Thiazolidin-4-one and thiazinan-4-one derivatives analogous to rosiglitazone as potential antihyperglycemic and antidyslipidemic agents.

A number of thiazolidin-4-one and thiazinan-4-one derivatives were prepared by three component condensation in one pot reaction method. These compounds were evaluated for anti-hyperglycemic activity by in vitro and in vivo assay systems. The compounds with thiazolidin-4-one and thiazinan-4-one moieties exhibited significant anti-hyperglycemic activity. A few compounds (3a, 3b, 4a and 4b) have exhibited both anti-hyperglycemic and anti-dyslipidemic activities. Among them the thiazinan-4-one derivative 4a showed maximal (45%) improvement in oral glucose tolerance test in db/db mice at 30 mg/kg oral dose.

No association between variant N-acetyltransferase genes, cigarette smoking and Prostate Cancer susceptibility among men of African descent.

OBJECTIVE: We evaluated the individual and combination effects of NAT1, NAT2 and tobacco smoking in a case-control study of 219 incident prostate cancer (PCa) cases and 555 disease-free men. METHODS: Allelic discriminations for 15 NAT1 and NAT2 loci were detected in germ-line DNA samples using TaqMan polymerase chain reaction (PCR) assays. Single gene, gene-gene and gene-smoking interactions were analyzed using logistic regression models and multi-factor dimensionality reduction (MDR) adjusted for age and subpopulation stratification. MDR involves a rigorous algorithm that has ample statistical power to assess and visualize gene-gene and gene-environment interactions using relatively small samples sizes (i.e., 200 cases and 200 controls). RESULTS: Despite the relatively high prevalence of NAT1*10/*10 (40.1%), NAT2 slow (30.6%), and NAT2 very slow acetylator genotypes (10.1%) among our study participants, these putative risk factors did not individually or jointly increase PCa risk among all subjects or a subset analysis restricted to tobacco smokers. CONCLUSION: Our data do not support the use of N-acetyltransferase genetic susceptibilities as PCa risk factors among men of African descent; however, subsequent studies in larger sample populations are needed to confirm this finding.

Tumor necrosis factor-related weak inducer of apoptosis augments matrix metalloproteinase 9 (MMP-9) production in skeletal muscle through the activation of nuclear factor-kappaB-inducing kinase and p38 mitogen-activated protein kinase: a potential role of MMP-9 in myopathy.

Destruction of skeletal muscle extracellular matrix is an important pathological consequence of many diseases involving muscle wasting. However, the underlying mechanisms leading to extracellular matrix breakdown in skeletal muscle tissues remain unknown. Using a microarray approach, we investigated the effect of tumor necrosis factor-related weak inducer of apoptosis (TWEAK), a recently identified muscle-wasting cytokine, on the expression of extracellular proteases in skeletal muscle. Among several other matrix metalloproteinases (MMPs), we found that the expression of MMP-9, a type IV collagenase, was drastically increased in myotubes in response to TWEAK. The level of MMP-9 was also higher in myofibers of TWEAK transgenic mice. TWEAK increased the activation of both classical and alternative nuclear factor-kappaB (NF-kappaB) signaling pathways. Inhibition of NF-kappaB activity blocked the TWEAK-induced production of MMP-9 in myotubes. TWEAK also increased the activation of AP-1, and its inhibition attenuated the TWEAK-induced MMP-9 production. Overexpression of a kinase-dead mutant of NF-kappaB-inducing kinase or IkappaB kinase-beta but not IkappaB kinase-alpha significantly inhibited the TWEAK-induced activation of MMP-9 promoter. The activation of MMP-9 also involved upstream recruitment of TRAF2 and cIAP2 proteins. TWEAK increased the activity of ERK1/2, JNK1, and p38 MAPK. However, the inhibition of only p38 MAPK blocked the TWEAK-induced expression of MMP-9 in myotubes. Furthermore the loss of body and skeletal muscle weights, inflammation, fiber necrosis, and degradation of basement membrane around muscle fibers were significantly attenuated in Mmp9 knock-out mice on chronic administration of TWEAK protein. The study unveils a novel mechanism of skeletal muscle tissue destruction in pathological conditions.

Genetic polymorphism of the N-acetyltransferase 2 gene, and susceptibility to prostate cancer: a pilot study in north Indian population.

BACKGROUND: N-acetyltransferase 2 is phase II metabolizing enzyme that participates in the bioconversion of heterocyclic arylamines into electrophilic nitrenium ions, which are important ultimate carcinogens that are directly implicated in tumor initiation process. This study was conducted to examine; (1) whether the N-acetyltransferase 2 (NAT2) genotype is a risk factor for prostate cancer, (2) to study effect of NAT2 genotype on modifying prostate cancer risk from tobacco use. METHODS: The case control study was undertaken over a period of 28 months and included 130 prostate cancer patients (CaP) and 140 controls. The NAT2 genotypes were identified by PCR-RFLP method in DNA extracted from peripheral blood. Genotype frequencies and the association of genotypes with patients and control groups were assessed by logistic regression model. RESULTS: We observed non-significant association of rapid acetylator genotype NAT2 (OR = 1.452, 95% CI: 0.54-1.87, P = 0.136) in prostate cancer patients. However significant association was observed between rapid acetylator genotype NAT2 and CaP tobacco users (OR = 3.43, 95% CI: 1.68-7.02, P-value < 0.001) when compared with controls. CONCLUSION: The data suggests that the NAT2 rapid acetylator genotypes may play an important role in determining the risk of developing prostate cancer particularly in the tobacco users of north Indian population.

NAT2 gene polymorphism in bladder cancer: a study from North India

PURPOSE: This study was conducted to examine: 1) whether the NAT2 genotypes are risk factors for bladder cancer, 2) to study possible association of tobacco usage with NAT2 genotype of these patients. MATERIALS AND METHODS: This case control study was undertaken over a period of 19 months and included 101 bladder cancer patients and 110 controls. The NAT2 genotypes were identified by PCR-RFLP method in peripheral blood DNA samples. Genotypes frequencies and the association of the genotypes among patients and controls group were assessed by chi2 test and Fisher exact test. RESULTS: The NAT2 fast acetylator genotype frequency of slow or fast acetylator genotypes was not significant in bladder cancer patients alone (OR = 1.18, 95 percent CI: 0.69 - 2.03, p value = 0.583) or combination with tobacco users (OR = 0.84, 95 percent CI: 0.328 - 2.125, p value = 0.813) when compared with controls. CONCLUSION: These data demonstrate that the NAT2 fast or slow acetylators genotype did not associated with the risk of developing bladder cancer in North Indian population when compared with controls.

NAT2 gene polymorphism in bladder cancer: a study from North India.

PURPOSE: This study was conducted to examine: 1) whether the NAT2 genotypes are risk factors for bladder cancer, 2) to study possible association of tobacco usage with NAT2 genotype of these patients. MATERIALS AND METHODS: This case control study was undertaken over a period of 19 months and included 101 bladder cancer patients and 110 controls. The NAT2 genotypes were identified by PCR-RFLP method in peripheral blood DNA samples. Genotypes frequencies and the association of the genotypes among patients and controls group were assessed by Chi2 test and Fisher exact test. RESULTS: The NAT2 fast acetylator genotype frequency of slow or fast acetylator genotypes was not significant in bladder cancer patients alone (OR = 1.18, 95% CI: 0.69 - 2.03, p value = 0.583) or combination with tobacco users (OR = 0.84, 95% CI: 0.328 - 2.125, p value = 0.813) when compared with controls. CONCLUSION: These data demonstrate that the NAT2 fast or slow acetylators genotype did not associated with the risk of developing bladder cancer in North Indian population when compared with controls.