Total ginsenosides decrease Aß production through activating PPARγ.

INTRODUCTION: Total ginsenosides (TG), the major active constituents of ginseng, have been proven to be beneficial in treatment of Alzheimer's disease (AD). However, the underlying mechanism of TG remains unclear. METHODS: APP/PS1 mice and N2a/APP695 cells were used as in vivo and in vitro model, respectively. Morris water maze (MWM) was used to investigate behavioral changes of mice; neuronal pathological changes were assessed by hematoxylin and eosin (H&E) and nissl staining; immunofluorescence staining was used to examine amyloid beta (Aß) deposition; Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to examine the expression of relative amyloidogenic genes and proteins. Moreover, the antagonist of PPARγ, GW9662, was used to determine whether the effects of TG on Aß production were associated with PPARγ activity. RESULTS: TG treatment increased the spatial learning and memory abilities of APP/PS1 mice while decreasing the Aß accumulation in the cortex and hippocampus. In N2a/APP695 cells, TG treatment attenuated the secretion of Aß1-40 and Aß1-42 acting as an PPARγ agonist by inhibiting the translocation of NF-κB p65. Additionally, TG treatment also decreased the expression of amyloidogenic pathway related gene BACE1, PS1 and PS2. CONCLUSIONS: TG treatment reduced the production of Aß both in vivo and in vitro. Activating PPARγ might be a potential therapeutic target of TG in facilitating Aß clearance and ameliorating cognitive deficiency in APP/PS1 mice.

Rosiglitazone-Mediated Activation of PPARγ Restores HO1 Expression in the Human Preeclamptic Placenta.

BACKGROUND: Preeclampsia is a hypertensive disorder of pregnancy characterized by chronic placental ischemia and suppression of proangiogenic proteins, causing oxidative stress, hypertension, and maternal systemic organ damage. The transcription factor, PPARγ (peroxisome proliferator-activated receptor-γ) promotes healthy trophoblast differentiation but is dysregulated in the preeclampsia placenta. Our study identifies the beneficial impact of Rosiglitazone-mediated PPARγ-activation in the stressed preeclampsia placenta. METHODS: We used first trimester placentas, preeclamptic and preterm control placentas, and human trophoblast cell lines to study PPARγ activation. RESULTS: Induction of PPARγ activates cell growth and antioxidative stress pathways, including the gene, heme oxygenase 1 (Hmox1). Protein expression of both PPARγ and HO1 (heme oxygenase 1) are reduced in preeclamptic placentas, but Rosiglitazone restores HO1 signaling in a PPARγ-dependent manner. CONCLUSIONS: Restoring disrupted pathways by PPARγ in preeclampsia offers a potential therapeutic pathway to reverse placental damage, extending pregnancy duration, and reduce maternal sequelae. Future research should aim to understand the full scope of impaired PPARγ signaling in the human placenta and focus on compounds for safe use during pregnancy to prevent severe perinatal morbidity and mortality.

Phenylethanoid glycosides extract from Cistanche deserticola ameliorates atherosclerosis in apolipoprotein E-deficient mice and regulates intestinal PPARγ-LXRα-ABCA1 pathway.

OBJECTIVES: This study was aimed to evaluate the protective effects of phenylethanoid glycosides extract from Cistanche deserticola against atherosclerosis and its molecular mechanism. METHODS: Total phenylethanoid glycosides were extracted and purified from C. deserticola, and the C. deserticola extract (CDE) was used to treat a mice model of atherosclerosis. KEY FINDINGS: CDE containing 81.00% total phenylethanoid glycosides, with the contents of echinacoside and acteoside being 31.36% and 7.23%, respectively. A 13-week of CDE supplementation (1000 mg/kg body weight/day) significantly reduced atherosclerotic lesions in the aortic sinus and entire aorta in ApoE-/- mice fed with a high-fat diet. In addition, varying doses of CDE (250, 500 and 1000 mg/kg body weight/day) lowered plasma total cholesterol, triglyceride and non-high-density lipoprotein cholesterol levels. Transcriptomic analysis of the small intestine revealed the changes enriched in cholesterol metabolic pathway and the activation of Abca1 gene. Further validation using real-time quantitative PCR and western blot confirmed that CDE significantly increased the mRNA levels and protein expressions of ABCA1, LXRα and PPARγ. CONCLUSIONS: Our results demonstrate the beneficial effects of C. deserticola on atherosclerotic plaques and lipid homeostasis, and it is, at least partially, by activating PPARγ-LXRα-ABCA1 pathway in small intestine.

Arctium lappa leaves based on network pharmacology and experimental validation attenuate atherosclerosis by targeting the AMPK-mediated PPARG/LXRα pathway.

Arctium lappa (A. lappa) leaves are widely used in various traditional Chinese herbal formulae to ameliorate atherosclerosis (AS) and its complications such as stroke; however, there is no literature reporting the anti-atherosclerotic effect and mechanism of A. lappa leaves thus far. In the present study, we used network pharmacology and molecular docking approaches to examine the protective effect and potential mechanism of A. lappa leaves against AS in vivo and in vitro. From the network pharmacology, PPARG, HMGCR and SREBF2 were identified as the core targets of A. lappa leaves against AS. Further enrichment analyses of GO and KEGG pathways suggested that A. lappa leaves might play an anti-AS role by regulating metabolic processes and PPAR signalling pathways. The results of molecular docking experiment revealed that the major components of A. lappa leaves interacted with cholesterol efflux-regulating core proteins (PPARG, LXRα, ABCA1, and ABCG1), AMPK and SIRT1. Both in vivo and in vitro experimental results demonstrated that treatment with A. lappa leaves significantly lowered TC and LDL-C, increased HDL-C, and reduced cholesterol accumulation in the liver and aorta of the AS rat model and the foam cell model. Importantly, both in vivo and in vitro experimental results demonstrated that A. lappa leaves regulate the activity of the PPARG/LXRα signalling and AMPK/SIRT1 signalling pathways. Moreover, after treatment with the AMPK inhibitor Compound C in vitro, the improvement induced by A. lappa leaves was significantly reversed. In conclusion, A. lappa leaves attenuated AS-induced cholesterol accumulation by targeting the AMPK-mediated PPARG/LXRα pathway and promoting cholesterol efflux.

Ethyl Gallate Dual-Targeting PTPN6 and PPARγ Shows Anti-Diabetic and Anti-Obese Effects.

The emergence of the high correlation between type 2 diabetes and obesity with complicated conditions has led to the coinage of the term "diabesity". AMP-activated protein kinase (AMPK) activators and peroxisome proliferator-activated receptor (PPARγ) antagonists have shown therapeutic activity for diabesity, respectively. Hence, the discovery of compounds that activate AMPK as well as antagonize PPARγ may lead to the discovery of novel therapeutic agents for diabesity. In this study, the knockdown of PTPN6 activated AMPK and suppressed adipogenesis in 3T3-L1 cells. By screening a library of 1033 natural products against PTPN6, we found ethyl gallate to be the most selective inhibitor of PTPN6 (Ki = 3.4 µM). Subsequent assay identified ethyl gallate as the best PPARγ antagonist (IC50 = 5.4 µM) among the hit compounds inhibiting PTPN6. Ethyl gallate upregulated glucose uptake and downregulated adipogenesis in 3T3-L1 cells as anticipated. These results strongly suggest that ethyl gallate, which targets both PTPN6 and PPARγ, is a potent therapeutic candidate to combat diabesity.

Baicalin Promotes CNS Remyelination via PPARγ Signal Pathway.

BACKGROUND AND OBJECTIVES: Demyelinating diseases in the CNS are characterized by myelin sheath destruction or formation disorder that leads to severe neurologic dysfunction. Remission of such diseases is largely dependent on the differentiation of oligodendrocytes precursor cells (OPCs) into mature myelin-forming OLGs at the demyelinated lesions, which is defined as remyelination. We discover that baicalin (BA), a natural flavonoid, in addition to its well-known antiinflammatory effects, directly stimulates OLG maturation and CNS myelin repair. METHODS: To investigate the function of BA on CNS remyelination, we develop the complementary in vivo and in vitro models, including physiologic neonatal mouse CNS myelinogenesis model, pathologic cuprizone-induced (CPZ-induced) toxic demyelination model, and postnatal OLG maturation assay. Furthermore, molecular docking, pharmacologic regulation, and transgenic heterozygous mice were used to clarify the target and action of the mechanism of BA on myelin repair promotion. RESULTS: Administration of BA was not only merely effectively enhanced CNS myelinogenesis during postnatal development but also promoted remyelination and reversed the coordination movement disorder in the CPZ-induced toxic demyelination model. Of note, myelin-promoting effects of BA on myelination or regeneration is peroxisome proliferator-activated receptor γ (PPARγ) signaling-dependent. DISCUSSION: Our work demonstrated that BA promotes myelin production and regeneration by activating the PPARγ signal pathway and also confirmed that BA is an effective natural product for the treatment of demyelinating diseases.

in Vitro Effect of Methamphetamine on Proliferation, Differentiation and Apoptosis of Adipose Tissue Stem Cells.

PURPOSE: Among abused substances, methamphetamine is a psychostimulant drug widely used recreationally with public health importance. This study investigated the effect of methamphetamine on proliferation, differentiation, and apoptosis of human adipose tissue stem cells (AdSCs). METHODS: AdSCs were isolated from human abdominal adipose tissue and were characterized for mesenchymal properties and growth kinetics. MTT assay was undertaken to assess methamphetamine toxicity on proliferation and differentiation properties and apoptosis of hAdSCs. RESULTS: Isolated cells were shown to have mesenchymal properties and a population doubling time (PDT) of 40.1 h. Following methamphetamine treatment, expressions of KI-67 and TPX2 as proliferation genes and Col1A1 and PPARg as differentiation genes decreased. Methamphetamine administration increased the expression of Bax and decreased Bcl-2 genes responsible for apoptosis. CONCLUSIONS: Our data suggested when AdSCs were exposed to methamphetamine, it decreased proliferation and differentiation properties of stem cells together with an increase in apoptosis. These findings can be added to the literature, especially when methamphetamine is used recreationally for weight loss purposes.

Saikosaponin A and D Inhibit Adipogenesis via the AMPK and MAPK Signaling Pathways in 3T3-L1 Adipocytes.

Obesity is a lipid metabolism disorder caused by genetic, medicinal, nutritional, and other environmental factors. It is characterized by a complex condition of excess lipid accumulation in adipocytes. Adipogenesis is a differentiation process that converts preadipocytes into mature adipocytes and contributes to excessive fat deposition. Saikosaponin A (SSA) and saikosaponin D (SSD) are triterpenoid saponins separated from the root of the Bupleurum chinensis, which has long been used to treat inflammation, fever, and liver diseases. However, the effects of these constituents on lipid accumulation and obesity are poorly understood. We investigated the anti-obesity effects of SSA and SSD in mouse 3T3-L1 adipocytes. The MTT assay was performed to measure cell viability, and Oil Red O staining was conducted to determine lipid accumulation. Various adipogenic transcription factors were evaluated at the protein and mRNA levels by Western blot assay and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Here, we showed that SSA and SSD significantly inhibited lipid accumulation without affecting cell viability within the range of the tested concentrations (0.938-15 µM). SSA and SSD also dose-dependently suppressed the expression of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer binding protein alpha (C/EBPα), sterol regulatory element binding protein-1c (SREBP-1c), and adiponectin. Furthermore, the decrease of these transcriptional factors resulted in the repressed expression of several lipogenic genes including fatty acid binding protein (FABP4), fatty acid synthase (FAS), and lipoprotein lipase (LPL). In addition, SSA and SSD enhanced the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and its substrate, acetyl-CoA carboxylase (ACC), and inhibited the phosphorylation of extracellular-regulated kinase 1/2 (ERK1/2) and p38, but not c-Jun-N-terminal kinase (JNK). These results suggest that SSA and SSD inhibit adipogenesis through the AMPK or mitogen-activated protein kinase (MAPK) pathways in the early stages of adipocyte differentiation. This is the first study on the anti-adipogenic effects of SSA and SSD, and further research in animals and humans is necessary to confirm the potential of saikosaponins as therapeutic agents for obesity.

Targeting Peroxisome Proliferator-Activated Receptor-ß/δ (PPARß/δ) for the Treatment or Prevention of Alcoholic Liver Disease.

Excessive, chronic alcohol consumption can lead to alcoholic liver disease. The etiology of alcoholic liver disease is multifactorial and is influenced by alterations in gene expression and changes in fatty acid metabolism, oxidative stress, and insulin resistance. These events can lead to steatosis, fibrosis, and eventually to cirrhosis and liver cancer. Many of these functions are regulated by peroxisome proliferator-activated receptors (PPARs). Thus, it is not surprising that PPARs can modulate the mechanisms that cause alcoholic liver disease. While the roles of PPARα and PPARγ are clearer, the role of PPARß/δ in alcoholic liver disease requires further clarification. This review summarizes the current understanding based on recent studies that indicate that PPARß/δ can likely be targeted for the treatment and/or the prevention of alcoholic liver disease.

Stigmasterol Restores the Balance of Treg/Th17 Cells by Activating the Butyrate-PPARγ Axis in Colitis.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with gut microbiota disequilibrium and regulatory T (Treg)/T helper 17 (Th17) immune imbalance. Stigmasterol, a plant-derived sterol, has shown anti-inflammatory effects. Our study aimed to identify the effects of stigmasterol on experimental colitis and the related mechanisms. Stigmasterol treatment restored the Treg/Th17 balance and altered the gut microbiota in a dextran sodium sulfate (DSS)-induced colitis model. Transplantation of the faecal microbiota of stigmasterol-treated mice significantly alleviated inflammation. Additionally, stigmasterol treatment enhanced the production of gut microbiota-derived short-chain fatty acids (SCFAs), particularly butyrate. Next, human naïve CD4+ T cells sorted from IBD patients were cultured under Treg- or Th17-polarizing conditions; butyrate supplementation increased the differentiation of Tregs and decreased Th17 cell differentiation. Mechanistically, butyrate activated peroxisome proliferator-activated receptor gamma (PPARγ) and reprogrammed energy metabolism, thereby promoting Treg differentiation and inhibiting Th17 differentiation. Our results demonstrate that butyrate-mediated PPARγ activation restores the balance of Treg/Th17 cells, and this may be a possible mechanism, by which stigmasterol attenuates IBD.

Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation.

Modulation of the innate immune system is emerging as a promising therapeutic strategy against Alzheimer's disease (AD). However, determinants of a beneficial therapeutic effect are ill-understood. Thus, we investigated the potential of 18 kDa translocator protein positron-emission-tomography (TSPO-PET) for assessment of microglial activation in mouse brain before and during chronic immunomodulation. Methods: Serial TSPO-PET was performed during five months of chronic microglia modulation by stimulation of the peroxisome proliferator-activated receptor (PPAR)-γ with pioglitazone in two different mouse models of AD (PS2APP, AppNL-G-F ). Using mixed statistical models on longitudinal TSPO-PET data, we tested for effects of therapy and sex on treatment response. We tested correlations of baseline with longitudinal measures of TSPO-PET, and correlations between PET results with spatial learning performance and ß-amyloid accumulation of individual mice. Immunohistochemistry was used to determine the molecular source of the TSPO-PET signal. Results: Pioglitazone-treated female PS2APP and AppNL-G-F mice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated male AppNL-G-F mice showed the opposite effect. Baseline TSPO-PET strongly predicted changes in microglial activation in treated mice (R = -0.874, p < 0.0001) but not in vehicle controls (R = -0.356, p = 0.081). Reduced TSPO-PET signal upon pharmacological treatment was associated with better spatial learning despite higher fibrillar ß-amyloid accumulation. Immunohistochemistry confirmed activated microglia to be the source of the TSPO-PET signal (R = 0.952, p < 0.0001). Conclusion: TSPO-PET represents a sensitive biomarker for monitoring of immunomodulation and closely reflects activated microglia. Sex and pre-therapeutic assessment of baseline microglial activation predict individual immunomodulation effects and may serve for responder stratification.

Anti-influenza A Virus Effects and Mechanisms of Emodin and Its Analogs via Regulating PPARα/γ-AMPK-SIRT1 Pathway and Fatty Acid Metabolism.

The peroxisome proliferator-activated receptor (PPAR) α/γ-adenosine 5'-monophosphate- (AMP-) activated protein kinase- (AMPK-) sirtuin-1 (SIRT1) pathway and fatty acid metabolism are reported to be involved in influenza A virus (IAV) replication and IAV-pneumonia. Through a cell-based peroxisome proliferator responsive element- (PPRE-) driven luciferase bioassay, we have investigated 145 examples of traditional Chinese medicines (TCMs). Several TCMs, such as Polygonum cuspidatum, Rheum officinale Baillon, and Aloe vera var. Chinensis (Haw.) Berg., were found to possess high activity. We have further detected the anti-IAV activities of emodin (EMO) and its analogs, a group of common important compounds of these TCMs. The results showed that emodin and its several analogs possess excellent anti-IAV activities. The pharmacological tests showed that emodin significantly activated PPARα/γ and AMPK, decreased fatty acid biosynthesis, and increased intracellular ATP levels. Pharmaceutical inhibitors, siRNAs for PPARα/γ and AMPKα1, and exogenous palmitate impaired the inhibition of emodin. The in vivo test also showed that emodin significantly protected mice from IAV infection and pneumonia. Pharmacological inhibitors for PPARα/γ and AMPK signal and exogenous palmitate could partially counteract the effects of emodin in vivo. In conclusion, emodin and its analogs are a group of promising anti-IAV drug precursors, and the pharmacological mechanism of emodin is linked to its ability to regulate the PPARα/γ-AMPK pathway and fatty acid metabolism.

Rosuvastatin alleviated the liver ischemia reperfusion injury by activating the expression of peroxisome proliferator-activated receptor gamma (PPARγ).

Liver ischemia and reperfusion could cause serious damage to liver tissues. Abnormal liver function could induce serious damage and threaten human health. Evidence emerged to suggest that rosuvastatin could relieve cerebral ischemia-reperfusion injury and alleviate the disease related to vessels by activating the expression of PPARγ. However, whether rosuvastatin could relieve the liver ischemia reperfusion injury by enhancing the expression of PPARγ is unclear. For the strictness of experimental findings, we established both the rat models and the cell model of liver ischemia reperfusion injury by respectively treating rats and cells with rosuvastatin. PPARγ inhibitor was also used for the stimulation of these cells and rats. Reactive oxygen species (ROS) levels, apoptosis and related protein levels were determined with ROS staining, ROS staining and western blotting for the detection of injury induced by oxygen-glucose deprivation and re-oxygenation (OGD/R). Pretreatment of rosuvastatin promoted the expression of PPARγ in liver tissues and MIHA cells. It also inhibited the ischemia reperfusion and OGD/R induced production of ROS while promoted the release of SOD in liver tissues and MIHA cells. Furthermore, rosuvastatin also alleviated the ischemia reperfusion -induced apoptosis of liver tissues and OGD/R-induced MIHA cells apoptosis. However, application of PPARγ inhibitor abolished the restorative effects of rosuvastatin on the apoptosis and oxidative stress on liver tissues and MIHA cells. Rosuvastatin prevented the liver ischemia reperfusion injury of rats by activating PPARγ.

Intranasal delivery of interleukin-4 attenuates chronic cognitive deficits via beneficial microglial responses in experimental traumatic brain injury.

Traumatic brain injury (TBI) is commonly followed by long-term cognitive deficits that severely impact the quality of life in survivors. Recent studies suggest that microglial/macrophage (Mi/MΦ) polarization could have multidimensional impacts on post-TBI neurological outcomes. Here, we report that repetitive intranasal delivery of interleukin-4 (IL-4) nanoparticles for 4 weeks after controlled cortical impact improved hippocampus-dependent spatial and non-spatial cognitive functions in adult C57BL6 mice, as assessed by a battery of neurobehavioral tests for up to 5 weeks after TBI. IL-4-elicited enhancement of cognitive functions was associated with improvements in the integrity of the hippocampus at the functional (e.g., long-term potentiation) and structural levels (CA3 neuronal loss, diffusion tensor imaging of white matter tracts, etc.). Mechanistically, IL-4 increased the expression of PPARγ and arginase-1 within Mi/MΦ, thereby driving microglia toward a global inflammation-resolving phenotype. Notably, IL-4 failed to shift microglial phenotype after TBI in Mi/MΦ-specific PPARγ knockout (mKO) mice, indicating an obligatory role for PPARγ in IL-4-induced Mi/MΦ polarization. Accordingly, post-TBI treatment with IL-4 failed to improve hippocampal integrity or cognitive functions in PPARγ mKO mice. These results demonstrate that administration of exogenous IL-4 nanoparticles stimulates PPARγ-dependent beneficial Mi/MΦ responses, and improves hippocampal function after TBI.

Addition of EP2 agonists to an FP agonist additively and synergistically modulates adipogenesis and the physical properties of 3D 3T3-L1 sphenoids.

The additive effects of prostaglandin (PG)-EP2 agonists on a PG-FP agonist toward adipogenesis in two- or three-dimension (2D or 3D) cultures of 3T3-L1 cells was examined by lipid staining, the mRNA expression of adipogenesis related genes, and extracellular matrixes (ECMs) including collagen molecules (Col) -1, -4 and -6, and fibronectin (Fn), and the sizes and physical properties of 3D sphenoids, as measured by a micro-squeezer. The results indicate that adipogenesis induced 1) an enlargement in the sizes of 3D sphenoids, 2) a substantial enhancement in lipid staining, the expression of the PParγ, Ap2 and Leptin genes, and 3) a significant decrease in the stiffness of the 3D sphenoids. These effects were inhibited by bimatoprost acid (BIM-A), but 4) adipogenesis induced significant down-regulation of Col1 and Fn, and the significant up-regulation of the Col4 and Col6 genes were unchanged by BIM-A. On the addition of an EP2 agonist, such as omidenepag (OMD) or butaprost (Buta), to BIM-A, 1) the sizes of the 3D sphenoids were further decreased, 2) lipid staining was decreased (2D; OMD, 3D; Buta) 3) the stiffness of the 3D sphenoids was increased by Buta, 4) the expression of PParγ was up-regulated (2D; Buta) or unchanged (3D), the expression of Ap2 was down-regulated (2D; OMD) or up-regulated (3D; Buta), and the expression of Leptin was increased (2D), 5) the expression of all four (OMD) or all except Col4 (buta) in 2D, and Col1and Col4 (OMD) in 3D were up-regulated. These collective findings indicate that the addition of an EP2 agonist, OMD or Buta significantly modulated the BIM-A induced suppression of adipogenesis as well as physical properties of 2D and 3D cultured 3T3-L1 cells in different manners.

Intranasal 15d-PGJ2 ameliorates brain glucose hypometabolism via PPARγ-dependent activation of PGC-1α/GLUT4 signalling in APP/PS1 transgenic mice.

Targeting the common molecular mechanism of type 2 diabetes mellitus and Alzheimer's disease (AD), including dysregulation of glucose metabolism, insulin resistance, and neuroinflammation, might be an efficient treatment strategy for AD. Previous studies have shown that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), an endogenous PPARγ agonist, has anti-inflammatory, insulin sensitizing and anti-diabetic effects. However, whether 15d-PGJ2 has beneficial effects on AD remains to be elucidated. In the present study, we found that intranasal administration of 15d-PGJ2 (300 ng/30 µL/day) for 3 months significantly inhibited Aß plaques, suppressed neuroinflammation, and attenuated cognitive deficits in APP/PS1 transgenic mice. Interestingly, 15d-PGJ2 treatment could increase brain glucose uptake, as detected by 18F-FDG microPET imaging, and co-localization of GLUT4 and NeuN in the hippocampus of APP/PS1 mice. Furthermore, 15d-PGJ2 markedly increased the expression of PPARγ and PGC-1α, upregulated GLUT4, and decreased the phosphorylation of IRS-1 (Ser616) in the hippocampus of APP/PS1 mice. Importantly, co-administration of a PPARγ antagonist GW9662 abrogated these protective effects of 15d-PGJ2. Collectively, intranasal 15d-PGJ2 conferred protective effects against AD by activating PPARγ-dependent PGC-1α/GLUT4 signalling. The PPARγ agonist 15d-PGJ2 might be a potential therapeutic drug for AD.

Systemic inflammation and oxidative stress induced by inhaled paraquat in rat improved by carvacrol, possible role of PPARγ receptors.

Control rats were exposed to saline aerosol, two groups were exposed to paraquat (PQ), 27 (PQ-L) and 54 (PQ-H) mg/m3 aerosols and six groups were treated with carvacrol, 20 (C-L) and 80 (C-H) mg/kg/day, pioglitazone, 5 (Pio-L) and 10 (Pio-H) mg/kg/day, C-L+Pio-L and dexamethasone, 0.03 mg/kg/day, for 16 days after the end of exposure to PQ-H. Different variables were measured after the end of treatment period. Total and differential white blood cells counts, nitrite, malondialdehyde, interleukin (IL)-10, and interferon-gamma levels were significant increased, but thiol, superoxide dismutase, catalase, IL-17, and tumor necrosis factor alpha were decreased in the blood due to both doses of PQ (p < 0.05-p < 0.001). Most measured parameters were significantly improved in treated groups with both doses of carvacrol, pioglitazone, the combination of C-L+Pio-L and dexamethasone compared to PQ-H group (p < 0.05-p < 0.001). Treatment with C-L+Pio-L showed significantly higher effects compared to each one alone (p < 0.05-p < 0.001). Systemic oxidative stress and inflammation due to inhaled PQ were improved by carvacrol and pioglitazone. Higher effects of C-L+Pio-L than each one alone suggests carvacrol modulating PPAR-γ receptors.

The Influence of Bosentan on MicroRNA-27a/PPARγ/ET-1 Signaling Pathway in Pulmonary Artery Hypertension.

Pulmonary artery hypertension (PAH) is a common and serious disease which is characterized by pulmonary vascular remodeling. Bosentan (BST) is the first approved oral targeted drug of endothelin-1 (ET-1) receptor antagonists for the treatment of PAH. MicroRNA-27a (miR-27a) and peroxisome proliferator-activated receptor γ (PPARγ) were found to be related to the pathogenesis of PAH. To further explore the signal transduction mechanism of BST in the treatment of PAH, we examined the effects of BST on endothelin receptors, miR-27a, and PPARγ. Meanwhile, the influence of miR-27a in the formation and development of PAH was discussed. Our results demonstrated that during the pathophysiology of PAH, miR-27a, PPARγ, and ET-1 were cross-inhibited, which indicated that the miR-27a/PPARγ/ET-1 signaling pathway was dysregulated; in addition, BST could competitively bind to ET-1 receptors and inhibit the miR-27a/PPARγ/ET-1 signaling pathway, thereby delaying the proliferation of PASMCs and affecting the development of PAH. Our results give a new understanding of the pathogenesis and treatment of PAH and provide more reliable evidence for the application of BST in the treatment of PAH in the clinic.

Kaempferide improves glycolipid metabolism disorder by activating PPARγ in high-fat-diet-fed mice.

AIMS: Kaempferide (Ka, 3,5,7-trihydroxy-4'-methoxyflavone), an active ingredient of Tagetes erecta L., has been demonstrated to possess many pharmacological effects, including antioxidant, anti-inflammation, anticancer and antihypertension in previous study. However, there is no evidence of Ka on metabolic disorder in former studies. This study investigated the effects of Ka on glycolipid metabolism and explored the underlying mechanisms of action in vivo and vitro. MATERIALS AND METHODS: The mouse model of glycolipid metabolism disorder was induced by high-fat diet (HFD). The effects of Ka were evaluated on bodyweight, lipid metabolism and glucose metabolism. Hypolipidemic effect was examined by blood sample analysis. The hypoglycemic effect was detected by several indicators, like blood glucose, serum insulin, HOMA index and intraperitoneal glucose tolerance tests (IPGTT). The signaling pathways of lipid metabolism (PPARγ/LXRα/ABCA1) and glucose metabolism (PPARγ/PI3K/AKT) were evaluated using Real-Time PCR and Western blot. The primary culture of hepatocyte was prepared to confirm the target of Ka by co-culturing with PPARγ agonist or inhibitor. KEY FINDINGS: The HFD mice developed obesity, hyperlipidemia, hyperglycemia and insulin resistance. Administration of Ka at a dose of 10 mg/kg.BW for 16 weeks effectively attenuated these changes. Further studies revealed the hypolipidemic and hypoglycemic effects of Ka depended on the activation of PPARγ/LXRα/ABCA1 and PPARγ/PI3K/AKT pathways, respectively. The primary hepatocyte test, co-cultured with PPARγ agonists or inhibitors, further confirmed the above signaling pathway and key protein. SIGNIFICANCE: These results suggested that Ka played an important role in improving glycolipid metabolism disorder. These favorable effects were causally associated with anti-obesity. The underlying mechanisms might have to do with the activation of the PPARγ and its downstream signaling pathway. Our study helped to understand the pharmacological actions of Ka, and played a role for Ka in the effective treatment of obesity, diabetes, nonalcoholic hepatitis and other metabolic diseases.

Prostaglandin 15d-PGJ2 targets PPARγ and opioid receptors to prevent muscle hyperalgesia in rats.

Pharmacological agents directed to either opioid receptors or peroxisome proliferator-activated receptor gamma (PPARγ) at peripheral tissues reduce behavioral signs of persistent pain. Both receptors are expressed in muscle tissue, but the contribution of PPARγ activation to muscle pain and its modulation by opioid receptors remains unknown. To address this question, we first tested whether the endogenous PPARγ ligand 15d-PGJ2 would decrease mechanical hyperalgesia induced by carrageenan administration into the gastrocnemius muscle of rats. Next, we used receptor antagonists to determine whether the antihyperalgesic effect of 15-deoxyΔ-12,14-prostaglandin J2 (15d-PGJ2) was PPARγ- or opioid receptor-dependent. Three hours after carrageenan, muscle hyperalgesia was quantified with the Randall-Selitto test. 15d-PGJ2 prevented carrageenan-induced muscle hyperalgesia in a dose-dependent manner. The antihyperalgesic effect of 15d-PGJ2 was dose-dependently inhibited by either the PPARγ antagonist, 2-chloro-5-nitro-N-phenylbenzamide, or by the opioid receptor antagonist, naloxone. We conclude that 15d-PGJ2 targets PPARγ and opioid receptors to prevent muscle hyperalgesia. We suggest that local PPARγ receptors are important pharmacological targets for inflammatory muscle pain.