Potent PPARγ Research Articles

PPARγ modulator predictor (PGMP_v1): chemical space exploration and computational insights for enhanced type 2 diabetes mellitus management.

Peroxisome proliferator-activated receptor gamma (PPARγ) plays a critical role in adipocyte differentiation and enhances insulin sensitivity. In contemporary drug discovery, in silico design strategies offer significant advantages by revealing essential structural insights for lead optimization. The study is guided by two main objectives: (i) a ligand-based approach to explore the chemical space of PPARγ modulators followed by molecular docking ensembles (MDEs) to investigate ligand-binding interactions, (ii) the development of a supervised ML model for a large dataset of compounds targeting PPARγ. Additionally, the combination of chemical space networks with ML models enables the rapid screening and prediction of PPARγ modulators. These modeling analyses will assist medicinal chemists in designing more potent PPARγ modulators. To further enhance accessibility for the scientific community, we developed an online tool, "PGMP_v1," aimed at prospective screening for PPARγ modulators. The tool "PGMP_v1" is available at the provided link https://github.com/Amincheminfom/PGMP_v1 . The integration of these computational methods has uncovered crucial structural motifs that are essential for PPARγ activity, advancing the development of more effective modulators in the future.

Design, synthesis and biological evaluation of truncated 1'-homologated 4'-selenonucleosides as PPARγ/δ dual modulators.

This study explores the synthesis and evaluation of truncated 1'-homologated 4'-selenonucleosides as dual modulators of PPARγ and PPARδ. Starting with d-lyxose, a 4'-selenosugar was synthesized and condensed with a nucleobase via an SN2 reaction, followed by modifications at the C2- and N6-positions, yielding compounds 3a-l. Structure-activity trend analysis identified compound 3h, featuring 2-chloro and N6-3-iodobenzylamine substituents, as a potent PPARγ partial agonist and PPARδ antagonist (PPARγ Ki=2.8μM, PPARδ Ki=43nM). This compound significantly enhanced adiponectin production and promoted adipogenic differentiation in hBM-MSCs. The 4'-seleno substitution preserved ligand functionality while enhancing binding affinity and pharmacological efficacy. In silico docking studies supported these binding affinities, demonstrating optimal binding poses for 3h at both PPARγ and PPARδ. These findings underscore the potential of 4'-selenonucleosides as therapeutic agents for metabolic disorders associated with hypoadiponectinemia, meriting further investigation and clinical development.

Identification of Novel Organo-Se BTSA-Based Derivatives as Potent, Reversible, and Selective PPARγ Covalent Modulators for Antidiabetic Drug Discovery.

Recent studies have identified selective peroxisome proliferator-activated receptor γ (PPARγ) modulators, which synergistically engage in the inhibition mechanism of PPARγ-Ser273 phosphorylation, as a promising approach for developing safer and more effective antidiabetic drugs. Herein, we present the design, synthesis, and evaluation of a new class of organo-Se compounds, namely, benzothiaselenazole-1-oxides (BTSAs), acting as potent, reversible, and selective PPARγ covalent modulators. Notably, 2n, especially (R)-2n, displayed a high binding affinity and superior antidiabetic effects with diminished side effects. This is mainly because it can reversibly form a unique covalent bond with the Cys285 residue in PPARγ-LBD. Further mechanistic investigations revealed that it manifested such desired pharmacological profiles primarily by effectively suppressing PPARγ-Ser273 phosphorylation, enhancing glucose metabolism, and selectively upregulating the expression of insulin-sensitive genes. Collectively, our results suggest that (R)-2n holds promise as a lead compound for treating T2DM and also provides an innovative reversible covalent warhead reference for future covalent drug design.

Identification of Novel PPARγ Partial Agonists Based on Virtual Screening Strategy: In Silico and In Vitro Experimental Validation.

Thiazolidinediones (TZDs) including rosiglitazone and pioglitazone function as peroxisome proliferator-activated receptor gamma (PPARγ) full agonists, which have been known as a class to be among the most effective drugs for the treatment of type 2 diabetes mellitus (T2DM). However, side effects of TZDs such as fluid retention and weight gain are associated with their full agonistic activities toward PPARγ induced by the AF-2 helix-involved "locked" mechanism. Thereby, this study aimed to obtain novel PPARγ partial agonists without direct interaction with the AF-2 helix. Through performing virtual screening of the Targetmol L6000 Natural Product Library and utilizing molecular dynamics (MD) simulation, as well as molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis, four compounds including tubuloside b, podophyllotoxone, endomorphin 1 and paliperidone were identified as potential PPARγ partial agonists. An in vitro TR-FRET competitive binding assay showed podophyllotoxone displayed the optimal binding affinity toward PPARγ among the screened compounds, exhibiting IC50 and ki values of 27.43 µM and 9.86 µM, respectively. Further cell-based transcription assays were conducted and demonstrated podophyllotoxone's weak agonistic activity against PPARγ compared to that of the PPARγ full agonist rosiglitazone. These results collectively demonstrated that podophyllotoxone could serve as a PPARγ partial agonist and might provide a novel candidate for the treatment of various diseases such as T2DM.

Impact of Sex on the Therapeutic Efficacy of Rosiglitazone in Modulating White Adipose Tissue Function and Insulin Sensitivity.

Obesity and type 2 diabetes mellitus are global public health issues. Although males show higher obesity and insulin resistance prevalence, current treatments often neglect sex-specific differences. White adipose tissue (WAT) is crucial in preventing lipotoxicity and inflammation and has become a key therapeutic target. Rosiglitazone (RSG), a potent PPARγ agonist, promotes healthy WAT growth and mitochondrial function through MitoNEET modulation. Recent RSG-based strategies specifically target white adipocytes, avoiding side effects. Our aim was to investigate whether sex-specific differences in the insulin-sensitizing effects of RSG exist on WAT during obesity and inflammation. We used Wistar rats of both sexes fed a high-fat diet (HFD, 22.5% fat content) for 16 weeks. Two weeks before sacrifice, a group of HFD-fed rats received RSG treatment (4 mg/kg of body weight per day) within the diet. HFD male rats showed greater insulin resistance, inflammation, mitochondrial dysfunction, and dyslipidemia than females. RSG had more pronounced effects in males, significantly improving insulin sensitivity, fat storage, mitochondrial function, and lipid handling in WAT while reducing ectopic fat deposition and enhancing adiponectin signaling in the liver. Our study suggests a significant sexual dimorphism in the anti-diabetic effects of RSG on WAT, correlating with the severity of metabolic dysfunction.

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.

Hepatotoxicity of oral exposure to 2-methyl-4-nitroaniline: toxicity prediction and in vivo evaluation

2-Methyl-4-nitroaniline (MNA), an intermediate in the synthesis of azo dyes, is widely distributed in various environmental media and organisms. Although there is speculation regarding MNA’s potential to be hepatotoxic, the underlying mechanisms of its hepatotoxicity and its definitive diagnostic process remain largely unexplored. In this research. In the present study, we initially predicted the toxicity and possible toxic effect pathways of MNA using ProTox-II, and found that MNA binds to the PPARγ receptor (binding energy －6.118 kcal/mol) with a potential PPARγ agonist effect. Subsequently, in vivo exposure evaluation was conducted on Wistar rats to assess the impact of MNA after a 90-day exposure period, by detecting serum biochemical indexes, hematological indexes, urinary indexes, inflammatory factors, liver histopathological observations and liver tissue PPARγ mRNA expression. The results showed that MNA causes liver function abnormalities, liver histopathological changes and inflammatory response, along with a pronounced increase in PPARγ mRNA levels. This study suggests that the hepatotoxic mechanism of MNA may be related to its possible upregulation of PPARγ expression, increased liver dysfunction and inflammatory responses. Based on these results, the benchmark dose lower limit (BMDL) of 1.503 mg/kg for male Wistar rats was also established, providing a vital benchmark for determining the safety threshold of MNA. Our data highlight the hepatotoxic mechanism of MNA and contribute to a better understanding of its potential etiological diagnosis.

New Insights into the Role of PPARγ in Skin Physiopathology.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor expressed in many tissues, including skin, where it is essential for maintaining skin barrier permeability, regulating cell proliferation/differentiation, and modulating antioxidant and inflammatory responses upon ligand binding. Therefore, PPARγ activation has important implications for skin homeostasis. Over the past 20 years, with increasing interest in the role of PPARs in skin physiopathology, considerable effort has been devoted to the development of PPARγ ligands as a therapeutic option for skin inflammatory disorders. In addition, PPARγ also regulates sebocyte differentiation and lipid production, making it a potential target for inflammatory sebaceous disorders such as acne. A large number of studies suggest that PPARγ also acts as a skin tumor suppressor in both melanoma and non-melanoma skin cancers, but its role in tumorigenesis remains controversial. In this review, we have summarized the current state of research into the role of PPARγ in skin health and disease and how this may provide a starting point for the development of more potent and selective PPARγ ligands with a low toxicity profile, thereby reducing unwanted side effects.

Moringin alleviates DSS-induced ulcerative colitis in mice by regulating Nrf2/NF-κB pathway and PI3K/AKT/mTOR pathway

Ulcerative colitis (UC) is a main form of inflammatory bowel disease (IBD), which is a chronic and immune-mediated inflammatory disease. Moringin (MOR) is an isothiocyanate isolated from Moringa oleifera Lam., and has been recognized as a promising potent drug for inflammatory diseases and antibacterial infections. The present study investigated the role of moringin in dextran sulfate sodium (DSS)-induced UC mice. Mouse colitis was induced by adding DSS to the drinking water for seven consecutive days. Our experimental results showed that MOR relieves DSS-induced UC in mice by increasing body weight and colonic length, and reducing the disease activity index and histological injury. Mechanistically, MOR improves intestinal barrier function by increasing the expression of tight junction proteins (TJPs) and enhancing the secretion of mucin in DSS-induced mice. MOR inhibits inflammatory response and intestinal damage by regulating Nrf2/NF-κB signaling pathway and modulating the PI3K/AKT/mTOR pathway. Furthermore, in Nrf2 knockout (Nrf2-/-) mice, the protective effects of MOR on DSS-induced UC were abolished. Meanwhile, treatment with MOR reduced inflammation and cell damage via regulating Nrf2/NF-κB pathway in a lipopolysaccharide (LPS)-induced inflammation model of Caco-2 cells. In contrast, ML385, an Nrf2 inhibitor, might eliminate the protection provided by MOR. Notably, treatment with MOR significantly up-regulated the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), suggesting that MOR may be a potential PPAR-γ activator. In conclusion, MOR exerts protective effect in UC by improving intestinal barrier function, regulating Nrf2/NF-κB and PI3K/AKT/mTOR signaling pathways, and another effect associated with the regulation of PPAR-γ expression.

Molecular docking, dynamics, and preclinical experimental studies identify Morin hydrate as a potent PPAR-γ and NRF-2 transcription factor agonist that mitigates colon inflammation

Introduction: Peroxisome proliferator-activated receptor gamma (PPAR-γ) plays a vital role in regulating intestine inflammation. PPAR-γ is highly expressed in the adipose tissue and the colon. The nuclear erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein1 (Keap1) system protects cells from oxidative stress and inflammation. Therefore, PPAR-γ and Nrf2 ligands offer a drug-targeting system that can be exploited to treat inflammatory bowel diseases (IBDs), especially ulcerative colitis. IBD prevalence is on the rise globally. Current mainstream therapies for IBD offer protection but with many side effects; therefore, up to 30% of IBD patients turn to alternate therapy using bioactive phytochemicals. Morin hydrate, a naturally occurring bioflavonoid in many fruits, stems, and leaves of the Moraceae family plant, possesses potent anti-inflammatory properties. The docking studies reveal that it is a potent activator of the PPAR-γ and Nrf2 transcription factors. Therefore, in this study, we investigated the role of morin hydrate modulating colon epithelial PPAR-γ transcription in colon inflammation. Aim: Therefore, this study aims to investigate morin hydrate’s anti-inflammatory properties using both in vivo and in vitro models of colon inflammation. Methodology: C57BL/6J black mice were administered 2% dextran sodium sulfate (DSS) morin hydrate administered at concentrations of 25 & 50mg/kg body for in vivo studies. The DAI, colon length, MPO, and histology changes were determined. Proinflammatory cytokines (IL-1β, IL-6, TNF-α, & IL17A) were measured using ELISA and mRNA using real-time PCR. PPAR-γ and Nrf2 expression and phosphoNF-κB/NF-κB expression were estimated. HT-29 cells were cultured in DMEM media and were stimulated using TNF-α (1ng/ml). Different concentrations of morin hydrate were treated to HT-29 cells to determine a safe dose range for further in vitro experiments by estimating cell toxicity assay. CXCL-1, IL-8, and mRNA levels were determined using real-time PCR after morin hydrate co-treatment. Morin hydrate effect on PPAR-γ and Nrf2 promoter activity was determined using full-length promoter transfection studies. Results: Morin treatment significantly ( p<0.01) decreased DAI, MPO level, and restored colon length dose-dependently in the treated group. Histological scoring for colonic inflammation was significantly ( p<0.001) improved upon morin treatment. Morin treatment also inhibited the proinflammatory cytokines (IL-1β, IL-6, TNF-α, & IL17A) significantly ( p<0.01) both at protein and mRNA levels. Morin significantly inhibited COX-2 and iNOS both at protein and mRNA levels and also decreased tissue nitrite levels. Morin also activated PPAR-γ protein expression NRF2 nuclear translocation and inhibited NF-κB expression in DSS-administered mice. Morin significantly decreased antioxidant surrogate markers superoxide dismutase (SOD) and catalase activity. Morin significantly ( p<0.01) decreased proinflammatory cytokine (CXCL-1 & IL-8) mRNA expression when HT-29 cells were challenged with TNF-α. Morin also increased PPAR-γ and Nrf2 promoter activity. Conclusion: Morin hydrate is a potent PPAR-γ and Nrf2 transcription factor activator that mitigates colon inflammation through its anti-inflammatory and antioxidant activities. This is supported from UAE University grant, fund number 12R006 and 12R169. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The cytotoxicity of 1,4-bis(3,4,5-trimethoxyphenyl)-tetrahydro-furo(3,4-c) furan isolated from Swietenia macrophylla King seed extract on 3T3-L1 and RAW 264.7 cells

The exploration of natural products as anti-obesity candidates needs to be performed urgently since obesity has become a worldwide epidemic and many drugs for this health condition were withdrawn due to their serious adverse events such as psychiatric disorders and drug dependence. The 1,4-bis(3,4,5-trimethoxyphenyl)-tetrahydro-furo(3,4-c) furan, a saponin isolated from Indonesian Swietenia macrophylla seeds extract has the potential to modulate obesity because it acts as a potent PPAR-γ agonist in silico and the seeds’ hypolipidemic effect has been proven. The cytotoxicity study is a crucial part of the early pharmaceutical development stage, whilst, the exploration of 1,4-bis(3,4,5- trimethoxyphenyl)-tetrahydro-furo(3,4-c) furan to ensure the compound’s safety in preadipocytes and macrophage cells which play a crucial role in obesity pathogenesis is still limited. This study aims to explore the cytotoxicity of saponin isolate on 3T3-L1 (preadipocytes) and RAW 264.7 (macrophages) cell lines to ensure its safety profile in vitro. Both cell lines were exposed to various concentrations of the isolate (3.125-200 µg/mL), then metformin was used as the standard drug and DMSO as solvent control for 24 hrs. The cytotoxicity test was conducted by MTT assay and IC50 was determined by probit analysis. Most of the 1,4-bis(3,4,5-trimethoxyphenyl)-tetrahydro-furo(3,4-c) furan did not affect the viability of 3T3-L1 and RAW 264.7 with the IC50 148.90±12.22 and 84.78±1.69 µg/mL, respectively. Metformin and DMSO also did not alter the viability of both cells. These results were promising as a basis for further development since the isolates’ IC50 value was more than the cytotoxic threshold of NCI guidelines.

Raloxifene-driven benzothiophene derivatives: Discovery, structural refinement, and biological evaluation as potent PPARγ modulators based on drug repurposing

By virtue of the drug repurposing strategy, the anti-osteoporosis drug raloxifene was identified as a novel PPARγ ligand through structure-based virtual high throughput screening (SB-VHTS) of FDA-approved drugs and TR-FRET competitive binding assay. Subsequent structural refinement of raloxifene led to the synthesis of a benzothiophene derivative, YGL-12. This compound exhibited potent PPARγ modulation with partial agonism, uniquely promoting adiponectin expression and inhibiting PPARγ Ser273 phosphorylation by CDK5 without inducing the expression of adipongenesis associated genes, including PPARγ, aP2, CD36, FASN and C/EBPα. This specific activity profile resulted in effective hypoglycemic properties, avoiding major TZD-related adverse effects like weight gain and hepatomegaly, which were demonstrated in db/db mice. Molecular docking studies showed that YGL-12 established additional hydrogen bonds with Ile281 and enhanced hydrogen-bond interaction with Ser289 as well as PPARγ Ser273 phosphorylation-related residues Ser342 and Glu343. These findings suggested YGL-12 as a promising T2DM therapeutic candidate, thereby providing a molecular framework for the development of novel PPARγ modulators with an enhanced therapeutic index.

Berberine modulates cardiovascular diseases as a multitarget-mediated alkaloid with insights into its downstream signals using in silico prospective screening approaches

Atherosclerosis is potentially correlated with several cardiac disorders that are greatly associated with cellular oxidative stress generation, inflammation, endothelial cells dysfunction, and many cardiovascular complications. Berberine is a natural isoquinoline alkaloid compound that widely modulates pathogenesis of atherosclerosis through its different curative potentials. This in silico screening study was designed to confirm the potent restorative properties of berberine chloride as a multitarget-mediated alkaloid against the CVDs and their complications through screening, identifying, visualizing, and evaluating its binding models, affinities, and interactions toward several CVDs-related targets as direct and/or indirect-mediated signals via inhibiting cellular ER stress and apoptotic signals and activating autophagy pathway. The drug-likeness properties of berberine were predicted using the computational QSAR/ADMET and Lipinski’s RO5 analyses as well as in silico molecular docking simulations. The potent berberine-binding modes, residues-interaction patterns, and free energies of binding scores towards several CVDs-related targets were estimated using molecular docking tools. Furthermore, the pharmacokinetic properties and toxicological features of berberine were clearly determined. According to this in silico virtual screening study, berberine chloride could restore cardiac function and improve pathogenic features of atherosclerotic CVDs through alleviating ER stress and apoptotic signals, activating autophagy, improving insulin sensitivity, decreasing hyperglycemia and dyslipidemia, increasing intracellular RCT signaling, attenuating oxidative stress and vascular inflammation, and upregulating cellular antioxidant defenses in many cardiovascular tissues. In this in silico study, berberine chloride greatly modulated several potent CVDs-related targets, including SIGMAR1, GRP78, CASP3, BECN1, PIK3C3, SQSTM1/p62, LC3B, GLUT3, INSR, LDLR, LXRα, PPARγ, IL1β, IFNγ, iNOS, COX-2, MCP-1, IL10, GPx1, and SOD3.

PPARγ antagonists induce aromatase transcription in adipose tissue cultures

Aromatase is the rate-limiting enzyme in the biosynthesis of estrogens and a key risk factor for hormone receptor-positive breast cancer. In postmenopausal women, estrogens synthesized in adipose tissue promotes the growth of estrogen receptor positive breast cancers. Activation of peroxisome proliferator-activated receptor gamma (PPARγ) in adipose stromal cells (ASCs) leads to decreased expression of aromatase and differentiation of ASCs into adipocytes. Environmental chemicals can act as antagonists of PPARγ and disrupt its function. This study aimed to test the hypothesis that PPARγ antagonists can promote breast cancer by stimulating aromatase expression in human adipose tissue.Primary cells and explants from human adipose tissue as well as A41hWAT, C3H10T1/2, and H295R cell lines were used to investigate PPARγ antagonist-stimulated effects on adipogenesis, aromatase expression, and estrogen biosynthesis. Selected antagonists inhibited adipocyte differentiation, preventing the adipogenesis-associated downregulation of aromatase. NMR spectroscopy confirmed direct interaction between the potent antagonist DEHPA and PPARγ, inhibiting agonist binding. Short-term exposure of ASCs to PPARγ antagonists upregulated aromatase only in differentiated cells, and a similar effect could be observed in human breast adipose tissue explants. Overexpression of PPARG with or without agonist treatment reduced aromatase expression in ASCs.The data suggest that environmental PPARγ antagonists regulate aromatase expression in adipose tissue through two mechanisms. The first is indirect and involves inhibition of adipogenesis, while the second occurs more acutely.

Identification of novel PPAR-γ agonist ameliorating triple negative breast cancer by in silico methods

Triple negative breast cancer (TNBC) is still considered a medical challenge as it is an aggressive cancer characterized by poor prognosis, frequent metastasis, distinct clinical and pathological features and lack of proper treatment options. In TNBC, estrogen, progesterone and Her2 neu receptors are absent, which are usually present in otherwise breast cancers. So, hormonal therapy cannot be given in case of TNBC, leaving chemotherapy as the mainstay for treatment. However, chemotherapy is an infamous therapeutic option due to several aweful side effects like loss of appetite, extreme weight loss, hair loss, vomiting, fatigue etc. Several reports have highlighted role of Peroxisome Proliferated Activated Receptor gamma (PPAR-γ) in ameliorating breast cancer, but it is still less explored receptor for TNBC. Moreover, synthetic PPAR gamma agonists like thiazolidinediones, have good capability of activating PPAR-γ receptor, but these are also gloomy therapeutic agent due to their dreadful side effects like hepatotoxicity, bladder cancer, congestive heart failure etc. So, there is serious urge among researchers to find safer therapeutic option for TNBC. Phytochemicals are nowadays grabbing attention worldwide to treat several diseases due to their fewer or no side effects. This in silico study was performed after thorough review to select a natural, potent PPAR-γ agonist Gallotanin, as a query compound for ligand based similarity searching in PubChem database with 80% filter. Top 10 obtained compounds having highest similarity index were chosen for molecular docking in AutoDock Vina, with PPAR-γ receptor (3V9T) to know their binding patterns. Further, top 5 compounds having highest dock scores underwent ADME studies in SwissADME to assess pharmacokinetic profile of these compounds. Finally, this in silico study resulted in discovery of compound called Chamuvaritin which is still not known as a PPAR-γ agonist, efficient enough to act as potent therapeutic agent against TNBC.

In silico analysis of polyphenols modulate bovine PPARγ to increase milk fat synthesis in dairy cattle via the MAPK signaling pathways.

This study investigates the potential phytochemicals that modulate bovine peroxisome proliferator-activated receptor gamma (PPARγ) and the mitogen-activated protein kinase (MAPK) pathways to enhance milk fat production in dairy animals. Bovine PPARγ, a key member of the nuclear hormone receptor superfamily, plays a vital role in regulating metabolic, cellular differentiation, apoptosis, and anti-inflammatory responses in livestock, while the MAPK pathway is contributory in cellular processes that impact milk fat synthesis. This approach involved an all-inclusive molecular docking analysis of 10,000 polyphenols to identify potential PPARγ ligands. From this extensive screening, top 10 compounds were selected that exhibited the highest binding affinities to bovine PPARγ. Particularly, curcumin sulfate, isoflavone, and quercetin emerged as the most promising candidates. These compounds demonstrated superior docking scores (-9.28 kcal/mol, -9.27 kcal/mol, and -7.31 kcal/mol, respectively) and lower RMSD values compared to the synthetic bovine PPARγ agonist, 2,4-thiazolidinedione (-4.12 kcal/mol), indicating a strong potential for modulating the receptor. Molecular dynamics simulations (MDS) further affirmed the stability of these polyphenols-bovine PPARγ complexes, suggesting their effective and sustained interactions. These polyphenols, known as fatty acid synthase inhibitors, are suggested to influence lipid metabolism pathways crucial to milk fat production, possibly through the downregulation of the MAPK pathway. The screened compounds showed favorable pharmacokinetic profiles, including nontoxicity, carcinogenicity, and high gastrointestinal absorption, positioning them as viable candidates for enhancing dairy cattle health and milk production. These findings may open new possibilities for the use of phytochemicals as feed additives in dairy animals, suggesting a novel approach to improve milk fat synthesis through the dual modulation of bovine PPARγ and MAPK pathways.

Innovation of 6-sulfonamide-2H-chromene derivatives as antidiabetic agents targeting α-amylase, α-glycosidase, and PPAR-γ inhibitors with in silico molecular docking simulation.

A new series of 2-imino or 2-oxo-2H-chromene-6-sulfonamide derivatives 2-9 with potential anti-diabetic activity were designed and synthesized. The new 6-sulfonamide chromenes were synthesized by reacting 3-formyl-4-hydroxybenzenesulfonyl chloride with activated methylene derivatives in the presence of ammonium acetate as a catalyst. The structure of the products was confirmed by spectroscopic analysis. All the designed derivatives 2-9 were evaluated for their activity against α-amylase and exhibited inhibitory percentage values higher than 93% at 100 μg mL-1. Additionally, the IC50 values represented a variable degree of activity with two derivatives 2 and 9 exhibiting the most promising derivative results with IC50 values of 1.76 ± 0.01 and 1.08 ± 0.02 μM, respectively, compared to Acarbose (IC50 = 0.43 ± 0.01 μM). Additionally, these derivatives showed potency against the α-glucosidase enzyme with IC50 values of 0.548 ± 0.02 and 2.44 ± 0.09 μg mL-1, compared to Acarbose (0.604 ± 0.02 μg mL-1). Moreover, the in vitro PPAR-γ transactivation assay revealed that chromene-6-sulfonamide derivatives 2 and 9 exhibited potential PPAR-γ activity with IC50 values of 3.152 ± 0.03 and 3.706 ± 0.32 μg mL-1, respectively, compared to Pioglitazone (4.884 ± 0.29 μg mL-1). This indicates that these derivatives have insulin sensitivity and glucose metabolism activity. The in silico ADMET prediction showed that these derivatives have an acceptable range of oral bioavailability, drug-likeness, and a safe toxicity profile, including being non-cytotoxic, non-mutagenic, non-immunotoxic, and non-carcinogenic. Finally, computational docking analysis demonstrated the ability of these derivatives to interact with α-amylase, α-glucosidase, and PPAR-γ enzymes, with confirmed successful placement due to good binding energy values and various interactions within the pocket.

Fluorinated thiazole–thiosemicarbazones hybrids as potential PPAR-γ agonist and α-amylase, α-glucosidase antagonists: Design, synthesis, in silico ADMET and docking studies and hypoglycemic evaluation

In addition to Peroxisome Proliferator-Activated Receptor-gamma (PPAR-γ), which is essential for controlling type-2 diabetes mellitus, α-amylase and α-glucosidase inhibition is a key strategy in managing postprandial hyperglycemia. In this work a series of 2-(1-(2-((4-fluorophenyl)amino)-4-methylthiazol-5-yl)ethylidene)hydrazine-1-carbothioamide derivatives (3–6) was designed and synthesized through theiosemicarbazide derivatives, the structural elucidation of the new synthesized compounds was established using elemental and spectroscopic analyses. The antidiabetic activities of the new thiazole-thiosemicarbazone hybrids were screened in vivo for blood glucose lowering activity in normal rats and compared with pioglitazone as antidiabetic standard. Male Sprague-Dawley rats had reduced blood sugar levels after exposure to compounds 5 and 6 compared to pioglitazone. Additionally, the PPAR-γ agonist activity of compounds 5 and 6 as well as their ability to inhibit α-amylase and α-glucosidase were assessed. When compared to standard acarbose, which had an IC50 value of 0.74 ± 0.15 mM/mL, compound 5 showed the highest α-glucosidase inhibitory activity with IC50 value of 0.446 ± 0.01 mM/mL, while compound 6 showed good activity with an IC50 value of 1. 914 ± 0.04 mM/mL. However, compound 5 and compound 6 had weak α-amylase inhibitory activity, with IC50 values of 11.78 ± 0.58 and 24.18 ± 1.2 µg/mL respectively. Furthermore, Peroxisome proliferator activated receptor γ [PPAR-γ] agonist activity for compound 5 and compound 6 was assessed and gave promising result as [PPAR-γ] agonist with IC50 value of 0.938 ± 0.023 and 0.947 ± 0.024 ng/mL respectively superior to that of pioglitazone with IC50 value of 1.912 ± 0.11 ng/mL. All the results supported compound 5 as promising candidates for construction of new antidiabetic agents. Also, in silico ADMET and docking studies for the most promising derivatives 5, 6, Acarbose, and Pioglitazone were done.

Inhibition of PPARγ by BZ26, a GW9662 derivate, attenuated obesity-related breast cancer progression by inhibiting the reprogramming of mature adipocytes into to cancer associate adipocyte-like cells.

Obesity has been associated with the development of 13 different types of cancers, including breast cancer. Evidence has indicated that cancer-associated adipocytes promote the proliferation, invasion, and metastasis of cancer. However, the mechanisms that link CAAs to the progression of obesity-related cancer are still unknown. Here, we found the mature adipocytes in the visceral fat of HFD-fed mice have a CAAs phenotype but the stromal vascular fraction of the visceral fat has not. Importantly, we found the derivate of the potent PPARγ antagonist GW9662, BZ26 inhibited the reprogramming of mature adipocytes in the visceral fat of HFD-fed mice into CAA-like cells and inhibited the proliferation and invasion of obesity-related breast cancer. Further study found that it mediated the browning of visceral, subcutaneous and perirenal fat and attenuated inflammation of adipose tissue and metabolic disorders. For the mechanism, we found that BZ26 bound and inhibited PPARγ by acting as a new modulator. Therefore, BZ26 serves as a novel modulator of PPARγ activity, that is, capable of inhibiting obesity-related breast cancer progression by inhibiting of CAA-like cell formation, suggesting that inhibiting the reprogramming of mature adipocytes into CAAs or CAA-like cells may be a potential therapeutic strategy for obesity-related cancer treatment.

Biomarker Quantification, Spectroscopic, and Molecular Docking Studies of the Active Compounds Isolated from the Edible Plant Sisymbrium irio L.

Phytochemical investigation of the ethanolic extract of the aerial parts of Sisymbrium irio L. led to the isolation of four unsaturated fatty acids (1-4), including a new one (4), and four indole alkaloids (5-8). The structures of the isolated compounds were characterized with the help of spectroscopic techniques such as 1D, 2D NMR, and mass spectroscopy, and by correlation with the known compounds. In terms of their notable structural diversity, a molecular docking approach with the AutoDock 4.2 program was used to analyze the interactions of the identified fatty acids with PPAR-γ and the indole alkaloids with 5-HT1A and 5-HT2A, subtypes of serotonin receptors, respectively. Compared to the antidiabetic drug rivoglitazone, compound 3 acted as a potential PPAR-γ agonist with a binding energy of -7.4 kcal mol-1. Moreover, compound 8 displayed the strongest affinity, with binding energies of -6.9 kcal/mol to 5HT1A and -8.1 kcal/mol to 5HT2A, using serotonin and the antipsychotic drug risperidone as positive controls, respectively. The results of docked conformations represent an interesting target for developing novel antidiabetic and antipsychotic drugs and warrant further evaluation of these ligands in vitro and in vivo. On the other hand, an HPTLC method was developed to quantify α-linolenic acid in the hexane fraction of the ethanol extract of S. irio. The regression equation/correlation coefficient (r2) for linolenic acid was Y = 6.49X + 2310.8/0.9971 in the linearity range of 100-1200 ng/band. The content of α-linolenic acid in S. irio aerial parts was found to be 28.67 μg/mg of dried extract.