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91.
Uehara H González N Sancho V Mantey SA Nuche-Berenguer B Pradhan T Coy DH Jensen RT 《Peptides》2011,32(8):1685-1699
The mammalian bombesin (Bn)-receptor family [gastrin-releasing peptide-receptor (GRPR-receptor), neuromedin B-receptor (NMB receptor)], their natural ligands, GRP/NMB, as well as the related orphan receptor, BRS-3, are widely distributed, and frequently overexpressed by tumors. There is increased interest in agonists for this receptor family to explore their roles in physiological/pathophysiological processes, and for receptor-imaging/cytotoxicity in tumors. However, there is minimal data on human pharmacology of Bn receptor agonists and most results are based on nonhuman receptor studies, particular rodent-receptors, which with other receptors frequently differ from human-receptors. To address this issue we compared hNMB-/GRP-receptor affinities and potencies/efficacies of cell activation (assessing phospholipase C activity) for 24 putative Bn-agonists (12 natural, 12 synthetic) in four different cells with these receptors, containing native receptors or receptors expressed at physiological densities, and compared the results to native rat GRP-receptor containing cells (AR42J-cells) or rat NMB receptor cells (C6-glioblastoma cells). There were close correlations (r = 0.92-99, p < 0.0001) between their affinities/potencies for the two hGRP- or hNMB-receptor cells. Twelve analogs had high affinities (≤1 nM) for hGRP receptor with 15 selective for it (greatest = GRP, NMC), eight had high affinity/potencies for hNMB receptors and four were selective for it. Only synthetic Bn analogs containing β-alanine11 had high affinity for hBRS-3, but also had high affinities/potencies for all GRP-/hNMB-receptor cells. There was no correlation between affinities for human GRP receptors and rat GRP receptors (r = 0.131, p = 0.54), but hNMB receptor results correlated with rat NMB receptor (r = 0.71, p < 0.0001). These results elucidate the human and rat GRP-receptor pharmacophore for agonists differs markedly, whereas they do not for NMB receptors, therefore potential GRP-receptor agonists for human studies (such as Bn receptor-imaging/cytotoxicity) must be assessed on human Bn receptors. The current study provides affinities/potencies on a large number of potential agonists that might be useful for human studies. 相似文献
92.
Infanticide by newly immigrated or newly dominant males is reported among a variety of taxa, such as birds, rodents, carnivores and primates. Here we present a game theoretical model to explain the presence and prevalence of infanticide in primate groups. We have formulated a three-player game involving two males and one female and show that the strategies of infanticide on the males' part and polyandrous mating on the females' part emerge as Nash equilibria that are stable under certain conditions. Moreover, we have identified all the Nash equilibria of the game and arranged them in a novel hierarchical scheme. Only in the subspace spanned by the males are the Nash equilibria found to be strict, and hence evolutionarily stable. We have therefore proposed a selection mechanism informed by adaptive dynamics to permit the females to transition to, and remain in, optimal equilibria after successive generations. Our model concludes that polyandrous mating by females is an optimal strategy for the females that minimizes infanticide and that infanticide confers advantage to the males only in certain regions of parameter space. We have shown that infanticide occurs during turbulent changes accompanying male immigration into the group. For changes in the dominance hierarchy within the group, we have shown that infanticide occurs only in primate groups where the chance for the killer to sire the next infant is high. These conclusions are confirmed by observations in the wild. This model thus has enabled us to pinpoint the fundamental processes behind the reproductive decisions of the players involved, which was not possible using earlier theoretical studies. 相似文献
93.
94.
Structural insights into the MDP binding and CARD–CARD interaction in zebrafish (Danio rerio) NOD2: a molecular dynamics approach 下载免费PDF全文
Bidhan Chandra De Bikash Ranjan Sahoo Bijay Kumar Behera Sachinandan De Sukanta Kumar Pradhan 《Journal of molecular recognition : JMR》2014,27(5):260-275
Nucleotide binding and oligomerization domain (NOD2) is a key component of innate immunity that is highly specific for muramyl dipeptide (MDP)—a peptidoglycan component of bacterial cell wall. MDP recognition by NOD2–leucine rich repeat (LRR) domain activates NF‐κB signaling through a protein–protein interaction between caspase activating and recruitment domains (CARDs) of NOD2 and downstream receptor interacting and activating protein kinase 2 (RIP2). Due to the lack of crystal/NMR structures, MDP recognition and CARD–CARD interaction are poorly understood. Herein, we have predicted the probable MDP and CARD–CARD binding surfaces in zebrafish NOD2 (zNOD2) using various in silico methodologies. The results show that the conserved residues Phe819, Phe871, Trp875, Trp929, Trp899, and Arg845 located at the concave face of zNOD2–LRR confer MDP recognition by hydrophobic and hydrogen bond (H‐bond) interactions. Molecular dynamics simulations reveal a stable association between the electropositive surface on zNOD2–CARDa and the electronegative surface on zRIP2–CARD reinforced mostly by H‐bonds and electrostatic interactions. Importantly, a 3.5 Å salt bridge is observed between Arg60 of zNOD2–CARDa and Asp494 of zRIP2–CARD. Arg11 and Lys53 of zNOD2–CARDa and Ser498 and Glu508 of zRIP2–CARD are critical residues for CARD–CARD interaction and NOD2 signaling. The 2.7 Å H‐bond between Lys104 of the linker and Glu508 of zRIP2–CARD suggests a possible role of the linker for shaping CARD–CARD interaction. These findings are consistent with existing mutagenesis data. We provide first insight into MDP recognition and CARD–CARD interaction in the zebrafish that will be useful to understand the molecular basis of NOD signaling in a broader perspective. Copyright © 2014 John Wiley & Sons, Ltd. 相似文献
95.
Gunjan Tyagi Shrikant Pradhan Tapasya Srivastava Ranjana Mehrotra 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014
Background
Allicin has received much attention due to its anti-proliferative activity and not-well elucidated underlying mechanism of action. This work focuses towards determining the cellular toxicity of allicin and understanding its interaction with nucleic acid at molecular level.Methods
MTT assay was used to assess the cell viability of A549 lung cancer cells against allicin. Fourier transform infrared (FTIR) and UV-visible spectroscopy were used to study the binding parameters of nucleic acid-allicin interaction.Results
Allicin inhibits the proliferation of cancer cells in a concentration dependent manner. FTIR spectroscopy exhibited that allicin binds preferentially to minor groove of DNA via thymine base. Analysis of tRNA allicin complex has also revealed that allicin binds primarily through nitrogenous bases. Some amount of external binding with phosphate backbone was also observed for both DNA and RNA. UV visible spectra of both DNA allicin and RNA allicin complexes showed hypochromic shift with an estimated binding constant of 1.2 × 104 M- 1 for DNA and 1.06 × 103 M− 1for RNA binding. No major transition from the B-form of DNA and A-form of RNA is observed after their interaction with allicin.Conclusions
The results demonstrated that allicin treatment inhibited the proliferation of A549 cells in a dose-dependent manner. Biophysical outcomes are suggestive of base binding and helix contraction of nucleic acid structure upon binding with allicin.General significance
The results describe cytotoxic potential of allicin and its binding properties with cellular nucleic acid, which could be helpful in deciphering the complete mechanism of cell death exerted by allicin. 相似文献96.
Jolyon Terragni Guoqiang Zhang Zhiyi Sun Sriharsa Pradhan Lingyun Song Gregory E Crawford Michelle Lacey Melanie Ehrlich 《Epigenetics》2014,9(6):842-850
Notch intercellular signaling is critical for diverse developmental pathways and for homeostasis in various types of stem cells and progenitor cells. Because Notch gene products need to be precisely regulated spatially and temporally, epigenetics is likely to help control expression of Notch signaling genes. Reduced representation bisulfite sequencing (RRBS) indicated significant hypomethylation in myoblasts, myotubes, and skeletal muscle vs. many nonmuscle samples at intragenic or intergenic regions of the following Notch receptor or ligand genes: NOTCH1, NOTCH2, JAG2, and DLL1. An enzymatic assay of sites in or near these genes revealed unusually high enrichment of 5-hydroxymethylcytosine (up to 81%) in skeletal muscle, heart, and cerebellum. Epigenetics studies and gene expression profiles suggest that hypomethylation and/or hydroxymethylation help control expression of these genes in heart, brain, myoblasts, myotubes, and within skeletal muscle myofibers. Such regulation could promote cell renewal, cell maintenance, homeostasis, and a poised state for repair of tissue damage. 相似文献
97.
Inhibition of pathogenic bacterial biofilm by biosurfactant produced by Lysinibacillus fusiformis S9
Arun Kumar Pradhan Nilotpala Pradhan Lala Behari Sukla Prasanna Kumar Panda Barda Kanta Mishra 《Bioprocess and biosystems engineering》2014,37(2):139-149
A biosurfactant producing microbe isolated from a river bank was identified as Lysinibacillus fusiformis S9. It was identified with help of biochemical tests and 16S rRNA gene phylogenetic analysis. The biosurfactant S9BS produced was purified and characterized as glycolipid. The biosurfactant showed remarkable inhibition of biofilm formation by pathogenic bacteria like Escherichia coli and Streptococcus mutans. It was interesting to note that at concentration of 40 μg ml?1 the biosurfactant did not show any bactericidal activity but restricted the biofilm formation completely. L. fusiformis is reported for the first time to produce a glycolipid type of biosurfactant capable of inhibiting biofilm formation by pathogenic bacteria. The biosurfactant inhibited bacterial attachment and biofilm formation equally well on hydrophilic as well as hydrophobic surfaces like glass and catheter tubing. This property is significant in many biomedical applications where the molecule should help in preventing biofouling of surfaces without being toxic to biotic system. 相似文献
98.
Summary and Conclusion The analysis contained in this paper brings out very clearly that the practice of breastfeeding and abstinence in the two
major states of India: Uttar Pradesh and Tamilnadu are highly related to socio-cultural factors and changes in generational
gaps. The findings reveal that literate, non-Hindu, and rich (high SLI) women have shorter breastfeeding durations than illiterates,
Hindus, and poor (low SLI) women of Uttar Pradesh and Tamilnadu. In addition, the breastfeeding practice in Uttar Pradesh
is influenced by residence background and generational age-gaps. The role of socio-cultural factors in influencing post-partum
sexual abstinence period has been found to be significantly important through the variables; residence background, generational
age-gaps, religion and working status of women. The results reveal that urban women, of younger cohorts (below 30 years),
non-Hindu, and non-working women have shorter abstinence periods compared to rural women, of older cohorts (above 30 years),
Hindus, and working women in both the states.
The findings from this analysis suggest that apart from modernization process, defined in terms of higher literacy levels,
higher developmental and urbanization levels, the changing perceptions and attitude towards lactational practices over the
generation has significant dent on shortening of breastfeeding durations and abstinence periods. Thus, the study support the
hypothesis that the process of modernization defined in terms of improvement in level of education, family income, urbanization
tends to shorten the period of breastfeeding and abstinence, and consequently, the post-partum infecundability is reduced.
Such reductions in the infertile periods can be expected to contribute to an increase in natural fertility levels of the population
and also on the observed fertility levels, if not counter balanced by the fertility reducing effects of contraception. 相似文献
99.
100.
Hedgehog is an evolutionarily conserved developmental pathway, widely implicated in controlling various cellular responses such as cellular proliferation and stem cell renewal in human and other organisms, through external stimuli. Aberrant activation of this pathway in human adult stem cell line may cause different types of cancers. Hence, targeting this pathway in cancer therapy has become indispensable, but the non availability of detailed molecular interactions, complex regulations by extra- and intra-cellular proteins and cross talks with other pathways pose a serious challenge to get a coherent understanding of this signaling pathway for making therapeutic strategy. This motivated us to perform a computational study of the pathway and to identify probable drug targets. In this work, from available databases and literature, we reconstructed a complete hedgehog pathway which reports the largest number of molecules and interactions to date. Using recently developed computational techniques, we further performed structural and logical analysis of this pathway. In structural analysis, the connectivity and centrality parameters were calculated to identify the important proteins from the network. To capture the regulations of the molecules, we developed a master Boolean model of all the interactions between the proteins and created different cancer scenarios, such as Glioma, Colon and Pancreatic. We performed perturbation analysis on these cancer conditions to identify the important and minimal combinations of proteins that can be used as drug targets. From our study we observed the under expressions of various oncoproteins in Hedgehog pathway while perturbing at a time the combinations of the proteins GLI1, GLI2 and SMO in Glioma; SMO, HFU, ULK3 and RAS in Colon cancer; SMO, HFU, ULK3, RAS and ERK12 in Pancreatic cancer. This reconstructed Hedgehog signaling pathway and the computational analysis for identifying new combinatory drug targets will be useful for future in-vitro and in-vivo analysis to control different cancers. 相似文献