Pushpinder Kaur

Possible mechanism of action in melatonin attenuation of haloperidol-induced orofacial dyskinesia.

Tardive dyskinesia (TD) is a late complication of prolonged neuroleptic treatment characterized by involuntary movements of the oral region. In spite of high incidence and much research, the pathophysiology of this devastating movement disorder remains elusive. Chronic treatment with neuroleptics leads to the development of abnormal oral movements in rats, referred to as vacuous chewing movements (VCMs). VCMs in rats are widely accepted as an animal model of TD. Rats chronically treated with haloperidol (1.5 mg/kg ip) significantly developed VCMs and tongue protrusions. Melatonin dose-dependently (1, 2, and 5 mg/kg) reversed the haloperidol-induced VCM and tongue protrusions frequencies. Biochemical analysis reveals that chronic haloperidol treatment significantly induced lipid peroxidation and decreased the forebrain glutathione (GSH) levels in the rats. Chronic haloperidol-treated rats also showed decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD), and catalase. Coadministration of melatonin (1, 2, and 5 mg/kg) along with haloperidol significantly reduced the lipid peroxidation and restored the decreased GSH levels by chronic haloperidol treatment, and significantly reversed the haloperidol-induced decrease in forebrain SOD and catalase levels in rats. However, a lower dose of melatonin (1 mg/kg) failed to reverse chronic haloperidol-induced decreases in forebrain GSH, SOD, and catalase levels. In conclusion, melatonin could be screened as a potential drug candidate for the prevention or treatment of neuroleptic-induced orofacial dyskinesia.

Combined effect of GSTM1, GSTT1 and GSTP1 polymorphisms on histological subtypes of lung cancer

Abstract Genetic polymorphisms are natural genetic variations in the gene sequence that occur at a frequency of >1% in the population. This genetic variability (polymorphisms) can be a factor in cancer risk. The functional polymorphisms in GST genes play an important role in susceptibility to lung cancer. In our previous study, we reported that the combination of certain genotypes of GSTM1, GSTT1 and CYP1A1 is associated with lung cancer. The study has been extended to investigate the potential role of polymorphism in GSTP1 alone or in combination with the status of GSTM1 and GSTT1 genes in the likelihood of development of lung cancer. A total of 302 subjects (151 cases and 151 controls) were evaluated. Using a case–control design, individuals were genotyped for GSTs using multiplex polymerase chain reaction and restriction fragment length polymorphism techniques. The data obtained were analyzed using multiple logistic regression. The combined ‘at risk’ genotypes of GSTM1 null and GSTT1 null in comparison with ‘wild-type’ genotypes seems to be associated with a greater risk of lung cancer, but the results are not significant (odds ratio (OR) 2.0, 95% confidence interval (CI) 0.68–5.96) and for squamous cell carcinoma (SqCC) it was 1.6-fold (OR 1.6, 95% CI 0.49–5.68). In summary, our case–control study of lung cancer revealed that the effect of these polymorphisms is not very marked for different genotypic combinations of GSTP1, GSTM1 and GSTT1 in the context of developing lung cancer in a north Indian population. However, the increased risk was limited to SqCC, and was not found for other histological subtypes. Further analyses on this topic are needed.

Role of hormonal genes and risk of prostate cancer: gene-gene interactions in a North Indian population

Prostate cancer represents a heterogeneous disease with varying degrees of aggressiveness, patterns of metastasis, and response to therapy. It arises from a complex etiology that involves both exogenous (diet, environment, etc.) and endogenous (hormonal and genetic) factors. The present study was performed to explore the role of various genotypes involved in steroid metabolism and synthesis in the causation of prostate cancer. Genetic polymorphism of the ER, CYP17, SRD5A2 (TA repeats), and PSA genes were analyzed in 157 cases of prostate cancer and 340 controls [170 healthy males and 170 patients of benign prostate hyperplasia (BPH)]. Mutant genotypes of ER and CYP17 showed 2- and 3- and 3.5-fold increased risk of prostate cancer, respectively, as compared to BPH and healthy controls. Interaction of mutant (homozygous and heterozygous) alleles of CYP17 with TA (0/0) led to a twofold increased risk of prostate cancer. Risk was more than twofold with the combination of mutant alleles of ER and CYP17. The PSA gene polymorphism did not show any increased risk of prostate cancer. This indicates the role of mutant allele of ER and CYP17 in the development and progression of prostate cancer and rules out any increased risk with PSA polymorphism in the north Indian population.

Impact of Interaction of Polymorphic Forms of p53 Codon 72 and N-Acetylation Gene (NAT2) on the Risk of Lung Cancer in the North Indian Population

The interaction of genetic and environmental factors can determine individual susceptibility to various cancers. We studied the influence of NAT2 and codon 72 p53 polymorphisms on 151 patients with lung cancer and an equal number of matched population controls. Polymorphisms of NAT2 and p53 were determined by PCR-RFLP techniques. The results were analyzed using logistic regression analysis. A statistically significant relationship between NAT2*5 and NAT2*6 alleles and lung cancer risk was observed. In addition, the population with slow acetylator alleles for NAT2*5 and NAT2*6 had a significantly higher risk of lung cancer compared with rapid acetylator alleles both in smokers and nonsmokers. The combined genotype of heterozygous arginine (Arg)/proline (Pro), Pro/Pro, and slow acetylator alleles of NAT2*5 and NAT2*6 showed higher, although not significant, risk of lung cancer compared with Arg/Arg and rapid acetylator alleles of NAT2*5 and NAT2*6. In conclusion, these findings suggest that the influence of NAT2 genotype, alone or in combination with p53 genotype, may confer increased susceptibility to lung cancer.

Interleukin 1 beta gene polymorphism and risk of cervical cancer

To determine whether a polymorphism at position + 3953 in exon 5 of the lL‐1β gene (IL‐1β + 3953), a condition associated with an increased risk for a number of inflammatory diseases, is also involved in the development of cervical cancer.

Effect of NBS1 gene polymorphism on the risk of cervix carcinoma in a northern Indian population

Cervical cancer is one of the most common neoplastic diseases affecting women, with a worldwide incidence of almost half a million cases. A history of smoking and use of oral contraceptives have been confirmed to be risk factors for cervical cancer. Genetic susceptibility and immune response, especially impaired cellular immune response, may well be related to the development of cervical cancer. NBS1 is one of the key proteins participating in the recognition and repair of double-strand breaks that may lead to genomic instability and cancer if unrepaired. The objective of the present study was therefore to investigate NBS1 Glu185Gln gene polymorphisms and the risk of cervix cancer in a northern Indian population. We found that passive smokers having particular NBS1 genotypes (Glu/Gln, Gln/Gln or Glu/Gln + Gln/Gln)have an increased risk of developing cervix cancer (OR 5.21, p=0.000001; OR 4.60, p=0.001; OR 5.10, p=0.0000009, respectively).The risk was increased 2.4-fold in oral contraceptive users with a Glu/Gln genotype. We conclude that the risk of cervical cancer is increased in passive smokers and in users of oral contraceptives with certain NBS1 genotypes.

Association of genetic polymorphism of the DNA base excision repair gene (APE-1 Asp/148 Glu) and HPV type (16/18) with the risk of cervix cancer in north Indian population.

Abstract Cervical cancer is one of the most common neoplastic diseases affecting women, with a combined world wide incidence of almost half a million new cases. Reduced DNA repair capacity (DRC) can render a high risk of developing many types of cancer; including cervical cancer. Polymorphisms in DNA repair genes may contribute the genetic instability and carcinogenesis. Smoking experience and use of oral contraceptives have been confirmed to be risk factors for cervical cancer. The purpose of the present study was, therefore to investigate APE-1 genotypes (Asp/Asp, Asp/Glu, Glu/Glu) with different histological subtypes in cases compared with controls. It has been observed that Asp/Glu with Glu/Glu genotypes that combined we observed statistically significant with protective effect for developing of cervix cancer (OR-0.51, 95% CI 0.31-0.83, p-0.006). The combined Asp/Glu with Glu/Glu genotypes who were using oral contraceptives were shown to be statistically significant with reduced risk of cervical cancer (OR-0.22 95% CI- 0.11-0.47, p-0.0002). It has been suggested that significantly correlation between HPV 16 and users of oral contraceptives in certain APE-1 genotypes with reduced risk in developing cervix cancer. In conclusion we observed statistical significant association with reduced risk of cervix cancer in APE-1 with different genotypes, though, on the other hand, in association between HPV type 18 and those having SCC, highly increased risk of cervical cancer was observed.

Amelioratory Effects of Zinc Supplementation on Salmonella-induced Hepatic Damage in the Murine Model

Zinc (Zn) has been reported to influence the susceptibility of the host to a diverse range of infectious pathogens, including viruses, bacteria, fungi and protozoa. We report here an evaluation of the effects of Zn supplementation on Salmonella enterica serovar Typhimurium (S. typhimurium)-induced hepatic injury in the murine model. Zinc levels in the plasma and liver tissues were measured by atomic absorption spectroscopy. The effect of Zn supplementation was evaluated by assessing the bacterial load and levels of lipid peroxidation (LPO), antioxidants and monokines present in the hepatic tissue as well as by histopathological studies. Zinc supplementation reduced the bacterial load in the liver and reversed hepatic microscopic abnormalities. It also decreased the levels of LPO but increased the levels of reduced glutathione (GSH) as well as the activities of superoxide-dismutase (SOD) and catalase in the livers of infected mice supplemented with Zn compared to the livers of infected mice not supplemented with Zn. Zinc supplementation was also able to modulate the levels of monokines such as tumour necrosis factor alpha (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6). Our results indicate a role for Zn in downregulating oxidative stress and upregulating antioxidant defense enzymes through the action of monokines, suggesting that supplementation with Zn has a protective function in Salmonella-induced liver injury.