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41.
Mulakayala N Kandagatla B Ismail Rapolu RK Rao P Mulakayala C Kumar CS Iqbal J Oruganti S 《Bioorganic & medicinal chemistry letters》2012,22(15):5063-5066
A convenient and practical methodology for the synthesis of 2-aryl quinazolin-4(3H)-ones by the condensation of o-aminobenzamides with aromatic aldehydes under mild conditions using catalytic InCl(3) with good yields and high selectivities. This method has been extended for the synthesis of 5-aryl pyrazolo[4,3-d]pyrimidin-7(6H)-ones which have potential applications in medicinal chemistry. Many of these compounds were evaluated for their anti-proliferative properties in vitro against four cancer cell lines and several compounds were found to be active. Further in vitro studies indicated that inhibition of sirtuins could be the possible mechanism of action of these molecules. 相似文献
42.
Organic anion transporting polypeptide 1a1 (Oatp1a1) is predominantly expressed in liver and is able to transport bile acids (BAs) in vitro. Male Oatp1a1-null mice have increased concentrations of taurodeoxycholic acid (TDCA), a secondary BA generated by intestinal bacteria, in both serum and livers. Therefore, in the present study, BA concentrations and intestinal bacteria in wild-type (WT) and Oatp1a1-null mice were quantified to investigate whether the increase of secondary BAs in Oatp1a1-null mice is due to alterations in intestinal bacteria. The data demonstrate that Oatp1a1-null mice : (1) have similar bile flow and BA concentrations in bile as WT mice; (2) have a markedly different BA composition in the intestinal contents, with a decrease in conjugated BAs and an increase in unconjugated BAs; (3) have BAs in the feces that are more deconjugated, desulfated, 7-dehydroxylated, 3-epimerized, and oxidized, but less 7-epimerized; (4) have 10-fold more bacteria in the small intestine, and 2-fold more bacteria in the large intestine which is majorly due to a 200% increase in Bacteroides and a 30% reduction in Firmicutes; and (5) have a different urinary excretion of bacteria-related metabolites than WT mice. In conclusion, the present study for the first time established that lack of a liver transporter (Oatp1a1) markedly alters the intestinal environment in mice, namely the bacteria composition. 相似文献
43.
Fanconi Anemia (FA) is a rare disorder with incidence of 1in 350,000 births. It is characterized by progressive bone marrow failure leading to death of many patients in their childhood while development of cancer at later stages of life in some. The treatment of FA is still a medical challenge. Current treatments of FA include androgen administration, hematopoietic growth factors administration and hematopoietic stem cell transplantation (HSCT). Clinical gene therapy trials are still ongoing. The partial success of current therapies has renewed interest in the search for new treatments. Generation of patient-specific induced pluripotent stem (iPS) has shown promising results for cell and gene based therapy. Small molecule interventions have been observed to delay tumor onset in FA. Tumors deficient in FA pathway can be treated by profiling of DNA repair pathway through synthetic lethality mechanism. Targeting toll-like receptor 8 (TLR8) dependent TNFα overexpression is yet another upcoming therapeutic approach to treat FA patients. In conclusion, in the present scenario of treatments available for FA, a proper algorithm of treatment decisions must be followed for better management of FA patients and to ensure their increased survival. Innovative therapeutic approaches that can prevent both anemia and cancer should be developed for more effective treatment of FA. 相似文献
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46.
Morgera F Sallah MR Dubuke ML Gandhi P Brewer DN Carr CM Munson M 《Molecular biology of the cell》2012,23(2):337-346
Trafficking of protein and lipid cargo through the secretory pathway in eukaryotic cells is mediated by membrane-bound vesicles. Secretory vesicle targeting and fusion require a conserved multisubunit protein complex termed the exocyst, which has been implicated in specific tethering of vesicles to sites of polarized exocytosis. The exocyst is directly involved in regulating soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) complexes and membrane fusion through interactions between the Sec6 subunit and the plasma membrane SNARE protein Sec9. Here we show another facet of Sec6 function-it directly binds Sec1, another SNARE regulator, but of the Sec1/Munc18 family. The Sec6-Sec1 interaction is exclusive of Sec6-Sec9 but compatible with Sec6-exocyst assembly. In contrast, the Sec6-exocyst interaction is incompatible with Sec6-Sec9. Therefore, upon vesicle arrival, Sec6 is proposed to release Sec9 in favor of Sec6-exocyst assembly and to simultaneously recruit Sec1 to sites of secretion for coordinated SNARE complex formation and membrane fusion. 相似文献
47.
Xianqiang Song Jun Yang Jamila Hirbawi Sheng Ye H Dhanuja Perera Esen Goksoy Pallavi Dwivedi Edward F Plow Rongguang Zhang Jun Qin 《Cell research》2012,22(11):1533-1545
The activation of heterodimeric (α/β) integrin transmembrane receptors by
cytosolic protein talin is crucial for regulating diverse cell-adhesion-dependent
processes, including blood coagulation, tissue remodeling, and cancer metastasis. This
process is triggered by the coincident binding of N-terminal FERM
(four-point-one-protein/ezrin/radixin/moesin) domain of talin (talin-FERM) to the inner
membrane surface and integrin β cytoplasmic tail, but how these binding events are
spatiotemporally regulated remains obscure. Here we report the crystal structure of a
dormant talin, revealing how a C-terminal talin rod segment (talin-RS) self-masks a key
integrin-binding site on talin-FERM via a large interface. Unexpectedly, the structure
also reveals a distinct negatively charged surface on talin-RS that electrostatically
hinders the talin-FERM binding to the membrane. Such a dual inhibitory topology for talin
is consistent with the biochemical and functional data, but differs significantly from a
previous model. We show that upon enrichment with phosphotidylinositol-4,5-bisphosphate
(PIP2) – a known talin activator, membrane strongly attracts a positively charged
surface on talin-FERM and simultaneously repels the negatively charged surface on
talin-RS. Such an electrostatic “pull-push” process promotes the relief of the
dual inhibition of talin-FERM, which differs from the classic “steric clash”
model for conventional PIP2-induced FERM domain activation. These data therefore unravel a
new type of membrane-dependent FERM domain regulation and illustrate how it mediates the
talin on/off switches to regulate integrin transmembrane signaling and cell adhesion. 相似文献
48.
SK Singh L Möckel P Thiagarajan-Rosenkranz M Wittlich D Willbold BW Koenig 《The FEBS journal》2012,279(19):3705-3714
Viral protein?U (VpU) of HIV-1 plays an important role in downregulation of the main HIV-1 receptor CD4 from the surface of infected cells. Physical binding of VpU to newly synthesized CD4 in the endoplasmic reticulum is an early step in a pathway leading to proteasomal degradation of CD4. In this study, regions in the cytoplasmic domain of VpU involved in CD4 binding were identified by NMR spectroscopy. Amino acids in both helices found in the cytoplasmic region of VpU in membrane-mimicking detergent micelles experience chemical shift perturbations upon binding to CD4, whereas amino acids between the two helices and at the C-terminus of VpU show no or only small changes, respectively. The topology of the complex was further studied with paramagnetic relaxation enhancement. Paramagnetic spin labels were attached at three sequence positions of a CD4 peptide comprising the transmembrane and cytosolic domains of the receptor. VpU binds to a membrane-proximal region in the cytoplasmic domain of CD4. STRUCTURED DIGITAL ABSTRACT: VpU?and?CD4?bind?by?nuclear magnetic resonance?(View interaction). 相似文献
49.
Ghosh R Chhabra A Phatale PA Samrat SK Sharma J Gosain A Mohanty D Saran S Gokhale RS 《The Journal of biological chemistry》2008,283(17):11348-11354
Dictyostelium discoideum exhibits the largest repository of polyketide synthase (PKS) proteins of all known genomes. However, the functional relevance of these proteins in the biology of this organism remains largely obscure. On the basis of computational, biochemical, and gene expression studies, we propose that the multifunctional Dictyostelium PKS (DiPKS) protein DiPKS1 could be involved in the biosynthesis of the differentiation regulating factor 4-methyl-5-pentylbenzene-1,3-diol (MPBD). Our cell-free reconstitution studies of a novel acyl carrier protein Type III PKS didomain from DiPKS1 revealed a crucial role of protein-protein interactions in determining the final biosynthetic product. Whereas the Type III PKS domain by itself primarily produces acyl pyrones, the presence of the interacting acyl carrier protein domain modulates the catalytic activity to produce the alkyl resorcinol scaffold of MPBD. Furthermore, we have characterized an O-methyltransferase (OMT12) from Dictyostelium with the capability to modify this resorcinol ring to synthesize a variant of MPBD. We propose that such a modification in vivo could in fact provide subtle variations in biological function and specificity. In addition, we have performed systematic computational analysis of 45 multidomain PKSs, which revealed several unique features in DiPKS proteins. Our studies provide a new perspective in understanding mechanisms by which metabolic diversity could be generated by combining existing functional scaffolds. 相似文献
50.
Pallavi B. Nahar Shuklangi A. Kulkarni Mahesh S. Kulye Santosh B. Chavan Girish Kulkarni Armugham Rajendran 《Biocontrol Science and Technology》2008,18(4):337-355
The effect of repeated conidial sub-culturing of Metarhizium anisopliae on its virulence against Helicoverpa armigera (Hübner) was studied. The LT50 observed against third instar larvae of H. armigera for the first sub-culture was 3.4 days; it increased to 4.5 and 5.6 days for the 20th and the 40th sub-cultures, respectively. The LT50 values after passage of the 40th sub-culture on H. armigera decreased to 4.4 and 3.7 days for the 40th (first in vivo) and the 40th (fifth in vivo) passages, respectively. Similarly, the LC50 of M. anisopliae towards third instar larvae of H. armigera increased from the first sub-culture (0.17×104) to (3.0×104) for the 40th conidial transfers on potato dextrose agar and again decreased to 0.74×104 and 0.23×104 in the 40th (first in vivo) and the 40th (fifth in vivo) passage, respectively. Similar trends for LC50 and LT50 values were seen when sugarcane woolly aphid, Ceratovacuna lanigera Zehntner was used as a host. Significant variation in appressorium formation and cuticle-degrading enzyme production such as chitinase, chitin deacetylase, chitosanase and protease during subsequent sub-culturing and passage through H. armigera was observed. Though there was no effect on internal transcribed spacer (ITS) sequence pattern, interestingly, in randomly amplified polymorphic DNA (RAPD), significant differences in the band intensities and in the banding pattern for different sub-cultures of M. anisopliae were observed. As stable virulence towards the insect pest is desirable for commercialisation of a mycoinsecticide, such changes in virulence due to repeated in vitro transfer need to be monitored and minimised. 相似文献