A 30-d course of oral administration of a semipurified extract of the root of Withania somnifera consisting predominantly of withanolides and withanosides reversed behavioral deficits, plaque pathology, accumulation of β-amyloid peptides (Aβ) and oligomers in the brains of middle-aged and old APP/PS1 Alzheimer's disease transgenic mice. It was similarly effective in reversing behavioral deficits and plaque load in APPSwInd mice (line J20). The temporal sequence involved an increase in plasma Aβ and a decrease in brain Aβ monomer after 7 d, indicating increased transport of Aβ from the brain to the periphery. Enhanced expression of low-density lipoprotein receptor-related protein (LRP) in brain microvessels and the Aβ-degrading protease neprilysin (NEP) occurred 14-21 d after a substantial decrease in brain Aβ levels. However, significant increase in liver LRP and NEP occurred much earlier, at 7 d, and were accompanied by a rise in plasma sLRP, a peripheral sink for brain Aβ. In WT mice, the extract induced liver, but not brain, LRP and NEP and decreased plasma and brain Aβ, indicating that increase in liver LRP and sLRP occurring independent of Aβ concentration could result in clearance of Aβ. Selective down-regulation of liver LRP, but not NEP, abrogated the therapeutic effects of the extract. The remarkable therapeutic effect of W. somnifera mediated through up-regulation of liver LRP indicates that targeting the periphery offers a unique mechanism for Aβ clearance and reverses the behavioral deficits and pathology seen in Alzheimer's disease models.herbal extract | dementia | neurodegenerative disease A lzheimer's disease (AD) is characterized by progressive dysfunction of memory and higher cognitive functions. Pathological hallmarks include senile plaques, neurofibrillary tangles, dystrophic neurites, gliosis, and neuroinflammation. Cholinesterase inhibitors and the NMDA antagonist memantine, the commonly used drugs for AD, provide symptomatic relief but do not alter the course of disease. No curative treatment is available, and research focuses on drugs for slowing disease progression or providing prophylaxis.The majority of AD cases are sporadic in nature. The small fraction of familial cases are caused primarily by mutations in three genes: amyloid precursor protein (APP), presenilin1 (PS1), and presenilin 2 (PS2). These mutations result in abnormal processing of APP and increased generation of β amyloid peptide 1-42 (Aβ42), which aggregates as β sheets (1). Treatment strategies have focused on reducing β-amyloid load through (i) inhibition of γ-or β-secretases or activation of α-secretase; (ii) inhibition of Aβ aggregation; (iii) activation of proteases, such as neprilysin (NEP); and (iv) active and passive immunotherapy (2, 3).Among other mechanisms, influx and efflux of brain Aβ are regulated by receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein (LRP), respectively (4). The soluble form of LRP in plasma (sLRP) is a peripheral sink for Aβ that aids i...

Analyses of frequency profiles of markers on disease or drug-response related genes in diverse populations are important for the dissection of common diseases. We report the results of analyses of data on 405 SNPs from 75 such genes and a 5.2 Mb chromosome, 22 genomic region in 1871 individuals from diverse 55 endogamous Indian populations. These include 32 large (>10 million individuals) and 23 isolated populations, representing a large fraction of the people of India. We observe high levels of genetic divergence between groups of populations that cluster largely on the basis of ethnicity and language. Indian populations not only overlap with the diversity of HapMap populations, but also contain population groups that are genetically distinct. These data and results are useful for addressing stratification and study design issues in complex traits especially for heterogeneous populations.

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Novel Schiff bases (SBs) were synthesized by condensation of 2-(1-Amino benzyl) benzimidazole with heterocyclic and aromatic carbonyl compounds. The structural characterization was done using 1H, 13C NMR, FTIR and ES-MS spectroscopic techniques. The in silico pharmacokinetics showed that nearly all compounds obeyed Lipinski rule of 5 with low toxicity and metabolic stability. The global reactivity descriptors were calculated using DFT approach. The molecular docking result of SBs with ct-DNA suggested interaction via groove binding mode. The antibacterial activity was tested against S. aureus and E. coli, indicated significant inhibition than reference drug. The compound 4d gave best results at 50 μg ml−1 concentrations. UV/Vis and Fluorescence spectroscopy tools were used to evaluate ct-DNA binding ability of compounds 4a–e through hypochromic shift. The steady state fluorescence predicted a moderate binding constant of 1.12 × 104 for 4d, indicative of non-intercalative mode.

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SVR rates in CHC patients treated in 'real-life' setting in India were better than those reported in western population. Therapy should be prolonged for patients with cirrhosis, while one-fifth of patients may qualify for abbreviated therapy. Factors significantly associated with SVR were age <40 years, absence of cirrhosis, RVR, and no reduction in interferon dose.

Thiazole derivatives R 0260 Novel Fluorinated Spiro[indole-indazolyl-thiazolidine]-2,4'-diones: Design and Synthesis. -A facile and elegant synthesis of the novel title spiro-compounds (V) (9 examples) via hitherto unknown Schiff bases (III) is described. -(JAIN, S. C.; KHANNA, P.; BHAGAT, S.; JAIN, M.; SAKHUJA, R.; Phosphorus, Sulfur Silicon Relat. Elem. 180 (2005) 8, 1829-1839; Dep. Chem., Univ. Delhi, Delhi 110 007, India; Eng.) -H. Toeppel 46-118