Nagla A. El-Shitany

Ellagic acid protects against carrageenan-induced acute inflammation through inhibition of nuclear factor kappa B, inducible cyclooxygenase and proinflammatory cytokines and enhancement of interleukin-10 via an antioxidant mechanism

There are several hypotheses that explain the process of acute inflammation, including free radical overproduction, pro-inflammatory enzyme activation, and release of pro-inflammatory cytokines. In this study, the protective role of ellagic acid against carrageenan-induced acute inflammation was assessed. In addition, the immunomodulatory action, the antioxidant effects, and the role of COX-2 and NF-κB were also investigated. Inflammation was induced by the injection of 100 μl of 1.5% carrageenan solution. Ellagic acid (10, 25, 50, 100 and 200mg/kg), indomethacin (10 mg/kg), meloxicam (4 mg/kg), and saline, were injected 2h before carrageenan injection. The percentage inhibition in the paw weight was calculated. Paws, MDA, NO, GSH, IL-1β, TNF-α, IL-10 and NF-κB mRNA expression were estimated. Formalin fixed hind paws were used for histopathological examination and immunohistochemical staining for COX-2 expression. Ellagic acid, meloxicam and indomethacin reduced paws, edema, MDA and NO formation. In addition, all of them restored the depleted GSH contents in the paws. Ellagic acid, meloxicam and indomethacin reduced NF-κB mRNA expression. Ellagic acid ameliorated COX-2 expression; meloxicam inhibited while indomethacin failed. Both ellagic acid and meloxicam increased IL-10 while indomethacin did not. The docking study revealed a high affinity of ellagic acid towards COX-2. Ellagic acid exhibited a potent anti-inflammatory effect against carrageenan-induced inflammation. The mechanisms of ellagic acid induced protection were proved to be due to reduction of NO, MDA, IL-1β, TNF-α, COX-2 and NF-κB expression and induction of GSH and IL-10 production.

Antioxidant, Anti-inflammatory, and Antiulcer Potential of Manuka Honey against Gastric Ulcer in Rats

Gastric ulcers are among the most common diseases affecting humans. This study aimed at investigating the gastroprotective effects of manuka honey against ethanol-induced gastric ulcers in rats. The mechanism by which honey exerts its antiulcer potential was elucidated. Four groups of rats were used: control, ethanol (ulcer), omeprazole, and manuka honey. Stomachs were examined macroscopically for hemorrhagic lesions in the glandular mucosa, histopathological changes, and glycoprotein detection. The effects of oxidative stress were investigated using the following indicators: gastric mucosal nitric oxide (NO), reduced glutathione (GSH), lipid peroxide (MDA, measured as malondialdehyde) glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase. Plasma tumour necrosis factor-α, interleukin-1β, and IL-6 were also measured. Manuka honey significantly decreased the ulcer index, completely protected the mucosa from lesions, and preserved gastric mucosal glycoprotein. It significantly increased gastric mucosal levels of NO, GSH, GPx, and SOD. Manuka honey also decreased gastric mucosal MDA and plasma TNF-α, IL-1β, and IL-6 concentrations. In conclusion, manuka honey likely exerted its antiulcer, effect by keeping enzymatic (GPx and SOD) and nonenzymatic (GSH and NO) antioxidants as well as inflammatory cytokines (TNF-α, IL-1β, and IL-6) in a reduced form, inhibited lipid peroxidation (MDA), and preserved mucous glycoproteins levels.

Red Sea Suberea mollis Sponge Extract Protects against CCl4-Induced Acute Liver Injury in Rats via an Antioxidant Mechanism

Recent studies have demonstrated that marine sponges and their active constituents exhibited several potential medical applications. This study aimed to evaluate the possible hepatoprotective role as well as the antioxidant effect of the Red Sea Suberea mollis sponge extract (SMSE) on carbon tetrachloride- (CCl4-) induced acute liver injury in rats. In vitro antioxidant activity of SMSE was evaluated by 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) assay. Rats were orally administered three different concentrations (100, 200, and 400 mg/kg) of SMSE and silymarin (100 mg/kg) along with CCl4 (1 mL/kg, i.p., every 72 hr) for 14 days. Plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin were measured. Hepatic malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were also measured. Liver specimens were histopathologically examined. SMSE showed strong scavenging activity against free radicals in DPPH assay. SMSE significantly reduced liver enzyme activities. Moreover, SMSE significantly reduced hepatic MDA formation. In addition, SMSE restored GSH, NO, SOD, GPx, and CAT. The histopathological results confirmed these findings. The results of this study suggested a potent protective effect of the SMSE against CCl4-induced hepatic injury. This may be due to its antioxidant and radical scavenging activity.

Strain Echocardiography in Early Detection of Doxorubicin-Induced Left Ventricular Dysfunction in Children with Acute Lymphoblastic Leukemia

Objective. To investigate the ability of two-dimensional longitudinal strain echocardiography (2DST), to detect the early doxorubicin cardiotoxicity. Patients and Methods. The study included 25 children with newly diagnosed acute lymphoblastic leukemia (ALL) aged 5–15 years and 30 healthy control children. They had echocardiographic examination with conventional 2-dimensional (2D), pulsed tissue Doppler (PTD), and 2DST echocardiography before and within 1 week after doxorubicin treatment. Results. There was no significant difference in left ventricle (LV) systolic and diastolic functions measured by conventional 2-D and PTD echocardiography between patients and controls. However, there was significant decrease in LV global and peak systolic strain detected by 2-DST echocardiography in study group than control. After doxorubicin treatment, there was no significant difference in LV systolic and diastolic functions measured by conventional 2-D and PTD echocardiography than before treatment except for prolonged IVCT and IVRT, but LV global and peak systolic strain was significantly lower after treatment. Conclusion. 2-D longitudinal strain echocardiography was more sensitive than conventional 2-D and PTD in detecting the early LV doxorubicin-induced cardiotoxicity in children with ALL.

Protective Effects of Carvedilol and Vitamin C against Azithromycin-Induced Cardiotoxicity in Rats via Decreasing ROS, IL1-β, and TNF-α Production and Inhibiting NF-κB and Caspase-3 Expression

The Food and Drug Administration recently warned of the fatal cardiovascular risks of azithromycin in humans. In addition, a recently published study documented azithromycin-induced cardiotoxicity in rats. This study aimed to justify the exact cardiovascular events accompanying azithromycin administration in rats, focusing on electrocardiographic, biochemical, and histopathological changes. In addition, the underlying mechanisms were studied regarding reactive oxygen species production, cytokine release, and apoptotic cell-death. Finally, the supposed protective effects of both carvedilol and vitamin C were assessed. Four groups of rats were used: (1) control, (2) azithromycin, (3) azithromycin + carvedilol, and (4) azithromycin + vitamin C. Azithromycin resulted in marked atrophy of cardiac muscle fibers and electrocardiographic segment alteration. It increased the heart rate, lactate dehydrogenase, creatine phosphokinase, malondialdehyde, nitric oxide, interleukin-1 beta (IL1-β), tumor necrosis factor alpha (TNF-α), nuclear factor kappa beta (NF-κB), and caspase-3. It decreased reduced glutathione, glutathione peroxidase, and superoxide dismutase. Carvedilol and vitamin C prevented most of the azithromycin-induced electrocardiographic and histopathological changes. Carvedilol and vitamin C decreased lactate dehydrogenase, malondialdehyde, IL1-β, TNF-α, NF-κB, and caspase-3. Both agents increased glutathione peroxidase. This study shows that both carvedilol and vitamin C protect against azithromycin-induced cardiotoxicity through antioxidant, immunomodulatory, and antiapoptotic mechanisms.

Manuka Honey Exerts Antioxidant and Anti-Inflammatory Activities That Promote Healing of Acetic Acid-Induced Gastric Ulcer in Rats

Gastric ulcers are a major problem worldwide with no effective treatment. The objective of this study was to evaluate the use of manuka honey in the treatment of acetic acid-induced chronic gastric ulcers in rats. Different groups of rats were treated with three different concentrations of honey. Stomachs were checked macroscopically for ulcerative lesions in the glandular mucosa and microscopically for histopathological alterations. Treatment with manuka honey significantly reduced the ulcer index and maintained the glycoprotein content. It also reduced the mucosal myeloperoxidase activity, lipid peroxidation (MDA), and the inflammatory cytokines (TNF-α, IL-1β, and IL-6) as compared to untreated control group. In addition, honey-treated groups showed significant increase in enzymatic (GPx and SOD) and nonenzymatic (GSH) antioxidants besides levels of the anti-inflammatory cytokine IL-10. Flow cytometry studies showed that treatment of animals with manuka honey has normalized cell cycle distribution and significantly lowered apoptosis in gastric mucosa. In conclusion, the results indicated that manuka honey is effective in the treatment of chronic ulcer and preservation of mucosal glycoproteins. Its effects are due to its antioxidant and anti-inflammatory properties that resulted in a significant reduction of the gastric mucosal MDA, TNF-α, IL-1β, and IL-6 and caused an elevation in IL-10 levels.

Ameliorative effect of lycopene against 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced rat liver microsomal toxicity An in vitro study

The objective of the current study was to investigate the potential oxidative damage of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in hepatic microsomal fractions in vitro and to further elucidate the potential modulatory effect of lycopene. Rat liver microsomes were divided into four groups. Group I served as a control and is incubated with vehicle (toluene). Groups II and IV were incubated with 20 µM lycopene for 1 h before further incubating; groups III and IV with 15 nM of TCDD for further 1 h. Hydrogen peroxide (H2O2) production, lipid peroxidation (LPO), protein carbonyl content and activities of uridine 5′-diphospho-glucuronyltransferase (UDPGT) and P450 were significantly increased. Moreover, the activity of antioxidant enzymes superoxide dismutase, glutathione peroxidase, catalse, glutathione-S-transferase and glutathione reductase as well as the microsomal thiol content were significantly decreased. Incubation with lycopene (group IV) maintained near normal activities of the enzymes, normalized thiol and carbonyl content and significantly reduced LPO and H2O2 production. In conclusion, the findings of the study indicate that TCDD induces a significant oxidative stress in liver microsomes as manifested by increased LPO, H2O2 production, protein carbonyl content and activities of UDPGT and P450 and decreased antioxidant enzymes activities and thiol content. By the reversal of biochemical and oxidative markers toward normalcy, the protective role of lycopene is illuminated in rat liver microsomal toxicity.

Evaluation of the Anti-Inflammatory, Antioxidant and Immunomodulatory Effects of the Organic Extract of the Red Sea Marine Sponge Xestospongia testudinaria against Carrageenan Induced Rat Paw Inflammation

Marine sponges are found to be a rich source of bioactive compounds which show a wide range of biological activities including antiviral, antibacterial, and anti-inflammatory activities. This study aimed to investigate the possible anti-inflammatory, antioxidant and immunomodulator effects of the methanolic extract of the Red Sea marine sponge Xestospongia testudinaria. The chemical composition of the Xestospongia testudinaria methanolic extract was determined using Gas chromatography-mass spectroscopy (GC-MS) analysis. DPPH (2, 2-diphenyl-1-picryl-hydrazyl) was measured to assess the antioxidant activity of the sponge extract. Carrageenan-induced rat hind paw edema was adopted in this study. Six groups of rats were used: group1: Control, group 2: Carrageenan, group 3: indomethacin (10 mg/kg), group 4–6: Xestospongia testudinaria methanolic extract (25, 50, and 100 mg/kg). Evaluation of the anti-inflammatory activity was performed by both calculating the percentage increase in paw weight and hisopathologically. Assessment of the antioxidant and immunomodulatory activity was performed. GC-MS analysis revealed that there were 41 different compounds present in the methanolic extract. Sponge extract exhibited antioxidant activity against DPPH free radicals. Xestospongia testudinaria methanolic extract (100 mg/kg) significantly decreased % increase in paw weight measured at 1, 2, 3 and 4 h after carrageenan injection. Histopathologically, the extract caused a marked decrease in the capillary congestion and inflammatory cells infiltrate. The extract decreased paw malondialdehyde (MDA) and nitric oxide (NO) and increased the reduced glutathione (GSH), glutathione peroxidase (GPx), and catalase (CAT) activity. It also decreased the inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1 β(IL-1β) and IL-6. The results of this study demonstrated the anti-inflammatory, antioxidant, and immunomodulatory effects of the methanolic extract of the Red Sea sponge Xestospongia testudinaria (100 mg/kg).

Proanthocyanidin protects against cisplatin‐induced oxidative liver damage through inhibition of inflammation and NF‐κβ/TLR‐4 pathway

Although cisplatin (CIS) is a highly effective anticancer drug, hepatotoxicity is one of the most common adverse effects associated with its use. Recently, reactive oxygen species (ROS) and inflammation are suggested to be key factors in the pathophysiology of CIS‐induced acute liver damage. The aim of this study is to investigate the possible protective effect of proanthocyanidin (PRO) against CIS‐induced acute hepatotoxicity. Rats were divided into four groups: 1, Control; 2, PRO; 3, CIS; and 4, PRO + CIS. Biochemical studies and histopathology were used to assess liver damage. ROS, inflammatory cytokines, nuclear factor kappa beta (NF‐κβ), inducible cyclooxygenase enzyme (COX‐2), inducible nitric oxide synthase (iNOS), toll‐like receptor‐4 (TLR‐4) gene expression, and apoptotic markers were also assessed. PRO pretreatment protected the liver against CIS‐induced toxicity as indicated by decreased plasma levels of liver function enzymes and the normal liver histopathology observed in the PRO + CIS group. PRO pretreatment also diminished indicators of oxidative stress in the liver, including nitric oxide (NO) and malondialdehyde (MDA). It also increased the antioxidants, reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) in the liver. Plasma interleukin‐1 beta (IL‐1β), IL‐6, and tumor necrosis factor‐alpha (TNF‐α) were all reduced. Liver gene expression of NF‐κβ, COX‐2, iNOS, and TLR‐4 were all downregulated. Furthermore, PRO administration downregulated the liver expression of the apoptotic marker, Bax, while upregulated the antiapoptotic marker, Bcl2. In conclusion, our results revealed that PRO may protect against CIS‐induced acute liver damage mainly through inhibition of ROS, inflammation, and apoptosis.

Cromoglycate, not ketotifen, ameliorated the injured effect of warm ischemia/reperfusion in rat liver: role of mast cell degranulation, oxidative stress, proinflammatory cytokine, and inducible nitric oxide synthase.

Hepatic ischemia/reperfusion (ISCH/REP) is a major clinical problem that is considered to be the most common cause of postoperative liver failure. Recently, mast cells have been proposed to play an important role in the pathophysiology of ISCH/REP in many organs. In contrast, the role played by mast cells during ISCH/REP-induced liver damage has remained an issue of debate. This study aimed to investigate the protective role of mast cells in order to search for an effective therapeutic agent that could protect against fatal ISCH/REP-induced liver damage. A model of warm ISCH/REP was induced in the liver of rats. Four groups of rats were used in this study: Group I: SHAM (normal saline, intravenously [iv]); Group II: ISCH/REP; Group III: sodium cromoglycate + ISCH/REP (CROM + ISCH/REP), and Group IV: ketotifen (KET) + ISCH/REP (KET + ISCH/REP). Liver damage was assessed both histopathologically and biochemically. Mast cell degranulation was assessed histochemically. Lipid peroxidation (malondialdehyde [MDA]) as well as the levels of glutathione (GSH), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), the formation of nitric oxide (NO), and the expression of inducible NO synthase (iNOS) were determined. The results of this study revealed increased mast cell degranulation in the liver during the acute phase of ISCH/REP. Moreover, CROM, but not KET, decreased the activity of alanine aminotransferase, aspartate aminotransferase, and lactic dehydrogenase and maintained normal liver tissue histology. Both CROM and KET protected against mast cell degranulation in the liver. In addition, both CROM and KET decreased IL-6 and TNF-α. However, CROM, but not KET, decreased MDA formation and increased GSH. Furthermore, KET, but not CROM, increased both NO formation and iNOS expression. In conclusion, this study clearly demonstrated mast cell degranulation in warm ISCH/REP in the liver of rats. More importantly, CROM, but not KET, ameliorated the effect of ISCH/REP-induced injury in rat liver. CROM may protect the liver through mast cell stabilization, inhibition of TNF-α, IL-6, MDA, and iNOS and increased GSH. KET may maintain ISCH/REP-induced liver injury through the NO/iNOS pathway.