排序方式: 共有51条查询结果,搜索用时 15 毫秒
31.
Farooq Riaz Qian Chen Kaikai Lu Ezra Kombo Osoro Litao Wu Lina Feng Rong Zhao Luyun Yang Yimeng Zhou Yingli He Li Zhu Xiaojuan Du Muhammad Sadiq Xudong Yang Dongmin Li 《Journal of cellular and molecular medicine》2021,25(8):4073-4087
Persistent hepatic damage and chronic inflammation in liver activate the quiescent hepatic stellate cells (HSCs) and cause hepatic fibrosis (HF). Several microRNAs regulate the activation and proliferation of HSCs, thereby playing a critical role in HF progression. Previous studies have reported that miR-188-5p is dysregulated during the process of HF. However, the role of miR-188-5p in HF remains unclear. This study investigated the potential role of miR-188-5p in HSCs and HF. Firstly, we validated the miR-188-5p expression in primary cells isolated from liver of carbon tetrachloride (CCl4)-induced mice, TGF-β1-induced LX-2 cells, livers from 6-month high-fat diet (HFD)-induced rat and 4-month HFD-induced mice NASH models, and human non-alcoholic fatty liver disease (NAFLD) patients. Furthermore, we used miR-188-5p inhibitors to investigate the therapeutic effects of miR-188-5p inhibition in the HFD + CCl4 induced in vivo model and the potential role of miR-188-5p in the activation and proliferation of HSCs. This present study reported that miR-188-5p expression is significantly increased in the human NAFLD, HSCs isolated from liver of CCl4 induced mice, and in vitro and in vivo models of HF. Mimicking the miR-188-5p resulted in the up-regulation of HSC activation and proliferation by directly targeting the phosphatase and tensin homolog (PTEN). Moreover, inhibition of miR-188-5p reduced the activation and proliferation markers of HSCs through PTEN/AKT pathway. Additionally, in vivo inhibition of miR-188-5p suppressed the HF parameters, pro-fibrotic and pro-inflammatory genes, and fibrosis. Collectively, our results uncover the pro-fibrotic role of miR-188-5p. Furthermore, we demonstrated that miR-188-5p inhibition decreases the severity of HF by reducing the activation and proliferation of HSCs through PTEN/AKT pathway. 相似文献
32.
David C. Kombo Anatoly A. Mazurov Jon-Paul Strachan Merouane Bencherif 《Bioorganic & medicinal chemistry letters》2013,23(18):5105-5113
We have carried out computational studies on interactions of diazabicyclic amide analogs with α4β2 nAChR using homology modeling, docking and pharmacophore elucidation techniques. We have found alternative ligand binding modes in most cases. All these diverse poses exhibit the quintessential hydrogen-bonding interaction between the ligand basic nitrogen and the backbone carbonyl oxygen atom of the highly conserved Trp-149. This hydrogen bond was always found to be shorter than the one contracted by the ligand carbonyl group and a second hydrogen-bond made by the cationic center with Tyr-93 of the principal face of the protein. In most of the poses observed, cation–π interactions involved three aromatic residues located in the principal face of the protein: Trp-149, Tyr-190 and Tyr-197. The latter amino acid residue appears to often donate a hydrogen-bond to the ligand carbonyl oxygen atom. We also describe two rings of alternative receptor-based hydrogen-bond donor features equidistantly separated from the carbonyl oxygen of the highly conserved Trp-149 approximately by 5 and 8 Å, respectively. These findings could be exploited to design diverse and selective novel chemical libraries for the treatment of diseases and conditions where the α4β2 nAChR is disrupted, such as Alzheimer disease, Parkinson’s disease and l-dopa-induced dyskinesia (LID). 相似文献
33.
David C. Kombo Vladimir P. Grinevich Terry A. Hauser Serguei Sidach Merouane Bencherif 《Bioorganic & medicinal chemistry letters》2013,23(17):4842-4847
Compounds containing a quinuclidine scaffold are promising drug candidates for pharmacological management of the central nervous system (CNS) pathologies implicating nAChRs. We have carried out binding affinity and in-silico docking studies of arylmethylene quinuclidine-like derivatives at the α4β2 receptor using in-vitro receptor binding assay and comparative modeling, respectively. We found that introducing a hydrogen-bond acceptor into the 3-benzylidene quinuclidine derivative resulted in a 266-fold increase in binding affinity and confers agonism properties. By contrast, addition of a phenyl group to 3-benzylidene quinuclidine derivative only results in an 18-fold increase in binding affinity, without conferring agonism. We also found that docking into the orthosteric binding site of the α4β2 nAChR is consistent with the fact that the basic nitrogen atom donates a hydrogen-bond to the carbonyl group of the highly conserved Trp-149, as initially observed by Dougherty and co-workers.1 The experimentally-observed trend in binding affinity at both α4β2 and α3β4 nAChRs was accurately and independently confirmed by quantum mechanics (QM)-polarized docking. The reduction in binding affinity to the α3β4 subtype primarily results from a dampening of both coulombic and cation–π interactions. 相似文献
34.
We have carried out molecular dynamics simulation of the N-terminal domain of the lambda repressor protein in a surrounding environment including explicit waters and ions. We observe two apparent dynamics substates in the nanosecond protein simulation, the transition occurring around 500 ps. The existence of these two apparent substates results from a high flexibility of the arm in each monomer, a relative flexibility of both arms with respect to each other, and a relative displacement of the recognition helices from 30 to 40 A of interhelical distance. Many amino acid residues, including those involved in DNA recognition, undergo a simultaneous transition in their side-chain conformations, consistent with the relationship between side-chain conformation and secondary structural elements, as observed in protein crystal structures. This result suggests plausible conformational changes experienced by the protein upon DNA binding. On the whole, the non-consensus monomer appears to be more flexible than its consensus counterpart. 相似文献
35.
A molecular dynamics simulation of the operator binding domain of the lambda repressor protein has been carried out. The protein was embedded in explicit waters, Na(+) and CL(-) ions. The Amber 4.1 computer package and the Cornell et al. Force field were used for energy-minimization and molecular dynamics simulation. We find that the atoms distributions in the environment of waters and Na(+) ions are in excellent agreement with those derived from the analysis of water molecules in crystal structures and ion-binding proteins. We also find that, on the whole, both distributions are similar to each other. 相似文献
36.
Restriction mapping and sequencing have shown that humans have
substantially lower levels of mitochondrial genome diversity (d) than
chimpanzees. In contrast, humans have substantially higher levels of
heterozygosity (H) at protein-coding loci, suggesting a higher level of
diversity in the nuclear genome. To investigate the discrepancy further, we
sequenced a segment of the mitochondrial genome control region (CR) from 49
chimpanzees. The majority of these were from the Pan troglodytes versus
subspecies, which was underrepresented in previous studies. We also
estimated the average heterozygosity at 60 short tandem repeat (STR) loci
in both species. For a total sample of 115 chimpanzees, d = 0.075 +/0
0.037, compared to 0.020 +/- 0.011 for a sample of 1,554 humans. The
heterozygosity of human STR loci is significantly higher than that of
chimpanzees. Thus, the higher level of nuclear genome diversity relative to
mitochondrial genome diversity in humans is not restricted to
protein-coding loci. It seems that humans, not chimpanzees, have an unusual
d/H ratio, since the ratio in chimpanzees is similar to that in other
catarrhines. This discrepancy in the relative levels of nuclear and
mitochondrial genome diversity in the two species cannot be explained by
differences in mutation rate. However, it may result from a combination of
factors such as a difference in the extent of sex ratio disparity, the
greater effect of population subdivision on mitochondrial than on nuclear
genome diversity, a difference in the relative levels of male and female
migration among subpopulations, diversifying selection acting to increase
variation in the nuclear genome, and/or directional selection acting to
reduce variation in the mitochondrial genome.
相似文献
37.
Hidenori Takahashi Shigetaka Shimodaira Masahiro Ogasawara Shuichi Ota Masanori Kobayashi Hirofumi Abe Yuji Morita Kazuhiro Nagai Shunichi Tsujitani Masato Okamoto Yukio Suzuki Yoichi Nakanishi Yoshikazu Yonemitsu for the DC Vaccine Study Group at the Japanese Society of Immunotherapy Cell Therapy 《Cancer immunology, immunotherapy : CII》2016,65(9):1099-1111
38.
TL Kieft EM Murphy DL Haldeman PS Amy BN Bjornstad EV McDonald DB Ringelberg DC White J Stair RP Griffiths TC Gsell WE Holben DR Boone 《Microbial ecology》1998,36(3):336-348
Abstract Two chronosequences of unsaturated, buried loess sediments, ranging in age from <10,000 years to >1 million years, were investigated to reconstruct patterns of microbial ecological succession that have occurred since sediment burial. The relative importance of microbial transport and survival to succession was inferred from sediment ages, porewater ages, patterns of abundance (measured by direct counts, counts of culturable cells, and total phospholipid fatty acids), activities (measured by radiotracer and enzyme assays), and community composition (measured by phospholipid fatty acid patterns and Biolog substrate usage). Core samples were collected at two sites 40 km apart in the Palouse region of eastern Washington State, near the towns of Washtucna and Winona. The Washtucna site was flooded multiple times during the Pleistocene by glacial outburst floods; the Winona site elevation is above flood stage. Sediments at the Washtucna site were collected from near surface to 14.9 m depth, where the sediment age was approximately 250 ka and the porewater age was 3700 years; sample intervals at the Winona site ranged from near surface to 38 m (sediment age: approximately 1 Ma; porewater age: 1200 years). Microbial abundance and activities declined with depth at both sites; however, even the deepest, oldest sediments showed evidence of viable microorganisms. Same-age sediments had equal quantities of microorganisms, but different community types. Differences in community makeup between the two sites can be attributed to differences in groundwater recharge and paleoflooding. Estimates of the microbial community age can be constrained by porewater and sediment ages. In the shallower sediments (<9 m at Washtucna, <12 m at Winona), the microbial communities are likely similar in age to the groundwater; thus, microbial succession has been influenced by recent transport of microorganisms from the surface. In the deeper sediments, the populations may be considerably older than the porewater ages, since microbial transport is severely restricted in unsaturated sediments. This is particularly true at the Winona site, which was never flooded. 相似文献
39.
Walter RB; Rolig RL; Kozak KA; McEntire B; Morizot DC; Nairn RS 《Molecular biology and evolution》1993,10(6):1227-1238
Fishes represent the stem vertebrate condition and have maintained several
gene arrangements common to mammalian genomes throughout the 450 Myr of
divergence from a common ancestor. One such syntenic arrangement includes
the GPI-PEPD enzyme association on Xiphophorus linkage group IV and human
chromosome 19. Previously we assigned the Xiphophorus homologue of the
human ERCC2 gene to linkage group U5 in tight association with the CKM
locus. CKM is also tightly linked to the ERCC2 locus on human chromosome
19, leading to speculation that human chromosome 19 may have arisen by
fusion of two ancestral linkage groups which have been maintained in
fishes. To investigate this hypothesis further, we isolated and sequenced
Xiphophorus fish genomic regions exhibiting considerable sequence
similarity to the human DNA ligase 1 amino acid sequence. Comparison of the
fish DNA ligase sequence with those of other species suggests several modes
of amino acid conservation in this gene. A 2.2-kb restriction fragment
containing part of an X. maculatus DNA ligase 1 exon was used in backcross
hybrid mapping with 12 enzyme or RFLP loci. Significant linkage was
observed between the nucleoside phosphorylase (NP2) and the DNA ligase
(LIG1) loci on Xiphophorus linkage group VI. This assignment suggests that
the association of four DNA repair-related genes on human chromosome 19 may
be the result of chance chromosomal rearrangements.
相似文献
40.