Activation Of Peroxisome Proliferator-activated Receptor Research Articles

The PPARβ/δ-AMPK Connection in the Treatment of Insulin Resistance.

The current treatment options for type 2 diabetes mellitus do not adequately control the disease in many patients. Consequently, there is a need for new drugs to prevent and treat type 2 diabetes mellitus. Among the new potential pharmacological strategies, activators of peroxisome proliferator-activated receptor (PPAR)β/δ show promise. Remarkably, most of the antidiabetic effects of PPARβ/δ agonists involve AMP-activated protein kinase (AMPK) activation. This review summarizes the recent mechanistic insights into the antidiabetic effects of the PPARβ/δ-AMPK pathway, including the upregulation of glucose uptake, muscle remodeling, enhanced fatty acid oxidation, and autophagy, as well as the inhibition of endoplasmic reticulum stress and inflammation. A better understanding of the mechanisms underlying the effects resulting from the PPARβ/δ-AMPK pathway may provide the basis for the development of new therapies in the prevention and treatment of insulin resistance and type 2 diabetes mellitus.

Atypical antipsychotic drugs deregulate the cholesterol metabolism of macrophage-foam cells by activating NOX-ROS-PPARγ-CD36 signaling pathway

BackgroundClinical reports indicate that schizophrenia patients taking atypical antipsychotic drugs suffer from metabolism diseases including atherosclerosis. However, the mechanisms underlying the detrimental effect of atypical antipsychotic drugs on atherosclerosis remain to be explored. MethodsIn this study, we used apolipoprotein E-deficient (apoe−/−) hyperlipidemic mice and apoe−/−cd36−/− mice to investigate the underlying mechanism of atypical antipsychotic drugs on atherosclerosis and macrophage-foam cells. ResultsIn vivo studies showed that genetic deletion of cd36 gene ablated the pro-atherogenic effect of olanzapine in apoe−/− mice. Moreover, in vitro studies revealed that genetic deletion or siRNA-mediated knockdown of cd36 or pharmacological inhibition of CD36 prevented atypical antipsychotic drugs-induced oxLDL accumulation in macrophages. Additionally, olanzapine and clozapine activated NADPH oxidase (NOX) to generate reactive oxygen species (ROS) which upregulated the activity of peroxisome proliferator-activated receptor γ (PPARγ) and subsequently elevated CD36 expression. Inhibition of NOX activity, ROS production or PPARγ activity suppressed CD36 expression and abolished the detrimental effects of olanzapine and clozapine on oxLDL accumulation in macrophages. ConclusionCollectively, our results suggest that atypical antipsychotic drugs exacerbate atherosclerosis and macrophage-foam cell formation by activating the NOX-ROS-PPARγ-CD36 pathway.

PPARα and PPARγ Signaling Is Enhanced in the Brain of the Naked Mole-Rat, a Mammal that Shows Intrinsic Neuroprotection from Oxygen Deprivation.

Naked mole-rats (NMRs) are a long-lived animal that do not develop age-related diseases including neurodegeneration and cancer. Additionally, NMRs have a profound ability to consume reactive oxygen species (ROS) and survive long periods of oxygen deprivation. Here, we evaluated the unique proteome across selected brain regions of NMRs at different ages. Compared to mice, we observed numerous differentially expressed proteins related to altered mitochondrial function in all brain regions, suggesting that the mitochondria in NMRs may have adapted to compensate for energy demands associated with living in a harsh, underground environment. Keeping in mind that ROS can induce polyunsaturated fatty acid peroxidation under periods of neuronal stress, we investigated docosahexaenoic acid (DHA) and arachidonic acid (AA) peroxidation under oxygen-deprived conditions and observed that NMRs undergo DHA and AA peroxidation to a far less extent compared to mice. Further, our proteomic analysis also suggested enhanced peroxisome proliferator-activated receptor (PPAR)-retinoid X receptor (RXR) activation in NMRs via the PPARα-RXR and PPARγ-RXR complexes. Correspondingly, we present several lines of evidence supporting PPAR activation, including increased eicosapetenoic and omega-3 docosapentaenoic acid, as well as an upregulation of fatty acid-binding protein 3 and 4, known transporters of omega-3 fatty acids and PPAR activators. These results suggest enhanced PPARα and PPARγ signaling as a potential, innate neuroprotective mechanism in NMRs.

Uncovering Mechanisms of Zanthoxylum piperitum Fruits for the Alleviation of Rheumatoid Arthritis Based on Network Pharmacology.

Simple SummaryThe aim of the study is to investigate the bioactives of Zanthoxylum piperitum fruits on rheumatoid arthritis. The methodology to identify the relationship between signaling pathways, targets, and bioactives is based on network pharmacology. The results show that Zanthoxylum piperitum fruits might alleviate inflammatory symptoms of rheumatoid arthritis. Thus, we suggest that Zanthoxylum piperitum fruit is a promising herbal plant to reduce the level of cytokines against rheumatoid arthritis.Zanthoxylum piperitum fruits (ZPFs) have been demonstrated favorable clinical efficacy on rheumatoid arthritis (RA), but its compounds and mechanisms against RA have not been elucidated. This study was to investigate the compounds and mechanisms of ZPFs to alleviate RA via network pharmacology. The compounds from ZPFs were detected by gas chromatography–mass spectrometry (GC-MS) and screened to select drug-likeness compounds through SwissADME. Targets associated with bioactive compounds or RA were identified utilizing bioinformatics databases. The signaling pathways related to RA were constructed; interactions among targets; and signaling pathways-targets-compounds (STC) were analyzed by RPackage. Finally, a molecular docking test (MDT) was performed to validate affinity between targets and compounds on key signaling pathway(s). GC-MS detected a total of 85 compounds from ZPFs, and drug-likeness properties accepted all compounds. A total of 216 targets associated with compounds 3377 RA targets and 101 targets between them were finally identified. Then, a bubble chart exhibited that inactivation of MAPK (mitogen-activated protein kinase) and activation of PPAR (peroxisome proliferator-activated receptor) signaling pathway might be key pathways against RA. Overall, this work suggests that seven compounds from ZPFs and eight targets might be multiple targets on RA and provide integrated pharmacological evidence to support the clinical efficacy of ZPFs on RA.

Modulation of PPAR signaling disrupts pancreas development in the zebrafish, Danio rerio

Peroxisome Proliferator Activated Receptors (PPARs) are transcription factors that regulate processes such as lipid and glucose metabolism. Synthetic PPAR ligands, designed as therapeutics for metabolic disease, provide a tool to assess the relationship between PPAR activity and pancreas development in vivo, an area that remains poorly characterized. Here, we aim to assess the effects of PPAR agonists and antagonists on gene expression, embryonic morphology and pancreas development in transgenic zebrafish embryos. To evaluate developmental perturbations, we assessed gross body and pancreas morphology at 4 days post fertilization (dpf) in response to developmental exposures with PPARα, PPARγ, and PPARβ/δ agonists and antagonists at 0, 0.01, 0.1, 1, and 10 μM concentrations. All ligand exposures, with the exception of the PPARα agonist, resulted in significantly altered fish length and yolk sac area. PPARγ agonist and antagonist had higher incidence of darkened yolk sac and craniofacial deformities, whereas PPARα antagonist had higher incidence of pericardial edema and death. Significantly reduced endocrine pancreas area was observed in both PPARγ ligands and PPARα agonist exposed embryos, some of which also exhibited aberrant endocrine pancreas morphology. Both PPARβ/δ ligands caused reduced exocrine pancreas length and novel aberrant phenotype, and disrupted gene expression of pancreatic targets pdx1, gcga, and try. Lipid staining was performed at 8 dpf and revealed altered lipid accumulation consistent with isoform function. These data indicate chronic exposure to synthetic ligands may induce morphological and pancreatic defects in zebrafish embryos.

Essential Roles of PPARs in Lipid Metabolism during Mycobacterial Infection.

The mycobacterial cell wall is composed of large amounts of lipids with varying moieties. Some mycobacteria species hijack host cells and promote lipid droplet accumulation to build the cellular environment essential for their intracellular survival. Thus, lipids are thought to be important for mycobacteria survival as well as for the invasion, parasitization, and proliferation within host cells. However, their physiological roles have not been fully elucidated. Recent studies have revealed that mycobacteria modulate the peroxisome proliferator-activated receptor (PPAR) signaling and utilize host-derived triacylglycerol (TAG) and cholesterol as both nutrient sources and evasion from the host immune system. In this review, we discuss recent findings that describe the activation of PPARs by mycobacterial infections and their role in determining the fate of bacilli by inducing lipid metabolism, anti-inflammatory function, and autophagy.

Ectopic Overexpression of PPARγ2 in the Heart Determines Differences in Hypertrophic Cardiomyopathy After Treatment With Different Thiazolidinediones in a Mouse Model of Diabetes.

The clinical controversy of rosiglitazone as a hypoglycemic agent is potentially associated with heart failure, mainly due to its potent activation of peroxisome proliferator-activated receptor γ (PPARγ). PPARγ partial agonists showed superior pharmacological profiles to rosiglitazone. This study compared differences in cardiac morphology and function of the PPARγ partial agonist CMHX008 with rosiglitazone. High-fat diet (HFD) induced obese mice, ob/ob mice and cardiomyocytes overexpressing PPARγ2 were treated with CMHX008 or rosiglitazone. Heart function, myocardial morphology, and hypertrophy-related gene expression were examined. Clinical information from patients with type 2 diabetes mellitus (T2DM) who had taken rosiglitazone and undergone Doppler echocardiography was collected. HFD and ob/ob mice significantly developed cardiac contractile dysfunction, with upregulated PPARγ2 protein levels in heart tissues. Cardiomyocytes of HFD and ob/ob mice were disorderly arranged, the cell areas expanded, and collagen accumulated. In vitro cardiomyocytes overexpressing PPARγ2 displayed obvious structural abnormalities and high mRNA levels of ANP and BNP, critical cardiac hypertrophy-related genes. HFD-fed mice treated with rosiglitazone or CMHX008 had significantly improved cardiac function, but rosiglitazone induced higher expression of ANP and βMHC and hypertrophic cardiomyopathy, while CMHX008 did not. Patients with T2DM taking rosiglitazone exhibited increased thickness of the posterior wall and the ventricular septum, suggesting cardiac hypertrophy. Our findings show that diabetic cardiomyopathy was associated with ectopic overexpression of PPARγ2. The full agonist rosiglitazone prevents cardiac dysfunction at the expense of compensatory hypertrophy, while the partial agonist CMHX008 shared a comparable protective effect without altering the structure of cardiomyocytes.

Artemisia scoparia promotes adipogenesis in the absence of adipogenic effectors.

Extracts of Artemisia scoparia (SCO) have antidiabetic properties in mice and enhance adipogenesisin vitro, but the underlying mechanisms are unknown. Thiazolidinediones, including rosiglitazone (ROSI), are pharmacological activators ofperoxisome proliferator-activated receptor gammathat also promote adipogenesis.The aim of this study was to examine adipogenic pathways responsible for SCO-mediated adipogenesis and identify potential differences between SCO and ROSI in the ability to promote adipocyte development. The ability of SCO or ROSI to promote adipogenesis in 3T3-L1 cells following systematic omission of the common triad of adipogenic effectors dexamethasone,1-methyl-3-isobutylxanthine (MIX), and insulin was examined. Adipogenesis was assessed by both neutral lipid quantitation and adipocyte marker gene expression. The results demonstratethat SCO and ROSI promote adipogenesis and increase the expression of severalperoxisome proliferator-activated receptor gamma target genes involved in lipid accumulation in the absence of MIX. However, ROSI can enhance adipogenesis in the absence of MIX and insulin and differentially regulates adipogenic and lipid metabolism genes as compared with SCO. These data demonstrate the adipogenic capabilities of SCO are similar but not identical to ROSI, thereby warranting further research into SCO as a promising source of therapeutic compounds in the treatment of metabolic disease states.

Activation Mediated By Peroxisome Proliferator-Activated Receptor (PPAR) Ligands and Brown Algae-Based Compounds: Different Mechanisms between Megakaryoblasts and Mature Platelets

Background: Nuclear receptors aretranscription factors that are activated by ligands and subsequently bind to regulatory regions in target genes. Recently ligand-activated transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) has been reported to promote the formation of platelets from megakaryocytes and accelerate platelet recovery after radiation-induced bone marrow injuries. The endogenous prostaglandin 15-deoxy-Δ12,14 prostaglandin J2 (15d-PGJ2) are ligands of PPARγ. Accumulating evidences also suggest that PPAR activation is involved in inflammation responses and atherosclerosis. In the present study, we analyzed how PPAR ligands and some brown algae-based compounds affect platelet differentiation and functions in vitro.Methods: Platelets were obtained from plateletpheresis products by centrifugation. DAMI and Meg-1 cells, both human megakaryocytic cell lines, were also obtained. Western blotting for PPARγ, PPARα and COX-2 was performed, and bands were visualized by chemiluminescence. The effects of 15d-PGJ2, GW9662, Fucoidan, Seanol, GW6471 and Celecoxib were evaluated. Morphology analysis, platelet flow cytometry, total thrombus formation analysis system (T-TAS) and microarray expression analysis were also used in order to analyze the effects of the treatment on platelets.Results: Megakaryoblasts and mature platelets showed different results in the expression of PPARα, COX-2, glycoproteins and platelet activation markers. PGJ2 induced morphological differentiation evidences in DAMI and Meg-1 cells. PGJ2 increased the levels of CD41, CD42b, CD62p and PAC-1 both in DAMI and Meg-1 cells. In mature platelets, Fucoidan and Seanol decreased the expression of PPARα and increased COX-2 expression. Fucoidan elevated the expression of CD62p and CD63 in mature platelets, suggesting that Fucoidan causes platelet activation. In microarray analysis, fucoidan showed early growth response (EGR)-1 gene upregulation. Unfortunately thrombogenesity by T-TAS was not evident from the study.Conclusions: The mechanism of platelet production and activation is not fully understood. Understanding the mechanisms underlying megakaryocyte maturation and platelet production will facilitate the development of methods to increase the production of platelets from precursor cells. Although platelets are non-nucleated cells, they contain transcription factors, especially PPAR and NF-κB. From the present study, our findings support the hypothesis that PPAR, both PPARγ and PPARα play a role in platelet differentiation and activation, and exact mechanisms need to be defined related to prostaglandin pathways. Fucoidan may activate platelets via different pathways than PGJ2. DisclosuresNo relevant conflicts of interest to declare.

Oleuropein-Induced Acceleration of Cytochrome P450-Catalyzed Drug Metabolism: Central Role for Nuclear Receptor Peroxisome Proliferator-Activated Receptor α.

Oleuropein (OLE), the main constituent of Olea europaea, displays pleiotropic beneficial effects in health and disease, which are mainly attributed to its anti-inflammatory and cardioprotective properties. Several food supplements and herbal medicines contain OLE and are available without a prescription. This study investigated the effects of OLE on the main cytochrome P450s (P450s) catalyzing the metabolism of many prescribed drugs. Emphasis was given to the role of peroxisome proliferator-activated receptor α (PPARα), a nuclear transcription factor regulating numerous genes including P450s. 129/Sv wild-type and Ppara-null mice were treated with OLE for 6 weeks. OLE induced Cyp1a1, Cyp1a2, Cyp1b1, Cyp3a14, Cyp3a25, Cyp2c29, Cyp2c44, Cyp2d22, and Cyp2e1 mRNAs in liver of wild-type mice, whereas no similar effects were observed in Ppara-null mice, indicating that the OLE-induced effect on these P450s is mediated by PPARα. Activation of the pathways related to phosphoinositide 3-kinase/protein kinase B (AKT)/forkhead box protein O1, c-Jun N-terminal kinase, AKT/p70, and extracellular signal-regulated kinase participates in P450 induction by OLE. These data indicate that consumption of herbal medicines and food supplements containing OLE could accelerate the metabolism of drug substrates of the above-mentioned P450s, thus reducing their efficacy and the outcome of pharmacotherapy. Therefore, OLE-induced activation of PPARα could modify the effects of drugs due to their increased metabolism and clearance, which should be taken into account when consuming OLE-containing products with certain drugs, in particular those of narrow therapeutic window. SIGNIFICANCE STATEMENT: This study indicated that oleuropein, which belongs to the main constituents of the leaves and olive drupes of Olea europaea, induces the synthesis of the major cytochrome P450s (P450s) metabolizing the majority of prescribed drugs via activation of peroxisome proliferator-activated receptor α. This effect could modify the pharmacokinetic profile of co-administered drug substrates of the P450s, thus altering their therapeutic efficacy and toxicity.

Anti-inflammatory and immunoregulatory effects of pinolenic acid in rheumatoid arthritis.

ObjectivesIn pre-clinical studies, pinolenic acid (PNLA), an omega-6-polyunsaturated fatty acid from pine nuts, has shown anti-inflammatory effects. We aimed to investigate the effect of PNLA in human cell lines and peripheral blood mononuclear cells (PBMCs) from RA patients and healthy controls (HCs).MethodsA modified Boyden chamber was used to assess chemokine-induced migration of THP-1 monocytes. Macropinocytosis was assessed using Lucifer yellow and oxidized low-density lipoprotein (oxLDL) uptake using DiI-labelled oxLDL in THP-1 macrophages and human monocyte-derived macrophages (HMDMs). IL-6, TNF-α and prostaglandin E2 (PGE2) release by lipopolysaccharide (LPS)-stimulated PBMCs from RA patients and HCs was measured by ELISA. The transcriptomic profile of PNLA-treated, LPS-activated PBMCs was investigated by RNA-sequencing.ResultsPNLA reduced THP-1 cell migration by 55% (P < 0.001). Macropinocytosis and DiI-oxLDL uptake were reduced by 50% (P < 0.001) and 40% (P < 0.01), respectively, in THP-1 macrophages and 40% (P < 0.01) and 25% (P < 0.05), respectively, in HMDMs. PNLA reduced IL-6 and TNF-α release from LPS-stimulated PBMCs from RA patients by 60% (P < 0.001) and from HCs by 50% and 35%, respectively (P < 0.01). PNLA also reduced PGE2 levels in such PBMCs from RA patients and HCs (P < 0.0001). Differentially expressed genes whose expression was upregulated included pyruvate dehydrogenase kinase-4, plasminogen activator inhibitor-1, fructose bisphosphatase1 and N-Myc downstream-regulated gene-2, which have potential roles in regulating immune and metabolic pathways. Pathway analysis predicted upstream activation of the nuclear receptors peroxisome proliferator-activated receptors involved in anti-inflammatory processes, and inhibition of nuclear factor-κB and signal transducer and activator of transcription 1.ConclusionsPNLA has immune-metabolic effects on monocytes and PBMCs that are pathogenic in RA and atherosclerosis. Dietary PNLA supplementation may be beneficial in RA.

1139-P: CD36/FABP4/PPAR-d Axis-Induced Inflammation Is Dependent on ACSL1 under the Influence of Acute High-Fat Feeding

Elevated levels of circulating inflammatory macrophages are associated with several metabolic syndrome (MetS) such as obesity and type II diabetes (T2D). The ingestion of high-fat meals was proven by several groups to act as a stimulus for systemic inflammatory responses via activation of peroxisome proliferator-activated receptors (PPARs). However, little is known about the lipid metabolism involved in macrophage-mediated inflammation under the influence of acute high fat feeding (AHFF). ACSL1 is a member of the long chain acyl-CoA synthetase (ACSL) family that plays key roles in fatty acid metabolism in various tissues. Our previous studies showed that attenuation of ACSL1 was sufficient to dampen inflammatory responses in macrophages challenged with TNF-α or LPS. In this study, we investigated the molecular mechanisms underlying AHFF-induced ACSL1 gene transcription in macrophages. In our work, we showed that four hours feeding of palmitic acid induced significant up-regulation of ACSL1 at both gene and protein levels. Both the inhibition and the deficiency of ACSL1, showed a significant impact on downregulating AHFF-induced inflammatory responses. Furthermore, the inhibition ACSL1 reduced mRNA levels of fatty acid uptake-related genes cluster of differentiation 36 (CD36) and fatty acid transport protein 4 (FATP4). However, inhibition of ACSL1 had no impact on lipogenesis related genes; SREBS, FAS and ACACA or fatty acid-oxidation genes; CPT-1a, CPT-1b and CPT2. Our data also showed that ACSL1 inhibition reduced PPARδ gene expression, while PPARα and PPARγ were not affected. Of note, macrophage intracellular lipid accumulation was attenuated during ACSL inhibition. Our findings suggest that targeting ACSL1 has a therapeutic potential to prevent AHFF-induced macrophage inflammation. Disclosure F. Alrashed: None. A. Al madhoun: None. S. T. Sindhu: None. A. Al-sayyar: None. F. Almulla: None. R. Ahmad: None. Funding Kuwait Foundation for the Advancement of Sciences (CB-2020-004)

Downregulation of NK cell activities in Apolipoprotein C-III-induced hyperlipidemia resulting from lipid-induced metabolic reprogramming and crosstalk with lipid-laden dendritic cells

ObjectiveApolipoprotein C-III (Apoc3) is a key component of triglyceride-rich lipoproteins (TRL). The Apoc3-transgenic mice are characterized by high levels of plasma triglyceride and free fatty acids (FFAs). Apoc3 stimulates human monocytes via activation of the NLRP3 inflammasome. Considering the NK cell downregulation in obese individuals and the possible stimulatory-effects of macrophages, variations of NK cell functions and underlying mechanisms were investigated in mice with Apoc3-induced hyperlipidemia. MethodsVariations of activities and glycolipid metabolism in NK cells of the Apoc3-transgenic mice with hyperlipidemia were detected. Molecular mechanisms of lipid-induced metabolic-reprogramming in NK cells were analyzed based on the transcriptome sequencing. Finally, effects of DCs in mice with hyperlipidemia on NK cell functions were determined. ResultsImpaired number and function of NK cells in Apoc3TG mice was involved with the increased fatty acid oxidation and decreased glycolysis. Increased uptake of FFAs in Apoc3TG-NK cells contributed to the peroxisome proliferator-activated receptor (PPAR) activation and the downstream PTEN–AKT–mTOR/FOXO1 signaling pathway. Inhibition of PPAR or CPT1α only partly reversed the IFN-γ production of Apoc3TG-NK cells, but completely restored IFN-γ secretion by palmitic acid-treated NK cells ex vivo, indicating that other factors contributed to the Apoc3TG-NK cell downregulation. Meanwhile, Apoc3TG-DCs, which contained more lipids in the cytoplasm, depended on reactive oxygen species (ROS) to increase the expressions PD-L1, TGF-β1, and NKG2D ligands and suppress NK cell activities. DCs of the Apoc3TG-CD36−/+ hybrid mice with less intracellular lipids and ROS production could not inhibit NK cells, indicating that intracellular FFAs promoted the immune-modulatory function of DCs. ConclusionsThe downregulation of NK cell activities in individuals with Apoc3-induced hyperlipidemia was due to the increased fatty acid oxidation in NK cells and the bystander suppression caused by lipid-laden DCs. The dual recovery function of NK cells and DCs would improve the prognosis of patients with metabolic syndrome.

PPARγ receptors are involved in the effects of cannabidiol on orofacial dyskinesia and cognitive dysfunction induced by typical antipsychotic in mice

Tardive dyskinesia (TD) is a movement disorder that appears after chronic use of drugs that block dopaminergic receptors such as antipsychotics. Besides the motor symptoms, patients with TD also present cognitive deficits. Neuroinflammatory mechanisms could be involved in the development of these symptoms. A previous study showed that cannabidiol (CBD), the major non-psychotomimetic compound of Cannabis sativa plant, prevents orofacial dyskinesia induced by typical antipsychotics by activating peroxisome proliferator-activated receptors gamma (PPARγ). Here, we investigated if CBD would also reverse haloperidol-induced orofacial dyskinesia and associated cognitive deficits. We also verified if these effects depend on PPARγ receptor activation. Daily treatment with haloperidol (3 mg/kg, 21 days) increased the frequency of vacuous chewing movements (VCM) and decreased the discrimination index in the novel object recognition test in male Swiss mice. CBD (60 mg/kg/daily) administered in the last 7 days of haloperidol treatment attenuated both behavioral effects. Furthermore, haloperidol increased IL-1β and TNF-α levels in the striatum and hippocampus while CBD reverted these effects. The striatal and hippocampal levels of proinflammatory cytokines correlated with VCM frequency and discrimination index, respectively. Pretreatment with the PPARγ antagonist GW9662 (2 mg/kg/daily) blocked the behavioral effects of CBD. In conclusion, these results indicated that CBD could attenuate haloperidol-induced orofacial dyskinesia and improve non-motor symptoms associated with TD by activating PPARγ receptors.

Invitro effect of pine bark extract on melanin synthesis, tyrosinase activity, production of endothelin-1, and PPAR in cultured melanocytes exposed to Ultraviolet, Infrared, and Visible light radiation.

French maritime pine bark (Pinus pinaster) extract (PBE), the registered trade name of which is Pycnogenol® , has been studied for its depigmenting action due to its antioxidant, anti-inflammatory, and anti-melanogenic activity. However, the mechanisms through which PBE are still not fully clear. Evaluate the impact of PBE on four in vitro parameters closely associated with cutaneous pigmentation, including melanin synthesis, tyrosinase activity, endothelin-1 (ED1), and production of peroxisome proliferator-activated receptor α, δ, and γ (PPAR α, δ, and γ), by studying the modulation of action of ultraviolet radiation A (UVA)/ultraviolet radiation B (UVB), infrared-A (IR-A), visible light (VL), and association of UVA/UVB, IR-A, and VL (ASS). Human melanocytes were incubated in a dry extract solution of PBE, exposed to UVA/UVB, IR-A, VL, and ASS for subsequent quantification of melanin, ED1, and PPAR α, δ, and γ. The effects of PBE on inhibition of tyrosinase activity were also performed by monophenolase activity assay. UVA/UVB, IR-A, VL, and ASS radiation caused significant increases in the synthesis of melanin, ED1, and PPAR α, δ, and γ when compared to baseline control. However, PBE significantly reduced the production of melanin, ED1, and PPAR α, δ, and γ, as well as reducing about 66.5% of the tyrosinase activity. PBE reduces in vitro melanin production by downregulating tyrosinase and reducing pigmentation-related mediators, such as ED1 and PPAR α, δ, and γ, therefore contributing to the inhibition of pathways associated with skin hyperpigmentation.

Lysosome-Dependent LXR and PPARδ Activation Upon Efferocytosis in Human Macrophages.

Efferocytosis is critical for tissue homeostasis, as its deregulation is associated with several autoimmune pathologies. While engulfing apoptotic cells, phagocytes activate transcription factors, such as peroxisome proliferator-activated receptors (PPAR) or liver X receptors (LXR) that orchestrate metabolic, phagocytic, and inflammatory responses towards the ingested material. Coordination of these transcription factors in efferocytotic human macrophages is not fully understood. In this study, we evaluated the transcriptional profile of macrophages following the uptake of apoptotic Jurkat T cells using RNA-seq analysis. Results indicated upregulation of PPAR and LXR pathways but downregulation of sterol regulatory element-binding proteins (SREBP) target genes. Pharmacological inhibition and RNA interference pointed to LXR and PPARδ as relevant transcriptional regulators, while PPARγ did not substantially contribute to gene regulation. Mechanistically, lysosomal digestion and lysosomal acid lipase (LIPA) were required for PPAR and LXR activation, while PPARδ activation also demanded an active lysosomal phospholipase A2 (PLA2G15). Pharmacological interference with LXR signaling attenuated ABCA1-dependent cholesterol efflux from efferocytotic macrophages, but suppression of inflammatory responses following efferocytosis occurred independently of LXR and PPARδ. These data provide mechanistic details on LXR and PPARδ activation in efferocytotic human macrophages.

PPARs and Tumor Microenvironment: The Emerging Roles of the Metabolic Master Regulators in Tumor Stromal-Epithelial Crosstalk and Carcinogenesis.

Simple SummaryThe roles of peroxisome proliferator-activated receptors (PPARs) in carcinogenesis are increasingly appreciated. With the growing interest in tumor stromal-epithelial crosstalk, we aim to provide an up-to-date overview of the implications of PPARs in the tumor microenvironment. In the tumor stromal cells, the nuclear receptors exhibit critical, but functionally diverse activities, rendering it hard to ascribe either an exclusive pro- or anti-tumorigenic role for different PPAR isotypes. Based on the existing evidence, we also highlight the knowledge gaps and future prospects of targeting PPARs in the tumor microenvironment. Essentially, a PPAR-based anticancer approach holds a great deal of untapped potential, but its success relies on innovative strategies for cell-specific or tumor microenvironment-triggered drug delivery systems.Peroxisome proliferator-activated receptors (PPARs) have been extensively studied for more than three decades. Consisting of three isotypes, PPARα, γ, and β/δ, these nuclear receptors are regarded as the master metabolic regulators which govern many aspects of the body energy homeostasis and cell fate. Their roles in malignancy are also increasingly recognized. With the growing interest in crosstalk between tumor stroma and epithelium, this review aims to highlight the current knowledge on the implications of PPARs in the tumor microenvironment. PPARγ plays a crucial role in the metabolic reprogramming of cancer-associated fibroblasts and adipocytes, coercing the two stromal cells to become substrate donors for cancer growth. Fibroblast PPARβ/δ can modify the risk of tumor initiation and cancer susceptibility. In endothelial cells, PPARβ/δ and PPARα are pro- and anti-angiogenic, respectively. Although the angiogenic role of PPARγ remains ambiguous, it is a crucial regulator in autocrine and paracrine signaling of cancer-associated fibroblasts and tumor-associated macrophages/immune cells. Of note, angiopoietin-like 4 (ANGPTL4), a secretory protein encoded by a target gene of PPARs, triggers critical oncogenic processes such as inflammatory signaling, extracellular matrix derangement, anoikis resistance and metastasis, making it a potential drug target for cancer treatment. To conclude, PPARs in the tumor microenvironment exhibit oncogenic activities which are highly controversial and dependent on many factors such as stromal cell types, cancer types, and oncogenesis stages. Thus, the success of PPAR-based anticancer treatment potentially relies on innovative strategies to modulate PPAR activity in a cell type-specific manner.

Lobeglitazone: A Novel Thiazolidinedione for the Management of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and β-cell dysfunction. Among available oral antidiabetic agents, only the thiazolidinediones (TZDs) primarily target insulin resistance. TZDs improve insulin sensitivity by activating peroxisome proliferator-activated receptor γ. Rosiglitazone and pioglitazone have been used widely for T2DM treatment due to their potent glycemic efficacy and low risk of hypoglycemia. However, their use has decreased because of side effects and safety issues, such as cardiovascular concerns and bladder cancer. Lobeglitazone (Chong Kun Dang Pharmaceutical Corporation), a novel TZD, was developed to meet the demands for an effective and safe TZD. Lobeglitazone shows similar glycemic efficacy to pioglitazone, with a lower effective dose, and favorable safety results. It also showed pleiotropic effects in preclinical and clinical studies. In this article, we summarize the pharmacologic, pharmacokinetic, and clinical characteristics of lobeglitazone.

Mitochondrial transfer from mesenchymal stem cells to macrophages restricts inflammation and alleviates kidney injury in diabetic nephropathy mice via PGC-1α activation.

Mesenchymal stem cells (MSCs) have fueled ample translation for treatment of immune-mediated diseases. Our previous study had demonstrated that MSCs could elicit macrophages (Mφ) into anti-inflammatory phenotypes, and alleviate kidney injury in diabetic nephropathy (DN) mice via improving mitochondrial function of Mφ, yet the specific mechanism was unclear. Recent evidence indicated that MSCs communicated with their microenvironment through exchanges of mitochondria. By a coculture system consisting of MSCs and Mφ, we showed that MSCs-derived mitochondria (MSCs-Mito) were transferred into Mφ, and the mitochondrial functions were improved, which contributed to M2 polarization. Furthermore, we found that MSCs-Mito transfer activated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)-mediated mitochondrial biogenesis. In addition, PGC-1α interacted with TFEB in high glucose-induced Mφ, leading to the elevated lysosome-autophagy, which was essential to removal of damaged mitochondria. As a result, in Mφ, the mitochondrial bioenergy and capacity to combat inflammatory response were enhanced. Whereas, the immune-regulatory activity of MSCs-Mito was significantly blocked in PGC-1α knockdown Mφ. More importantly, MSCs-Mito transfer could be observed in DN mice, and the adoptive transfer of MSCs-Mito educated Mφ (MφMito ) inhibited the inflammatory response and alleviated kidney injury. However, the kidney-protective effects of MφMito were abolished when the MSCs-Mito was impaired with rotenone, and the similar results were also observed when MφMito were transfected with sipgc-1α before administration. Collectively, these findings suggested that MSCs elicited Mφ into anti-inflammatory phenotype and ameliorated kidney injury through mitochondrial transfer in DN mice, and the effects were relied on PGC-1α-mediated mitochondrial biogenesis and PGC-1α/TFEB-mediated lysosome-autophagy.

Proteome analysis of human adipocytes identifies depot-specific heterogeneity at metabolic control points.

Adipose tissue is a primary regulator of energy balance and metabolism. The distribution of adipose tissue depots is of clinical interest because the accumulation of upper-body subcutaneous (ASAT) and visceral adipose tissue (VAT) is associated with cardiometabolic diseases, whereas lower-body glutealfemoral adipose tissue (GFAT) appears to be protective. There is heterogeneity in morphology and metabolism of adipocytes obtained from different regions of the body, but detailed knowledge of the constituent proteins in each depot is lacking. Here, we determined the human adipocyte proteome from ASAT, VAT, and GFAT using high-resolution Sequential Window Acquisition of all Theoretical (SWATH) mass spectrometry proteomics. We quantified 4,220 proteins in adipocytes, and 2,329 proteins were expressed in all three adipose depots. Comparative analysis revealed significant differences between adipocytes from different regions (6% and 8% when comparing VAT vs. ASAT and GFAT, 3% when comparing the subcutaneous adipose tissue depots, ASAT and GFAT), with marked differences in proteins that regulate metabolic functions. The VAT adipocyte proteome was overrepresented with proteins of glycolysis, lipogenesis, oxidative stress, and mitochondrial dysfunction. The GFAT adipocyte proteome predicted the activation of peroxisome proliferator-activated receptor α (PPARα), fatty acid, and branched-chain amino acid (BCAA) oxidation, enhanced tricarboxylic acid (TCA) cycle flux, and oxidative phosphorylation, which was supported by metabolomic data obtained from adipocytes. Together, this proteomic analysis provides an important resource and novel insights that enhance the understanding of metabolic heterogeneity in the regional adipocytes of humans.NEW & NOTEWORTHY Adipocyte metabolism varies depending on anatomical location and the adipocyte protein composition may orchestrate this heterogeneity. We used SWATH proteomics in patient-matched human upper- (visceral and subcutaneous) and lower-body (glutealfemoral) adipocytes and detected 4,220 proteins and distinguishable regional proteomes. Upper-body adipocyte proteins were associated with glycolysis, de novo lipogenesis, mitochondrial dysfunction, and oxidative stress, whereas lower-body adipocyte proteins were associated with enhanced PPARα activation, fatty acid, and BCAA oxidation, TCA cycle flux, and oxidative phosphorylation.