reduce RA severity.

Comparison of transcriptomic profiles between HFPO-DA and prototypical PPARα, PPARγ, and cytotoxic agents in mouse, rat, and pooled human hepatocytes.

Like many per- or polyfluorinated alkyl substances (PFAS), toxicity studies with HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate), a short-chain PFAS used in the manufacture of some types of fluorinated polymers, indicate that the liver is the primary target of toxicity in rodents following oral exposure. Although the current weight of evidence supports the PPARα mode of action (MOA) for liver effects in HFPO-DA-exposed mice, alternate MOAs have also been hypothesized including PPARγ or cytotoxicity. To further evaluate the MOA for HFPO-DA in rodent liver, transcriptomic analyses were conducted on samples from primary mouse, rat, and pooled human hepatocytes treated for 12, 24, or 72 h with various concentrations of HFPO-DA, or agonists of PPARα (GW7647), PPARγ (rosiglitazone), or cytotoxic agents (ie, acetaminophen or d-galactosamine). Concordance analyses of enriched pathways across chemicals within each species demonstrated the greatest concordance between HFPO-DA and PPARα agonist GW7647-treated hepatocytes compared with the other chemicals evaluated. These findings were supported by benchmark concentration modeling and predicted upstream regulator results. In addition, transcriptomic analyses across species demonstrated a greater transcriptomic response in rodent hepatocytes treated with HFPO-DA or agonists of PPARα or PPARγ, indicating rodent hepatocytes are more sensitive to HFPO-DA or PPARα/γ agonist treatment. These results are consistent with previously published transcriptomic analyses and further support that liver effects in HFPO-DA-exposed rodents are mediated through rodent-specific PPARα signaling mechanisms as part of the MOA for PPARα activator-induced rodent hepatocarcinogenesis. Thus, effects observed in mouse liver are not appropriate endpoints for toxicity value development for HFPO-DA in human health risk assessment.

Comparison of transcriptomic profiles between HFPO-DA and prototypical PPARα, PPARγ, and cytotoxic agents in wild-type and PPARα knockout mouse hepatocytes.

Recent in vitro transcriptomic analyses for the short-chain polyfluoroalkyl substance, HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate), support conclusions from in vivo data that HFPO-DA-mediated liver effects in mice are part of the early key events of the peroxisome proliferator-activated receptor alpha (PPARα) activator-induced rodent hepatocarcinogenesis mode of action (MOA). Transcriptomic responses in HFPO-DA-treated rodent hepatocytes have high concordance with those treated with a PPARα agonist and lack concordance with those treated with PPARγ agonists or cytotoxic agents. To elucidate whether HFPO-DA-mediated transcriptomic responses in mouse liver are PPARα-dependent, additional transcriptomic analyses were conducted on samples from primary PPARα knockout (KO) and wild-type (WT) mouse hepatocytes exposed for 12, 24, or 72 h with various concentrations of HFPO-DA, or well-established agonists of PPARα (GW7647) and PPARγ (rosiglitazone), or cytotoxic agents (acetaminophen or d-galactosamine). Pathway and predicted upstream regulator-level responses were highly concordant between HFPO-DA and GW7647 in WT hepatocytes. A similar pattern was observed in PPARα KO hepatocytes, albeit with a distinct temporal and concentration-dependent delay potentially mediated by compensatory responses. This delay was not observed in PPARα KO hepatocytes exposed to rosiglitazone, acetaminophen, d-galactosamine. The similarity in transcriptomic signaling between HFPO-DA and GW7647 in both the presence and absence of PPARα in vitro indicates these compounds share a common MOA.

Deciphering the molecular pathways of saroglitazar: A dual PPAR α/γ agonist for managing metabolic NAFLD.

Saroglitazar (SARO), a dual peroxisome proliferator activated receptor (PPAR)-α/γ agonist, has been used to treat metabolic diseases such as insulin resistance and diabetic dyslipidemia in patients with non-alcoholic fatty liver disease (NAFLD). SARO, administered at a dose of 4 mg/day, has been consistently studied in clinical trials with different time points ranging from 4 to 24 weeks with NAFLD patients. Due to its PPAR-γ agonistic action, SARO prevents adipose tissue-mediated fatty acid delivery to the liver by increasing insulin sensitivity and regulating adiponectin and leptin levels in adipose tissue. In hepatocytes, SARO induces fatty acid ß-oxidation in mitochondria and transcriptionally activates lipid metabolizing genes in peroxisomes. SARO inhibits insulin resistance, thereby preventing the activation of sterol regulatory element-binding proteins -1c and carbohydrate response element binding protein in hepatocytes through its PPAR-α agonistic action. SARO treatment reduces lipotoxicity-mediated oxidative stress by activating the nuclear factor erythroid 2-related factor 2 and transcriptionally expressing the antioxidants from the antioxidant response element in the nucleus through its PPAR-γ agonistic action. SARO provides a PPAR-α/γ-mediated anti-inflammatory effect by preventing the phosphorylation of mitogen-activated protein kinases (JNK and ERK) and nuclear factor kappa B in hepatocytes. Additionally, SARO interferes with transforming growth factor-ß/Smad downstream signaling, thereby reducing liver fibrosis progression through its PPAR-α/γ agonistic actions. Thus, SARO improves insulin resistance and dyslipidemia in NAFLD, reduces lipid accumulation in the liver, and thereby prevents mitochondrial toxicity, oxidative stress, inflammation, and fibrosis progression. This review summarizes the possible molecular mechanism of SARO in the NAFLD.

Prospective de novo drug design with deep interactome learning.

De novo drug design aims to generate molecules from scratch that possess specific chemical and pharmacological properties. We present a computational approach utilizing interactome-based deep learning for ligand- and structure-based generation of drug-like molecules. This method capitalizes on the unique strengths of both graph neural networks and chemical language models, offering an alternative to the need for application-specific reinforcement, transfer, or few-shot learning. It enables the "zero-shot" construction of compound libraries tailored to possess specific bioactivity, synthesizability, and structural novelty. In order to proactively evaluate the deep interactome learning framework for protein structure-based drug design, potential new ligands targeting the binding site of the human peroxisome proliferator-activated receptor (PPAR) subtype gamma are generated. The top-ranking designs are chemically synthesized and computationally, biophysically, and biochemically characterized. Potent PPAR partial agonists are identified, demonstrating favorable activity and the desired selectivity profiles for both nuclear receptors and off-target interactions. Crystal structure determination of the ligand-receptor complex confirms the anticipated binding mode. This successful outcome positively advocates interactome-based de novo design for application in bioorganic and medicinal chemistry, enabling the creation of innovative bioactive molecules.