Peroxisome Proliferator-activated Receptor-γ Expression Research Articles

Microglial forkhead box O3a deficiency attenuates LPS-induced neuro-inflammation and depressive-like behaviour through regulating the expression of peroxisome proliferator-activated receptor-γ.

Depression is closely linked with microglial activation and neuro-inflammation. Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays an important role in M2 activation of microglia. Forkhead box (FOX) O3a has been implicated in the regulation of mood-relevant behaviour. However, little is known about the inflammatory mechanisms of in the microglia of the brain. Here, we have investigated the role of microglial FOXO3a/PPAR-γ in the development of depression. The effect of FOXO3a on microglia inflammation was analysed in vitro and in lipopolysaccharide (LPS)-induced depression-like behaviours in vivo. ChIP-seq and Dual-luciferase reporter assays were used to confirm the interaction between FOXO3a and PPAR-γ. Behavioural changes were measured, while inflammatory cytokines, microglial phenotype and morphological properties were determined by ELISA, qRT-PCR, western blotting and immunostaining. Overexpression of FOXO3a significantly attenuated expression of PPAR-γ and enhanced the microglial polarization towards the M1 phenotype, while knockdown of FOXO3a had the opposite effect. FOXO3a binds to the promoters of PPAR-γ and decreases its transcription activity. Importantly, deacetylation and activation of FOXO3a regulate LPS-induced neuro-inflammation by inhibiting the expression of PPAR-γ in microglia cells, supporting the antidepressant potential of histone deacetylase inhibitors. Microglial FOXO3a deficiency in mice alleviated LPS-induced neuro-inflammation and depression-like behaviours but failed to reduce anxiety behaviour, whereas pharmacological inhibition of PPAR-γ by GW9662 restored LPS-induced microglial activation and depressive-like behaviours in microglial FOXO3a-deficient mice. FOXO3a/PPAR-γ axis plays an important role in microglial activation and depression, identifying a new therapeutic avenue for the treatment of major depression.

Antihyperlipidemic activity of myricetin

AbstractMyricetin has been reported to have a wide variety of beneficial physiological functions. The present study investigated the antihyperlipidaemic activity of myricetin against hyperlipidaemia of high-fat diet-fed obese rats. The four-week antihyperlipidaemic activity was assayed by giving different doses of myricetin to hyperlipidaemic rats. Results showed that myricetin could reduce the harm caused by oxidative stress, decrease thiobarbituric acid reactive substances value, and decrease total cholesterol and triacylglycerol levels of hyperlipidaemic rats. Quantitative analysis of gene expression showed that myricetin's lipid-lowering activity can be activated by downregulating gene expression of fatty acid synthase (FAS) and peroxisome proliferator-activated receptor-γ (PPARγ) with upregulation of hormone-sensitive lipase (HSL) mRNA level. Thus, myricetin had significant health benefits and could be explored as a potentially promising dietary supplement for treating hyperlipidaemia.

Norisoboldine, a Natural Alkaloid from Lindera aggregata (Sims) Kosterm, Promotes Osteogenic Differentiation via S6K1 Signaling Pathway and Prevents Bone Loss in OVX Mice.

Norisoboldine (NOR) is a major isoquinoline alkaloid component in the traditional Chinese herbal plant Lindera aggregata (Sims) Kosterm, with previously reported anti-osteoclast differentiation and antiarthritis properties. However, the roles of NOR on osteoblasts, bone marrow mesenchymal stem cells (BMSCs), and osteoporosis in vivo have never been well established. This study investigates the ability of NOR to improve bone formation in vitro and in vivo. Osteoblasts and BMSCs are used to study the effect of NOR on osteogenic and adipogenic differentiation. It finds that NOR promotes osteogenic differentiation of osteoblasts and BMSCs, while inhibiting adipogenic differentiation of BMSCs by reducing the relative expression of peroxisome proliferator-activated receptorγ (Ppar-γ) and adiponectin, C1Q and collagen domain containing (Adipoq). Mechanistic studies show that NOR increases osteoblast differentiation through the mechanistic target of rapamycin kinase (mTOR)/ribosomal protein S6 kinase; polypeptide 1 (S6K1) pathway, and treatment with an mTOR inhibitor rapamycin blocked the NOR-induced increase in mineral accumulation. Finally, the study evaluates the therapeutic potential of NOR in a mouse model of ovariectomy (OVX)-induced bone loss. NOR prevents bone loss in both trabecular and cortical bone by increasing osteoblast number and phospho-S6K1 (p-S6K1) expression in osteoblasts. NOR effects in enhancing osteoblast-induced bone formation via S6K1 pathway, suggesting the potential of NOR in osteoporosis treatment by increasing bone formation.

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

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

L-arginine mitigates bleomycin-induced pulmonary fibrosis in rats through regulation of HO-1/PPAR-γ/β-catenin axis

Pulmonary fibrosis is a chronic and progressively deteriorating lung condition that can be replicated in laboratory animals by administering bleomycin, a chemotherapeutic antibiotic known for its lung fibrosis-inducing side effects. L-arginine, a semi-essential amino acid, is recognized for its diverse biological functions, including its potential to counteract fibrosis. This study aimed to evaluate the antifibrotic properties of L-arginine on bleomycin-induced pulmonary fibrosis in rats. The administration of a single intratracheal dose of bleomycin resulted in visible and microscopic damage to lung tissues, an uptick in oxidative stress markers, and an elevation in inflammatory, apoptotic, and fibrotic indicators. A seven-day treatment with L-arginine post-bleomycin exposure markedly improved the gross and histological architecture of the lungs, prevented the rise of malondialdehyde and carbonyl content, and enhanced total antioxidant capacity alongside the activities of antioxidant enzymes. Also, L-arginine attenuated the expression of the pro-fibrotic factors, transforming growth factor-β and lactate dehydrogenase in bronchoalveolar lavage fluid. In the lung tissue, L-arginine reduced collagen deposition, hydroxyproline concentration, and mucus production, along with decreasing expression of α-smooth muscle actin, tumor necrosis factor-α, caspase-3, matrix metalloproteinase-9, and β-catenin. Moreover, it boosted levels of nitric oxide and upregulated the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), heme oxygenase-1 (HO-1), and E-cadherin and downregulating the expression of β-catenin. These findings suggest that L-arginine has preventive activities against bleomycin-induced pulmonary fibrosis. This effect can be attributed to the increased production of nitric oxide, which modulates the HO-1/PPAR-γ/β-catenin axis.

Effects of Clostridium tyrobutyricum on Lipid Metabolism, Intestinal Barrier Function, and Gut Microbiota in Obese Mice Induced by High-Fat Diet.

Obesity and its complications constitute a main threat to global human health. The purpose of this investigation was to explore the influences of Clostridium tyrobutyricum (Ct) on lipid metabolism, intestinal barrier function, and intestinal microbiome in obese mice induced by a high-fat diet (HFD). After establishing the obesity model, 107 CFU/mL and 108 CFU/mL C. tyrobutyricum were used to intervene in HFD-fed mice by gavage for six weeks, and indexes related to obesity were measured. In the liver of HFD-fed mice, the results revealed that C. tyrobutyricum reduced liver weight and the levels of triglyceride (TG), total cholesterol (TC), and nonesterified fatty acid (NEFA), along with decreasing red lipid droplets and fat vacuoles. After C. tyrobutyricum intervention, the mRNA expression of peroxisome proliferator-activated receptor-γ (PPARγ) was downregulated, and AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-α (PPARα), adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL) were upregulated in the liver. Additionally, C. tyrobutyricum alleviated intestinal morphology injury caused by HFD, decreased the expression of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and IL-1β in the colon, and upregulated tight junction protein expression. In addition, 16S rRNA sequencing revealed that C. tyrobutyricum increases the diversity of intestinal microbiota. Overall, C. tyrobutyricum improved HFD-induced lipid metabolism disorders, preserved the intestinal barrier's integrity, and modulated the structure of the intestinal microbiome. These findings provide a novel insight into the role of C. tyrobutyricum as a probiotic in regulating lipid metabolism.

Hypolipidemic effect of dill seed (Anethum graveolens L.) essential oil on lipid profile and peroxisome proliferator-activated receptor- γ expression in hyperlipidemic male rats

Herbal medicines have been suggested for the treatment of hyperlipidemic disorders. The hypolipidemic activities of dill essential oil on lipid profile and peroxisome proliferator-activated receptor-γ (PPARγ) expression in adipose tissue were studied in male rats with hyperlipidemia. The effects were studied and compared of dill essential oil and atorvastatin on serum lipid profile and aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels, histopathological damage of liver and PPARγ gene expression in the adipose tissue of male rats with hyperlipidemia. The treatment with dill decreased body weight, serum cholesterol, triglyceride, LDL-C, ALT and AST levels, histopathological damage to the liver and PPARγ expression of adipose tissue, and increased serum HDL-C levels in experimental hyperlipidemic rats compared to the hyperlipidemic control rats, both significantly. The plant and atorvastatin improved hyperlipidemia, attenuated liver tissue damage and down-regulated PPARγ expression. So, dill could be defined as an excellent candidate for treatment of hyperlipidemia.

Effect of tetracycline hydrochloride application on dental pulp stem cell metabolism-booster or obstacle for tissue engineering?

Introduction: Stem cells and scaffolds are an important foundation and starting point for tissue engineering. Human dental pulp stem cells (DPSC) are mesenchymal stem cells with self-renewal and multi-directional differentiation potential, and are ideal candidates for tissue engineering due to their excellent biological properties and accessibility without causing major trauma at the donor site. Tetracycline hydrochloride (TCH), a broad-spectrum antibiotic, has been widely used in recent years for the synthesis of cellular scaffolds to reduce the incidence of postoperative infections. Methods: In order to evaluate the effects of TCH on DPSC, the metabolism of DPSC in different concentrations of TCH environment was tested. Moreover, cell morphology, survival rates, proliferation rates, cell migration rates and differentiation abilities of DPSC at TCH concentrations of 0-500μg/ml were measured. Phalloidin staining, live-dead staining, MTS assay, cell scratch assay and real-time PCR techniques were used to detect the changes in DPSC under varies TCH concentrations. Results: At TCH concentrations higher than 250μg/ml, DPSC cells were sequestered, the proportion of dead cells increased, and the cell proliferation capacity and cell migration capacity decreased. The osteogenic and adipogenic differentiation abilities of DPSC, however, were already inhibited at TCH con-centrations higher than 50μg/ml. Here, the expression of the osteogenic genes, runt-related transcription factor 2 (RUNX2) and osteocalcin (OCN), the lipogenic genes lipase (LPL), as well as the peroxisome proliferator-activated receptor-γ (PPAR-γ) expression were found to be down-regulated. Discussion: The results of the study indicated that TCH in concentrations above 50µg/ml negatively affects the differentiation capability of DPSC. In addition, TCH at concentrations above 250µg/ml adversely affects the growth status, percentage of living cells, proliferation and migration ability of cells.

Irisin: A Possible Marker of Adipose Tissue Dysfunction in Obesity.

Adipose tissue (AT) secretes pro- and anti-inflammatory cytokines involved in AT homeostasis, including tumor necrosis factor-α (TNFα) and irisin. The functionality of AT is based on a regulated equilibrium between adipogenesis and extracellular matrix (ECM) remodeling. We investigated the contributions of adipose progenitors (ASCs) and adipocytes (AMCs) to TNFα-induced ECM remodeling and a possible implication of irisin in AT impairment in obesity. ASCs and AMCs were exposed to TNFα treatment and nuclear factor-kappa (NF-kB) pathway was investigated: Tissue Inhibitor of Metalloproteinase (TIMP-1), Twist Family Transcription Factor 1 (TWIST-1), and peroxisome proliferator-activated receptor-γ (PPARγ) expression levels were analyzed. The proteolytic activity of matrix metalloproteinases (MMPs) -2 and -9 was analyzed by zymography, and the irisin protein content was measured by ELISA. In inflamed AMCs, a TIMP-1/TWIST-1 imbalance leads to a drop in PPARγ. Adipogenesis and lipid storage ability impairment come with local tissue remodeling due to MMP-9 overactivation. In vitro and ex vivo measurements confirm positive correlations among inflammation, adipose secreting irisin levels, and circulating irisin levels in patients with visceral obesity. Our findings identify the NF-kB downstream effectors as molecular initiators of AT dysfunction and suggest irisin as a possible AT damage and obesity predictive factor.

Effect of PPARγ on oxidative stress in diabetes-related dry eye

Oxidative stress is closely associated with diabetes and can cause free radical accumulation and eventually lead to ocular surface tissue damage. The purpose of this study was to investigate peroxisome proliferator-activated receptor-γ (PPARγ) expression in the lacrimal gland (LG), meibomian gland, and cornea of diabetes-related dry eye mice and whether the PPARγ agonist rosiglitazone can alleviate the oxidative stress of the ocular surface, thereby improving the condition of diabetes-related dry eye. Quantitative RT-PCR (Q-PCR) showed that the PPARγ, catalase, glutathione peroxidase 3, and heme oxygenase-1 (HO-1) mRNA expression levels in the LG of diabetes-related dry eye mice decreased at 8 and 12 weeks. In addition, the increased levels of oxidative stress were confirmed by western blot. Although the mRNA expression levels of antioxidant enzymes in the cornea and meibomian gland decreased at 8 weeks, some of them recovered by 12 weeks. Rosiglitazone alleviated ocular surface damage and increased corneal sensitivity and tear production in diabetes-related dry eye mice. Moreover, the reactive oxygen species accumulation was reduced and the PPARγ, HO-1, and glutathione peroxidase 3 mRNA expression levels were increased in the LG. The PPARγ, HO-1, translocase of the outer membrane 20, and mitochondrial transcription factor A protein levels were also significantly increased. These results demonstrated that rosiglitazone reduced oxidative stress in the LG of diabetes-related dry eye mice, at least in part, by activating PPARγ to up-regulate antioxidant enzyme expression.

Muscone promotes functional recovery by facilitating microglia polarization into M2 phenotype through PPAR-γ pathway after ischemic stroke

Exploring regimens to facilitate microglia transformation from M1 to M2 phenotype is a feasible strategy to suppress neuroinflammation, therefore reinforcing functional recovery after ischemic stroke. Muscone easily crosses the blood brain barrier (BBB) and distributes throughout the brain. Here, the results illustrated the administration of 8mg/kg muscone promoted functional recovery through reducing the infarct volume by 2,3,5-triphenyltetrazolium chloride (TTC) staining after ischemic stroke in mice. Then, the expression of pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), was significantly decreased, whereas the level of anti-inflammatory agents including C-X-C Motif Chemokine Ligand 1 (CXCL1), transforming growth factor-β (TGF-β) and interleukin-10 (IL-10) was obviously elevated in penumbra with the treatment of 8mg/kg muscone using real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), western blot and enzyme-linked immunosorbent assay (ELISA) tests. Subsequently, the results showed the application of muscone upregulated the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) to facilitate microglia transformation into M2 phenotype using RT-qPCR, western blot and immunofluorescence analysis. Collectively, the present study provides evidence for our hypothesis that muscone intensifies microglia transformation into M2 phenotype via activating PPAR-γ signaling pathway in penumbra after ischemic stroke. These findings demonstrate muscone is a promising candidate for the treatment of ischemic stroke.

Swimming in cold water upregulates genes involved in thermogenesis and the browning of white adipose tissues.

The purpose of this study was to investigate whether there is an interacting effect of six weeks of swimming in cold water on the gene expression of browning markers in adipose tissue in rodents. Twenty male Wistar rats were randomly divided into four groups: Control (C, 25 °C), Cold Exposure (CE, 4 °C), Swimming in tepid Water (STW, 30 °C), and Swimming in Cold Water (SCW, 15 °C). The swimming included 2-3 min intervals, 1 min rest, until exhaustion, three days a week for six weeks, with 3 to 6% of bodyweight overload. Rats from CE were exposed to cold for 2 h per day, five days per week. After the experimental protocol, interscapular brown (BAT) and inguinal subcutaneous white (WAT) fat tissues were excised, weighed, and processed for beiging and mitochondrial biogenesis markers gene expression. The experimental protocols resulted in an apparent increase in the number of brown adipocytes (per mm2) in the adipose deposits compared to the C group; substantial changes were observed in the SCW group. Compared to other groups, cold exposure alone increased significantly serum norepinephrine, and also β2-adrenergic receptor expression was upregulated in the adipocytes compared to the C group. The STW group increased the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) coactivator-1 alpha (PGC-1α), β2-adrenergic receptor, and CCAAT/enhancer-binding proteins-α(c/EBP-α) in WAT in comparison with the C group(p < 0.05). In both adipocytes, the SCW intervention significantly upregulated the expression of PGC-1α, PPAR-γ, and c/EBP-α genes in comparison with the C and CE groups. In addition, the expression of TFAM and UCP1 was upregulated substantially in the SCW group compared to other groups. Our data demonstrate that swim training and cold exposure present additive effects in the expression of genes involved in the beiging process and mitochondrial biogenesis markers in BAT and WAT. In addition, it seems that the upregulation of these genes is related to the activation of β2-adrenergic receptors.

Niclosamide modulates cyclosporin A-induced hepatotoxicity in a mouse model: PPAR-γ and Wnt/β-catenin crosstalk.

The aim of this study was to evaluate whether: 1) Wnt/β-catenin signaling is involved in cyclosporin A (CsA)-induced hepatotoxicity, and 2) knockdown of this pathway by niclosamide (NCL) attenuate CsA-induced hepatotoxicity. The experiment was accomplished in 21days. Adult male mice were randomly distributed into five groups: control group, CsA (25mg/kg/day) group, CsA+NCL (2.5mg/kg/day) group, CsA+NCL (5mg/kg/day) group, and NCL (5mg/kg/day) group. NCL showed marked hepatoprotection by significantly decreasing liver enzymes activities and ameliorating the histopathological alterations induced by CsA. Besides, NCL alleviated oxidative stress and inflammation. NCL-treated groups (2.5 and 5mg/kg) displayed rise in the expression of hepatic peroxisome proliferator-activated receptor-γ (PPAR-γ) by 2.1- and 2.5-fold, respectively. Notably, NCL (2.5 and 5mg/kg) significantly inhibited Wnt/β-catenin signaling, evidenced by a marked decrease in the hepatic expression of Wnt3a by 54% and 50%, frizzled-7 receptor by 50% and 50%, β-catenin by 22% and 49%, and c-myc by 50% and 50%, respectively. NCL can be regarded as a potential agent to mitigate CsA-induced hepatotoxicity.

Chemical constituents isolated from Actinidia polygama and their α-glucosidase inhibitory activity and insulin secretion effect

Actinidia polygama has been used as a traditional medicine for treating various diseases. In the present study, 13 compounds, including three new monoterpenoids (1–3), were isolated from the leaves of A. polygama to investigate the bioactive constituents of the plant. The structures were characterized by analyzing spectroscopic and chiroptical data. These compounds were preliminarily screened for their ability to increase insulin secretion levels after glucose stimulation. Of these, 3-O-coumaroylmaslinic acid (4) and jacoumaric acid (5) showed activity. In further biological studies, these compounds exhibited increased glucose‐stimulated insulin secretion (GSIS) activity without cytotoxicity in rat INS-1 pancreatic β-cells as well as α-glucosidase inhibitory activity. Furthermore, both compounds increased insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), pancreatic and duodenal homeobox-1 (PDX-1), and peroxisome proliferator-activated receptor-γ (PPAR-γ) expression. Hence, these compounds may be developed as potential antidiabetic agents.

Conjugated linoleic acids inhibit lipid deposition in subcutaneous adipose tissue and alter lipid profiles in serum of pigs.

Conjugated linoleic acids (CLAs) have served as a nutritional strategy to reduce fat deposition in adipose tissues of pigs. However, the effects of CLAs on lipid profiles in serum and how these lipid molecules regulate fat deposition are still unclear. In this study, we explored the effects of CLAs on regulating lipid deposition in adipose tissues in terms of lipid molecules and microbiota based on a Heigai pig model. A total of 56 Heigai finishing pigs (body weight: 85.58 ± 10.39 kg) were randomly divided into two treatments and fed diets containing 1% soyabean oil or 1% CLAs for 40 d. CLAs reduced fat deposition and affected fatty acids composition in adipose tissues of Heigai pigs via upregulating the expression of the lipolytic gene (hormone-sensitive lipase, HSL) in vivo and in vitro. CLAs also altered the biochemical immune indexes including reduced content of total cholesterol (TChol), high-density lipoprotein (HDL-C), and low-density lipoprotein (LDL-C) and changed lipids profiles including decreased sphingolipids especially ceramides (Cers) and sphingomyelins (SMs) in serum of Heigai pigs. Mechanically, CLAs may decrease peroxisome proliferator-activated receptorγ (PPARγ) expression and further inhibit adipogenic differentiation in adipose tissues of pigs by suppressing the function of Cers in serum. Furthermore, Pearson's correlation analysis showed HSL expression was positively related to short-chain fatty acids (SCFAs) in the gut (P ≤ 0.05) but the abundance of Cers was negatively related to the production and functions of SCFAs (P ≤ 0.05). CLAs altered the distribution of the lipid in serum and inhibited adipogenic differentiation by suppressing the function of Cers and further decreasing PPARγ expression in adipose tissues of Heigai pigs. Besides, the HSL expression and the abundance of Cers are associated with the production and functions of SCFAs in the gut.

Hexahydrocurcumin mitigates angiotensin II-induced proliferation, migration, and inflammation in vascular smooth muscle cells.

The proliferation and migration of vascular smooth muscle cells (VSMCs) play vital roles in the pathogenesis of atherosclerosis and hypertension. It has been proposed and verified that hexahydrocurcumin (HHC), a metabolite form of curcumin, has cardiovascular protective effects. This study examined the effect of HHC on angiotensin II (Ang II)-induced proliferation, migration, and inflammation in rat aortic VSMCs and explored the molecular mechanisms related to the processes. The results showed that HHC significantly suppressed Ang II-induced proliferation, migration, and inflammation in VSMCs. HHC inhibited Ang II-induction of the increase in cyclin D1 and decrease in p21 expression in VSMCs. Moreover, HHC attenuated the generation of reactive oxygen species (ROS), and the expression of nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and matrix metalloproteinases-9 (MMP9) in Ang II-induced VSMCs. The proliferation, migration, inflammation, and ROS production were also inhibited by GKT137831 (NADPH oxidase, NOX1/4 inhibitor) and the combination of HHC and GKT137831. In addition, HHC restored the Ang-II inhibited expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) and peroxisome proliferator activated receptor-γ coactivator-1α (PGC-1α). These findings indicate that HHC may play a protective role in Ang II-promoted proliferation, migration, and inflammation by suppressing NADPH oxidase mediated ROS generation and elevating PPAR-γ and PGC-1α expression. See also Figure 1(Fig. 1).

ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection.

Interferon-stimulated gene 15 (ISG15) is a 15-kDa ubiquitin-like modifier that binds to target proteins in a process termed ISGylation. ISG15, first described as an antiviral molecule against many viruses, participates in numerous cellular processes, from immune modulation to the regulation of genome stability. Interestingly, the role of ISG15 as a regulator of cell metabolism has recently gained strength. We previously described ISG15 as a regulator of mitochondrial functions in bone marrow-derived macrophages (BMDMs) in the context of Vaccinia virus (VACV) infection. Here, we demonstrate that ISG15 regulates lipid metabolism in BMDMs and that ISG15 is necessary to modulate the impact of VACV infection on lipid metabolism. We show that Isg15-/- BMDMs demonstrate alterations in the levels of several key proteins of lipid metabolism that result in differences in the lipid profile compared with Isg15+/+ (wild-type [WT]) BMDMs. Specifically, Isg15-/- BMDMs present reduced levels of neutral lipids, reflected by decreased lipid droplet number. These alterations are linked to increased levels of lipases and are independent of enhanced fatty acid oxidation (FAO). Moreover, we demonstrate that VACV causes a dysregulation in the proteomes of BMDMs and alterations in the lipid content of these cells, which appear exacerbated in Isg15-/- BMDMs. Such metabolic changes are likely caused by increased expression of the metabolic regulators peroxisome proliferator-activated receptor-γ (PPARγ) and PPARγ coactivator-1α (PGC-1α). In summary, our results highlight that ISG15 controls BMDM lipid metabolism during viral infections, suggesting that ISG15 is an important host factor to restrain VACV impact on cell metabolism. IMPORTANCE The functions of ISG15 are continuously expanding, and growing evidence supports its role as a relevant modulator of cell metabolism. In this work, we highlight how the absence of ISG15 impacts macrophage lipid metabolism in the context of viral infections and how poxviruses modulate metabolism to ensure successful replication. Our results open the door to new advances in the comprehension of macrophage immunometabolism and the interaction between VACV and the host.

Moringa oleifera leaf polysaccharide alleviates experimental colitis by inhibiting inflammation and maintaining intestinal barrier.

The characteristic of ulcerative colitis (UC) is extensive colonic mucosal inflammation. Moringa oleifera (M. oleifera) is a medicine food homology plant, and the polysaccharide from M. oleifera leaves (MOLP) exhibits antioxidant and anti-inflammatory activity. The aim of this study to investigate the potential effect of MOLP on UC in a mouse model as well as the underlying mechanism. Dextran sulfate sodium (DSS) 4% in drinking water was given for 7 days to mice with UC, at the same time, MOLP (25, 50, and 100 mg/kg/day) was intragastric administered once daily during the experiment. Structural analysis revealed that MOLP had an average molecular weight (Mw) of 182,989 kDa and consisted of fucose, arabinose, rhamnose, galactose, glucose, xylose, mannose, galactose uronic acid, glucuronic acid, glucose uronic acid and mannose uronic acid, with a percentage ratio of 1.64, 18.81, 12.04, 25.90, 17.57, 12.01, 3.51, 5.28, 0.55, 1.27, and 1.43%, respectively. In addition, the features of MOLP were identified by Fourier-transform infrared (FT-IR) and spectra, X-ray diffraction (XRD). The results showed that MOLP exhibited protective efficacy against UC by alleviating colonic pathological alterations, decreasing goblet cells, crypt destruction, and infiltration of inflammatory cells caused by DSS. Furthermore, MOLP notably repressed the loss of zonula occludens-1 (ZO-1) and occludin proteins in mucosal layer, as well as up-regulating the mRNA expression of interleukin-10 (IL-10) and peroxisome proliferator-activated receptor-γ (PPAR-γ), whereas down-regulating the activation of Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor-kappa B (NF-κB) signaling pathway and the production of pro-inflammatory cytokines. Therefore, these results will help understand the protective action procedure of MOLP against UC, thereby providing significance for the development of MOLP.

CIDEA Regulates De Novo Fatty Acid Synthesis in Bovine Mammary Epithelial Cells by Targeting the AMPK/PPARγ Axis and Regulating SREBP1.

Cell-death-inducing DNA fragmentation factor-α-like effector A (CIDEA) is a lipid-droplet-associated protein that helps to promote lipid metabolism in adipocytes of mice and humans. However, studies on the regulatory mechanism of CIDEA on lipid metabolism in the mammary glands of dairy cows are rare. Therefore, the role of CIDEA in bovine mammary epithelial cells (bMECs) was investigated in this study. The CIDEA expression levels in the mammary glands of high-fat-milk-producing cows were significantly higher compared to those in low-fat-milk-producing cows. Results of in vitro studies in bMECs showed that the inhibition of CIDEA inhibited the expression of fatty acid synthesis-related genes and triglyceride (TAG) synthesis-related genes. Conversely, the overexpression of CIDEA leads to an increase in the content of TAG and fatty acid. The results of mechanistic studies indicated that the overexpression of CIDEA inhibits AMP-activated protein kinase (AMPK) activity, which enhances the expression of peroxisome proliferator-activated receptor-γ (PPARγ) and consequently increases the TAG content. Furthermore, the overexpression of CIDEA promoted the nuclear translocation of sterol regulatory element-binding protein 1 (SREBP1). Therefore, a theoretical framework is provided by this study for the regulation of lipid metabolism in dairy cows by means of nutrition and the hormone targeting of CIDEA.

Pioglitazone attenuates ischaemic stroke aggravation by blocking PPARγ reduction and inhibiting chronic inflammation in diabetic mice

Diabetes can cause vascular remodelling and is associated with worse outcome after ischaemic stroke. Pioglitazone is a commonly used anti-diabetic agent. However, it is not known whether pioglitazone use before ischaemia could reduce brain ischaemic injury. Pioglitazone was administered to 5-week-old db+ or db/db mice. Cerebral vascular remodelling was examined at the age of 9weeks. Expression of peroxisome proliferator-activated receptor-γ (PPARγ), p-PPARγ (S112 and S273), nucleotide-binding domain (NOD)-like receptor protein 3 (Nlrp3), interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α) was evaluated in the somatosensory cortex of mice. Neurological outcome was evaluated 24 h after brain ischaemia. Results showed that early pioglitazone treatment provided a long-lasting effect of euglycaemia but enhanced hyperlipidaemia in the db/db mice. Diabetic mice exhibited increased vascular tortuosity, narrower middle cerebral artery (MCA) width and IgG leakage in the brain. These changes were blocked by early pioglitazone treatment. In diabetic animals, PPARγ expression was reduced, and p-PPARγ at S273 but not S112, Nlrp3, IL-1β and TNF-α were increased in the somatosensory cortex. PPARγ decrease and Nlrp3 increase were mainly in the neurons of the diabetic brain, which was reversed by early pioglitazone treatment. Pioglitazone attenuated the aggravated neurological outcome after stroke in diabetic mice. But this protective effect was abolished through restoring cerebral inflammation by intracerebroventricular administration of IL-1β and TNF-α in pioglitazone-treated diabetic mice before MCAO. In summary, early pioglitazone treatment attenuates cerebral vascular remodelling and ischaemic brain injury possibly via blocking chronic neuroinflammation in the db/db mice.