Modulation of gastrointestinal inflammation and colorectal tumorigenesis by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

Critical physiological roles of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) include the regulation glucose and lipid homeostasis, cellular differentiation, and modulation of inflammation. The potential for targeting PPARβ/δ for the prevention and treatment of metabolic diseases or cancer, is compromised because of major inconsistencies in the literature. This is due primarily to uncertainty regarding the effect of PPARβ/δ and its activation on cell proliferation, apoptosis and cell survival. This review summarizes both the confirmed and conflicting mechanisms that have been described for PPARβ/δ and the potential for targeting this nuclear receptor for the prevention and treatment of colon cancer.     

Cd modifies hepatic Zn deposition and modulates δ-ALA-D activity and MT levels by distinct mechanisms

Cadmium (Cd) is a pollutant that is harmful to human and animals. The liver is a target for Cd accumulation and it can disrupt Zn homeostasis. Here we examined the interaction of Zn and Cd to determine how these two metals could affect δ-aminolevulinate-dehydratase (δ-ALA-D) and metallothionein (MT), two potential molecular endpoints for Cd hepatotoxicity. Cd exposure (0.25 and 1 mg kg1 body weight, i.p., for 10 days) caused a marked increase in hepatic Zn deposition, which was not modified by treatment with Zn (2 mg kg1 , i.p.). Cd caused a dose-dependent increase in hepatic Cd content that was not modified by Zn. Zn and/or Cd treatment increased hepatic δ-ALA-D activity, although the increase caused by Cd was less marked. Reactivation index of δ-ALA-D by DTT was decreased by Zn and Cd exposure, which indicates that Zn protects enzyme from oxidation. Hepatic MT was increased only after exposure to 1 mg kg(-1) Cd and Zn reduced the stimulation of MT synthesis. The results presented here indicate that Cd can redistribute Zn from non-hepatic tissues to liver and the increase in hepatic Zn deposition can account for the increase in hepatic δ-ALA-D activity after Cd exposure. However, Zn blocked the increase in hepatic MT levels caused by Cd. Thus, the modulation of the two molecular endpoints of Cd toxicity used here was distinct, which indicates that the mechanism(s) involved in Zn and Cd distribution, δ-ALA-D and MT regulation are not coincident.     

Targeting PPARβ/δ for the treatment of type 2 diabetes mellitus

INTRODUCTION: The nuclear receptors Peroxisome Proliferator-Activated Receptors (PPAR)α and PPARγ are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively. Evidence is now emerging that the PPARβ/δ isotype is a potential pharmacological target for the treatment of insulin resistance and type 2 diabetes mellitus. AREAS COVERED: In this review, the capacity of PPARβ/δ to prevent the development of insulin resistance and type 2 diabetes mellitus is discussed. Special emphasis is placed on preclinical studies and the molecular mechanisms responsible for its actions in the main cell types involved in these pathologies: adipocytes, β-cells, skeletal muscle cells and hepatocytes. EXPERT OPINION: While several concerns remain for the development of PPARβ/δ agonists, these drugs have demonstrated their efficacy in the treatment of insulin resistance and type 2 diabetes mellitus in preclinical studies, as well as in a few short clinical studies in humans. Although this data is promising, additional studies must be performed to confirm the efficacy and safety of these drugs in the treatment of type 2 diabetes mellitus.     

Anti-apoptotic effects of protein kinase C-δ and c-fos in cisplatin-treated thyroid cells

Background and purpose:

We showed previously that cisplatin inititates a signalling pathway mediated by PKC-δ/extracellular signal-regulated kinase (ERK), important for maintaining viability in PC Cl3 thyroid cells. The studies described herein examined whether c-fos was associated with cisplatin resistance and the signalling link between c-fos and PKC-δ/ERK.

Experimental approach:

Cells were treated with various pharmacological inhibitors of PKCs and ERK, or were depleted of c-fos, PKC-δ, PKC-ε and caspase-3 by small interfering RNA (siRNA), then incubated with cisplatin and cytotoxicity assessed.

Key results:

Cisplatin provokes the induction of c-fos and the activation of conventional PKC-β, and novel PKC-δ and -ε. The cisplatin-provoked c-fos induction was decreased by Gö6976, a PKC-β inhibitor; by siRNA for PKC-δ- but not that for PKC-ε or by PD98059, a mitogen-activated protein kinase/ERK kinase inhibitor. Expression of c-fos was abolished by GF109203X, an inhibitor of all PKC isoforms, or by PD98059 plus Gö6976 or by PKC-δ-siRNA plus Gö6976. When c-fos expression was blocked by siRNA, cisplatin cytotoxicity was strongly enhanced with increased caspase-3 activation. In PKC-δ-depleted cells treated with cisplatin, caspase-3 activation was increased and cell viability decreased. In these PKC-δ-depleted cells, PD98059 did not affect caspase-3 activation.

Conclusions and implications:

In PC Cl3 cells, in the cell signalling pathways that lead to cisplatin resistance, PKC-δ controls ERK activity and, together with PKC-β, also the induction of c-fos. Hence, the protective role of c-fos in thyroid cells has the potential to provide new opportunities for therapeutic intervention.     

Vascular effects of prostacyclin: does activation of PPARδ play a role?

Prostacyclin (PGI(2)) is a potent vasodilator that exerts multiple vasoprotective effects in the cardiovascular system. The effects of PGI(2) are mediated by activation of the cell membrane G-protein-coupled PGI(2) receptor (IP receptor). More recently, however, it has been suggested that PGI(2) might also serve as an endogenous ligand and activator of nuclear peroxisome proliferator-activated receptorδ (PPARδ). Consistent with this concept, studies designed to define pharmacological properties of stable PGI(2) analogs revealed that beneficial effects of these compounds appear to be mediated, in part, by activation of PPARδ. This review discusses emerging evidence regarding the contribution of PPARδ activation to vasoprotective and regenerative functions of PGI(2) and stable analogs of PGI(2).     

Inhibition of hepatic δ-aminolevulinate dehydratase activity induced by mercuric chloride is potentiated by N-acetylcysteine in vitro

Mercuric chloride (HgCl)₂ is a toxic metal that causes oxidative damage in several tissues. N-acetylcysteine (NAC) is a sulfhydryl compound with antioxidant activity. In the present study, we investigated the in vitro effects of the association between HgCl₂ and NAC in tissues of mice. For this purpose, we evaluated the in vitro effect of HgCl₂ + NAC association on δ-aminolevulinate dehydratase (δ-ALA-D) activity and on thiobarbituric acid reactive substances (TBARS) levels in liver and kidney of mice. The results demonstrate that HgCl₂ inhibited δ-ALA-D activity in both tissues. Hepatic δ-ALA-D activity inhibited by HgCl₂ was potentiated by the highest concentration of NAC. The inhibition of hepatic δ-ALA-D activity seems to be related to sulfhydryl groups oxidation of the enzyme. We observed also that HgCl₂ increased TBARS levels in kidney and liver. Hepatic TBARS levels were reduced by NAC, at higher concentration. In contrast, NAC, at higher concentration, increased renal TBARS levels. In conclusion, the inhibition of hepatic δ-aminolevulinate dehydratase activity induced by HgCl₂ is potentiated by NAC in vitro, and this effect is not related to hepatic lipid peroxidation.     

Cafestol preconditioning attenuates apoptosis and autophagy during hepatic ischemia-reperfusion injury by inhibiting ERK/PPARγ pathway

ObjectiveThe study was aimed to explore the hepatocellular protective functions of cafestol during hepatic ischemia-reperfusion injury and the possible mechanisms.MethodsNinety male Balb/c mice were randomly divided into seven groups, including normal control group, L-cafestol(20mg/kg) group, H-cafestol(40mg/kg) group, sham group, IR group, L-cafestol(20mg/kg) + IR group, H-cafestol(40mg/kg) + IR group. Serum liver enzymes (ALT, AST), inflammation mediators, proteins associated with apoptosis and autophagy, indicators linked with ERK/PPARγ pathway, and liver histopathology were measured using ELISA, qRT-PCR, immunohistochemical staining, and western blotting at 2, 8, and 24 hours after reperfusion.ResultsOur findings confirmed that cafestol preconditioning groups could reduce the levels of ALT and AST, alleviate liver pathological damage, suppress the release of inflammation mediators, inhibit the production of pro-apoptosis protein including caspase-3, caspase-9 and Bax, decrease the expression of autophagy-linked protein including Beclin-1 and LC3, increase anti-apoptosis protein Bcl-2, and restrain the activation of ERK and PPARγ.ConclusionCafestol preconditioning could attenuate inflammatory response, apoptosis and autophagy on hepatic ischemia reperfusion injury by suppressing ERK/PPARγ pathway.     

Modulation of ammonium perfluorooctanoate-induced hepatic damage by genetically different PPARα in mice

Perfluorooctanoic acid is a ligand for peroxisome proliferator-activated receptor (PPAR??). Ammonium perfluorooctanoate (APFO) at 0.1 and 0.3?mg/kg doses activated mouse PPAR??, but not human PPAR??. This study aimed to clarify whether milligram-order APFO can activate human PPAR??, and the receptor is involved in APFO-induced chronic hepatic damage. Male Sv/129 wild-type (mPPAR??), Ppar??-null, and humanized PPAR?? (hPPAR??) mice (8 weeks old) were divided into three groups. The first was treated with water and the other two with 1.0 and 5.0?mg/kg APFO for 6?weeks, orally, respectively. Both doses activated mouse and human PPAR?? to a similar or lower degree in the latter. APFO dose dependently increased hepatic triglyceride levels in Ppar??-null and hPPAR?? mice, but conversely decreased those in mPPAR?? ones. APFO-induced hepatic damage differed markedly among the three genotyped groups: single-cell necrosis was observed in all genotyped mice; inflammatory cells and macrovesicular steatosis only in Ppar??-null mice; and microvesicular steatosis and hydropic degenerations in hPPAR?? and Ppar??-null mice. The molecular mechanism underlying these differences may be attributable to those of gene expressions involved in lipid homeostasis (PPAR??, ??- and ??-oxidation enzymes, and diacylglycerol acyltransferases) and uncoupling protein 2. Thus, milligram-order APFO activated both mouse and human PPAR?? in a different manner, which may reflect histopathologically different types of hepatic damage.     

The antiplatelet activity of magnolol is mediated by PPAR-β/γ

Activation of peroxisome proliferator-activated receptor (PPAR) isoforms (α, β/δ, and γ) is known to inhibit platelet aggregation. In the present study, we examined whether PPARs-mediated pathways contribute to the antiplatelet activity of magnolol, a compound purified from Magnolia officinalis. Magnolol (20-60μM) dose-dependently enhanced the activity and intracellular level of PPAR-β/γ in platelets. In the presence of selective PPAR-β antagonist (GSK0660) or PPAR-γ antagonist (GW9662), the inhibition of magnolol on collagen-induced platelet aggregation and intracellular Ca(2+) mobilization was significantly reversed. Moreover, magnolol-mediated up-regulation of NO/cyclic GMP/PKG pathway and Akt phosphorylation leading to increase of eNOS activity were markedly abolished by blocking PPAR-β/γ activity. Additionally, magnolol significantly inhibited collagen-induced PKCα activation through a PPAR-β/γ and PKCα interaction manner. The arachidonic acid (AA) or collagen-induced thromboxane B(2) formation and elevation of COX-1 activity caused by AA were also markedly attenuated by magnolol. However, these above effects of magnolol on platelet responses were strongly reduced by simultaneous addition of GSK0660 or GW9662, suggesting that PPAR-β/γ-mediated processes may account for magnolol-regulated antiplatelet mechanisms. Similarly, administration of PPAR-β/γ antagonists remarkably abolished the actions of magnolol in preventing platelet plug formation and prolonging bleeding time in mice. Taken together, we demonstrate for the first time that the antiplatelet and anti-thrombotic activities of magnolol are modulated by up-regulation of PPAR-β/γ-dependent pathways.     

Δ8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors

BACKGROUND AND PURPOSE

Activation of cannabinoid CB₂ receptors protects against various forms of ischaemia-reperfusion (I/R) injury. Δ⁸-Tetrahydrocannabivarin (Δ⁸-THCV) is a synthetic analogue of the plant cannabinoid Δ⁹-tetrahydrocannabivarin, which exhibits anti-inflammatory effects in rodents involving activation of CB₂ receptors. Here, we assessed effects of Δ⁸-THCV and its metabolite 11-OH-Δ⁸-THCV on CB₂ receptors and against hepatic I/R injury.

EXPERIMENTAL APPROACH

Effects in vitro were measured with human CB₂ receptors expressed in CHO cells. Hepatic I/R injury was assessed in mice with 1h ischaemia and 2, 6 or 24h reperfusion in vivo.

KEY RESULTS

Displacement of [³H]CP55940 by Δ⁸-THCV or 11-OH-Δ⁸-THCV from specific binding sites in CHO cell membranes transfected with human CB₂ receptors (hCB₂) yielded K_i values of 68.4 and 59.95 nM respectively. Δ⁸-THCV or 11-OH-Δ⁸-THCV inhibited forskolin-stimulated cAMP production by hCB₂ CHO cells (EC₅₀= 12.95 and 14.3 nM respectively). Δ⁸-THCV, given before induction of I/R, attenuated hepatic injury (measured by serum alanine aminotransferase and aspartate aminotransferase levels), decreased tissue protein carbonyl adducts, 4-hydroxy-2-nonenal, the chemokines CCL3 and CXCL2,TNF-α, intercellular adhesion molecule 1 (CD54) mRNA levels, tissue neutrophil infiltration, caspase 3/7 activity and DNA fragmentation. Protective effects of Δ⁸-THCV against liver damage were still present when the compound was given at the beginning of reperfusion. Pretreatment with a CB₂ receptor antagonist attenuated the protective effects of Δ⁸-THCV, while a CB₁ antagonist tended to enhance it.

CONCLUSIONS AND IMPLICATIONS

Δ⁸-THCV activated CB₂ receptors in vitro, and decreased tissue injury and inflammation in vivo, associated with I/R partly via CB₂ receptor activation.

LINKED ARTICLES

This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7     

PPARα-dependent modulation of hepatic CYP1A by clofibric acid in rats

Fibrates, hypolipidemic drugs, have been reported to suppress the metabolic activities of cytochrome P450 1A1 and 1A2 in rats but the mechanism has not been elucidated. In the present study we tested the hypothesis that the inhibitory effect of fibrates on arylhydrocarbon receptor (AhR) function may be due to their stimulatory effects on PPAR. Sudan III (S.III) treatment induced CYP 1A1 and CYP 1A2 protein expression, mRNA and their metabolic activities, methoxyresorufin-O-demethylase (MROD) and ethoxyresorufin-O-deethylase (EROD), in Wistar rats higher than those in the control. Co-treatment of rats with S.III and clofibric acid (CA) caused a 40–50% decrease in the induced levels of CYP1A1 and CYP1A2 protein, mRNA expression and their metabolic activities and reduced AhR protein expression. When we treated HepG2 cells with S.III and/or CA, no suppressive effect on S.III-induced CYP1A1 protein expression due to CA was found. HepG2 cells were transiently transfected with increasing concentrations of PPAR mammalian expression vector and exposed to the same treatment. CA co-treatment with S.III decreased AhR protein and S.III-induced CYP1A1 protein expression with increasing dose of PPAR transfected into HepG2 cells. Our results demonstrate that the suppressive effect of fibrates on CYP1A is PPAR-dependent and suggest that PPARhas an inhibitory effect on AhR function.Abbreviations AhR Arylhydrocarbon receptor - CA Clofibric acid - CYP1A1 Cytochrome P450 1A1 - CYP1A2 Cytochrome P450 1A2 - EROD Ethoxyresorufin-O-deethylase - MROD Methoxyresorufin-O-demethylase - PPAR Peroxisome proliferator activated receptor alpha - PPRE Peroxisome proliferator response element - RXR Retinoid-X receptor - S.III Sudan III - TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin - TNF Tumor necrosis factor-alpha - XAP2 Hepatitis B virus X-associated protein     

PPARβ/δ在炎症中的作用

过氧化物酶体增殖物激活受体(peroxisome prolifera-tors-activated receptors,PPARs)是配体激活的转录因子,属于核受体超家族成员。PPARs有3种亚型,即PPARα(NR1C1)、PPARβ/δ(NUC1;NR1C2)和PPARγ(NR1C3)。大量研究表明PPARs广泛参与机体的脂质代谢、糖代谢、能量代谢、血压调节、细胞生长分化及生殖过程,并在炎症过程中发挥重要的作用。近年来,PPARβ/δ在炎症发生中的作用及其调控机制日益受到人们的关注,该文对PPARβ/δ在炎症发生中的作用作一综述。     

β3-adrenergic receptor activity modulates melanoma cell proliferation and survival through nitric oxide signaling

We have recently shown in B16F10 melanoma cells that blockade of β3-adrenergic receptors (β3-ARs) reduces cell proliferation and induces apoptosis, likely through the involvement of nitric oxide (NO) signaling. Here, we tested the hypothesis that the effects of β3-AR blockade on melanoma cells are mainly mediated by a decrease in the activity of the NO pathway, possibly due to reduced expression of inducible NO synthase (iNOS). B16F10 cells were used. Nitrite production, iNOS expression, cell proliferation, and apoptosis were evaluated. β3-AR blockade with L-748,337 reduced basal nitrite production, while β3-AR stimulation with BRL37344 increased it. The effects of β3-AR blockade were prevented by NOS activation, while the effects of β3-AR activation were prevented by NOS inhibition. Treatments increasing nitrite production also increased iNOS expression, while treatments decreasing nitrite production reduced iNOS expression. Among the different NOS isoforms, experiments using L-748,337 or BRL37344 with activators or inhibitors targeting specific NOS isoforms demonstrated a prominent role of iNOS in nitrite production. β3-AR blockade decreased cell proliferation and induced apoptosis, while β3-AR activation had the opposite effects. The effects of β3-AR blockade/activation were prevented by iNOS activation/inhibition, respectively. Taken together, these results demonstrate that iNOS-produced NO is a downstream effector of β3-ARs and that the beneficial effects of β3-AR blockade on melanoma B16F10 cell proliferation and apoptosis are functionally linked to reduced iNOS expression and NO production. Although it is difficult to extrapolate these data to the clinical setting, the targeted inhibition of the β3-AR-NO axis may offer a new therapeutic perspective to treat melanomas.     

β-1,3-Glucan given orally modulates immunomyelopoietic activity and enhances the resistance of tumour-bearing mice

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