The original version of this article unfortunately contained a mistake. Fig. 4 image and its cita... more The original version of this article unfortunately contained a mistake. Fig. 4 image and its citation must be deleted from the manuscript as the content for the same has already deleted during revision by a suggestion of reviewers. The original article has been corrected.
Liver fibrosis is a common chronic hepatic disease. This study was done to examine the effect of ... more Liver fibrosis is a common chronic hepatic disease. This study was done to examine the effect of pyridoxamine against thioacetamide-induced hepatic fibrosis. Animals were divided into four groups (1) control group; (2) Thioacetamide group (200 mg/kg, i.p.) twice a week for eight weeks; (3) Pyridoxamine-treated group treated with pyridoxamine (100 mg/kg/day, i.p.) for eight weeks; (4) Thioacetamide and pyridoxamine group, in which pyridoxamine was given (100 mg/kg/day, i.p.) during thioacetamide injections. Thioacetamide treatment resulted in hepatic dysfunction manifested by increased serum levels of bilirubin, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Oxidative stress was noted by increased hepatic lipid peroxidation and decreased glutathione (GSH). Increased concentrations of total nitrite/nitrate, advanced glycation end products (AGEs), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), matrix metalloproteinases (MMP-2&9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were noticed in hepatic tissues. Immunostaining sections also revealed overexpression of MMP-2, MMP-9 and collagen IV. Liver fibrosis was confirmed by severe histopathological changes. Pyridoxamine improved the assessed parameters. Moreover, histopathological and immunohistological studies supported the ability of pyridoxamine to reduce liver fibrosis. The findings of the present study provide evidence that pyridoxamine is a novel target for the treatment of liver fibrosis.
Canadian Journal of Physiology and Pharmacology, 2005
Pyrrolidinedithiocarbamate (PDTC) is a potent antioxidant and an inhibitor of nuclear factor-κB (... more Pyrrolidinedithiocarbamate (PDTC) is a potent antioxidant and an inhibitor of nuclear factor-κB (NF-κB). The present study examined the impact of PDTC preconditioning on gastric protection in response to ischemia-reperfusion (I/R) injury to the rat stomach. Male Wistar rats were recruited and divided into 3 groups (n=7). One group was subjected to gastric ischemia for 30 min and reperfusion for 1 hour. The second group of rats was preconditioned with PDTC (200 mg/kg body mass i.v.) 15 min prior to ischemia and before reperfusion. The third group of rats was sham-operated and served as the control group. Gastric I/R injury increased serum lactate dehydrogenase level, vascular permeability of gastric mucosa (as indicated by Evans blue dye extravasation) and gastric content of inflammatory cytokine; tumor necrosis factor-α (TNF-α). Moreover, oxidative stress was increased as indicated by elevated lipid peroxides formation (measured as thiobarbituric acid reactive substances) and deplet...
... Hanan H. Hagar Corresponding Author Contact Information , E-mail The Corresponding Author ,Az... more ... Hanan H. Hagar Corresponding Author Contact Information , E-mail The Corresponding Author ,Azza H. and Fahmy. Department of Pharmacology, College of Medicine, King Khalid University Hospital, King Saud University, PO Box 2925, Riyadh 11461, Saudi Arabia. ...
The present work was conducted to assess the possible protective effects of zafirlukast against t... more The present work was conducted to assess the possible protective effects of zafirlukast against the toxic damage induced by acetic acid in rat colon. Zafirlukast is a potent and selective cysteinyl leukotriene receptor antagonist which is used mainly in the prophylaxis of bronchial ...
AIM Tamoxifen (TAMO) is a chemotherapeutic drug used for the treatment of breast cancer. Neverthe... more AIM Tamoxifen (TAMO) is a chemotherapeutic drug used for the treatment of breast cancer. Nevertheless, there is a lack of information available in regarding its nephrotoxicity. The purpose of this work was to investigate the impact of cyanocobalamin (COB) and/or calcitriol (CAL) injections on TAMO-induced nephrotoxicity. MAIN METHODS Animals were allocated into five groups as follows: normal control group; TAMO (45 mg/kg) administered group; TAMO+COB (6mg/kg, i.p) treated group; TAMO+CAL (0.3 μg/kg, i.p) treated group; TAMO+COB+CAL combination groups. KEY FINDINGS Renal injury induced by TAMO was confirmed by the alteration in renal function parameters in the serum (urea and creatinine), as well as in the urine (creatinine clearance, total protein and albumin). These results were supported by histopathological examination. Upregulation of renal inflammatory parameters; tumor necrosis factor (TNF)-α, interleukin (IL)-6, C-reactive protein (CRP); and transforming growth factor (TGF)-β...
The current article was designed to assess the role of chitosan nanoparticles (CNPs) in the manag... more The current article was designed to assess the role of chitosan nanoparticles (CNPs) in the management of hepatic injury induced by the hepatocarcinogen 2-nitropropane (2-NP). Rats were divided into three groups. The first group served as a control, the second group was injected with 2-NP, while the third group was treated with CNPs 1 h before 2-NP injection every other day for 4 weeks. The 2-NP injection upregulated serum AST and ALT activities, as well as hepatic TNF- α, IL-6, and MDA levels and the expression of vascular endothelial growth factor (VEGF) and caspase-3, whereas GSH contents and SOD activity were decreased. Immunohistochemistry investigations revealed that the hepatic protein expression of collagen I, inducible nitric oxide synthetase, proliferating cell nuclear antigen, cluster of differentiation, and p53 were upregulated. hematoxylin and eosin (H&E) and Masson’s trichrome stains supported the previous parameters, and CNPs ameliorated most of the previous biochemic...
The purpose of this research was to evaluate the efficacy of carsil (CAR) either alone or in comb... more The purpose of this research was to evaluate the efficacy of carsil (CAR) either alone or in combination with α-tocopherol (α-TOCO) and/or turmeric (TUMR) against tetrachloromethane (TCM)-induced cardiomyocyte injury in rats. Administration of CAR either alone or in combination with α-TOCO and/or TUMR post-TCM injection, significantly mitigated the increases in serum troponin T, creatine kinase-MB (CK-MB) as well as interleukin-6 (IL-6), interferon γ (IFN-γ), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP). They also decline the elevation of caspase-3, vascular endothelial growth factor (VEGF) protein expression as well as DNA damage in cardiac tissues induced by TCM. The biochemical results were confirmed by histopathological investigation. Conclusion: The combination of the three antioxidants showed greater cardioprotective potential, compared to individual drugs. Therefore, this combination may be recommended as a complementary therapy to antagonize cardiac injury induced by different insults.
The finding of “glycogen synthase kinase-3” (GSK-3) was initially identified as a protein kinase ... more The finding of “glycogen synthase kinase-3” (GSK-3) was initially identified as a protein kinase that phosphorylate and inhibited glycogen synthase. However, it was soon discovered that GSK-3 also has significant impact in regulation of truly astonishing number of critical intracellular signaling pathways ranging from regulation of cell growth, neurology, heart failure, diabetes, aging, inflammation, and cancer. Recent studies have validated the feasibility of targeting GSK-3 for its vital therapeutic potential to maintain normal myocardial homeostasis, conversely, its loss is incompatible with life as it can abrupt cell cycle and endorse fatal cardiomyopathy. The current study focuses on its expanding therapeutic action in myocardial tissue, concentrating primarily on its role in diabetes-associated cardiac complication, apoptosis and metabolism, heart failure, cardiac hypertrophy, and myocardial infarction. The current report also includes the finding of our previous investigation that has shown the impact of GSK-3β inhibitor against diabetes-associated myocardial injury and experimentally induced myocardial infarction. We have also discussed some recent identified GSK-3β inhibitors for their cardio-protective potential. The crosstalk of various underlying mechanisms that highlight the significant role of GSK-3β in myocardial pathophysiology have been discussed in the present report. For these literatures, we will rely profoundly on our previous studies and those of others to reconcile some of the deceptive contradictions in the literature.
Although titanium dioxide nanoparticles (TDO-ns) are extensively used in the food, medicine, and ... more Although titanium dioxide nanoparticles (TDO-ns) are extensively used in the food, medicine, and cosmetic industries, discussions about the possible hazards of nanomaterials are just beginning to emerge. This study aimed to detect the inflammatory stress, oxidative stress, and apoptotic cell death induced in the livers of rats exposed to TDO-ns (600 mg/kg, particle size ≤ 100 nm). Furthermore, the modulation of these toxic effects by two potent naturally occurring antioxidants, carnosine (Carno) or melatonin (Melato), was evaluated. The co-administration of carnosine or melatonin to rats intoxicated with TDO-ns significantly attenuated the increases in serum tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), immunoglobulin G (IgG), vascular endothelial growth factor (VEGF), nitric oxide (NO), and alanine aminotransferase (ALT) levels. The two agents markedly ameliorated hepatic DNA damage and the alterations in hepatic malondialdehyde (MDA), glutathione (GSH), cytochrome P450, caspase-3, total phospholipid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, and triglyceride (TG) levels. These results support the use of Carno or Melato as prophylactic agents against TDO-ns-induced liver damage.
Titanium dioxide nanoparticles (TiO2-NPs) are extensively used in a wide range of applications; h... more Titanium dioxide nanoparticles (TiO2-NPs) are extensively used in a wide range of applications; however, many reports have investigated their nanotoxicological effect at the molecular level either in vitro or in vivo systems. The defensive roles of quercetin (Qur) or idebenone (Id) against the hepatotoxicity induced by TiO2-NPs were evaluated in the current study. The results showed that the coadministration of Qur or Id to rats intoxicated with TiO2-NPs markedly ameliorated the elevation in hepatic malondialdehyde (MDA), serum alanine amino-transferase (ALT), glucose, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), immunoglobin G (IgG), and C-reactive protein (CRP) levels compared to their levels in TiO2-NPs-treated rats. The aforementioned antioxidants also effectively modulated the changes in the levels of serum vascular endothelial growth factor (VEGF), nitric oxide (NO), hepatic DNA breakage, caspase-3, and inhibition of drug metabolizing enzymes (cytochrome P450s; CYP45...
ABSTRACT Aim: Focal segmental glomerulosclerosis (FSGS) is a common progressive chronic renal dis... more ABSTRACT Aim: Focal segmental glomerulosclerosis (FSGS) is a common progressive chronic renal disease. Podocyte injury and loss are the postulated pivotal events that trigger FSGS. In this study, the authors aim to examine the evolution of FSGS in murine models histologically, ultrastructurally and immunohistochemically with special emphasis on podocytes and parietal epithelial cells (PECs). Material and methods: FSGS resembling primary FSGS in humans was initiated in Wistar rats using intravenous Adriamycin injections. Blood and urine analysis were performed at 0, 8, and 12 weeks. Both the control kidneys and the test kidneys were harvested at 8 and 12 weeks, examined histologically and ultrastructurally and the findings correlated with the glomerular expression of immunostains specific for podocytes (WT-1) and for activated PECs (CD44). Results: FSGS developed in both 8 and 12 weeks test groups showing progressive proteinuria, podocytopathy and segmental glomerular scarring. There was a decrease in the glomerular expression of WT-1 with a concurrent increase in the glomerular expression of CD44, indicating podocyte loss with synchronous increase in activated PECs. The evolving FSGS correlated negatively with podocytes and positively with activated PECs. Conclusion: Our study shows that with podocyte injury there is podocyte effacement and loss, proteinuria, glomerular segmental adhesion and scarring, all culminating in FSGS. In addition, there is activation, hyperplasia and hypertrophy of PECs. This demonstrates that both podocyte loss and PEC activation promote FSGS. Our findings are consistent with recent investigations. More studies are required to further understand the role of these cells in the evolution of FSGS and subsequently introduce new targeted treatment modalities.
Canadian Journal of Physiology and Pharmacology, 2005
Pyrrolidinedithiocarbamate (PDTC) is a potent antioxidant and an inhibitor of nuclear factor-κB (... more Pyrrolidinedithiocarbamate (PDTC) is a potent antioxidant and an inhibitor of nuclear factor-κB (NF-κB). The present study examined the impact of PDTC preconditioning on gastric protection in response to ischemia-reperfusion (I/R) injury to the rat stomach. Male Wistar rats were recruited and divided into 3 groups (n=7). One group was subjected to gastric ischemia for 30 min and reperfusion for 1 hour. The second group of rats was preconditioned with PDTC (200 mg/kg body mass i.v.) 15 min prior to ischemia and before reperfusion. The third group of rats was sham-operated and served as the control group. Gastric I/R injury increased serum lactate dehydrogenase level, vascular permeability of gastric mucosa (as indicated by Evans blue dye extravasation) and gastric content of inflammatory cytokine; tumor necrosis factor-α (TNF-α). Moreover, oxidative stress was increased as indicated by elevated lipid peroxides formation (measured as thiobarbituric acid reactive substances) and depleted reduced glutathione in gastric tissues. NF-κB translocation was also detected by electrophoretic mobility shift assay. Microscopically, gastric tissues subjected to I/R injury showed ulceration, hemorrhages, and neutrophil infiltration. Immunohistochemical studies of gastric sections revealed increased expression of p53 and Bcl-2 proteins. PDTC pretreatment reduced Evans blue extravasation, serum lactate dehydrogenase levels, gastric TNF-α levels, and thiobarbituric acid reactive substances content, and increased gastric glutathione content. Moreover, PDTC pretreatment abolished p53 expression and inhibited NF-κB translocation. Finally, histopathological changes were nearly restored by PDTC pretreatment. These results clearly demonstrate that NF-κB activation and pro-apoptotic protein p53 induction are involved in gastric I/R injury. PDTC protects against gastric I/R injury by an antioxidant, NF-κB inhibition, and by reduction of pro-apoptotic protein p53 expression, which seems to be downstream to NF-κB, thus promoting cell survival.
Clinical and Experimental Pharmacology and Physiology, 2006
1Cyclosporine A (CsA) is the first-line immunosuppressant used for the management of solid organ ... more 1Cyclosporine A (CsA) is the first-line immunosuppressant used for the management of solid organ transplantation and autoimmune diseases. Nephrotoxicity is the major limitation of CsA use. Recent evidence suggests that reactive oxygen species (ROS) play an important role in mediating CsA-induced hypertension and nephrotoxicity. Taurine, the major intracellular free β-amino acid, is known to be an endogenous anti-oxidant and membrane-stabilizing agent. The present study was designed to investigate the effects of taurine on CsA-induced oxidative stress, hypertension and renal dysfunction.2Animals were assigned into four groups of seven rats each as follows: (i) control group, receiving vehicle (olive oil; 1 mL/kg, s.c.); (ii) CsA group, given CsA (25 mg/kg per day, s.c.) for 21 days; (iii) taurine group, supplemented with taurine (1% in the drinking water); and (iv) taurine + CsA group, treated with taurine 3 days before and concurrently during CsA injections for 21 days.3Cyclosporine...
Hyperhomocysteinemia (Hhcy) is an independent risk factor for cardiovascular disease. Oxidative s... more Hyperhomocysteinemia (Hhcy) is an independent risk factor for cardiovascular disease. Oxidative stress may contribute to the deleterious effects of homocysteine (Hcy). The aim of the present study is to study the effect of folic acid and Vitamin B 12 supplementation on isoprenaline (ISO)-induced myocardial infarction (MI) in hyperhomocysteinemic rats. Hhcy was induced by daily intake of methionine (1 g kg −1 body weight) in the drinking water for 4 weeks. MI was then produced by a single subcutaneous injection of ISO (300 mg kg −1 , s.c.). Electrocardiographic parameters, heart rate, ST segment, and blood pressure as well as serum marker enzymes, creatine kinase (CK) and lactate dehydrogenase (LDH) were measured. Lipid peroxidation measured as malondialdehyde (MDA) and reduced glutathione (GSH) concentrations in heart tissue were estimated as indices of oxidative stress. Hhcy resulted in significant blood pressure reduction, ST segment elevation and increase in heart rate and serum CK and LDH levels. Cardiac MDA was significantly increased, while GSH was decreased in Hhcy group compared to the normal control group. All the measured parameters were greatly exaggerated in Hhcy rats treated with ISO in comparison with Hhcy rats alone. Administration of folic acid (10 mg kg −1 , orally via gavage) and Vitamin B 12 (500 µg kg −1 , i.m.) concurrently for 4 weeks during the induction of Hhcy markedly reduced the increase in heart rate, ST segment elevation and blood pressure reduction as well as the increase in serum CK and LDH levels. Cardiac MDA content was decreased while cardiac GSH was elevated in the treated group compared to Hhcy + ISO group. Moreover, the severe cardiac histopathological changes observed in Hhcy + ISO group were attenuated by folic acid and Vitamin B 12. These results suggest that Hhcy aggravates MI via oxidative stress mechanisms and that lowering Hcy level with folic acid and Vitamin B 12 can ameliorate the detrimental effects of Hhcy and may reduce the risk of MI.
The original version of this article unfortunately contained a mistake. Fig. 4 image and its cita... more The original version of this article unfortunately contained a mistake. Fig. 4 image and its citation must be deleted from the manuscript as the content for the same has already deleted during revision by a suggestion of reviewers. The original article has been corrected.
Liver fibrosis is a common chronic hepatic disease. This study was done to examine the effect of ... more Liver fibrosis is a common chronic hepatic disease. This study was done to examine the effect of pyridoxamine against thioacetamide-induced hepatic fibrosis. Animals were divided into four groups (1) control group; (2) Thioacetamide group (200 mg/kg, i.p.) twice a week for eight weeks; (3) Pyridoxamine-treated group treated with pyridoxamine (100 mg/kg/day, i.p.) for eight weeks; (4) Thioacetamide and pyridoxamine group, in which pyridoxamine was given (100 mg/kg/day, i.p.) during thioacetamide injections. Thioacetamide treatment resulted in hepatic dysfunction manifested by increased serum levels of bilirubin, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Oxidative stress was noted by increased hepatic lipid peroxidation and decreased glutathione (GSH). Increased concentrations of total nitrite/nitrate, advanced glycation end products (AGEs), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), matrix metalloproteinases (MMP-2&9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were noticed in hepatic tissues. Immunostaining sections also revealed overexpression of MMP-2, MMP-9 and collagen IV. Liver fibrosis was confirmed by severe histopathological changes. Pyridoxamine improved the assessed parameters. Moreover, histopathological and immunohistological studies supported the ability of pyridoxamine to reduce liver fibrosis. The findings of the present study provide evidence that pyridoxamine is a novel target for the treatment of liver fibrosis.
Canadian Journal of Physiology and Pharmacology, 2005
Pyrrolidinedithiocarbamate (PDTC) is a potent antioxidant and an inhibitor of nuclear factor-κB (... more Pyrrolidinedithiocarbamate (PDTC) is a potent antioxidant and an inhibitor of nuclear factor-κB (NF-κB). The present study examined the impact of PDTC preconditioning on gastric protection in response to ischemia-reperfusion (I/R) injury to the rat stomach. Male Wistar rats were recruited and divided into 3 groups (n=7). One group was subjected to gastric ischemia for 30 min and reperfusion for 1 hour. The second group of rats was preconditioned with PDTC (200 mg/kg body mass i.v.) 15 min prior to ischemia and before reperfusion. The third group of rats was sham-operated and served as the control group. Gastric I/R injury increased serum lactate dehydrogenase level, vascular permeability of gastric mucosa (as indicated by Evans blue dye extravasation) and gastric content of inflammatory cytokine; tumor necrosis factor-α (TNF-α). Moreover, oxidative stress was increased as indicated by elevated lipid peroxides formation (measured as thiobarbituric acid reactive substances) and deplet...
... Hanan H. Hagar Corresponding Author Contact Information , E-mail The Corresponding Author ,Az... more ... Hanan H. Hagar Corresponding Author Contact Information , E-mail The Corresponding Author ,Azza H. and Fahmy. Department of Pharmacology, College of Medicine, King Khalid University Hospital, King Saud University, PO Box 2925, Riyadh 11461, Saudi Arabia. ...
The present work was conducted to assess the possible protective effects of zafirlukast against t... more The present work was conducted to assess the possible protective effects of zafirlukast against the toxic damage induced by acetic acid in rat colon. Zafirlukast is a potent and selective cysteinyl leukotriene receptor antagonist which is used mainly in the prophylaxis of bronchial ...
AIM Tamoxifen (TAMO) is a chemotherapeutic drug used for the treatment of breast cancer. Neverthe... more AIM Tamoxifen (TAMO) is a chemotherapeutic drug used for the treatment of breast cancer. Nevertheless, there is a lack of information available in regarding its nephrotoxicity. The purpose of this work was to investigate the impact of cyanocobalamin (COB) and/or calcitriol (CAL) injections on TAMO-induced nephrotoxicity. MAIN METHODS Animals were allocated into five groups as follows: normal control group; TAMO (45 mg/kg) administered group; TAMO+COB (6mg/kg, i.p) treated group; TAMO+CAL (0.3 μg/kg, i.p) treated group; TAMO+COB+CAL combination groups. KEY FINDINGS Renal injury induced by TAMO was confirmed by the alteration in renal function parameters in the serum (urea and creatinine), as well as in the urine (creatinine clearance, total protein and albumin). These results were supported by histopathological examination. Upregulation of renal inflammatory parameters; tumor necrosis factor (TNF)-α, interleukin (IL)-6, C-reactive protein (CRP); and transforming growth factor (TGF)-β...
The current article was designed to assess the role of chitosan nanoparticles (CNPs) in the manag... more The current article was designed to assess the role of chitosan nanoparticles (CNPs) in the management of hepatic injury induced by the hepatocarcinogen 2-nitropropane (2-NP). Rats were divided into three groups. The first group served as a control, the second group was injected with 2-NP, while the third group was treated with CNPs 1 h before 2-NP injection every other day for 4 weeks. The 2-NP injection upregulated serum AST and ALT activities, as well as hepatic TNF- α, IL-6, and MDA levels and the expression of vascular endothelial growth factor (VEGF) and caspase-3, whereas GSH contents and SOD activity were decreased. Immunohistochemistry investigations revealed that the hepatic protein expression of collagen I, inducible nitric oxide synthetase, proliferating cell nuclear antigen, cluster of differentiation, and p53 were upregulated. hematoxylin and eosin (H&E) and Masson’s trichrome stains supported the previous parameters, and CNPs ameliorated most of the previous biochemic...
The purpose of this research was to evaluate the efficacy of carsil (CAR) either alone or in comb... more The purpose of this research was to evaluate the efficacy of carsil (CAR) either alone or in combination with α-tocopherol (α-TOCO) and/or turmeric (TUMR) against tetrachloromethane (TCM)-induced cardiomyocyte injury in rats. Administration of CAR either alone or in combination with α-TOCO and/or TUMR post-TCM injection, significantly mitigated the increases in serum troponin T, creatine kinase-MB (CK-MB) as well as interleukin-6 (IL-6), interferon γ (IFN-γ), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP). They also decline the elevation of caspase-3, vascular endothelial growth factor (VEGF) protein expression as well as DNA damage in cardiac tissues induced by TCM. The biochemical results were confirmed by histopathological investigation. Conclusion: The combination of the three antioxidants showed greater cardioprotective potential, compared to individual drugs. Therefore, this combination may be recommended as a complementary therapy to antagonize cardiac injury induced by different insults.
The finding of “glycogen synthase kinase-3” (GSK-3) was initially identified as a protein kinase ... more The finding of “glycogen synthase kinase-3” (GSK-3) was initially identified as a protein kinase that phosphorylate and inhibited glycogen synthase. However, it was soon discovered that GSK-3 also has significant impact in regulation of truly astonishing number of critical intracellular signaling pathways ranging from regulation of cell growth, neurology, heart failure, diabetes, aging, inflammation, and cancer. Recent studies have validated the feasibility of targeting GSK-3 for its vital therapeutic potential to maintain normal myocardial homeostasis, conversely, its loss is incompatible with life as it can abrupt cell cycle and endorse fatal cardiomyopathy. The current study focuses on its expanding therapeutic action in myocardial tissue, concentrating primarily on its role in diabetes-associated cardiac complication, apoptosis and metabolism, heart failure, cardiac hypertrophy, and myocardial infarction. The current report also includes the finding of our previous investigation that has shown the impact of GSK-3β inhibitor against diabetes-associated myocardial injury and experimentally induced myocardial infarction. We have also discussed some recent identified GSK-3β inhibitors for their cardio-protective potential. The crosstalk of various underlying mechanisms that highlight the significant role of GSK-3β in myocardial pathophysiology have been discussed in the present report. For these literatures, we will rely profoundly on our previous studies and those of others to reconcile some of the deceptive contradictions in the literature.
Although titanium dioxide nanoparticles (TDO-ns) are extensively used in the food, medicine, and ... more Although titanium dioxide nanoparticles (TDO-ns) are extensively used in the food, medicine, and cosmetic industries, discussions about the possible hazards of nanomaterials are just beginning to emerge. This study aimed to detect the inflammatory stress, oxidative stress, and apoptotic cell death induced in the livers of rats exposed to TDO-ns (600 mg/kg, particle size ≤ 100 nm). Furthermore, the modulation of these toxic effects by two potent naturally occurring antioxidants, carnosine (Carno) or melatonin (Melato), was evaluated. The co-administration of carnosine or melatonin to rats intoxicated with TDO-ns significantly attenuated the increases in serum tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), immunoglobulin G (IgG), vascular endothelial growth factor (VEGF), nitric oxide (NO), and alanine aminotransferase (ALT) levels. The two agents markedly ameliorated hepatic DNA damage and the alterations in hepatic malondialdehyde (MDA), glutathione (GSH), cytochrome P450, caspase-3, total phospholipid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, and triglyceride (TG) levels. These results support the use of Carno or Melato as prophylactic agents against TDO-ns-induced liver damage.
Titanium dioxide nanoparticles (TiO2-NPs) are extensively used in a wide range of applications; h... more Titanium dioxide nanoparticles (TiO2-NPs) are extensively used in a wide range of applications; however, many reports have investigated their nanotoxicological effect at the molecular level either in vitro or in vivo systems. The defensive roles of quercetin (Qur) or idebenone (Id) against the hepatotoxicity induced by TiO2-NPs were evaluated in the current study. The results showed that the coadministration of Qur or Id to rats intoxicated with TiO2-NPs markedly ameliorated the elevation in hepatic malondialdehyde (MDA), serum alanine amino-transferase (ALT), glucose, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), immunoglobin G (IgG), and C-reactive protein (CRP) levels compared to their levels in TiO2-NPs-treated rats. The aforementioned antioxidants also effectively modulated the changes in the levels of serum vascular endothelial growth factor (VEGF), nitric oxide (NO), hepatic DNA breakage, caspase-3, and inhibition of drug metabolizing enzymes (cytochrome P450s; CYP45...
ABSTRACT Aim: Focal segmental glomerulosclerosis (FSGS) is a common progressive chronic renal dis... more ABSTRACT Aim: Focal segmental glomerulosclerosis (FSGS) is a common progressive chronic renal disease. Podocyte injury and loss are the postulated pivotal events that trigger FSGS. In this study, the authors aim to examine the evolution of FSGS in murine models histologically, ultrastructurally and immunohistochemically with special emphasis on podocytes and parietal epithelial cells (PECs). Material and methods: FSGS resembling primary FSGS in humans was initiated in Wistar rats using intravenous Adriamycin injections. Blood and urine analysis were performed at 0, 8, and 12 weeks. Both the control kidneys and the test kidneys were harvested at 8 and 12 weeks, examined histologically and ultrastructurally and the findings correlated with the glomerular expression of immunostains specific for podocytes (WT-1) and for activated PECs (CD44). Results: FSGS developed in both 8 and 12 weeks test groups showing progressive proteinuria, podocytopathy and segmental glomerular scarring. There was a decrease in the glomerular expression of WT-1 with a concurrent increase in the glomerular expression of CD44, indicating podocyte loss with synchronous increase in activated PECs. The evolving FSGS correlated negatively with podocytes and positively with activated PECs. Conclusion: Our study shows that with podocyte injury there is podocyte effacement and loss, proteinuria, glomerular segmental adhesion and scarring, all culminating in FSGS. In addition, there is activation, hyperplasia and hypertrophy of PECs. This demonstrates that both podocyte loss and PEC activation promote FSGS. Our findings are consistent with recent investigations. More studies are required to further understand the role of these cells in the evolution of FSGS and subsequently introduce new targeted treatment modalities.
Canadian Journal of Physiology and Pharmacology, 2005
Pyrrolidinedithiocarbamate (PDTC) is a potent antioxidant and an inhibitor of nuclear factor-κB (... more Pyrrolidinedithiocarbamate (PDTC) is a potent antioxidant and an inhibitor of nuclear factor-κB (NF-κB). The present study examined the impact of PDTC preconditioning on gastric protection in response to ischemia-reperfusion (I/R) injury to the rat stomach. Male Wistar rats were recruited and divided into 3 groups (n=7). One group was subjected to gastric ischemia for 30 min and reperfusion for 1 hour. The second group of rats was preconditioned with PDTC (200 mg/kg body mass i.v.) 15 min prior to ischemia and before reperfusion. The third group of rats was sham-operated and served as the control group. Gastric I/R injury increased serum lactate dehydrogenase level, vascular permeability of gastric mucosa (as indicated by Evans blue dye extravasation) and gastric content of inflammatory cytokine; tumor necrosis factor-α (TNF-α). Moreover, oxidative stress was increased as indicated by elevated lipid peroxides formation (measured as thiobarbituric acid reactive substances) and depleted reduced glutathione in gastric tissues. NF-κB translocation was also detected by electrophoretic mobility shift assay. Microscopically, gastric tissues subjected to I/R injury showed ulceration, hemorrhages, and neutrophil infiltration. Immunohistochemical studies of gastric sections revealed increased expression of p53 and Bcl-2 proteins. PDTC pretreatment reduced Evans blue extravasation, serum lactate dehydrogenase levels, gastric TNF-α levels, and thiobarbituric acid reactive substances content, and increased gastric glutathione content. Moreover, PDTC pretreatment abolished p53 expression and inhibited NF-κB translocation. Finally, histopathological changes were nearly restored by PDTC pretreatment. These results clearly demonstrate that NF-κB activation and pro-apoptotic protein p53 induction are involved in gastric I/R injury. PDTC protects against gastric I/R injury by an antioxidant, NF-κB inhibition, and by reduction of pro-apoptotic protein p53 expression, which seems to be downstream to NF-κB, thus promoting cell survival.
Clinical and Experimental Pharmacology and Physiology, 2006
1Cyclosporine A (CsA) is the first-line immunosuppressant used for the management of solid organ ... more 1Cyclosporine A (CsA) is the first-line immunosuppressant used for the management of solid organ transplantation and autoimmune diseases. Nephrotoxicity is the major limitation of CsA use. Recent evidence suggests that reactive oxygen species (ROS) play an important role in mediating CsA-induced hypertension and nephrotoxicity. Taurine, the major intracellular free β-amino acid, is known to be an endogenous anti-oxidant and membrane-stabilizing agent. The present study was designed to investigate the effects of taurine on CsA-induced oxidative stress, hypertension and renal dysfunction.2Animals were assigned into four groups of seven rats each as follows: (i) control group, receiving vehicle (olive oil; 1 mL/kg, s.c.); (ii) CsA group, given CsA (25 mg/kg per day, s.c.) for 21 days; (iii) taurine group, supplemented with taurine (1% in the drinking water); and (iv) taurine + CsA group, treated with taurine 3 days before and concurrently during CsA injections for 21 days.3Cyclosporine...
Hyperhomocysteinemia (Hhcy) is an independent risk factor for cardiovascular disease. Oxidative s... more Hyperhomocysteinemia (Hhcy) is an independent risk factor for cardiovascular disease. Oxidative stress may contribute to the deleterious effects of homocysteine (Hcy). The aim of the present study is to study the effect of folic acid and Vitamin B 12 supplementation on isoprenaline (ISO)-induced myocardial infarction (MI) in hyperhomocysteinemic rats. Hhcy was induced by daily intake of methionine (1 g kg −1 body weight) in the drinking water for 4 weeks. MI was then produced by a single subcutaneous injection of ISO (300 mg kg −1 , s.c.). Electrocardiographic parameters, heart rate, ST segment, and blood pressure as well as serum marker enzymes, creatine kinase (CK) and lactate dehydrogenase (LDH) were measured. Lipid peroxidation measured as malondialdehyde (MDA) and reduced glutathione (GSH) concentrations in heart tissue were estimated as indices of oxidative stress. Hhcy resulted in significant blood pressure reduction, ST segment elevation and increase in heart rate and serum CK and LDH levels. Cardiac MDA was significantly increased, while GSH was decreased in Hhcy group compared to the normal control group. All the measured parameters were greatly exaggerated in Hhcy rats treated with ISO in comparison with Hhcy rats alone. Administration of folic acid (10 mg kg −1 , orally via gavage) and Vitamin B 12 (500 µg kg −1 , i.m.) concurrently for 4 weeks during the induction of Hhcy markedly reduced the increase in heart rate, ST segment elevation and blood pressure reduction as well as the increase in serum CK and LDH levels. Cardiac MDA content was decreased while cardiac GSH was elevated in the treated group compared to Hhcy + ISO group. Moreover, the severe cardiac histopathological changes observed in Hhcy + ISO group were attenuated by folic acid and Vitamin B 12. These results suggest that Hhcy aggravates MI via oxidative stress mechanisms and that lowering Hcy level with folic acid and Vitamin B 12 can ameliorate the detrimental effects of Hhcy and may reduce the risk of MI.
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Papers by Hanan Hagar