Inhaled paraquat-induced lung injury in rat, improved by the extract of Zataria multiflora boiss and PPARγ agonist, pioglitazone.

The effects of a PPAR-γ agonist, pioglitazone and Zataria multiflora (Z. multiflora) on inhaled paraquat (PQ)-induced lung oxidative stress, inflammation, pathological changes and tracheal responsiveness were examined. The study was carried out in control rats exposed to normal aerosol of saline, PQl and PQh groups exposed to aerosols of 27 and 54 mg/m3 PQ, groups exposed to high PQ concentration (PQh) and treated with 200 and 800 mg/kg/day Z. multiflora, 5 and 10 mg/kg/day pioglitazone, low doses of Z. multiflora + pioglitazone, and 0.03 mg/kg/day dexamethasone. Increased tracheal responsiveness, transforming growth factor beta (TGF-ß) and lung pathological changes due to PQh were significantly improved by high doses of Z. multiflora and pioglitazone, dexamethasone and extract + pioglitazone, (p < 0.05 to p < 0.001). In group treated with low doses of the extract + pioglitazone, the improvements of most measured variables were significantly higher than the low dose of two agents alone (p < 0.05 to p < 0.001). Z. multiflora improved lung injury induced by inhaled PQ similar to dexamethasone and pioglitazone which could be mediated by PPAR-γ receptor.

A novel approach towards obesity: The use of a bacterial product, gassericin A, in 3T3-L1 cells.

BACKGROUND AND OBJECTIVE: The problem of obesity and its related complications are adversely affecting human society. We studied the effects of gassericin A, a bacteriocin produced by the intestinal bacteria, on adipocyte differentiation and development. DESIGN: Gassericin A was purified from Lactobacillus gasseri LA39 and was added to the culture medium of 3T3-L1 cells in two phases: Phase 1, 3T3-L1 cells were incubated with gassericin A while being induced to adipocytes (days 1-7); phase 2, the cells were incubated with the bacteriocin after being induced to adipocytes (days 8-12). The resultant changes in the pattern of expression of some of the important genes involved in adipogenesis were evaluated by RT-qPCR. The viability of cells and their numbers were also studied. RESULTS: In phase 1 of the study, the levels of transcripts for stearoyl CoA desaturase (SCD-1), zinc finger protein 423 (zfp-423), and glucose transporter 4 (GLUT4) genes were significantly reduced, while that of 422ap2 gene showed a significant increment (p < 0.05). In phase 2, the zfp-423 gene showed a reduction of expression and the 422ap2 gene showed an increase in expression (p < 0.05). The other genes including UCP-1 and TNF-α did not show any significant changes in neither of the groups. Gassericin A did not affect the morphology or viability of the cells, however, the numbers of cells had nearly doubled in the treatment groups. CONCLUSION: It seems that gassericin A could significantly alter the properties of adipocytes while they are in the process of development and after they have developed.

Carvacrol and PPARγ agonist, pioglitazone, affects inhaled paraquat-induced lung injury in rats.

Exposed rats to normal saline and paraquat (PQ) aerosol as control and PQ group, rats exposed to PQ and treated with 20 and 80 mg/kg/day carvacrol, 5 and 10 mg/kg/day pioglitazone, low dose of pioglitazone + carvacrol and 0.03 mg/kg/day dexamethasone (Dexa) for 16 days after the end of PQ exposure were studied (n = 6 in each group). Lung pathological changes, tracheal responsiveness to methacholine and ovalbumin (OVA) as well as transforming growth factor beta (TGF-ß) and interleukin (IL)-6 level in the lung tissue homogenize as well as TGF-ß, IL-6, oxidant and antioxidant levels oxidant and antioxidants were increased in PQ group (p < 0.01 to p < 0.001). Lung pathological changes, tracheal responsiveness to methacholine and OVA as well as TGF-ß, IL-6 oxidant and antioxidant levels were improved in all treated groups except lung pathological changes in treated group with low dose of pioglitazone (p < 0.05 to p < 0.001). The effects of low dose of pioglitazone and carvacrol alone were significantly lower than in the combination group of low dose of pioglitazone + carvacrol (p < 0.05 to p < 0.001). Carvacrol treatment improved inhaled PQ-induced lug injury similar to the effects of dexamethasone. The synergic effect of carvacrol and pioglitazone suggests PPAR-γ receptor mediated effects of carvacrol on inhaled PQ-induced lung injury.

Immediate and late systemic and lung effects of inhaled paraquat in rats.

The immediate and the late effects of inhaled Paraquat (PQ) on systemic and lung inflammation and oxidative stress were investigated. Rats were exposed to saline (control group) and two doses of inhaled PQ (27 and 54 mg/m3) and studied variables were measured: 1) one day after the end of PQ exposure as "immediate condition", 2) 16 days after the end of PQ exposure as "late condition". Total and differential white blood cells (WBC) counts, lipid peroxidation and nitrite were increased but thiol, superoxide dismutase and catalase in the blood and BALF as well as methacholine EC50 was reduced in both conditions in the animals exposed to PQ compared to control groups (p < 0. 05 to p < 0.001). Most studied parameters in the immediate condition were significantly higher than the late condition (p < 0.05 to p < 0.001). Systemic and lung inflammation and oxidative stress due to inhaled PQ in both the immediate and the late conditions were shown. Although most measured parameters in the immediate condition were higher, all variables were significantly different with the control group even in late condition, indicating a long-term effect of inhaled PQ toxicity, which may help in a more effective treatment of PQ poising in the future.

Paraquat-induced systemic inflammation and increased oxidative markers in rats improved by Zataria multiflora extract and carvacrol.

OBJECTIVE: Paraquat (PQ) is a herbicide which induces oxidative stress and inflammation. Anti-inflammatory and anti-oxidant effects were shown for Zataria multiflora (Z. multiflora) and carvacrol previously. The effects of Z. multiflora hydroalcoholic extract and carvacrol on systemic inflammation and oxidative stress induced by inhaled PQ were examined in this study. MATERIALS AND METHODS: Six groups of male rats used in this study were as follows: control group exposed to normal saline aerosol, one group exposed to PQ 54 mg/m3 aerosol, animals exposed to PQ 54 mg/m3 and treated with Z. multiflora (200 and 800 mg/kg/day) or carvacrol (20 and 80 mg/kg/day) for 16 days after the end of exposure to PQ. Exposure to PQ was performed 8 times, every other day, each time for 30 min. After the end of the treatment period, different variables were measured. RESULTS: Significant increases in nitrite (NO2), malondialdehyde (MDA) and interleukin (IL)-6 serum levels but significant reduction of interferon-gamma (IFN-γ) serum levels as well as IFN-γ/IL-6 ratio were observed in PQ-exposed compared to control group (p<0.01 for MDA and IL-6, p<0.001 for other cases). Treatment with both doses of the extract and carvacrol specially at high dose, reduced MDA, NO2, and IL-6 but increased IFN-γ and IFN-γ/IL-6 ratio compared to un-treated PQ exposed group (p<0.05 to p<0.001). CONCLUSION: Treatment with Z. multiflora and carvacrol improved systemic inflammation oxidative biomarkers induced by inhaled PQ which may indicate therapeutic potential of the plant and its constituent, carvacrol in systemic inflammation and oxidative biomarkers induced by inhaled PQ.

Carvacrol and Zataria multiflora influenced the PPARγ agonist effects on systemic inflammation and oxidative stress induced by inhaled paraquat in rat.

OBJECTIVES: The effects of PPAR-γ agonist alone and in combination with carvacrol and Zataria multiflora on inhaled paraquat (PQ) induced-systemic inflammation and oxidative stress were examined. MATERIALS AND METHODS: Control group exposed to normal saline aerosol, one group exposed to 54 mg/m3 PQ aerosol and four groups exposed to PQ aerosol and treated with 5 mg/kg/day pioglitazone, pioglitazone + 200 mg/kg/day Z. multiflora extract, pioglitazone + 20 mg/kg/day carvacrol, and 0.03 mg /kg/day dexamethasone for 16 days after the end of exposure to PQ were studied. Exposure to normal saline or PQ was performed every other days for 30 min (8 times). Different variables were measured after the end of treatment period. RESULTS: PQ exposure significantly increased serum levels of NO2, MDA and IL-6 but dexreased CAT and IFN-γ levels and IFN-γ/IL-6 ratio compared to control group (P<0.01 to P<0.001). Treatment with pioglitazone only improved serum level of MDA (P<0.01). Treatment with combination of pioglitazone and carvacrol as well as treatment with dexamethasone improved all measured variables compared to PQ exposed group (P<0.05 to P<0.001). The effects of pioglitazone + Z. multiflura and pioglitazone + carvacrol on almost all measured variables were significantly higher than pioglitazone alone (P<0.05 to P<0.001). CONCLUSION: The effects of combination therapy of pioglitazone with Z. multiflora or carvacrol on inhaled paraquat (PQ) induced-oxidative stress and systemic inflammation were higher than the effects of pioglitazone alone. These results suggested that the effects of the extract and carvacrol may mediated through PPAR-γ receptors.

Cardioprotective effects of resveratrol following myocardial ischemia and reperfusion.

Resveratrol (RSV), a plant origin polyphenol, has shown beneficial cardiovascular effects. In this study, isolated hearts from male Wistar rats were studied using the Langendorff technique. Following 30 min stabilization, the hearts underwent 30 min global ischemia and 120 min reperfusion. The perfusion solution in the test group contained RSV (10 µM). Hemodynamics of the hearts, the markers of myocardial damage including creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and troponin I were studied during the study. Furthermore, the infarct size and the markers of oxidative stress including catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GPX) were assayed in the homogenates of the hearts. The release of nitrite from the hearts and the occurrence of ventricular arrhythmias were also monitored throughout the experiment. Resveratrol caused a significant improvement in the restoration of the mechanical performance of the hearts following myocardial ischemia and reperfusion (MIR). Besides, the infarct size, CK-MB, LDH, and troponin I declined in the test group. Besides, the cardiac release of nitrite increased, and the redox status of the heart was improved as indicated by the levels of CAT, SOD, GPX, and MDA. Finally, the treatment caused significant decreases in the occurrences of single and salvo arrhythmias, ventricular tachycardia, and ventricular fibrillation. The current study suggests strong cardioprotective and antiarrhythmic effects for RSV following MIR.

Nitric oxide plays a pivotal role in cardioprotection induced by pomegranate juice against myocardial ischemia and reperfusion.

Pomegranate juice (Pg) has demonstrated cardiovascular beneficial effects. The current research intends to investigate the roles of nitric oxide (NO) and antioxidants in Pg-induced cardioprotection against ischemia and reperfusion (I/R). Isolated hearts from anesthetized rats were subjected to 30-min global ischemia followed by 120-min reperfusion. The hearts in the test groups were treated with Pg, NG -nitro-L-arginine methyl ester (L-NAME) or both throughout the experiment. In Pg group, left ventricular developed pressure, rate of rise in left ventricular pressure (dp/dt max), and rate pressure product were 83%, 55%, and 127%, respectively, higher than those of the control group (p < 0.05). The infarct size declined to less than 40% (p < 0.0001), and biomarkers of myocardial damage including creatine kinase-MB, lactate dehydrogenase, and troponin-I, showed significant reductions (59%, 36%, and 94%, respectively) compared with the control. Furthermore, the indices of oxidative status including superoxide dismutase, glutathione peroxidase, catalase, and malondialdehyde showed significant improvement (2.4, 1.7, 1.9, and 2.4 fold, respectively). Most of these effects were mainly blocked by L-NAME. These results suggest potent cardioprotective effects for Pg against myocardial I/R injury. The current results suggest a key role for NO for this cardioprotection; however, other mechanisms seem to be also involved.

Cardioprotective Effects of Pomegranate (Punica granatum) Juice in Patients with Ischemic Heart Disease.

Ischemic heart disease is the leading cause of mortality worldwide. The purpose of this study was to evaluate the cardioprotective effects of pomegranate juice in patients with ischemic heart disease. One hundred patients, diagnosed with unstable angina or myocardial infarction, were randomly assigned to the test and the control groups (n = 50, each). During 5 days of hospitalization, in addition to the conventional medical therapies, the test groups received 220 mL pomegranate juice, daily. During the hospitalization period, the blood pressure, heart rate, as well as the intensity, occurrence, and duration of the angina were evaluated on a regular basis. At the end of the hospitalization period, the serum levels of malondialdehyde, interleukin-6, and tumor necrosis factor alpha were measured in all patients. The levels of serum troponin and high-sensitive C-reactive protein levels were also assayed in patients diagnosed with myocardial infarction. Pomegranate juice caused significant reductions in the intensity, occurrence, and duration of angina pectoris in patients with unstable angina. Consistently, the test patients had significantly lower levels of serum troponin and malondialdehyde. Other studied parameters did not change significantly. The results of this study suggest protective effects of pomegranate juice against myocardial ischemia and reperfusion injury. Copyright © 2017 John Wiley & Sons, Ltd.

Liver ischemia preconditions the heart against ischemia-reperfusion arrhythmias.

OBJECTIVES: This study aimed to examine the hypothesis that an antiarrhythmic effect might be obtained by ischemic preconditioning of the liver, and also to characterize the potential underlying mechanisms. MATERIALS AND METHODS: Male Wistar rats were anesthetized by thiopental sodium (50 mg/kg, IP) followed by IV injection of heparin (250 IU). Remote ischemic preconditioning (RIPC) was induced by 3 cycles of 5 min liver ischemia followed by 5 min of reperfusion. The hearts were excised within 5 min after the final cycle of preconditioning and perfused using Langendorff's system. The isolated perfused hearts were subjected to 30 min global ischemia followed by 90 min reperfusion. The myocardial arrhythmias induced by ischemia- reperfusion (I/R) were determined in accordance with the guidelines of Lambeth Conventions. The potential role of KATP channels on RIPC was assessed by injection of glibenclamide (nonselective KATP blocker) or 5-hydroxydecanoate (mitochondrial KATP blocker) on rats 30 and 15 min before induction of RIPC in the liver, respectively. RESULTS: Hepatic remote preconditioning of the heart significantly (P<0.0001) prevented the incidence of myocardial arrhythmias induced by I/R in the perfused hearts (5.33±1.54 vs. 32.33±6.44,). However, the protective effects of remote preconditioning was significantly (P<0.01) abolished by the KATP blocker, glibenclamide (25.5±4.9 vs. 5.33±1.54,). CONCLUSION: Hepatic RIPC may prevent the arrhythmias induced by I/R in the isolated perfused hearts via KATP channels.

Lack of effect of proteinase-activated receptor-2 (PAR-2) deletion on the pathophysiological changes produced by lipopolysaccharide in the mouse: comparison with dexamethasone.

This study tested the hypothesis that activation of proteinase-activated receptor-2 (PAR-2) contributes towards the pathophysiology of lipopolysaccharide (LPS)-induced shock in the mouse. The effects of LPS on plasma glucose, biochemical markers of hepatic, renal and pancreatic exocrine function and lung content of myeloperoxidase (MPO) were examined in homozygous PAR-2 knockout mice (PAR-2 -/-) and genetically equivalent, homozygous PAR-2 +/+ mice. The effect of LPS was also examined in normal mice receiving dexamethasone (10 mg kg(-1), i. p.) or saline as a positive control. At six hours after intraperitoneal injection, LPS (40 mg kg(-1)) produced an increase in rectal temperature, hypoglycaemia and elevations in serum concentrations of alanine aminotransferase (ALT), creatinine and lipase, as well as an increase in lung MPO content. Dexamethasone treatment reduced LPS-induced hypoglycaemia and elevation of serum ALT concentrations but did not modify elevations in serum creatinine and lipase concentrations or the increase in lung MPO content. The changes in serum concentrations of glucose, ALT, creatinine and lipase produced by LPS in PAR-2 -/- mice were not different from those seen in wild-type or PAR-2 +/+ mice. These data suggest that activation of PAR-2 may not play a pivotal role in LPS-induced multi-organ dysfunction.