Upregulated Peroxisome Proliferator-activated Receptor Gamma Research Articles

The Preventative Effect of Chitooligosaccharides against Chronic Alcoholic Liver Disease by Regulating Alcohol Metabolism, Fatty Acid Metabolism, and Intestinal Barrier Damage

Since chronic alcoholic liver disease (ALD) is a significant global health concern, several studies have shown that chitooligosaccharides (COS) exhibit hepatoprotective effects. This paper examined the COS protective effect on chronic ALD mice. Results showed that COS improved the lipid accumulation, liver injury, and oxidative stress levels in the mice while inhibiting cytochrome P450 protein 2E1 (CYP2E1) expression in the liver and promoting alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH1) expression, indicating that COS could ameliorate alcohol metabolism. Moreover, COS intervention also enhanced the antioxidant capacity of the liver and upregulated peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1), silent information regulator 1 (SIRT1), HO-1, and nuclear factor-erythroid 2-related factor 2 (NRF2) protein levels. In addition, COS increased peroxisome proliferator-activated receptor α (PPARα), acyl-CoA oxidase (ACOX), acyl-CoA synthetase long-chain family member (ACSL), carnitine palmitoyltransferase 1A (CPT-1A), and carnitine palmitoyltransferase 2 (CPT2) protein levels by upregulating the fatty acid β oxidation pathway and restoring mitochondrial genesis. From a liver-gut axis perspective, COS enhanced intestinal barrier function by increasing the adhesion junction (AJ) and intestinal tight junction (TJ) protein expression. Therefore, COS displayed a protective ability against chronic ALD. The results provide a theoretical basis for utilizing supplemental dietary COS as a functional food alternative for treating chronic ALD.

Myelin repair of spinal cord injury in adult mice induced by treadmill training upregulated peroxisome proliferator-activated receptor gamma coactivator 1 alpha.

Growing evidence has proven the efficacy of physical exercise in remyelination and motor function performance after spinal cord injury (SCI). However, the molecular mechanisms of treadmill training on myelin repair and functional recovery after SCI have not yet been fully studied. Here, we explored the effect of treadmill training on upregulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α)-mediated myelin repair and functional recovery in a mouse model of thoracic T10 contusion injury. A 4-week treadmill training scheme was conducted on mice with SCI. The expression levels of oligodendrogenesis-related protein and PGC1α were detected by immunofluorescence, RNA fluorescence in situ hybridization and western blotting. Transmission electron microscopy (TEM) was used to observe myelin structure. The Basso Mouse Scale (BMS) and CatWalk automated gait analysis system were used for motor function recovery evaluation. Motor evoked potentials (MEPs) were also identified. In addition, adeno-associated virus (AAV)-mediated PGC1α knockdown in OLs was used to further unravel the role of PGC1α in exercise-induced remyelination. We found that treadmill training boosts oligodendrocyte precursor cells (OPCs) proliferation, potentiates oligodendrocytes (OLs) maturation, and increases myelin-related protein and myelin sheath thickness, thus impelling myelin repair and hindlimb functional performance as well as the speed and amplitude of nerve conduction after SCI. Additionally, downregulating PGC1α through AAV attenuated these positive effects of treadmill training. Collectively, our results suggest that treadmill training enhances remyelination and functional recovery by upregulating PGC1α, which should provide a step forward in the understanding of the effects of physical exercise on myelin repair.

Discovery of 5,7-Dimethoxy-2-(3,4,5-trimethoxyphenoxy)-chromen-4-one with Lipid Lowering Effects in Hepatocytes.

The population with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is increasing. However, no medicine is indicated for treating these diseases clinically nowadays. Therefore, there is an urgent need to develop a new drug to overcome NAFLD and NASH. Capillarisin, a 2-phenoxychromone originating from Artemisia capillaris Thunb., is well-known for its liver-protective effects. As a result, a series of 2-phenoxychromones was prepared and evaluated for its protective activity against lipid droplet formation in oleic acid (OA)-treated Huh7 cells by means of high-content screening. In the light of the results, the compounds with trimethoxy groups on the phenyl ring possessed better inhibitory properties against lipid accumulation in Huh7 cells, compared to other functional groups on the same ring. Nonetheless, the compounds with a hydroxy group at the C-5 position of the chromone exhibited apparent cytotoxicity. Finally, the active compound, 5,7-dimethoxy-2-(3,4,5-trimethoxyphenoxy)-chromen-4-one (7e), with an IC50 value of 32.2 ± 2.1 μM against lipid accumulation and no significant cytotoxicity, reduced the accumulation of lipid droplets by up-regulating peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) to facilitate the catabolism of fat, which shows promise for further optimization to manage NAFLD and NASH.

Lipid-lowering activity of metformin-soluble soybean polysaccharide nanoparticles.

Soybean dregs are one of the most important albeit underutilized byproducts in soybean processing. In this study, soluble soybean polysaccharides with lipid-lowering activity were extracted from soybean dregs and used as a wall material for embedding metformin. Metformin-soluble soybean polysaccharide nanoparticles (MET-SSPS-NPs) were prepared by electrostatic interaction. The lipid-lowering activity and possible mechanism of MET-SSPS-NPs were investigated. Western blotting was used to detect the expression levels of cell-related protein proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein receptor (LDLR) in vitro. The results showed that MET-SSPS-NPs lowered the expression of PCSK9 and improved LDLR levels. A high-fat diet (HFD) animal model was established to study the lipid-lowering effect of MET-SSPS-NPs by real-time quantitative PCR and western blotting. MET-SSPS-NPs significantly upregulated peroxisome proliferator-activated receptor gamma (PPARγ) expression and downregulated PCSK9, fatty acid-binding protein (FABP)7 and FABP5 expression more strongly than MET or SSPS alone. In conclusion, MET-SSPS-NPs can inhibit PCSK9 expression and improve the level of adipokines, providing a theoretical basis for the application of MET-SSPS-NPs in lipid lowering.

Construction of adipose tissue using a silica expander capsule and cell sheet-assembled of decellularized adipose tissue

Delayed neovascularization and unstable adipose formation are major confounding factors in adipose tissue engineering. A system using decellularized adipose tissue (DAT), adipose-derived stem cells (ADSCs), and human umbilical vein endothelial cells (HUVECs) has been preliminarily studied, but it requires optimization, as adipogenic and angiogenic capabilities for maintaining a stable construct shape are limited. The current study aimed to address these limitations. Our initial modification involved the addition of exogenous chemokine (C–C motif) ligand 2 (CCL2), which resulted in enhanced adipogenesis and angiogenesis. However, further improvement was required due to delayed blood recanalization. To further optimize the system, a vascularized fibrous capsule derived from an implanted silica expander was utilized as a second modification. We hypothesized this would function as both a microbioreactor to fix the seed cells and exogenous CCL2 locally and as a vascular bed to promote neovascularization. Compared with that of the CCL2 loaded ADSC-HUVECs cell sheet assembled DAT system, adding the silica expander capsule resulted in significantly increased construct stability, new vessel intensity, a greater number of Oil Red O-positive lipid droplets, more enhanced tissue remodeling, and upregulated peroxisome proliferator-activated receptor gamma (PPARγ) & leptin expression. Thus, these two modifications helped optimize the currently available ADSC-HUVEC cell sheet assembled DAT system, providing an adipose tissue construction strategy with enhanced adipogenesis and angiogenesis to reconstruct soft tissue defects. Moreover, close-to-normal leptin expression provided the engineered adipose tissue with a glucometabolic function, in addition to remodeling capabilities. Statement of significanceDelayed neovascularization and unstable adipose formation are the two major problems in tissue engineering adipose. Here, we introduced an adipose tissue engineering construction strategy using a silica expander capsule along with hADSCs-HUVECs cell sheet-assembled DAT in a CCL2-rich microenvironment. Our data suggested that CCL2 could improve angiogenesis and adipogenesis in vitro and in vivo. The addition of tissue expander capsule could further improve the stability of construction and fabricated adipose tissue with increased new vessel intensity, greater numbers of Oil Red O-positive lipid droplets, more enhanced tissue remodeling, and upregulated leptin expression. CCL2 and expander capsule can have clinical utility for soft tissue defects repair, and these two factors can be useful in other tissue engineering.

Evodiamine Lowers Blood Lipids by Up-Regulating the PPARγ/ABCG1 Pathway in High-Fat-Diet-Fed Mice.

The natural alkaloid evodiamine enhances cholesterol efflux from cultured THP-1-derived macrophages, but whether it has any impact on blood lipids in vivo remains unknown. In this study, the effect of evodiamine on hyperlipidemia induced by a high-fat diet (HFD) was investigated in mice. Intragastric administrations of evodiamine (10 and 20 mg/kg) for 8 weeks resulted in a significant improvement of metabolic lipid profiles by reducing the plasma levels of triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C). Evodiamine also significantly decreased hepatic lipid accumulation and hepatic total bile acids (TBA). Mechanistically, evodiamine increased ATP-binding cassette transporter G1 (ABCG1) mRNA and protein expression and up-regulated peroxisome proliferator-activated receptor gamma (PPARγ) expression in the liver. Taken together, the natural product evodiamine lowers blood lipids in HFD-fed mice likely through promoting the PPARγ-ABCG1 signaling pathway.

Low-intensity pulsed ultrasound prevents angiotensin II-induced aortic smooth muscle cell phenotypic switch via hampering miR-17-5p and enhancing PPAR-γ

Vascular events can trigger a pathological phenotypic switch in vascular smooth muscle cells (VSMCs), decreasing and disrupting the plasticity and diversity of vascular networks. The development of novel therapeutic approaches is necessary to prevent these changes. We aimed to investigate the effects and associated mechanisms of low-intensity pulsed ultrasound (LIPUS) irradiation on the angiotensin II (AngII)-induced phenotypic switch in VSMCs. In vivo, AngII was infused subcutaneously for 4 weeks to stimulate vascular remodeling in mice, and LIPUS irradiation was applied for 20min every 2 days for 4 weeks. In vitro, cultured rat aortic VSMCs (RAVSMCs) were pretreated once with LIPUS irradiation for 20min before 48-h AngII stimulation. Our results showed that LIPUS irradiation prevents AngII-induced vascular remodeling of the whole wall artery without discriminating between adventitia and media in vivo and RAVSMC phenotypic switching in vitro. LIPUS irradiation downregulated miR-17-5p expression and upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) expression. The PPAR-γ activator rosiglitazone could mimic the favorable effects of LIPUS irradiation on AngII-treated RAVSMCs. In contrast, GW9662 could impede the LIPUS-mediated downregulation of RAVSMC proliferation and inflammation under AngII stimulation conditions in vivo and in vitro. Also, the miR-17-5p agomir has the same effects as GW9662 in vitro. Besides, the inhibitory effects of GW9662 against the anti-remodeling effects of LIPUS irradiation in AngII-induced RAVSMCs could be blocked by pretreatment with the miR-17-5p antagomir. Overall, LIPUS irradiation prevents AngII-induced RAVSMCs phenotypic switching through hampering miR-17-5p and enhancing PPAR-γ, suggesting a new approach for the treatment of vascular disorders.

Gut Microbiota Composition Affects Procyanidin A2-Attenuated Atherosclerosis in ApoE-/- Mice by Modulating the Bioavailability of Its Microbial Metabolites.

Procyanidin A2 (PCA2) has been shown to improve lipid metabolism. However, it remains to know whether it can play a role in preventing atherosclerosis (AS) through gut microbiota. This study examined the effect of PCA2 on high fat diet (HFD)-induced AS in ApoE-/- mice with an intact and antibiotic-depleted microbiota. PCA2 administration for 12 weeks attenuated HFD-induced AS in ApoE-/- mice, evidenced by obviously alleviating the histological abnormalities of the aorta, lipid accumulation, oxidative stress, and inflammation, which were accompanied by downregulating the expression of vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 and upregulating peroxisome proliferator-activated receptor gamma, cholesterol 7 alpha-hydroxylase, and ATP-binding cassette transporter A1. Moreover, PCA2 treatment reshaped the gut microbiota imbalance caused by HFD, especially reducing the ratio of Firmicutes/Bacteroidetes and increasing the abundance of Verrucomicrobia. However, antibiotic intervention almost offset the alleviation of AS by PCA2 and prevented the biotransformation of PCA2 by gut microbiota, thus resulting in a 2327.21-6.27-fold decrease in its microbial metabolites of plasma. There was a marked correlation among the microbiota composition, the bioavailability of PCA2-derived microbial metabolites, and AS indicators. The findings indicate that the gut microbiota robustly influences the bioavailability of microbial metabolites that may partially drive the AS resilience property of PCA2.

RETRACTED: Echinacoside improves diabetic liver injury by regulating the AMPK/SIRT1 signaling pathway in db/db mice

Echinacoside (ECH) is a natural compound extracted from the stem of the Cistanche deserticola plant, has significant biological properties, including antioxidant, anti-inflammatory, neuroprotective, anti-tumor, hepatoprotective, and immunomodulatory properties. In this study, we aimed to explore the protection effects and mechanisms of ECH on diabetic liver injury in db/db mice. Overall, 6-week-old db/db mice (n=20) were randomly allocated to 2 groups: diabetic model group (db/db group, intragastric administration of normal saline, n=10) and ECH-treated group (db/db+ECH group, n=10). Additionally, the normal control group comprised 6-week-old db/m mice (db/m group, normal saline intragastric administration, n=10). ECH was administered once a day for 10weeks. Weight and fasting blood glucose (FBG) were measured biweekly. HE staining and Oil O staining were used to evaluate liver tissue pathological changes and lipid accumulation respectively. Immunofluorescence staining, Western blot and RT-PCR analysis were used to detect the expression of components of the AMPK/SIRT1 signaling axis. The results showed that the administration of echinacoside for 10weeks could significantly improve liver injury and insulin resistance in db/db mice (p<0.01). Also, echinacoside treatment helped to reduce blood lipids and blood glucose (p<0.01). Moreover, ECH actived AMPK/SIRT1 signaling, upregulated peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), proliferator-activated receptor-α (PPARα), carnitine palmitoyl transferase-1A (CPT1A) in db/db mice (p<0.01). The effect of ECH may be elicited by the activation of the liver AMPK/SIRT1 pathway and its downstream factors to improve adiposity, insulin resistance, and dyslipidemia.

Curcumin administration and the effects on psychological status and markers of inflammation and oxidative damage in patients with type 2 diabetes and coronary heart disease.

This study assessed the effects of curcumin intake on psychological status, markers of inflammation and oxidative damage in patients with type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD). This randomized, double-blind, placebo-controlled trial was performed in 60 patients with T2DM and CHD, aged 45-85 years with 2- and 3-vessel CHD. Patients were randomized into two groups to receive either 1000mg/day curcumin (n=30) or placebo (n=30) for 12 weeks. Using RT-PCR method, gene expression related to insulin metabolism and inflammatory markers on mononuclear cells from peripheral blood was evaluated. Curcumin intake significantly decreased Pittsburgh Sleep Quality Index (PSQI) (β-1.27; 95% CI,-2.27,-0.31; P=0.01) compared to the placebo group. Curcumin intake caused a significant reduction in malondialdehyde (MDA) (β-0.20μmol/L; 95% CI,-0.36,-0.04; P=0.01), significant increase in total antioxidant capacity (TAC) (β 75.82mmol/L; 95% CI, 3.400, 148.25; P=0.04) and glutathione (GSH) levels (β 63.48μmol/L; 95% CI, 26.58, 100.37; P=0.001) when compared with the placebo. Additionally, curcumin intake upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) (P=0.01). Curcumin intake for 12 weeks in patients with T2DM and CHD had beneficial effects on PSQI, TAC, GSH, MDA values, and gene expression of PPAR-γ. This study was retrospectively registered in the Iranian website (www.irct.ir) for registration of clinical trials (http://www.irct.ir: IRCT20170513033941N63).

Ubiquitin Pathway Is Associated with Worsening Left Ventricle Function after Mitral Valve Repair: A Global Gene Expression Study.

The molecular mechanism for worsening left ventricular (LV) function after mitral valve (MV) repair for chronic mitral regurgitation remains unknown. We wished to assess the LV transcriptome and identify determinants associated with worsening LV function post-MV repair. A total of 13 patients who underwent MV repair for chronic primary mitral regurgitation were divided into two groups, preserved LV function (N = 8) and worsening LV function (N = 5), for the study. Specimens of LV from the patients taken during surgery were used for the gene microarray study. Cardiomyocyte cell line HL-1 cells were transfected with gene-containing plasmids and further evaluated for mRNA and protein expression, apoptosis, and contractile protein degradation. Of 67,258 expressed sequence tags, microarrays identified 718 genes to be differentially expressed between preserved-LVF and worsening-LVF, including genes related to the protein ubiquitination pathway, bone morphogenetic protein (BMP) receptors, and regulation of eIF4 and p70S6K signaling. In addition, worsening-LVF was associated with altered expressions of genes pathologically relevant to heart failure, such asdownregulated apelin receptors and upregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A). HL-1 cardiomyocyte cells transfected with ubiquitination-related genes demonstrated activation of the protein ubiquitination pathwaywith an increase in the ubiquitin activating enzyme E1 (UAE-E1). It also led to increased apoptosis, downregulated and ubiquitinated X-linked inhibitor of apoptosis protein (XIAP), and reduced cell viability. Overexpression of ubiquitination-related genes also resulted in degradation and increased ubiquitination of α-smooth muscle actin (SMA). In conclusion, worsening-LVF presented differential gene expression profiles from preserved-LVF after MV repair. Upregulation of protein ubiquitination-related genes associated with worsening-LVF after MV repair may exert adverse effects on LV through increased apoptosis and contractile protein degradation.

The 5,7-Dimethoxyflavone Suppresses Sarcopenia by Regulating Protein Turnover and Mitochondria Biogenesis-Related Pathways.

Sarcopenia is a muscle disease featured by the loss of muscle mass and dysfunction with advancing age. The 5,7-dimethoxyflavone (DMF), a major flavone found in Kaempferia parviflora, has biological activities, including anti-diabetes, anti-obesity, and anti-inflammation. However, its anti-sarcopenic effect remains to be elucidated. This current study investigated the inhibitory activity of DMF on sarcopenia. Eighteen-month-old mice were orally administered DMF at the dose of 25 mg·kg−1·day−1 or 50 mg·kg−1·day−1 for 8 weeks. DMF not only stimulated grip strength and exercise endurance but also increased muscle mass and volume. Besides, DMF stimulated the phosphatidylinositol 3-kinase-Akt pathway, consequently activating the mammalian target of rapamycin-eukaryotic initiation factor 4E-binding protein 1-70-kDa ribosomal protein S6 kinase pathway for protein synthesis. DMF reduced the mRNA expression of E3 ubiquitin ligase- and autophagy-lysosomal-related genes involved in proteolysis via the phosphorylation of Forkhead box O3. DMF upregulated peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, nuclear respiratory factor 1, and mitochondrial transcription factor A along with the increase of relative mitochondrial DNA content. DMF alleviated inflammatory responses by reducing the tumor necrosis factor-alpha and interleukin-6 serum and mRNA levels. Collectively, DMF can be used as a natural agent to inhibit sarcopenia via improving protein turnover and mitochondria function.

Free Fatty Acids Promote the Development of Prostate Cancer by Upregulating Peroxisome Proliferator-Activated Receptor Gamma.

IntroductionAs one of the most common forms of cancer that threatens men’s health, prostate cancer (PCa) is under a trend of increasing morbidity and mortality in most countries. More and more studies have pointed out that obesity is closely linked to the occurrence and development of PCa, although there are still many undiscovered molecular mechanisms between the two.MethodsIn the present study, we compare serum lipid levels in patients with PCa and normal individuals. PCa cells (PC3 and 22RV1) were cultured in vitro, the TC/TG/HDL/GLU assay kit was used to detect the glucose and lipid metabolism level of PCa cells, the flow cytometry technique was used to detect the proliferation ability of PCa cells, and the Transwell was used to detect the invasion and migration ability of PCa cells. Western blot/quantitative real-time PCR was used to detect peroxisome proliferator-activated receptor γ (PPARγ) and vimentin/vascular endothelial growth factor-A (VEGF-A) expression levels, and immunohistochemistry was used to observe tumor-associated gene expression levels in nude mice. All data were analysed using the Independent samples t-test or rank sum test.ResultsWe found higher levels of FFA in the serum of patients with PCa. In vitro experiments have demonstrated that high levels of FFA can promote the proliferation, migration and invasion of two PCa cells (PC3 and 22RV1) and affect the energy metabolism of PCa cells. The upregulated PPARγ plays a key role in this process, and vimentin may be involved in this signaling pathway.ConclusionWe infer that high levels of FFA may promote PCa development by upregulating PPARγ expression.

3D microtissue–derived human stem cells seeded on electrospun nanocomposites under shear stress: Modulation of gene expression

ObjectiveDifferent microenvironments trigger distinct differentiation of stem cells. Even without chemical supplementation, mechanical stimulation by shear stress may help to induce the desired differentiation. The cell format, such as three-dimensional (3D) microtissues (MTs), MT-derived cells or single cells (SCs), may have a pivotal impact as well. Here, we studied modulation of gene expression in human adipose–derived stem cells (ASCs) exposed to shear stress and/or after MT formation. Materials and methodsElectrospun meshes of poly-lactic-co-glycolic acid and amorphous calcium phosphate nanoparticles (PLGA/aCaP) at a weight ratio of 60:40 were seeded with human ASCs as MTs or as SCs and cultured in Dulbecco's modified Eagle's medium without chemical supplementation. After 2 weeks of static culture, the scaffolds were cultured statically for another 2 weeks or placed in a Bose® bioreactor with a flow rate per area of 0.16 mL cm−2 min−1. Stiffness of the scaffolds was assessed as a function of time. After 4 weeks, minimum stem cell criteria markers and selected markers of osteogenesis, endothelial cell differentiation, adipogenesis and chondrogenesis were analysed by quantitative real-time polymerase chain reaction. Additionally, cell distribution within the scaffolds and the allocation of the yes-associated protein (YAP) in the cells were assessed by immunohistochemistry. ResultsMTs decayed completely within 2 weeks after seeding on PLGA/aCaP. The osteogenic marker gene alkaline phosphatase and the endothelial cell marker gene CD31 were upregulated in MT-derived ASCs compared with SCs. Shear stress realised by fluid flow perfusion upregulated peroxisome proliferator–activated receptor gamma 2 expression in MT-derived ASCs and in SCs. The nuclear-to-cytoplasmic ratio of YAP expression was doubled under perfusion compared with that under static culture for MT-derived ASCs and SCs. ConclusionsOsteogenic and angiogenic commitments were more pronounced in MT-derived ASCs seeded on bone biomimetic electrospun nanocomposite PLGA/aCaP than in SCs seeded without induction medium. Furthermore, the static culture was superior to the perfusion regimen used here, as shear stress resulted in adipogenic commitment for MT-derived ASCs and SCs, although the YAP nuclear-to-cytoplasmic ratio indicated higher cell tensions under perfusion, usually associated with preferred osteogenic differentiation.

Effects of gold nanostructures on differentiation of mesenchymal stem cells

Nanoparticles are nanocrystals with complex facets and defective structures that do not adopt an idealised shape. Various physicochemical parameters of nanoparticles, such as surface composition, size, and stiffness, can regulate differentiation in mesenchymal stem cells (MSCs), but the influence of shapes with many edges and corner regions has not been investigated. Herein, we investigated the effects of two gold nanostructures modified with 11-mercaptoundecanoic acid, namely gold nanocubes (MUA-AuNCs) and nanooctahedras (MUA-AuNOs), on viability and differentiation in rat bone marrow MSCs (bMSCs). Analysis of cytotoxicity and proliferation demonstrated good biocompatibility, with concentrations <100 μg·mL−1 not significantly different from untreated controls. Alkaline phosphatase activity and Alizarin Red S staining revealed weaker potential for bMSCs to differentiate into osteoblasts following treatment with both low (5 μg·mL−1) and high (25 μg·mL−1) concentrations of the gold nanostructures. By contrast, Oil Red O staining showed that both nanostructures enhanced adipogenic differentiation, and upregulated peroxisome proliferator-activated receptor gamma (PPARγ) and fatty acid binding protein-4 (Fabp4) expression at both mRNA and protein levels. The effects on differentiation were both structure- and dose-dependent; MUA-AuNOs were more effective for enhancing adipogenic differentiation and weakening osteogenic differentiation, possibly due to generating higher levels of reactive oxygen species (ROS). These findings lay the foundation for using these nanoparticles as ex vivo labels in MSC-based imaging and therapy.

Hypoxia-induced PGC-1α Regulates Mitochondrial Function and Tumorigenesis of Colorectal Cancer Cells.

Hypoxia promotes tumor proliferation and metastasis in colorectal cancer (CRC). Since the tumor microenvironment is generally characterized by hypoxia, its understanding is important for cancer therapy. We hypothesized that hypoxia promotes the mitochondrial function, mobility, and proliferation of CRC by up-regulating peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). To assess the effects of PGC-1α under hypoxia, we investigated the mitochondrial function, cell motility, and sphere formation as well as proliferation and apoptosis of CRC. Under hypoxia, we confirmed the increased expression of PGC-1α and reduced production of reactive oxygen species (ROS) by activating anti-oxidant enzymes. Also, up-regulation of PGC-1α enhanced the motility, sphere formation, and proliferation of CRC. Under the presence of the anti-cancer drug 5-fluorouracil (5FU), up-regulation of PGC-1α under hypoxia promoted resistance of CRC against 5FU-induced apoptosis. Targeting PGC-1α could to be a powerful strategy for CRC therapy.

Tanshinone IIA ameliorates non-alcoholic fatty liver disease through targeting peroxisome proliferator-activated receptor gamma and toll-like receptor 4.

ObjectiveTo investigate the cellular mechanisms of action of tanshinone IIA on the fatty liver disease induced by a high-fat diet in an animal model of non-alcoholic fatty liver disease (NAFLD).MethodsAdult male Sprague Dawley rats were randomized into one of three groups: regular rat diet (CON group) for 4 months; high-fat diet (HFD group) for 4 months; HFD for 2 months followed by tanshinone IIA treatment plus HFD (TAN group) for a further 2 months. A range of physical and biochemical markers of lipid accumulation and fatty liver disease were measured and compared between the groups.ResultsTanshinone IIA treatment significantly reduced fat accumulation in the liver and plasma lipid levels that had been increased by HFD. The toll-like receptor (TLR4)/nuclear factor kappa B (NF-κB) signalling pathway was silenced by tanshinone IIA treatment. Tumour necrosis factor-α and interleukin-6 were reduced by tanshinone IIA. Hepatocyte apoptosis was inhibited by tanshinone IIA. Tanshinone IIA upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ), which resulted in an improvement in the oxidative status.ConclusionTanshinone IIA ameliorates NAFLD by targeting PPAR-γ and TLR4, resulting in decreased plasma lipids and oxidative stress, suggesting this strategy may form the basis of novel NAFLD therapies.

The Effects of Selenium Supplementation on Gene Expression Related to Insulin and Lipid Metabolism, and Pregnancy Outcomes in Patients with Gestational Diabetes Mellitus: a Randomized, Double-Blind, Placebo-Controlled Trial.

This study was performed to evaluate the effects of selenium supplementation on gene expression related to insulin and lipid metabolism, and pregnancy outcomes in patients with gestational diabetes mellitus (GDM). The current randomized, double-blind, placebo-controlled clinical trial was conducted in 36 patients with GDM. Participants were randomly divided into two groups to intake either 200μg/day selenium supplements as selenium yeast or placebo (n = 18 each group) for 6weeks. Selenium supplementation upregulated peroxisome proliferator-activated receptor gamma (P = 0.03) and glucose transporter 1 (GLUT-1) (P = 0.01) in lymphocytes of subjects with GDM compared with the placebo. Selenium supplementation did not affect gene expression of low-density lipoprotein receptor (LDLR) and lipoprotein(a) [Lp(a)]. Supplementation with selenium had a significant decrease in incidence of newborns' hyperbilirubinemia (5.6% vs. 33.3%, P = 0.03) and newborns' hospitalization (5.6% vs. 33.3%, P = 0.03) compared with the placebo. Overall, we found that selenium supplementation for 6weeks among patients with GDM significantly increased PPAR-γ and GLUT-1 expression, but did not affect gene expression of LDLR and LP(a). It also reduced incidence of newborns' hyperbilirubinemia and newborns' hospitalization. Clinical trial registration number: http://www.irct.ir: IRCT20170513033941N35.

YAP1 regulates PPARG and RXR alpha expression to affect the proliferation and differentiation of ovine preadipocyte

Adipose tissue development is regulated by a serial of developmental signaling pathways. The Hippo pathway is a novel signaling cascade closely associated with adipogenesis. While most of Hippo pathway components had been verified that have a vital role in preadipocytes proliferation and differentiation, little is known about the function of Yes-associated protein 1 (YAP1) in mammalian adipose tissue development. Therefore, we investigated the role of YAP1 in ovine adipose tissue development by in vitro and in vivo experiments. We observed that the adipocyte size in subcutaneous adipose tissue increased with development. YAP1 expression increased during adipose tissue development, while decreased during the differentiation of ovine preadipocytes in vitro. YAP1 knockdown notably promoted lipid accumulation and suppressed ovine preadipocyte proliferation. In addition, we observed that YAP1 deficiency significantly upregulated peroxisome proliferator-activated receptor gamma (PPARG) and retinoid X receptor alpha (RXR alpha) expression. By contrast, overexpression of YAP1 led to the suppression of preadipocyte differentiation, lipid droplets formation, and PPARG expression. In brief, our findings demonstrated that YAP1 regulates the proliferation and differentiation of ovine preadipocyte via altering PPARG and RXR alpha expression.

Cocoa Shell Phenolic Compounds Preserve Mitochondrial Function and Insulin Sensitivity in Adipocytes by Attenuating Their Inflammatory Interplay with Macrophages (FS15-06-19)

ObjectivesThe objective was to evaluate the effect of an aqueous phenolic extract from cocoa shell (CAE) and its main phenolic compounds to prevent the adipogenesis-induced loss of mitochondrial function and insulin sensitivity, targeting the inflammatory interplay macrophages-adipocytes in vitro. MethodsCAE and its main phenolic compounds (protocatechuic acid, procyanidin B2, and epicatechin) were tested in cell culture of RAW264.7 macrophages and 3T3-L1 mature adipocytes. Macrophages were stimulated with lipopolysaccharide (LPS, 1 μg/mL). Adipocytes were treated with the conditioned media (CM) from LPS-stimulated macrophages. Biomarkers for inflammation, mitochondrial function, and insulin sensitivity were determined after 24 h co-treatment with CAE and LPS/CM using chemical and immunochemical techniques. ResultsLPS-stimulated macrophages showed reduced inducible nitric oxide synthase and cyclooxygenase-2 expression and lowered NO and pro-inflammatory cytokines release when treated with CAE and pure phenolics. Inflammatory crosstalk created by stimulating adipocytes with CM was arrested; CAE diminished tumor necrosis factor-α (67%, p < 0.05) and highly promoted adiponectin secretion (12.3-fold, p < 0.05). Mitochondrial function, measured by reactive oxygen species production, mitochondrial content, and activity, was preserved in CM-treated adipocytes through up-regulating peroxisome proliferator-activated receptor gamma coactivator 1-α expression (46%, p < 0.05). Significant (p < 0.05) increases in insulin receptor (9-fold, p < 0.05), phosphoinositide 3-kinase (3-fold, p < 0.05), protein kinase B (4-fold, p < 0.05) phosphorylation and a decrease in insulin receptor substrate 1 serine phosphorylation induced increased glucose uptake (34%, p < 0.05) and glucose transporter 4 translocation (14-fold, p < 0.05) in CM-induced adipocytes. ConclusionsCocoa shell extract polyphenols reduced macrophages-adipocytes inflammatory interaction preventing mitochondrial dysfunction and insulin resistance. For the first time, cocoa shell aqueous extract showed a positive effect on adipogenesis and inflammation-related disorders. Funding SourcesUniversidad Autónoma de Madrid-Banco Santander, United States Department of Agriculture-National Institute of Food and Agriculture-HATCH, and the Spanish Ministry of Science and Innovation.