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981.
982.
Synthesis of novel mono and bis nitric oxide donors with high cytocompatibility and release activity
Tanya Sahyoun Caroline Gaucher Yi Zhou Naïm Ouaini Raphaël Schneider Axelle Arrault 《Bioorganic & medicinal chemistry letters》2018,28(20):3329-3332
Four compounds bearing amidoxime functions were synthetized: (1) 2a,b bearing an aromatic amidoxime function, (2) 2c bearing an aliphatic amidoxime function, and (3) 2d bearing aromatic and aliphatic amidoximes functions. The ability of these compounds to release NO was evaluated in vitro using the oxidative metabolism of cytochrome P450 from rat liver microsomes. Results obtained demonstrate that all amidoximes were able to release NO with a highest amount of NO produced by the 2a aromatic amidoxime. Moreover, all amidoximes exhibit cytocompatibility with human aorta smooth muscle cells. Using intracellular S-nitrosothiol formation as a marker of NO bioavailability, compounds 2a–c were demonstrated to deliver a higher amount of NO in the intracellular environment than the reference. Considering that the concentration of the bis-amidoxime 2d was two times lower that than of 2a and 2b, we can assume that 2d is the most potent molecule among the tested compounds for NO release. 相似文献
983.
Yundong Xie Lihua Shao Qiutang Wang Yue Bai Zizhang Chen Na Li Yanhong Xu Yiping Li Guangde Yang Xiaoli Bian 《Bioorganic & medicinal chemistry letters》2018,28(23-24):3731-3735
Nitric oxide (NO) dysfunction has been found to be an important factor in both the development and progression of diabetic complications due to its many roles in the vascular system. Multifunctional compounds with hypoglycemic and endothelial protective action will be promising agents for the treatment of diabetes and its complications. In this study, a series of novel NO-donating sitagliptin derivatives and relevant metabolites were synthesized and evaluated as potential multifunctional hypoglycemic agents. All of synthetic compounds shown remarkable inhibitory activity against dipeptidyl peptidase IV (DPP-IV) in vitro and demonstrated excellent hypoglycemic activities in diabetic mice, similar to the activity of sitagliptin, and compounds T1-T4 shown different extents of NO-releasing abilities and potent antioxidant abilities in vivo. By screening in DPP-4, compound T4 was recognized as a potent DPP-4 inhibitor with the IC50 value of 0.060?μM. Docking study revealed compound T4 has a favorable binding mode. Furthermore, compounds T1-T4 exhibited different extents of NO-releasing abilities and excellent anti-platelet aggregation in vitro. The overall results suggested that T4 could help to the amelioration of endothelial dysfunction by reducing blood glucose, lessening oxidative stress and raising NO levels as well as inhibiting platelet aggregation. Based on this research, compound T4 deserves further investigation as potential new multifunctional anti-diabetic agent with antioxidant, anti-platelet aggregation and endothelial protective properties. 相似文献
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985.
Xiaoguang Li Na Liu Bin Gu Wei Hu Ying Li Bin Guo Dongsheng Zhang 《Molecular biology reports》2018,45(6):1691-1704
In bone marrow mesenchymal stem cell (BMSCs), type 2 diabetes mellitus (T2DM) induces metabolic and functional disorders, leading to imbalanced bone resorption and formation and bone loss. Brain and muscle ARNT-like protein 1 (BMAL1) is involved in regulating T2DM-related suppression of BMSCs osteogenesis and bone formation. However, the relationship between BMAL1 and bone remodelling, especially bone resorption in T2DM, is unclear. We investigated the antergic role played by BMAL1 in T2DM-prompted imbalance in BMSCs osteogenic–osteoclastic function. BMAL1 was inhibited and the receptor activator of nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) ratio was increased in diabetic BMSCs. Inhibitor κB (IκB) expression was decreased, whereas phosphorylated-p65 (p-p65), caspase-3, and p-IκB expression were increased in diabetic BMSCs. BMAL1 overexpression recovered the osteogenesis ability and suppressed osteoclastic induction capability of BMSCs to improve bone metabolism and function, which was partially due to NF-κB pathway activity inhibition. Our results provide evidence about the role of BMAL1 in T2DM-prompted BMSCs differentiation dysfunction, i.e. partially decreasing NF-κB pathway expression. In T2DM, it might be possible to use overexpressed BMAL1 to re-establish the homeostasis of bone metabolism. 相似文献
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The α1‐adrenergic receptor is involved in hepcidin upregulation induced by adrenaline and norepinephrine via the STAT3 pathway 下载免费PDF全文
990.
Identification and characterization of two novel C‐type lectins from the larvae of housefly,Musca domestica L. 下载免费PDF全文
Jing Zhou Nai‐ Nai Fang Ya Zheng Kai‐ Yu Liu Bin Mao Li‐ Na Kong Ya Chen Hui Ai 《Archives of insect biochemistry and physiology》2018,98(3)
Lectins and antimicrobial peptides (AMPs) are widely distributed in various insects and play crucial roles in primary host defense against pathogenic microorganisms. Two AMPs (cecropin and attacin) have been identified and characterized in the larvae of housefly. In this study, two novel C‐type lectins (CTLs) were obtained from Musca domestica, while their agglutinating and antiviral properties were evaluated. Real‐time PCR analysis showed that the mRNA levels of four immune genes (MdCTL1, MdCTL2, Cecropin, and Attacin) from M. domestica were significantly upregulated after injection with killed Gram‐negative Escherichia coli. Moreover, purified MdCTL1‐2 proteins can agglutinate E. coli and Staphylococcus aureus in the presence of calcium ions, suggesting their immune function is Ca2+ dependent. Sequence analysis indicated that typical WND and QPD motifs were found in the Ca2+‐binding site 2 of carbohydrate recognition domain from MdCTL1‐2, which was consistent with their agglutinating activities. Subsequently, antiviral experiments indicated that MdCTL1‐2 proteins could significantly reduce the infection rate of Spodoptera frugiperda 9 cells by the baculovirus Autographa californica multicapsid nucleopolyhedrovirus, indicating they might play important roles in insect innate immunity against microbial pathogens. In addition, MdCTL1‐2 proteins could effectively inhibit the replication of influenza H1N1 virus, which was similar to the effect of ribavirin. These results suggested that two novel CTLs could be considered a promising drug candidate for the treatment of influenza. Moreover, it is believed that the discovery of the CTLs with antiviral effects in M. domestica will improve our understanding of the molecular mechanism of insect immune response against viruses. 相似文献