Activated Receptor Gamma Research Articles

In-silico analysis of ethanol peel extract of Citrus sinensis on mercury chloride-induced prefrontal cortex damage in Wistar rat

This study evaluated the effect of ethanolic extract of Citrus sinensis peel on mercury chloride-induced changes in the prefrontal cortex of adult Wistar rats. Twenty-five Wistar rats were purchased and divided into five groups containing five animals in each group. Group 1 was administered with distilled water, Group 2, Group 3, Group 4, and Group 5 were administered with 5 mg/kg of mercury chloride only, 5 mg/kg of mercury chloride and 140 mg/kg Silymarin, 5 mg/kg mercury chloride and 1000 mg/kg of ethanoic extract of orange peel, and 5 mg/kg mercury chloride and 1500 mg/kg of ethanoic extract of orange peel. All administration was done orally and the administration lasted for 14 days. The animals were sacrificed humanely using 75 mg/kg ketamine intraperitoneally and prefrontal was dissected out. Part was homogenized in 0.1M phosphate buffered saline for the estimation of superoxide dismutase (SOD), and catalase (CAT) activities, and Malondialdehyde (MDA) level and the other part was fixed by immersion in 10 neutral buffered formal-saline for histological evaluation. The chemical structure of sixteen compounds from Citrus sinensis peel obtained from GC-MS analysis reported in the literature were retrieved from the PubChem compound database and the crystal structure of human peroxisome proliferator- activated receptor gamma (PPARγ; PDB:ID: 2P4Y) reported to increase the expression of catalase gene, human extracellular copper-zinc superoxide dismutase enzyme (PDB ID: 2JLP) and mammalian 15-lipoxygenase - 1 enzyme (PDB ID: 2P0M) responsible for the production of lipid peroxidation were retrieved from the PDB database. Ligands and protein preparation, docking and MM-GBSA relative binding free energy calculation were done in Maestro 2023.1. Data obtained was analyzed using the IBM SPSS (version 25) using one-way ANOVA and p-value < 0.05 was considered statistically significant. The results indicate that the MDA level in control Group(13.29±1.183 μmol) is statistically significantly lower compared to the Group 2 (21.88±1.96 μmol), group 3 (27.44±3.52 μmol), Group 4 (22.20±1.16 μmol) and Group 5 (25.40±3.13 μmol). No statistically significant difference was observed in SOD activity. The CAT activities in control group (53.51±6.83 nmol/ml) was statistically significantly lower compared to the group 2 (26.21±3.70 nmol/ml), Group 3 (27.17±5.32 nmol/ml), Group 4 (25.30±4.24 nmol/ml) and Group5 (26.59±4.22 nmol/ml).The present study suggests, ethanolic extract of Citrus sinensis peel have protective effects on mercury-induced changes in prelimbic part of the prefrontal cortex of adult Wistar rats.

Investigating In Silico and In Vitro Therapeutic Potential of Diosmetin as the Anti-Parkinson Agent.

This study aimed to investigate how diosmetin interacts with seven target receptors associated with oxidative stress (OS) and validate its antioxidant properties for the potential management of Parkinson's disease (PD). In PD, the degeneration of dopaminergic cells is strongly influenced by OS. This stressor is intricately connected to various mechanisms involved in neurodegeneration, such as mitochondrial dysfunction, neuroinflammation, and excitotoxicity induced by nitric oxide. The aim of this research was to establish a molecular connection between diosmetin and OS-associated target receptors was the goal, and it investigated how this interaction can lessen PD. Seven molecular targets - Adenosine A2A (AA2A), Peroxisome Proliferator- Activated Receptor Gamma (PPARγ), Protein Kinase AKT1, Nucleolar Receptor NURR1, Liver - X Receptor Beta (LXRβ), Monoamine Oxidase - B (MAO-B) and Tropomyosin receptor kinase B (TrkB) were obtained from RCSB. Molecular docking software was employed to determine molecular interactions, while antioxidant activity was assessed through in-vitro assays against various free radicals. Diosmetin exhibited interactions with all seven target receptors at their binding sites. Notably, it showed superior interaction with AA2A and NURR1 compared to native ligands, with binding energies of -7.55, and -6.34 kcal/mol, respectively. Additionally, significant interactions were observed with PPARγ, AKT1, LXRβ, MAO-B, and TrkB with binding energies of -8.34, -5.42, -7.66, -8.82, -8.45 kcal/mol, respectively. Diosmetin also demonstrated antioxidant activity against various free radicals, particularly against hypochlorous acid (HOCl) and nitric oxide (NO) free radicals. Diosmetin possibly acts on several target receptors linked to the pathophysiology of PD, demonstrating promise as an OS inhibitor and scavenger.

Potential Therapeutic Effects of Thiazolidinedione on Malignant Glioma.

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant tumor of the central nervous system. GBM has a very low 5-year survival rate and reaching merely a median of ~15 months even with aggressive treatments. PPARγ (Peroxisome proliferator- activated receptor gamma) agonists (ciglitazone), while being widely used on patients of type 2 diabetes mellitus, also have approved anticancer effects. Their action mechanisms on malignant glioma are not fully understood. The aim of this study is to investigate the potential therapeutic effect of PPARγ agonists on maligant glioma. Glioma cell line and in-vivo/ex-vivo animal model intervened by ciglitazone were used to assess the associated mechanism and therapeutic effect. Our results from in vivo and ex vivo experiments showed that ciglitazone not only inhibited tumor growth and its associated angiogenesis, but it also reduced colony formation and migration of tumors. Ciglitazone inhibited the phosphorylation of STAT3 (signal transducer and activator of transcription 3) (at the point of tyrosine 705 by increasing both the amount and activity of SHP-2 (Src homology region 2-containing protein tyrosine phosphatase 2) proteins, based on evidence obtained from immunoprecipitation and immunohistochemistry. Furthermore, ciglitazone activated proteasomes and lysosomes to degrade cell-cycle-related proteins like Cyclin D1, Cyclin E, CDK2 (Cyclin-dependent kinase 2), and CDK4 (Cyclin-dependent kinase 4). Ciglitazone triggered expressions of LC3 (Microtubule-associated protein 1A/1B-light chain 3) and formation of acidic vesicular organelles (AVOs), both of which were implicated in the autophagy pathway. In conclusion, ciglitazone showed the multiple actions to regulate the growth of glioma, which appeared to be a potential candidate for treating malignant glioma.

Neurokinin 3 receptor antagonist-induced adipocyte activation improves obesity and metabolism in PCOS-like mice

AimsNeurokinin-B (NKB)-Neurokinin-3-receptor (NK3R) pathway is remarkably sensitive to energy equilibrium; however, its role in metabolic regulation remains unexplored in polycystic ovary syndrome (PCOS). Therefore, this work aimed to investigate the role of NK3R antagonists (NK3Ra) on metabolic dysfunction and obesity in in vitro and in vivo PCOS models. Main methodsFirst, an observational study using serum samples collected from 19 PCOS patients was performed. Second, prospective case-control experimental studies where NK3Ra (SB222200) was used to treat PCOS-like mice (BALB/c mice), ovariectomized+estrogen implanted obese mice (C57BL/6J mice) and 3T3-L1 murine preadipocytes were carried out to investigate its effect on metabolism in vivo and in vitro. The fat volumes, serum biochemical indexes, adipokines and inflammatory cytokines, metabolism-related gene expression and the concentrations of ATP, NAD+, NADPH…etc. were studied. Key findingsWe found a positive correlation between serum NKB and lipid metabolism indicators in PCOS women. Using the mouse models, we demonstrated that administration of NK3Ra regulates serum adipokines, inhibits weight gain with a marked decrease in fat volume, adipocyte size, and inflammatory cytokines, and promotes oxidative metabolism and energy consumption. NK3Ra reduces lipid accumulation in mature murine adipocytes by inhibiting the expression of peroxisome proliferator- activated receptor gamma (PPAR-γ) and fatty acid binding protein 4 (FABP4) genes. NK3Ras also enhances oxidative metabolism and energy consumption by maintaining intracellular redox homeostasis. SignificanceThis study backs the use of NK3Ras as a potential therapeutic for PCOS since it ameliorates both reproductive and metabolic aberrations.

Studies on the partial characterization of extracted glycosaminoglycans from fish waste and its potentiality in modulating obesity through in-vitro and in-vivo.

Glycosaminoglycans (GAGs) are bioactive polysaccharides or glycoconjugates found in the fish waste having significant health impacts. In the present study it has been attempted to extract GAGs from mackerel fish waste through chemical and enzymatic methods. Further, the extracted GAGs (e-GAGs) were analyzed for their composition (uronic acid, total sugar & sulfate), chemical characterization was carried out through techniques of scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) & Proton NMR. Further, probable major GAGs present was identified by enzymatic digestion. The biological potential of the extracted glycoconjugate was assessed further through in-vitro and in-vivo studies. In-vitro biological activity showed good lipase inhibition (IC50, 2.6mg/mL) and bile acid binding properties (dose-dependent). Lipid accumulation lowered in the e-GAGs differentiated 3T3L1 preadipocyte cells have also been observed. The high fat fed animal (in-vivo) study showed ameliorative effect via reducing blood sugar∼1.28↓, lipid profile↓, plasma insulin∼3.5↓, improved glucose tolerance, and homeostatic model assessment for insulin resistance (HOMA-IR, ∼3.0↓). Furthermore, elimination of bile acid (BA) due to GAG-BA binding properties resultant in removal of elevated fecal triglyceride and cholesterol suggesting its lipid lowering activity. Regulation of various proteins linked to carbohydrate and lipid metabolism including fatty acid synthase (FAS), low density lipoproteins receptor (LDL-R), 7α-hydroxylase, glucose transporter-4 (GLUT4) and Peroxisome proliferator- activated receptor gamma (PPAR-γ) were significant (p < 0.05) with e-GAGs treatment when compared to HFD group. Thus, the e-GAGs showed potential hypolipidemic activity through elimination of bile acid binding property together with regulating the specific protein related to obesity and its associated complications.

Effects of Vitamin A on Yanbian Yellow Cattle and Their Preadipocytes by Activating AKT/mTOR Signaling Pathway and Intestinal Microflora.

Simple SummaryVitamin A is a fat-soluble vitamin that not only plays a role in vision, growth, and development, but also in fat production and metabolism in animals. To improve the production of high-grade beef, it is necessary to explore the molecular mechanism of intramuscular fat deposition in beef cattle through molecular biology techniques. In this study, we selected Yanbian yellow cattle, one of the five major cattle breeds in China, to investigate the effects of vitamin A and its metabolite, all-trans retinoic acid (ATRA), on the proliferation and differentiation of preadipocytes and changes in intestinal microorganisms. It was found that ATRA inhibited adipogenic differentiation of preadipocytes in Yanbian yellow cattle via the AKT/mTOR signaling pathway. This study provides insight into nutritional management and reveals the role of vitamin A in lipid metabolism in Yanbian yellow cattle.In this study, the effects of vitamin A and its metabolite, all-trans retinoic acid (ATRA), on the proliferation and differentiation of preadipocytes and the intestinal microbiome in Yanbian yellow cattle were investigated. Preadipocytes collected from Yanbian yellow cattle treated with different concentrations of ATRA remained in the G1/G0 phase, as determined by flow cytometry. Quantitative reverse-transcription polymerase chain reaction and western blotting analyses showed that the mRNA and protein expression levels of key adipogenic factors, peroxisome proliferator- activated receptor gamma (PPARγ), CCAAT enhancer-binding protein α (C/EBPα), and extracellular signal-regulated kinase 2 (ERK2), decreased. ATRA was found to regulate the mTOR signaling pathway, which is involved in lipid metabolism, by inhibiting the expression of AKT2 and the adipogenic transcription factors SREBP1, ACC, and FAS; the protein and mRNA expression levels showed consistent trends. In addition, 16S rRNA sequencing results showed that a low concentration of vitamin A promoted the growth of intestinal microflora beneficial to lipid metabolism and maintained intestinal health. The results indicated that ATRA inhibited the adipogenic differentiation of preadipocytes from Yanbian yellow cattle through the AKT/mTOR signaling pathway, and that low concentrations of vitamin A may help maintain the intestinal microbes involved in lipid metabolism in cattle.

BMP-2 Long-Term Stimulation of Human Pre-Osteoblasts Induces Osteogenic Differentiation and Promotes Transdifferentiation and Bone Remodeling Processes.

Bone morphogenic protein (BMP-) 2 plays an important role in the regeneration of bone defects by promoting osteogenic differentiation. However, several animal studies have reported adverse side effects of BMP-2, including osteoclast activation, induction of peroxisome proliferator- activated receptor gamma (PPARG)expression, and inflammation. High BMP-2 concentrations are thought to be responsible for these side effects. For this reason, primary pre-osteoblasts were exposed to lower BMP-2 concentrations (1 and 2 µg/mL). Long-term exposure (up to 28 days) was performed to investigate whether this stimulation protocol may promote osteogenic differentiation without causing the side effects mentioned above. The results showed that BMP-2 treatment for 14 or 28 days resulted in increased osteogenesis, through an increase in runt-related transcription factor 2, osterix, alkaline phosphatase, and integrin-binding sialoprotein expression. However, an increase in tumor necrosis factor alpha and receptor activator of nuclear factor kappa-Β ligand protein levels was observed after BMP-2 exposure, indicating also an increased potential for osteoclast activation by osteoblasts. Additionally, morphological changes like intracellular, filled vacuoles could be detected. Enhanced PPARG and perilipin 1 mRNA transcripts and lipid droplets indicated an induced adipogenic differentiation. Overall, the data demonstrate that long-term BMP-2 exposure promotes not only osteogenic differentiation but also adipogenesis and regulates mediators involved in osteoclast activation in vitro.

Comparison of the Robustness of Spectrophotometric Method and High-Performance Liquid Chromatographic Method for the Determination of Pioglitazone in Solid Dosage Form

Pioglitazone is a drug that reduces the amount of glucose (sugar) in the blood. It is included in the class of anti-diabetic drugs called “thiazolidinedione” that are used in the treatment of type II diabetes. It attaches to the peroxisomes proliferated- activated receptor gamma (PPARϒ) on tissues throughout the body and causes the cells to become more sensitive to insulin. As a result, more glucose is removed from the blood.The aim of the study is more precisely to find out the better analytical method for the quantitative measurement of the content of pioglitazone in commercially available drugs using two analytical methods i-e Spectrophotometric method and HPLC method.The analytical method for the pioglitazone hydrochloride was developed by HPLC, and then validated the method according to compendial requirements. Pioglitazone in various Dowglit and Gliden tablets was determined by this developed methodPrecision, Accuracy and stability of Pioglitazone was checked which came out to be100.40% and 100.19% respectively. The analysis of pioglitazone hydrochloride in solid dosage form using the HPLC method shows the results are more sensitive, accurate, validated and economical and can be easily applied to raw materials and finished goods compared to the Spectrophotometer method.

Meta-analysis of the association between PPARγ2 gene Pro12Ala polymorphism and obesity in Chinese population

To explore the relationship between the peroxisome proliferator-activated receptor γ(PPARγ) 2 gene Pro12 Ala polymorphism and the risk of obesity in the Chinese population. Take "peroxisome proliferator activated receptor gamma2", "PPAR gamma2", "pparg2", "peroxisome proliferator-activated receptor gamma2", "obesity", "Pro12 Ala", "gene polymorphism", "Chinese" as searchable words, Chinese people were selected as study subjects from Chinese databases such as CNKI, Wanfang Database, VIP and foreign language databases such as PubMed, Embase, Cochrane Library and Web of Science, which were published from the establishment of the database until December 31, 2019. RevMan 5. 3 software was used for Meta-analysis of the literature with literature score ≥ 5 points. A total of 12 articles were included, including 2233 cases and 1795 healthy controls. Meta-analysis showed that:(1) Dominant gene model: the risk of obesity for those carrying Ala/Ala+Pro/Ala was 1. 86 times that of those carrying Pro/Pro(OR=1. 86, 95%CI 1. 07-3. 21). (2) Additive gene model: the risk of obesity for those carrying Pro/Ala was 1. 79 times that of those carrying Pro/Pro(OR=1. 79, 95% CI 1. 04-3. 08). (3) Allelic model: the risk of obesity in those carrying the allele Ala was 1. 75 times that of those carrying the allele Pro(OR=1. 75, 95% CI 1. 11-2. 78). The subgroup analysis of different regions showed that the combined OR(95% CI) values of the dominant gene model, additive gene model and allelic model in the southern region were 1. 96(1. 12-3. 42), 2. 02(1. 14-3. 56) and 1. 79(1. 06-3. 03), the combined OR(95% CI) values of the dominant gene model, additive gene model and allele model in the northern region were 1. 89(0. 90-3. 97), 1. 77(0. 85-3. 67) and 1. 80(0. 97-3. 36). The polymorphic allele Ala or genotype Ala/Ala or Pro/Ala of PPARγ2 gene may increase the risk of obesity in Chinese population. The correlation between the PPARγ2 gene Pro12 Ala polymorphism and the risk of obesity in the southern population is more obvious.

Nicotine induces a dual effect on the beige-like phenotype in adipocytes

Nicotine, the main component of cigarette smoke, affects white/brown adipocytes. Few studies have concentrated on beige adipocytes. In this study, 3T3-L1 cells were differentiated in the presence of nicotine (25, 50 and 100 ?mol/L) during early differentiation and maintenance stages. Cell viability and the state of lipid droplets were assessed by the MTT assay and Oil Red O, respectively, and the expression of beige-related genes and proteins was examined by RT-qPCR, Western blotting and flow cytometry. Nicotine did not alter adipocyte differentiation; however, it increased the expression of peroxisome proliferator- activated receptor gamma (PPAR?) protein during early differentiation and maintenance. Nicotine treatment during early differentiation downregulated gene and protein expression of PPAR? coactivator 1-alpha (PGC-1?), uncoupling protein 1 (UCP1) and cluster of differentiation 137 (CD137), and gene expression of Cbp/p300 interacting transactivator with Glu/ Asp rich carboxy-terminal domain 1 (Cited1), transmembrane protein 26 (Tmem26), and short stature homeobox 2 (Shox2). Nicotine treatment during the maintenance stage upregulated these beige-related genes/proteins. Nicotine treatment of immature adipocytes damaged beige function through a decrease in PGC-1?/UCP1 expression, but nicotine treatment of mature adipocytes or both immature and mature cells enhanced beige functioning. Nicotine induced beige-like phenotype dysfunction in 3T3-L1 adipocytes. This process may affect thermogenesis in adipose tissue and cause a dysfunction in fat metabolism.

Upregulation of PPAR-gamma activity inhibits cyclooxygenase 2 expression in cortical neurons with N-methyl-d-aspartic acid induced excitatory neurotoxicity

This study aimed to investigate the effect of upregulated peroxisome proliferator-activated receptor-gamma (PPAR-γ) activity on cyclooxygenase 2 (COX-2) expression and N-methyl-d-aspartic acid (NMDA)-induced excitatory neurotoxicity in primary cultured cortical neurons. Rat cortical neurons were cultured for 8 days in vitro, and divided into control, NMDA, MK-801 (selective NMDA antagonist), rosiglitazone (ROSI, PPAR-γ agonist), GW9662 (PPAR-γ antagonist), NS398 (selective COX-2 antagonist) and NS398 + ROSI groups. Two hours after treatment in each group, cell viability, intracellular Ca2+ concentrations, PPAR-γ and COX-2 protein expression were detected by CCK-8 assay, flow cytometry and western blot assay, respectively. The results showed that compared with the control group, 100 μmol/L of NMDA significantly decreased the neuronal cell viability, increased Ca2+ concentrations, which also increased the COX-2 protein expression and decreased PPAR-γ expression in neurons. Compared with the NMDA group, the cell viability was increased, Ca2+ concentrations and COX-2 protein expression were significantly decreased, PPAR-γ expression was significantly increased in the MK-801, ROSI, NS398 and ROSI + NS398 groups (both P < 0.01). This finding suggested that upregulation of PPAR-γ activity can inhibit COX-2 expression, decrease Ca2+ concentrations in primary cultured cortical neurons, and protect neurons against NMDA-induced excitatory neurotoxicity.

AMPK activating and anti adipogenic potential of Hibiscus rosa sinensis flower in 3T3-L1 cells

Ethnopharmacological relevanceThe flowers of Hibiscus rosa sinensis has array of pharmacological actions. They are used in preparation of herbal decoction and teas, which have been used traditionally to reduce body weight and for its effect on metabolic syndrome. Aim of the studyTo investigate the anti adipogenic efficacy of major fraction from ethyl acetate extract of the Hibiscus rosa sinensis flower at 25 and 50 µg/mL (HRF 25 and 50 µg/mL) in 3T3-L1 cells and delineate its possible mechanism of action. Materials and methodsPre adipocyte 3T3-L1 cells were differentiated in the presence and absence of HRF 25 and 50 µg/mL, their lipid accumulation was measured qualitatively by Oil red O staining and quantitatively by triglyceride estimation. Effect on adipolysis was determined, adipogenic and its regulatory gene and protein expression were studied and effect of HRF 25 and 50 µg/mL on AMPK was confirmed in the presence of dorsomorphin. ResultsTreatment with HRF 25 and 50 µg/mL activated AMP-activated protein kinase (AMPK) and was found to alleviate triglyceride accumulation significantly (p < 0.001) by 1.6 and 2.3 times respectively in pre adipocytes during differentiation. HRF 25 and 50 µg/mL also nonsignificantly reduced lipolysis which releases free fatty acids, a major contributing factor for insulin resistance. Activation of AMPK by phosphorylation has led to reduced gene and protein expression of adipogenic factors Peroxisome proliferator- activated receptor gamma (PPAR-γ), CCAT/enhancer binding protein alpha (C/EBPα), Sterol regulatory element- binding protein-1c (SREBP-1c) and their targets Fatty acid binding protein 4 (FABP4), Fatty acid synthase (FAS), Perilipin and enhanced Adiponectin expression. Treatment with HRF 25 and 50 µg/mL also resulted in inactivation of Acetyl-CoA carboxylase (ACC) by enhancing ACC phosphorylation, which reduced the levels of malonyl-CoA an allosteric inhibitor of carnitine palmitoyl transferase 1 (CPT1). Enhanced CPT1 levels causes induction of fatty acid β- oxidation. Effects of HRF were nullified in the presence of AMPK antagonist dorsomorphin. ConclusionIn summary, HRF treatments reduced adipogenesis, enhanced factors regulating fatty acid oxidation and this is mediated by AMPK activation. The results conclusively showed anti-obesity potential of HRF and it might be helpful in treatment of associated complications.

Elevation of serum oxidative stress in patients with retina vein occlusions.

Retina vein occlusion (RVO) is a visual-threatening retinal disease that causes irreversible impaired quality of life. The contribution of oxidative stress behind clinical course of RVO was rarely investigated. The study aimed to measure the serum oxidative biomarker in patients with RVO to investigate further physical response. We measured the serum levels of malondialdehyde (MDA), 8-hydroxy-2-deoxyguanosine (8OHdG), Sirutin 1 (SIRT1), peroxisome proliferator- activated receptor gamma (PPAR-r), Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), orkhead box protein O1 (FOXO1), orkhead box protein O3 (FOXO3), catalase, (SOD) and hydrogen peroxide (H2 O2 ) among 19 patients with cataract as control group and 36 patients with RVO, respectively. The mean MDA, 8OHdG and hydrogen peroxide in the serum were significantly higher in patients with RVO compared with the results in control group subjects. Whereas SIRT1, PPAR-r, PGC-1, FOXO1, FOXO3, catalase and SOD levels in serum were significantly decreased in patients with RVO compared with control group. We demonstrated that the serum level of MDA, 8OHdG and hydrogen peroxide is increased in patients with RVO. Among these, the elevation of MDA, 8OHdG and hydrogen peroxide suggests the increasing of serum oxidative stress in RVO patients. All enzymes related reactive oxygen species scavenge were decreased. Thus, focal RVO may increase systemic oxidative stress within serum.

MH84 improves mitochondrial dysfunction in a mouse model of early Alzheimer\u2019s disease

BackgroundCurrent approved drugs for Alzheimer’s disease (AD) only attenuate symptoms, but do not cure the disease. The pirinixic acid derivate MH84 has been characterized as a dual gamma-secretase/proliferator activated receptor gamma (PPARγ) modulator in vitro. Pharmacokinetic studies in mice showed that MH84 is bioavailable after oral administration and reaches the brain. We recently demonstrated that MH84 improved mitochondrial dysfunction in a cellular model of AD. In the present study, we extended the pharmacological characterization of MH84 to 3-month-old Thy-1 AβPPSL mice (harboring the Swedish and London mutation in human amyloid precursor protein (APP)) which are characterized by enhanced AβPP processing and cerebral mitochondrial dysfunction, representing a mouse model of early AD.MethodsThree-month-old Thy-1 AβPPSL mice received 12 mg/kg b.w. MH84 by oral gavage once a day for 21 days. Mitochondrial respiration was analyzed in isolated brain mitochondria, and mitochondrial membrane potential and ATP levels were determined in dissociated brain cells. Citrate synthase (CS) activity was determined in brain tissues and MitoTracker Green fluorescence was measured in HEK293-AβPPwt and HEK293-AβPPsw cells. Soluble Aβ1–40 and Aβ1–42 levels were determined using ELISA. Western blot analysis and qRT-PCR were used to measure protein and mRNA levels, respectively.ResultsMH84 reduced cerebral levels of the β-secretase-related C99 peptide and of Aβ40 levels. Mitochondrial dysfunction was ameliorated by restoring complex IV (cytochrome-c oxidase) respiration, mitochondrial membrane potential, and levels of ATP. Induction of PPARγ coactivator-1α (PGC-1α) mRNA and protein expression was identified as a possible mode of action that leads to increased mitochondrial mass as indicated by enhanced CS activity, OXPHOS levels, and MitoTracker Green fluorescence.ConclusionsMH84 modulates β-secretase processing of APP and improves mitochondrial dysfunction by a PGC-1α-dependent mechanism. Thus, MH84 seems to be a new promising therapeutic agent with approved in-vivo activity for the treatment of AD.

Synthesis, Biological Screening and &lt;I&gt;in Silico&lt;/I&gt; Studies of Chalcone Based Novel Phenyl Urea Derivatives as Potential Antihyperglycemics

Aim : Current work was aimed to explore the effect of synthesized novel chalcone based1-(4-methoxyphenyl)-3-{4- [(2E)-3-phenylprop-2-enoyl] phenyl} ureaderivatives, on adult male Wister rats in an experimental model of type 2 diabetes. Methods : Type 2 Diabetes was induced in overnight fasted rats by a high fat diet followed by a single intraperitoneal injection of low dose streptozotocin (35mg/kg body weight) leading to hyperglycemia and considerable augmentation in blood urea nitrogen and creatinine levels. Treatment with compounds 2(a-d) and 3(a-c)(dose; 30mg/kg) continued for 28 days followed by oral glucose tolerance test. Docking studies of synthesized compounds with ligand binding domain of the human peroxisome proliferator activated receptor gamma-2(2PRG) were performedto correlate the antihypergycemic activity for possible mode of action. Result : Oral administration of compounds 2(a-d) and 3(a-c)in 35mg/kg for 4 weeks reduced blood glucose level significantly by 68-71% and 71-75% respectively comparable to that of glipizide(80%) in a dose of 1mg/kg/day coupled with significant reduction (p≤0.05) in the increased blood urea nitrogen and serum triglyceride level. Compound 2c have been found most active on the PPAR gamma receptor displaying docking score (-21) comparable to reference ligands Rosiglitazone and pioglitazone. Conclusion : This observation indicates that chalcone based novel phenylureas have the potential to be an effective antihypergycemic agent with probable PPAR gamma agonistic action.

Neuroprotective Effects of Piracetam Versus Peroxisome Proliferator-Activated Receptor-Gamma Agonist Pioglitazone in Drug-Induced Parkinsonism

Parkinsonism is a common and disabling neurodegenerative disease. Drug-induced Parkinsonism is not uncommon. The neuroprotective actions of Piracetam and peroxisome proliferator–activated receptor gamma (PPAR I³) agonist pioglitazone have been reported. The aim of the current work was to investigate and compare the neuroprotective effect of piracetam versus pioglitazone on haloperidol-induced Parkinsonism. 36 male rats constituted the animal model for our study and had been divided into six groups (6 rats/group); control, Haloperidol, Piracetam, Piracetam with haloperidol, Pioglitazone, and Pioglitazone with Haloperidol groups. Hypokinesia was tested by stepping test and blood samples were collected for measurement of serum glucose, calcium, Creatine phosphokinase (CPK), Transforming growth factor beta 1 (TGF-I²1), Fibroblast growth factor 21(FGF-21), Glial cell-Derived Neurotrophic Factor (GDNF). Brains extracted for measurement of basal ganglia Tyrosin hydroxylase (TH) and Beclin gene expression. Haloperidol caused hypokinesia, increased serum glucose, CPK, TGF-I²1, FGF-21, GDNF, basal ganglia TH expression and decreased serum calcium and basal ganglia Beclin expression. Both piracetam and pioglitazone provided neuroprotection and improved hypokinesia and the biochemical markers measured in blood and brains of haloperidol-induced Parkinsonism when administered before haloperidol, however; Pioglitazone had a better effect regarding the improvement of serum glucose, CPK and brain expression of Beclin.

In vitro Studies on Antidiabetic Potential of New Dosage Forms of AYUSH 82

AYUSH 82 powder is an Ayurvedic antidiabetic formulation developed by the Central Council for Research in Ayurvedic Sciences (CCRAS), Ministry of AYUSH, Government of India. It comprises ingredients traditionally used for their beneficial effect in diabetes (Prameha/Madhumeha). The hypoglycemic effects of AYUSH 82 powder have been reported in diabetic subjects. In the current study, the antidiabetic potential of AYUSH 82 powder along with its two new dosage forms – AYUSH 82 mixture extract and AYUSH 82 compound extract- was investigated in vitro for elucidating mechanism of their action by possible α-amylase inhibitory property, insulindependent glucose uptake in skeletal muscle cell line (C2C12 myotubes), and effect on peroxisome proliferator-activated receptor gamma (PPAR-γ) activity. All the three dosage forms of AYUSH 82 – powder, mixture extract, and compound extract – exhibited inhibition of α-amylase activity. AYUSH 82 mixture extract, however, demonstrated highest extent of inhibition in both methanolic (87.4%) and aqueous (48.2%) format. All the three dosage forms of AYUSH 82 also demonstrated an increase in insulin-dependent glucose uptake in C2C12 myotubes as compared with control. However, none of the test items (TIs) exhibited activation of PPAR-γ expression in tested ranges, indicating that antidiabetic potential of TIs may not be mediated via PPAR-γ activation. Results indicated that the new dosage forms of AYUSH 82 (mixture extract and compound extract) may be useful for making new dosage forms of AYUSH 82 as tablets/capsule, etc.

The Role of Peroxisome Proliferator-activated Receptor Gamma in Insulin Resistance Enhanced Alzheimer Disease Pathophysiology.

Background Alzheimer's disease (AD) shares Pathophysiological features with type 2 diabetes (T2D). The nuclear receptor peroxisome Proliferator- activated receptor GAMMA (PPARγ) is a ligand- activated transcription factor that regulates glucose and lipid metabolism and suppress inflammatory gene expression. Aim and hypothesis The potential therapeutic role of PPARγ on cognitive impairment and visuospatial memory in insulin resistance-induced AD using Pioglitazone; a PPARγ agonist. Methods AD was induced in 6 weeks old male rats by adding 6mg/L copper sulphate to drinking water for 8 weeks. Rats were randomly divided into 4 groups(n=10). (1) Normal control group on plain water, (2) AD control group, (3) Fructose drinking induced insulin resistance (IR) AD group, (4) Pioglitazone-treated group received orally (10mg/kg/day) at a volume of 2 ml/kg/day for the last 12 weeks of the 16 weeks period. Groups (3),(4) received 10% fructose solution in drinking water for 16 weeks after developing AD. Cognitive functions were assessed using discrimination index (DI) in object recognition test (ORT) and escape latency in Morris water maze(MWM) test. PPARγ was investigated for its role on γ-secretase and α secretes as well as glucose homeostasis. Results PPARγ level was significantly elevated in IR-induced rats. However, Pioglitazone treatment was associated with restoration of PPARγ level to approximately normal values. Moreover, IR produced significant reduction in DI and prolongation of escape latency. Activation of PPARγ through Pioglitazone showed significant improvement in IR-induced dysfunctions in cognitive function and visuospatial memory in ORT and MWM tasks. Conclusion PPAR γ agonists have a therapeutic potential in AD

Effects of energy expenditure gene polymorphisms on obesity-related traits in obese children

To assess the frequencies of common polymorphisms of genes associated with energy expenditure among Hungarian obese children and investigate their influences on obesity-related traits and metabolic complications of common childhood obesity. In a total of 528 obese children (age 13.2±2.6 years) an oral glucose tolerance test and determination of fasting serum lipid levels were carried out, blood pressure and resting energy expenditure were measured and the children were genotyped for the following gene polymorphisms: Trp64Arg of β3-adrenoreceptor (ADRB3), -3826 A/G of uncoupling protein (UCP)-1, exon 8 45 bp del/ins and -866 G/A of UCP-2, -55 C/T of UCP-3, and Pro12Ala of peroxisome-proliferator activated receptor gamma-2. Carriers of the ADRB3 Arg64 allele had a significantly higher relative body weight and relative body mass index compared with non-carriers. The UCP-2 exon 8 del/ins polymorphism was associated with higher degree of obesity, insulin resistance, dyslipideamia and lower adjusted metabolic rate. Children with UCP-3 -55 T/T genotype had a significantly lower adjusted metabolic rate than the C allele carriers. We found evidence for associations between common polymorphisms of the ADRB3, the UCP-2 and UCP-3 genes and basic metabolic rate as well as level and metabolic consequences of common obesity among Hungarian school-aged children.

Comparison of Gene Expression Levels of Porcine Satellite Cells from Postnatal Muscle Tissue during Differentiation

Muscular satellite cell (SC), which is stem cell of postnatal pig, is an important for study of differentiation into adipogenesis, myogenesis, and osteoblastogenesis. In this study, we isolated and examined from pig muscle tissue to determine capacity in proliferate, differentiate, and expression of various genes. Porcine satellite cells (PSC) were isolated from semimembranosus (SM) muscles of 90∼100 days old pigs according to standard conditions. The cell proliferation increased in multi-potent cell by Masson’s, oil red O, and Alizarin red staining respectively. We per-formed the expression levels of differentiation related genes using real-time PCR. We found that the differentiation into adipocyte increased expression levels of both fatty acid binding protein 4 (FABP4) and peroxisome proliferator- acti-vated receptor gamma (PPARγ) genes (p<0.01). Myocyte increased the expression levels of the myosin heavy chain (MHC), myogenic factor 5 (Myf5), myogenic regulatory factor (MyoD), and Myogenic factor 4 (myogenin) (p<0.01). Osteo-blast increased the expression levels of alkaline phosphatase (ALP) (p<0.01). Finally, porcine satellite cells were indu-ced to differentiate towards adipogenic, myogenic, and osteoblastogenic lineages. Our results suggest that muscle satellite cell in porcine may influence cell fate. Understanding the progression of PSC may lead to improved strat-egies for augmenting meat quality.