Basim Anwar Shehata Messiha

Protective effect of ursodeoxycholic acid, resveratrol, and N-acetylcysteine on nonalcoholic fatty liver disease in rats

Abstract Context: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Resveratrol (RSV) and N-acetylcysteine (NAC) are safe representatives of natural and synthetic antioxidants, respectively. Objective: The objective of this study was to evaluate protective effects of RSV and NAC, compared with ursodeoxycholic acid (UDCA), on experimental NAFLD. Materials and methods: NAFLD was induced by feeding rats a methionine choline-deficient diet (MCDD) for four cycles, each of 4 d of MCDD feeding and 3 d of fasting. Animals were divided into normal control, steatosis control, and five treatment groups, receiving UDCA (25 mg/kg/d), RSV (10 mg/kg/d), NAC (20 mg/kg/d), UDCA + RSV, and UDCA + NAC orally for 28 d. Liver integrity markers (liver index and serum transaminases), serum tumor necrosis factor-α (TNF-α), glucose, albumin, renal functions (urea, creatinine), lipid profile (total cholesterol; TC, triglycerides, high density lipoproteins, low density lipoproteins; LDL-C, very low density lipoproteins, leptin), and oxidative stress markers (hepatic malondialdehyde; MDA, glutathione; GSH, glutathione-S-transferase; GST) were measured using automatic analyzer, colorimetric kits, and ELISA kits, supported by a liver histopathological study. Results: RSV and NAC administration significantly improved liver index (RSV only), alanine transaminase (52, 52%), TNF-α (70, 70%), glucose (69, 80%), albumin (122, 114%), MDA (55, 63%), GSH (160, 152%), GST (84, 84%), TC (86, 86%), LDL-C (83, 81%), and leptin (59, 70%) levels compared with steatosis control values. A combination of RSV or NAC with UDCA seems to ameliorate their effects. Discussion and conclusion: RSV and NAC are effective on NAFLD through antioxidant, anti-inflammatory, and lipid-lowering potentials, where as RSV seems better than UDCA or NAC.

Protective effects of fenofibrate and resveratrol in an aggressive model of rheumatoid arthritis in rats.

Abstract Context Fibrates were reported to have anti-inflammatory effects while the naturally occurring polyphenol resveratrol was traditionally known as a potent antioxidant agent. Objective The effects of fenofibrate and resveratrol were investigated on complete Freund’s adjuvant (CFA)-induced rheumatoid arthritis (RA) in adult female albino rats. Materials and methods Rats were divided into a normal control group, an arthritis control group receiving CFA, two reference treatment groups receiving dexamesathone (1.5 mg/kg/day) and methotrexate (1 mg/kg/day), and two treatment groups receiving fenofibrate (100 mg/kg/day) and resveratrol (10 mg/kg/day) for seven consecutive days. Assessment of RA was performed by measuring serum rheumatoid factor (RF), matrix metalloprotinease-3 (MMP-3) and cartilage oligomeric matrix protein (COMP) as specific rheumatoid biomarkers, immunoglobulin G (IgG) and antinuclear antibody (ANA) as immunological biomarkers, tumour necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) as immunomodulatory cytokines, myeloperoxidase (MPO) and C-reactive protein (CRP) as inflammatory biomarkers and malondialdehyde (MDA) and glutathione (GSH) as oxidative stress biomarkers, supported by a histopathological study on joints and spleens. Results Serum RF, MMP-3, COMP, IgG, ANA, TNF-α, MPO, CRP and MDA were decreased to about 36, 56, 66, 65, 9, 35, 24, 44 and 31% by fenofibrate, and to about 37, 59, 44, 70, 5, 30, 23, 33 and 28% by resveratrol treatments, respectively. Alternatively, serum IL-10 and GSH were significantly increased to about 215 and 251% by fenofibrate and to about 225 and 273% by resveratrol treatments, respectively. Discussion and conclusion Fenofibrate and resveratrol protect against RA, possibly through their immunomodulatory, anti-inflammatory and antioxidant potential.

Protective effects of fish oil, allopurinol, and verapamil on hepatic ischemia-reperfusion injury in rats.

Background: The major aim of this work was to study the protective effects of fish oil (FO), allopurinol, and verapamil on hepatic ischemia-reperfusion (IR)-induced injury in experimental rats. Materials and Methods: Sixty male Wistar albino rats were randomly assigned to six groups of 10 rats each. Group 1 served as a negative control. Group 2 served as hepatic IR control injury. Groups 3, 4, 5, and 6 received N-acetylcysteine (standard), FO, allopurinol, and verapamil, respectively, for 3 consecutive days prior to ischemia. All animals were fasted for 12 h, anesthetized and underwent midline laparotomy. The portal triads were clamped by mini-artery clamp for 30 min followed by reperfusion for 30 min. Blood samples were withdrawn for estimation of serum alanine transaminase (ALT) and aspartate transaminase (AST) activities as well as hepatic thiobarbituric acid reactive substances, reduced glutathione, myeloperoxidase, and total nitrate/nitrite levels, in addition to histopathological examination. Results: Fish oil, allopurinol, and verapamil reduced hepatic IR injury as evidenced by significant reduction in serum ALT and AST enzyme activities. FO and verapamil markedly reduced oxidative stress as compared to control IR injury. Levels of inflammatory biomarkers in liver were also reduced after treatment with FO, allopurinol, or verapamil. In accordance, a marked improvement of histopathological findings was observed with all of the three treatments. Conclusion: The findings of this study prove the benefits of FO, allopurinol, and verapamil on hepatic IR-induced liver injury and are promising for further clinical trials.

Zinc oxide nanoparticles as a novel anticancer approach; in vitro and in vivo evidences

Currently, the outcomes of conventional chemotherapeutic approaches are unsatisfactory. Clinical application of nanoparticles seems promising. We aim to evaluate the possible antitumor activity of zinc oxide nanoparticles (ZnONPs) as a chemotherapeutic approach in in vitro and in vivo experimental models. An in vitro study was performed on three different cell lines, namely human hepatocellular carcinoma (HEPG2), human prostate cancer (PC3), and none‐small cell lung cancer (A549) cell lines. An in vivo study using diethylnitrosamine (DENA)‐induced HCC in adult male Wistar rats was conducted to investigate the potential antitumor activity of ZnONPs in HCC and the possible underlying mechanisms. Hepatocellular carcinoma (HCC) was induced by oral administration of DENA given in drinking water (100 mg/L) for 8 weeks. Rats were allocated into four groups, namely a control group, an HCC control group receiving DENA alone, a ZnONPs (10 μg/kg per week, intravenous (i.v.) for 1 month) control group, and a ZnONPs treatment group (receiving ZnONPs + DENA). ZnONPs significantly reduced the elevated serum levels of HCC‐related tumor markers alphafetoprotein and alpha‐l‐fucosidase and the apoptotic marker caspase‐3 compared with the untreated HCC rats. In addition, treatment with ZnONPs significantly decreased the elevated levels of hepatocyte integrity and oxidative stress markers as compared with the untreated HCC control group. Furthermore, the histopathological study revealed anaplasia and fibrous degenerations which were significantly corrected by ZnONPs treatment. In conclusion, administration of ZnONPs exhibited a promising preclinical anticancer efficacy in HCC and could be considered as a novel strategy for the treatment HCC in clinical practices.

Effect of amlodipine, lisinopril and allopurinol on acetaminophen-induced hepatotoxicity in rats

Background Exposure to chemotherapeutic agents such as acetaminophen may lead to serious liver injury. Calcium deregulation, angiotensin II production and xanthine oxidase activity are suggested to play mechanistic roles in such injury. Objective This study evaluates the possible protective effects of the calcium channel blocker amlodipine, the angiotensin converting enzyme inhibitor lisinopril, and the xanthine oxidase inhibitor allopurinol against experimental acetaminophen-induced hepatotoxicity, aiming to understand its underlying hepatotoxic mechanisms. Material and methods Animals were allocated into a normal control group, a acetaminophen hepatotoxicity control group (receiving a single oral dose of acetaminophen; 750 mg/kg/day), and four treatment groups receive N-acetylcysteine (300 mg/kg/day; a reference standard), amlodipine (10 mg/kg/day), lisinopril (20 mg/kg/day) and allopurinol (50 mg/kg/day) orally for 14 consecutive days prior to acetaminophen administration. Evaluation of hepatotoxicity was performed by the assessment of hepatocyte integrity markers (serum transaminases), oxidative stress markers (hepatic malondialdehyde, glutathione and catalase), and inflammatory markers (hepatic myeloperoxidase and nitrate/nitrite), in addition to a histopathological study. Results Rats pre-treated with amlodipine, lisinopril or allopurinol showed significantly lower serum transaminases, significantly lower hepatic malondialdehyde, myeloperoxidase and nitrate/nitrite, as well as significantly higher hepatic glutathione and catalase levels, compared with acetaminophen control rats. Serum transaminases were normalized in the lisinopril treatment group, while hepatic myeloperoxidase was normalized in the all treatment groups. Histopathological evaluation strongly supported the results of biochemical estimations. Conclusion Amlodipine, lisinopril or allopurinol can protect against acetaminophen-induced hepatotoxicity, showing mechanistic roles of calcium channels, angiotensin converting enzyme and xanthine oxidase enzyme in the pathogenesis of hepatotoxicity induced by acetaminophen.

Protective Effects of Simvastatin and Hesperidin against Complete Freund's Adjuvant-Induced Rheumatoid Arthritis in Rats.

Background/Aims: Rheumatoid arthritis (RA) is a disabling autoimmune disease for which most current treatments cause massive complications, thereby limiting treatment dose and duration. The anti-arthritic effects of the 3-hydroxy-3-metylglutary-CoA reductase inhibitor, simvastatin, and the natural flavonoid, hesperidin, were investigated against complete Freunds adjuvant-induced RA in rats. Methods: A normal control group, an arthritis control group, 2 reference treatment groups receiving dexamethasone (1.5 mg/kg/day) and methotrexate (1 mg/kg/day), and 2 treatment groups receiving simvastatin (0.5 mg/kg/day) and hesperidin (200 mg/kg/day) were included in the study. Serum rheumatoid factor, matrix metalloprotinease-3 (MMP-3) and cartilage oligomeric matrix protein (COMP) as specific rheumatoid biomarkers, serum immunoglobulin G (IgG) and antinuclear antibody (ANA) as immunological biomarkers, serum tumor necrosis factor-alpha and interleukin-10 as immunomodulatory cytokines, serum myeloperoxidase (MPO) and C-reactive protein as inflammatory biomarkers, and malondialdehyde (MDA) and glutathione (GSH) as oxidative stress biomarkers were assessed, supported by joint and spleen histopathological study. Results: Simvastatin significantly improved all the measured biomarkers, with MMP-3, COMP, and GSH restored to normal levels. Hesperidin significantly improved all the measured biomarkers, with COMP, IgG, ANA, MPO, MDA and GSH restored to normal levels. Conclusion: Simvastatin and hesperidin may be promising protective agents against RA through immunomodulatory, anti-inflammatory and antioxidant potentials.

Protective effects of telmisartan and tempol on lipopolysaccharide-induced cognitive impairment, neuroinflammation, and amyloidogenesis: possible role of brain-derived neurotrophic factor

Angiotensin II has pro-inflammatory and pro-oxidant potentials. We investigated the possible protective effects of the Angiotensin II receptor blocker telmisartan, compared with the superoxide scavenger tempol, on lipopolysaccharide (LPS)-induced cognitive decline and amyloidogenesis. Briefly, mice were allocated into a normal control group, an LPS control group, a tempol treatment group, and 2 telmisartan treatment groups. A behavioral study was conducted followed by a biochemical study via assessment of brain levels of beta amyloid (Aβ) and brain-derived neurotropic factor (BDNF) as amyloidogenesis and neuroplasticity markers, tumor necrosis factor alpha (TNF-α), nitric oxide end products (NOx), neuronal and inducible nitric oxide synthase (nNOS and iNOS) as inflammatory markers, and superoxide dismutase (SOD), malondialdehyde (MDA), glutathione reduced (GSH), and nitrotyrosine (NT) as oxido-nitrosative stress markers. Finally, histopathological examination of cerebral cortex, hippocampus, and cerebellum sections was performed using routine and special Congo red stains. Tempol and telmisartan improved cognition, decreased brain Aβ deposition and BDNF depletion, decreased TNF-α, NOx, nNOS, iNOS, MDA, and NT brain levels, and increased brain SOD and GSH contents, parallel to confirmatory histopathological evidences. In conclusion, tempol and telmisartan are promising drugs in managing cognitive impairment and amyloidogenesis, at least via upregulation of BDNF with inhibition of neuroinflammation and oxido-nitrosative stress.

Granisetron and carvedilol can protect experimental rats againstadjuvant-induced arthritis

Abstract Context: Rheumatoid arthritis (RA), a disabling autoimmune disorder of the joints as well as other organs, affects about 1% of population. Unfortunately, all current treatments of RA cause severe gastrointestinal, renal and other complications. Objective: We aimed to evaluate the possible antiarthritic effects of a serotonin 5-HT3 receptor blocker, granisetron, and a nonselective adrenergic receptor blocker, carvedilol, on complete Freunds adjuvant-induced RA in adult female albino rats. Materials and methods: Rats were allocated into a normal control group, an arthritis control group, two reference treatment groups receiving dexamethasone (1.5 mg/kg/day) and methotrexate (1 mg/kg/day), and two treatment groups receiving granisetron (2.5 mg/kg/day) and carvedilol (10 mg/kg/day). Serum-specific rheumatoid, immunological, inflammatory and oxidative stress biomarkers were assessed. A confirmatory histopathological study on joints and spleens was performed. Results: Granisetron administration significantly improved all the measured biomarkers, with the values of rheumatoid factor, matrix metalloproteinase-3, cartilage oligomeric matrix protein, immunoglobulin G, antinuclear antibody and myeloperoxidase being restored back to normal levels. Carvedilol administration significantly improved all biomarkers, with serum MPO value restored back to normal levels. Discussion and conclusions: Serotonin 5-HT3 receptor blockers and adrenergic receptor blockers, represented by granisetron and carvedilol, may represent new promising protective strategies against RA, at least owing to immune-modulator, anti-inflammatory and antioxidant potentials.

Assessment of the Mechanistic Role of Cinnarizine in Modulating Experimentally-Induced Bronchial Asthma in Rats.

Background/Aims: Calcium influx, inflammatory infiltration, cytokine production, immunoglobulin E activation and oxidative stress play coordinated roles in bronchial asthma pathogenesis. We aim to assess the protective effect of cinnarizine against experimentally induced bronchial asthma. Methods: Bronchial asthma was induced by ovalbumin sensitization and challenge. Rats were allocated into a normal control, an asthma control, a dexamethasone (standard) treatment, and 2 cinnarizine treatment groups. The respiratory functions tidal volume (TV) and peak expiratory flow rate (PEFR), the inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-5 (IL-5) in lung tissue, the allergic immunoglobulin IgE in serum, the absolute eosinophil count (AEC) in bronchoalveolar lavage fluid (BALF), as well as the oxidative and nitrosative markers glutathione reduced (GSH) and superoxide dismutase (SOD) in lung tissue and nitric oxide end products (NOx) in BALF were assessed, followed by a histopathological study. Results: Cinnarizine administration significantly restored TV, PEFR, TNF-α, IL-5, IgE, AEC, GSH, SOD and NOx values back to normal levels, and significantly decreased perivascular and peribronchiolar inflammatory scores. Conclusion: Cinnarizine may protect against experimental bronchial asthma. Suppressant effect of cinnarizine on pro-inflammatory cytokines release, IgE antibody production, eosinophil infiltration as well as oxidative and nitrosative stress may explain its anti-asthmatic potential.

Nicorandil and theophylline can protect experimental rats against complete Freund's adjuvant-induced rheumatoid arthritis through modulation of JAK/STAT/RANKL signaling pathway

Abstract Signaling pathways are interesting fields of study of pathogenesis and treatment trials. We elucidated the possible protective effects of nicorandil (15 mg/kg/day) and theophylline (20 mg/kg/day) on experimentally‐induced RA, focusing on the role of JAK (Janus Kinase) / STAT (Signal Transducer and Activator of Transcription) / RANKL (Receptor Activator of Nuclear factor‐Kappa B Ligand) / cytokine signaling pathway. Four sets of experiments were performed. First, effect of test agents on normal animals was evaluated. Second, effect of test agents was evaluated on Complete Freunds Adjuvant (CFA; 0.3 ml, s.c.)‐induced RA to investigate anti‐arthritic effect. Third, effect of test agents was evaluated on growth hormone (GH; 2 mg/kg/day, s.c.)‐induced stimulation of JAK/STAT/RANKL/cytokine signaling pathway to investigate the role of this signaling pathway in their anti‐arthritic effect. Fourth, the effect of test agents was performed on CFA/GH‐induced RA. To fulfill this purpose, serum anti‐citrullinated peptide antibody (ACPA), interleukin‐6 (IL‐6), and cartilage oligomeric matrix protein (COMP), together with tissue JAK2, STAT3, RANKL, inducible and endothelial nitric oxide synthases (iNOS and eNOS) as well as macrophage inflammatory protein (MIP1&agr;) were estimated using ELISA, Western blotting and PCR techniques, confirmed by a histopathological study. Test agents significantly corrected JAK2, STAT3, RANKL and IL‐6 values in animals receiving GH. Additionally, test agents could correct ACPA, IL‐6, COMP, JAK2, STAT3, RANKL, iNOS, eNOS and MIP1&agr; levels compared with the respective CFA or CFA/GH controls. These results conclude that nicorandil and theophylline have good anti‐arthritic effects related to modulation of JAK/STAT/RANKL signaling pathway. Further clinical trials are claimed. Graphical abstract Figure. No Caption available.