排序方式: 共有134条查询结果,搜索用时 15 毫秒
1.
Jason D. Roh Nicholas Houstis Andy Yu Bliss Chang Ashish Yeri Haobo Li Ryan Hobson Carolin Lerchenmüller Ana Vujic Vinita Chaudhari Federico Damilano Colin Platt Daniel Zlotoff Richard T. Lee Ravi Shah Michael Jerosch‐Herold Anthony Rosenzweig 《Aging cell》2020,19(6)
Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training (ExT) has emerged as the most effective intervention to improving functional outcomes in this age‐related disease. The molecular mechanisms by which ExT induces its beneficial effects in HFpEF, however, remain largely unknown. Given the strong association between aging and HFpEF, we hypothesized that ExT might reverse cardiac aging phenotypes that contribute to HFpEF pathophysiology and additionally provide a platform for novel mechanistic and therapeutic discovery. Here, we show that aged (24–30 months) C57BL/6 male mice recapitulate many of the hallmark features of HFpEF, including preserved left ventricular ejection fraction, subclinical systolic dysfunction, diastolic dysfunction, impaired cardiac reserves, exercise intolerance, and pathologic cardiac hypertrophy. Similar to older humans, ExT in old mice improved exercise capacity, diastolic function, and contractile reserves, while reducing pulmonary congestion. Interestingly, RNAseq of explanted hearts showed that ExT did not significantly modulate biological pathways targeted by conventional HF medications. However, it reversed multiple age‐related pathways, including the global downregulation of cell cycle pathways seen in aged hearts, which was associated with increased capillary density, but no effects on cardiac mass or fibrosis. Taken together, these data demonstrate that the aged C57BL/6 male mouse is a valuable model for studying the role of aging biology in HFpEF pathophysiology, and provide a molecular framework for how ExT potentially reverses cardiac aging phenotypes in HFpEF. 相似文献
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Lasha Gogokhia Kate Buhrke Rickesha Bell Brenden Hoffman D. Garrett Brown Christin Hanke-Gogokhia Nadim J. Ajami Matthew C. Wong Arevik Ghazaryan John F. Valentine Nathan Porter Eric Martens Ryan O’Connell Vinita Jacob Ellen Scherl Carl Crawford W. Zac Stephens Sherwood R. Casjens June L. Round 《Cell host & microbe》2019,25(2):285-299.e8
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Vinita Mishra 《Journal of biomolecular structure & dynamics》2019,37(8):1968-1991
Toll-like receptor 4 (TLR4) is a member of Toll-Like Receptors (TLRs) family that serves as a receptor for bacterial lipopolysaccharide (LPS). TLR4 alone cannot recognize LPS without aid of co-receptor myeloid differentiation factor-2 (MD-2). Binding of LPS with TLR4 forms a LPS?TLR4?MD-2 complex and directs downstream signaling for activation of immune response, inflammation and NF-κB activation. Activation of TLR4 signaling is associated with various pathophysiological consequences. Therefore, targeting protein–protein interaction (PPI) in TLR4?MD-2 complex formation could be an attractive therapeutic approach for targeting inflammatory disorders. The aim of present study was directed to identify small molecule PPI inhibitors (SMPPIIs) using pharmacophore mapping-based approach of computational drug discovery. Here, we had retrieved the information about the hot spot residues and their pharmacophoric features at both primary (TLR4?MD-2) and dimerization (MD-2?TLR4*) protein–protein interaction interfaces in TLR4?MD-2 homo-dimer complex using in silico methods. Promising candidates were identified after virtual screening, which may restrict TLR4?MD-2 protein–protein interaction. In silico off-target profiling over the virtually screened compounds revealed other possible molecular targets. Two of the virtually screened compounds (C11 and C15) were predicted to have an inhibitory concentration in μM range after HYDE assessment. Molecular dynamics simulation study performed for these two compounds in complex with target protein confirms the stability of the complex. After virtual high throughput screening we found selective hTLR4?MD-2 inhibitors, which may have therapeutic potential to target chronic inflammatory diseases. 相似文献
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Pathak R Pant CS Shaw AK Bhaduri AP Gaikwad AN Sinha S Srivastava A Srivastava KK Chaturvedi V Srivastava R Srivastava BS 《Bioorganic & medicinal chemistry》2002,10(10):3187-3196
A series of acyclic deoxy carbohydrate derivatives from easily available carbohydrate enals 1, 2, 3 or 5 were prepared involving the Baylis-Hillman reaction. These newly formed carbohydrate based Baylis-Hillman adducts and their amino derivatives were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H(37)R(v). Among the compounds evaluated for their antimycobacterial activity, compound (10) showed the desired activity in the range of 3.125 microg/mL. 相似文献
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Verma V Raju SC Kapley A Kalia VC Kanade GS Daginawala HF Purohit HJ 《Bioresource technology》2011,102(3):3227-3233
A strain, Stenotrophomonas HPC383 is isolated from effluent treatment plant treating wastewater from pesticide industry; degrades various aromatic compounds (cresols, phenol, catechol, 4methyl-catechol and hydroquinone) and crude oil, as determined through HPLC and GC analysis. Culture HPC383 could degrade (%) various compounds (1 mM) from a mixture: phenol - 99, p-cresol - 100, 4-methylcatechol - 96 and hydroquinone - 43 within 48 h of incubation, whereas it took 7 days to degrade 94% of 0.5% crude oil. Gene locus dmpN, to identify phenol degrading capacity was determined by PCR followed by southern analysis. The sequenced DNA fragment exhibited 99% sequence similarity to phenol hydroxylase gene from Arthrobacter sp. W1 (FJ610336). Amino acid sequence analysis of phenol hydroxylase reveals it to belong to high-Ks (affinity constant) group. Application of HPC383 in bioremediation of aquatic and terrestrial sites contaminated with petrochemical has been suggested. 相似文献
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Singh N Pandey SK Anand N Dwivedi R Singh S Sinha SK Chaturvedi V Jaiswal N Srivastava AK Shah P Siddiqui MI Tripathi RP 《Bioorganic & medicinal chemistry letters》2011,21(15):4404-4408
An economical and efficient one step synthesis of a series of 8-(arylidene)-4-(aryl)-5,6,7,8-tetrahydro-quinazolin-2-ylamines and 9-(arylidene)-4-(aryl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-2-ylamines by the reaction of bis-benzylidene cycloalkanones and guanidine hydrochloride in presence of NaH has been developed. All the synthesized compounds were evaluated against Mycobacterium tuberculosis H37Rv strain and the α-glucosidase and glycogen phosphorylase enzymes. Few of the compounds have shown interesting in vitro activity with MIC up to 3.12 μg/mL against M. tuberculosis and very good inhibition of α-glucosidase and glycogen phosphorylase enzymes. The most potent non toxic compound 40 exhibited about 58% ex vivo activity at MIC of 3.12 μg/mL. The present study opens a new gate to synthesize antitubercular agents for diabetic TB patients. In silico docking studies indicate that mycobacterial dihydrofolate reductase is the possible target of these compounds. 相似文献
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Thachamvally Riyesh Vinayagamurthy Balamurugan Arnab Sen Veerakyathappa Bhanuprakash Gnanavel Venkatesan Vinita Yadav Raj Kumar Singh 《中国病毒学》2011,26(5):324-337
In this study, thermo-adapted (Ta) PPR vaccines were assessed for their stability at 25, 37, 40, 42 and 45°C in lyophilized
form using two extrinsic stabilizers {lactalbumin hydrolysate-sucrose (LS) and stabilizer E} and in reconstituted form with
the diluents (1 mol/L MgSO4 or 0.85% NaCl). The lyophilized vaccines showed an expiry period of 24–26 days at 25°C, 7–8 days at 37°C and 3–4 days at
40°C. LS stabilizer was superior at 42°C with a shelf-life of 44 h, whereas in stabilizer E, a 40 h shelf-life with a comparable
half-life was observed. At 45°C, the half-life in stabilizer E was better than LS and lasted for 1 day. Furthermore, the reconstituted
vaccine maintained the titre for 48 h both at 4°C and 25°C and for 24–30 h at 37°C. As both the stabilizers performed equally
well with regard to shelf-life and half-life, the present study suggests LS as stabilizer as a choice for lyophilization with
0.85% NaCl diluent, because it has better performance at higher temperature. These Ta vaccines can be used as alternatives
to existing vaccines for the control of the disease in tropical countries as they are effective in avoiding vaccination failure
due to the breakdown in cold-chain maintenance, as this vaccine is considerably more stable at ambient temperatures. 相似文献
10.
Wadhawan V Karim ZA Mukhopadhyay S Gupta R Dikshit M Dash D 《Archives of biochemistry and biophysics》2004,422(2):183-190
Platelets are cleared from circulation after a life span of 8-10 days. The molecular mechanisms underlying platelet senescence remain poorly characterized. Here we report that, progressive functional impairment in the platelets incubated in vitro in a plasma-free isotonic medium for up to 24 h at 37 degrees C is associated with release of cytochrome c from platelet mitochondria and cleavage of procaspase-9, but without evidence of caspase-3 activation. Concomitantly, there was proteolysis of survival proteins like focal adhesion kinase, Src, gelsolin, and specific cytoskeleton-associated peptides, in a manner regulated by extracellular calcium and calpain activity. Cytoskeleton played a critical role as evidenced from the association of these proteins and their degradation products, as well as procaspase-3 and the actin regulatory small GTPase, CDC42Hs, with the cytoskeleton of the stored platelets. The cytoskeletal enrichment with specific proteins was not associated with increase in the content of F-actin and was cytochalasin-resistant, thus signifying a novel mechanism of interaction of the translocating proteins with the pre-existing cytoskeleton. There was progressive exposure of phosphatidylserine on the outer leaflet of platelet membrane and specific electron microscopic changes suggestive of apoptotic lesions. Based on these observations we discuss the caspase-independent but calpain-mediated signaling events in the stored platelets resembling the features of apoptosis in the nucleated cells. 相似文献