PPARgamma Activation Research Articles

Evodiamine might inhibit TGF‐beta1‐induced epithelial–mesenchymal transition in NRK52E cells via Smad and PPAR‐gamma pathway

Epithelial-mesenchymal transition (EMT) is involved in renal tubulointerstitial fibrosis. Transforming growth factor (TGF)-beta1 is the main inducer of EMT. Phosphorylation of Smad proteins and PPAR-gamma activation are required for the process of TGF-beta1-induced EMT. Evodiamine possesses anti-inflammatory, anti-obesity, anti-cancer, and anti-nociceptive effects. We have examined the effects of evodiamine in EMT induced by TGF-beta1 and the role of Smad and PPAR-gamma signal pathway in rat renal proximal tubular epithelial (NRK52E) cells in vitro. E-cadherin, alpha-smooth muscle actin (SMA), Smad 2 and PPAR-gamma mRNA and protein expressions were detected by real-time PCR and Western blot, respectively. NRK52E treated with TGF-beta1 for 48 h induced EMT, as evidenced by loss of E-cadherin and de novo expression of alpha-SMA. EMT was almost completely blocked by evodiamine and rosiglitazone. TGF-beta1 significantly increased Smad 2 expression and decreased PPAR-gamma expression in NRK52E cells compared with the control group, while evodiamine and rosiglitazone almost reversed these effects. These observations suggest that evodiamine and rosiglitazone inhibit TGF-beta1-induced EMT in NRK52E cells. Smad 2 and PPAR-gamma signal pathway might participate in the effects of evodiamine and rosiglitazone in EMT induced by TGF-beta1.

Cross-talk between heme oxygenase and peroxisome proliferator-activated receptors in the regulation of physiological functions.

Peroxisome-proliferator-activated-receptors (PPARs) are transcription factors belonging to the superfamily of nuclear receptors. The isoforms of PPAR include PPAR alpha, PPAR gamma and PPAR delta (also known as PPAR beta). Generally, PPARs potentiate insulin sensitivity, improve glucose/lipid metabolism, suppress inflammation/oxidative stress, attenuate excessive immune responses, regulate cell-growth and differentiation. Interestingly, agonists of PPAR gamma and PPAR alpha have been shown to upregulate the heme-oxygenase (HO)-system. Conversely, the HO-system also enhances PPAR alpha, and potentiates the expression and activity of PPAR gamma. Moreover, the HO-system and related products including bilirubin, biliverdin, carbon monoxide and ferritin have been shown to increase insulin sensitivity, improve glucose/lipid metabolism, suppress inflammation/oxidative stress, abate immune response, and modulate cell-growth/differentiation. Therefore, an intimate, reciprocal, stimulatory and synergistic relationship between PPAR-signaling and the HO-system can be envisaged in the regulation of physiological functions. Thus, both the HO-system and PPARs-signaling participate in fine-tuning similar physiological functions, so novel pharmacological agents capable of optimizing this interaction should be sought. The coordinated regulation of PPAR-signaling and the HO-system may constitute the basis for future drug design.

Telmisartan, an AT1 receptor blocker and a PPAR gamma activator, alleviates liver fibrosis induced experimentally by Schistosoma mansoni infection

BackgroundHepatic schistosomiasis is considered to be one of the most prevalent forms of chronic liver disease in the world due to its complication of liver fibrosis. The demonstration of the pro-fibrogenic role of angiotensin (Ang) II in chronic liver disease brought up the idea that anti-Ang II agents may be effective in improving hepatic fibrosis by either blocking Ang II type 1 (AT1) receptors or inhibiting the angiotensin converting enzyme. Peroxisome proliferator-activated receptors gamma (PPARγ) activation has been also shown to inhibit hepatic stellate cell activation and progression of fibrosis. The present study has aimed at testing the anti-fibrogenic effects of telmisartan; an AT1 receptor blocker and a PPARγ partial agonist, alone or combined with praziquantel (PZQ) on Schistosoma mansoni-induced liver fibrosis in mice.MethodsTo achieve the aim of the study, two sets of experiments were performed in which telmisartan was initiated at the 5th (set 1) and the 10th (set 2) weeks post infection to assess drug efficacy in both acute and chronic stages of liver fibrosis, respectively. Schistosoma mansoni-infected mice were randomly divided into the following four groups: infected-control (I), telmisartan-treated (II), PZQ-treated (III), and telmisartan+PZQ-treated (IV). In addition, a normal non-infected group was used for comparison. Parasitological (hepatomesenteric worm load and oogram pattern), histopathological, morphometric, immunohistochemical (hepatic expressions of matrix metalloproteinase-2; MMP-2 and tissue inhibitor of metalloproteinase-2; TIMP-2), and biochemical (serum transforming growth factor beta 1; TGF-β1 and liver function tests) studies were performed.ResultsTelmisartan failed to improve the parasitological parameters, while it significantly (P<0.05) decreased the mean granuloma diameter, area of fibrosis, and serum TGF-β1. Additionally, telmisartan increased MMP-2 and decreased TIMP-2 hepatic expression. Combined treatment failed to show any additive properties, yet it did not affect the anti-schistosomal activity of PZQ.ConclusionsThese results suggest potential anti-fibrotic effects of telmisartan, an AT1 receptor blocker and a PPARγ partial agonist, in acute and chronic stages of Schistosoma mansoni–induced liver fibrosis in mice.

AMP-Activated Protein Kinase Signaling Protects Oligodendrocytes that Restore Central Nervous System Functions in an Experimental Autoimmune Encephalomyelitis Model

AMP-activated protein kinase (AMPK) signaling is reported to protect neurons under pathologic conditions; however, its effect on oligodendrocytes (OLs) remains to be elucidated. We investigated whether AMPK signaling protects OLs to restore central nervous system (CNS) functions in an experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Increased inflammation and demyelination in the CNS and peripheral immune responses were consistent with the observed clinical impairments in EAE animals, which were attenuated by treatment with metformin compared with vehicle. In addition, expressions of neurotrophic factors and of signatory genes of OL lineages were increased in the CNS of metformin-treated EAE animals. Likewise, metformin attenuated inflammatory response and enhanced expressions of neurotrophic factors, thereby protecting OLs via AMPK activation in mixed glial cultures stimulated with lipopolysaccharide/interferon γ invitro, as evidenced by analysis of the expression of signatory genes of O1(+)/MBP(+) OLs and their cellular populations. Metformin also attenuated oxidative stress and malondialdehyde-containing protein levels, with corresponding induction of antioxidative defenses in OLs exposed to cytokines via AMPK activation. These effects of metformin were evident in the CNS of EAE animals. These data provide evidence that AMPK signaling is crucial to protect OLs and, thus, CNS functions in EAE animals. We conclude that AMPK activators, including metformin, have the potential to limit neurologic deficits in multiple sclerosis and related neurodegenerative disorders.

Peroxisome Proliferator-Activated Receptors-Alpha and Gamma Are Targets to Treat Offspring from Maternal Diet-Induced Obesity in Mice

AimThe aim of the present study was to evaluate whether activation of peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma by Bezafibrate (BZ) could attenuate hepatic and white adipose tissue (WAT) abnormalities in male offspring from diet-induced obese dams.Materials and MethodsC57BL/6 female mice were fed a standard chow (SC; 10% lipids) diet or a high-fat (HF; 49% lipids) diet for 8 weeks before mating and during gestation and lactation periods. Male offspring received SC diet at weaning and were subdivided into four groups: SC, SC/BZ, HF and HF/BZ. Treatment with BZ (100 mg/Kg diet) started at 12 weeks of age and was maintained for three weeks.ResultsThe HF diet resulted in an overweight phenotype and an increase in oral glucose intolerance and fasting glucose of dams. The HF offspring showed increased body mass, higher levels of plasmatic and hepatic triglycerides, higher levels of pro-inflammatory and lower levels of anti-inflammatory adipokines, impairment of glucose metabolism, abnormal fat pad mass distribution, higher number of larger adipocytes, hepatic steatosis, higher expression of lipogenic proteins concomitant to decreased expression of PPARalpha and carnitine palmitoyltransferase I (CPT-1) in liver, and diminished expression of PPARgamma and adiponectin in WAT. Treatment with BZ ameliorated the hepatic and WAT abnormalities generated by diet-induced maternal obesity, with improvements observed in the structural, biochemical and molecular characteristics of the animals' livers and epididymal fat.ConclusionDiet-induced maternal obesity lead to alterations in metabolism, hepatic lipotoxicity and adverse liver and WAT remodeling in the offspring. Targeting PPAR with Bezafibrate has beneficial effects reducing the alterations, mainly through reduction of WAT inflammatory state through PPARgamma activation and enhanced hepatic beta-oxidation due to increased PPARalpha/PPARgamma ratio in liver.

The PPARγ Agonist Efatutazone Increases the Spectrum of Well-Differentiated Mammary Cancer Subtypes Initiated by Loss of Full-Length BRCA1 in Association with TP53 Haploinsufficiency

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have anticancer activity and influence cell differentiation. We examined the impact of the selective PPARγ agonist efatutazone on mammary cancer pathogenesis in a mouse model of BRCA1 mutation. Mice with conditional loss of full-length BRCA1 targeted to mammary epithelial cells in association with germline TP53 insufficiency were treated with efatutazone through the diet starting at age 4 months and were euthanized at age 12months or when palpable tumor reached 1 cm(3). Although treatment did not reduce percentage of mice developing invasive cancer, it significantly reduced prevalence of noninvasive cancer and total number of cancers per mouse and increased prevalence of well-differentiated cancer subtypes not usually seen in this mouse model. Invasive cancers from controls were uniformly estrogen receptor α negative and undifferentiated, whereas well-differentiated estrogen receptor α-positive papillary invasive cancers appeared in efatutazone-treated mice. Expression levels of phosphorylated AKT and CDK6 were significantly reduced in the cancers developing in efatutazone-treated mice. Efatutazone treatment reduced rates of mammary epithelial cell proliferation and development of hyperplastic alveolar nodules and increased expression levels of the PPARγ target genes Adfp, Fabp4, and Pdhk4 in preneoplastic mammary tissue. Intervention efatutazone treatment in mice with BRCA1 deficiency altered mammary cancer development by promoting development of differentiated invasive cancer and reducing prevalence of noninvasive cancer and preneoplastic disease.

PPARgamma-Dependent Control of Renin Expression: Molecular Mechanisms and Pathophysiological Relevance

During the last years accumulating evidence demonstrated that the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates the expression of renin gene and thus the overall renin production. This review summarizes the current knowledge of the transcriptional control of the renin gene by PPARgamma received from variety of models ranging from cell culture to transgenic animals. The molecular mechanisms of the PPARgamma action on renin are particularly interesting because they are featured by two newly described characteristics: one of them is the recently identified PPARgamma target sequence Pal3 which is specific for the human renin gene and mediates exceptionally high sensitivity to transactivation; the other is the potentiating effect of PPARgamma on the cAMP signaling in the renin-producing cells. Furthermore, I discuss the need for generating of additional transgenic animal models which are more appropriate with regard to the role of the PPARgamma-dependent regulation of the renin gene expression in human diseases such as arterial hypertension and metabolic syndrome.

M2/M1 ratio of tumor associated macrophages and PPAR-gamma expression in uveal melanomas with class 1 and class 2 molecular profiles

Macrophages have been found to be negative predictors of outcome in patients with uveal melanoma. In particular, recent studies point toward a disease-progressing role of proangiogenic M2 macrophages in melanomas with monosomy 3. Although most studies implicate a protective effect of PPAR-gamma activation in tumors, PPAR-gamma has also been shown to promote the polarization of M1 macrophages toward the M2 phenotype. The purpose of this investigation was first, to characterize the phenotype of tumor infiltrating macrophages and second, to study PPAR-gamma expression in uveal melanomas with molecular gene expression profile as prognostic predictors for patients' outcome. Twenty specimens from patients with uveal melanoma were analyzed for clinical and histologic tumor characteristics. The molecular RNA profile (class 1 or class 2) was commercially determined. Using immunohistochemical techniques, the specimens were dual labeled for CD68 and CD163. CD68 + CD163− M1 macrophages and CD68 + CD163+ M2 macrophages were analyzed in ten high power fields sparing macrophage-poor areas and a mean value was calculated for each tumor. The tumors were immunostained for von Willebrand factor and the micro vascular density (MVD) was analyzed according to Foss. To assess the proliferative rate of each tumor, Ki67 expression was evaluated in ten high power fields followed by calculation of a mean value. Expression of PPAR-gamma was evaluated using a score from 0 (no staining) to 3 (tumor entirely stained). Statistical analysis and a respective correlation were made between histologic characteristics, molecular profile, type of tumor infiltrating macrophages (M1 vs. M2), MVD, proliferative rate, and PPAR-gamma expression. Our results showed a correlation between the ratio of M2/M1 macrophages and the molecular profile with a ratio of approximately 1 corresponding to molecular class 1 and a ratio of approximately 2 corresponding to molecular class 2 (p = 0.01). The ratio of M2/M1 macrophages was higher in tumors with extraocular extension (p = 0.01). PPAR-gamma was predominantly expressed in the cytoplasm of tumor cells. Its expression showed no association with the molecular RNA profile (p = 0.83). This study confirmed that the ratio of M2/M1 macrophages is another prognostic factor in uveal melanoma. Thus, polarization of macrophages plays an important role for patients' outcome. PPAR-gamma is expressed in uveal melanoma tumor cells and further studies are warranted to determine its role in tumor biology.

PEDF inhibits AGE-induced podocyte apoptosis via PPAR-gamma activation

Advanced glycation end products (AGEs) formed at an accelerated rate under diabetes, elicit oxidative and pro-apoptotic reactions in various types of cells, including podocytes, thus being involved in the development and progression of diabetic nephropathy. Recently, we, along with others, have found that pigment epithelium-derived factor (PEDF), a glycoprotein with potent neuronal differentiating activity, inhibits AGE-elicited mesangial and tubular cell damage through its anti-oxidative properties. However, the effects of PEDF on podocyte loss, one of the characteristic features of diabetic nephropathy remain unknown. In this study, we investigated whether and how PEDF could protect against AGE-elicited podocyte apoptosis in vitro. AGEs decreased PEDF mRNA level in podocytes, which was blocked by neutralizing antibody raised against receptor for AGEs (RAGE-Ab). PEDF or RAGE-Ab was found to inhibit the AGE-induced up-regulation of RAGE mRNA level, oxidative stress generation and resultant apoptosis in podocytes. All of the beneficial effects of PEDF on AGE-exposed podocytes were blocked by the treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ (PPARγ). Further, although PEDF did not affect protein expression levels of PPARγ, it significantly restored the PPARγ transcriptional activity in AGE-exposed podocytes. The present results demonstrated for the first time that PEDF could block the AGE-induced apoptotic cell death of podocytes by suppressing RAGE expression and subsequent ROS generation partly via PPARγ activation. Our present study suggests that substitution of PEDF proteins may be a promising strategy for preventing the podocyte loss in diabetic nephropathy.

Telmisartan protects against cognitive decline via up-regulation of brain-derived neurotrophic factor/tropomyosin-related kinase B in hippocampus of hypertensive rats

Cognitive decline may occur as a result of hypertension, and is dependent on the function of hippocampus. Brain-derived neurotrophic factor (BDNF) mediated by angiotensin II-induced oxidative stress protects against cell death in hippocampus. Angiotensin II receptor blocker (ARB), candesartan, activates BDNF in the hippocampus. Furthermore, peroxisome proliferator-activated receptor (PPAR)-gamma activation in the brain prevents brain damage. Telmisartan, a unique ARB with PPAR-gamma stimulating activity, protects against cognitive decline partly because of PPAR-gamma activation. The aim of the present study was to determine whether telmisartan protects against cognitive decline via up-regulation of BDNF and its receptor tropomyosin-related kinase B (TrkB) in the hippocampus of hypertensive rats, partly because of PPAR-gamma activation. We divided stroke-prone spontaneously hypertensive rats (SHRSPs), as hypertensive and vascular dementia model rats, into five groups, telmisartan-treated (TLM), TLM+GW9662, a PPAR-gamma inhibitor, -treated (T+G), GW9662-treated (GW), TLM+ANA-12, a TrkB antagonist, -treated (T+A), and vehicle-treated SHRSPs (VEH). After the treatment for 28 days, systolic blood pressure did not change in all groups. However, BDNF expression in the hippocampus was significantly higher in TLM than in VEH to a greater extent than in T+G. Cognitive performance was significantly higher in TLM than in VEH to a greater extent than in T+G, and was not different between T+A, GW, and VEH. Telmisartan protects against cognitive decline via up-regulation of BDNF/TrkB in the hippocampus of SHRSPs, partly because of PPAR-gamma activation independent of blood pressure-lowering effect.

Abstract 364: Nrf2-PPAR gamma Signaling Suppresses Exaggerated Renal Tubular AT1R Gene Expression and Function and Mitigates Hypertension During Oxidative Stress

Oxidative stress plays an important role in the development of hypertension. Interestingly, angiotensin type 1 receptor (AT1R) function, a major contributor to the etiology of hypertension, is positively regulated by oxidative stress. It is shown that antioxidant treatment can reduce blood pressure (BP) and redox-sensitive transcription factor Nrf2 could provide important clues for antihypertensive properties of antioxidants. Here in we investigated how induction of renal proximal tubular Nrf2 in response to antioxidants will activate PPAR gamma (a pleiotropic nuclear receptor whose ligands exhibit BP reducing effects) which in turn will normalize AT1R expression and reduce BP. Wild type (WT) and renal proximal tubular specific Nrf2 knockout (KO) mice were treated with 10 mM L-buthionine-sulfoximine (BSO, a pro-oxidant) without and with sulforaphane (S, an antioxidant; 5 μM daily by gavage) for 5 wks. BSO-treatment increased oxidative stress, AT1R mRNA, AT1R expression and Ang II-induced activation of renal sodium transporters and these animals exhibited high BP (mm Hg, WT: 102±3, WT-BSO: 123±4, Nrf2 KO: 98±2). However, the onset and severity of hypertension (Nrf2-KO-BSO: 136±4) as well as oxidative stress and AT1R function was more robust in BSO-treated Nrf2 KO compared to WT mice. More importantly, sulforaphane activated Nrf2, reduced oxidative stress, normalized proximal tubular AT1R function and reduced BP (WT-S: 99±5, WT-BSO+S: 106±6) in BSO-treated WT mice but failed to mitigate AT1R function or reduce BP (Nrf2 KO-S: 97±4, Nrf2 KO-BSO+S: 130±3) in Nrf2 KO mice. Further studies showed that BSO-induced hypertension is also more severe in renal proximal tubular specific PPAR gamma KO mice and sulforaphane fails to protect PPAR gamma KO mice from hypertension. Experiments in human renal proximal tubular cells indicated that 1) sulforaphane, via Nrf2 activation, reduced oxidant-induced AT1R upregulation and 2) Nrf2 dependent PPAR gamma activation suppresses AT1R gene transcription. These findings suggest that antioxidants via Nrf2 activation reduce oxidative stress, normalize AT1R signaling and prevent hypertension during oxidative stress. More importantly, Nrf2 induction activates PPAR gamma which suppresses AT1R gene transcription.

Further insights about the beneficial effects of n-3 fatty acids in the early molecular events of renal fibrosis in vitro

Accumulating experimental and clinical evidence reveals beneficial effects of n-3 polyunsaturated fatty acids (PUFAs) in kidney disease by modulating inflammation and fibrosis mechanisms that lead to renal failure. EPA, DHA (n-3 PUFAs) and AA (n-6 PUFA) effects, compared to those of AngII, on renal fibrotic processes at the extracellular matrix (ECM) level were verified in human mesangial cells in vitro, by means of RT-PCR, mitogenic assay and Western-blot analysis. Unlike AngII, EPA and DHA enhanced the expression of MMP2 and DN, a TGFbeta inhibitor, while decreasing mitogenic factors such as PDGF and bFGF, and cell proliferation. Moreover, n-3 PUFAs elicited Bax expression in AngII-treated cells and downregulated COX-2--an enzyme involved in the inflammatory cascade. The mechanism of action could implicate PPARgamma activation, as this transcription factor was shown to translocate to the nucleus upon n-3 PUFA treatment. These results complement our previous reports demonstrating that EPA and DHA prevent ECM accumulation and inflammation that typify the fibrotic process, providing new insights into the cellular and molecular mechanisms underlying their beneficial effects. We confirm that n-3 PUFAs could effectively counteract kidney fibrosis development providing a rationale for their use in clinical settings.

Beta-Mecaptoethanol Suppresses Inflammation and Induces Adipogenic Differentiation in 3T3-F442A Murine Preadipocytes

Preadipocytes are present in adipose tissues throughout adult life that can proliferate and differentiate into mature adipocytes in response to environmental cues. Abnormal increase in adipocyte number or size leads to fat tissue expansion. However, it is now recognized that adipocyte hypertrophy is a greater risk factor for metabolic syndrome whereas fat tissue that continues to produce newer and smaller fat cells through preadipocyte differentiation is “metabolically healthy”. Because adipocyte hypertrophy is often associated with increased oxidant stress and low grade inflammation, both are linked to disturbed cellular redox, we tested how preadipocyte differentiation may be regulated by beta-mercaptoethanol (BME), a pharmacological redox regulator and radical scavenger, using murine 3T3-F442A preadipocytes as the cell model. Effects of BME on adipogenesis were measured by microphotography, real-time PCR, and Western analysis. Our data demonstrated that preadipocyte differentiation could be regulated by extracellular BME. At an optimal concentration, BME enhanced expression of adipogenic gene markers and lipid accumulation. This effect was associated with BME-mediated down-regulation of inflammatory cytokine expression during early differentiation. BME also attenuated TNFalpha-induced activation of NFkappaB in differentiating preadipocytes and partially restored TNFalpha-mediated suppression on adipogenesis. Using a non-adipogenic HEK293 cell line transfected with luciferase reporter genes, we demonstrated that BME reduced basal and TNFalpha-induced NFkappaB activity and increased basal and ciglitazone-induced PPARgamma activity; both may contribute to the pro-adipogenic effect of BME in differentiating F442A preadipocytes.

Telmisartan at 80 mg/Day Increases High-Molecular-Weight Adiponectin Levels and Improves Insulin Resistance in Diabetic Patients

The clinical dose of telmisartan necessary for activation of peroxisome proliferator-activated receptor gamma (PPAR-gamma) has not been established. The authors investigated the effect of high-dose telmisartan on serum levels of the high-molecular-weight (HMW) adiponectin in patients with diabetes and hypertension. In this open-label, prospective, randomized study, patients with type 2 diabetes and hypertension with poor control of blood pressure by 40 mg/day telmisartan were randomly assigned into the telmisartan 80 mg/day (Tel80) group (dose increase from 40 to 80 mg/day) or the telmisartan 40 mg + amlodipine 5 mg (Tel40 + Aml5) group. Serum levels of HMW adiponectin and parameters of glucose and lipid metabolism were measured at baseline and end of 3-months of treatment. Although the antihypertensive effects of the two doses of telmisartan were similar, a significant increase in HMW adiponectin levels was noted only in the Tel80 group. The increase was evident particularly in a group of patients whose HMW adiponectin levels were less than 4.0 μg/dL. A significant improvement in homeostasis model assessment of insulin resistance (HOMA-IR), a measure of insulin resistance, was also observed in the Tel80 group only. In diabetic patients with hypertension, high-dose telmisartan increased HMW adiponectin levels and improved insulin resistance through activation of PPAR-gamma.

PPAR gamma activation protects the brain against microvascular dysfunction in sepsis

Sepsis is a severe disorder characterized by systemic inflammatory responses in the presence of an infection and may progress to multiple organ dysfunction and death. Alterations in cerebral microcirculation fulfill a crucial role in the pathogenesis of severe sepsis, and include a decrease in capillary density and disturbances in leukocyte movement along capillaries. Nevertheless, the mechanisms involved in sepsis-associated cerebral microcirculatory alterations have so far not been defined. We investigated the effect of the peroxisome proliferator-activated receptor gamma (PPARγ) selective agonist rosiglitazone on leukocyte/endothelial cell interaction and functional capillary density in the brain in the cecal ligation and puncture (CLP) model of sepsis. Anti-inflammatory effects of rosiglitazone on the cerebral microcirculation were marked. Functional capillary density increased and leukocyte rolling and adhesion were decreased in animals submitted to CLP and treated with rosiglitazone. Our data provide evidence for involvement of PPARγ activation in leukocyte–endothelium interactions and alterations in capillary density. Improved cerebral perfusion in animals treated with rosiglitazone, suggests that PPARγ activation is protective against cerebral microvascular dysfunction in sepsis.

Combined activation of PPAR-gamma and PPAR-alpha reduces the negative effects of PPAR-gamma agonism on bone and may attenuate PPAR-gamma-mediated loss of bone strength

Combined activation of PPAR-gamma and PPAR-alpha reduces the negative effects of PPAR-gamma agonism on bone and may attenuate PPAR-gamma-mediated loss of bone strength

Combined activation of PPAR-gamma and PPAR-alpha reduces the negative effects of PPAR-gamma agonism on bone and may attenuate PPAR-gamma-mediated loss of bone strength

Combined activation of PPAR-gamma and PPAR-alpha reduces the negative effects of PPAR-gamma agonism on bone and may attenuate PPAR-gamma-mediated loss of bone strength

Активатор ППАР-гама піоглітазон знижує експресію транскрипційного фактора NF-kB та апоптоз в мононуклеарних клітинах СD64+ крові in vitro

In order to examine the impact of PPAR-gamma activator on the expression of kB nuclear transcription factor and apoptosis, the peripheral blood mononuclear cells (PBMC) were incubated with pioglitazone at concentrations 10, 30 and 100 MM. Expression of NF-kB in CD64+ cells was evaluated by flow cytometry using monoclonal antibodies. The development of apoptosis was evaluated using annexin V and propidium iodide. Activation of PPAR-y resulted in a reduction of the number of CD64+ cells and expression of the maximum levels of these receptors. We also obesrved a dose-dependent decrease of NF-kB concentration in PBMC suspension and in CD64+ cells. While analyzing the apoptosis, the reduction of apoptotic cells (reduction of AnV+PI+ cells) has been observed. The results obtained allow to prove that PPAR-gamma activation participates in the PBMC apoptosis regulation and in the expression of transcriptional factor NF-kB. Our results indicate for the involvement of PPAR-gamma in the regulation of NF-kB activity which plays one of the most significant roles in the inflammation realization, oncogenesis, and so on.

The PPAR-gamma agonist pioglitazone protects cortical neurons from inflammatory mediators via improvement in peroxisomal function

BackgroundInflammation is known to play a pivotal role in mediating neuronal damage and axonal injury in a variety of neurodegenerative disorders. Among the range of inflammatory mediators, nitric oxide and hydrogen peroxide are potent neurotoxic agents. Recent evidence has suggested that oligodendrocyte peroxisomes may play an important role in protecting neurons from inflammatory damage.MethodsTo assess the influence of peroxisomal activation on nitric oxide mediated neurotoxicity, we investigated the effects of the peroxisomal proliferator activated receptor (PPAR) gamma agonist, pioglitazone in primary cortical neurons that were either exposed to a nitric oxide donor or co-cultured with activated microglia.ResultsPioglitazone protected neurons and axons against both nitric-oxide donor-induced and microglia-derived nitric oxide-induced toxicity. Moreover, cortical neurons treated with this compound showed a significant increase in the protein and gene expression of PPAR-gamma, which was associated with a concomitant increase in the enzymatic activity of catalase. In addition, the protection of neurons and axons against hydrogen peroxide-induced toxicity afforded by pioglitazone appeared to be dependent on catalase.ConclusionsCollectively, these observations provide evidence that modulation of PPAR-gamma activity and peroxisomal function by pioglitazone attenuates both NO and hydrogen peroxide-mediated neuronal and axonal damage suggesting a new therapeutic approach to protect against neurodegenerative changes associated with neuroinflammation.

Activation and dephosphorylation of PPARgamma induce PCSK9 production

PCSK9 plays an important role in cholesterol homeostasis by enhancing the degradation of LDLR protein. PPARγ, a ligand activated transcriptional factor, has been shown to be atheroprotective. PPARγ can be phosphorylated by ERK1/2 and the phosphorylated status of PPARγ greatly impacts its biological activity. However, the interplay between PCSK9 and PPARγ/phosph‐PPARγ remains unknown. We observed that PPARγ ligands induced PCSK9 mRNA and protein expression in HepG2 cells. Inhibition of ERK1/2 induced while activation of ERK1/2 inhibited PCSK9 expression. Co‐treatment of PPARγ ligand and ERK1/2 inhibitor had no additive effect on the induction of PCSK9 expression. The induction of PCSK9 expression by ERK1/2 inhibitor was tightly linked to the dephosphorylation of PPARγ. In vivo, the administration of PPARγ ligand or ERK1/2 inhibitor alone increased PCSK9 expression in mouse liver but had no effect on PCSK9 secretion. However, the co‐administration of PPARγ ligand and ERK1/2 inhibitor enhanced both PCSK9 expression and secretion. Interestingly, the up‐regulation of PCSK9 expression by PPARγ ligand and/or ERK1/2 inhibitor was associated with the increased LDLR expression in the liver and the decreased LDL‐cholesterol levels in serum. Our study discloses a new mechanism involving in regulation of PCSG9 expression and may have implication in the development of strategies for PCSK9 expression and function.