Prophylactic role of α-lipoic acid and vitamin E against zinc oxide nanoparticles induced metabolic and immune disorders in rat's liver.

OBJECTIVES: Potential health hazard is associated with the wide use of nanoparticles. The prophylactic role of either α-lipoic acid (α-lip) or vitamin E (vit E) against the toxic effect of zinc oxide nano-particles (ZnO-NPs) induced metabolic disorder, inflammation and DNA damage in rat livers was studied. MATERIALS AND METHODS: ZnO-NPs were administered orally using two doses (600 mg and 1 g/kg body weight/day for 5 conscutive days). Some biomarkers of tissue damage, metabolic disorder, and DNA damage were investigated to explore the protective mechanisms of α-lip or vit E against ZnO-NPs induced hepatotoxicity. RESULTS: Co-administration of either α-lip (200 mg/kg body weight) or vit E (100 mg/kg body weight) daily for three weeks to ZnO-NPs intoxicated rats, significantly down-modulated the marked increase in serum ALT (marker of liver damage) and also serum glucose level (marker of metabolic disorder) as well as the pro-inflammatory biomarkers including nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), and immunoglobin G (IGg). Reduced glutathione level was decreased while caspase3 level was elevated in liver tissues of ZnO-NPs treated group compared with intoxicated one. Moreover histopathological examination of liver tissue supported the previous biochemical markers. Furthermore, ZnO-NPs induced hepatic oxidative DNA damage. CONCLUSIONS: Either α-lip or vit E proved to be hepatoprotective agents against ZnO-NPs toxicity because they ameliorated metabolic and immune disorders related to liver damage and modulated the previous measured parameters.

Induction of inflammation, DNA damage and apoptosis in rat heart after oral exposure to zinc oxide nanoparticles and the cardioprotective role of α-lipoic acid and vitamin E.

Although zinc oxide nanoparticles (ZnO-NP) are being used on a wide scale in the world consumer market, their potential hazards on humans remain largely unknown. The present study was aimed at investigating the oral toxicity of ZnO-NP in 2 dose regimen (600 mg/kg and 1 g/kg body weight for 5 consecutive days) in rats. In addition, the protective role of either α-lipoic acid (Lipo) or vitamin E (Vit E) against this cardiotoxic effect of ZnO-NPs was assessed. Results revealed that, co-administration of Lipo (200 mg/Kg body weight) or Vit E (100 mg/Kg body weight) daily for 3 weeks to rats intoxicated with ZnO-NPs (in either of the 2 dose regimen) significantly ameliorated the cardiotoxic effect of these nanoparticles. As, both agents significantly reduced the increase in serum cardiac injury markers including troponin-T, creatine kinase-MB (CK-MB), and myoglobin. Additionally, Lipo and Vit E significantly decreased the increase in serum pro-inflammatory biomarkers level including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP). Moreover, either of the 2 used agents successfully alleviated the alteration in nitric oxide (NO) and vascular endothelial growth factor (VEGF) in ZnO-NPs in sera of intoxicated group. They also significantly reduced the increase in cardiac calcium concentration and the consequent oxidative deoxyribonucleic acid (DNA) damage, as well as the increase in cardiac caspase-3 activity of intoxicated rats. Conclusively, these results indicate that early treatment with either α-lipoic acid or vitamin E may offer protection against cardiac tissue injury induced by the deleterious toxic impacts of ZnO-NPs.

Salubrious effects of dexrazoxane against teniposide-induced DNA damage and programmed cell death in murine marrow cells.

The intention of the present study was to answer the question whether the catalytic topoisomerase-II inhibitor, dexrazoxane, can be used as a modulator of teniposide-induced DNA damage and programmed cell death (apoptosis) in the bone marrow cells in vivo. The alkaline single cell gel electrophoresis, scoring of chromosomal aberrations, micronuclei and mitotic activity were undertaken in the current study as markers of DNA damage. Apoptosis was analysed by the occurrence of a hypodiploid DNA peak and caspase-3 activity. Oxidative stress marker such as intracellular reactive oxygen species production, lipid peroxidation, reduced and oxidised glutathione were assessed in bone marrow as a possible mechanism underlying this amelioration. Dexrazoxane was neither genotoxic nor apoptogenic in mice at the tested dose. Moreover, for the first time, it has been shown that dexrazoxane affords significant protection against teniposide-induced DNA damage and apoptosis in the bone marrow cells in vivo and effectively suppresses the apoptotic signalling triggered by teniposide. Teniposide induced marked biochemical alterations characteristic of oxidative stress including accumulation of intracellular reactive oxygen species, enhanced lipid peroxidation, accumulation of oxidised glutathione and reduction in the reduced glutathione level. Prior administration of dexrazoxane ahead of teniposide challenge ameliorated these biochemical alterations. It is thus concluded that pretreatment with dexrazoxane attenuates teniposide-induced oxidative stress and subsequent DNA damage and apoptosis in bone marrow cells. Based on our data presented, strategies can be developed to decrease the teniposide-induced DNA damage in normal cells using dexrazoxane. Therefore, dexrazoxane can be a good candidate to decrease the deleterious effects of teniposide in the bone marrow cells of cancer patients treated with teniposide.

Potent activation of multiple signalling pathways by C-peptide in opossum kidney proximal tubular cells.

AIMS/HYPOTHESIS: Proinsulin C-peptide is generally believed to be inert without any appreciable biological functions. However, it has been shown to modulate a variety of cellular processes important in the pathophysiology of diabetic complications. We therefore investigated the ability of C-peptide to stimulate intracellular signalling pathways in kidney proximal tubular cells, the altered activation of which may possibly be related to the development of diabetic nephropathy. METHODS: Extracellular signal-regulated kinase (ERK) and Akt phosphorylation were evaluated by western blotting. ERK activity was measured by in vitro kinase assay. Intracellular Ca(2+) was evaluated by confocal imaging. The membrane and cytosol-associated fractions of protein kinase C (PKC) isoforms were evaluated by western blotting. Proliferation was assessed by thymidine incorporation assay. RESULTS: Using the opossum proximal tubular kidney cell line as a model, we demonstrated that at high picomolar to low nanomolar concentrations, C-peptide stimulates extracellular signal-regulated mitogen-activated kinase (3.3+/-0.1-fold over basal at 3 minutes) and phosphatidylinositol 3-kinase (4.1+/-0.05-fold over basal at 5 minutes). ERK activation was attenuated by pre-treatment with a PKC inhibitor and abolished by pertussis toxin. Elevations of intracellular [Ca(2+)] are seen in response to 5 nmol/l C-peptide with consequent activation of PKC-alpha. Pre-treatment with pertussis toxin abolished PKC-alpha. C-peptide is also a functional mitogen in this cell type, stimulating significantly increased cell proliferation. Proliferation was attenuated by wortmannin and pertussis toxin pre-treatments. None of these effects is reproduced by scrambled C-peptide. CONCLUSIONS/INTERPRETATION: This study provides evidence that C-peptide, within physiological concentration ranges, stimulates many signalling pathways in opossum kidney cells.

Effects of two newly synthesized analogues of lidocaine on rat arterial blood pressure and heart rate.

Two new analogues of lidocaine were synthesized at the College of Pharmacy, King Saud University: compound I (Methyl-2-[2-(N,N-diethylamino) acetamido]-3-cyano-4,5-dimethylbenzoate) and compound II (Methyl-2-[2-(piperidino) acetamido]-3-cyano-4,5-dimethylbenzoate). Their influence on the arterial blood pressure and the heart rate of urethane-anaesthetized rats was studied and compared with the actions of lidocaine. Compounds I, II and lidocaine induced significant dose-dependent decreases in the arterial blood pressure and heart rate, which usually returned to basal values within 3-5 min. There were significant differences in the potency of the three compounds in producing their effects on blood pressure and heart rate (P< 0.0001, ANOVA). Compound II was 14 and 6 times more potent in reducing blood pressure and 8 and 2 times more capable of reducing the heart rate than lidocaine and compound I, respectively. The results of this study also indicated the ineffectiveness of antagonists of autonomic, histaminergic and 5-HT receptor, and various vasodilators in blocking the actions of the three compounds on blood pressure and heart rate. Pretreatment with CaCl(2)significantly reduced the hypotension and bradycardia induced by the three compounds, suggesting the involvement of calcium channels, probably of the L type. Several possible mechanisms are postulated. In conclusion, the results direct attention to the capability of the two new compounds to decrease blood pressure and heart rate; affects that may have clinical potential.