Shiekh Tanveer Ahmad

Hesperidin alleviates acetaminophen induced toxicity in wistar rats by abrogation of oxidative stress, apoptosis and inflammation

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but at high dose it leads to undesirable side effects, such as hepatotoxicity and nephrotoxicity. The present study demonstrates the comparative hepatoprotective and nephroprotective activity of hesperidin (HD), a naturally occurring bioflavonoid against APAP induced toxicity. APAP induces hepatotoxicity and nephrotoxicity as was evident by abnormal deviation in the levels of antioxidant enzymes. Moreover, APAP induced renal damage by inducing apoptotic death and inflammation in renal tubular cells, manifested by an increase in the expression of caspase-3, caspase-9, NFkB, iNOS, Kim-1 and decrease in Bcl-2 expression. These results were further supported by the histopathological examination of kidney. All these features of APAP toxicity were reversed by the co-administration of HD. Therefore, our study favors the view that HD may be a useful modulator in alleviating APAP induced oxidative stress and toxicity.

Preclinical renal cancer chemopreventive efficacy of geraniol by modulation of multiple molecular pathways

In the present study, we have evaluated the chemopreventive potential of geraniol (GOH), an acyclic monoterpene alcohol against ferric nitrilotriacetate (Fe-NTA) induced renal oxidative stress and carcinogenesis in Wistar rats. Chronic treatment of Fe-NTA induced oxidative stress, inflammation and cellular proliferation in Wistar rats. The chemopreventive efficacy of GOH was studied in terms of xenobiotic metabolizing enzyme activities, LPO, redox status, serum toxicity markers and the expression of putative nephrotoxicity biomarker Kim-1, tumor suppressor gene P53, inflammation, cell proliferation and apoptosis related genes in the kidney tissue. Oral administration of GOH at doses of 100 and 200mg/kg b wt effectively suppressed renal oxidative stress and tumor incidence. Chemopreventive effects of GOH were associated with upregulation of xenobiotic metabolizing enzyme activities and down regulation of serum toxicity markers. GOH was able to down regulate expression of Kim-1, NFκB, PCNA, P53 along with induction of apoptosis. However, higher dose of GOH was more effective in modulating these multiple molecular targets both at transcriptional and protein level. These results provide a powerful evidence for the chemopreventive efficacy of GOH against renal carcinogenesis possibly by modulation of multiple molecular pathways.

Alleviation of doxorubicin-induced nephrotoxicity and hepatotoxicity by chrysin in Wistar rats

Abstract Objective: Doxorubicin (DXR) is an anticancer drug used in the treatment of many human malignancies. However, its clinical use is limited because of several side effects like cardiotoxicity, nephrotoxicity and hepatotoxicity. In the present study, we investigated the protective efficacy of chrysin against DXR-induced oxidative stress, nephro- and hepatotoxicity in male Wistar rats using biochemical and histopathological approaches. Methodology: Wistar rats were subjected to concomitant pre- and post-phylactic oral treatment of chrysin (40 and 80 mg/kg b.wt.) against nephro- and hepatotoxicity induced by single i.p. injection of DXR (40 mg/kg b.wt). Nephrotoxicity and hepatotoxicity were assessed by measuring the level of serum creatinine, BUN, AST, ALT and LDH. The level of antioxidant armory of kidney and liver tissue was also measured. Key findings: Treatment with chrysin significantly decreased the levels of serum toxicity markers and additionally elevated antioxidant defense enzyme levels. Histopathological changes further confirmed the biochemical results showing that DXR caused significant structural damage to kidney and liver tissue architecture which were reversed with chrysin. Conclusion: The results suggest that chrysin attenuated nephro and hepatic damage induced by DXR.

Review of the current knowledge on the epidemiology, pathogenesis, and prevention of human papillomavirus infection.

Human papillomavirus (HPV) infection is a central and necessary, although not sufficient, cause of cervical cancer. Besides HPV, the additional multiple risk factors related with the onset of cervical cancer are early-age sexual activities; high number of sexual partners, which is the most salient risk factor; suppression and alteration of the immune status; long-term use of oral contraceptives; and other hormonal influences. The tumor-suppressor proteins p53 and pRb are degraded and destabilized through ubiquitination by viral oncoproteins E6 and E7. Over 95% of cervical cancer cases worldwide test positive for oncogenic HPV DNA. Although cervical screening procedures have been successful in reducing the disease burden associated with HPV infection because of lack of resources or inadequate infrastructure many countries have failed to reduce cervical cancer mortality. Therefore, prevention may be a valuable strategy for reducing the economic and disease burden of HPV infection. At present, two successful prophylactic HPV vaccines are available, quadrivalent (HPV16/18/6/11) ‘Gardasil’ and bivalent (HPV16/18) ‘Cervarix’ for vaccinating young adolescent girls at or before the onset of puberty. Recent data indicate that vaccination prevents the development of cervical lesions in women who have not already acquired the vaccine-specific HPV types. Moreover, several therapeutic vaccines that are protein/peptide-based, DNA-based, or cell-based are in clinical trials but are yet to establish their efficacy; these vaccines are likely to provide important future health benefits. The therapeutic vaccination mode of prevention is a promising area of research, as revealed in preclinical trials; however, clinical trials based on large populations are warranted before reaching a valid conclusion. This review summarizes the studies on the epidemiology of HPV infection, the pathogenesis of viral oncoproteins in the oncogenesis of cervical cancer, the economic and health burden of HPV-related diseases, and, finally, focuses on the results of recent clinical vaccination trials.

Vitamin D receptor FokI and BsmI gene polymorphism and its association with grade and stage of renal cell carcinoma in North Indian population

Vitamin D exerts its activity through binding to the high-affinity nuclear vitamin D receptor (VDR), and majority of genetic studies have primarily focused on variation within this gene. Therefore, analysis of genetic variation in VDR genes may provide insight into the role of vitamin D in renal cell carcinoma (RCC) etiology in our study population. This study investigated whether VDR gene polymorphisms were associated with increased risk and prognosis of RCC in the North Indian population. Genotyping of two polymorphic sites (FokI and BsmI) in the VDR gene of 196 RCC cases and 250 healthy controls was performed via PCR-RFLP. The frequency of homozygous genotype FF was 31.6%, heterozygous Ff was 48.0%, and homozygous ff was 20.4% in cases, whereas in controls it was 45.6%, 39.2%, and 15.2%, respectively; thus, there was a significant difference between the two groups (pTrend = 0.011) in the univariate model. The frequencies of the BB, Bb, and bb genotypes were 25.5%, 44.9% and 29.6% in cases, respectively, while in controls it was 33.2%, 52.0% and 14.8%, respectively; thus, there was a significant difference between the two groups (pTrend = 0.001) in the univariate model. The two high-risk genotype ff of FokI and bb of BsmI of VDR showed a cumulative 1.87-fold increase in risk to RCC. Moreover, the FF genotype was associated with lower pathological stage and histological grade. Our results suggest that the FokI and BsmI genotypes of VDR gene may be implicated in the pathogenesis of RCC.

Methylation of the APAF-1 and DAPK-1 promoter region correlates with progression of renal cell carcinoma in North Indian population

Aberrant promoter hypermethylation of cancer associated genes occur frequently during carcinogenesis and may serve as a cancer biomarker. The aim of this study was to investigate the occurrence and relevance of promoter methylation of the tumor suppressor DAPK-1, APAF-1 () and SPARC in relation to different pathological stages and histological grades of tumor progression that might act as possible independent prognostic factor in the susceptibility towards renal cell carcinoma (RCC) in North Indian population. Three tumor suppressor gene promoters namely APAF-1, DAPK-1 and SPARC were assessed by methylation-specific PCR (MS-PCR) in 196 primarily resected renal cell tumors paired with the corresponding normal tissue samples. After genomic DNA isolation and sodium bisulfite modification, methylation levels were determined and correlated with standard clinicopathological parameters, pathological stage and Fuhrman nuclear grade of RCC. Significant differences in methylation frequency among the four subtypes of renal tumors were found for APAF-1 (p < 0.001), DAPK-1 (p < 0.001) and SPARC (p = 0.182), when compared with the corresponding normal tissue. Male subjects showed stronger association of methylation frequency of all the three genes with RCC than the female subjects. Additionally, higher frequency of APAF-1, DAPK-1 and SPARC promoter methylation were directly correlated with higher tumor stage (ptrend < 0.001). Higher frequency of promoter methylation of APAF-1 and SPARC were also associated with higher nuclear grade (p < 0.001 and p = 0.036, respectively). This gene panel might contribute to a more optimal diagnostic coverage and information, improving preoperative assessment and therapeutic decision-making in patients harboring suspicious renal masses.

Carvacrol ameliorates thioacetamide-induced hepatotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in liver of Wistar rats.

The present study was designed to investigate the protective effects of carvacrol against thioacetamide (TAA)-induced oxidative stress, inflammation and apoptosis in liver of Wistar rats. In this study, rats were subjected to concomitant prophylactic oral pretreatment of carvacrol (25 and 50 mg kg−1 body weight (b.w.)) against the hepatotoxicity induced by intraperitoneal administration of TAA (300 mg kg−1 b.w.). Efficacy of carvacrol against the hepatotoxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, histopathological changes, and expressions of inflammation and apoptosis. Carvacrol pretreatment prevented deteriorative effects induced by TAA through a protective mechanism in a dose-dependent manner that involved reduction of oxidative stress, inflammation and apoptosis. We found that the protective effect of carvacrol pretreatment is mediated by its inhibitory effect on nuclear factor kappa B activation, Bax and Bcl-2 expression, as well as by restoration of histopathological changes against TAA administration. We may suggest that carvacrol efficiently ameliorates liver injury caused by TAA.

Modulatory effects of gentisic acid against genotoxicity and hepatotoxicity induced by cyclophosphamide in Swiss albino mice

Objectives  This study evaluated the protective effects of gentisic acid (GA) against genotoxicity and hepatotoxicity induced by cyclophosphamide (CP) in Swiss albino mice.

Impact of glutathione transferase M1, T1, and P1 gene polymorphisms in the genetic susceptibility of North Indian population to renal cell carcinoma.

In this study, we investigated the association of GSTP1, GSTM1, and GSTP1 genetic variants with renal cell carcinoma (RCC) among North Indian patients. The difference in frequency of the GSTT1 null genotype between cases and control subjects was statistically significant (active ver. null, odds ratio [OR]=0.368; confidence intervals [CI] 95%=0.243-0.557, p=0.001). The differences in the frequency of GSTP1 genotypes were statistically significant (AA ver. AG/GG, OR=1.879; CI 95%=0.355-0.797, p=0.002). Higher allelic frequency of the GSTP1 G allele was associated with RCC cases (G ver. A allele, OR=1.534; 95% CI=1.159-2.030, p=0.003). The gene-gene interaction in terms of three-way combination of GSTM1 null, GSTT1 null, and GSTP1 (AG/GG) resulted in 4.5-fold increase in RCC risk (OR=4.452; 95% CI=2.220-9.294). Similarly, our study revealed that GST polymorphism might be a vital determinant of advancement to higher pathological stages and histological grades of RCC. Our findings suggest that genetic variability in members of the GST gene family may be associated with an increased susceptibility to RCC and its progression.

Loss of Expression and Aberrant Methylation of the CDH1 (E-cadherin) Gene in Breast Cancer Patients from Kashmir

BACKGROUND Aberrant promoter hypermethylation has been recognized in human breast carcinogenesis as a frequent molecular alteration associated with the loss of expression of a number of key regulatory genes and may serve as a biomarker. The E-cadherin gene (CDH1), mapping at chromosome 16q22, is an intercellular adhesion molecule in epithelial cells, which plays an important role in establishing and maintaining intercellular connections. The aim of our study was to assess the methylation pattern of CDH1 and to correlate it with the expression of E-cadherin, clinicopathological parameters and hormone receptor status in breast cancer patients of Kashmir. MATERIALS AND METHODS Methylation specific PCR (MSP) was used to determine the methylation status of CDH1 in 128 invasive ductal carcinomas (IDCs) paired with the corresponding normal tissue samples. Immunohistochemistry was used to study the expression of E-cadherin, ER and PR. RESULTS CDH1 hypermethylation was detected in 57.8% of cases and 14.8% of normal adjacent controls. Reduced levels of E-cadherin protein were observed in 71.9% of our samples. Loss of E-cadherin expression was significantly associated with the CDH1 promoter region methylation (p<0.05, OR=3.48, CI: 1.55-7.79). Hypermethylation of CDH1 was significantly associated with age at diagnosis (p=0.030), tumor size (p=0.008), tumor grade (p=0.024) and rate of node positivity or metastasis (p=0.043). CONCLUSIONS Our preliminary findings suggest that abnormal CDH1 methylation occurs in high frequencies in infiltrating breast cancers associated with a decrease in E-cadherin expression. We found significant differences in tumor-related CDH1 gene methylation patterns relevant to tumor grade, tumor size, nodal involvement and age at diagnosis of breast tumors, which could be extended in future to provide diagnostic and prognostic information.