Aggregation prone regions in human proteome: Insights from large‐scale data analyses

Protein aggregation leads to several burdensome human maladies, but a molecular level understanding of how human proteome has tackled the threat of aggregation is currently lacking. In this work, we survey the human proteome for incidence of aggregation prone regions (APRs), by using sequences of experimentally validated amyloid‐fibril forming peptides and via computational predictions. While approximately 30 human proteins are currently known to be amyloidogenic, we found that 260 proteins (～1% of human proteome) contain at least one experimentally validated amyloid‐fibril forming segment. Computer predictions suggest that more than 80% of the human proteins contain at least one potential APR and approximately two‐thirds (65%) contain two or more APRs; spanning 3–5% of their sequences. Sequence randomizations show that this apparently high incidence of APRs has been actually significantly reduced by unique amino acid composition and sequence patterning of human proteins. The human proteome has utilized a wide repertoire of sequence‐structural optimization strategies, most of them already known, to minimize deleterious consequences due to the presence of APRs while simultaneously taking advantage of their order promoting properties. This survey also found that APRs tend to be located near the active and ligand binding sites in human proteins, but not near the post translational modification sites. The APRs in human proteins are also preferentially found at heterotypic interfaces rather than homotypic ones. Interestingly, this survey reveals that APRs play multiple, often opposing, roles in the human protein sequence‐structure‐function relationships. Insights gained from this work have several interesting implications towards novel drug discovery and development. Proteins 2017; 85:1099–1118. © 2017 Wiley Periodicals, Inc.     

Bioefficacy of root extracts of a medicinal plant,Withania somnifera (Dunal) against a polyphagous pest,Spodoptera litura (Fabricius) (Lepidoptera: Noctuidae)

Oral administration of root extracts of a medicinal plant, Ashwagandha (Withania somnifera) to last instar larvae of a polyphagous pest, Spodoptera litura resulted into abnormal morphogenesis and the effects comprised mortality, delay in larval-pupal and pupal-adult ecdysis, ecdysial stasis, formation of larval-pupal and pupal-adult intermediates, reduced pupation and formation of abnormal pupae, complete suppression of normal adult emergence and formation of adultoids. These effects are similar to those produced by the administration of JHAs and may be due to interference with the normal hormonal mechanism of moulting and metamorphosis.     

Inhibitory Activities of Butanol Fraction from Butea monosperma (Lam.) Taub. Bark Against Free Radicals,Genotoxins and Cancer Cells

The present study was undertaken to investigate antioxidant, antigenotoxic, and antiproliferative activity of butanol fraction (Bmbu) from bark of medicinal plant Butea monosperma. Antioxidant potency of Bmbu was examined by various in vitro assays. It was also investigated for antigenotoxic activity using Escherichia coli. PQ37 employing SOS chromotest. Further, cytotoxic and apoptosis inducing activity of Bmbu was evaluated in MCF‐7 breast cancer cells. Bmbu showed potent free radical scavenging ability in ABTS assay (IC₅₀ 56.70 μg/ml) and anti‐lipid peroxidation ability (IC₅₀ 40.39 μg/ml). 4NQO and H₂O₂ induced genotoxicity was suppressed by Bmbu in SOS chromotest by 74.26% and 82.02% respectively. It also inhibited the growth of MCF‐7 cells with GI₅₀ value of 158.71 μg/ml. Induction of apoptosis in MCF‐7 cells by Bmbu treatment was deciphered using confocal microscopy, flow cytometry, and neutral comet assay. Bmbu treatment increased cell population in sub‐G₁ phase (69.6%) indicating apoptotic cells. Further, Bmbu treatment resulted in increased reactive oxygen species generation and decreased mitochondrial membrane potential indicating involvement of mitochondrial dependent pathway of apoptosis. HPLC profiling showed the presence of polyphenols such as ellagic acid, catechin, quercetin, and gallic acid as its major constituents. Consequently, it is suggested that the phytoconstituents from this plant may be further exploited for development of novel drug formulation with possible therapeutic implication.     

Antifungal and anthelmintic activity of novel benzofuran derivatives containing thiazolo benzimidazole nucleus: an in vitro evaluation

A novel series of thiazolo[3,2-a]benzimidazole derivatives containing benzofuran nucleus (5a–l) have been synthesized. The key intermediate, substituted benzimidazol-sulfanyl benzofuran ethanone (3a–d) was prepared by refluxing the mixture of substituted 2-acetyl benzofuran and substituted 2-mercaptobenzimidazole in acetic acid. The cyclisation of compounds (3a–d) using polyphosphoric acid furnished the corresponding 6-substituted benzofuran thiazolo[3,2-a]benzimidazoles (4a–d). Further, the cyclized compounds (4a–d) were subjected for Mannich reaction to give corresponding Mannich bases (5a–l). All newly synthesized compounds were screened for antifungal and anthelmintic activity. Amongst the tested compounds, 4b and 4d exhibited potential antifungal activity. From the anthelmintic activity data, it was found that the compounds 3a, 3b and 5i were found to be more effective against the tested earthworm Pheretima posthuma. In correlation to anthelmintic activity, the selected compounds were subjected for molecular docking studies and the compounds 3a and 5i have emerged as active anthelmintic agents with maximum binding affinity (?3.7 and ?5.4 kcal/mol).     

Aluminum-mediated metabolic changes in rat serum and urine: a proton nuclear magnetic resonance study

The toxic effects of Al(3+) have been studied in 90-days AlCl(3) orally treated male albino rats (n = 7) using (1)H NMR spectroscopy-based metabolic profile of rat serum and urine, serum enzyme tests, behavioral impairment, and histopathology of kidney and liver. Metabolic profile of 90-days Al(3+)-treated rat sera showed significantly elevated levels of alanine, glutamine, beta-hydroxy-butyrate, and acetoacetate and significantly decreased level of acetone when compared with that of control rats. However, metabolic profile of 90-days Al(3+)-treated rat urine showed significantly decreased levels of citrate, creatinine, allantoin, trans-aconitate, and succinate and significantly increased level of acetate when compared to control rats. The overall perturbations observed in the metabolic profile of serum and urine demonstrate the impairment in the tricarboxylic acid cycle, liver and kidney metabolism, which was further reinstated by clinical chemistry and histopathological observations. Moreover, "in vivo" behavioral impairment has also been observed as the indication of aluminum neurotoxicity.     

The SarA protein family of Staphylococcus aureus

Staphylococcus aureus is widely appreciated as an opportunistic pathogen, primarily in hospital-related infections. However, recent reports indicate that S. aureus infections can now occur in other wise healthy individuals in the community setting. The success of this organism can be attributed to the large array of regulatory proteins, including the SarA protein family, used to respond to changing microenvironments. Sequence alignment and structural data reveal that the SarA protein family can be divided into three subfamilies: (1) single domain proteins; (2) double domain proteins; (3) MarR homologs. Structural studies have also demonstrated that SarA, SarR, SarS, MgrA and thus possibly all members of this protein family are winged helix proteins with minor variations. Mutagenesis studies of SarA disclose that the winged helix motifs are important for DNA binding and function. Recent progress concerning the functions and plausible mechanisms of regulation of SarA and its homologs are discussed.     

Facile synthesis, ex-vivo and in vitro screening of 3-sulfonamide derivative of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (SR141716) a potent CB1 receptor antagonist

Facile synthesis of biaryl pyrazole sulfonamide derivative of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (SR141716, 1) and an investigation of the effect of replacement of the –CO group in the compound 1 by the –SO₂ group in the aminopiperidine region is reported. Primary ex-vivo pharmacological testing and in vitro screening of sulfonamide derivative 2 showed the loss of CB1 receptor antagonism.     

Bioisosteric replacement of dihydropyrazole of 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-caboxamidine (SLV-319) a potent CB1 receptor antagonist by imidazole and oxazole

Design, synthesis and conformational analysis of few imidazole and oxazole as bioisosters of 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-caboxamidine (SLV-319) 2 is reported. Computer assisted conformational analysis gave a direct clue for the loss of CB1 antagonistic activity of the ligands without a fine docking simulation for the homology model.