Mohammed S. El-Awady

Agmatine ameliorates atherosclerosis progression and endothelial dysfunction in high cholesterol-fed rabbits.

The aim of this work was to explore possible effects of agmatine, an endogenous inhibitor of inducible nitric oxide synthase (iNOS), against hypercholesterolemia‐induced lipid profile changes and endothelial dysfunction.

Apocynin ameliorates endotoxin-induced acute lung injury in rats

Acute lung injury (ALI) is a serious clinical syndrome with a high rate of mortality. In this study, the effects of apocynin, a NADPH-oxidase (NOX) inhibitor on lipopolysaccharide (LPS)-induced ALI in rats were investigated. Male Sprague-Dawley rats were treated with apocynin (10mg/kg) intraperitoneally (i.p.) 1h before LPS injection (10mg/kg, i.p.). The results revealed that apocynin attenuated LPS-induced ALI as it decreased total protein content, lactate dehydrogenase (LDH) activity and the accumulation of the inflammatory cells in the bronchoalveolar lavage fluid (BALF), In addition, apocynin significantly increased superoxide dismutase (SOD) and reduced glutathione (GSH) activities with significant decrease in the lung malondialdehyde (MDA) content as compared to LPS group in lung tissue and decreased pulmonary artery contraction induced by LPS. It also upregulated mRNA expression of inhibitory protein kappaB-alpha (NFκBia) and downregulated mRNA expression of Toll-Like receptor 4 (TLR4) and decreased inflammation observed in lung tissues. Collectively, these results demonstrate the protective effects of apocynin against the LPS-induced ALI in rats through its antioxidant and antiinflammatory effect that may be attributed to the decrease in mRNA expression of TLR4 and increasing that of NFκBia.

Pomegranate protects liver against cecal ligation and puncture-induced oxidative stress and inflammation in rats through TLR4/NF‐κB pathway inhibition

Acute liver injury secondary to sepsis is a major challenge in intensive care unit. This study was designed to investigate potential protective effects of pomegranate against sepsis-induced acute liver injury in rats and possible underlying mechanisms. Pomegranate was orally given (800mg/kg/day) for two weeks before sepsis induction by cecal ligation and puncture (CLP). Pomegranate improved survival and attenuated liver inflammatory response, likely related to downregulation of mRNA expression of toll like recptor-4, reduced nuclear translocation and DNA binding activity of proinflammatory transcription factor NF-κB subunit p65, decreased mRNA and protein expression of tumor necrosis factor-alpha and reduction in myeloperoxidase activity and mRNA expression. Pomegranate also decreased CLP-induced oxidative stress as reflected by decreased malondialdehyde content, and increased reduced glutathione level and superoxide dismutase activity. These results confirm the antiinflammatory and antioxidant effects of pomegranate in CLP-induced acute liver injury mediated through inhibiting TLR4/NF-κB pathway, lipid peroxidation and neutrophil infiltration.

The ergogenic supplement β-hydroxy-β-methylbutyrate (HMB) attenuates insulin resistance through suppressing GLUT-2 in rat liver

This study investigates the effect of the ergogenic supplement β-hydroxy-β-methylbutyrate (HMB) on insulin resistance induced by high-fructose diet (HFD) in rats. Male Sprague Dawley rats were fed 60% HFD for 12 weeks and HMB (320 mg·kg(-1)·day(-1), orally) for 4 weeks. HFD significantly increased fasting insulin, fasting glucose, glycosylated hemoglobin (HBA1C), liver glycogen content, and homeostasis model assessment of insulin resistance (HOMA-IR) index, while it decreased glucose and insulin tolerance. Furthermore, HFD significantly increased serum triglycerides (TG), low density lipoprotein cholesterol (LDL-C), and very low density lipoprotein cholesterol (VLDL-C) levels, while it significantly decreased high density lipoprotein cholesterol (HDL-C). Moreover, HFD significantly increased mRNA expression of glucose transporter type-2 (GLUT-2), the mammalian target of rapamycin (mTOR), and sterol regulatory element-binding protein-1c (SREBP-1c) but decreased peroxisome proliferator-activated receptor-alpha (PPAR-α) in liver. Aortic relaxation to acetylcholine (ACh) was impaired and histopathology showed severe hepatic steatosis. HMB significantly increased insulin tolerance and decreased fasting insulin, HOMA-IR, HBA1C, hepatic glycogen content, serum TG, LDL-C, and VLDL-C. Additionally, HMB enhanced ACh-induced relaxation, ameliorated hepatic steatosis, and decreased mRNA expression of GLUT-2. In conclusion, HMB may attenuate insulin resistance and hepatic steatosis through inhibiting GLUT-2 in liver.

The NF-κB inhibitor celastrol attenuates acute hepatic dysfunction induced by cecal ligation and puncture in rats

Acute hepatic dysfunction associating sepsis is mediated mainly by toll-like receptor-4 (TLR-4)/nuclear factor kappa-B (NF-κB) inflammatory pathway. This study explores potential hepatoprotective effect of the NF-κB inhibitor celastrol in cecal ligation and puncture (CLP) model in rats. Protective effect of celastrol (1mg/kg, i.p., 1h before CLP) was illustrated after 24h by preventing CLP-induced hepatic histopathological changes and elevation in serum hepatic biomarkers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB) and gamma aminotransferase (γ-GT)] without affecting mortality. Celastrol anti-inflammatory effect was illustrated by inhibiting increased serum and hepatic mRNA expression of interleukin-6 (IL-6) without affecting IL-10 elevation. Furthermore, celastrol inhibited CLP-induced elevations in hepatic mRNA expression of nuclear factor inhibitory protein kappa-B alpha (NFκBia), TLR-4, 5-lipoxygenase (5-LOX) and prevented NF-κB/p65 nuclear translocation and activation. In conclusion, celastrol prevented CLP-induced acute hepatic dysfunction through its anti-inflammatory effect by attenuating NF-κB activation, TLR-4 and 5-LOX expression with subsequent reduction in pro-inflammatory IL-6.

LPS-RS attenuation of lipopolysaccharide-induced acute lung injury involves NF-κB inhibition.

In this study, we studied the effect of lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), an inhibitor of Toll-like receptor 4 (TLR4), in LPS-induced acute lung injury (ALI). Male Sprague-Dawley rats were treated with LPS-RS (0.1 mg/kg body mass, by intraperitoneal (i.p.) injection) 1 h before LPS injection (10 mg/kg, i.p.). Bronchoalveolar lavage fluid (BALF) and lung tissues were collected 24 h later to determine total and differential cell count, total protein content, levels of lactate dehydrogenase (LDH), histopathological changes, markers of oxidative stress, and mRNA expression of the inhibitory protein nuclear factor kappaB-α (NFκBIA) and TLR4. Additionally, rings of pulmonary artery were isolated for measuring vascular reactivity. LPS-induced ALI was indicated by increases in total and differential cell count, total protein, and LDH in BALF, and increased lung levels of malondialdehyde (MDA), as well as decreased activity of reduced glutathione (GSH) and superoxide dismutase (SOD). Moreover, LPS increased pulmonary artery contraction in response to phenylephrine (PE). Additionally, LPS downregulated mRNA expression of NFκBIA and upregulated mRNA expression of TLR4. LPS caused a marked inflammation in the lung tissue, with tubercular granuloma and numerous neutrophils. Pretreatment with LPS-RS protected against LPS-induced ALI by decreasing total and differential cell count, total protein, and LDH in BALF, and increased pulmonary GSH content and SOD activity without affecting MDA content. Additionally, it decreased the elevated PE-induced pulmonary artery contraction. LPS-RS upregulated mRNA expression of NFκBIA and downregulated mRNA expression of TLR4. Moreover, LPS-RS prevented inflammation in lung tissues. In conclusion, pretreatment with LPS-RS protects against LPS-induced ALI in rats through its anti-inflammatory effects, possibly by decreasing the mRNA expression of TLR4 and increasing that of NFκBIA.

Paclitaxel alleviates liver fibrosis induced by bile duct ligation in rats: Role of TGF-β1, IL-10 and c-Myc

ABSTRACT Liver fibrosis is a global health issue that causes morbidity and mortality with no currently available treatment. It has been shown that low dose paclitaxel (PTX) can stabilize microtubules and inhibit the profibrotic transforming growth factor‐beta 1 (TGF‐&bgr;1) signaling pathway. In this study the effect of treatment with low dose PTX was examined using a model of cholestatic liver fibrosis. Bile‐duct ligation (BDL) was induced in rats for 2 weeks then PTX (0.3 mg/kg/ip) was administered three times a week for 2 weeks. Administration of PTX ameliorated BDL‐induced elevation in biomarkers of hepatocellular damage (alanine transaminase; ALT and aspartate transaminase; AST) and obstructive cholestatic injury (total bilirubin and gamma glutamyl transferase; &ggr;‐GT). PTX was able to correct the increase in liver weight to body weight ratio and the bile duct proliferation induced by BDL. Additionally, PTX treatment corrected the BDL‐induced fibrosis of portal tracts, elevation of hydroxyproline content and increased alpha smooth muscle actin (&agr;‐SMA) mRNA and protein expression. This antifibrotic effect of PTX was further examined through its inhibitory effect on TGF‐&bgr;1 mRNA and protein expression in addition to c‐Myc mRNA expression. Furthermore, PTX rectified the BDL‐induced decrease in interleukin‐10 (IL‐10) mRNA and protein expression. In conclusion, this study suggests that PTX at low dose has the potential to treat BDL‐induced liver fibrosis in rats possibly through suppression of TGF‐&bgr;1 and c‐Myc and activation of IL‐10 pathways.

Antioxidant and anti-inflammatory effects of dimethyl fumarate in hypercholesterolemic rabbits

Abstract The present study aimed to determine the possible beneficial effects of dimethyl fumarate (DMF) against oxidative stress and inflammation in hypercholesterolemic rabbits. Twenty four New Zealand male rabbits were randomly allocated into 4 groups as the following: Group I (control): rabbits received standard rabbit chow; Group II high cholesterol diet (HCD): rabbits received 1% cholesterol-enriched chow for 4 weeks; Group III (HCD-DMF): rabbits received 1% cholesterol-enriched chow and administered DMF (12.5 mg/kg/day, orally) for 4 weeks; Group IV (DMF): rabbits received standard chow plus DMF (12.5 mg/kg/day, orally) for 4 weeks. At the end of experiment (day 30), blood samples were collected for measuring serum total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C) and C-reactive protein (CRP). In addition, the aorta was removed for measurement of malondialdehyde (MDA), superoxide dismutase (SOD), mRNA expression of cholesteryl ester transfer protein (CETP) and histological assessment of intima/media (I/M) ratio. HCD-fed rabbits showed significant increases in TGs, TC, low-density lipoprotein cholesterol (LDL-C), aortic MDA and aortic I/M ratio levels while they significantly exhibited a reduced SOD level relative to control animals. Moreover, HCD rabbits demonstrated upregulated mRNA expression of CETP. DMF administration significantly decreased HCD-induced elevations in serum TC and LDL-C. Additionally, DMF decreased aortic level of MDA while increased SOD level. Moreover, DMF significantly downregulated mRNA expression of CETP and reduced the elevation in I/M ratio.