Cisplatin-induced testicular damage is a major obstacle in the application of cisplatin as chemot... more Cisplatin-induced testicular damage is a major obstacle in the application of cisplatin as chemotherapeutic agent. However, it remains as one of the most widely employed anticancer agents in treating various solid tumors including prostate cancer. Since heme-oxygenase-1 (HO-1) is a cytoprotective enzyme with anti-oxidative stress, anti-inflammatory and anticancer activities, we investigated the effects of up-regulation of HO-1 by hemin and its inhibition by zinc protoporphyrin-IX (ZnPP) on cisplatin-induced testicular toxicity in adult rats. Furthermore, the anticancer effect of hemin and ZnPP, with and without cisplatin, was evaluated on human prostate cancer cell line, PC3. Results of the animal study showed that hemin reversed cisplatin-induced perturbations in sperm characteristics, normalized serum testosterone level, and ameliorated cisplatin-induced alterations in testicular and epididymal weights, and restored normal testicular architecture. Moreover, hemin increased the expression and activity of HO-1 protein and prevented cisplatin-induced testicular toxicity by virtue of its antioxidant and anti-inflammatory effects. This effect was evidenced by amelioration of testicular oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione contents, and catalase activity) and inflammatory mediators (tumor necrosis factor-α and nitric oxide synthase expressions). In contrast, administration of ZnPP (HO-1 inhibitor) did not show significant improvement against cisplatin-induced testicular toxicity. Finally, in vitro analyses showed that, hemin augmented the anticancer efficacy of cisplatin, while ZnPP inhibited its apoptotic effect in PC3 cells. In conclusion, the induction of HO-1 represents a potential therapeutic approach to protect the testicular tissue from the detrimental effects of cisplatin without repressing, but rather augmenting, its cytotoxic effects on PC3 cells.
AIM The neuronal damage and accompanied functional deficits induced by cerebral ischemia are amon... more AIM The neuronal damage and accompanied functional deficits induced by cerebral ischemia are among the most common causes of disabilities in adults. Activation of subtypes of peroxisome proliferator-activated receptors (PPARs); PPAR-α and PPAR-γ have shown neuroprotective effects in different neurodegenerative diseases including stroke. Thus, this study aimed to compare the effects of two different agonists: PPAR-α (fenofibrate) and PPAR-γ (pioglitazone) as well as the effect of their combination in ameliorating post-ischemia behavioral deficits. METHODS Male Wistar rats were either pretreated with vehicle, fenofibrate (100 mg/kg/day p.o), pioglitazone (10 mg/kg/day p.o) or their combination for 14 days prior to bilateral common carotid artery occlusion followed by reperfusion for 24 h. The sensory motor functions of rats were assessed, then rats were sacrificed to determine infarct volume and histopathological changes as well as oxidative stress, inflammatory and apoptotic markers in the brain tissue. KEY FINDINGS Pre-treatment with fenofibrate and pioglitazone in addition to their combination improved neurobehavioral dysfunction, reduced cerebral infarct volume, attenuated inflammatory and apoptotic markers and ameliorated histopathological changes in I/R injured rats. The effect of pioglitazone in cerebral cortex was higher than its corresponding effect in fenofibrate while the combined administration of both drugs had additive neuroprotective effect and normalized inflammatory and apoptotic mediators in ischemic rats. SIGNIFICANCE The study compared the neuroprotective effects of PPAR-α and PPAR-γ agonists, and tested the impact of their combination. We concluded that no additional benefits on the functional outcomes might be gained upon their combination.
Journal of Biochemical and Molecular Toxicology, Jul 23, 2023
Gastric ulcer is a common disease with increased prevalence in the aged population. Aged gastric ... more Gastric ulcer is a common disease with increased prevalence in the aged population. Aged gastric mucosa has increased susceptibility to injury along with nonsteroidal anti‐inflammatory drugs use due to impaired mucosal defense and decreased vasodilator release. We investigated whether l‐arginine could protect against age‐related gastric ulceration induced by indomethacin. Aged and adult male Wistar rats were administered sole and combined treatment of l‐arginine and Nω‐nitro‐l‐arginine methyl ester ( l‐NAME) before induction of gastric ulceration by indomethacin. The gastroprotective effect of l‐arginine was displayed only in adult rats with indomethacin‐induced gastric ulceration, as evidenced by a significant decrease in ulcer index, oxidative stress parameters, and mucosal myeloperoxidase activity along with increased mucosal PGE2 levels. Interestingly, the mucosal gene expressions of NF‐кB, iNOS, and COX‐2 were significantly suppressed by l‐arginine pretreatment and aggregated upon pretreatment with l‐NAME in both adult and aged rats treated with indomethacin. In conclusion, l‐arginine protected the rats' gastric mucosa against indomethacin‐induced gastric ulceration, possibly, at least in part, by enhancement of mucosal nitric oxide/PGE2 content along with suppressing gastric inflammation and oxidative stress. This study supposed that the gastroprotective effect of l‐arginine depends on aging, and even so, the adoption of a new approach to gastric ulcer treatment for the aged population is warranted.
Despite being extremely potent against malignancies, cisplatin (CIS) has limited practical applic... more Despite being extremely potent against malignancies, cisplatin (CIS) has limited practical applicability due to its adverse effects such as testicular damage. Consequently, it becomes necessary to reduce its toxicity. In this study, cilostazol, a selective phosphodiesterase-3 inhibitor that is frequently used in the treatment of intermittent claudication, was examined for its ability to abrogate CIS-induces testicular toxicity and its ameliorative effect was compared with two phosphodiesterase inhibitors, tadalafil and pentoxifylline. The study also focused on the possible mechanisms involved in the proposed protective effect. Ten groups of rats were included; Group (1): control, Groups (2-4): 5 mg/kg tadalafil or 75 mg/kg pentoxifylline or 20 mg/kg cilostazol respectively), Group (5):7 mg/kg CIS, Group (6&7): CIS + 5 mg/kg tadalafil or 75 mg/kg pentoxifylline, Group (8-10) CIS+ 5, 10 or 20 mg/kg cilostazol respectively. CIS treated rats showed a significant decrease in testicular f...
Hydrogen sulfide (H2S) is an endogenously gas transmitter signaling molecule with known antioxida... more Hydrogen sulfide (H2S) is an endogenously gas transmitter signaling molecule with known antioxidant, anti-inflammatory, and cytoprotective properties. Although accumulating evidence shows the therapeutic potential of H2S in various hepatic diseases, its role in cyclophosphamide (CP)-induced hepatotoxicity remains elusive. The present study was undertaken to investigate the impact of endogenous and exogenous H2S on toll-like receptors (TLRs)-mediated inflammatory response and apoptosis in CP-induced hepatotoxicity. Either an H2S donor (NaHS (100 μM/kg) or an H2S blocker [dl-propargylglycine (PAG) (30 mg/kg, i. p.)], was administered for 10 days before a single ip injection of CP (200 mg/kg). NaHS attenuated conferred hepatoprotection against CP-induced toxicity, significantly decreasing serum hepatic function tests and improving hepatic histopathology. Additionally, NaHS-treated rats exhibited antioxidant activity in liver tissues compared with the CP group. The upregulated hepatic l...
Background and Objectives: Nephroprotective effect of statins is still controversial. The aim of ... more Background and Objectives: Nephroprotective effect of statins is still controversial. The aim of this study was to investigate the possible hemin-like nephroprotective effect of rosuvastatin (RSV) in streptozotocin (STZ)-induced diabetic rats. Materials and Methods: DN was induced in rats via a single dose of 50 mg/kg STZ i.p., with or without RSV (10 mg/kg orally) for 30 days. To investigate hemin-like effect of RSV on renal heme oxygenase-1 (HO-1), RSV was administered in the presence or absence of an inhibitor of HO-1; zinc protoporphyrin-XI (ZnPP), in a dose of 50 µmol/kg i.p. Results: Induction of diabetes with STZ caused, as expected, significant hyperglycemia, as well as deteriorated kidney function, lipid profile and histopathological architecture. The DN group also showed renal oxidative stress, indicated by decreased superoxide dismutase, catalase, and reduced glutathione, with increased malondialdehyde, myeloperoxidase and nitric oxide. Renal expression of inflammatory ma...
Uncontrolled diabetes mellitus (DM) has been associated with poor clinical outcomes in patients w... more Uncontrolled diabetes mellitus (DM) has been associated with poor clinical outcomes in patients with ischemic stroke. Limited knowledge is available regarding the molecular mechanisms and the etiological complexity of both pathologies. Hence, this study aimed to investigate the interplay between long-term DM and ischemic stroke. A comparative study was held between long-term DM-induced adult male Wistar rats which were subjected to sham operation or global cerebral ischemia/reperfusion (I/R) injury on one hand, and adult male Wistar rats which were subjected to sham operation or global cerebral I/R injury on the other hand. Results showed a disturbance in cerebral oxidative stress parameters (catalase, reduced glutathione and malondialdehyde) in diabetic rats compared to non-diabetic ones. Additionally, in comparison with sham diabetic group, diabetic I/R-injured rats showed up regulation of cerebral oxidative stress, caspase-3 and tumor necrosis factoralpha (TNF-α) protein expressi...
AIMS Diabetic nephropathy, a major threat to diabetic patients, is considered as the main reason ... more AIMS Diabetic nephropathy, a major threat to diabetic patients, is considered as the main reason for end-stage renal disease. Fortunately, incretin-based therapy has been aroused as considerable source to attenuate diabetic renal damage. This study aimed to investigate whether superior protective effects on the progression of diabetic kidney are exerted by glucagon-like peptide-1 analog, exenatide, or dipeptidyl peptidase-4 inhibitor, sitagliptin. MATERIALS AND METHODS Male Wistar rats were fed high-fat diet for 2 weeks followed by injection of low dose streptozotocin to induce type 2 diabetes mellitus. Four weeks after induction of diabetes, diabetic rats were administered vehicle, exenatide (5 μg/kg/day, SC) or sitagliptin (10 mg/kg/day, orally) for 4 weeks. KEY FINDINGS Different incretin mimetic agents improved renal function as evident by significant decreases in serum creatinine and urea levels with decline in urinary microalbuminuria and marked improvement in histological alterations. Both treated diabetic rats also exhibited a significant improvement in metabolic intolerance with more pronounced effect of exenatide on glucose regulation. Ameliorated renal oxidative stress alongside significant downregulation in transforming growth factor-beta, tumor necrosis factor-alpha and cleaved-caspase-3 protein expressions in renal tissues were recorded in treated diabetic rats. SIGNIFICANCE Administration of either exenatide or sitagliptin showed ameliorative effects on early diabetic nephropathy without notable differences between their renal protective effects. However, further clinical studies are still required to ensure their comparative promising effects on the management of renal complication of diabetes.
Diabetic nephropathy is the principal cause of end-stage renal failure and current interventions ... more Diabetic nephropathy is the principal cause of end-stage renal failure and current interventions for its recession remains unsatisfactory. Mesenchymal stem cells (MSCs) hold an attractive source for renovating injured tissues. Unfortunately, limited self-renewal and migration capacity of MSCs after transplantation hinder their clinical applicability which demands a new policy for enhancing their biological functions. This study aimed to investigate whether the renoprotective potential of adipose-derived MSCs (ADMSCs) in diabetic rats could be promoted by exenatide, a glucagon-like peptide-1 (GLP-1) analogue. These effects were studied in type 2 diabetes mellitus rats which were administrated ADMSCs, exenatide or their combination four weeks post-induction. Four weeks later, renal function parameters were evaluated. To address the possible underlying mechanisms, parameters indicating glycolipid metabolism tolerance and oxidative stress biomarkers were assessed in renal tissues alongside evaluation of protein expression of tumor necrosis factor-alpha, transforming growth factor-beta1 and cleaved caspase-3. The results showed that the combined therapy had superior renoprotective effect as evident by significant improvement in kidney function and renal architecture changes through rebalancing of inflammatory, fibrotic and apoptotic markers. Based on these outcomes, ADMSCs with exenatide were supposed to effectively ameliorate diabetic renal dysfunction compared to ADMSCs solely, presenting a promise therapy for diabetic nephropathy with further clinical studies warranted to validate this effect.
AIM Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. This study w... more AIM Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. This study was performed to investigate the possible protective effect of lixisenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, on early diabetic nephropathy induced in diabetic rats and explore the various mechanisms underlie this postulated effect. MAIN METHODS Early DN was induced after 3 weeks in diabetic rats fed with a high-fat diet (HFD) and treated with low dose STZ. One week after induction of diabetes, diabetic rats were administered lixisenatide at two dose levels (1 and 10 nmole/kg/day, ip) or glimepiride (2 mg/kg/day, p.o.) for 2 weeks. KEY FINDINGS Lixisenatide, in a low dose regimen, induced a nephroprotective effect evident by significant decreases in serum creatinine and serum urea along with improved renal histology. Low lixisenatide dose showed an antioxidant effect, exhibited by a significant decrease in renal malondialdehyde and total NOx- levels along with a marked rise in total antioxidant capacity. Apart from ameliorating glucose intolerance and insulin resistance, significant down-regulation in renal expressions of iNOS, COX-2, and TGF-B1 were recorded in the diabetic group treated with low dose lixisenatide. Furthermore, low dose lixisenatide was reported to be superior to glimepiride as a nephroprotective. On the contrary, treatment with large dose lixisenatide was founded to be deleterious. SIGNIFICANCE Low-dose lixisenatide treatment was able to protect against early diabetic nephropathy, which might represent a promising approach in the management of diabetes and its renal complication however, further clinical studies are warranted.
Ginger has been proposed as quite a promising candidate for cancer prevention. The purpose of thi... more Ginger has been proposed as quite a promising candidate for cancer prevention. The purpose of this study was to assess the chemo-preventive effects of ginger. Furthermore, this study investigated the possible mechanisms of a standardized extract drawn from the rhizomes of ginger against diethylnitrosamine (DEN)-induced liver cancer in Wistar rats. The chemo-preventive effects of ginger at doses of 75 mg/kg, 150 mg/kg and 300 mg/kg per day were determined using a liver cancer model which was induced by DEN (Ali et al., 2008) and 2-acetylaminofluorene (2-AAF) in rats. Ginger attenuated carcinogenic changes after 22 weeks of cancer induction by decreasing the quantity and occurrences of hepatic dyschromatic nodules and positive focal areas as well as decreasing the amount of placental glutathione S-transferase (GST) in the livers of DEN/2-AAF-treated rats. Moreover, in rats, ginger counteracts DEN-influenced oxidative stress and decreases myeloperoxidase, malondialdehyde and protein carbonyl concentrations in the liver. This was determined by observing the restoration of superoxide dismutase, catalase, GST and glutathione. Immunohistochemical bleaching in rat livers showed that ginger prevented the increase in cell-positive numbers for Ki-67, cyclooxygenase-2 and nuclear factor kappa B p65. Ginger also inhibited the number of positive cells in DEN/2-AAF-treated rats for TUNEL, M30 and caspase-3 liver tissues. This research shows that ginger has an important chemo-preventative impact on liver cancer by inhibiting the growth of cells and inducing apoptosis. By reducing oxidative and inflammatory damage, ginger protects rat liver against cancer.
Cisplatin-induced testicular damage is a major obstacle in the application of cisplatin as chemot... more Cisplatin-induced testicular damage is a major obstacle in the application of cisplatin as chemotherapeutic agent. However, it remains as one of the most widely employed anticancer agents in treating various solid tumors including prostate cancer. Since heme-oxygenase-1 (HO-1) is a cytoprotective enzyme with anti-oxidative stress, anti-inflammatory and anticancer activities, we investigated the effects of up-regulation of HO-1 by hemin and its inhibition by zinc protoporphyrin-IX (ZnPP) on cisplatin-induced testicular toxicity in adult rats. Furthermore, the anticancer effect of hemin and ZnPP, with and without cisplatin, was evaluated on human prostate cancer cell line, PC3. Results of the animal study showed that hemin reversed cisplatin-induced perturbations in sperm characteristics, normalized serum testosterone level, and ameliorated cisplatin-induced alterations in testicular and epididymal weights, and restored normal testicular architecture. Moreover, hemin increased the expression and activity of HO-1 protein and prevented cisplatin-induced testicular toxicity by virtue of its antioxidant and anti-inflammatory effects. This effect was evidenced by amelioration of testicular oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione contents, and catalase activity) and inflammatory mediators (tumor necrosis factor-α and nitric oxide synthase expressions). In contrast, administration of ZnPP (HO-1 inhibitor) did not show significant improvement against cisplatin-induced testicular toxicity. Finally, in vitro analyses showed that, hemin augmented the anticancer efficacy of cisplatin, while ZnPP inhibited its apoptotic effect in PC3 cells. In conclusion, the induction of HO-1 represents a potential therapeutic approach to protect the testicular tissue from the detrimental effects of cisplatin without repressing, but rather augmenting, its cytotoxic effects on PC3 cells.
AIM The neuronal damage and accompanied functional deficits induced by cerebral ischemia are amon... more AIM The neuronal damage and accompanied functional deficits induced by cerebral ischemia are among the most common causes of disabilities in adults. Activation of subtypes of peroxisome proliferator-activated receptors (PPARs); PPAR-α and PPAR-γ have shown neuroprotective effects in different neurodegenerative diseases including stroke. Thus, this study aimed to compare the effects of two different agonists: PPAR-α (fenofibrate) and PPAR-γ (pioglitazone) as well as the effect of their combination in ameliorating post-ischemia behavioral deficits. METHODS Male Wistar rats were either pretreated with vehicle, fenofibrate (100 mg/kg/day p.o), pioglitazone (10 mg/kg/day p.o) or their combination for 14 days prior to bilateral common carotid artery occlusion followed by reperfusion for 24 h. The sensory motor functions of rats were assessed, then rats were sacrificed to determine infarct volume and histopathological changes as well as oxidative stress, inflammatory and apoptotic markers in the brain tissue. KEY FINDINGS Pre-treatment with fenofibrate and pioglitazone in addition to their combination improved neurobehavioral dysfunction, reduced cerebral infarct volume, attenuated inflammatory and apoptotic markers and ameliorated histopathological changes in I/R injured rats. The effect of pioglitazone in cerebral cortex was higher than its corresponding effect in fenofibrate while the combined administration of both drugs had additive neuroprotective effect and normalized inflammatory and apoptotic mediators in ischemic rats. SIGNIFICANCE The study compared the neuroprotective effects of PPAR-α and PPAR-γ agonists, and tested the impact of their combination. We concluded that no additional benefits on the functional outcomes might be gained upon their combination.
Journal of Biochemical and Molecular Toxicology, Jul 23, 2023
Gastric ulcer is a common disease with increased prevalence in the aged population. Aged gastric ... more Gastric ulcer is a common disease with increased prevalence in the aged population. Aged gastric mucosa has increased susceptibility to injury along with nonsteroidal anti‐inflammatory drugs use due to impaired mucosal defense and decreased vasodilator release. We investigated whether l‐arginine could protect against age‐related gastric ulceration induced by indomethacin. Aged and adult male Wistar rats were administered sole and combined treatment of l‐arginine and Nω‐nitro‐l‐arginine methyl ester ( l‐NAME) before induction of gastric ulceration by indomethacin. The gastroprotective effect of l‐arginine was displayed only in adult rats with indomethacin‐induced gastric ulceration, as evidenced by a significant decrease in ulcer index, oxidative stress parameters, and mucosal myeloperoxidase activity along with increased mucosal PGE2 levels. Interestingly, the mucosal gene expressions of NF‐кB, iNOS, and COX‐2 were significantly suppressed by l‐arginine pretreatment and aggregated upon pretreatment with l‐NAME in both adult and aged rats treated with indomethacin. In conclusion, l‐arginine protected the rats' gastric mucosa against indomethacin‐induced gastric ulceration, possibly, at least in part, by enhancement of mucosal nitric oxide/PGE2 content along with suppressing gastric inflammation and oxidative stress. This study supposed that the gastroprotective effect of l‐arginine depends on aging, and even so, the adoption of a new approach to gastric ulcer treatment for the aged population is warranted.
Despite being extremely potent against malignancies, cisplatin (CIS) has limited practical applic... more Despite being extremely potent against malignancies, cisplatin (CIS) has limited practical applicability due to its adverse effects such as testicular damage. Consequently, it becomes necessary to reduce its toxicity. In this study, cilostazol, a selective phosphodiesterase-3 inhibitor that is frequently used in the treatment of intermittent claudication, was examined for its ability to abrogate CIS-induces testicular toxicity and its ameliorative effect was compared with two phosphodiesterase inhibitors, tadalafil and pentoxifylline. The study also focused on the possible mechanisms involved in the proposed protective effect. Ten groups of rats were included; Group (1): control, Groups (2-4): 5 mg/kg tadalafil or 75 mg/kg pentoxifylline or 20 mg/kg cilostazol respectively), Group (5):7 mg/kg CIS, Group (6&7): CIS + 5 mg/kg tadalafil or 75 mg/kg pentoxifylline, Group (8-10) CIS+ 5, 10 or 20 mg/kg cilostazol respectively. CIS treated rats showed a significant decrease in testicular f...
Hydrogen sulfide (H2S) is an endogenously gas transmitter signaling molecule with known antioxida... more Hydrogen sulfide (H2S) is an endogenously gas transmitter signaling molecule with known antioxidant, anti-inflammatory, and cytoprotective properties. Although accumulating evidence shows the therapeutic potential of H2S in various hepatic diseases, its role in cyclophosphamide (CP)-induced hepatotoxicity remains elusive. The present study was undertaken to investigate the impact of endogenous and exogenous H2S on toll-like receptors (TLRs)-mediated inflammatory response and apoptosis in CP-induced hepatotoxicity. Either an H2S donor (NaHS (100 μM/kg) or an H2S blocker [dl-propargylglycine (PAG) (30 mg/kg, i. p.)], was administered for 10 days before a single ip injection of CP (200 mg/kg). NaHS attenuated conferred hepatoprotection against CP-induced toxicity, significantly decreasing serum hepatic function tests and improving hepatic histopathology. Additionally, NaHS-treated rats exhibited antioxidant activity in liver tissues compared with the CP group. The upregulated hepatic l...
Background and Objectives: Nephroprotective effect of statins is still controversial. The aim of ... more Background and Objectives: Nephroprotective effect of statins is still controversial. The aim of this study was to investigate the possible hemin-like nephroprotective effect of rosuvastatin (RSV) in streptozotocin (STZ)-induced diabetic rats. Materials and Methods: DN was induced in rats via a single dose of 50 mg/kg STZ i.p., with or without RSV (10 mg/kg orally) for 30 days. To investigate hemin-like effect of RSV on renal heme oxygenase-1 (HO-1), RSV was administered in the presence or absence of an inhibitor of HO-1; zinc protoporphyrin-XI (ZnPP), in a dose of 50 µmol/kg i.p. Results: Induction of diabetes with STZ caused, as expected, significant hyperglycemia, as well as deteriorated kidney function, lipid profile and histopathological architecture. The DN group also showed renal oxidative stress, indicated by decreased superoxide dismutase, catalase, and reduced glutathione, with increased malondialdehyde, myeloperoxidase and nitric oxide. Renal expression of inflammatory ma...
Uncontrolled diabetes mellitus (DM) has been associated with poor clinical outcomes in patients w... more Uncontrolled diabetes mellitus (DM) has been associated with poor clinical outcomes in patients with ischemic stroke. Limited knowledge is available regarding the molecular mechanisms and the etiological complexity of both pathologies. Hence, this study aimed to investigate the interplay between long-term DM and ischemic stroke. A comparative study was held between long-term DM-induced adult male Wistar rats which were subjected to sham operation or global cerebral ischemia/reperfusion (I/R) injury on one hand, and adult male Wistar rats which were subjected to sham operation or global cerebral I/R injury on the other hand. Results showed a disturbance in cerebral oxidative stress parameters (catalase, reduced glutathione and malondialdehyde) in diabetic rats compared to non-diabetic ones. Additionally, in comparison with sham diabetic group, diabetic I/R-injured rats showed up regulation of cerebral oxidative stress, caspase-3 and tumor necrosis factoralpha (TNF-α) protein expressi...
AIMS Diabetic nephropathy, a major threat to diabetic patients, is considered as the main reason ... more AIMS Diabetic nephropathy, a major threat to diabetic patients, is considered as the main reason for end-stage renal disease. Fortunately, incretin-based therapy has been aroused as considerable source to attenuate diabetic renal damage. This study aimed to investigate whether superior protective effects on the progression of diabetic kidney are exerted by glucagon-like peptide-1 analog, exenatide, or dipeptidyl peptidase-4 inhibitor, sitagliptin. MATERIALS AND METHODS Male Wistar rats were fed high-fat diet for 2 weeks followed by injection of low dose streptozotocin to induce type 2 diabetes mellitus. Four weeks after induction of diabetes, diabetic rats were administered vehicle, exenatide (5 μg/kg/day, SC) or sitagliptin (10 mg/kg/day, orally) for 4 weeks. KEY FINDINGS Different incretin mimetic agents improved renal function as evident by significant decreases in serum creatinine and urea levels with decline in urinary microalbuminuria and marked improvement in histological alterations. Both treated diabetic rats also exhibited a significant improvement in metabolic intolerance with more pronounced effect of exenatide on glucose regulation. Ameliorated renal oxidative stress alongside significant downregulation in transforming growth factor-beta, tumor necrosis factor-alpha and cleaved-caspase-3 protein expressions in renal tissues were recorded in treated diabetic rats. SIGNIFICANCE Administration of either exenatide or sitagliptin showed ameliorative effects on early diabetic nephropathy without notable differences between their renal protective effects. However, further clinical studies are still required to ensure their comparative promising effects on the management of renal complication of diabetes.
Diabetic nephropathy is the principal cause of end-stage renal failure and current interventions ... more Diabetic nephropathy is the principal cause of end-stage renal failure and current interventions for its recession remains unsatisfactory. Mesenchymal stem cells (MSCs) hold an attractive source for renovating injured tissues. Unfortunately, limited self-renewal and migration capacity of MSCs after transplantation hinder their clinical applicability which demands a new policy for enhancing their biological functions. This study aimed to investigate whether the renoprotective potential of adipose-derived MSCs (ADMSCs) in diabetic rats could be promoted by exenatide, a glucagon-like peptide-1 (GLP-1) analogue. These effects were studied in type 2 diabetes mellitus rats which were administrated ADMSCs, exenatide or their combination four weeks post-induction. Four weeks later, renal function parameters were evaluated. To address the possible underlying mechanisms, parameters indicating glycolipid metabolism tolerance and oxidative stress biomarkers were assessed in renal tissues alongside evaluation of protein expression of tumor necrosis factor-alpha, transforming growth factor-beta1 and cleaved caspase-3. The results showed that the combined therapy had superior renoprotective effect as evident by significant improvement in kidney function and renal architecture changes through rebalancing of inflammatory, fibrotic and apoptotic markers. Based on these outcomes, ADMSCs with exenatide were supposed to effectively ameliorate diabetic renal dysfunction compared to ADMSCs solely, presenting a promise therapy for diabetic nephropathy with further clinical studies warranted to validate this effect.
AIM Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. This study w... more AIM Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. This study was performed to investigate the possible protective effect of lixisenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, on early diabetic nephropathy induced in diabetic rats and explore the various mechanisms underlie this postulated effect. MAIN METHODS Early DN was induced after 3 weeks in diabetic rats fed with a high-fat diet (HFD) and treated with low dose STZ. One week after induction of diabetes, diabetic rats were administered lixisenatide at two dose levels (1 and 10 nmole/kg/day, ip) or glimepiride (2 mg/kg/day, p.o.) for 2 weeks. KEY FINDINGS Lixisenatide, in a low dose regimen, induced a nephroprotective effect evident by significant decreases in serum creatinine and serum urea along with improved renal histology. Low lixisenatide dose showed an antioxidant effect, exhibited by a significant decrease in renal malondialdehyde and total NOx- levels along with a marked rise in total antioxidant capacity. Apart from ameliorating glucose intolerance and insulin resistance, significant down-regulation in renal expressions of iNOS, COX-2, and TGF-B1 were recorded in the diabetic group treated with low dose lixisenatide. Furthermore, low dose lixisenatide was reported to be superior to glimepiride as a nephroprotective. On the contrary, treatment with large dose lixisenatide was founded to be deleterious. SIGNIFICANCE Low-dose lixisenatide treatment was able to protect against early diabetic nephropathy, which might represent a promising approach in the management of diabetes and its renal complication however, further clinical studies are warranted.
Ginger has been proposed as quite a promising candidate for cancer prevention. The purpose of thi... more Ginger has been proposed as quite a promising candidate for cancer prevention. The purpose of this study was to assess the chemo-preventive effects of ginger. Furthermore, this study investigated the possible mechanisms of a standardized extract drawn from the rhizomes of ginger against diethylnitrosamine (DEN)-induced liver cancer in Wistar rats. The chemo-preventive effects of ginger at doses of 75 mg/kg, 150 mg/kg and 300 mg/kg per day were determined using a liver cancer model which was induced by DEN (Ali et al., 2008) and 2-acetylaminofluorene (2-AAF) in rats. Ginger attenuated carcinogenic changes after 22 weeks of cancer induction by decreasing the quantity and occurrences of hepatic dyschromatic nodules and positive focal areas as well as decreasing the amount of placental glutathione S-transferase (GST) in the livers of DEN/2-AAF-treated rats. Moreover, in rats, ginger counteracts DEN-influenced oxidative stress and decreases myeloperoxidase, malondialdehyde and protein carbonyl concentrations in the liver. This was determined by observing the restoration of superoxide dismutase, catalase, GST and glutathione. Immunohistochemical bleaching in rat livers showed that ginger prevented the increase in cell-positive numbers for Ki-67, cyclooxygenase-2 and nuclear factor kappa B p65. Ginger also inhibited the number of positive cells in DEN/2-AAF-treated rats for TUNEL, M30 and caspase-3 liver tissues. This research shows that ginger has an important chemo-preventative impact on liver cancer by inhibiting the growth of cells and inducing apoptosis. By reducing oxidative and inflammatory damage, ginger protects rat liver against cancer.
Uploads
Papers by Gehan Heeba