Rosmarinic acid ameliorates the complications of monocrotaline-induced right ventricular hypertrophy on the left ventricle: Investigating the signaling pathway of Wnt/ß-catenin in the heart.

Objectives: Right ventricular hypertrophy (RVH) often results in failure of the right ventricle or even the left ventricle. Rosmarinic acid (RA), a natural polyphenol, is commonly found in Boraginaceae species and some species of ferns and hornworts. This study looked at how RA affects oxidative stress and left ventricular hemodynamic functions as well as RVH in monocrotaline (MCT) induced RVH model rats. Materials and Methods: To cause RVH, MCT (60 mg/kg) was intraperitoneally (IP) injected. Rats were given saline or RA (10, 15, and 30 mg/kg, gavage, over 21 days). In anesthetized rats, the lead II electrocardiogram was recorded. The hemodynamic functions of the isolated heart were measured using the Langendorff apparatus (at constant pressure). Investigations were made into the right ventricular hypertrophy index (RVHI), the activities of superoxide dismutase, catalase, glutathione, and Wnt and ß-catenin gene expressions in the left ventricle. H&E staining was used. Results: A significant decline in electrocardiogram parameters and anti-oxidant enzyme activities, an increase in QTc (Q-T corrected) intervals, MDA (Malondialdehyde), RVHI, and Wnt/ß-catenin gene expression, and also significant changes in the hemodynamic parameters were demonstrated in the MCT group. RA improved the above-mentioned factors. Conclusion: According to the findings, RA may act as a cardioprotective agent against cardiovascular complications brought on by RVH due to its capacity to boost the activity of cardiac anti-oxidant enzymes and decrease the expression of genes involved in vascular calcification.

The Role of Rosmarinic Acid in the Protection Against Inflammatory Factors in Rats Model With Monocrotaline-Induced Pulmonary Hypertension: Investigating the Signaling Pathway of NFκB, OPG, Runx2, and P-Selectin in Heart.

ABSTRACT: Shortness of breath and syncope are common symptoms of right ventricular failure caused by pulmonary arterial hypertension (PAH), which is the result of blockage and increased pressure in the pulmonary arteries. There is a significant amount of evidence supporting the idea that inflammation and vascular calcification (VC) are important factors in PAH pathogenesis. Therefore, we aimed to investigate the features of the inflammatory process and gene expression involved in VC in monocrotaline (MCT)-induced PAH rats. MCT (60 mg/kg, i.p.) was used to induce PAH. Animals were given normal saline or rosmarinic acid (RA) (10, 15, and 30 mg/kg, gavage) for 21 days. An increase in right ventricular systolic pressure was evaluated as confirming PAH. To determine the level of inflammation in lung tissue, pulmonary edema and the total and differential white blood cell counts in the bronchoalveolar lavage fluid were measured. Also, the expression of NFκB, OPG, Runx2, and P-selectin genes was investigated to evaluate the level of VC in the heart. Our experiment showed that RA significantly decreased right ventricular hypertrophy, inflammatory factors, NFκB, Runx2, and P-selectin gene expression, pulmonary edema, total and differential white blood cell count, and increased OPG gene expression. Therefore, our research showed that RA protects against MCT-induced PAH by reducing inflammation and VC in rats.

Dose-dependent renoprotective effect of vanillic acid on methotrexate-induced nephrotoxicity via its anti-apoptosis, antioxidant, and anti-inflammatory properties.

Methotrexate-induced nephrotoxicity is a medical emergency which is associated with a variety of side effects. Vanillic acid (VA), as an antioxidant, removes free radical oxygen to protect cell defense. Therefore, this study investigated VA's beneficial effects on nephrotoxicity induced by methotrexate through its anti-apoptosis, antioxidant, and anti-inflammatory properties. Our study included five groups of male Wistar rats (n = 8): sham, MTX (Methotrexate) group: rats receiving methotrexate (20 mg/kg, intraperitoneally) on Day 2. Moreover, the remaining groups consisted of animals that received vanillic acid (25, 50, and 100 mg/kg, orally for seven days) plus MTX on the 2nd day. The rats were deeply anesthetized on the eighth day to obtain blood and renal tissue samples. The results showed that MTX can increase blood urea nitrogen and creatinine. However, VA (50 and 100 mg/kg) improved renal function as approved by histological findings. Compared with MTX-treated rats, VA enhanced the contents of total antioxidant capacity (TAC) and reduced renal malondialdehyde (MDA). Moreover, VA reduced mRNA expressions of caspase-3 and Bcl-2-associated x protein (Bax) and caused mRNA overexpression of the renal B-cell lymphoma-2 (Bcl-2), and Nrf-2 (Nuclear factor erythroid 2-related factor 2) compared to the MTX group. Also, VA administration significantly reduced inflammatory agents. Overall, VA protects the kidneys against methotrexate-induced nephrotoxicity via anti-apoptosis, antioxidant, and anti-inflammatory properties. Our results revealed that the most effective dose of VA was 100 mg/kg.

Effect of Gallic Acid Pretreatment and SGK1 Enzyme Inhibition on Cardiac Function and Inflammation in a Rat Model of Ischemia-Reperfusion Injury.

Background: Serum and glucocorticoid-induced kinase 1 (SGK1) is an enzyme that may play an important role in ischemic-reperfusion (I/R) injury and myocardial dysfunction. Although many studies have been conducted on individual antioxidants, little attention has been paid to the effects of co-administration of an antioxidant with an SGK1 inhibitor on cardiac function after I/R. Methods: This study aimed to determine the effects of gallic acid (as an antioxidant) combined with an SGK1 inhibitor on I/R-induced cardiac dysfunction and inflammation. Sixty male Wistar rats were randomized into 6 groups, pretreated with gallic acid or vehicle for 10 days. Subsequently, the heart was isolated and exposed to I/R. In groups that received the SGK1 inhibitor, the heart was perfused with the SGK1 inhibitor GSK650394, 5 min before induction of ischemia. After that, cardiac function, inflammatory factors, and myocardial damage were evaluated. Results: The combination of these two compounds improved cardiac contractility, heart rate, rate pressure product, left ventricular developed pressure, left ventricular systolic pressure, perfusion pressure, and QRS voltage significantly (P < 0.05). In addition, concomitant therapy of these two agents reduced tumor necrosis factor-alpha and interleukin-6, and the activity of creatine kinase-MB, lactate dehydrogenase, and troponin-I (P < 0.05). Conclusion: The results indicated that administration of gallic acid with the SGK1 inhibitor may have a potentiating effect on the improvement of cardiac dysfunction and I/R-induced inflammation.

The renoprotective effects of hesperidin on kidney injury induced by exposure to severe chronic dust storm particulate matter through inhibiting the Smads/TGF-ß1 signaling in rat.

Exposure to dust storm particulate matter (PM) is detrimental to kidney tissue. In this study, the impacts of chronic intake of dusty PM were explored as a major objective in a specified compartment to make a real-like dust storm (DS) model, and the role of hesperidin (HSP) as an antioxidant on kidney tissue was assessed in rats. Thirty-two male Wistar rats (200-220 g) were randomly allocated into 4 groups: CA+NS: (clean air and normal saline as a vehicle of HSP). Dusty PM and NS (DS+NS). HSP+ CA: rats received 200 mg/kg of HSP by gavage for 28 days, once daily in addition to exposure to clean air. HSP+DS: HSP plus DS. In DS groups, the animals were exposed to dust storms at a concentration of 5000-8000 µg/m3 in the chamber for 1 h daily, for 4 consecutive weeks, except Thursdays and Fridays. At the end of the experiment, the animals were sacrificed for biochemical, inflammatory, oxidative stress, molecular parameters, and histological evaluation. DS significantly enhanced blood urea nitrogen and creatinine, inflammatory (tumor necrosis factor-α, and interleukin-1ß), and oxidative stress indexes. Likewise, a significant increase was seen in mRNA Smads, collagen-I, and transforming growth factor-ß1 (TGF-ß1) expressions in the kidney. Histological findings showed contracted glomeruli and kidney structure disorder. In addition, Masson's trichrome staining demonstrated renal fibrosis. Nevertheless, HSP could significantly reverse these changes. Our data confirmed that DS results in kidney fibrosis through enhancing Smads/TGF-ß1 signaling. However, HSP was able to inhibit these changes as confirmed by histological findings.

The renoprotective effects of gallic acid on cisplatin-induced nephrotoxicity through anti-apoptosis, anti-inflammatory effects, and downregulation of lncRNA TUG1.

Cisplatin, an antineoplastic drug used in cancer therapy, -induced nephrotoxicity mediated by the production of reactive oxygen species (ROS). Gallic acid (GA) is identified as an antioxidant substance with free radical scavenging properties. This research was designed to examine the ameliorative impact of GA caused by cisplatin-induced nephrotoxicity through apoptosis and long non-coding RNA (lncRNA) Taurine-upregulated gene 1 (TUG1) expression. Thirty-two male Sprague Dawley rats (200 - 220 g) were randomly allocated to four groups: (1) control group; (2) rats treated with cisplatin (7.5 mg/kg, i.p.) on the fourth day; and the two other groups include rats pretreated with GA (20 and 40 mg/kg by gavage) for s7 days and cisplatin (7.5 mg/kg, i.p.) at the fourth day. The rats were anesthetized and sacrificed for collecting samples, 72 h after cisplatin administration. The blood samples were used to investigate biochemical factors and kidney tissue was evaluated for measuring oxidative stress and inflammatory factors and the gene expression of molecular parameters. The results indicated that GA administration increased the B-cell lymphoma-2 (Bcl-2) mRNA and lncRNA TUG1 expression, and reduced Bcl-2-associated x protein (Bax), and caspase-3 expression. Likewise, the TAC level increased, and kidney MDA content decreased by administration of GA. GA also decreased the inflammatory factor levels, including IL-1ß and TNF-α. Moreover, GA led to the improvement of kidney dysfunction as evidenced by reducing plasma BUN (blood urea nitrogen) and Cr (creatinine). Taken together, GA could protect the kidney against cisplatin-induced nephrotoxicity through antioxidant, anti-inflammatory, and anti-apoptosis properties and reduction of lncRNA TUG1 expression.

A new combination of naringin and trimetazidine protect kidney Mitochondria dysfunction induced by renal Ischemia / Reperfusion injury in rat

Abstract Ischemia/reperfusion (IR) injury leads to overproduction of Reactive Oxygen Species (ROS), and disrupts membrane potential that contributes to cell death. The aim of this study was to determine if naringin (NAR), trimetazidine (TMZ) or their combination, protect the kidney mitochondrial from IR injury. Forty rats were randomly allocated into five groups, harboring eight rats each: Sham, IR, NAR (100 mg/kg), TMZ (5 mg/kg) and NAR plus TMZ. Ischemia was induced by obstructing both renal pedicles for 45 min, followed by reperfusion for 4 hours. The mitochondria were isolated to examine the ROS, Malondialdehyde (MDA), Glutathione (GSH), mitochondrial membrane potential (MMP) and mitochondrial viability (MTT). Our findings indicated that IR injury resulted in excessive ROS production, increased MDA levels and decreased GSH, MMP and MMT levels. However, NAR, TMZ or their combination reversed these changes. Interestingly, a higher protection was noted with the combination of both, compared to each drug alone. We speculate that this combination demonstrates a promising process for controlling renal failure, especially with the poor clinical outcome, acquired with NAR alone. This study revealed that pretreatment their combination serves as a promising compound against oxidative stress, leading to suppression of mitochondrial stress pathway and elevation of GSH level.

Naringin and trimetazidine improve baroreflex sensitivity and nucleus tractus solitarius electrical activity in renal ischemia-reperfusion injury / Naringin and trimetazidine improve baroreflex sensitivity and nucleus tractus solitarius electrical activity in renal ischemia-reperfusion injury

Resumo Fundamento: O núcleo do trato solitário (NTS) é uma área do cérebro que desempenha um papel fundamental na regulação renal e cardiovascular através dos impulsos dos barorreceptores. Objetivos: O objetivo deste estudo foi avaliar o efeito da Naringina (NAR) e trimetazidina (TMZ), isoladamente e combinadas, na atividade elétrica do NTS e na sensibilidade barorreflexa (SBR) na lesão de isquemia e reperfusão (I/R) renal. Métodos: Foram utilizados quarenta ratos machos Sprague-Dawley (200-250 g), alocados em 5 grupos com 8 ratos cada. Grupos: 1) Sham; 2) I/R; 3) TMZ 5 mg/kg; 4) NAR 100 mg/kg; e 5) TMZ5 + NAR100. A veia femoral esquerda foi canulada para infundir a solução salina ou droga e avaliar a SBR. A I/R foi induzida por oclusão dos pedículos renais por 45 min, seguida de reperfusão de 4 horas. O eletroencefalograma local do NTS foi registrado antes, durante a isquemia e durante a reperfusão. A fenilefrina foi injetada por via intravenosa para avaliar a SBR ao final do tempo de reperfusão. Os dados foram analisados por ANOVA de duas vias com medidas repetidas seguida pelo teste post hoc de Tukey. Um valor de p<0,05 foi considerado como significativo. Resultados: As ondas elétricas do NTS não se alteraram durante o tempo de isquemia, mas diminuíram significativamente durante todos os tempos de reperfusão. A atividade elétrica do NTS e a SBR foram reduzidas drasticamente em ratos com lesão I/R; no entanto, a administração de NAR e TMZ, isoladamente e combinadas, melhorou significativamente essas alterações em ratos com lesão I/R. Conclusões: Os resultados mostraram que a lesão de I/R leva à redução da atividade elétrica da SBR e do NTS, e pode haver uma ligação entre a I/R e a diminuição da SBR. Além disso, a NAR e a TMZ são agentes promissores para tratar complicações de I/R.

Abstract Background: Nucleus tractus solitarius (NTS) is a brain area that plays a key role in kidney and cardiovascular regulation via baroreceptors impulses. Objectives: The aim of this study was to evaluate the effect of naringin (NAR) and trimetazidine (TMZ) alone and their combination on NTS electrical activity and baroreceptor sensitivity (BRS) in renal ischemia- reperfusion (I/R) injury. Methods: Forty male Sprague-Dawley rats (200- 250 g) were allocated into 5 groups with 8 in each. 1) Sham; 2) I/R; 3) TMZ 5 mg/kg; 4) NAR 100 mg/kg; and 5) TMZ5+ NAR100. The left femoral vein was cannulated to infuse saline solution or drug and the BRS was evaluated. I/R was induced by occlusion of renal pedicles for 45 min, followed by 4 hours of reperfusion. The NTS local electroencephalogram (EEG) was recorded before, during ischemia and throughout the reperfusion. Phenylephrine was injected intravenously to evaluate BRS at the end of reperfusion time. The data were analyzed by two-way repeated measurement ANOVA followed by Tukey's post hoc test. A p-value <0.05 was considered significant. Results: NTS electrical waves did not change during ischemia time, while they significantly decreased during the entire reperfusion time. NTS electrical activity and BRS dramatically reduced in rats with I/R injury; however, administration of NAR, TMZ alone or their combination significantly improved these changes in rats with I/R injury. Conclusions: The results showed that I/R injury leads to reduced BRS and NTS electrical activity and there may be an association between I/R and decreased BRS. In addition, NAR and TMZ are promising agents to treat I/R complications.

Neuroprotective Effects of Chrysin Mediated by Estrogenic Receptors Following Cerebral Ischemia and Reperfusion in Male Rats.

INTRODUCTION: Ischemic stroke is one of the leading causes of morbidity and mortality worldwide. Neuroprotective strategies were reported to attenuate cognitive deficits after ischemic incidents. Here we studied the neuroprotective potential of chrysin in a rat model of cerebral Ischemia/Reperfusion (I/R) in the presence or absence of Estrogen Receptors (ERs). METHODS: Adult male Wistar rats were pretreated with chrysin (CH) (CH; 30 mg/kg; gavage; for 21 consecutive days) alone or with selective ERs antagonists (ERα antagonist MPP; ERß antagonist PHTPP; IP) or nonselective ERs antagonist (ICI182780; IP). Then, the bilateral common carotid arteries were occluded for 20 min, which was followed by 72 h reperfusion. Subsequently, cognitive performance was evaluated by Morris Water Maze (MWM) and shuttle box tasks, and afterward, their hippocampi were removed for ELISA assays and H&E staining. Oxidative indicators Malondialdehyde (MDA) and Glutathione Peroxidase (GPx), as well as inflammation mediators interleukin (IL)-1ß and tumor necrosis factor-alpha (TNFα), were measured using commercial kits. RESULTS: Results of the current study showed that the anti-oxidative and anti-inflammatory properties of CH are possible mechanisms that could improve cognitive deficits and prevent neuronal cell death following I/R (P<0.001). These effects were reversed by ICI182780 (P>0.05). Furthermore, when chrysin was co-treated with ERß antagonist, PHTPP showed a weak neuroprotective effect in I/R rats. However, these parameters were not significantly different when chrysin was combined with ERα antagonist MPP. CONCLUSION: Our data confirm that chrysin could potentially serve as a neuroprotective agent against devastating effects of cerebral I/R injury, which may be mediated via its interaction with ERs, especially ERß.

Does gallic acid improve cardiac function by attenuation of oxidative stress and inflammation in an elastase-induced lung injury?

OBJECTIVES: Cardiovascular disease has an important role in mortality caused by lung injury. Emphysema is associated with impaired pulmonary gas exchange efficiency and airflow limitation associated with small airway inflammation. The aim was to evaluate the interactions between lung injury, inflammation, and cardiovascular disease. Since gallic acid has antioxidant and anti-inflammatory effects, we hypothesized that gallic acid protects the lung and the related heart dysfunction in elastase-induced lung injury. MATERIALS AND METHODS: Forty-eight Sprague-Dawley male rats were randomly divided into six groups: Control, Porcine pancreatic elastase (PPE) , PPE+GA, and 3 groups for different doses of gallic acid (GA 7.5, GA 15, GA 30 mg/kg). PPE was injected intra-tracheally on days 1 and 10 of the test. In each group, electrocardiography, hemodynamic parameters, oxidative stress, and bronchoalveolar lavage fluid were examined. RESULTS: PPE administration showed a decrease in HR and QRS voltage of electrocardiogram parameters, as well as in hemodynamic parameters (P<0.05, P<0.01, and P<0.001) and superoxide dismutase (SOD) (P<0.05). Tumor Necrosis Factor α (TNF-α) (P<0.001), interleukin 6 (IL-6) (P<0.001), interleukin 6 (MDA) (P<0.001), and the total number of white blood cells (P<0.001) showed an increase in PPE groups. Gallic acid preserved the values of hemodynamic properties, oxidative stress, inflammation, and electrocardiogram parameters in comparison to the PPE group. CONCLUSION: Briefly, this study showed the valuable effect of gallic acid in cardiac dysfunction related to elastase-induced lung injury. These findings suggested that gallic acid, as a natural antioxidant, has a potential therapeutic effect on preventing oxidative stress, inflammation, and subsequent cardiovascular disease.

Ellagic Acid Ameliorates Lung Inflammation and Heart Oxidative Stress in Elastase-Induced Emphysema Model in Rat.

Chronic obstructive pulmonary disease (COPD) is one of the most important factors in the progress of cardiovascular disease (CVD) which is associated with limited airflow and alveolar demolition. The aim of this study is to investigate the possible protective effect of ellagic acid (EA), as a natural anti-oxidant, against pulmonary arterial hypertension (PAH) and development of lung and heart injuries induced by elastase. Sixty healthy male Sprague-Dawley rats (150-180 g) were divided into six groups: control (saline 0.9%, 1 ml/kg, by gavage), porcine pancreatic elastase (PPE) (25 UI/kg, intratracheal), EA (10, 15, and 30 mg/kg, gavage), PPE + EA (30 mg/kg, by gavage). Lead II electrocardiogram was used to evaluate the inotropic and chronotropic parameters of rat heart using Bio-Amp device and the LabChart software. The anti-oxidant levels (superoxide dismutase, catalase, and glutathione) and malondialdehyde were measured by appropriate kits, and right ventricular systolic pressure (RVSP) was recorded by the PowerLab system and measured by the LabChart software (ADInstruments). Elastase administration caused an increase in RVSP which was in line with elevated inflammatory cells and cytokines, as well as lipid peroxidation, and decreased anti-oxidant levels. Also, electrocardiogram parameters significantly changed in elastase group compared with control rats. Co-treatment with EA not only restored elastase-depleted anti-oxidant levels and prevented pulmonary arterial hypertension but also improved cardiac chronotropic and inotropic properties. Our results documented that elastase administration leads to pulmonary arterial hypertension and EA, as an anti-inflammatory and anti-oxidant factor, can protect development of lung and heart injuries induced by elastase.

Trimetazidine Increases Plasma MicroRNA-24 and MicroRNA-126 Levels and Improves Dyslipidemia, Inflammation and Hypotension in Diabetic Rats.

Trimetazidine (TMZ) improves endothelial dysfunction. However, its beneficial effect on endothelial miRNAs is unexplored in diabetes. The aim of the present study was to evaluate the effects of TMZ on plasma miRNA-24 and miRNA-126, dyslipidemia, inflammation, and blood pressure in the diabetic rats. Adult male Sprague-Dawley rats were randomly assigned into four groups (250 ± 20 g, n = 8): a control (C), an untreated diabetic (D), a diabetic group administrated with TMZ at 10 mg/kg (T10), and a diabetic group administrated with TMZ at 30 mg/kg (T30) for eight weeks. Diabetes was induced by injection of alloxan (120 mg/kg). The plasma levels of miR-24, miR-126, lipid profile, malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), blood glucose, body weight and systolic blood pressure were measured. The diabetic rats showed decreased plasma miR-24, HDL-c (P < 0.05), miR-126 (P < 0.01), body weight changes percent, body weight, and systolic blood pressure (P < 0.001) and increased triglycerides (TG), VLDL-c (P < 0.05), TNF-α, total cholesterol (TC) (P < 0.01) glucose, MDA and IL-6 (P < 0.001). Interestingly, all these changes were significantly improved by TMZ treatment. Our findings propose that TMZ has protective effects on decreased plasma miR-24 and miR-126 levels, inflammation, dyslipidemia and hypotension, and it may participate in endothelial dysfunction and atherosclerosis.

Protective effects of Chrysin against memory impairment, cerebral hyperemia and oxidative stress after cerebral hypoperfusion and reperfusion in rats.

Stroke is devastating and a leading cause of morbidity and mortality worldwide. Cerebral ischemia-reperfusion and its subsequent reactive hyperemia lead to neuronal damage in the hippocampus and cognitive decline. Chrysin (5, 7-dihydroxyflavone) is a well-known member of the flavonoid family with antioxidant and neuroprotective effects. Therefore, in the present study, the aim was to investigate whether chrysin will be able to recover the brain function caused by ischemia-reperfusion (I/R) in rats. Adult male Wistar rats (250-300 g) were randomly divided into five groups: and submitted to cerebral I/R or a sham surgery after three-weeks of pretreatment with chrysin (CH; 10, 30 and 100 mg/kg; P.O.) and/or normal saline containing %5 DMSO. Subsequently, sensorimotor scores, cognition, local cerebral blood flow, extracellular single unit, and histological parameters were evaluated following I/R. Hippocampus was used to evaluate biomarkers including: oxidative stress parameters and prostaglandin E2 (PGE2) using ELISA kits. Data showed that pretreatment with chrysin significantly improved sensorimotor signs, passive avoidance memory, and attenuated reactive hyperemia, and increased the average number of spikes/bin (p < 0.001). Furthermore, chrysin pre-treatment significantly decreased the levels of MDA, NO, and PGE2 (p < 0. 001), while increased the levels of GPX and the number of surviving cells in the hippocampal CA1 region (p < 0.01, p < 0.001; respectively). This study demonstrates that chrysin may have beneficial effects in the treatment of cognitive impairment and help recover the brain dysfunction induced by I/R.

The Association of Cigarette Smoke Exposure with Lung Cellular Toxicity and Oxidative Stress: the Protective Role of Crocin.

Cigarette smoke (CS) contains many free radicals and toxic chemicals. Nuclear erythroid-related factor-2 (Nrf2) is a transcriptional regulator of several phase II antioxidant genes, including glutamate-cysteine ligase (GCL). In this study, it was hypothesized that Crocin may mediate antioxidant signaling pathway to protect human lung epithelial cells against CS-mediated toxicity and oxidative stress via inducing glutathione (GSH) biosynthesis and activation of Nrf2 pathway. Alveolar epithelial cells (A549) were exposed to 1, 2.5 and 5% cigarette smoke extracts (CSE) with or without Crocin (500 µM). After 48 h exposure, the cytotoxicity, oxidant/antioxidant parameters and the Nrf2 pathway modification were assayed. Treatment of A549 cells with all concentrations of CSE dose dependently decreased cell viability, antioxidant levels, GCL and Nrf2 gene expression, which was associated with increased production of reactive oxygen species. Crocin not only restored CSE-depleted GSH levels by enhancing GCL expression via activation of Nrf2 but also quenched the CSE-generation and release of reactive oxygen species. Crocin attenuated CSE-mediated Nrf2 modifications, thereby inducing its nuclear accumulation associated with GCL gene transcription leading to enhanced GSH levels. By inducing GSH synthesis, Crocin attenuates CSE-mediated GSH depletion and protects cells against CSE-induced oxidative stress via Nrf2 pathway. These results may have implications in dietary modulation of natural antioxidants in treatment of pulmonary diseases.

p-Coumaric acid protects cardiac function against lipopolysaccharide-induced acute lung injury by attenuation of oxidative stress.

OBJECTIVES: Acute lung injury (ALI) has a high mortality rate and is characterized by damage to pulmonary system giving rise to symptoms such as histological alteration, lung tissue edema and production of proinflammatory cytokine. p-Coumaric acid (p-CA), as a phenolic compound, that is found in many types of fruits and vegetables has been reported to exhibit a therapeutic effect in several inflammatory disorders. The aim of our study was evaluation of pretreatment with p-CA against heart dysfunction, oxidative stress and nuclear factor-erythroid 2 -related factor 2 (Nrf2) modifications following lipopolysaccharide (LPS)-induced acute lung inflammation. MATERIALS AND METHODS: The rats were divided into four groups (n=8): Control, LPS (5 mg/kg, it), p-CA (100 mg/kg, IP), and LPS+pCA. Inflammatory response and oxidative stress were evaluated by measurement of interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α) and malondialdehyde (MDA) levels in heart tissue. For evaluation of the effect of LPS on cardiac response, electrocardiography (ECG) and hemodynamic parameters were recorded. RESULTS: A significant increase in lipid peroxidation (P<0.001, cytokine parameters (TNF-α and IL-6 (P<0.01), gene expression of Nrf2 (P<0.05), and antioxidant activity of superoxide dismutase and glutathione (P< 0.05) in addition to glutathione peroxidase (P<0.01) was demonstrated in heart tissue of ALI rats. LPS can impair cardiac function (in in vitro measurement of hemodynamic parameters by using Langendorff setup, and in in vivo measurement of ECG parameters), and pretreatment with p-CA recovered these parameters to control levels in heart. Pretreatment with p-CA causes modulation of cytokines and MDA level that protected cardiac injury caused by LPS in ALI model. CONCLUSION: Our results showed anti-inflammatory and antioxidative effect of p-CA on LPS-induced ALI.

A new method to induce nonalcoholic steatohepatitis (NASH) in mice.

BACKGROUND: General overnutrition is one of the key factors involved in the development of nonalcoholic fatty liver disease (NAFLD) as the most common liver disease occur by two steps of liver injury ranges from steatosis to nonalcoholic steatohepatitis (NASH). Here the effect of fructose, fat-rich and western diet (WD) feeding was studied along with aggravative effect of cigarette smoking on liver status in mice. METHODS: Sixty-four male NMRI mice were included in this study and assigned into 4 groups that fed standard, fructose-rich, high fat-, and western-diet for 8 weeks and then each group divided in two smoker and nonsmoker subgroups according to smoke exposing in the last 4 weeks of feeding time (n = 8). Histopathological studies, serum biochemical analyses and hepatic TNF-α level were evaluated in mice to compare alone or combination effects of dietary regimen and cigarette smoking. RESULTS: Serum liver enzymes and lipid profile levels in WD fed mice were significantly higher than in other studied diets. Exposing to cigarette smoke led to more elevation of serum biochemical parameters that was also accompanied by a significant increase in hepatic damage shown as more severe fat accumulation, hepatocyte ballooning and inflammation infiltrate. Elevated TNF-α level confirmed incidence of liver injury. CONCLUSION: The finding of this study demonstrated that a combination of cigarette smoke exposure and WD (rich in fat, fructose, and cholesterol) could induce a more reliable mouse model of NASH.

Ellagic acid protects against diabetes-associated behavioral deficits in rats: Possible involved mechanisms.

AIMS: Diabetes mellitus (DM), a chronic metabolic disease, is associated with behavioral deficits. It has been suggested that ellagic acid (EA), a natural polyphenol compound, has potent anti-diabetic, anti-inflammatory, and neuroprotective properties. The present study was aimed to explore the potential protective effects of EA against diabetes-associated behavioral deficits and verified possible involved mechanisms. MAIN METHODS: Fifty adult male Wistar rats were randomly divided into five groups: i.e., CON: normal rats treated with vehicle (5 ml/kg/day; P.O.), EA: normal rats treated with EA (50 mg/kg/day; P.O.), STZ: diabetic rats treated with vehicle (5 ml/kg/day; P.O.), STZ + INS: diabetic rats treated with insulin (6 IU/rat/day; S.C.), STZ + EA: diabetic rats treated with EA (50 mg/kg/day; P.O.). All the groups were under treatment for eight consecutive weeks. During the seventh and eighth weeks, behavioral functions of the rats were assessed by commonly used behavioral tests. Subsequently, pro- and anti-inflammatory cytokines, neurotrophic factors, and also histological changes were evaluated in both cerebral cortex and hippocampus of the rats. KEY FINDINGS: Chronic EA treatment attenuated anxiety/depression-like behaviors, improved exploratory/locomotor activities, and ameliorated cognitive deficits in diabetic rats. These results were accompanied by decreased blood glucose levels, modulation of inflammation status, improved neurotrophic support, and amelioration of neuronal loss in diabetic rats. In some aspects, treatment with EA was even more effective than insulin therapy. SIGNIFICANCE: The current work's data confirms that EA could potentially serve as a novel, promising, and accessible protective agent against diabetes-associated behavioral deficits, owing to its anti-hyperglycemic, anti-inflammatory, and neurotrophic properties.

Chrysin prevents cognitive and hippocampal long-term potentiation deficits and inflammation in rat with cerebral hypoperfusion and reperfusion injury.

INTRODUCTION: Ischemic stroke is one of the leading causes of death worldwide, and extensive efforts have focused on the neuroprotective strategies to minimize complications due to ischemia. This study aimed to examine neuroprotective potential of chrysin, as a natural potent antioxidative and anti-inflammatory agent in an animal model of bilateral common carotid artery occlusion and reperfusion (BCCAO/R). METHODS: Adult male Wistar rats (250-300 g) were randomly divided into 6 groups and submitted to either sham surgery or BCCAO/R after pretreatment with chrysin (10, 30 and 100 mg/kg, once daily, for 21 consecutive days) or saline containing %5 DMSO. To make the animal model of BCCAO/R, bilateral common carotid arteries were occluded for 20 min, followed by reperfusion. Subsequently, spatial cognitive performance was evaluated in a Morris water maze (MWM), hippocampal long-term potentiation (LTP) was recorded from hippocampal dentate gyrus region, after then the hippocampal tissue content of IL-1ß and TNF-α were assayed using ELISA kits. RESULTS: The results showed that pretreatment with chrysin significantly prevented BCCAO/R-induced cognitive and hippocampal LTP impairments (p < 0.001). Additionally, BCCAO/R- induced elevation in hippocampal content of IL-1ß and TNF-α significantly (p < 0.01, p < 0.01 respectively) while pre-treatment with chrysin restored them (p < 0.01). CONCLUSION: Our data confirm that chrysin could prevent brain inflammation and thereby prevents cognitive and LTP impairments due to cerebral ischemia. So it could be a promising neuroprotective agent against cerebrovascular insufficiency states.

Evaluation of the therapeutic potential effect of Fas receptor gene knockdown in experimental model of non-alcoholic steatohepatitis.

Aim: Stimulation of Fas death receptor is introduced as a major cause of non-alcoholic steatohepatitis (NASH) progression through suppression of cell viability. Therefore, the blocking of death pathways is hypothesised to be express new approaches to NASH therapy. For this purpose, current experiment applied synthetic small interference RNA (SiRNA) to trigger Fas death receptor and to show its potential therapeutic role in designed NASH model. Methods: Male mice were placed on a western diet (WD) for 8 weeks and exposed to cigarette smoke during the last 4 weeks of feeding to induce NASH model. In the next step, Fas SiRNA was injected to mice aiming to examine specific Fas gene silencing, after 8 weeks. As a control, mice received scrambled SiRNA. Reversible possibility of disease was examined by 3 weeks of recovery. Results: Analysis of data is accompanied with the significant histopathological changes (steatosis, ballooning and inflammation), increased lipid profile and hepatic enzyme activities (AST, ALT, ALP) plus TBARS as well as decreased antioxidants levels in NASH model. Upon Fas-SiRNA injection, almost all measured parameters of NASH such as overexpression of Fas receptor, caspase3, NF-kB genes and marked increase of hepatic TNF-α were significantly restored and were remained nearly unchanged following recovery liking as scrambled groups. Conclusions: The suppression of Fas receptor signalling subsequent RNAi therapy may represent an applicable strategy to decline hepatocyte damages and so NASH progression in mice.