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991.
Anna Drzazga Agata Sowińska Agnieszka Krzemińska Andrzej Okruszek Piotr Paneth Maria Koziołkiewicz Edyta Gendaszewska-Darmach 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2018,1863(1):91-103
GPR119 receptor has been proposed as a metabolic regulator playing a pivotal role in the modulation of glucose homeostasis in type 2 diabetes. GPR119 was identified on pancreatic β cells and its ligands have the ability to enhance glucose-stimulated insulin secretion (GSIS). Lysophosphatidylcholine (LPC) was shown to potentiate GSIS and our present studies indicate that 2-methoxy-lysophosphatidylcholine (2-OMe-LPC) analogues, unable to undergo 1 → 2 acyl migration, stimulate GSIS from murine βTC-3 pancreatic cells even more efficiently. Moreover, biological assays in engineered Tango? GPR119-bla U2OS cells were carried out to ascertain the agonist activity of 2-OMe-LPC at GPR119. 2-OMe-LPC possessing in sn-1 position the residues of myristic, palmitic, stearic and oleic acid were also evaluated as factors regulating [Ca2 +]i mobilization and cAMP levels. Extension of these studies to R- and S-enantiomers of 14:0 2-OMe-LPC revealed that the overall impact on GSIS does not depend on chirality, however, the intracellular calcium mobilization data show that the R enantiomer is significantly more active than S one. Taking into account differences in chemical structure between various native LPCs and their 2-methoxy counterparts the possible binding mode of 2-OMe-LPC to the GPR119 receptor was determined using molecular modeling approach. 相似文献
992.
Maria Billert Tatiana Wojciechowicz Mariami Jasaszwili Dawid Szczepankiewicz Jadwiga Waśko Sandra Kaźmierczak Mathias Z. Strowski Krzysztof W. Nowak Marek Skrzypski 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2018,1863(12):1449-1457
Phoenixin-14 (PNX) is a newly discovered peptide produced by proteolytic cleavage of the small integral membrane protein 20 (Smim20). Previous studies showed that PNX is involved in controlling reproduction, pain, anxiety and memory. Furthermore, in humans, PNX positively correlates with BMI suggesting a potential role of PNX in controlling fat accumulation in obesity. Since the influence of PNX on adipose tissue formation has not been so far demonstrated, we investigated the effects of PNX on proliferation and differentiation of preadipocytes using 3T3-L1 and rat primary preadipocytes. We detected Smim20 and Gpr173 mRNA in 3T3-L1 preadipocytes as well as in rat primary preadipocytes. Furthermore, we found that PNX peptide is produced and secreted from 3T3-L1 and rat primary adipocytes. PNX increased 3T3-L1 preadipocytes proliferation and viability. PNX stimulated the expression of adipogenic genes (Pparγ, C/ebpβ and Fabp4) in 3T3-L1 adipocytes. 3T3-L1 preadipocytes differentiated in the presence of PNX had increased lipid content. Stimulation of cell proliferation and differentiation by PNX was also confirmed in rat preadipocytes. PNX failed to induce AKT phosphorylation, however, PNX increased cAMP levels in 3T3-L1 cells. Suppression of Epac signalling attenuated PNX-induced Pparγ expression without affecting cell proliferation. Our data show that PNX stimulates differentiation of 3T3-L1 and rat primary preadipocytes into mature adipocytes via cAMP/Epac-dependent pathway. In conclusion our data shows that phoenixin promotes white adipogenesis, thereby may be involved in controlling body mass regulation. 相似文献
993.
Shao-Lin Zhang Zheng Yang Xiaohui Hu Kin Yip Tam 《Bioorganic & medicinal chemistry letters》2018,28(21):3441-3445
Dichloroacetophenone is a pyruvate dehydrogenase kinase 1 (PDK1) inhibitor with suboptimal kinase selectivity. Herein, we report the synthesis and biological evaluation of a series of novel dichloroacetophenones. Structure-activity relationship analyses (SARs) enabled us to identify three potent compounds, namely 54, 55, and 64, which inhibited PDK1 function, activated pyruvate dehydrogenase complex, and reduced the proliferation of NCI-H1975 cells. Mitochondrial bioenergetics assay suggested that 54, 55, and 64 enhanced the oxidative phosphorylation in cancer cells, which might contribute to the observed anti-proliferation effects. Collectively, these results suggested that 54, 55, and 64 could be promising compounds for the development of potent PDK1 inhibitors. 相似文献
994.
Tomoyuki Ohe Ryutaro Umezawa Yumina Kitagawara Daisuke Yasuda Kyoko Takahashi Shigeo Nakamura Akiko Abe Shuichi Sekine Kousei Ito Kentaro Okunushi Hanae Morio Tomomi Furihata Naohiko Anzai Tadahiko Mashino 《Bioorganic & medicinal chemistry letters》2018,28(23-24):3708-3711
We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and hURAT1 inhibition. It was found that all of the derivatives demonstrate lower cytotoxicity in mouse hepatocytes and lower levels of metabolic activation than BBR, while maintaining their inhibitory activity toward the uric acid transporter. We propose that these derivatives could serve as effective uricosuric agents that have much better safety profiles than BBR. 相似文献
995.
Lin Wang Ziru Yu Shuyue Ren Junke Song Jinhua Wang Guanhua Du 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(10):2281-2292
Background
Metabolic reprogramming and hypoxia contribute to the resistance of conventional chemotherapeutic drugs in kinds of cancers. In this study, we investigated the effect of dihydrotanshinone I (DHTS) on reversing dysregulated metabolism of glucose and fatty acid in colon cancer and elucidated its mechanism of action.Methods
Cell viability was determined by MTT assay. Oxidative phosphorylation, glycolysis, and mitochondrial fuel oxidation were assessed by Mito stress test, glycolysis stress test, and mito fuel flex test, respectively. Anti-cancer activity of DHTS in vivo was evaluated in Colon cancer xenograft. Hexokinase activity and free fatty acid (FFA) content were assessed using respective Commercial kits. Gene expression patterns were determined by performing DNA microarray analysis and real-time PCR. Protein expression was assessed using immunoblotting and immunohistochemistry.Results
DHTS showed similar cytotoxicity against colon cancer cells under hypoxia and normoxia. DHTS decreased the efficiency of glucose and FA as mitochondrial fuels in HCT116 cells, which efficiently reversed by VO-OHpic trihydrate. DHTS reduced hexokinase activity and free fatty acid (FFA) content in tumor tissue of xenograft model of colon cancer. Gene expression patterns in metabolic pathways were dramatically differential between model and treatment group. Increases in PTEN and a substantial decrease in the expression of SIRT3, HIF1α, p-AKT, HKII, p-MTOR, RHEB, and p-ACC were detected.Conclusions
DHTS reversed metabolic reprogramming in colon cancer through PTEN/AKT/HIF1α-mediated signal pathway.General significance
The study is the first to report the reverse of metabolic reprogramming by DHTS in colon cancer. Meantime, SIRT3/PTEN/AKT/HIF1α mediated signal pathway plays a critical role during this process. 相似文献996.
Sheng-Wei Chang Jack Wellmerling Xiaoli Zhang Rachael E. Rayner Wissam Osman Sara Mertz Amal O. Amer Mark E. Peeples Prosper N. Boyaka Estelle Cormet-Boyaka 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(9):1988-1994
Background
Marijuana consumption is on the rise in the US but the health benefits of cannabis smoking are controversial and the impact of cannabis components on lung homeostasis is not well-understood. Lung function requires a fine regulation of the ion channel CFTR, which is responsible for fluid homeostasis and mucocilliary clearance. The goal of this study was to assess the effect that exposure to Δ9-tetrahydrocannabinol (THC), the psychoactive substance present in marijuana, has on CFTR expression and function.Methods
Cultures of human bronchial epithelial cell line 16HBE14o- and primary human airway epithelial cells were exposed to THC. The expression of CFTR protein was determined by immunoblotting and CFTR function was measured using Ussing chambers. We also used specific pharmacological inhibitors of EGFR and ERK to determine the role of this pathway in THC-induced regulation of CFTR.Results
THC decreased CFTR protein expression in primary human bronchial epithelial cells. This decrease was associated with reduced CFTR-mediated short-circuit currents. THC also induced activation of the ERK MAPK pathway via activation of EGFR. Inhibition of EGFR or MEK/ERK prevented THC-induced down regulation of CFTR protein expression.Conclusions and general significance
THC negatively regulates CFTR and this is mediated through the EGFR/ERK axis. This study provides the first evidence that THC present in marijuana reduces the expression and function of CFTR in airway epithelial cells. 相似文献997.
根据信号肽N端电荷数,选择Sec及Tat两种途径的信号肽构建枯草芽孢杆菌穿梭质粒,首次实现Bacillus cereus源亮氨酸脱氢酶基因在Bacillus subtilis中的分泌表达。Tat途径信号肽Pho D促进蛋白质分泌的效果最好,胞外酶活力达20.25U/ml,为不添加信号肽的2.2倍,信号肽N端较多的电荷数,可能有利于多聚体蛋白的分泌。对表达产物进行纯化和酶学性质测定。结果表明,纯酶比酶活为13U/mg;L-Leucine为底物时酶的K_m为6.17mmol/L,V_(max)为14.49μmol/(L·min);底物特异性研究发现,酶与天然底物L-Leucine的亲和性最好,对一些脂肪族氨基酸也有活性,对芳香族氨基酸L-Phenylalanine无活性;酶的最适pH为10.5~12.0,pH稳定范围为5.0~11.0;最适反应温度为55℃;圆二色谱变温扫描酶二级结构变化,α螺旋含量随温度升高逐渐降低;差示扫描微量热技术(DSC)测定酶的解折叠温度(Tm值)为64.13℃,表明该酶具有较好耐热性。 相似文献
998.
999.
Nancy L. Charó Natalia M. Galigniana Graciela Piwien-Pilipuk 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2018,1865(2):432-443
Confocal and electron microscopy images, and WB analysis of cellular fractions revealed that HP1γ is in the nucleus but also in the cytoplasm of C2C12 myoblasts, myotubes, skeletal and cardiac muscles, N2a, HeLa and HEK293T cells. Signal specificity was tested with different antibodies and by HP1γ knockdown. Leptomycin B treatment of myoblasts increased nuclear HP1γ, suggesting that its nuclear export is Crm-1-dependent. HP1γ exhibited a filamentous pattern of staining partially co-localizing with actin in the cytoplasm of myotubes and myofibrils. Immunoelectron microscopic analysis showed high-density immunogold particles that correspond to HP1γ localized to the Z-disk and A-band of the sarcomere of skeletal muscle. HP1γ partially co-localized with actin in C2C12 myotubes and murine myofibrils. Importantly, actin co-immunoprecipitated with HP1γ in the nuclear and cytosolic fractions of myoblasts. Actin co-immunoprecipitated with HP1γ in myoblasts incubated in the absence or presence of the actin depolymerizing agent cytochalasin D, suggesting that HP1γ may interact with G-and F-actin. In the cytoplasm, HP1γ was associated to the perinuclear actin cap that controls nuclear shape and position. In the nucleus, re-ChIP assays showed that HP1γ-actin associates to the promoter and transcribed regions of the house keeping gene GAPDH, suggesting that HP1γ may function as a scaffold protein for the recruitment of actin to control gene expression. When HP1γ was knocked-down, myoblasts were unable to differentiate or originated thin myotubes. In summary, HP1γ is present in the nucleus and the cytoplasm interacting with actin, a protein complex that may exert different functions depending on its subcellular localization. 相似文献
1000.
W.F. Theeuwes H.R. Gosker R.C.J. Langen N.A.M. Pansters A.M.W.J. Schols A.H.V. Remels 《生物化学与生物物理学报:疾病的分子基础》2018,1864(9):2913-2926