[Show abstract][Hide abstract] ABSTRACT: The present study demonstrates that curcumin acts as pro-oxidant and sensitizes human lung adenocarcinoma epithelial cells (A549) to apoptosis via intracellular redox status mediated pathway. Results indicated that curcumin induced cell toxicity (light microscopy and MTT assay) and apoptosis (AnnexinV-FITC/PI labeling and caspase-3 activity) in these cells. These events seem to be mediated through generation of reactive oxygen species (ROS) and superoxide radicals (SOR) and enhanced levels of lipid peroxidation. These changes were accompanied by increase in oxidized glutathione (GSSG), reduced glutathione (GSH) and gamma-glutamylcysteine synthetase (gamma-GCS) activity, but decrease in GSH/GSSG ratio. The induction of apoptosis and decrease in GSH/GSSG ratio was also accompanied by sustained phosphorylation and activation of p38 mitogen activated protein kinase (MAPK). On the other hand, addition of N-acetyl cysteine (NAC), an antioxidant, blocked the curcumin-induced ROS production and rescued malignant cells from curcumin-induced apoptosis through caspase-3 deactivation. However, L-buthionine sulfoximine (BSO), a GSH synthesis blocking agent, further enhanced curcumin-induced ROS production and apoptosis in A549 cells. Decreased GSH/GSSG ratio seems to be a crucial factor for the activation of MAPK signaling cascade by curcumin. The study therefore, provides an insight into the molecular mechanism involved in sensitization of lung adenocarcinoma cells to apoptosis by curcumin.
Indian journal of experimental biology 12/2012; 50(12):853-61. · 0.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oxidative stress is a leading cause of male infertility. To combat this, germ cells and spermatozoa are endowed with various enzymes, vitamins and proteins. Certain other components of food, including bioflavonoids, also provide protection against free radicals. This study analysed the effect of quercetin, a bioflavonoid, on male reproductive function in adult mice, after intraperitoneal treatment with varying concentrations of quercetin (2, 8 and 20 mg kg(-1) b.wt.) for 2 weeks. Quercetin increased the generation of reactive oxygen species and lipid peroxidation in the testis with concomitant decrease in sperm count and motility in a dose-dependent manner. Activities of antioxidant enzymes catalase, superoxide dismutase and levels of reduced glutathione were found to be decreased in a dose-dependent manner. Also, the levels of oxidised glutathione were increased leading to a shift in redox ratio. The testicular histomorphology was also altered dose dependently. Germ cell kinetic study revealed significant loss of various germ cell populations with increasing dose of quercetin. Interestingly, there was a reduction in germinal epithelium thickness concomitant with an increase in seminiferous tubule lumen diameter. In conclusion, the deleterious effects of quercetin on germ cells could be attributed to its pro-oxidant ability that might affect the Sertoli cell functions.
[Show abstract][Hide abstract] ABSTRACT: Although oxidative stress is implicated in renal cell carcinoma pathogenesis, to our knowledge changes in oxidative stress parameters in patients who undergo surgery for renal cell carcinoma have not been studied previously. We investigated the status of oxidative stress in patients with renal cell carcinoma.
Reactive oxygen species, nitric oxide and glutathione were measured in the blood of 68 patients with renal tumor and in 30 age matched normal controls. Levels were measured again 1 week, and 1 and 2 months postoperatively in patients who underwent surgery for renal cell carcinoma. Levels of superoxide dismutase, catalase and lipid peroxidation were measured in tumor tissue and in normal renal parenchyma in 51 patients with renal tumor.
Significantly increased reactive oxygen species and nitric oxide, and decreased glutathione were observed in patients with renal cell carcinoma compared to normal subjects and in patients with benign tumors. Superoxide dismutase and lipid peroxidation were increased and catalase was decreased in tumor tissue compared to normal renal tissue. Oxidative stress correlated with renal cell carcinoma grade and stage but decreased after curative resection. Patients with metastatic disease had persistently increased oxidative stress parameters. Antioxidant enzyme levels in benign tumor tissue were significantly higher than in renal cell carcinoma.
Patients with renal cell carcinoma have increased oxidative stress, which is effectively alleviated by curative resection. In patients with benign tumors antioxidant defense mechanisms maintain normal redox status.
The Journal of urology 02/2012; 187(4):1172-6. DOI:10.1016/j.juro.2011.11.105 · 4.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Airways inflammation, a pathological hallmark of asthma, is associated with the recruitment of pro-inflammatory and inflammatory cells like eosinophils, polymorphonuclear leucocytes cells, mononuclear cells, macrophages, epithelial desquamation, and airways remodeling with sub-epithelial fibrosis. Activated inflammatory cells along with the resident cells can generate pro-inflammatory mediators including oxidants such as superoxide radicals, reactive oxygen species (ROS), and reactive nitrogen species. One of such inflammatory mediator that has received considerable attention is the nitric oxide (NO(•)) generated by pulmonary macrophageal/epithelial cells. In this study, we have explored that systemic monocytes also get activated in asthma to produce oxidants like ROS and NO(•). We estimated the NO(•) production, nitric oxide synthase (NOS) activity, inducible NOS (iNOS) mRNA levels and total free radical activity (TFRA) in blood monocytes of healthy control subjects, untreated asthmatic patients, patients on corticosteroid for less than 6 months and patients on corticosteroid for more than 6 months. Increase in NOS activity, NO(•) levels, and TFRA was observed in monocytes of asthmatic patients. The increase was found to be associated with the transcriptional upregulation of iNOS gene and severity of disease. Highest values of NOS activity, NO(•), and iNOS mRNA were found in the patients with acute asthma. Corticosteroid administration was found to be effective in reversing the induction of iNOS mRNA levels, NOS activity and NO(•) levels. Corticosteroids controlled asthma appears to have association with NOS, NO(•), and TFRA in systemic monocytes of the patients.
[Show abstract][Hide abstract] ABSTRACT: In the present study, an attempt was made to study the acute and sub-acute toxicity profile of G3-COOH Poly (propyl ether imine) [PETIM] dendrimer and its use as a carrier for sustained delivery of model drug ketoprofen. Drug-dendrimer complex was prepared and characterized by FTIR, solubility and in vitro drug release study. PETIM dendrimer was found to have significantly less toxicity in A541 cells compared to Poly amido amine (PAMAM) dendrimer. Further, acute and 28 days sub-acute toxicity measurement in mice showed no mortality, hematological, biochemical or histopathological changes up to 80 mg/kg dose of PETIM dendrimer. The results of study demonstrated that G3-COOH PETIM dendrimer can be used as a safe and efficient vehicle for sustained drug delivery.
European Journal of Medicinal Chemistry 11/2010; 45(11):4997-5005. DOI:10.1016/j.ejmech.2010.08.006 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Present study was initiated to evaluate the effects of cigarette smoke condensate (CSC) on the cellular changes at molecular levels in non-small lung carcinoma cells (A549). Cigarette smoke condensate at low concentration (0.1 microg/ml) induced cancer cell proliferation, DNA synthesis, reduced glutathione (GSH) levels and intercellular adhesion molecule-1 (ICAM-1) expression without any significant change in reactive oxygen species (ROS) and superoxide radicals (SOR) production. The increased levels of GSH and ICAM-1 due to increased gamma-glutamylcysteine synthetase (gamma-GCS) activity and transcriptional activation of ICAM-1 gene respectively might be via activation of p38 mitogen activated protein kinase (p38 MAPK). The induction of ICAM-1 expression and cell proliferation reflect the tumor promoting activity of low CSC concentration. On the other hand, high CSC concentration (50 microg/ml), which is doubtful to be achieved in the lungs even in the chain smokers, induced killing effects on cancer cells by increasing apoptosis, ROS and SOR production, inducing cell cycle arrest, and increased ICAM-1 levels. These changes were found to be associated with altered GSH/GSSG ratio which shifted the redox balance towards more oxidizing equivalent followed by activation of p38 MAPK and stress-activated protein kinase (SAPK) involved in signaling cascade and finally transcriptional activation of gamma-GCS and ICAM-1 genes. These changes were found to be p38 and SAPK dependent.
Cancer letters 07/2008; 270(1):120-31. DOI:10.1016/j.canlet.2008.04.039 · 5.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The study was designed to investigate the effect of nimesulide on lipopolysaccharide (LPS)-induced proinflammatory oxidants production by rat alveolar macrophages (AMs). Effects of LPS and nimesulide on antioxidant defense and the expression of inducible nitric oxide synthase (iNOS) were also studied. It was found that nimesulide could scavenge superoxide anions (O2*-), nitric oxide (NO*) and total oxidant burden induced by LPS in AMs in vitro. Approximately 850 nmoles of nimesulide had activity equivalent to one IU of superoxide dismutase (SOD). Further, to confirm the in vitro observation, Male Wistar rats were orally administered with nimesulide (9 mg/kg b. wt. twice daily) for one week followed by intratracheal instillation of 2 microg LPS to stimulate lung inflammation. AMs from bronchoalveolar lavage fluid were collected 18 h after instillation of LPS. Nimesulide pretreatment could inhibit O2*-, NO() and lipid peroxidation in AMs. Nimesulide also suppressed LPS-induced iNOS expression in AMs in vivo and in vitro. Nimesulide could also normalize LPS-induced changes in the levels of superoxide dismutase (SOD), glutathione reductase (GR) and reduced glutathione (GSH) in AMs. Inhibition in production of oxidants in LPS-challenged AMs by nimesulide could be one of the pathways for its anti-inflammatory action.
Life Sciences 04/2006; 78(15):1662-9. DOI:10.1016/j.lfs.2005.07.033 · 2.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Esophageal carcinoma has a high incidence in India but its etiology remains unknown. In the present study the correlation between apoptosis regulatory proteins and anti-oxidant enzymes in 40 esophageal carcinoma patients was examined. Patients in one group were operated by transhiatal esophagectomy and in the second group were administered cisplatin (30 mg/m2/day) and 5-fluorouracil (5-FU) (750 mg/m2/day) daily for three days followed by surgery after four weeks of neo-adjuvant therapy (NAT). Complete pathological response was achieved in 15% of patients. Results obtained by Western blot analysis showed over-expressed p53 and COX-2 protein levels in the tumor tissues as compared to the adjoining tissue and its paired normal mucosa in both groups of patients. Immunohistochemical studies showed heterogenous p53 staining pattern with sections showing both nuclear and cytoplasmic staining with 36.8% mild, 10.5% moderate and 52.6% intense p53 immunoreactivity. Both COX-2 and iNOS immunostaining revealed 25% negative and 75% mild to strongly positive immunoreactivity. Correlation studies demonstrated a positive relationship between p53 and COX-2 (P=0.030; r = +0.70) in surgically treated patients. The association of COX-2 and p53 with various anti-oxidant enzymes showed a significantly positive correlation between COX-2 expression and catalase activity and an inverse correlation between p53 expression and superoxide dismutase and catalase activity in the tumor tissue of patients given NAT. In addition, we observed a negative trend between p53 expression levels and GPx enzyme levels in both the adjoining and tumor tissue of patients having undergone surgery as main mode of treatment.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the effect of low-dose (<50 cGy) whole body ?-irradiation on the antioxidant defense system in the liver and the lungs of mice at various post-irradiation intervals.
Male Balb/c mice, 5 - 6 weeks of age, were divided into irradiated and non-irradiated groups. Whole body irradiation was done with gamma-rays from a (60)Co source at doses of 10, 25 and 50 cGy (48.78 cGy/min). Lipid peroxidation and antioxidant status were measured in the liver and the lungs at 4, 12 and 24 h after irradiation.
Lipid peroxidation increased by 1.38 and 2.0 fold in lung and liver respectively at 12 h after exposure to 25 cGy. Whole body exposure to 25 and 50 cGy significantly (p < 0.05) increased the hepatic reduced glutathione at 4 h. Reduced glutathione continued to rise until 12 h and returned to the basal level at 24 h, whereas in the lungs it remained elevated until 24 h at 10 and 25 cGy. Antioxidant enzymes activities for superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase increased by 1.22, 1.13, 1.22 and 1.11 fold respectively (p < 0.05) in the liver at 4 h after exposure to 50 cGy and remained elevated at almost the same level up to 12 h after exposure. Surprisingly these antioxidant defense enzymes remained unaltered in the lung at the above radiation doses.
Low-dose whole body gamma-irradiation differentially modulates the antioxidant defense system in the liver and lungs of mice. The induction of endogenous glutathione, immediately after exposure to low-dose -irradiation, may be beneficial in protecting the cells from reactive oxygen species (ROS) induced oxidative stress.
International Journal of Radiation Biology 12/2005; 81(12):901-10. DOI:10.1080/09553000600567996 · 1.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Increased levels or overexpression of ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine biosynthesis pathway, is characteristic of tumor cells. Similarly, prostaglandins (PGs) appear to be important in the pathogenesis of cancer because these affect mitogenesis, cellular adhesion, immune surveillance and apoptosis. Cancers form much more PGs than the original tissue from which they have arisen. This study has revealed that pretreatment of mice with resveratrol at a dose of 2.5 mg/kg body weight for two weeks blocked the N-nitrosodiethylamine(NDEA)-induced cytosolic ODC levels in the liver and lungs. The blockage was pronounced in hepatic tissue compared to pulmonary tissue. Resveratrol feeding caused a significant reduction in microsomal cyclooxygenase (COX) activities in the liver and lungs, while the dosage of NDEA (200 mg/kg body weight) induced COX activity 24 h after its administration. In any case, resveratrol pretreatment turned out to effectively block the induction of COX activity in the lungs by NDEA.
Journal of Nutritional Science and Vitaminology 03/2004; 50(1):61-5. DOI:10.3177/jnsv.50.61 · 0.83 Impact Factor