Targeting Peroxisome Proliferator-activated Receptor Gamma Research Articles

Effect of Insulin and Pioglitazone on Protein Phosphatase 2A Interaction Partners in Primary Human Skeletal Muscle Cells Derived from Obese Insulin-Resistant Participants.

Skeletal muscle insulin resistance is a major contributor to type-2 diabetes (T2D). Pioglitazone is a potent insulin sensitizer of peripheral tissues by targeting peroxisome proliferator-activated receptor gamma. Pioglitazone has been reported to protect skeletal muscle cells from lipotoxicity by promoting fatty acid mobilization and insulin signaling. However, it is unclear whether pioglitazone increases insulin sensitivity through changes in protein-protein interactions involving protein phosphatase 2A (PP2A). PP2A regulates various cell signaling pathways such as insulin signaling. Interaction of the catalytic subunit of PP2A (PP2Ac) with protein partners is required for PP2A specificity and activity. Little is known about PP2Ac partners in primary human skeletal muscle cells derived from lean insulin-sensitive (Lean) and obese insulin-resistant (OIR) participants. We utilized a proteomics method to identify PP2Ac interaction partners in skeletal muscle cells derived from Lean and OIR participants, with or without insulin and pioglitazone treatments. In this study, 216 PP2Ac interaction partners were identified. Furthermore, 26 PP2Ac partners exhibited significant differences in their interaction with PP2Ac upon insulin treatments between the two groups. Multiple pathways and molecular functions are significantly enriched for these 26 interaction partners, such as nonsense-mediated decay, metabolism of RNA, RNA binding, and protein binding. Interestingly, pioglitazone restored some of these abnormalities. These results provide differential PP2Ac complexes in Lean and OIR in response to insulin/pioglitazone, which may help understand molecular mechanisms underpinning insulin resistance and the insulin-sensitizing effects of pioglitazone treatments, providing multiple targets in various pathways to reverse insulin resistance and prevent and/or manage T2D with less drug side effects.

Investigation of Active Compounds of Brucea Javanica In Treating Hypertension Using A Network Pharmacology‐Based Analysis Combined with Homology Modeling, Molecular Docking and Molecular Dynamics Simulation

AbstractHypertension is a disease that can increase the risk of stroke, cardiovascular, and heart failure. In this letter, we investigated the potency of active compounds of Brucea javanica (BJ) in treating hypertension by using network pharmacology combined with several in silico approaches, including molecular docking, homology modeling and molecular dynamics (MD) simulations. Twenty protein targets at the intersection of BJ and hypertension were identified by using network pharmacology. We found that peroxisome proliferator‐activated receptor gamma (PPARG) was the first‐degree rank that might strongly connect with the disease. Therefore, the tertiary structure of PPARG, generated using homology modeling, was assigned as a receptor. In docking analysis, two ligands, i. e., Javanicin and Yadanziolide A, could be potential inhibitors for PPARG due to the higher binding energy score than the control (Hydrochlorothiazide). To confirm the stability of the ligand‐receptor complex in water solvent, MD simulation was performed. We found that complexes 1 and 2 reached stable structures during the simulation indicated by no significant fluctuation in the validation parameters. Furthermore, based on the binding energies calculated by Molecular Mechanics‐Generalized Born Surface Area (MM‐GBSA), we confirm that the ligands of these complexes strongly bind to the catalytic site of the receptor. This points out the potency of these complexes as promising drugs against hypertension targeting PPARG.

PPARG in osteocytes controls sclerostin expression, bone mass, marrow adiposity and mediates TZD-induced bone loss.

The peroxisome proliferator activated receptor gamma (PPARG) nuclear receptor regulates energy metabolism and insulin sensitivity. In this study, we present novel evidence for an essential role of PPARG in the regulation of osteocyte function, and support for the emerging concept of the conjunction between regulation of energy metabolism and bone mass. We report that PPARG is essential for sclerostin production, a recently approved target to treat osteoporosis. Our mouse model of osteocyte-specific PPARG deletion (Dmp1CrePparγflfl or γOTKO) is characterized with increased bone mass and reduced bone marrow adiposity, which is consistent with upregulation of WNT signaling and increased bone forming activity of endosteal osteoblasts. An analysis of osteocytes derived from γOTKO and control mice showed an excellent correlation between PPARG and SOST/sclerostin at the transcript and protein levels. The 8kb sequence upstream of Sost gene transcription start site possesses multiple PPARG binding elements (PPREs) with at least two of them binding PPARG with dynamics reflecting its activation with full agonist rosiglitazone and correlating with increased levels of Sost transcript and sclerostin protein expression (Pearson's r=0.991, p=0.001). Older γOTKO female mice are largely protected from TZD-induced bone loss providing proof of concept that PPARG in osteocytes can be pharmacologically targeted. These findings demonstrate that transcriptional activities of PPARG are essential for sclerostin expression in osteocytes and support consideration of targeting PPARG activities with selective modulators to treat osteoporosis.

Tributyltin triggers lipogenesis in macrophages via modifying PPARγ pathway.

Tributyltin (TBT), a bioaccumulative and persistent environmental pollutant, has been proposed as a metabolism disruptor and obesogen through targeting peroxisome proliferator-activated receptor gamma (PPARγ) receptor pathway. However, it remains unknown whether this biological effect occurs in macrophage, a cell type which cooperates closely with hepatocytes and adipocytes to regulate lipid metabolism. This study for the first time investigated the effect of TBT on PPARγ pathway in macrophages. Our results indicated that nanomolar levels of TBT was able to strongly activate PPARγ in human macrophages. TBT treatment also markedly increased the intracellular lipid accumulation, and enhanced the expression of lipid metabolism-related genes in macrophages, while these effects were all significantly down-regulated in PPARγ-deficient macrophages, confirming the involvement of PPARγ in TBT-induced lipogenesis. Next, a mouse model that C57BL/6 mice were orally exposed to TBT with the doses (250 and 500μg/kg body weight) lower than NOAEL (no observed adverse effect level) was used to further investigate the invivo mechanisms. And the invivo results were consistent with cellular assays, confirming the induction of PPARγ and the increased expression of lipogenesis-regulating and lipid metabolism-related genes by TBT invivo. In conclusion, this study not only provided the first evidence that TBT stimulated lipogenesis, activated PPARγ and related genes in human macrophages, but also provided insight into the mechanism of TBT-induced metabolism disturbance and obesity through targeting PPARγ via both invitro cellular assays and invivo animal models.

Tanshinone IIA ameliorates non-alcoholic fatty liver disease through targeting peroxisome proliferator-activated receptor gamma and toll-like receptor 4.

ObjectiveTo investigate the cellular mechanisms of action of tanshinone IIA on the fatty liver disease induced by a high-fat diet in an animal model of non-alcoholic fatty liver disease (NAFLD).MethodsAdult male Sprague Dawley rats were randomized into one of three groups: regular rat diet (CON group) for 4 months; high-fat diet (HFD group) for 4 months; HFD for 2 months followed by tanshinone IIA treatment plus HFD (TAN group) for a further 2 months. A range of physical and biochemical markers of lipid accumulation and fatty liver disease were measured and compared between the groups.ResultsTanshinone IIA treatment significantly reduced fat accumulation in the liver and plasma lipid levels that had been increased by HFD. The toll-like receptor (TLR4)/nuclear factor kappa B (NF-κB) signalling pathway was silenced by tanshinone IIA treatment. Tumour necrosis factor-α and interleukin-6 were reduced by tanshinone IIA. Hepatocyte apoptosis was inhibited by tanshinone IIA. Tanshinone IIA upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ), which resulted in an improvement in the oxidative status.ConclusionTanshinone IIA ameliorates NAFLD by targeting PPAR-γ and TLR4, resulting in decreased plasma lipids and oxidative stress, suggesting this strategy may form the basis of novel NAFLD therapies.

Macrophages exposed to HIV viral protein disrupt lung epithelial cell integrity and mitochondrial bioenergetics via exosomal microRNA shuttling

Antiretroviral therapy extends survival but does not eliminate HIV from its cellular reservoirs. Between immune and stromal cells in the tissue microenvironment, a dynamic intercellular communication might influence host viral immune responses via intercellular transfer of extracellular vehicles (EVs) (microvesicles, exosome, or apoptotic bodies). It is increasingly recognized that HIV-infected macrophage-secreted nucleotide-rich exosomes might play a critical role in mediating communication between macrophages and other structural cells; however, molecular mechanisms underlying cell–cell crosstalk remain unknown. Here we show that HIV-1-infected macrophages and HIV-1 proteins Tat or gp120-treated macrophages express high levels of microRNAs, including miR-23a and miR-27a. Identical miRNAs expression patterns were detected in macrophage-secreted exosomes isolated from bronchoalveolar lavage fluid of HIV transgenic rats. Tat-treated macrophage-derived exosomal miR-23a attenuated posttranscriptional modulation of key tight junction protein zonula occludens (ZO-1) 3′-UTR in epithelial cells. In parallel, exosomal miR-27a released from Tat-treated macrophages altered the mitochondrial bioenergetics of recipient lung epithelial cells by targeting peroxisome proliferator-activated receptor gamma (PPARγ), while simultaneously stimulating glycolysis. Together, exosomal miRNAs shuttle from macrophages to epithelial cells and thereby explain in part HIV-mediated lung epithelial barrier dysfunction. These studies suggest that targeting miRNAs may be of therapeutic value to enhance lung health in HIV.

Peroxisome Proliferator-Activated Receptor-gamma agonists exhibit anti-inflammatory and antiviral effects in an EcoHIV mouse model

The widespread use of combination antiretroviral therapy (cART) has resulted in significantly reduced deaths from HIV-1 associated complications and opportunistic infections. However, it is estimated that up to 50% of HIV-1 infected individuals still develop HIV-1 associated neurocognitive disorders (HAND). With no treatment currently available for patients, there is a critical need to identify therapeutic approaches that can treat this disorder. Evidence suggests that targeting Peroxisome Proliferator-Activated Receptor-gamma (PPARγ) can be anti-inflammatory in neurological disorders. Here we show that treatment with PPARγ agonists (rosiglitazone or pioglitazone) in primary cultures of mouse glial cells reversed EcoHIV-induced inflammatory genes (TNFα, IL-1β, CCL2, CCL3, CXCL10) and indicator of oxidative stress (iNOS). Furthermore, in vivo, mice administered with EcoHIV through intracranial injection resulted in upregulation of inflammatory genes (TNFα, IL-1β, IFNγ, CCL2, CCL3, CXCL10) and oxidative stress marker (iNOS) in the brain which was reversed through intraperitoneal administration of PPARγ agonists (rosiglitazone or pioglitazone). Finally, we demonstrated that treatment with these compounds in vivo reduced EcoHIV p24 protein burden in the brain. Our results suggest that treatment with PPARγ agonists are anti-inflammatory and antiviral in an in vivo model of EcoHIV infection. These drugs hold promise as potential candidates for HAND treatment in the future.

MiR-23b-3p suppressing PGC1\u03b1 promotes proliferation through reprogramming metabolism in osteosarcoma

Metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis is a hallmark of osteosarcoma (OS). However, the mechanisms of the metabolic switch have not been completely elucidated. Here we reported that the miR-23b-3p was significantly upregulated in OS cells. Functional studies suggested that knockdown of miR-23b-3p could inhibit OS cell proliferation in vitro or in vivo. In addition, suppression of miR-23b-3p could lead to upregulation of OXPHOS and suppression of glycolysis. Mechanistically, miR-23b-3p promoted OS cell proliferation and inhibited OXPHOS in OS, at least in part, by directly targeting peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1α) and inhibiting its expression. Our data highlights important roles of miR-23b-3p and PGC1α in glucose metabolism reprogram of OS. The suppression of miR-23b-3p may provide effective therapeutic strategies for the treatment of OS.

Targeting Peroxisome Proliferator-Activated Receptor-Gamma Decreases Host Mortality After Influenza Infection in Obese Mice.

Obesity is an independent risk factor for severe influenza infection. However, the underlying cellular and molecular mechanisms are still incompletely understood. In this study, we have utilized a murine influenza infection model in genetic-induced obese (db/db) mice to explore the mechanisms by which obesity increases host susceptibility to influenza infection. We find that db/db mice have enhanced viral replication, exaggerated inflammatory responses, and dysregulated lung repair process after influenza infection, and consequently increased host mortality. Furthermore, we demonstrate that the transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ), an important inflammation regulator, was downregulated in the lung macrophages of db/db mice after influenza infection. Strikingly, the treatment of 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2), a PPAR-γ agonist, largely rescued the survival of db/db mice after influenza infection. Interestingly, macrophage PPAR-γ-deficient mice exhibited enhanced mortality after influenza infection and 15d-PGJ2 fails to rescue host mortality in macrophage PPAR-γ-deficient mice, suggesting that PPAR-γ expression in macrophages is critical for the action of 15d-PGJ2. These data indicate that obesity attenuates lung antiviral immunity and hampers host recovery through the modulation of macrophage PPAR-γ expression. Furthermore, modalities targeting macrophage PPAR-γ expression and/or function may serve as promising therapeutics to treat severe influenza infection in obese patients.

Time-dependent therapeutic roles of nitazoxanide on high-fat diet/streptozotocin-induced diabetes in rats: effects on hepatic peroxisome proliferator-activated receptor-gamma receptors.

Targeting peroxisome proliferator-activated receptor-gamma (PPAR-γ) is an approved strategy in facing insulin resistance (IR) for diabetes mellitus (DM) type 2. The PPAR-γ modulators display improvements in the insulin-sensitizing and adverse effects of the traditional thiazolidinediones. Nitazoxanide (NTZ) is proposed as a PPAR-γ receptor ligand with agonistic post-transcriptional effects. Currently, NTZ antidiabetic activities versus pioglitazone (PIO) in a high-fat diet/streptozotocin rat model of type 2 diabetes was explored. Diabetic adult male Wistar rats were treated orally with either PIO (2.7 mg·kg-1·day-1) or NTZ (200 mg·kg-1·day-1) for 14, 21, and 28 days. Body masses, fasting blood glucose, IR, lipid profiles, and liver and kidney functions of rats were assayed. Hepatic glucose metabolism and PPAR-γ protein expression levels as well as hepatic, pancreatic, muscular, and renal histopathology were evaluated. Significant time-dependent euglycemic and insulin-sensitizing effects with preservation of liver and kidney functions were offered by NTZ. Higher hepatic levels of glucose-6-phosphatase and glucose-6-phosphate dehydrogenase enzymes and PPAR-γ protein expressions were acquired by NTZ and PIO, respectively. NTZ could be considered an oral therapeutic strategy for DM type 2. Further systematic NTZ/PPAR-γ receptor subtype molecular activations are recommended. Simultaneous use of NTZ with other approved antidiabetics should be explored.

Bta-miR-130a regulates the biosynthesis of bovine milk fat by targeting peroxisome proliferator-activated receptor gamma.

Milk fat determines the quality of milk and is also a main targeted trait in dairy cow breeding. Recent studies have revealed important regulatory roles of microRNAs (miRNA) in milk fat synthesis in the mammary gland. However, the role of miRNA in bovine mammary epithelial cells (BMEC) remains largely unknown. In this study, we found that the overexpression of miR-130a significantly decreased cellular triacylglycerol (TAG) levels and suppressed lipid droplet formation, whereas the inhibition of miR-130a resulted in greater lipid droplet formation and TAG accumulation in BMEC. MiR-130a also significantly affected mRNA expression related to milk fat metabolism. Specifically, the overexpression of miR-130a reduced the mRNA expression of , , , and , whereas the downregulation of miR-130a increased the mRNA expression of , , , , , and . Furthermore, western blot analysis revealed the protein level of PPARG in miR-130a mimic and inhibitor transfection groups to be consistent with the mRNA expression response. Finally, luciferase reporter assays verified that PPARG was the direct target of miR-130a. This study provides the first experimental evidence that miR-130a directly affects TAG synthesis in BMEC by targeting PPARG, suggesting that miR-130a potentially could be used to improve beneficial milk components in dairy cows.

MiR-27a controls triacylglycerol synthesis in bovine mammary epithelial cells by targeting peroxisome proliferator-activated receptor gamma

Growing evidence has revealed that microRNA are central elements in milk fat synthesis in mammary epithelial cells. A negative regulator of adipocyte fat synthesis, miR-27a has been reported to be involved in the regulation of milk fat synthesis in goat mammary epithelial cells; however, the regulatory role of miR-27a in bovine milk fat synthesis remains unclear. In the present study, primary bovine mammary epithelial cells (BMEC) were harvested from mid-lactation cows and cultured in Dulbecco's modified Eagle's medium/F-12 medium with 10% fetal bovine serum, 5 μg/mL of insulin, 1 μg/mL of hydrocortisone, 2 μg/mL of prolactin, 1 μg/mL of progesterone, 100 U/mL of penicillin, and 100 μg/mL of streptomycin. We found that the overexpression of miR-27a significantly suppressed lipid droplet formation and decreased the cellular triacylglycerol (TAG) levels, whereas inhibition of miR-27a resulted in a greater lipid droplet formation and TAG accumulation in BMEC. Meanwhile, overexpression of miR-27a inhibited mRNA expression of peroxisome proliferator-activated receptor gamma (PPARG), CCAAT/enhancer-binding protein beta (C/EBPβ), perilipin 2 (PLIN2), and fatty acid binding protein 3 (FABP3), whereas miR-27a downregulation increased PPARG, C/EBPβ, FABP3, and CCAAT enhancer binding protein alpha (C/EBPα) mRNA expression. Furthermore, Western blot analysis revealed the protein level of PPARG in miR-27a mimic and inhibitor transfection groups to be consistent with the mRNA expression response. Moreover, luciferase reporter assays verified that PPARG was the direct target of miR-27a. In summary, these results indicate that miR-27a has the ability to control TAG synthesis in BMEC via targeting PPARG, suggesting that miR-27a could potentially be used to improve beneficial milk components in dairy cows.

Bta-miR-130a regulates the biosynthesis of bovine milk fat by targeting peroxisome proliferator-activated receptor gamma

Bta-miR-130a regulates the biosynthesis of bovine milk fat by targeting peroxisome proliferator-activated receptor gamma

MicroRNA-130b promotes cell migration and invasion by targeting peroxisome proliferator-activated receptor gamma in human glioma.

MircroRNA-130b (miR-130b) has been recognized as an oncogenic miRNA and is implicated in the initiation and development of human cancers. Deregulation of miR-130b has been reported in several tumors. However, the clinical significance and its underlying role in human glioma are poorly explored. Herein, we found that the expression of miR-130b was significantly up-regulated in glioma tissues as compared with that in normal brain (NB) tissues. Clinical association analysis disclosed that high-expression of miR-130b was evidently associated with advanced tumor stage (grade III+IV) in glioma. Moreover, we disclosed that the high-expression of miR-130b conferred an obviously reduced survival of glioma patients. Multivariate Cox regression analysis showed that miR-130b expression was an independent prognostic indicator for glioma patients. Our gain- or loss-of-function studies showed that miR-130b promoted invasion and migration of glioma cells. Notably, miR-130b regulated peroxisome proliferator-activated receptor gamma (PPARγ) abundance and epithelial-mesenchymal transition (EMT) in glioma cells. Hereby, PPARγ was identified as a functional target of miR-130b in glioma. Furthermore, an inverse correlation between miR-130b and PPARγ expression was observed in glioma tissues. In conclusion, miR-130b is an independent prognostic biomarker for indicating survival of glioma patients and promotes glioma cell migration and invasion by targeting PPARγ.

Insulin Sensitivity in Adipose and Skeletal Muscle Tissue of Dairy Cows in Response to Dietary Energy Level and 2,4-Thiazolidinedione (TZD).

The effects of dietary energy level and 2,4-thiazolidinedione (TZD) injection on feed intake, body fatness, blood biomarkers and TZD concentrations, genes related to insulin sensitivity in adipose tissue (AT) and skeletal muscle, and peroxisome proliferator-activated receptor gamma (PPARG) protein in subcutaneous AT (SAT) were evaluated in Holstein cows. Fourteen nonpregnant nonlactating cows were fed a control low-energy (CON, 1.30 Mcal/kg) diet to meet 100% of estimated nutrient requirements for 3 weeks, after which half of the cows were assigned to a higher-energy diet (OVE, 1.60 Mcal/kg) and half of the cows continued on CON for 6 weeks. All cows received an intravenous injection of TZD starting 2 weeks after initiation of dietary treatments and for an additional 2 weeks, which served as the washout period. Cows fed OVE had greater energy intake and body mass than CON, and TZD had no effect during the administration period. The OVE cows had greater TZD clearance rate than CON cows. The lower concentration of nonesterified fatty acids (NEFA) and greater concentration of insulin in blood of OVE cows before TZD injection indicated positive energy balance and higher insulin sensitivity. Administration of TZD increased blood concentrations of glucose, insulin, and beta-hydroxybutyrate (BHBA) at 2 to 4 weeks after diet initiation, while the concentration of NEFA and adiponectin (ADIPOQ) remained unchanged during TZD. The TZD upregulated the mRNA expression of PPARG and its targets FASN and SREBF1 in SAT, but also SUMO1 and UBC9 which encode sumoylation proteins known to down-regulate PPARG expression and curtail adipogenesis. Therefore, a post-translational response to control PPARG gene expression in SAT could be a counteregulatory mechanism to restrain adipogenesis. The OVE cows had greater expression of the insulin sensitivity-related genes IRS1, SLC2A4, INSR, SCD, INSIG1, DGAT2, and ADIPOQ in SAT. In skeletal muscle, where PPARA and its targets orchestrate carbohydrate metabolism and fatty acid oxidation, the OVE cows had greater glyceroneogenesis (higher mRNA expression of PC and PCK1), whereas CON cows had greater glucose transport (SLC2A4). Administration of TZD increased triacylglycerol concentration and altered expression of carbohydrate- and fatty acid oxidation-related genes in skeletal muscle. Results indicate that overfeeding did not affect insulin sensitivity in nonpregnant, nonlactating dairy cows. The bovine PPARG receptor appears TZD-responsive, with its activation potentially leading to greater adipogenesis and lipogenesis in SAT, while differentially regulating glucose homeostasis and fatty acid oxidation in skeletal muscle. Targeting PPARG via dietary nutraceuticals while avoiding excessive fat deposition might improve insulin sensitivity in dairy cows during times such as the peripartal period when the onset of lactation naturally decreases systemic insulin release and sensitivity in tissues such as AT.

Inhibition of microRNA-29c protects the brain in a rat model of prolonged hypothermic circulatory arrest

ObjectiveWe sought to investigate the cerebroprotection of a novel microRNA mechanism by targeting peroxisome proliferator-activated receptor gamma coactivator 1-alpha in a rat model of prolonged deep hypothermia circulatory arrest. MethodsThe right carotid artery and jugular vein of male Sprague–Dawley rats were cannulated for cardiopulmonary bypass. Circulatory arrest was conducted for 60 minutes when the pericranial temperature was cooled to 18°C. The sham group received the surgical procedure without cardiopulmonary bypass and deep hypothermia circulatory arrest; the deep hypothermia circulatory arrest group received cardiopulmonary bypass and deep hypothermia circulatory arrest; lentivirus control vector or lentiviral vector containing antagomiR-29c was given to the deep hypothermia circulatory arrest + vector group or the deep hypothermia circulatory arrest + antagomiR-29c group by intracerebroventricular administration 5 days before cardiopulmonary bypass (n = 8, for each of the 4 groups). Neurologic function was evaluated by the modified hole board test and beam balance task during 14 postoperative days. Expressions of caspase-3, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and miR-29c in the hippocampus were measured by Western blot and quantitative reverse transcription polymerase chain reaction. Malondialdehyde was measured using the Malondialdehyde Assay Kit (Beyotime, Jiangsu, China). ResultsPretreatment with antagomiR-29c significantly decreased the expression of microRNA-29c and increased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha in the hippocampus (P < .05 vs deep hypothermia circulatory arrest group). The level of malondialdehyde in the hippocampus was lower in the deep hypothermia circulatory arrest + antagomiR-29c group (P < .05 vs deep hypothermia circulatory arrest group). The neurologic functions were markedly protected in rats pretreated with antagomiR-29c as evidenced by improvement of vestibulomotor and cognitive performance during the early postoperative period. In the deep hypothermia circulatory arrest + antagomiR-29c group, histologic scores of the hippocampus were improved and the level of caspase-3 in the hippocampus was lower (P < .05 vs deep hypothermia circulatory arrest group). ConclusionsInhibition of miR-29c attenuates neurologic injuries induced by prolonged deep hypothermia circulatory arrest through a peroxisome proliferator-activated receptor gamma coactivator 1-alpha pathway.

TR4 nuclear receptor enhances prostate cancer initiation via altering the stem cell population and EMT signals in the PPARG-deleted prostate cells.

A recent report indicated that the TR4 nuclear receptor might suppress the prostate cancer (PCa) initiation via modulating the DNA damage/repair system. Knocking-out peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that shares similar ligands/activators with TR4, promoted PCa initiation. Here we found 9% of PCa patients have one allele of PPARG deletion. Results from in vitro cell lines and in vivo mouse model indicated that during PCa initiation TR4 roles might switch from suppressor to enhancer in prostate cells when PPARG was deleted or suppressed (by antagonist GW9662). Mechanism dissection found targeting TR4 in the absence of PPARG might alter the stem cell population and epithelial-mesenchymal transition (EMT) signals. Together, these results suggest that whether TR4 can enhance or suppress PCa initiation may depend on the availability of PPARG and future potential therapy via targeting PPARG to battle PPARG-related diseases may need to consider the potential side effects of TR4 switched roles during the PCa initiation.