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Eur J Pharmacol [journal]
- Anti-pruritic activity of pioglitazone on serotonin-induced scratching in mice: Possible involvement of PPAR-gamma receptor and nitric oxide. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Oct 10.
Pioglitazone is a member of peroxisome proliferator-activated receptor gamma (PPARγ) agonists, particularly used in management of type II diabetes. However it also has effects in some dermatological disorders. The current study was designed to investigate the effects of oral administration of pioglitazone and the association of nitric oxide, in serotonin-induced scratching in mice. In order to produce the scratching activity, serotonin (141nm/site) was administered intradermally in the nape of the neck. Pioglitazone in concentrations of 10, 20, 40 and 80mg/kg, was peroral administered (p.o) as a single dose, four h before the serotonin injection. PPAR-γ antagonist, GW9662 (2mg/kg, i.p); a non-specific nitric oxide synthase (NOS) inhibitor, NG-nitro-l-arginine methyl ester (L-NAME; 1mg/kg, i.p); or a nitric oxide precursor, L-arginine (100mg/kg, i.p.); adminstrated 15min before pioglitazone, were analyzed for anti-scratching activity. Results obtained showed that pioglitazone (40 and 80mg/kg, p.o) reduced the scratching in a dose-dependent manner. GW9662 inverted the anti-scratching effect of pioglitazone (80mg/kg). Acute dose of L-NAME (1mg/kg,i.p) also prevented the anti-scratching property of pioglitazone (80mg/kg, p.o); Although L-arginine, was used in sub-effective dose (100mg/kg,i.p), however it potentiated the anti-scratching behaviour when co-injected with pioglitazone (20mg/kg, p.o). The results indicate that, acute pioglitazone has anti-scratching effect on serotonin-induced scratching in mice. It is concluded that anti-scratching outcome of acute pioglitazone is initiated via activation of PPAR-γ receptor and to some extent by the NO pathway.
- Role of mitogen-activated protein kinase phosphatase-1 in corticosteroid insensitivity of chronic oxidant lung injury. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Oct 10.
Oxidative stress plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and in the induction of corticosteroid (CS) insensitivity. Chronic ozone exposure leads to a model of COPD with lung inflammation and emphySEMa. Mitogen-activated protein kinase phosphatase-1 (MKP-1) may underlie CS insensitivity in COPD. We determined the role played by MKP-1 by studying the effect of corticosteroids in wild-type C57/BL6J and MKP-1(-/-) mice after chronic ozone exposure. Mice were exposed to ozone (3ppm, 3h) 12 times over 6 weeks. Dexamethasone (0.1 or 2mg/kg; intraperitoneally) was administered before each exposure. Mice were studied 24h after final exposure. In ozone-exposed C57/BL6J mice, bronchial hyperresponsiveness (BHR) was not inhibited by both doses of dexamethasone, but in MKP-1(-/-) mice, there was a small inhibition by high dose dexamethasone (2mg/kg). There was an increase in mean linear intercept after chronic ozone exposure in both strains which was CS-insensitive. There was lesser inflammation after low dose of dexamethasone in MKP-1(-/-) mice compared to C57/Bl6J mice. Epithelial and collagen areas were modulated in ozone-exposed MKP-1(-/-) mice treated with dexamethasone compared to C57/Bl6J mice. MKP-1 regulated the expression of MMP-12, IL-13 and KC induced by ozone but did not alter dexamethasone's effects. Bronchial hyperresponsiveness, lung inflammation and emphySEMa after chronic exposure are CS-insensitive, and the contribution of MKP-1 to CS sensitivity in this model was negligible.
- Cardioprotective effects of oxymatrine on isoproterenol-induced heart failure via regulation of DDAH/ADMA metabolism pathway in rats. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Oct 10.
The present study was designed to investigate whether oxymatrine could attenuate isoproterenol-induced heart failure via regulation of asymmetric dimethylarginine (ADMA) metabolism in rats. Heart failure model was established by once daily subcutaneous injection of isoproterenol (5mg/kg/d) to rats for 7 days. Simultaneously, oral administration of oxymatrine (25, 50 and 100mg/kg/d, respectively) was started from day 1 to day 7, or with vehicle as corresponding controls. After continuous preventive administration of oxymatrine for 7 days, significant isoproterenol-induced heart failure characterized by hypertrophy and dysfunction of left ventricular, and elevation of brain natruretic peptide (BNP, a heart failure biomarker) and cardiac troponin I (cTn-I, a cardiac injury biomarker) was observed. Preventive oxymatrine significantly ameliorated the cardiac hypertrophy, improved the left ventricular dysfunction and reduced the increased BNP and cTn-I in serum of isoproterenol-treated rats. And obvious changes with decrease of systolic blood pressure and increase of heart rate were present in isoproterenol group and normalized by oxymatrine. Besides, prevention with oxymatrine significantly up-regulated the dimethylarginine dimethylaminohydrolase 2 (DDAH2) expression, which was followed by decreased serum ADMA, but it had no effect on protein arginine methyltransferase1 (PRMT1) expression that is up-regulated in isoproterenol-induced heart failure rats. These results manifested that preventive oxymatrine could ameliorate the hypertrophy and dysfunction of left ventricle of rats with heart failure, which is attributed to modulation of DDAH/ADMA metabolism pathway by oxymatrine.
- Polydatin improves glucose and lipid metabolism in experimental diabetes through activating the Akt signaling pathway. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Oct 10.
Recently, the effect of polydatin on lipid regulation has gained considerable attention. And previous study has demonstrated that polydatin has hypoglycemic effect on experimental diabetic rats. Repressed Akt pathway contributes to glucose and lipid disorders in diabetes. Thus, whether polydatin regulates glucose and lipid metabolism in experimental diabetic models through the Akt pathway arouses interest. The purpose was to explore the regulatory mechanism of polydain on glucose and lipid through Akt pathway. We used a diabetic rat model induced by high-fat and -sugar diet with low-dose of streptozocin and an insulin resistant HepG2 cell model induced by palmitic acid to clarify the role of polydatin on glucose and lipid metabolism. Here, we found that polydatin significantly attenuated fasting blood-glucose, glycosylated hemoglobin, glycosylated serum protein, total cholesterol, triglyceride, and low-density lipoprotein cholesterol in diabetic rats. Furthermore, polydatin significantly increased glucose uptake and consumption and decreased lipid accumulation in insulin resistant HepG2 cells. Polydatin markedly increased serum insulin levels in diabetic rats, and obviously activated the Akt signaling pathway in diabetic rat livers and insulin resistant HepG2 cells. Polydatin markedly increased phosphorylated GSK-3β, decreased the protein levels of G6Pase and SREBP-1c, and increased protein levels of GCK, LDLR, and phosphorylated IRS in livers and HepG2 cells. Overall, the results indicate that polydatin regulates glucose and lipid metabolism in experimental diabetic models, the underlying mechanism is probably associated with regulating the Akt pathway. The effect of polydatin on increased Akt phosphorylation is independent of prompting insulin secretion, but dependent of increasing IRS phosphorylation.
- Celastrol suppresses obesity process via increasing antioxidant capacity and improving lipid metabolism. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Oct 7.
High fat diet, as an important risk factor, plays a pivotal role in atherosclerotic process. Celastrol is one of the active triterpenoid compounds with antioxidative and anti-inflammatory characters. The aims of this study were to evaluate the effect of celastrol on weight, blood lipid and oxidative injury induced by high fat emulsion, and investigate its potential pharmacological mechanisms. Male Sprague-Dawley rats were fed with high fat emulsion for 6wk to mimic high fat mediated oxidative injury. The effects of celastrol on weight and blood lipid were evaluated, and its mechanisms were disclosed by applying western blot, ELISA and assay kits. Long-term consumption of high fat emulsion could significantly increase weight by enhancing total cholesterol (TC), triacylglycerol (TG), apolipoprotein B (Apo B), low-density lipoprotein cholesterol (LDL-c) levels, attenuating ATP-binding cassette transporter A1 (ABCA1) expression, and decreasing the levels of high-density lipoprotein cholesterol (HDL-c) and apolipoprotein A-I (Apo A-I), and inhibit antioxidant enzymes activities, improve nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Comparing with model group, celastrol was able to effectively suppress weight and attenuate high fat mediated oxidative injury by improving ABCA1 expression, reducing the levels of TC, TG, LDL-c and Apo B in plasma, and increasing antioxidant enzymes activities and inhibiting NADPH oxidase activity, and decreasing the serum levels of Malondialdehyde (MDA) and reactive oxygen species in dose-dependent way. These data demonstrated that celastrol was able to effectively suppress weight and alleviate high-fat mediated cardiovascular injury via mitigating oxidative stress and improving lipid metabolism.
- Modulation of cGMP accumulation by adenosine A1 receptors at the hippocampus: Influence of cGMP levels and gender. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Oct 7.
Adenosine A1 receptor is highly expressed in hippocampus where it inhibits neurotransmitter release and has neuroprotective activity. Similar actions are obtained by increasing cGMP concentration, but a clear link between adenosine A1 receptor and cGMP levels remains to be established. The present work aims to investigate if cGMP formation is modulated by adenosine A1 receptors at the hippocampus and if this effect is gender dependent. cGMP accumulation, induced by phosphodiesterases inhibitors Zaprinast (100μM) and Bay 60-7550 (10μM), and cAMP accumulation, induced by Forskolin (20μM) and Rolipram (50μM), were quantified in rat hippocampal slices using specific enzymatic immunoassays. N6-cyclopentyladenosine (CPA, 100nM) alone failed to modify basal cGMP accumulation. However, the presence of adenosine deaminase (ADA, 2U/ml) unmasked a CPA (0.03-300nM) stimulatory effect on basal cGMP accumulation (EC50: 4.2±1.4nM; Emax: 17±0.9%). ADA influence on CPA activity was specific for cGMP, since inhibition of cAMP accumulation by CPA was not affected by the presence of ADA, though ADA inhibited cAMP accumulation in the absence of CPA. Increasing cGMP accumulation, by about four-fold, with sodium nitroprusside (SNP, 100μM) abolished the CPA (100nM) effect on cGMP accumulation in males but did not modify the effect of CPA in female rats. This effect was reversed by 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX, 100nM), indicating an adenosine A1 receptor mediated effect on cGMP accumulation. In conclusion, adenosine A1 receptors increase intracellular cGMP formation at hippocampus both in males and females under basal conditions, but only in females when cGMP levels are increased by SNP.
- Ondansetron, a 5HT3 receptor antagonist reverses depression and anxiety-like behavior in streptozotocin-induced diabetic mice: Possible implication of serotonergic system. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Oct 2.
Increased prevalence and high comorbidity of depression-like mood disorders and diabetes have prompted investigation of new targets and potential contributing agents. There is considerable evidence supporting the inconsistent clinical efficacy and persistent undesirable effects of existing antidepressant therapy for depression associated with diabetes. Therefore, the present study was aimed at investigating the effect of ondansetron, a selective 5HT3 receptor antagonist in attenuating depression and anxiety-like behavior comorbid with diabetes. Experimentally, Swiss albino mice were rendered diabetic by a single intraperitoneal (i.p.) injection of streptozotocin (STZ, 200mg/kg). After 8-weeks, diabetic mice received a single dose of vehicle/ondansetron (0.5 and 1mg/kg, p.o.)/fluoxetine (the positive control, 10mg/kg p.o.) for 28 days. Thereafter, behavioral studies were conducted to test depression-like behavior using forced swim test (FST) and anxiety-like deficits using hole-board and light-dark tests, followed by biochemical estimation of serotonin content in discrete brain regions. The results demonstrated that, STZ-induced diabetic mice exhibited increased duration of immobility and decreased swimming behavior in FST, reduced exploratory behavior during hole-board test and increased aversion to brightly illuminated light area in light-dark test as compared to non-diabetic mice, while ondansetron (similar to fluoxetine) treatment significantly reversed the same. Biochemical assay revealed that ondansetron administration attenuated diabetes-induced neurochemical impairment of serotonin function, indicated by elevated serotonin levels in discrete brain regions of diabetic mice. Collectively, the data indicate that ondansetron may reverse depression and anxiety-like behavioral deficits associated with diabetes in mice and modulation of serotonergic activity may be a key mechanism of the compound.
- Co-administration of the flavanol (-)-epicatechin with doxycycline synergistically reduces infarct size in a model of ischemia reperfusion injury by inhibition of mitochondrial swelling. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Oct 1.
(-)-Epicatechin (EPI) is cardioprotective in the setting of ischemia/reperfusion (IR) injury and doxycycline (DOX) is known to preserve cardiac structure/function after myocardial infarction (MI). The main objective of this study was to examine the effects of EPI and DOX co-administration on MI size after IR injury and to determine if cardioprotection may involve the mitigation of mitochondrial swelling. For this purpose, a rat model of IR was used. Animals were subjected to a temporary 45min occlusion of the left anterior descending coronary artery. Treatment consisted of a single or double dose of EPI (10mg/kg) combined with DOX (5mg/kg). The first dose was given 15min prior to reperfusion and the second 12h post-MI. The effects of EPI +/- DOX on mitochondrial swelling (i.e. mPTP opening) were determined using isolated mitochondria exposed to calcium overload and data examined using isobolographic analysis. To ascertain for the specificity of EPI effects on mitochondrial swelling other flavonoids were also evaluated. Single dose treatment reduced MI size by ∼46% at 48h and 44% at three weeks. Double dosing evidenced a synergistic, 82% reduction at 3 weeks. EPI plus DOX also inhibited mitochondrial swelling in a synergic manner thus, possibly accounting for the cardioprotective effects whereas limited efficacy was observed with the other flavonoids. Given the apparent lack of toxicity in humans, the combination of EPI and DOX may have clinical potential for the treatment of myocardial IR injury.
- Combination therapy with losartan and L-carnitine protects against endothelial dysfunction of streptozotocin-induced diabetic rats. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Oct 1.
Endothelial dysfunction is a critical factor during the initiation of diabetic cardiovascular complications and angiotensin II appears to play a pivotal role in this setting. The present study aimed to investigate whether the combination therapy with losartan and the nutritional supplement, L-carnitine can provide an additional protection against diabetes-associated endothelial dysfunction and elucidate the possible mechanism(s) underlying this effect. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) (60mg/kg) in rat. Effects of losartan (20mg/kg, orally, 3 months) and L-carnitine (200mg/kg, orally, 3 months) on tumor necrosis factor- (TNF)-α, oxidative stress parameters, endothelial nitric oxide synthase expression (eNOS), and vascular function were evaluated. Our results showed a marked increase in aortic superoxide anion (O2¯) production and serum malondialdehyde (MDA) level alongside attenuating antioxidant enzyme capacities in diabetic rats. This was associated with a significant increase in anigiotensin II type 1 receptor gene expression and TNF-α serum level of diabetic rats alongside reducing aortic eNOS gene expression and nitric oxide (NO) bioavailability. The single or combined administration of losartan or L-carnitine significantly inhibited these changes. Additionally, the vascular endothelium-dependent relaxation with acetylcholine (ACh) in aortic diabetic rat was significantly ameliorated by the single and combined administration of losartan or L-carnitine. Noteworthy, the combination therapy exhibited a more profound response over the monotherapy. Collectively, our results demonstrate that the combined therapy of losartan and L-carnitine affords additive beneficial effects against diabetes-associated endothelial dysfunction, possibly via normalizing the dysregulated eNOS and reducing the inflammation and oxidative stress in diabetic rats.
- Citral inhibits lipopolysaccharide-induced acute lung injury by activating PPAR-γ [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Sep 30.
Citral, a component of lemongrass oil, has been reported to have many pharmacological activities such as anti-bacterial and anti-inflammatory effects. However, the effects of citral on acute lung injury (ALI) and the molecular mechanisms have not been reported. The aim of this study was to detect the effects of citral on lipopolysaccharide (LPS)-induced acute lung injury and investigate the molecular mechanisms. LPS-induced acute lung injury model was used to detect the anti-inflammatory effect of citral in vivo. The alveolar macrophages were used to investigate the molecular mechanism of citral in vitro. The results showed that pretreatment with citral remarkably attenuated pulmonary edema, histological severities, TNF-α, IL-6 and IL-1β production in LPS-induced ALI in vivo. In vitro, citral inhibited LPS-induced TNF-α, IL-6 and IL-1β production in alveolar macrophages. LPS-induced NF-κB activation was also inhibited by citral. Furthermore, we found that citral activated PPAR-γ and the anti-inflammatory effects of citral can be reversed by PPAR-γ antagonist GW9662. In conclusion, this is the first to demonstrate that critral protects LPS-induced ALI in mice. The anti-inflammatory mechanism of citral is associated with activating PPAR-γ, thereby inhibiting LPS-induced inflammatory response.