Tetranortriterpenoids from Melia dubia

Two new tetranortriterpenoids, compositin and compositolide, have been isolated from leaves and seeds of Melia dubia. The structures of the two new compounds were determined by spectroscopic methods and chemical reactions.     

Understanding the Basis of Drug Resistance of the Mutants of αβ-Tubulin Dimer via Molecular Dynamics Simulations

The vital role of tubulin dimer in cell division makes it an attractive drug target. Drugs that target tubulin showed significant clinical success in treating various cancers. However, the efficacy of these drugs is attenuated by the emergence of tubulin mutants that are unsusceptible to several classes of tubulin binding drugs. The molecular basis of drug resistance of the tubulin mutants is yet to be unraveled. Here, we employ molecular dynamics simulations, protein-ligand docking, and MMPB(GB)SA analyses to examine the binding of anticancer drugs, taxol and epothilone to the reported point mutants of tubulin - T274I, R282Q, and Q292E. Results suggest that the mutations significantly alter the tubulin structure and dynamics, thereby weaken the interactions and binding of the drugs, primarily by modifying the M loop conformation and enlarging the pocket volume. Interestingly, these mutations also affect the tubulin distal sites that are associated with microtubule building processes.     

Association of common DNA sequence variants at 33 genetic loci with blood lipids in individuals of African ancestry from Jamaica

The relevance of loci associated with blood lipids recently identified in European populations in individuals of African ancestry is unknown. We tested association between lipid traits and 36 previously described single-nucleotide polymorphisms (SNPs) in 1,466 individuals of African ancestry from Spanish Town, Jamaica. For the same allele and effect direction as observed in individuals of European ancestry, SNPs at three loci (1p13, 2p21, and 19p13) showed statistically significant association (p < 0.05) with LDL, two loci (11q12 and 20q13) showed association with HDL cholesterol, and two loci (11q12 and 2p24) showed association with triglycerides. The most significant association was between a SNP at 1p13 and LDL cholesterol (p = 4.6 × 10^?8). This SNP is in a linkage disequilibrium region containing four genes (CELSR2, PSRC1, MYBPHL, and SORT1) and was recently shown to relate to risk for myocardial infarction. Overall, the results of this study suggest that much of the genetic variation which influences blood lipids is shared across ethnic groups.     

The mouse QTL map helps interpret human genome-wide association studies for HDL cholesterol

Genome-wide association (GWA) studies represent a powerful strategy for identifying susceptibility genes for complex diseases in human populations but results must be confirmed and replicated. Because of the close homology between mouse and human genomes, the mouse can be used to add evidence to genes suggested by human studies. We used the mouse quantitative trait loci (QTL) map to interpret results from a GWA study for genes associated with plasma HDL cholesterol levels. We first positioned single nucleotide polymorphisms (SNPs) from a human GWA study on the genomic map for mouse HDL QTL. We then used mouse bioinformatics, sequencing, and expression studies to add evidence for one well-known HDL gene (Abca1) and three newly identified genes (Galnt2, Wwox, and Cdh13), thus supporting the results of the human study. For GWA peaks that occur in human haplotype blocks with multiple genes, we examined the homologous regions in the mouse to prioritize the genes using expression, sequencing, and bioinformatics from the mouse model, showing that some genes were unlikely candidates and adding evidence for candidate genes Mvk and Mmab in one haplotype block and Fads1 and Fads2 in the second haplotype block. Our study highlights the value of mouse genetics for evaluating genes found in human GWA studies.     

Chikungunya virus outbreak in Kerala, India, 2007: a seroprevalence study

India was affected by a major outbreak of chikungunya fever caused by Chikungunya virus (CHIKV) during 2006-2007. Kerala was the worst affected state during 2007 with a contribution of 55.8% suspected cases in the country. However, except for clinically reported case records, no systematic information is available on infection status of CHIKV in the region. Hence, we carried out a post-epidemic survey to estimate seroprevalence status [immunoglobulin G (IgG)] in the community using commercially available indirect immunofluorescence test. This methodology had been reported to be highly specific and sensitive for CHIKV infection. The study area selected was the worst affected mid-highlands region of Kerala which harbour vast area of rubber plantations. The study evidenced 68% of the population to be seropositive for CHIKV IgG. Males were found more affected than females (χ2 = 9.86; p = 0.002). Among males, prevalence was significantly higher in the age classes 21-30 (χ2 = 5.46; p = 0.019) and 31-40 (χ2 = 5.84; p = 0.016) years. This may be due to high occupational risk of the male population engaged in plantation activities exposed to infective bites of Aedes albopictus. The current study provides an insight into the magnitude of CHIKV outbreak in Kerala.     

Effect of Mangrove Tea Extract from <Emphasis Type="Italic">Ceriops decandra</Emphasis> (Griff.) Ding Hou. on Salivary Bacterial Flora of DMBA Induced Hamster Buccal Pouch Carcinoma

The objective of this study was to investigate the effects of mangrove tea on salivary bacterial flora in DMBA induced hamster buccal pouch carcinoma. Tea from mangrove plant Ceriops decandra was administered against DMBA induced buccal pouch carcinoma in hamster rats. The chemical constitutions and quality of mangrove tea is similar with the commercial tea Camellia sinensis. The Hamster rats were painted thrice a week with DMBA in their right buccal pouch, and also administrated orally with 1.25% of Ceriops tea extract, on alternate days of the DMBA treatment. Appropriate control animals were maintained. After 14 weeks of treatment, bacterial species in saliva were enumerated, tumor incidences were analyzed using histopathological section and tumor volume in the animals was quantified using water-displaced method. The decreased counts of beneficial bacteria and increased counts of harmful bacteria were associated with increased volume of tumors. The present study concluded that the tea extract from C. decandra prevents the oral cancer incidences and maintain the good health conditions of the animals.     

Temporal relation of cardiac hypertrophy, oxidative stress, and fatty acid metabolism in spontaneously hypertensive rat

Left ventricular hypertrophy is an adaptive response to hypertension, and an independent clinical risk factor for cardiac failure, sudden death, and myocardial infarction. As regression of cardiac hypertrophy is associated with a lower likelihood of cardiovascular events, it is recognized as a target of antihypertensive therapy. This necessitates identification of factors associated with the initiation and progression of hypertrophy. Oxidative stress and metabolic shift are intimately linked with myocardial hypertrophy, but their interrelationship is not clearly understood. This study proposes to identify the temporal sequence of events so as to distinguish whether oxidative stress and metabolic shift are a cause or consequence of hypertrophy. Spontaneously hypertensive rat (SHR) was used as the experimental model. Cardiac hypertrophy was apparent at 2 months of age, as assessed by hypertrophy index and brain natriuretic peptide gene expression. Enhanced myocardial lipid peroxidation accompanied by nuclear factor-kappa B gene expression in one-month-old SHR suggests that oxidative stress precedes the development of hypertrophy. Metabolic shift identified by reduction in the expression of peroxisome proliferator-activated receptor-alpha, medium chain acyl CoA dehydrogenase, and carnitine palmitoyltransferase 1β was seen at 4 months of age, implying that reduction of fatty acid oxidation is a consequence of hypertrophy. Information on the temporal sequence of events associated with hypertrophy will help in the prevention and reversal of cardiac remodeling. Investigations aimed at prevention of hypertrophy should address reduction of oxidative stress. Both, oxidative stress and metabolic modulation have to be considered for studies that focus on the regression of hypertrophy.