Activation Of Peroxisome Proliferator-activated Receptor Research Articles

Peroxisome Proliferator-Activated Receptor α Attenuates Hypertensive Vascular Remodeling by Protecting Vascular Smooth Muscle Cells from Angiotensin II-Induced ROS Production.

Vascular remodeling is the fundamental basis for hypertensive disease, in which vascular smooth muscle cell (VSMC) dysfunction plays an essential role. Previous studies suggest that the activation of peroxisome proliferator-activated receptor α (PPARα) by fibrate drugs has cardiovascular benefits independent of the lipid-lowering effects. However, the underlying mechanism remains incompletely understood. This study explored the role of PPARα in angiotensin II (Ang II)-induced vascular remodeling and hypertension using VSMC-specific Ppara-deficient mice. The PPARα expression was markedly downregulated in the VSMCs upon Ang II treatment. A PPARα deficiency in the VSMC significantly aggravated the Ang II-induced hypertension and vascular stiffness, with little influence on the cardiac function. The morphological analyses demonstrated that VSMC-specific Ppara-deficient mice exhibited an aggravated vascular remodeling and oxidative stress. In vitro, a PPARα deficiency dramatically increased the production of mitochondrial reactive oxidative species (ROS) in Ang II-treated primary VSMCs. Finally, the PPARα activation by Wy14643 improved the Ang II-induced ROS production and vascular remodeling in a VSMC PPARα-dependent manner. Taken together, these data suggest that PPARα plays a critical protective role in Ang II-induced hypertension via attenuating ROS production in VSMCs, thus providing a potential therapeutic target for hypertensive diseases.

Eosinophils protect against pulmonary hypertension through 14-HDHA and 17-HDHA.

Pulmonary hypertension (PH) is a life-threatening disease featuring pulmonary vessel remodelling and perivascular inflammation. The effect, if any, of eosinophils (EOS) on the development of PH remains unclear. EOS infiltration and chemotaxis were investigated in peripheral blood and lung tissues from pulmonary arterial hypertension (PAH) patients without allergic history and from sugen/hypoxia-induced PH mice. The role of EOS deficiency in PH development was investigated using GATA1-deletion (ΔdblGATA) mice and anti-interleukin 5 antibody-treated mice and rats. Ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was conducted to identify the critical oxylipin molecule(s) produced by EOS. Culture supernatants and lysates of EOS were collected to explore the mechanisms in co-culture cell experiments. There was a lower percentage of EOS in peripheral blood but higher infiltration in lung tissues from PAH patients and PH mice. PAH/PH lungs showed increased EOS-related chemokine expression, mainly C-C motif chemokine ligand 11 derived from adventitial fibroblasts. EOS deficiency aggravated PH in rodents, accompanied by increased neutrophil and monocyte/macrophage infiltration. EOS highly expressed arachidonate 15-lipoxygenase (ALOX15). 14-hydroxy docosahexaenoic acid (14-HDHA) and 17-HDHA were critical downstream oxylipins produced by EOS, which showed anti-inflammatory effects on recruitment of neutrophils and monocytes/macrophages through N-formyl peptide receptor 2. They also repressed pulmonary artery smooth muscle cell (PASMC) proliferation by activating peroxisome proliferator-activated receptor γ and blunting Stat3 phosphorylation. In PH development without external stimuli, peripheral blood exhibits a low EOS level. EOS play a protective role by suppressing perivascular inflammation and maintaining PASMC homeostasis via 14/17-HDHA.

Diaporisoindole B Reduces Lipid Accumulation in THP-1 Macrophage Cells via MAPKs and PPARγ-LXRα Pathways and Promotes the Reverse Cholesterol Transport by Upregulating SR-B1 and LDLR in HepG2 Cells.

Diaporisoindole B (DPB), an isoprenylisoindole alkaloid isolated from the mangrove endophytic fungus Diaporthe sp. SYSU-HQ3, has been proved to have a good anti-inflammatory activity in macrophage cells. In this study, we found that DPB was able to reduce lipid accumulation in THP-1 macrophage-derived foam cells. DPB could inhibit the lipid influx-related gene CD36 and increase the expression of lipid efflux-related genes ATP binding cassette transporter A1 (ABCA1), ATP binding cassette transporter G1 (ABCG1), and scavenger receptor B1 (SR-B1). Moreover, DPB elevated low-density lipoprotein receptor (LDLR) protein expression in HepG2 cells, which can increase the transport of LDL. Meanwhile, DPB could downregulate the expression levels of proteins related to cholesterol and fatty acid synthesis. Further study showed that DPB could activate peroxisome proliferator-activated receptor gamma (PPARγ) and inhibit mitogen-activated protein kinase (MAPK) phosphorylation. Taken together, our findings demonstrated that DPB could reduce lipid accumulation in THP-1 macrophage cells by reducing the intake of lipids and promoting the efflux of lipids and also could promote the reverse cholesterol transport (RCT) mechanism by upregulating SR-B1 and LDLR in HepG2 cells.

Hydroethanolic Extract of Morus nigra L. Leaves: A Dual PPAR-α/γ Agonist with Anti-Inflammatory Properties in Lipopolysaccharide-Stimulated RAW 264.7

Inhibition of systemic inflammation has been a beneficial strategy in treating several non-communicable diseases, which represent one of the major causes of mortality in the world. The Peroxisome Proliferator-Activated Receptors (PPAR) are interesting pharmacological targets, since they can act both through the metabolic and anti-inflammatory pathways. Morus nigra L. has flavonoids in its chemical composition with recognized anti-oxidant activity and often associated with anti-inflammatory activity. Therefore, this study aimed to evaluate the hydroethanolic extract of M. nigra leaves' ability to activate PPAR and promote anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated murine macrophage cells. The leaf extract was prepared by cold maceration, and the chemical profile was obtained by HPLC-DAD. Activation of PPAR α and γ was evaluated by the luciferase reporter assay. The anti-inflammatory activity was assessed by measuring the reactive oxygen species (ROS), nitric oxide (NO), and Tumor Necrosis Factor-α (TNF-α) in RAW 264.7 cells after stimulation with LPS from Escherichia coli. The HPLC-DAD analysis identified two major compounds: rutin and isoquercitrin. The extract showed agonist activity for the two types of PPAR, α and γ, although its major compounds, rutin and isoquercitrin, did not significantly activate the receptors. In addition, the extract significantly reduced the production of ROS, NO, and TNF-α. Treatment with the specific PPAR-α antagonist, GW 6471, was able to partially block the anti-inflammatory effect caused by the extract.

Leptin signaling in breast cancer and its crosstalk with peroxisome proliferator-activated receptors α and γ.

Obesity may create a mitogenic microenvironment that influences tumor initiation and progression. The obesity-associated adipokine, leptin regulates energy metabolism and has been implicated in cancer development. It has been shown that some cell types other than adipocytes can express leptin and leptin receptors in tumor microenvironments. It has been shown that peroxisome proliferator-activated receptors (PPAR) agonists can affect leptin levels and vice versa leptin can affect PPARs. Activation of PPARs affects the expression of several genes involved in aspects of lipid metabolism. In addition, PPARs regulate cancer cell progression through their action on the tumor cell proliferation, metabolism, and cellular environment. Some studies have shown an association between obesity and several types of cancer, including breast cancer. There is some evidence that suggests that there is crosstalk between PPARs and leptin during the development of breast cancer. Through a systematic review of previous studies, we have reviewed the published relevant articles regarding leptin signaling in breast cancer and its crosstalk with peroxisome proliferator-activated receptors α and γ.

Engineered Fenofibrate as Oxidation-Sensitive Nanoparticles with ROS Scavenging and PPARα-Activating Bioactivity to Ameliorate Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in western countries and China. Fenofibrate (FNB) can activate peroxisome proliferator-activated receptor α (PPARα) to increase fatty acid oxidation and ameliorate NAFLD. However, the application of FNB is limited in clinic due to its poor water solubility and low oral bioavailability. In this study, FNB-loaded nanoparticles (FNB-NP) based on a reactive oxygen species (ROS)-responsive peroxalate ester derived from vitamin E (OVE) and an amphiphilic conjugate 1,2-distearoyl-sn-glycerol-3-phosphoethanolamine-N-[methoxy(poly(ethylene glycol))-2000] (DSPE-PEG) were developed to enhance the preventive effects of FNB against NAFLD. In in vitro studies, FNB-NP displayed a high encapsulation efficiency of 97.25 ± 0.6% and a drug loading efficiency of 29.67 ± 0.1%, with a size of 197.0 ± 0.2 nm. FNB released from FNB-NP was dramatically accelerated in the medium with high H2O2 concentrations. Moreover, FNB-NP exhibited well storage stability and plasma stability. In pharmacokinetic (PK) studies, FNB-NP, compared with FNB crude drug, significantly increased the AUC0→t and AUC0→∞ of the plasma FNB acid by 3.3- and 3.4-fold, respectively. In pharmacodynamics (PD) studies, compared with an equal dose of FNB crude drug, FNB-NP more significantly reduced hepatic lipid deposition via facilitating FNB release in the liver and further upregulating PPARα expression in NAFLD mice. Meanwhile, oxidative stress in NAFLD was significantly suppressed after FNB-NP administration, suggesting that OVE plays a synergistic effect on antioxidation. Therefore, ROS-sensitive FNB delivery formulations FNB-NP enhance the preventive effects of FNB against NAFLD and could be further studied as a promising drug for the treatment of NAFLD in clinic.

Anticancer Properties of Aqueous Extracts from Leguminosae

Inflammation and cancer are diseases caused by genetic and environmental factors as well as altered microbiota. Diet plays a role, with leguminous such as beans (Phaseolus vulgaris, Vicia faba), chickpeas (Cicer arietinum), lentils (Lens culinaris), peas (Pisum sativum) and soybeans (Glycine max), known to prevent such diseases. Processing of food leguminous yields aqueous side streams. These products are nothing short of water extracts of leguminous, containing albumin, globulin, saponins, and oligosaccharides. This review analysed the most recent findings on the anticancer activities of legume-soluble nutrients. Albumin from chickpeas and peas inhibits the pro-inflammatory mediator interleukins, while soy Bowman–Birk Inhibitor inhibits serine proteases. The peptide vicilin activates peroxisome proliferator-activated receptor, mediating triglyceride metabolism. Soyasaponins promote apoptosis of cancer cells by activating caspases and by enhancing the concentration of intracellular calcium. Soyasapogenol regulates specific protein pathways, leading to apoptosis. Oligosaccharides such as raffinose and stachyose promote the synthesis of short chain fatty acids, balancing the intestinal microbiota, as result of their prebiotic activity. Verbascoside also modulate signalling pathways, leading to apoptosis. In closing, water extracts of leguminous have the potential to be efficient anticancer ingredients, by means of numerous mechanisms based on the raw material and the process.

Antibiotics disrupt lipid metabolism in zebrafish (Danio rerio) larvae and 3T3-L1 preadipocytes

Antibiotics are emerging environmental contaminants with wide attention due to their high consumption and pseudo-persistence in the environment. They have been shown to induce obesity or obesity-related metabolic diseases in experimental animals, but the underlying toxicological mechanisms remain unclear. Here, the disruptive effects of four commonly used antibiotics, namely doxycycline (DC), enrofloxacin (ENR), florfenicol (FF) and sulfamethazine (SMT) on lipid metabolism were investigated in zebrafish (Danio rerio) larvae and murine preadipocyte cell line. Triglyceride (TG) content was reduced after 1 ng/L DC or ENR exposure but was increased at higher concentrations up to 100 mg/L. FF increased and SMT reduced TG content but did not show any concentration dependence. None of the antibiotics had any significant effect on total cholesterol (TC) content in zebrafish except 100 μg/L SMT. Expression levels of 8 lipid metabolism-related genes were also quantified. SMT was most disruptive by up-regulating six genes, followed by FF which up-regulated four genes and down-regulated one gene, whereas DC and ENR both up-regulated one gene. In 3T3-L1 preadipocytes, ENR, FF, and SMT in general increased TG content, while 100 mg/L FF reduced TG substantially. DC did not show any effect up to 10 mg/L, at which TG increased significantly. FF and SMT increased TC slightly at low concentrations but reduced it at high concentrations, whereas TC, DC and ENR had no effect at any tested concentrations. Gene expression measurement also indicated that SMT was most disruptive, followed by FF, DC, and ENR. Reporter gene assays showed that only SMT inhibited the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ). The above experimental results and clustering analysis demonstrate that the four antibiotics exerted disruption on lipid metabolism through different mechanisms, and one of the mechanisms for SMT may be inhibition of PPARγ transcriptional activity.

Treatment with 1,25-Dihydroxyvitamin D3 Delays Choroid Plexus Infiltration and BCSFB Injury in MRL/lpr Mice Coinciding with Activation of the PPARγ/NF-κB/TNF-α Pathway and Suppression of TGF-β/Smad Signaling.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious complication of systemic lupus erythematosus (SLE) involving the nervous system with high morbidity and mortality. A key hypothesis in NPSLE is that a disrupted barrier allows autoantibodies and immune components of peripheral blood to penetrate into the central nervous system (CNS), resulting in inflammation and damage. The blood cerebrospinal fluid barrier (BCSFB), which consists of the choroid plexus and the hypothalamic tanycytes, has long been regarded as an immunological sanctuary site. 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] is the active form of vitamin D, which plays multiple roles in inflammation and immunoregulation. In this study, we investigated the possible protective effects of 1,25-dihydroxyvitamin D3 against BCSFB dysfunction in NPSLE in MRL/lpr mice and explored the mechanism by which 1,25-dihydroxyvitamin D3 inhibits the progression of NPSLE. In this study, we found that supplementation with 1,25-dihydroxyvitamin D3 markedly improved serological and immunological indices, delayed inflammatory infiltration, delayed neuronal deformation, and upregulated the expression of brain-derived neurotrophic factor (BDNF) proteins in the brain. Furthermore, 1,25-dihydroxyvitamin D3 downregulated proinflammatory cytokines such as nuclear factor kappa-B (NF-κB) and tumor necrosis factor-α (TNF-α) by activating peroxisome proliferator-activated receptor γ (PPARγ), and it reduced the expression of the TGF-β/Smad signaling pathway. Our findings demonstrate that 1,25-dihydroxyvitamin D3 delayed cell infiltration into the choroid plexus and decreased markers suggestive of cognitive decline in MRL/lpr mice, and the mechanism may be related to protection against BCSFB disruption through activation of the anti-inflammatory PPARγ/NF-κB/TNF-α pathway as well as upregulation of BDNF and inhibition of the TGF-β/Smad signaling pathway. These findings provide a novel direction for the study of NPSLE.

Efficacy and safety of pemafibrate versus bezafibrate in coronary artery disease patients receiving statin treatment: a randomized, open-label, cross-over study

Abstract Background Fibrates activate peroxisome proliferator-activated receptor (PPAR)-α which is associated with lipid metabolism. Bezafibrate is a non-selective PPAR-α agonist, whereas pemafibrate has been developed as a higher selective PPAR-α agonist. Objective The efficacy and safety of pemafibrate for 24-week in patients with dyslipidemia was examined in comparison with bezafibrate. Methods Sixty patients with hypertriglyceridemia (fasting triglyceride (TG) level of ≥150 mg/dL) were treated with pemafibrate of 0.2 mg/day or bezafibrate of 400 mg/day for 24-week in a randomized cross-over study. Percent change from baseline in TG levels was the primary endpoint, and that in HDL-C and apolipoprotein A-I (Apo A-I) levels was the secondary endpoints. Results A significantly greater reduction in TG percent change was observed in pemafibrate than in bezafibrate (−46.1% vs. −34.7%, p<0.001). There was no significant difference in HDL-C percent change between pemafibrate and bezafibrate (18.4% vs. 14.0%, p=0.067), whereas Apo A-I percent change was significantly greater in pemafibrate than in bezafibrate (9.2% vs. 5.7%, p=0.018). Pemafibrate and bezafibrate significantly decreased alanine aminotransferase (ALT) and gamma-glutamyltransferase (γ-GT) levels, and pemafibrate showed a greater reduction than bezafibrate (ALT: −21.9% vs. −10.6%, p=0.048; γ-GT: −43.5% vs. −33.1%, p=0.025). Creatinine levels significantly increased in both treatments (both p<0.001), however, creatinine percent change was significantly smaller in pemafibrate than in bezafibrate (5.72% vs. 15.5%, p<0.001). There was no difference in frequency of adverse event (AE) or serious AE between two treatments, but frequency of creatinine elevation (≥0.5 mg/d and/or 25%) was significantly higher in bezafibrate than in pemafibrate (16/60 vs. 3/60, p=0.004). Conclusion As compared with bezafibrate, pemafibrate is more effective to reduce TG levels and to elevate Apo A-I levels, and it is safer in terms of liver and renal function. Funding Acknowledgement Type of funding sources: None.

Molecular mechanism of benign biliary stricture inhibition by rosiglitazone-activated peroxisome proliferator-activated receptor gamma.

The aim of this study was to investigate whether rosiglitazone-activated peroxisome proliferator-activated receptor gamma can inhibit the occurrence of benign biliary stricture and further elucidate the relevant molecular signaling mechanism. The primary cultured rat biliary fibroblasts following experiments were performed using within the fifth generation cells, which were separated from the bile ducts of Sprague-Dawley rats. The primary cultured rat biliary fibroblasts were co-cultured with 10 ng/mL transforming growth factor-beta 1 for stimulating collagen formation. Competent cells were transfected with siRNA that specifically target Smad3 or connective tissue growth factor to inhibit the expression of the corresponding proteins. The cells were incubated with 10 μmol/L rosiglitazone to activate peroxisome proliferator-activated receptor gamma. The cells were incubated with 10 μmol/L GW9662 in the pretreatment session to inactivate peroxisome proliferator-activated receptor gamma. ELISA was used to determine the levels of connective tissue growth factor and type I collagen in the cell supernatant. Western blotting was used to detect the levels of intracellular p-Smad3/t-Smad3. Rosiglitazone-activated peroxisome proliferator-activated receptor gamma inhibited the secretion of type I collagen induced by transforming growth factor-beta 1. Peroxisome proliferator-activated receptor gamma inhibitor GW9662 could significantly reverse the rosiglitazone-triggered inhibition of transforming growth factor-beta 1-induced type I collagen secretion by suppressing peroxisome proliferator-activated receptor gamma activation (p<0.01). Furthermore, we also found that the activation of peroxisome proliferator-activated receptor gamma was accompanied by the inhibition of transforming growth factor-beta 1-induced Smad3 phosphorylation (p<0.01), increased connective tissue growth factor expression (p<0.01), and production of type I collagen (p<0.01), all of which effects elicited by rosiglitazone could be reversed by peroxisome proliferator-activated receptor gamma inhibitor GW9662. Peroxisome proliferator-activated receptor gamma activated by rosiglitazone inhibits the transforming growth factor-beta1 -induced phosphorylation of Smad3 and the increased connective tissue growth factor expression as well as inhibits the secretion of type I collagen in biliary fibroblasts.

Lactic acid bacteria–derived γ-linolenic acid metabolites are PPARδ ligands that reduce lipid accumulation in human intestinal organoids

Gut microbiota regulate physiological functions in various hosts, such as energy metabolism and immunity. Lactic acid bacteria, including Lactobacillus plantarum, have a specific polyunsaturated fatty acid saturation metabolism that generates multiple fatty acid species, such as hydroxy fatty acids, oxo fatty acids, conjugated fatty acids, and trans-fatty acids. How these bacterial metabolites impact host physiology is not fully understood. Here, we investigated the ligand activity of lactic acid bacteria-produced fatty acids in relation to nuclear hormone receptors expressed in the small intestine. Our reporter assays revealed two bacterial metabolites of γ-linolenic acid (GLA), 13-hydroxy-cis-6,cis-9-octadecadienoic acid (γHYD), and 13-oxo-cis-6,cis-9-octadecadienoic acid (γKetoD) activated peroxisome proliferator-activated receptor delta (PPARδ) more potently than GLA. We demonstrate that both γHYD and γKetoD bound directly to the ligand-binding domain of human PPARδ. A docking simulation indicated that four polar residues (T289, H323, H449, and Y473) of PPARδ donate hydrogen bonds to these fatty acids. Interestingly, T289 does not donate a hydrogen bond to GLA, suggesting that bacterial modification of GLA introducing hydroxy and oxo group determines ligand selectivity. In human intestinal organoids, we determined γHYD and γKetoD increased the expression of PPARδ target genes, enhanced fatty acid β-oxidation, and reduced intracellular triglyceride accumulation. These findings suggest that γHYD and γKetoD, which gut lactic acid bacteria could generate, are naturally occurring PPARδ ligands in the intestinal tract and may improve lipid metabolism in the human intestine.

Randomized placebo-controlled double-blind phase II study of zaltoprofen for patients with diffuse-type and unresectable localized tenosynovial giant cell tumors: The REALIZE study.

BackgroundA tenosynovial giant cell tumor (TGCT) is a locally aggressive benign neoplasm arising from intra- or extra-articular tissue, categorized as localized (L-TGCT, solitary lesion) and diffuse (D-TGCT, multiple lesions) TGCT. Surgical excision is the mainstay of the treatment, and a high local recurrence rate of approximately 50% has been reported. We focused on zaltoprofen, a nonsteroidal anti-inflammatory drug that can activate peroxisome proliferator-activated receptor gamma (PPARγ) and inhibit the proliferation of TGCT stromal cells. Therefore, we conducted a randomized trial to evaluate the safety and effectiveness of zaltoprofen in patients with D-TGCTs or unresectable L-TGCTs.MethodsThis randomized, placebo-controlled, double-blind, multicenter trial evaluated the safety and efficacy of zaltoprofen. In the treatment group, zaltoprofen (480 mg/day) was administered for 48 weeks; the placebo group received similar dosages without zaltoprofen. The primary outcome was progression-free rate (PFR) 48 weeks after treatment administration. Disease progression was defined as the following conditions requiring surgical intervention: 1) repetitive joint swelling due to hemorrhage, 2) joint range of motion limitation, 3) invasion of the adjacent cartilage or bone, 4) severe joint space narrowing, and 5) increased tumor size (target lesion).ResultsForty-one patients were allocated to the zaltoprofen (n=21) or placebo (n=20) groups. The PFR was not significant between the zaltoprofen group and the placebo group at 48 weeks (84.0% and 90.0%, respectively; p=0.619). The mean Japanese Orthopedic Association knee score significantly improved from baseline to week 48 in the zaltoprofen group (85.38 versus 93.75, p=0.027). There was a significant difference between the values at 48 weeks of placebo and zaltoprofen group (p=0.014). One severe adverse event (grade 3 hypertension) was observed in the zaltoprofen group.DiscussionThis is the first study to evaluate the efficacy and safety of zaltoprofen in patients with TGCT. No significant differences in PFR were observed between the groups at 48 weeks. Physical function significantly improved after zaltoprofen treatment. The safety profile of zaltoprofen was acceptable. This less invasive and safer treatment with zaltoprofen, compared to surgical removal, could be justified as a novel approach to treating TGCT. Further analysis of long-term administration of zaltoprofen should be considered in future studies.Clinical Trial RegistrationUniversity Hospital Medical Information Network Clinical Trials Registry, identifier (UMIN000025901).

Pharmacological activation of PPARβ/δ preserves mitochondrial respiratory function in ischemia/reperfusion via stimulation of fatty acid oxidation-linked respiration and PGC-1α/NRF-1 signaling.

Myocardial ischemia/reperfusion (I/R) injury leads to significant impairment of cardiac function and remains the leading cause of morbidity and mortality worldwide. Activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) confers cardioprotection via pleiotropic effects including antioxidant and anti-inflammatory actions; however, the underlying mechanisms are not yet fully elucidated. The aim of this study was to investigate the effect of PPARβ/δ activation on myocardial mitochondrial respiratory function and link this effect with cardioprotection after ischemia/reperfusion (I/R). For this purpose, rats were treated with the PPARβ/δ agonist GW0742 and/or antagonist GSK0660 in vivo. Mitochondrial respiration and ROS production rates were determined using high-resolution fluororespirometry. Activation of PPARβ/δ did not alter mitochondrial respiratory function in the healthy heart, however, inhibition of PPARβ/δ reduced fatty acid oxidation (FAO) and complex II-linked mitochondrial respiration and shifted the substrate dependence away from succinate-related energy production and towards NADH. Activation of PPARβ/δ reduced mitochondrial stress during in vitro anoxia/reoxygenation. Furthermore, it preserved FAO-dependent mitochondrial respiration and lowered ROS production at oxidative phosphorylation (OXPHOS)-dependent state during ex vivo I/R. PPARβ/δ activation was also followed by increased mRNA expression of components of FAO -linked respiration and of transcription factors governing mitochondrial homeostasis (carnitine palmitoyl transferase 1b and 2-CPT-1b and CPT-2, electron transfer flavoprotein dehydrogenase -ETFDH, peroxisome proliferator-activated receptor gamma co-activator 1 alpha- PGC-1α and nuclear respiratory factor 1-NRF-1). In conclusion, activation of PPARβ/δ stimulated both FAO-linked respiration and PGC-1α/NRF -1 signaling and preserved mitochondrial respiratory function during I/R. These effects are associated with reduced infarct size.

PPARγ activation inhibits PDGF-induced pulmonary artery smooth muscle cell proliferation and migration by modulating TERT.

Vascular remodeling is a significant feature of pulmonary artery hypertension (PAH), and is characterized by abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Telomerase reverse transcriptase (TERT), as a determining factor for controlling telomerase activity, has been proven to be associated with cell proliferation. This study aims to explore whether TERT mediates the proliferation and migration of PASMCs and the underlying molecular mechanism. Primary PASMCs from Sprague-Dawley (SD) rats were used in this experiment. Cell proliferation and migration were evaluated by Cell Counting Kit-8, EdU incorporation assay and transwell assay, respectively. Telomerase activity was assessed with a rat TE ELISA kit. Small interfering RNA (siRNA) transfection was conducted to silence c-MYC expression. The protein levels of p-Akt, c-MYC, PPARγ and TERT were determined through western blotting. Our work demonstrates that PDGF upregulated TERT expression and telomerase activation by activating Akt and upregulating of c-MYC in PASMCs. Inhibition of Akt with LY294002, knockdown of c-MYC by siRNA or suppression of telomerase activity with BIBR1532 repressed PDGF-induced PASMC proliferation and migration. Furthermore, activation of peroxisome proliferator-activated receptor γ (PPARγ) with pioglitazone suppressed PDGF-induced TERT expression and telomerase activation, leading to inhibition of PASMC proliferation and migration.

Peroxisome Proliferator-Activated Receptor Activation in Precision-Cut Bovine Liver Slices Reveals Novel Putative PPAR Targets in Periparturient Dairy Cows.

Metabolic challenges experienced by dairy cows during the transition between pregnancy and lactation (also known as peripartum), are of considerable interest from a nutrigenomic perspective. The mobilization of large amounts of non-esterified fatty acids (NEFA) leads to an increase in NEFA uptake in the liver, the excess of which can cause hepatic accumulation of lipids and ultimately fatty liver. Interestingly, peripartum NEFA activate the Peroxisome Proliferator-activated Receptor (PPAR), a transcriptional regulator with known nutrigenomic properties. The study of PPAR activation in the liver of periparturient dairy cows is thus crucial; however, current in vitro models of the bovine liver are inadequate, and the isolation of primary hepatocytes is time consuming, resource intensive, and prone to errors, with the resulting cells losing characteristic phenotypical traits within hours. The objective of the current study was to evaluate the use of precision-cut liver slices (PCLS) from liver biopsies as a model for PPAR activation in periparturient dairy cows. Three primiparous Jersey cows were enrolled in the experiment, and PCLS from each were prepared prepartum (−8.0 ± 3.6 DIM) and postpartum (+7.7± 1.2 DIM) and treated independently with a variety of PPAR agonists and antagonists: the PPARα agonist WY-14643 and antagonist GW-6471; the PPARδ agonist GW-50156 and antagonist GSK-3787; and the PPARγ agonist rosiglitazone and antagonist GW-9662. Gene expression was assayed through RT-qPCR and RNAseq, and intracellular triacylglycerol (TAG) concentration was measured. PCLS obtained from postpartum cows and treated with a PPARγ agonist displayed upregulation of ACADVL and LIPC while those treated with PPARδ agonist had increased expression of LIPC, PPARD, and PDK4. In PCLS from prepartum cows, transcription of LIPC was increased by all PPAR agonists and NEFA. TAG concentration tended to be larger in tissue slices treated with PPARδ agonist compared to CTR. Use of PPAR isotype-specific antagonists in PCLS cultivated in autologous blood serum failed to decrease expression of PPAR targets, except for PDK4, which was confirmed to be a PPARδ target. Transcriptome sequencing revealed considerable differences in response to PPAR agonists at a false discovery rate-adjusted p-value of 0.2, with the most notable effects exerted by the PPARδ and PPARγ agonists. Differentially expressed genes were mainly related to pathways involved with lipid metabolism and the immune response. Among differentially expressed genes, a subset of 91 genes were identified as novel putative PPAR targets in the bovine liver, by cross-referencing our results with a publicly available dataset of predicted PPAR target genes, and supplementing our findings with prior literature. Our results provide important insights on the use of PCLS as a model for assaying PPAR activation in the periparturient dairy cow.

Treadmill exercise reduces α-synuclein spreading via PPARα.

SUMMARYThis study underlines the importance of treadmill exercise in reducing α-synuclein (α-syn) spreading in the A53T brain and protecting nigral dopaminergic neurons. Preformed α-syn fibril (PFF) seeding in the internal capsule of young A53T α-syn mice leads to increased spreading of α-syn to substantia nigra and motor cortex and concomitant loss of nigral dopaminergic neurons. However, regular treadmill exercise decreases α-syn spreading in the brain and protects nigral dopaminergic neurons in PFF-seeded mice. Accordingly, treadmill exercise also mitigates α-synucleinopathy in aged A53T mice. While investigating this mechanism, we have observed that treadmill exercise induces the activation of peroxisome proliferator-activated receptor α (PPARα) in the brain to stimulate lysosomal biogenesis via TFEB. Accordingly, treadmill exercise remains unable to stimulate TFEB and reduce α-synucleinopathy in A53T mice lacking PPARα, and fenofibrate, a prototype PPARα agonist, reduces α-synucleinopathy. These results delineate a beneficial function of treadmill exercise in reducing α-syn spreading in the brain via PPARα.

The combined anti-osteoporotic effects of simvastatin and exercise in ovariectomized mice fed a high-fat diet.

To evaluate and compare the effects of the combined intervention of simvastatin and exercise on the bone degeneration in a mice model of osteoporosis (OP) induced by obesity and estrogen deficiency. 56 female 3-month-old C57BL/6 mice were given a standard diet or a high-fat diet after ovariectomy (OVX) or sham surgery. Drug administration and exercise training were initiated 72h after surgical operation, which were treated with simvastatin (10mg/kg/day) or exercise (15m/min for 30min/day) or combined with simvastatin and exercise at 72h for 8weeks. The pathology of OP was assessed by histomorphology analyses, immunohistochemistry (IHC), micro-computed tomography (Micro-CT), enzyme-linked immunosorbent assay (ELISA) and cell culture. The coexistence of obesity and estrogen deficiency significantly further exacerbated OP pathology, and combined intervention showed a better significant anti-osteoporosis effect than monotherapy. In details, simvastatin combined with exercise ameliorated the abnormal bone mass, microstructure and bone marrow adipocyte differentiation, significantly increased osteoprotegerin (OPG), type 1 collagen (Col-I), RUNX2 and osteocalcin (OCN) expression, decreased the expression of receptor activator of nuclear factor-kappaB ligand (RANKL) and peroxisome proliferator-activated receptor γ (PPARγ). Furthermore, combined intervention markedly improved abnormal metabolic status, reduced the levels of serum glucose, insulin, triglycerides (TG), low-density lipoprotein (LDL), leptin, CTX-1 and IL-1β, and increased the level of OCN. The coexistence of obesity and estrogen deficiency further aggravates bone tissue degeneration and abnormal metabolic pathology, which could be better inhibited by the combination with simvastatin and exercise instead of single intervention, suggesting that combined intervention may be a potential candidate for amelioration of the progression of OP.

Role of PPAR Receptor and Ligands in the Pathogenesis and Therapy of Hematologic Malignancies

The Peroxisome proliferator-activated receptors (PPARs) play vital roles in regulating cellular differentiation, proliferation, and caspase-mediated cell death pathways. They are regarded as promising targets for anti-tumor drug development, particularly for multiple myeloma (MM) and different hematological malignancies. Several early section clinical trials are conducted to measure the clinical practicableness of PPAR agonists, notably PPARα and PPARγ agonists, against various cancers. A spread of studies has investigated PPARs expression in metabolic regulation. Furthermore, it has been suggested that careful designing of partial agonists for PPARs may show improvement with side effects and increase the therapeutic value. This review summarizes the organic chemistry and metabolic actions of PPARs, and the therapeutic potential of their agonists underneath clinical development. It investigates therapeutic agents for hematologic malignancies.

In vitro activity of a panel of per- and polyfluoroalkyl substances (PFAS), fatty acids, and pharmaceuticals in peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, and estrogen receptor assays

Data demonstrate numerous per- and polyfluoroalkyl substances (PFAS) activate peroxisome proliferator-activated receptor alpha (PPARα), however, additional work is needed to characterize PFAS activity on PPAR gamma (PPARγ) and other nuclear receptors. We utilized in vitro assays with either human or rat PPARα or PPARγ ligand binding domains to evaluate 16 PFAS (HFPO-DA, HFPO-DA-AS, NBP2, PFMOAA, PFHxA, PFOA, PFNA, PFDA, PFOS, PFBS, PFHxS, PFOSA, EtPFOSA, and 4:2, 6:2 and 8:2 FTOH), 3 endogenous fatty acids (oleic, linoleic, and octanoic), and 3 pharmaceuticals (WY14643, clofibrate, and the metabolite clofibric acid). We also tested chemicals for human estrogen receptor (hER) transcriptional activation. Nearly all compounds activated both PPARα and PPARγ in both human and rat ligand binding domain assays, except for the FTOH compounds and PFOSA. Receptor activation and relative potencies were evaluated based on effect concentration 20% (EC20), top percent of max fold induction (pmaxtop), and area under the curve (AUC). HFPO-DA and HFPO-DA-AS were the most potent (lowest EC20, highest pmaxtop and AUC) of all PFAS in rat and human PPARα assays, being slightly less potent than oleic and linoleic acid, while NBP2 was the most potent in rat and human PPARγ assays. Only PFHxS, 8:2 and 6:2 FTOH exhibited hER agonism >20% pmax. In vitro measures of human and rat PPARα and PPARγ activity did not correlate with oral doses or serum concentrations of PFAS that induced increases in male rat liver weight from the National Toxicology Program 28-d toxicity studies. Data indicate that both PPARα and PPARγ activation may be molecular initiating events that contribute to the in vivo effects observed for many PFAS.