Expression Of Peroxisome Proliferator-activated Receptor Research Articles

NLRP3 inflammasome mediates white adipose tissue browning after burn.

A hallmark after burn is the stress and inflammatory-induced hypermetabolic response. Recently, we and others found that browning of white adipose tissue (WAT) is a critical component of this complex detrimental response. Although browning and inflammation have been independently delineated to occur after injury, their interaction is currently not well defined. One of the master regulators of inflammation and adipose tissue remodeling after burns is nucleotide-binding and oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) inflammasome. The aim of this this study was to determine whether NLRP3 modulates and activates WAT browning after burn. To obtain molecular and mechanistic insights, we used an NLRP3 knockout (NLRP3-/-) murine burn model. We demonstrated that genetic deletion of NLRP3 promoted persistent and augmented browning in adipocytes, evidenced by increased gene expression of peroxisome proliferator-activated receptor γ and CIDEA at 3 days (5.74 vs. 0.29, P < 0.05; 26.0 vs. 0.71, P < 0.05) and uncoupling protein 1 (UCP1) and PGC1α at 7 days (7,406 vs. 3,894, P < 0.05; 20.6 vs. 2.52, P < 0.01) and enhanced UCP1 staining and multilocularity. Additionally, the main regulator of postburn WAT browning, IL-6, was elevated in the plasma acutely after burn in NLRP3-/- compared with wild-type counterparts (478.9 vs. 67.1 pg/mL, P < 0.05 at 3 days). These results suggest that NLRP3 has antibrowning effects and that blocking NLRP3 increases thermogenesis and augments browning via increased levels of IL-6. Our findings provide insights into targeting innate inflammatory systems for regulation of adaptive thermogenesis, a critical response after burns and other hypermetabolic conditions.

Hypoxylonol F Isolated from Annulohypoxylon annulatum Improves Insulin Secretion by Regulating Pancreatic β-cell Metabolism.

Insulin plays a key role in glucose homeostasis and is hence used to treat hyperglycemia, the main characteristic of diabetes mellitus. Annulohypoxylon annulatum is an inedible ball-shaped wood-rotting fungus, and hypoxylon F is one of the major compounds of A. annulatum. The aim of this study is to evaluate the effects of hypoxylonol F isolated from A. annulatum on insulin secretion in INS-1 pancreatic β-cells and demonstrate the molecular mechanisms involved. Glucose-stimulated insulin secretion (GSIS) values were evaluated using a rat insulin ELISA kit. Moreover, the expression of proteins related to pancreatic β-cell metabolism and insulin secretion was evaluated using Western blotting. Hypoxylonol F isolated from A. annulatum was found to significantly enhance glucose-stimulated insulin secretion without inducing cytotoxicity. Additionally, hypoxylonol F enhanced insulin receptor substrate-2 (IRS-2) levels and activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway. Interestingly, it also modulated the expression of peroxisome proliferator-activated receptor γ (PPARγ) and pancreatic and duodenal homeobox 1 (PDX-1). Our findings showed that A. annulatum and its bioactive compounds are capable of improving insulin secretion by pancreatic β-cells. This suggests that A. annulatum can be used as a therapeutic agent to treat diabetes.

The role of angiopoietin-like protein 4 in phenylephrine-induced cardiomyocyte hypertrophy.

Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional secreted protein that can be induced by fasting, hypoxia and glucocorticoids. ANGPTL4 has been associated with a variety of diseases; however, the role of ANGPTL4 in cardiac hypertrophy remains poorly understood. In our study, we aimed to explore the effect of ANGPTL4 on phenylephrine-induced cardiomyocyte hypertrophy. Our results showed that knockdown of ANGPTL4 expression significantly exacerbated cardiomyocyte hypertrophy, as demonstrated by increased hypertrophic marker expression, including ANP and cell surface area. Moreover, significantly reduced fatty acid oxidation, as featured by decreased CPT-1 levels, was observed in hypertrophic cardiomyocytes following ANGPTL4 down-regulation. Furthermore, knockdown of ANGPLT4 led to down-regulated expression of peroxisome proliferator-activated receptor α (PPARα), which is the key regulator of cardiac fatty acid oxidation. In addition, ANGPTL4 silencing promoted the activation of JNK1/2, and JNK1/2 signaling blockade could restore the level of PPARα and significantly ameliorate the ANGPTL4 knockdown-induced cardiomyocyte hypertrophy. Therefore, our study demonstrated that ANGPTL4 regulates PPARα through JNK1/2 signaling and is required for the inhibition of cardiomyocyte hypertrophy.

Toll-like receptors control p38 and JNK MAPK signaling pathways in rat astrocytes differently, when cultured in normal or high glucose concentrations

Astrocytes play a vital role in regulating central nervous system inflammation, energy metabolism and brain homeostasis. Unlike macrophages and microglia, which are cells of myeloid ancestry, astrocytes are of ectodermal origin. However, regulatory specificities of signaling pathways connecting inflammatory and metabolic processes are still largely unknown. We analyzed firstly cellular responses to toll-like receptor (TLR) agonists and secondly, modulation of the mRNA of the three isoforms of the transcription factors PPARs (peroxisome proliferator-activated receptors) in primary rat astrocytes exposed to normal glucose (5.5 mM) and high glucose (25 mM). Cell culturing of rat brain astrocytes for 2 days in high glucose did not alter cellular morphology, but i) enhanced the release of TNFα that was induced by TLR4 agonist LPS or TLR3 agonist PIC and the synthesis of prostaglandin E2 (PGE2), ii) changed the signaling pathways of TLR4/MAPK (increase in p38 MAPK, and decrease in JNK activities at early stages of TLR activation) and iii) modulated mRNA expression of PPARs. High glucose cultivation reduced PPARα and PPARβ mRNA levels, without altering PPARγ mRNA level and changed the sensitivity of expressions to agonists of TLR1/2 (PGN), TLR4 (LPS), TLR3 (PIC), and TLR5 (FGN). Differences between low and high glucose-adapted cells were obtained for agonists of TLR1/2 (PPARα, PPARβ), TLR4 (PPAR β), TLR3 (PPARα). In the TLR4/p38/PPARβ signaling pathway, there was a stimulatory connection in normal glucose but an inhibitory connection in high glucose. TLR4/JNK/activated PPARβ, TLR4/JNK/inhibited PPARγ both in cells adapted to normal or high glucose, but PPARα expression was not affected. As PPARs in astrocytes are involved in inflammatory processes in the form of the recently published PPAR triad, the changes in expression revealed here are most likely resulting in implications of high glucose in inflammatory processes. Our data underline the complexity of multiple regulatory interactions between inflammatory responses and energy metabolism in astrocytes.

Protective effect of ganoderic acid against the streptozotocin induced diabetes, inflammation, hyperlipidemia and microbiota imbalance in diabetic rats.

Diabetes mellitus (DM) is a metabolic disorder with numerous symptoms categorized via serves hyperglycemia effect along with altered fat, protein and carbohydrate metabolism mainly resultant from defects in insulin action/secretion or both. The aim of the current experimental study was to comfort the neuroprotective effect of ganoderic acid against the streptozotocin (STZ)-induced type I diabetes mellitus in mice and explore the underlying mechanism. Differentiation of 3T3-L1 preadipocytes effect; hepatic and glucose consumption effect of ganoderic acid was estimated on HepG2 cell lines and peroxisome proliferator-activated receptor (PPAR). FFA content was estimated in adipose and hepatic tissues. Ganoderic acid induced the 3T3-L1 preadipocytes differentiation. The mRNA expression of PPAR was increased in the high glucose-treated group in HepG2 and ganoderic acid treatment down-regulated the mRNA expression of PPAR. Ganoderic acid exhibited the inhibitory effect of α-glucosidase and α-amylase. Ganoderic acid demonstrated the reduced blood glucose and increase insulin level and also reduced the free fatty in hepatic and adipose tissue. Histopathological study showed the enhancement of β-cells in ganoderic acid-treated mice. Finally, their prebiotic effects on gut microbiota were illustrated via enhancing the population of diabetes resistant bacteria and also reducing the quantity of diabetes sensitive bacteria. Ganoderic acid attenuated STZ induced T1DM in mice via inflammatory pathways.

Dichotomy of bisphenol A-induced expression of peroxisome proliferator-activated receptors in hepatic and testicular tissues in mice

Environmental and dietary exposure to bisphenol A (BPA) and its toxicological consequences are extensively reported. BPA has multiple cellular targets. One of the mechanisms of action of BPA involves interaction with and activation of nuclear receptors (NRs) including peroxisome proliferator activated-receptors (PPARs). PPARs regulate genes involved in adipogenesis, and metabolism of glucose, lipid and cholesterol. Study of tissue and dose specific PPAR expression may decipher the toxicity outcome of BPA exposure. We studied expression of three forms of PPARs in mouse liver and testes exposed to BPA for 14 days. mRNA and protein expression of all forms of PPAR increased linearly (monotonic) with the dose in the liver while non-monotonic but dose specific effects were observed in the testes showing a differential pattern of expression. However, histopathological study showed a dose-dependent pattern of changes in liver as well as testes demonstrating a monotonic effect. These findings imply that other PPAR-independent mechanisms may play a role in BPA-induced pathological changes. The present study warrants exploration of the role of PPARs in BPA-induced effects on male reproductive functions and offers an insight into the peculiar response of BPA at low subchronic levels which may be helpful in designing appropriate risk assessment framework.

The PPAR-microbiota-metabolic organ trilogy to fine-tune physiology.

The human gut is colonized by commensal microorganisms, predominately bacteria that have coevolved in symbiosis with their host. The gut microbiota has been extensively studied in recent years, and many important findings on how it can regulate host metabolism have been unraveled. In healthy individuals, feeding timing and type of food can influence not only the composition but also the circadian oscillation of the gut microbiota. Host feeding habits thus influence the type of microbe-derived metabolites produced and their concentrations throughout the day. These microbe-derived metabolites influence many aspects of host physiology, including energy metabolism and circadian rhythm. Peroxisome proliferator-activated receptors (PPARs) are a group of ligand-activated transcription factors that regulate various metabolic processes such as fatty acid metabolism. Similar to the gut microbiota, PPAR expression in various organs oscillates diurnally, and studies have shown that the gut microbiota can influence PPAR activities in various metabolic organs. For example, short-chain fatty acids, the most abundant type of metabolites produced by anaerobic fermentation of dietary fibers by the gut microbiota, are PPAR agonists. In this review, we highlight how the gut microbiota can regulate PPARs in key metabolic organs, namely, in the intestines, liver, and muscle. Knowing that the gut microbiota impacts metabolism and is altered in individuals with metabolic diseases might allow treatment of these patients using noninvasive procedures such as gut microbiota manipulation.-Oh, H. Y. P., Visvalingam, V., Wahli, W. The PPAR-microbiota-metabolic organ trilogy to fine-tune physiology.

Liraglutide Alleviates Hepatic Steatosis and Liver Injury in T2MD Rats via a GLP-1R Dependent AMPK Pathway

Nonalcoholic fatty liver diseases (NAFLD) ranging from nonalcoholic fatty liver to non-alcoholic steatohepatitis have a high preference in Type 2 diabetes mellitus (T2DM) patients. However, no antidiabetic drug is approved for the treatment of NAFLD in T2DM patients. Although multiple daily injection of basal-bolus insulin is the final therapeutic process for T2DM, we found that insulin treatment aggravated hepatic steatosis and oxidative stress in ZDF rats. Here, besides glycemic control, we demonstrated a stimulatory role of liraglutide in relieving hepatic steatosis and liver injury in ZDF rats. Interestingly, liraglutide could also alleviate the insulin aggravated hepatic fatty accumulation. GLP-1 agonist (liraglutide and Ex-4) activated the expression of peroxisome proliferator-activated receptor α (PPARα) via a GLP-1R dependent AMPK pathway. As a nuclear transcription factor, PPARα could mediate the effect of GLP-1 in alleviating hepatic steatosis through differentially regulating the expression of its targeting genes including acetyl CoA carboxylase (ACC) and carnitine palmitoyl transferase la (CPT1a) both in vitro and in vivo. Moreover, our results indicated that GLP-1 could relieve liver injury through decreasing the oxidative stress that stimulated by hepatic steatosis. Insulin might aggravate hepatic steatosis and liver injury through inhibiting the expression of GLP-1R. In this research, we investigated the feasibility of liraglutide treatment combined with basal insulin in attenuating hepatic steatosis and liver injury in ZDF rats, as well as the mechanism behind, which will provide a theoretical basis for the combination treatment recommended by the latest clinical practice guidelines for T2DM. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (Grant Nos. 81270966, 81500679, 81702903, 81770821), the Natural Science Foundation of Guangdong Province, China (Grant Nos. 2014A030310036, 2014A030310472, 2017A030310038, 2017A030313519 and 2018A030313609), Science and Technology Plan of Guangdong Province (Grant No. 2016A020215097, 2017A020215045) and the Guangdong Provincial Department of Education High-level University Construction Funding Southern Medical University Clinical Research Startup Program (LC2016YM007). Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: All animal experiments were approved by the Institutional Animal Care and Use Committee of Southern Medical University (Guangzhou, China).

Trigonelline reduced diabetic nephropathy and insulin resistance in type 2 diabetic rats through peroxisome proliferator-activated receptor-γ.

Trigonelline has been reported to serve an important role in cell cycle control, oxidative and ultraviolet stress and DNA methylation. In the present study, the effects of trigonelline were examined on type-2 diabetes mellitus (T2DM)-induced renal dysfunction, and its possible mechanism was investigated. Sprague-Dawley rats were fed with high-fat diet (HFD) for 4 weeks and intraperitoneally injected with 35 mg/kg of streptozotocin for 4 weeks. As a result, trigonelline increased body weight, inhibited the kidney weight/body weight ratio and blood glucose levels, and reduced the levels of blood urea nitrogen, creatinine and albumin in type 2 diabetic rats. In addition, trigonelline also reduced inflammation, oxidative stress and kidney cell apoptosis in T2DM rats. In terms of the molecular mechanisms involved, trigonelline induced the protein expression of peroxisome proliferator-activated receptor (PPAR)-γ and suppressed glucose transporter 4 but suppressed the protein expression of tumor necrosis factor-α and leptin in T2DM rats. The present results demonstrated that trigonelline reduced diabetic nephropathy and insulin resistance in T2DM rats through PPAR-γ.

Macrophage Smad3 Protects the Infarcted Heart, Stimulating Phagocytosis and Regulating Inflammation.

TGF (transforming growth factor)-β is critically involved in myocardial injury, repair, and fibrosis, activating both Smad (small mothers against decapentaplegic)-dependent and non-Smad pathways. The in vivo role of TGF-β signaling in regulation of macrophage function is poorly understood. We hypothesized that in the infarcted myocardium, activation of TGF-β/Smad signaling in macrophages may regulate repair and remodeling. To investigate the role of macrophage-specific TGF-β Smad3 signaling in a mouse model of myocardial infarction and to dissect the mechanisms mediating Smad-dependent modulation of macrophage function. TGF-βs markedly activated Smad3 in macrophages, without affecting Smad-independent pathways. Phagocytosis rapidly and directly activated macrophage Smad3, in the absence of active TGF-β release. MyS3KO (myeloid cell-specific Smad3 knockout) mice had no baseline defects but exhibited increased late mortality and accentuated dilative postmyocardial infarction remodeling. Adverse outcome in infarcted MyS3KO mice was associated with perturbations in phagocytic activity, defective transition of macrophages to an anti-inflammatory phenotype, scar expansion, and accentuated apoptosis of border zone cardiomyocytes. In vitro, Smad3 null macrophages exhibited reduced expression of genes associated with eat-me signals, such as Mfge8 (milk fat globule-epidermal growth factor factor 8), and reduced capacity to produce the anti-inflammatory mediators IL (interleukin)-10 and TGF-β1, and the angiogenic growth factor VEGF (vascular endothelial growth factor). Mfge8 partly rescued the phagocytic defect of Smad3 null macrophages, without affecting inflammatory activity. Impaired anti-inflammatory actions of Smad3 null macrophages were associated with marked attenuation of phagocytosis-induced PPAR (peroxisome proliferator-activated receptor) expression. MyS3KO mice had no significant alterations in microvascular density and interstitial fibrosis in remodeling myocardial segments. We demonstrate that Smad3 critically regulates function of infarct macrophages, by mediating acquisition of a phagocytic phenotype and by contributing to anti-inflammatory transition. Smad3-dependent actions in macrophages protect the infarcted heart from adverse remodeling.

Alterations in protein expression patterns of spinal peroxisome proliferator-activated receptors after spinal cord injury

ABSTRACTObjectives: Peroxisome proliferator-activated receptors (PPARs) control wound healing processes in damaged tissues. PPAR agonists have neuroprotective effects in spinal cord injury (SCI); however, isotype-specific roles of PPARs are not well understood. Therefore, we evaluated protein expression changes for three isotypes of PPARs at different time points and locations relative to the epicenter after SCI in rats.Methods: A 10-g rod was dropped on the spinal cord which located at the T10 vertebra of rats from a height of 6.25, 12.5, or 50 mm using New York University impactor. We collected the spinal cord at 6, 12, 24, and 72 h and 1, 3, and 5 weeks after SCI. The protein expression of PPARs was analyzed using western blot.Results: The protein expression of PPAR-α declined gradually up to 5 weeks at the epicenter. PPAR-β/δ expression increased from 3 days to 5 weeks at the caudal region, but decreased at the epicenter in the severe injury group. PPAR-γ expression increased significantly at all regions in all three injury groups up to 5 weeks after SCI and increased to a greater extent in the severe injury group. In addition, PPAR-β/δ controlled protein expression of PPAR-α positively, and -γ negatively.Conclusions: The present results suggest that different PPAR isotypes have varied protein expression patterns at the epicenter and in adjacent regions after SCI. Our results suggest that PPARs may have overlapping but distinct roles. These findings will be useful for further studies investigating PPARs in neurological disorders including SCI.

Influence of Dietary Ratios of n-6: n-3 Fatty Acid on Gene Expression, Fatty Acid Profile in Liver and Breast Muscle Tissues, Serum Lipid Profile, and Immunoglobulin in Broiler Chickens

The study was conducted to investigate the influence of varying concentrations of dietary n-6: n-3 fatty acid ratio (FAR) on fatty acid (FA) structure, expression of peroxisome proliferator-activated receptor (PPAR)α, PPARγ, and stearoyl-CoA desaturase (SCD) on liver and breast muscle tissue, lipid profile in serum and immunoglobulin in broiler birds. A total of 180 one-day-old Cobb 500 broiler birds were randomly allotted to 5 dietary treatments as follows: (T1) basal diet containing 6% palm oil (PO) as a control; (T2) basal diet containing 4% PO + 1% soybean oil (SO) + 1% linseed oil (LO); (T3) basal diet containing 3% PO + 2% SO + 1% LO; (T4) basal diet containing 3% PO + 1% SO + 2% LO; (T5) basal diet containing 2% PO + 2% SO + 2% LO. The n-6: n-3 ratio for the T1, T2, T3, T4, and T5 were 17.68, 3.70, 3.67, 2.18, and 2.05, respectively, whereas the ratios were 19.02, 3.28, 3.82, 2.28, and 2.23 for the T1, T2, T3, T4, and T5 in the finisher diets, respectively. The ratios of C22:6n-3, C18:3n-3, and C22:5n-3 in liver and breast muscle tissue amplified in response to a decrease in the proportion of n-6: n-3 FAR in diets. In addition, reducing the n-6: n-3 FAR in broiler diets up regulated the expression of PPARγ and PPARα but down regulates the expression of SCD (P < 0.05) in the breast and liver tissues. Moreover, reducing the dietary n-6: n-3 FAR improved plasma immunoglobulin and decreased the amount of cholesterol in breast meat and serum. The results suggest that decreasing the n-6: n-3 FAR in broiler diets may improve the immune response and enriched broiler meat with lower ratio of n-6: n-3 fatty acids and potential health beneficial n-3 FA for human diet.

Effects of PPARs/20-HETE on the renal impairment under diabetic conditions

Diabetic nephropathy (DN) is one of the most severe complications of diabetes mellitus. The pathomolecular events behind DN remain uncertain. Peroxisome proliferator-activated receptors (PPARs) play essential functions in the development of DN. Meanwhile, 20-hydroxyeicosatetraenoic acid (20-HETE) also plays central roles in the regulation of renal function. However, the relationship between PPARs and 20-HETE is rarely studied in DN. It was revealed in our study that both PPARs expression and CYP4A-20-HETE level were decreased under DN conditions in vivo and in vitro. Supplementation with bezafibrate, a PPAR pan-agonist, improved the damage of kidney in DN mice and in high glucose-induced NRK-52E cells, following the up-regulation of PPARs and the increase of CYP4A-20-HETE. PPARα antagonist (MK886), PPARβ antagonist (GSK0660), and PPARγ antagonist (GW9662) reversed the protection of bezafibrate in NRK-52E, and abrogated the up-regulation of CYP4A-20-HETE produced by bezafibrate. Noteworthily, 20-HETE synthetase inhibitor, HET0016, also blocked the bezafibrate-mediated improvement of NRK-52E, and abolished the up-regulation of PPARs expression. Collectively, our data suggest that the concurrent down-regulation and interaction of PPARs and 20-HETE play crucial roles in the pathogenesis process of DN, and we provide a novel evidence that PPARs/20-HETE signaling may be served as a therapeutic target for DN patients.

Hydrangea serrata Tea Enhances Running Endurance and Skeletal Muscle Mass.

Skeletal muscle mass and quality can be negatively affected by aging, inactivity, and disease, while a loss of muscle mass is associated with chronic disease status, falls, and mortality. We investigate the effects of Hydrangea serrata on skeletal muscle mass and function, along with the underlying mechanisms. H. serrata, identified through MyoD transcription activity screening, increases myogenic differentiation via Akt and p38. C57BL/6 mice are fed a 0.25% or 0.5% H. serrata diet for 8 weeks. H. serrata increased treadmill running distance and maximum speed, as well as skeletal muscle mass. H. serrata promotes the expression of myosin heavy chain 1 (MHC1) and MHC2A but not MHC2B. H. serrata also upregulates the protein expression of peroxisome proliferator-activated receptor δ (PPARδ) and mitochondrial complexes, and enhances citrate synthase and mitochondrial complex І activity. Transforming growth factor-β (TGF-β), myostatin, and growth differentiation factor 11 (GDF11) are attenuated by H. serrata, together with associated downstream signaling factors including phospho-Smad3 and NADPH oxidase 4 (NOX4). H. serrata enhances exercise endurance by upregulating PPARδ and downregulating TGF-β, myostatin, and GDF11. H. serrata is a potential candidate for the development of functional food to maintain skeletal muscle mass and function.

Placental P-glycoprotein inhibition enhances susceptibility to Di-(2-ethylhexyl)-phthalate induced cardiac malformations in mice: A possibly promising target for congenital heart defects prevention.

BackgroundsReducing toxicants transplacental rates could contribute to the prevention of congenital heart defects (CHDs). Placental P-glycoprotein (P-gp) plays a vital role in fetal toxicants exposure and subsequently affects the risk of toxicants-induced birth defects. However, data on the role of placental P-gp in decreasing toxicants-induced cardiac anomalies is extremely limited. This study aimed to explore the protective role of placental P-gp in reducing the risk of Di-(2-ethylhexyl)-phthalate (DEHP) induced cardiac anomalies in mice.MethodsThe C57BL mice were randomly divided into four groups: the vehicle group (corn oil, n = 10), 500mg/Kg DEHP group (n = 15), 3mg/Kg verapamil group (n = 10) and 500mg/Kg DEHP & 3mg/Kg verapamil group (n = 20). Pregnant dams in different group received respective intervention by gavage once daily from E6.5–14.5. Maternal weights were monitored every day and samples were collected at E15.5. HE staining was used to examine fetal cardiac malformations. Real-time quantitative PCR (RT-qPCR) and Western-Blot were applied to detect Nkx2.5/Gata4/Tbx5/Mef2c/Chf1 mRNA and protein expression, respectively. The mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ) was also determined using RT-qPCR.ResultsCo-administration of verapamil and DEHP significantly elevated fetal cardiac malformation rates, in comparison with the DEHP group, the verapamil group and the vehicle group. Different phenotypes of cardiac anomalies, including septal defects and ventricular myocardium noncompaction, were noted both in the DEHP group and the DEHP & verapamil group. The ventricular myocardium noncompaction appeared to be more severe in the DEHP & verapamil group. Fetal cardiac PPARγ mRNA expression was notably increased and Gata4/Mef2c/Chf1 expression was markedly decreased in the DEHP & verapamil group.ConclusionPlacental P-gp inhibition enhances susceptibility to DEHP induced cardiac malformations in mice.

The fucoidan A3 from the seaweed Ascophyllum nodosum enhances RCT-related genes expression in hyperlipidemic C57BL/6J mice

Reverse cholesterol transport (RCT) has been demonstrated to reduce hyperlipidemia, and fucoidans are found to possess hypolipidemic effect. This study was designed to investigate the lipid-lowering effect of the fucoidan from the brown seaweed A. nodosum and whether it improves RCT-related genes expression in C57 BL/6J mice. Our results indicated that fucoidan A3 (100 mg/kg/day) intervention significantly reduced plasma total cholesterol (~23.2%), triglyceride (~48.7%) and fat pad index. This fucoidan significantly increased the mRNA expression of low-density lipoprotein receptor (LDLR), scavenger receptor B type 1 (SR-B1), cholesterol 7 alpha-hydroxylase A1 (CYP7A1), liver X receptor (LXR) β, ATP-binding cassette transporter (ABC) A1 and sterol regulatory element-binding protein (SREBP) 1c, and decreased the expression of peroxisome proliferator-activated receptor (PPAR) γ, however, it had no effect on the expression of proprotein convertase subtilisin/kexin type 9, PPARα, LXRα, SREBP-2, ABCG1, ABCG8 and Niemann-Pick C1-like 1. These results demonstrated that this fucoidan improved lipid transfer from plasma to the liver by activating SR-B1 and LDLR, and up-regulated lipid metabolism by activating LXRβ, ABCA1 and CYP7A1. In conclusion, this fucoidan lowers lipid by enhancing RCT-related genes expression, and it can be explored as a potential candidate for prevention or treatment of lipid disorders.

Fucoidan A2 from the Brown Seaweed Ascophyllum nodosum Lowers Lipid by Improving Reverse Cholesterol Transport in C57BL/6J Mice Fed a High-Fat Diet.

Reverse cholesterol transport (RCT) is a physiological process, in which excess peripheral cholesterol is transported to the liver and further excreted into the bile and then feces. Recently, fucoidans are reported to have a lipid-lowering effect. This study was designed to investigate whether fucoidan from the brown seaweed Ascophyllum nodosum lowers lipid by modulating RCT in C57BL/6J mice fed a high-fat diet. Our results indicated that fucoidan intervention significantly reduced plasma triglyceride, total cholesterol, and fat pad index and markedly increased high-density lipoprotein cholesterol in a dose-dependent manner. In the liver, fucoidan significantly increased the expression of peroxisome proliferator-activated receptor (PPAR)α, PPARγ, liver X receptor (LXR)β, adenosine triphosphate (ATP) binding cassette (ABC)A1, ABCG8, low-density lipoprotein receptor (LDLR), scavenger receptor B type 1 (SR-B1), and cholesterol 7-α-hydroxylase A1 (CYP7A1) and decreased the triglyceride level and expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) and PPARβ but had no effect on LXRα, ABCG1, and ABCG5. In the small intestine, the fucoidan treatment significantly reduced the expression of Niemann-Pick C1-like 1 (NPC1L1) and improved ABCG5 and ABCG8. These results demonstrated that fucoidan can improve lipid transfer from plasma to the liver by activating SR-B1 and LDLR and inactivating PCSK9 and upregulate lipid metabolism by activating PPARα, LXRβ, ABC transporters, and CYP7A1. In the small intestine, this fucoidan can decrease cholesterol absorption and increase cholesterol excretion by activating NPC1L1 and ABCG5 and ABCG8, respectively. In conclusion, fucoidan from A. nodosum may lower lipids by modulating RCT-related protein expression and can be explored as a potential compound for prevention or treatment of hyperlipidemia-related diseases.

PPARγ promotes diabetes-associated centrosome amplification via increasing the expression of SKA1 directly at the transcriptional level.

We haverecently published that type 2 diabetes can induce cell centrosome amplification due to the action of high glucose, palmitic acid, and insulin, and ROCK1 and 14-3-3σ are signal mediators. In this study, we further investigated the molecular mechanisms of the centrosome amplification in colon cancer HCT116 cells. Treatment of the cells with high glucose, palmitic acid, and insulin increased the expression of peroxisome proliferator-activated receptor γ (PPARγ) as well as the spindle and kinetochore associated protein 1 (SKA1), knockdown of each of which resulted in the inhibition of the treatment-triggered centrosome amplification. Knockdown of PPARγ inhibited the treatment-evoked increase in the SKA1 level, whereas knockdown of SKA1 did not modify the treatment-increased PPARγ level. We found a predicted binding site for PPARγ in the promoter region of the SKA1 gene from the JASPAR database. Experimental results showed that the treatment increased the messenger RNA level of SKA1, which could be inhibited by PPARγ chemical inhibitor or small interfering RNA. Moreover, we were able to show that PPARγ could bind to the binding site in the SKA1 gene promoter, which was increased by the experimental treatment. In conclusion, it is suggested that the pathophysiological factors in type 2 diabetes, high glucose, palmitic acid, and insulin, induce the cell centrosome amplification through the PPARγ-SKA1 pathway, in which PPARγ increases the expression of SKA1 via directly enhancing the SKA1 gene transcription.

Morin reduces inflammatory responses and alleviates lipid accumulation in hepatocytes.

Morin (MO), a natural bioflavinoid, exists in many herbs. Previous studies have acclaimed MO's anti-inflammatory, antidiabetic, antioxidant, antifibrotic, anticancer, and antihyperglycemic biological effects. This study aimed to assess the molecular mechanism of MO involved in the oleic acid (OA)-induced inflammatory damage and lipid accumulation in HepG2 cell and tyloxapol (Ty)-induced hyperlipidemia in mice. We found that MO can efficaciously mitigate reactive tumor necrosis factor-α (TNF-α) level and triglyceride (TG) accumulation in OA-induced HepG2 cell and in tyloxapol-induced mice. Next, the study testified that MO apparently suppressed OA-excited nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways in HepG2 cell. In addition, MO distinctly upregulated the expression of peroxisome proliferator-activated receptor α (PPARα) and decreased the expression of sterol regulatory element-binding protein 1c (SREBP-1c) in OA-induced HepG2 cell and in tyloxapol-induced mice, both of which are dependent upon the phosphorylation of acetyl-CoA carboxylase (ACC), adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and protein kinase B (AKT). In conclusion, these results suggest that MO has protective potential against hyperlipidemia and steatosis, and the potential mechanism may have a close relation with activation of PPARα and inhibition of SREBP-1c.

Biological Evaluation and Molecular Docking Studies of Dimethylpyridine Derivatives.

Cyclooxygenase inhibitors as anti-inflammatory agents can be used in chemoprevention. Many in vitro and in vivo studies on human and animal models have explained the mechanisms of the chemopreventive effect of COX inhibitors such as: induction of apoptosis, inhibition of neoplasia, angiogenesis suppression, induction of cell cycle inhibition and inhibition of the expression of peroxisome proliferator-activated receptors. Here, biological evaluation of twelve different Schiff base derivatives of N-(2-hydrazine-2-oxoethyl)-4,6-dimethyl-2-sulfanylpyridine- 3-carboxamide are presented. Their in vitro anti-COX-1/COX-2, antioxidant and anticancer activities were studied. The molecular docking study was performed in order to understand the binding interaction of compounds in the active site of cyclooxygenases. Compounds PS18 and PS33 showed a significant inhibitory activity on COX-1 at lower concentrations compared to meloxicam and piroxicam. The IC50 of COX-1 of these compounds was 57.3 µM for PS18 and 51.8 µM for PS33. Out of the tested compounds, the highest therapeutic index was demonstrated by PS18, PS19, PS33, PS40 and PS41. Lower molar concentrations of these compounds inhibit the growth of cancer cells while not inhibiting the healthy cells. Compounds PS18, PS19 and PS33 simultaneously demonstrated a statistically-significant inhibition of COX-1 or COX-2. This opens up the possibility of applying these compounds in the chemoprevention of cancer.