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Background: A cross-linking agent commonly used for cancer chemotherapy is a platinum compound such as cisplatin. However, with the acquisition of cellular drug resistance and adverse side effects, the potency of cisplatin is, therefore, often tempered. To overcome these issues, the present study has established the use of cathepsin k (CTSK) inhibitor as a potent chemosensitizer. Methods: The cytotoxic effect of cisplatin and odanacatib (ODN) on two different breast cancer patient- derived cell lines, MDA-MB-231 and MCF-7, was assessed by MTT-based colorimetric assay. The drug interaction coefficient CDI was used to evaluate the synergistically inhibitory impact of the drug combination and immunoblot was used to examine the expression of certain proteins responsible for cell survival and the mechanism of apoptosis. Results: In this study, we found that IC50 of ODN in combination with cisplatin (half of IC25) induced a synergistic cytotoxic effect in different breast cancer cells. Diminished expression of Bcl-2 and increased expression of Bax aroused the cytochrome release, that triggered caspase-9 and -3 activation in the combinatorial group. ODN with a lower dose of cisplatin significantly inhibited the protein expression of novel chemoresistant factors such as STAT3, NFκB and IL-6. Conclusion: This study highlights the potential effects of the combination of ODN with a reduced dose of cisplatin on improving the growth inhibition and apoptosis-inducing effect on breast cancer cells via combined inhibition of NF-κB-induced IL-6 and STAT3 activation. The study result suggests that the further development of this novel inhibitor in combination with a low dose of standard cisplatin-based chemotherapy may contribute to an alternative treatment option for certain cancers.

Background: Multivariate analysis is a chemometric tool that has been little explored to determine physiological status under heavy metal stress. Nevertheless, PCA has an unexplored potential to determine the plant physiologic status and its modification under stress factors like heavy metals. Objectives: This work aims to assess the physiological and biochemical effects and responses of wheat plants under the different exposition of As and Cd using multivariate models. Materials and Methods: Wheat plants growing in a greenhouse were exposed to 0, 10 and 50 mg kg-1 soil of As and 0, 10 and 33 50 mg kg-1 soil of Cd until growth stage 5. After 56 days, wheat leaves and roots were collected to determine dry weight, lipid peroxidation and the activity of three enzymes: catalase, ascorbate peroxidase and guaiacol peroxidase. These measures were considered as the variables of three performed multivariate models to determine physiological status. Results: Through the interpretation of score plot and loading plot in combination, it was possible to determine that both As and Cd affect chlorophyll content and antioxidant response. However, a chlorophyll decrease and a lipid peroxidation increase were observed together with an inhibition of antioxidant response more accentuated in wheat plants exposed to As than those exposed to Cd. Conclusions: Multivariate analysis allows us to determine the differences between the physiological behavior of both stressors, which turn this chemometric tools useful for the characterization of a physiological response.

BACE1, a @b secretase candidate enzyme, initiates the Alzheimer's disease (AD) pathogenesis via amyloid @b (A@b) peptide production serving as a potential therapeutic target. Previous experimental evidence suggested that ginsenosides, a key component of Panax ginseng, are effective against AD. In this study, we implemented a molecular modeling method to reveal the inhibitory action of ginsenosides on BACE1 activity. We selected 12 ginsenosides and performed molecular docking studies to evaluate its interaction with the BACE1 active site, which is essential for inhibition. Further ADMET filtration was applied to find drug-like molecules with a specific ability to cross blood brain barrier (BBB), and to determine toxicity. The BACE1-ginsenosides complex was further subjected to a molecular dynamics simulation to study the stability of the complex and its hydrogen bond interactions. In summary, our findings show ginsenosides CK, F1, Rh1 and Rh2 are potential BACE1 inhibitors from Panax ginseng.

Impaired antioxidant defense mechanisms and oxidative stress are implicated in the pathogenesis of arsenic toxicity. Our study was designed to determine whether alpha-lipoic acid, which has been shown to have substantial antioxidant properties, when administered (70 mg/kg body weight) once daily for 60 days along with arsenic (100 ppm sodium arsenite mixed in drinking water) would prevent arsenic-induced changes in antioxidant defense system, superoxide dismutase (SOD-total SOD, Mn SOD, Cu/Zn SOD), catalase (CAT) and glutathione peroxidase (GSH-PX) in rat brain regions such as cortex, hypothalamus, striatum, cerebellum and hippocampus. The present study also examined the effect of alpha-lipoic acid over arsenic-induced oxidant production and lipid peroxidation level (LPO) in discrete brain regions of rats. The cortex, striatum and hippocampus showed greater decreases in GSH-Px enzyme activity than cerebellum and hypothalamus with arsenic exposure. Striatum had the greatest percentage of decreased activities of total SOD and Mn SOD, whereas cortex had the greatest percentage decrease in the activity of Cu/Zn SOD in arsenic-alone treated rats. Hypothalamus and cerebellum exhibited the lowest catalase activity among all tested regions in arsenic-only treated rats. Rate of dichlorofluorescin oxidation, an indication of reactive oxygen species and other intracellular oxidants production was increased with arsenic exposure in all brain regions studied. Cortex, hippocampus and striatum exhibited greater increase of LPO levels than cerebellum and hypothalamus. SOD, CAT, GSH-Px activities were upregulated in arsenic plus lipoic acid treated versus arsenic-only treated rats. Also, simultaneous lipoic acid treatment along with arsenic proved to be sufficient in reducing oxidant production and LPO level in all rat brain regions. Our results demonstrate that arsenic-induced deficits in antioxidant enzyme activities and increase in oxidant production and lipid peroxidation level in brain regions can be overcome through simultaneous treatment with lipoic acid.

The purpose of this study was to examine the effects of DL: -alpha-lipoic acid (LA) on arsenic (As) induced alteration of glutathione (GSH) level and of the activity of glutathione-related enzymes-glutathione peroxidase (GSH-Px), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G6PDH)-in rat brain regions (cortex, hypothalamus, striatum, cerebellum and hippocampus). Male Wistar rats of 150+/-10 g weight were divided into four groups: control and three experimental groups supplemented with arsenic (sodium arsenite) alone (100 ppm mixed in drinking water), lipoic acid alone (70 mg kg(-1) body weight), arsenic plus lipoic acid (100 ppm arsenic in drinking water plus 70 mg lipoic acid kg(-1) body weight). The arsenic content of brain regions was found to increase with the administration of sodium arsenite. Arsenic exposure elicited a significant decline in glutathione content and in the activity of related enzymes, with the greatest decreases seen in the cortex, striatum, and hippocampus, whereas there were no significant differences between control rats and the group treated with lipoic acid alone. Highly elevated content of the thiobarbituric acid-reactive substance malondialdehyde (MDA) in the brain regions of arsenic-exposed rats reflected extensive lipid peroxidation (LPO) processes. Simultaneous lipoic acid treatment was effective in reducing brain regional arsenic levels and lipid peroxidation and in increasing the glutathione content and the activity of its related enzymes. Lipoic acid, by acting as an alternative sulfhydryl nucleophile to glutathione, prevents its oxidation to glutathione disulfide in detoxifying reactions against reactive oxygen species and consequently increases the activity of glutathione-related enzymes.

Arsenic, a naturally occurring element, is present in food, soil, air and water. All human populations are exposed to arsenic and its compounds through occupational or environmental processes. Since arsenic compounds have been shown to exert their toxicity chiefly by generating reactive oxygen species, we have evaluated the effect of ascorbic acid and a-tocopherol on oxidative damage, antioxidant status and on xenobiotic metabolizing systems in arsenic-exposed rat liver and kidney microsomes. Arsenic exposure increases oxidative damage to lipids and proteins and decreases the levels of antioxidants and the activities of xenobiotic metabolizing enzymes. Coadministration of ascorbic acid and a-tocopherol to arsenic-exposed rats resulted in a reduction in the levels of lipid peroxidation, protein carbonyls and hydrogen peroxide and an elevation in the levels of reduced glutathione, ascorbic acid and a-tocopherol. Ascorbic acid and a-tocopherol treatment decreases the activity of haem oxygenase, whereas it increases the levels/ activity of cytochrome P450, cytochrome b5 and NADPH-cytochrome P450 reductase in arsenic-intoxicated rats. The results of this study provide evidence that ascorbic acid and a-tocopherol supplementation can improve the arsenic-induced altered microsomal functions in liver and kidney.

It is hypothesized that a reduction in the level of antioxidants with age leads to an impairment in the quenching of free radicals, which in turn increases the risk of succumbing to age-associated disorders. Male albino rats of Wistar strain (both young and aged rats) were treated with lipoic acid for 7 and 14 days. Analyses were carried out in blood, liver, kidney, and brain for lipid peroxidation, reduced glutathione, ascorbic acid, and α-tocopherol. The levels of reduced glutathione, and vitamins C and E were found to be lowered in aged rats, whereas the level of lipid peroxidation was found to be high. After intraperitoneal administration of lipoate (a thiol antioxidant) to the aged rats, a time-dependent reduction in the level of lipid peroxidation and elevation in the levels of reduced glutathione, and vitamins C and E were observed. From our observations, we conclude that lipoic acid, a dithiol, normalizes lipid peroxidation and prevents the oxidation of reduced glutathione, possibly through recycl...

The effect of DL-α-lipoic acid on lipid peroxidation and antioxidant enzymes were evaluated in various brain regions of young and aged rats. Lipoate contents of discrete brain regions were also measured. In aged rats, the activities of superoxide dismutase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase were low whereas thiobarbituric acid reactive substances were found to be high. Catalase activity in various brain regions was little altered in aged rats. Lipoic acid an antioxidant was administered intraperitoneally (100 mg/kg body weight per day) for 7 and 14 days. Lipoate administered aged rats showed a duration dependent reduction in the level of lipid peroxidation and elevation in the activities of antioxidant enzymes. There was a rise in the level of lipoate in aged rats after supplementation of lipoate in all the brain regions examined. From our results we conclude that lipoate supplementation had a beneficial effect in both preventing and reversing abnormalities in ageing brain. This beneficial effect was associated with normalization of lipid peroxidation and partial restoration in the activities of various enzymatic antioxidants suggesting that lipoate supplementation could improve brain antioxidant functions in the elderly.

Mitochondrial damage has implicated a major contributor for ageing process. In the present study, we measured mitochondrial membrane swelling, mitochondrial respiration (state 3 and 4) by using oxygen electrode in skeletal muscle of young (3–4 months old) and aged rats (above 24 months old) with supplementation of l-carnitine and dl-α-lipoic acid. Our results shows that the mitochondrial membrane swelling and state 4 respiration were increased more in skeletal muscle mitochondria of aged rats than in young control rats, whereas the state 3 respiration, respiratory control ratio (RCR) and ADP:O ratio decreased more in aged rats than in young rats. After supplementation of carnitine and lipoic acid to aged rats for 30 days, the state 3 respiration and RCR were increased, whereas the state 4 and mitochondrial membrane swelling were decreased to near normal rats. From our results, we conclude that combined supplementation of carnitine and lipoic acids to aged rats increases the skeletal muscle mitochondrial respiration, thereby increasing the level of ATP. (Mol Cell Biochem xxx: 83–89, 2005)

Free radicals have been hypothesized to play an important role in ageing process. There exists an imbalance between free radical production and antioxidant defense mechanism, which may lead to cell death during ageing. Our study was designed to determine whether extract of Centella asiatica, an antioxidant, when administered orally (300 mg/kg body weight/day) for 60 days would prevent age-related changes in antioxidant defense system, lipid peroxidation (LPO) and protein carbonyl (PCO) content in rat brain regions such as cortex, hypothalamus, striatum, cerebellum and hippocampus. Aged rats elicited a significant decline in the antioxidant status and increased the LPO and PCO as compared to control rats in all five regions studied. The increase in LPO and PCO contents were (64%, 34%) in cortex, (86%, 30%) in cerebellum, (51%, 47%) in striatum, (77%, 27%) in hypothalamus and (58%, 45%) in hippocampus, respectively, in aged rats as compared to young rats. Supplementation of C. asiatica was effective in reducing brain regional LPO and PCO levels and in increasing the antioxidant status. Thus, C. asiatica by acting as a potent antioxidant exerted significant neuroprotective effect and proved efficacious in protecting rat brain against age related oxidative damage.

Arsenic exists ubiquitously in our environment and various forms of arsenic circulate in air, water, soil and living organisms. Since arsenic compounds have shown to exert their toxicity chiefly by generating reactive oxygen species, we have evaluated the effect of antioxidants ascorbic acid and alpha-tocopherol on lipid peroxidation, antioxidants and mitochondrial enzymes in liver and kidney of arsenic exposed rats. A significant increase in the level of lipid peroxidation and decrease in the levels of antioxidants and in the activities of mitochondrial enzymes were observed in arsenic intoxicated rats. Co-administration of arsenic treated rats with ascorbic acid and alpha-tocopherol showed significant reduction in the level of lipid peroxidation and elevation in the levels of ascorbic acid, alpha-tocopherol, glutathione and total sulfhydryls and in the activities of isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, NADH-dehydrogenase and cytochrome c oxidase. From our results, we conclude that ascorbic acid and alpha-tocopherol alleviate arsenic- induced alterations in mitochondria.