Receptor PPARγ Research Articles

Blumea balsamifera and Sargassum aquifolium extracts reduce fatty liver damage through lipid metabolism signalling pathways

Non-alcoholic fatty liver disease (NAFLD) is a condition marked by excessive fat accumulation in the liver and poses a significant health challenge. The leaves of Blumea balsamifera and Sargassum aquifolium have been reported to have anti-atherogenic effects. This study aims to determine the effectiveness of B. balsamifera extract (BBLE) and S. aquifolium extract (SAE) in preventing and treating liver fat accumulation in Wistar rats induced by a high-cholesterol diet through the expression of the AMP-activated protein kinase (AMPK)/ Sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor γ (PPARγ) pathway, and the leptin receptor. The experimental design of this study is laboratory-based, involving, 20 Wistar rats were fed a high-cholesterol diet over a period of 21 days. The rats were divided into four groups for the evaluation of BBLE and SAE effect: negative control (P0): induced with a high-cholesterol diet + distilled water, positive control (P1): induced with a high-cholesterol diet + simvastatin, P2: induced with a high-cholesterol diet + 4 mg/kg/bw BBLE, and P3: induced with a high-cholesterol diet + 4 mg/kg/bw BBLE and 4 mg/kg/bw SAE. The treatment duration extended over three months. Immunohistochemical analyses were performed on liver tissues to measure AMPK, SIRT1, PPARγ, and leptin receptor expression. The results indicated that leptin expression was lower in the BBLE+SAE group compared to the simvastatin group, and differences were significant between the BBLE and BBLE+SAE groups. No significant differences were noted in AMPK, SIRT1, and PPARγ expression between the simvastatin and BBLE+SAE groups (p≥0.05). In conclusion, BBLE and SAE effectively reduce liver lipid accumulation and enhance fat metabolism in hypercholesterolemic rats.

Evaluation of the Effect of an α-Adrenergic Blocker, a PPAR-γ Receptor Agonist, and a Glycemic Regulator on Chronic Kidney Disease in Diabetic Rats.

Diabetic nephropathy (DN) is a globally widespread complication of diabetes mellitus (DM). Research indicates that pioglitazone and linagliptin mitigate the risk of DN by reducing inflammation, oxidative stress, and fibrosis. The role of tamsulosin in DN is less studied, but it may contribute to reducing oxidative stress and inflammatory responses. The protective effects of combining pioglitazone, linagliptin, and tamsulosin on the kidneys have scarcely been investigated. This study examines the individual and combined effects of these drugs on DN in Wistar rats. Diabetic rats were treated with tamsulosin, pioglitazone, and linagliptin for six weeks. We assessed food and water intake, estimated glomerular filtration rate (eGFR), histological markers, urea, creatinine, glucose, NF-κB, IL-1, IL-10, TGF-β, and Col-IV using immunofluorescence and qPCR. The DN group exhibited hyperglycaemia, reduced eGFR, and tissue damage. Tamsulosin and linagliptin improved eGFR, decreased urinary glucose, and repaired tissue damage. Pioglitazone and its combinations restored serum and urinary markers and reduced tissue damage. Linagliptin lowered serum creatinine and tissue injury. In conclusion, tamsulosin, linagliptin, and pioglitazone demonstrated renoprotective effects in DN.

Computational Drug Design Approaches for the Identification of Novel Antidiabetic Compounds from Natural Resources through Molecular Docking, ADMET, and Toxicological Studies.

Type 2 diabetes mellitus (T2DM) is usually depicted by relative insulin deficiency, raised blood glucose levels, and the predominant risk factor, insulin resistance. Hence, the development of insulin sensitizer drugs targeting PPAR-γ receptors has expanded enormous interest as an attractive choice for T2DM treatment. Thiazolidinediones (TZD) enhance insulin sensitivity either by directly functioning on gene transcription of the PPARγ receptor related to glucose homeostasis or by systemic sensitization of insulin and, therefore, improved hyperglycemia in a wide range of patients. However, severe complications and adverse effects of TZDs necessitate the development of an efficacious and reliable insulin sensitizer from alternative resources. On the contrary, Nature is a rich source of anticipated effective and safer medicine; more than fifty percent of drugs on the market are developed from natural products. Hence, searching for a new PPAR-γ agonist from bioactive secondary compounds of medicinal plants along with greater efficacy and safety is a recognized and consistent tactic for developing novel antidiabetic agents. Pulicaria jaubertii is a fragrant perennial aromatic plant with anti-inflammatory, antidiabetic, antimicrobial, antimalarial, and insecticidal properties. The current study was designed to use a computer-aided drug design to explore the best antidiabetic compounds from P. jaubertii. Herein, the molecular docking study of 80 investigated ligands against the PPAR-γ receptor identifies the highest docking score for five ligands ranging from -8.9 kcal/mol to 8.0 kcal/mol, which is also more significant than the standard drug pioglitazone (-7.7 kcal/mol) determined by the PyRx 8.0 virtual screening software. GLN286, CYS285, SER289, TYR473, MET364, ARG288, ILE341, and LEU333 residues are found to be significant contributors to the non-bonded interaction between ligands and receptors. Molecular electrostatic potential (MEP), DFT, molecular orbital (MO), ADMET, and toxicological analyses were performed on the selected five high-scored ligands of P. jaubertii. Results documented that all investigated ligands, especially L4, show considerably excellent profiles in molecular docking, MEP, DFT, MO, ADMET, and toxicological predictions, suggesting our drug-designing approaches may contribute to the development of a novel antidiabetic drug for the treatment of T2DM from natural resources.

Mechanisms of Cinnamomi Cortex against Diabetes Mellitus Explored by Network Pharmacology combined with Molecular Docking and Experimental Validation.

Cinnamomi cortex (CC), a traditional Chinese herbal medicine, exhibits antidiabetic properties, yet the underlying mechanisms are not fully understood. Our study combined network pharmacology, molecular docking, and experimental validation to elucidate the antidiabetic mechanisms of CC. Active components of CC and their potential antidiabetic targets were identified through TCMSP, DisGeNET, and GeneCards. The PPI networks were constructed with STRING and analyzed with Cytoscape, while GO and KEGG analyses utilized the DAVID database. Molecular docking with core targets was performed using Autodock Vina. The efficacy of CC in diabetes mellitus was evaluated through H&E staining, qPCR, and Western blot in the T2DM mouse. Eleven active components and sixty-six potential antidiabetic targets of CC were identified. The enrichment analysis revealed 288 GO terms and 37 pathways. The molecular docking showed high affinity for PPAR-γ and IL-6 receptors. In vivo studies further confirmed CC's ability to modulate PPAR-γ and IL-6, contributing to its antidiabetic effects. CC manages diabetes by regulating the PPAR-γ pathway and suppressing associated inflammation, providing a multi-pathway therapeutic approach.

The preventive effectiveness of Crocus sativus extract in treating lung injuries caused by inhaled paraquat in rats

Ethnopharmacological relevanceThe herbicide paraquat (PQ) is highly toxic, capable of inducing severe lung inflammation and oxidative stress, resulting in lung fibrosis and respiratory failure. Previous research has demonstrated a range of pharmacological effects associated with Crocus sativus. L (Cs) through its anti-inflammatory, antioxidant and immunomodulatory properties. Pharmacological studies support the widespread use of Cs in traditional medicine to treat respiratory disorders such as coughs and asthma. Aim of studyThis study aimed to investigate the preventive impact of Cs extract and pioglitazone (Pio) on lung inflammation, oxidative stress, pathological alterations, and tracheal reactivity induced by inhaled PQ in rats as compared to dexamethasone (Dexa). MethodsThe control (Ctrl) group of rats was administered with saline aerosol, while the remaining six groups received PQ aerosol eight times every other day. The six PQ exposure groups were treated daily during the exposure period to PQ with either; saline alone, low dose Cs, High dose Cs, Pio alone, Pio combined with low dose Cs, or Dexa of 16 days. ResultsIn the PQ group, the levels of superoxide dismutase (SOD), catalase (CAT), and thiol in the bronchoalveolar lavage fluid (BALF) were declined whereas, the levels of MDA, total and differential WBC, and lung tissue levels of tumor necrosis factor (TNF-α) and Interleukin 10 (IL-10), tracheal responsiveness (TR) to methacholine and lung pathological changes were enhanced. The measured variables showed significant improvement in all treated groups, except for a few variables in Cs (L). The combined Cs (L) + Pio showed higher effects than Cs (L) and Pio alone. For all comparisons, p values were <0.05 to <0.001. ConclusionsThe results showed preventive effect of Cs comparable to that of Dexa and the potential additive preventive capabilities of the Cs and Pio indicate that the involvement of the PPARγ receptor is implicated in the effects induced by Cs.

In Silico and In Vitro Investigation of Phytoconstituents from Flacourtia Jangomas as a Potential Candidate for the Treatment of Type 2 Diabetes Mellitus

AbstractFlacourtia jangomas is a plant used for centuries in Brazil, China, India, and the Malaya Peninsula to treat conditions such as diabetes, asthma, anaemia, and diarrhoea. Despite its therapeutic and economic benefits, the plant has not been popular among farmers due to its limited yield and lack of knowledge about its potential. Targeting PPARγ agonists is a promising approach for discovering and developing effective drugs to treat type 2 diabetes. Due to the activation of the PPARγ through PPARγ agonists, target genes implicated in inflammation, adipogenesis, lipid metabolism, and glucose metabolism are transcriptionally regulated. This study analysed the curated datasets of F. jangomas to identify the binding conformations of the phytoconstituents with different T2DM targets through molecular docking, molecular dynamics, and ADMET prediction approach. To determine the most favourable binding conformations of phytoconstituents that bind with the PPARγ receptors, density functional theory and principal component analysis were performed. The study reveals that the phytoconstituents of F. jangomas can act as PPARγ agonists and could be used to design and optimise the potential antidiabetic agents inspired by natural products. These findings provide a promising approach towards developing effective antidiabetic drugs.

Exploring maternal and developmental toxicity of perfluoroalkyl ether acids PFO4DA and PFO5DoA using hepatic transcriptomics and serum metabolomics

Production of per- and polyfluoroalkyl substances (PFAS) has shifted from long-chain perfluoroalkyl acids to short-chain compounds and those with ether bonds in the carbon chain. Next-generation perfluoroalkylether PFAS include HFPO-DA (“GenX chemicals”), Nafion Byproducts, and the PFOx homologous series that includes perfluoro-3,5,7,9-butaoxadecanoic acid (PFO4DA) and perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoA). PFO4DA and PFO5DoA have been detected in serum and/or tissues from humans and wildlife proximal to contamination point sources. However, toxicity data are extremely limited, with no in vivo developmental toxicology data. To address these data gaps, pregnant Sprague-Dawley rats were exposed via oral gavage to vehicle, PFO4DA, or PFO5DoA across a series of doses (0.1 to 62.5 mg/kg/day) from gestation day (GD) 18–22. Hepatic transcriptomics were assayed in dams and fetuses, and serum metabolomics in dams. These data were overlaid with serum PFO4DA and PFO5DoA concentrations to perform dose-response modeling. Both dams and fetuses exhibited dose-responsive disruption of hepatic gene expression in response to PFO4DA or PFO5DoA, with fetal expression disrupted at lower doses than dams. Several differentially expressed genes were upregulated by every dose of PFO5DoA in both maternal and fetal samples, including genes encoding enzymes that hydrolyze acyl-coA to free fatty acids. Maternal serum metabolomics revealed PFO4DA exposure did not induce significant changes at any tested dose, whereas PFO5DoA exposure resulted in dose-dependent differential metabolite abundance for 149 unique metabolites. Multi-omics pathway analyses of integrated maternal liver transcriptomics and serum metabolomics revealed significant convergent changes as low as 3 mg/kg/d PFO4DA and 0.3 mg/kg/d PFO5DoA exposure. Overall, transcriptomic and metabolomic effects of PFO4DA and PFO5DoA appear consistent with other carboxylic acid PFAS, with primary changes related to lipid metabolism, bile acids, cholesterol, and cellular stress. Importantly, PFO5DoA exposure more potently induced changes in maternal and fetal hepatic gene expression and maternal circulating metabolites, despite high structural similarity. Further, we report in vitro PPARα and PPARγ receptor activation for both compounds as putative molecular mechanisms. This work demonstrates the potential developmental toxicity of alternative moiety perfluoroethers and highlights the developing liver as particularly vulnerable to transcriptomic disruption.Synopsis: Developmental exposure to fluoroether carboxylic acids PFO4DA and PFO5DoA result in differential impacts on hepatic transcriptome in dams and offspring and circulating metabolome in dams, with PFO5DoA exhibiting higher potency than PFO4DA.

Anticancer Properties of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Potential Agonists 4-Thiazolidinone-Pyrazoline Hybrids Les-4368 and Les-4370 in Colorectal Adenocarcinoma Cells In Vitro

Presently, a major challenge is the search for new compounds that may exhibit an inhibitory effect on tumor progression. Recently, the 4-thiazolidinone (4-TZD) group has gained attention in this research field. The aim of the present study was to evaluate the anticancer effects of two new 4-TZD-based derivatives (Z)-5-[5-(2-hydroxyphenyl)- (Les- 4368) and (Z)-5-[5-(4-dimethylaminophenyl)-3-phenyl-4,5-dihydropyrazol-1-ylmethylene]-3-(3-acetoxyphenyl)-2-thioxothiazolidin-4-ones (Les-4370) on peroxisome proliferator-activated receptor gamma (PPARγ)-dependent cytotoxicity in human colorectal adenocarcinoma cells (CACO-2) and in normal human fibroblasts (BJ) in vitro. Les-4368 and Les-4370 exerted a toxic effect on both tested cell lines in high (micromolar) concentrations (10–100 µM). In addition, Les-4368 and Les-4370 applied in the BJ and CACO-2 cells in the concentration range of 10 µM to 100 µM increased the activity of caspase-3 and the production of reactive oxygen species (ROSs). The mRNA expression of PPARγ-related genes (PPARγ, AhR, PXR, and NF-κB) showed certain changes in these parameters, proving the engagement of this receptor in the induction of the biological effects of both tested 4-TZD derivatives. Moreover, the treatment of the BJ and CACO-2 cells with Les-4368, Les-4370, an antagonist (GW9662), or an agonist (rosiglitazone) of the PPARγ receptor also resulted in changes in the above-mentioned parameters. Unfortunately, the tested substances studied cell line work in a non-selective way at a relatively high concentration, which reduces their potential for clinical application. Our research is the preliminary study with the use of these compounds and requires further studies to elucidate the mechanisms of action of their anticancer potential.

MLR-1023 Improves Cognition Deficiency and Oxidative Stress in Lipopolysaccharide-Induced Mice Model of Alzheimer’s Disease: Role of PPAR-gamma Receptors and NO-cGMP-KATP Channels Pathway

Background: This study investigates the effects of MLR-1023 on cognitive deficiency and oxidative stress in a lipopolysaccharide (LPS)-induced mouse model. Objectives: The role of PPAR-gamma receptors and the NO- cyclic GMP (cGMP)-KATP channel pathway were examined to identify the likely mechanisms. Methods: The model was established by LPS injection. Behavioral assays included shuttle box and Y-maze tests. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels were then measured in hippocampal tissue. To explore the probable mechanisms, the mice were pre-treated with agonists and antagonists 15 minutes before MLR-1023 (20 - 40 mg/kg, i.p.) administration. Results: Lipopolysaccharide increased the initial latency (IL) time, while MLR-1023 (40 mg) reduced it. Administration of L-NAME, methylene blue, and glibenclamide with MLR-1023 increased IL duration, while L-arginine, sildenafil, and diazoxide reduced it. Lipopolysaccharide reduced the duration of step-through latency (STL), whereas MLR-1023 increased it. L-NAME, methylene blue, and glibenclamide with MLR-1023 reduced STL duration, but L-arginine, sildenafil, and diazoxide increased it. The spontaneous alternation index decreased with LPS, while MLR-1023 increased it. L-NAME, methylene blue, glibenclamide, and GW9662 decreased this index, whereas L-arginine, sildenafil, diazoxide, and pioglitazone increased it. Lipopolysaccharide increased MDA concentration, while MLR-1023 decreased it. L-NAME, methylene blue, and glibenclamide increased MDA concentration, while L-arginine, diazoxide, and pioglitazone decreased it. Lipopolysaccharide reduced SOD activity, which was improved by MLR-1023. L-NAME, methylene blue, glibenclamide, and GW9662 decreased SOD activity, while sildenafil and pioglitazone increased it. Conclusions: MLR-1023 can improve LPS-induced learning-memory impairment and oxidative stress. The KATP/cGMP/NO pathway and PPARγ receptors are involved in this effect.

Molecular docking of sterol derivatives in Tagetes erecta Linn. as an antiatherosclerotic agents through activation of PPARγ and LXRα receptors

Atherosclerosis is a condition characterized by inflammation in the arteries, which is linked with the accumulation of lipids and alterations in metabolism. Considering that atherosclerosis is the main factor causing death in the world, it is necessary to carry out immediate prevention and treatment to reduce the risk of developing clinical severity. The creation of foam cells, which originate from macrophages, is considered a key element in cardiovascular ailments, particularly in the advancement of atherosclerosis. Two types of the nuclear receptors known as Peroxisome proliferator-activated receptor γ (PPARγ) and liver X receptor α (LXRα), which serve as a primary regulator of cholesterol, intracellular lipid homeostasis and they are instrumental in the process of reverse cholesterol transport (RCT). Activation of these receptors could potentially decrease foam cell formation, consequently lowering the risk of atherogenesis and reducing cardiovascular disease risk. This research aims to determine sterol derivative compounds in Tagetes erecta Linn. which have the best interaction and potential as anti-atherosclerosis through peroxisome proliferator-activated receptor γ (PPARγ) and liver X receptor α (LXRα) activation. The analysis of this study is using docking molecular analysis. The parameters observed in this study were docking score, visualization results, absorption, distribution, metabolism, excretion profile, and toxicity value. The molecular docking outcomes indicate that β-sitosterol and 7β-hydroxysitosterol possess the most favorable binding energy values. They exhibit a positive pharmacokinetic profile, with the exception of gastrointestinal absorption and respiratory toxicity.

RETRACTION: Systemic inflammation and oxidative stress induced by inhaled Paraquat in rat improved by Carvacrol, possible role of PPARγ receptors.

F. Amin, A. Memarzia, H. K. Rad, F. Shakeri and M. H. Boskabady, "Systemic Inflammation and Oxidative Stress Induced by Inhaled Paraquat in Rat Improved by Carvacrol, Possible Role of PPARγ Receptors," Biofactors 47, no. 5 (2021): 778-787, https://doi.org/10.1002/biof.1761. The above article, published online on 05 June 2021 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Irene Diaz-Moreno; the International Union of Biochemistry and Molecular Biology; and Wiley Periodicals LLC. The retraction has been agreed due to considerable overlap with previously published articles from a similar group of authors. As a result, the editors consider a significant portion of the results reported in this study redundant. The authors disagree with the retraction.

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.

Development of an analytical platform for the affinity screening of natural extracts by SEC-MS towards PPARα and PPARγ receptors

BackgroundPeroxisome proliferator-activated receptors (PPARs) belong to the superfamily of nuclear receptors and represent the targets for the therapeutical treatment of type 2 diabetes, dyslipidemia and hyperglycemia associated with metabolic syndrome. Some medicinal plants have been traditionally used to treat this kind of metabolic diseases. Today only few drugs targeting PPARs have been approved and for this reason, the rapid identification of novel ligands and/or chemical scaffolds starting from natural extracts would benefit of a selective affinity ligand fishing assay. ResultsIn this paper we describe the development of a new ligand fishing assay based on size exclusion chromatography (SEC) coupled to LC-MS for the analysis of complex samples such as botanical extracts. The known PPARα and PPARγ ligands, WY-14643 and rosiglitazone respectively, were used for system development and evaluation. The system has found application on an Allium lusitanicum methanolic extract, containing saponins, a class of chemical compounds which have attracted interest as PPARs ligands because of their hypolipidemic and insulin-like properties. SignificanceA new SEC-AS-MS method has been developed for the affinity screening of PPARα and PPARγ ligands. The system proved to be highly specific and will be used to improve the throughput for the identification of new selective metabolites from natural souces targeting PPARα and PPARγ.

Synthesis and In vitro and In silico Anti-inflammatory Activity of New Thiazolidinedione-quinoline Derivatives.

Inflammation is a series of complex defense-related reactions. The inflammation cascade produces various pro-inflammatory mediators. Unregulated production of these pro-inflammatory mediators can lead to a wide range of diseases, including rheumatoid arthritis, sepsis, and inflammatory bowel disease. In the literature, the anti-inflammatory action of quinoline and thiazolidinedione nuclei are well established, alone, and associated with other nuclei. The synthesis of hybrid molecules is a strategy for obtaining more efficient molecules due to the union of pharmacophoric nuclei known to be related to pharmacological activity. Based on this, this work presents the synthesis of thiazolidinedione-quinoline molecular hybrids and their involvement in the modulation of cytokines involved in the inflammatory reaction cascade. After synthesis and characterization, the compounds were submitted to cell viability test (MTT), ELISA IFN-γ and TNF-α, adipogenic differentiation, and molecular docking assay with PPARy and COX-2 targets. LPSF/ZKD2 and LPSF/ZKD7 showed a significant decrease in the concentration of IFN- γ and TNF-α, with a dose-dependent behavior. LPSF/ZKD4 at a concentration of 50 μM significantly reduced IL-6 expression. LPSF/ZKD4 demonstrates lipid accumulation with significant differences between the untreated and negative control groups, indicating a relevant agonist action on the PPARγ receptor. Molecular docking showed that all synthesized compounds have good affinity with PPARγ e COX-2, with binding energy close to -10,000 Kcal/mol. These results demonstrate that the synthesis of quinoline-thiazolidinedione hybrids may be a useful strategy for obtaining promising candidates for new anti-inflammatory agents.

Effect of Myristica fragrans on PGC1α and Synaptophysin Expression in Male Wistar Rats Hippocampus

Background: Nutmeg is an indigenous plant from Indonesia that has been used extensively in herbal treatment. Nutmeg seed extract (NuSE) contains the active compound macelignan, which exhibits pharmacological activities. A previous study stated that NuSE is PPARγ or peroxisome proliferator-activated receptor gamma agonist that potentially enhances synaptic signal modulation. PPARγ activation can activate PGC1α or peroxisome proliferator-activated receptor gamma coactivator-1 alpha as the primary regulator of mitochondrial biogenesis. Mitochondria are involved in synaptic transmission. Increased modulation of signals at synapses can increase neuroplasticity, potentially improving the brain's cognitive function, as seen by the amount of Synaptophysin in the synaptic vesicle membrane for evaluating synaptogenesis.Objective: This research demonstrates how nutmeg seed extract (NuSE) affects PGC1α and synaptophysin expression compared with DHA or docosahexanoieac acid, which has been evidenced to promote neurite growth.Methods: Twenty-four Wistar male rats aged eight weeks were divided into four groups (control, PGA group, NuSE group, and DHA group). The treatment group was administered for 12 weeks using a gavage. After that, the rats were sacrificed, and the hippocampus neurons were collected. The PGC1α and Synaptophysin mRNA expression was measured using semiquantitative reversed PCR, visualized with electrophoresis, and then quantified with ImageJ.Results: This study showed that NuSE increased synaptophysin and PGC1α mRNA expressions compared to the control group with significance statistic (p=0.017, p&lt;0,05) in synaptophysin expression but did not increase PGC1α expression significantly (p=0.364, p&gt;0,05).Conclusion: In conclusion, nutmeg seed extract (NuSE) impacts synaptogenesis in synaptophysin expression to modulate synaptic transmission.

The Pathophysiological, Genetic, and Hormonal Changes in Preeclampsia: A Systematic Review of the Molecular Mechanisms.

Preeclampsia, a serious complication of pregnancy, involves intricate molecular and cellular mechanisms. Fetal microchimerism, where fetal cells persist within maternal tissues and in circulation, acts as a mechanistic link between placental dysfunction and maternal complications in the two-stage model of preeclampsia. Hormones, complements, and cytokines play pivotal roles in the pathophysiology, influencing immune responses, arterial remodeling, and endothelial function. Also, soluble HLA-G, involved in maternal-fetal immune tolerance, is reduced in preeclampsia. Hypoxia-inducible factor 1-alpha (Hif-α) dysregulation leads to placental abnormalities and preeclampsia-like symptoms. Alterations in matrix metalloproteinases (MMPs), endothelins (ETs), chemokines, and cytokines contribute to defective trophoblast invasion, endothelial dysfunction, and inflammation. Preeclampsia's genetic complexity includes circRNAs, miRNAs, and lncRNAs. CircRNA_06354 is linked to early-onset preeclampsia by influencing trophoblast invasion via the hsa-miR-92a-3p/VEGF-A pathway. The dysregulation of C19MC, especially miR-519d and miR-517-5p, affects trophoblast function. Additionally, lncRNAs like IGFBP1 and EGFR-AS1, along with protein-coding genes, impact trophoblast regulation and angiogenesis, influencing both preeclampsia and fetal growth. Besides aberrations in CD31+ cells, other potential biomarkers such as MMPs, soluble HLA-G, and hCG hold promise for predicting preeclampsia and its complications. Therapeutic interventions targeting factors such as peroxisome PPAR-γ and endothelin receptors show potential in mitigating preeclampsia-related complications. In conclusion, preeclampsia is a complex disorder with a multifactorial etiology and pathogenesis. Fetal microchimerism, hormones, complements, and cytokines contribute to placental and endothelial dysfunction with inflammation. Identifying novel biomarkers and therapeutic targets offers promise for early diagnosis and effective management, ultimately reducing maternal and fetal morbidity and mortality. However, further research is warranted to translate these findings into clinical practice and enhance outcomes for at-risk women.

Neuroprotective effects of VCE-004.8 in a rat model of neonatal stroke

BackgroundCurrently there is no effective treatment for neonatal stroke, an acute neurologic syndrome with sequelae, due to focal ischemic, thrombotic, or hemorrhagic event occurring in the perinatal period. VCE-004.8, an aminoquinone exhibiting activity on CB2 and PPARγ receptors, is neuroprotective in adult mice models of acute and chronic brain damaging conditions. We hereby aimed to study VCE-004.8 neuroprotection in a rat model of neonatal stroke. Methods7-day-old (P7) Wistar rats of both sexes were submitted to Middle Cerebral Artery Occlusion (MCAO), receiving i.p. 30 min after vehicle (MCAO + VEH) or VCE-004.8 5 mg/kg (MCAO + VCE). Non-occluded rats served as controls (SHAM). MCAO consequences were assessed at P14 by MRI, histological (TUNEL staining), biochemical (lactate/n-acetyl aspartate ratio by 1H-NMR spectroscopy) and motor studies (grasp test), and at P37 assessing myelination (MBP signal), hemiparesis and hyperlocomotion. Effects of VCE-004.8 on excitotoxicity (glutamate/n-acetyl aspartate, 1H-NMR), oxidative stress (protein nitrosylation, Oxyblot) and neuroinflammation (Toll-like receptor 4 and TNFa expression, Western blot) were assessed at P14. Therapeutic window was assessed by delaying drug administration for 12 or 18 h. ResultsPost-MCAO administration of VCE-004.8 reduced the volume of infarct and histological and biochemical brain damage, reducing hyperlocomotion, restoring motor performance and preserving myelination, in a manner linked to the modulation of excitotoxicity, oxidative stress and neuroinflammation. VCE-004.8 was still effective being administered 12–18 h post-insult. ConclusionsThese data suggest that this drug could be effective for the treatment of stroke in newborns.

Modular Hub Genes in DNA Microarray Suggest Potential Signaling Pathway Interconnectivity in Various Glioma Grades.

Gliomas have displayed significant challenges in oncology due to their high degree of invasiveness, recurrence, and resistance to treatment strategies. In this work, the key hub genes mainly associated with different grades of glioma, which were represented by pilocytic astrocytoma (PA), oligodendroglioma (OG), anaplastic astrocytoma (AA), and glioblastoma multiforme (GBM), were identified through weighted gene co-expression network analysis (WGCNA) of microarray datasets retrieved from the Gene Expression Omnibus (GEO) database. Through this, four highly correlated modules were observed to be present across the PA (GSE50161), OG (GSE4290), AA (GSE43378), and GBM (GSE36245) datasets. The functional annotation and pathway enrichment analysis done through the Database for Annotation, Visualization, and Integrated Discovery (DAVID) showed that the modules and hub genes identified were mainly involved in signal transduction, transcription regulation, and protein binding, which collectively deregulate several signaling pathways, mainly PI3K/Akt and metabolic pathways. The involvement of several hub genes primarily linked to other signaling pathways, including the cAMP, MAPK/ERK, Wnt/β-catenin, and calcium signaling pathways, indicates potential interconnectivity and influence on the PI3K/Akt pathway and, subsequently, glioma severity. The Drug Repurposing Encyclopedia (DRE) was used to screen for potential drugs based on the up- and downregulated hub genes, wherein the synthetic progestin hormones norgestimate and ethisterone were the top drug candidates. This shows the potential neuroprotective effect of progesterone against glioma due to its influence on EGFR expression and other signaling pathways. Aside from these, several experimental and approved drug candidates were also identified, which include an adrenergic receptor antagonist, a PPAR-γ receptor agonist, a CDK inhibitor, a sodium channel blocker, a bradykinin receptor antagonist, and a dopamine receptor agonist, which further highlights the gene network as a potential therapeutic avenue for glioma.

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.

Structure–Activity relationship (SAR) of 18β-glycyrrhetinic acid derivatives on their antitumor activity through the PPARγ receptor and caspase-3 pathway

Licorice is extensively utilized in the food industry, and glycyrrhetinic acid is among the most critical active constituents in licorice. This ingredient has garnered increasing attention in recent years. In a previous study, we identified a new series of Glycyrrhetinic acid derivatives containing piperazine skeleton, using virtual screening techniques based on docking. In this study, we conducted further optimization of the lead compound 4c, with a focus on enhancing the hydrophobic interactions in the binding site to improve agonist efficacy for peroxisome proliferator-activated receptor γ (PPARγ). The obtained compounds were characterized using 1H NMR, 13C NMR, HRMS, and HPLC. Furthermore, these compounds were evaluated strong antitumor activity. Some compounds with potent antitumor activities were tested for their PPARγ agonist activity. Especially, compound 4f showed the most potent antitumor activity with half maximal inhibitory concentration (IC50) values of 2.382 μM against the tested tumor cell lines Siha. Docking simulation was performed to position compound 4f into the PPARγ active site to determine the probable binding conformation. Consequently, we discovered a novel PPARγ agonist 4f that demonstrated high in vitro agonist activity.