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311.
M Ravinder B Mahendar S Mattapally KV Hamsini TN Reddy C Rohit K Srinivas SK Banerjee VJ Rao 《Bioorganic & medicinal chemistry letters》2012,22(18):6010-6015
Twenty-six 2-pyridone derivatives (8a-8z), which are structurally analogous to amrinone and milrinone two important cardiotonic drugs, are synthesized and characterized. The synthesis of 2-pyridone derivatives involves addition, followed by cyclization between Baylis-Hillman acetates (7a-7k) and enamino esters or nitriles (3a-3e). Thus synthesized pyridones were subjected to PDE3 inhibitory activity, 14 pyridones were found to be hits out of 26 pyridones synthesized and out of 14 hits, there are 5 pyridones found to be lead compounds having excellent PDE3 inhibitory activity. Further we have carried out computational analysis to understand protein/enzyme and 2-pyridone derivative interactions to identify amino acid residues involved in the vicinity of binding and compared with milrinone drug. 相似文献
312.
AimsHigh-fat diet (HFD) is associated with adipose inflammation, which contributes to key components of metabolic abnormalities. The expanded adipose tissue mass associated with obesity is the result of hyperplasia and hypertrophy of adipocytes. In this study, we investigated the effects of long-term HFD on adipocyte progenitor cell (APC) population and adipose-specific gene profiles in both white and brown adipose, and the role of perivascular adipose in the alteration of vascular function in response to HFD.Main methodsMale C57BL/6 mice were fed a standard normal diet (ND) or HFD for about 8 months. Glucose metabolism was assessed by an intraperitoneal glucose tolerance test. APC population and adipose-related gene profile were evaluated, and vascular function was measured in the presence or absence of perivascular adipose. Adiponectin and AMPK activity were also investigated.Key findingsHFD induced insulin resistance and glucose intolerance, and resulted in a decrease in APC population in brown, but not in white adipose tissue, when compared with animals fed a ND, with differential alterations of white and brown adipocyte-specific gene expression in brown and white adipose. Additionally, HFD led to altered vascular function in arteries in the presence of perivascular adipose tissue, which is associated with increased superoxide production. Adiponectin and AMPK activity were significantly decreased in response to long-term HFD.SignificanceThese findings suggest that long-term high-fat intake differentially alters adipocyte progenitor population and adipose-related gene expression in adipose tissue, and adiponectin-AMPK signaling might be involved. In addition, HFD induces changes in perivascular adipose-mediated vascular function. 相似文献
313.
Chromatophores show significant changes during healing of skin wounds in Labeo rohita (Common Name - Rohu). Wound area can be divided into regions I, II and III. After infliction of wound, skin colour becomes significantly dark by 2 h that is gradually restored by 2 d. In regions II and III at 5 min, epidermal melanophores appear with beaded dendrites. In these regions at 2 h and in region I at 6 h, epidermal melanophores appear small, rounded or irregular shaped having dendritic processes with aggregated melanosomes. Subsequently, melanophores appear having elongated dendrites with dispersed or aggregated melanosomes. At 24 h, clusters of pigmented bodies appear in regions I and II. These bodies increase up to 2 d, and then diminish gradually and disappear by 8 d. Changes in dermal melanophores in region II at 5 min indicate the onset of degeneration. Degenerating melanophores increase up to 12 h, then gradually decline, and disappear by 4 d. Simultaneously, stellate melanophore reappear, gradually increase and appear like control by 8 d. Dermal melanophores in region III at different intervals appear stellate. In region I stellate dermal melanophores appear at 4 d. Stellate melanophores in all regions show different distribution of dispersed or aggregated melanosomes. With the appearance of dermal melanophores, highly refractive, crystalline structures, possibly the refractive platelets of the iridophores, are visualized around them. At subsequent intervals, these are frequently observed. This study provides interesting insights in injury induced changes in chromatophores in fish. The findings could be considered useful in perception of intriguing features in the development of pigment research in future. 相似文献
314.
Wei Z Yang H Liu Z Tremblay M Johnstone S Béha S Yue SY Srivastava S Tomaszewski MJ Brown W Walpole C St-Onge S Lessard E Archambault AJ Groblewski T Pagé D 《Bioorganic & medicinal chemistry letters》2012,22(12):3884-3889
Cannabinoid CB(1) receptor agonists exhibit potent analgesic effects in rodents and humans, but their clinical utility as analgesic drugs is often limited by centrally mediated side effects. We report herein the preparation of N-methyl-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamides as a novel class of hCB(1)/hCB(2) dual agonists with attractive physicochemical properties. More specifically, (R)-N,9-dimethyl-N-(4-(methylamino)-4-oxobutyl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide, displayed an extremely low level of CNS penetration (Rat Cbr/Cplasma=0.005 or 0.5%) and was devoid of CNS side effects during pharmaco-dynamic testing. 相似文献
315.
Althoff EA Wang L Jiang L Giger L Lassila JK Wang Z Smith M Hari S Kast P Herschlag D Hilvert D Baker D 《Protein science : a publication of the Protein Society》2012,21(5):717-726
Enzyme catalysts of a retroaldol reaction have been generated by computational design using a motif that combines a lysine in a nonpolar environment with water-mediated stabilization of the carbinolamine hydroxyl and β-hydroxyl groups. Here, we show that the design process is robust and repeatable, with 33 new active designs constructed on 13 different protein scaffold backbones. The initial activities are not high but are increased through site-directed mutagenesis and laboratory evolution. Mutational data highlight areas for improvement in design. Different designed catalysts give different borohydride-reduced reaction intermediates, suggesting a distribution of properties of the designed enzymes that may be further explored and exploited. 相似文献
316.
317.
318.
Bendlin BB Carlsson CM Johnson SC Zetterberg H Blennow K Willette AA Okonkwo OC Sodhi A Ries ML Birdsill AC Alexander AL Rowley HA Puglielli L Asthana S Sager MA 《PloS one》2012,7(6):e37720
Cerebrospinal fluid (CSF) biomarkers T-Tau and Aβ(42) are linked with Alzheimer's disease (AD), yet little is known about the relationship between CSF biomarkers and structural brain alteration in healthy adults. In this study we examined the extent to which AD biomarkers measured in CSF predict brain microstructure indexed by diffusion tensor imaging (DTI) and volume indexed by T1-weighted imaging. Forty-three middle-aged adults with parental family history of AD received baseline lumbar puncture and MRI approximately 3.5 years later. Voxel-wise image analysis methods were used to test whether baseline CSF Aβ(42), total tau (T-Tau), phosphorylated tau (P-Tau) and neurofilament light protein predicted brain microstructure as indexed by DTI and gray matter volume indexed by T1-weighted imaging. T-Tau and T-Tau/Aβ(42) were widely correlated with indices of brain microstructure (mean, axial, and radial diffusivity), notably in white matter regions adjacent to gray matter structures affected in the earliest stages of AD. None of the CSF biomarkers were related to gray matter volume. Elevated P-Tau and P-Tau/Aβ(42) levels were associated with lower recognition performance on the Rey Auditory Verbal Learning Test. Overall, the results suggest that CSF biomarkers are related to brain microstructure in healthy adults with elevated risk of developing AD. Furthermore, the results clearly suggest that early pathological changes in AD can be detected with DTI and occur not only in cortex, but also in white matter. 相似文献
319.
Deobagkar DD Panikar C Rajpathak SN Shaiwale NS Mukherjee S 《Methods (San Diego, Calif.)》2012,56(2):260-267
DNA methylation is an important epigenetic modification involved in the ability of an organism to respond to stress and adaptation. It has been implicated in development, differentiation, oncogenesis, chromatin remodelling, nutrigenomics, and appears to play a pivotal role in many regulatory and adaptive functions. It is therefore important to analyze the status of DNA methylation and its changes under various developmental, carcinogenic, pharmacological, and environmental conditions. In this report we describe an immunochemical method for the detection of genome wide DNA methylation and its alterations under various conditions along with the analysis of DNA methyltransferase activity. The ability of this approach to detect and provide a map of methylomic changes in a genome facilitates assessment of various agents and conditions which can alter this important epigenetic signal. This experimental system permits rapid evaluation of potential target genes which would be modulated by DNA methylation changes and thus the gene networks that govern the processes. 相似文献
320.
J. Saadi Imam Jason R. Plyler Hima Bansal Suresh Prajapati Sanjay Bansal Jennifer Rebeles Hung-I Harry Chen Yao-Fu Chang Subbarayalu Panneerdoss Behyar Zoghi Kalyan C. Buddavarapu Russell Broaddus Peter Hornsby Gail Tomlinson Jeffrey Dome Ratna K. Vadlamudi Alexander Pertsemlidis Yidong Chen Manjeet K. Rao 《PloS one》2012,7(12)
Increasing evidence suggests that chromosomal regions containing microRNAs are functionally important in cancers. Here, we show that genomic loci encoding miR-204 are frequently lost in multiple cancers, including ovarian cancers, pediatric renal tumors, and breast cancers. MiR-204 shows drastically reduced expression in several cancers and acts as a potent tumor suppressor, inhibiting tumor metastasis in vivo when systemically delivered. We demonstrated that miR-204 exerts its function by targeting genes involved in tumorigenesis including brain-derived neurotrophic factor (BDNF), a neurotrophin family member which is known to promote tumor angiogenesis and invasiveness. Analysis of primary tumors shows that increased expression of BDNF or its receptor tropomyosin-related kinase B (TrkB) parallel a markedly reduced expression of miR-204. Our results reveal that loss of miR-204 results in BDNF overexpression and subsequent activation of the small GTPase Rac1 and actin reorganization through the AKT/mTOR signaling pathway leading to cancer cell migration and invasion. These results suggest that microdeletion of genomic loci containing miR-204 is directly linked with the deregulation of key oncogenic pathways that provide crucial stimulus for tumor growth and metastasis. Our findings provide a strong rationale for manipulating miR-204 levels therapeutically to suppress tumor metastasis. 相似文献