Canagliflozin ameliorates aortic and hepatic dysfunction in dietary-induced hypercholesterolemia in the rabbit.

AIMS: Canagliflozin is an antidiabetic agent which lowers blood glucose levels by inhibiting the glucose reabsorption machinery in the proximal tubules. There have not been conducted any study on its direct impact on hypercholesterolemia and associated vascular disorders independently of blood glucose lowering activity. MATERIALS AND METHODS: Rabbits were arranged in 3 groups: Group 1 (Control): regular rabbit chow; Group 2 (HCD): 1% cholesterol-enriched chow was given to rabbits for 4 weeks; Group 3 (HCD-CANA): 1% cholesterol-enriched chow was fed to rabbits concurrently with canagliflozin (10 mg/kg/day, orally) for 4 weeks. At the end of experiment, blood and tissue samples were obtained for biochemical, histological, immunohistochemical, and vascular reactivity assessment. KEY FINDINGS: When statistically compared to Control (P < 0.05), HCD showed a significant increase in the serum triglycerides, low-density lipoprotein, total cholesterol, C-reactive protein, alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase. Furthermore, a significant decrease was seen in both liver and aortic levels of glutathione peroxidase and superoxide dismutase concurrently with a significant elevation in malondialdehyde levels. Aortic levels of nitrate/nitrite ratio were significantly elevated. Acetylcholine-induced relaxation was impaired as the Emax decreased significantly in aortae. Moreover, a significant increase was seen in the level of aortic intima/media ratio. Canagliflozin treatment significantly improved vascular function, lipid profile and inflammation and reduced liver injury. SIGNIFICANCE: Our data suggest that SGLT-2 inhibition via canagliflozin not only possesses an antihyperglycemic activity, but also improves hypercholesterolemia, vascular and liver function in dietary-induced hypercholesterolemia in the rabbit.

The potential effect of imatinib against hypercholesterolemia induced atherosclerosis, endothelial dysfunction and hepatic injury in rabbits.

AIMS: Imatinib is an effective tyrosine kinase inhibitor which has different therapeutic actions. The recent work demonstrated the possible beneficial effects of imatinib on the progression of atherosclerosis, endothelial dysfunction, and hypercholesterolemia-associated liver damage in rabbits. MAIN METHODS: Animals had been distributed in 4 groups: group 1 (non-treated): animals fed regular diet; group 2 high cholesterol [HC]: animals fed 1% cholesterol supplemented diet for 30 days; group 3 (HC-Imatinib): animals fed 1% cholesterol supplemented diet+imatinib (0.01 g/kg daily, p.o) for 30 days; group 4 (Imatinib): animals fed regular diet with imatinib (0.01 g/kg daily, p.o). After thirty days, tissue samples and blood were isolated to be detected biochemically, histologically, and for in vitro analysis. KEY FINDINGS: HC exhibited significant elevations in serum lipid parameters, CRP, ALT, AST and ALP. Additionally, HC induced significant increases for aortic and hepatic MDA, aortic NO and hepatic PDGFR-ß, while significantly exhibited reductions in aortic and hepatic GSH, SOD and hepatic PPARγ1. Moreover, HC produced impairment in ACh-enhanced aortic relaxation and aortic pathological changes. Histopathological examination of HC-fed rabbits revealed hepatic steatosis compared with non-treated group. Imatinib administration exhibited significant decreases in serum lipid parameters, CRP, ALT, AST and ALP. Additionally, imatinib induced significant decreases for aortic and hepatic MDA, aortic NO and hepatic PDGFR-ß, while significantly exhibited elevations in aortic and hepatic GSH, SOD and hepatic PPARγ1 compared with HC animals. Furthermore, imatinib significantly protected against HC produced attenuation in ACh-induced aortic relaxation and pathological changes in aortic and hepatic tissues. Interestingly, imatinib could return serum CRP, ALP, hepatic SOD and PDGFR-ß to basal values. SIGNIFICANCE: The recent observation reports that imatinib could have beneficial effect against atherosclerosis progression, vascular malfunction, and liver damage in high cholesterol diet (HCD)-fed rabbits.

Modulation of cyclophosphamide-induced early lung injury by allicin.

CONTEXT: Cyclophosphamide (CP) causes lung injury in rats through its ability to generate free radicals with subsequent epithelial and endothelial cell damage. OBJECTIVE: This study was conducted to assess whether allicin can ameliorate CP-induced early lung injury in rats. MATERIALS AND METHODS: Male Sprague Dawely rats were divided into four groups. Group I was the control group. Group II received allicin (50 mg/kg/d, p.o.) for 14 consecutive days. Group III was injected once with CP (150 mg/kg, i.p.). Group IV received allicin for seven consecutive days, before and after CP injection (150 mg/kg, i.p.). The parameters of study were serum biomarkers, lung tissue antioxidant profile and histopathological changes in lung tissue. RESULTS: A single intraperitoneal injection of CP markedly altered the levels of several biomarkers in lung homogenates. Significant increases in lung content of lipid hydroperoxides were seen that paralleled the decreased levels of total reduced glutathione. Superoxide dismutase activity (SOD) was significantly increased. CP increased the level of serum biomarkers; total protein, lactate dehydrogenase (LDH) and tumor necrosis factor-alpha (TNF-α). Pretreatment of rats daily with oral allicin seven days prior to and seven days after CP inject significantly inhibited the development of lung injury, prevented the alterations in lung and serum biomarkers associated with inflammatory reactions, with less lipid peroxidation (LP) and restoration of antioxidants. Moreover, allicin attenuated the secretion of proinflammatory cytokine, TNF-α expression in rat serum. In addition, allicin effectively blunted CP-induced histopathological changes in lung tissue. DISCUSSION AND CONCLUSION: Our results suggest that allicin is efficient in blunting CP-induced pulmonary damage.

Thymoquinone attenuates cyclophosphamide-induced pulmonary injury in rats.

OBJECTIVE: Antioxidant therapy may be useful in diseases with impaired oxidant-antioxidant balance. This study was designed to examine the effects of thymoquinone (TQ), an anti-inflammatory, antioxidant agent against cyclophosphamide (CP)-induced pulmonary oxidative damage. MATERIALS AND METHODS: Male Sprague-Dawley rats were categorized into four groups. Group I was control. Group II received TQ (100 mg/kg/day, p.o.) for 14 consecutive days. Group III was injected once with CP (150 mg/kg, i.p.). Group IV received TQ for 7 consecutive days, before and after CP injection. The parameters of study were tissue oxidant/antioxidant biomarkers and histological changes in rat lungs. RESULTS: A single intraperitoneal injection of CP markedly altered the levels of several biomarkers in lung homogenates. Significant increases in the content of lipid peroxides in lung were seen that paralleled the decreased levels of reduced glutathione. Cyclophosphamide increased the level of serum biomarkers: total protein, lactate dehydrogenase, and tumor necrosis factor-alpha (TNF-α). Treatment of rats with TQ 7 days before and after cyclophosphamide injection significantly attenuated the alterations in lung and serum biomarkers associated with inflammatory reactions, with less lipid peroxidation and restoration of antioxidants. Moreover, TQ attenuated the secretion of pro-inflammatory cytokine, TNF-α in rat serum. In addition, TQ effectively alleviated CP-induced histopathological changes in lung tissue. DISCUSSION AND CONCLUSION: Our results suggest that TQ produces a protective mechanism against CP-induced pulmonary damage and suggest a role of oxidative stress and inflammation in the pathogenesis.