Carbonic anhydrase inhibitors: inhibition of the tumor-associated isozymes IX and XII with a library of aromatic and heteroaromatic sulfonamides

The inhibition of the two transmembrane, tumor-associated isozymes of carbonic anhydrase (CA, EC 4.2.1.1) of human origin, hCA IX and XII, with a library of aromatic and heteroaromatic sulfonamides has been investigated. Most of them were sulfanilamide, homosulfanilamide, and 4-aminoethyl-benzenesulfonamide derivatives, to which tails that should induce diverse physico-chemical properties have been attached at the amino moiety, whereas several of these compounds were derived from metanilamide, benzene-1,3-disulfonamide or the 1,3,4-thiadiazole/thiadiazoline-2-sulfonamides. The tails were of the alkyl/aryl-carboxamido/sulfonamido-, ureido or thioureido type. Against hCA IX the investigated compounds showed inhibition constants in the range of 3-294 nM, whereas against hCA XII in the range of 1.9-348 nM, respectively. The best hCA IX inhibitors were ureas/thioureas incorporating 4-aminoethyl-benzenesulfonamide and metanilamide moieties. The best hCA XII inhibitors were 1,3,4-thiadiazole/thiadiazoline-2-sulfonamides incorporating 5-acylamido or 5-arylsulfonylamido moieties. These compounds also inhibited appreciably the cytosolic isozymes hCA I and II, but some selectivity for the transmembrane, tumor-associated isozymes was observed for some of them, which is an encouraging result for the design of novel therapies targeting hypoxic tumors, in which these carbonic anhydrases are highly overexpressed.     

Protective effect of melatonin on contractile activity and oxidative injury induced by ischemia and reperfusion of rat ileum

Free radicals derived from molecular oxygen have been reported to be responsible for changes in motility and mucosal damage observed in intestinal ischemia-reperfusion injury. Melatonin has been considered as an antioxidant that prevents injuries resulted from I/R in various tissues. The present study was designed to determine the effect of melatonin on the contractile responses of acetylcholine (Ach) and KCl, on malondialdehyde (MDA), a product of lipid peroxidation, and reduced glutathione (GSH) levels and to assess histopathological changes in the smooth muscle of terminal ileum subjected to ischemia-reperfusion. The intestinal ischemia-reperfusion was induced by occlusion of superior mesenteric artery of rat for 30 min, followed by a period of reperfusion for 3 h. Melatonin at doses of 10 or 50 mg/kg was administered via the tail vein in 5 min prior to reperfusion. Following reperfusion, segments of terminal ileum were rapidly taken and transferred into isolated organ bath and responses to Ach and KCl were recorded. Samples of terminal ileum were also taken for measuring the MDA and GSH levels. EC50 values of these contracting substances were seriously reduced in the ischemia-reperfusion group compared to that of the sham-operated control group. The decreased contraction response to Ach and KCl was significantly ameliorated by a dosage of 50 mg/kg of melatonin, while not by a dosage of 10 mg/kg. Similar pattern of the effect was observed in the tissue levels of MDA and GSH as well as in histological improvement. Melatonin appeared to be restoring the amounts of tissue MDA and GSH back to about control levels. These results suggest that the high dose of melatonin not only physiologically but also biochemically and morphologically could be useful to normalize contractility injured by oxidative stress in intestinal ischemia-reperfusion.     

Genetic Polymorphisms in Vitamin D Metabolism and Signaling Genes and Risk of Breast Cancer: A Nested Case-Control Study

Genetic polymorphisms in vitamin D metabolism and signaling genes have been inconsistently associated with risk of breast cancer, though few studies have examined SNPs in vitamin D-related genes other than the vitamin D receptor (VDR) gene and particularly have not examined the association with the retinoid X receptor alpha (RXRA) gene which may be a key vitamin D pathway gene. We conducted a nested case-control study of 734 cases and 1435 individually matched controls from a population-based prospective cohort study, the Northern Sweden Mammary Screening Cohort. Tag and functional SNPs were genotyped for the VDR, cytochrome p450 24A1 (CYP24A1), and RXRA genes. We also genotyped specific SNPs in four other genes related to vitamin D metabolism and signaling (GC/VDBP, CYP2R1, DHCR7, and CYP27B1). SNPs in the CYP2R1, DHCR7, and VDBP gene regions that were associated with circulating 25(OH)D concentration in GWAS were also associated with plasma 25(OH)D in our study (p-trend <0.005). After taking into account the false discovery rate, these SNPs were not significantly associated with breast cancer risk, nor were any of the other SNPs or haplotypes in VDR, RXRA, and CYP24A1. We observed no statistically significant associations between polymorphisms or haplotypes in key vitamin D-related genes and risk of breast cancer. These results, combined with the observation in this cohort and most other prospective studies of no association of circulating 25(OH)D with breast cancer risk, do not support an association between vitamin D and breast cancer risk.     

Prevalence and Correlates of Smokeless Tobacco Consumption among Married Women in Rural Bangladesh

Objective

To estimate the prevalence and identify correlates of smokeless tobacco consumption among married rural women with a history of at least one pregnancy in Madaripur, Bangladesh.

Materials and Methods

We conducted a cross-sectional survey using an interviewer administered, pre-tested, semi-structured questionnaire. All women living in the study area, aged 18 years and above with at least one pregnancy in their lifetime, who were on the electoral roll and agreed to participate were included in the study. Information on socio-demographic characteristics and smokeless tobacco consumption was collected. Smokeless tobacco consumption was categorized as ‘Current’, ‘Ever but not current’ and ‘Never’. Associations between smokeless tobacco consumption and the explanatory variables were estimated using simple and multiple binary logistic regression.

Results

8074 women participated (response rate 99.9%). The prevalence of ‘Current consumption’, ‘Ever consumption but not current’, and ‘Never consumption’ was 25%, 44% and 31%, respectively. The mean age at first use was 31.5 years. 87% of current consumers reported using either Shadapata or Hakimpuree Jarda. Current consumption was associated with age, level of education, religion, occupation, being an income earner, marital status, and age at first use of smokeless tobacco. After adjustment for demographic variables, current consumption was associated with being over 25 years of age, a lower level of education, being an income earner, being Muslim, and being divorced, separated or widowed.

Conclusion

The prevalence of smokeless tobacco consumption is high among rural women in Bangladesh and the age of onset is considerably older than that for smoking. Smokeless tobacco consumption is likely to be producing a considerable burden of non-communicable disease in Bangladesh. Smokeless tobacco control strategies should be implemented.     

Genetic Control of Obesity and Gut Microbiota Composition in Response to High-Fat,High-Sucrose Diet in Mice

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Highlights? Detailed analysis of diet-induced obesity in more than 100 inbred mouse strains ? Identification of 11 genetic loci associated with obesity and dietary responsiveness ? Significant overlap between mouse loci with human GWAS loci for obesity ? Strain-specific shifts in gut microbiota composition in response to dietary intervention