Although lung cancer (LC) is a highly environmentally associated disease, genetic factors are also thought to play a role in this disease. In recent years, genome-wide association studies have identified various susceptible genetic regions for LC. Herein, we used high-resolution melting analysis to genotype 2 significant single nucleotide polymorphisms previously reported in Caucasians, that is, rs401681 at 5p15.33 and rs8034191 at 15q25, in a case-control study with 492 LC cases and 486 cancer-free controls in a Chinese population. We found that the rs401681C/T allele in the TERT-CLPTM1L gene was associated with the risk of non-small cell lung cancer [NSCLC; P = 0.012, odds ratio (OR) = 1.29, 95% confidence interval (95%CI) = 1.09-1.50], but was not associated with the risk of small cell lung cancer (P = 0.571, OR = 1.15, 95%CI = 0.82-1.47). However, no significant association was found between rs8034191T/C and LC risk. These results suggest that genetic variants in the TERT-CLPTM1L gene may predispose individuals to be susceptible to LC, particularly NSCLC, in the Chinese population.
Acute myocardial infarction (AMI) is a cardiovascular disease with a high fatality rate. In this study, we combined network pharmacology and experimental pharmacology and discovered the potential mechanism of action and the active ingredients of the lily, Tricyrtis maculata was discovered. The monomer compound with stronger activity was discovered through in vitro cell experiments.Forty known compounds were isolated from T. maculata. Using TCMSP, Swiss Target Prediction, metaTarFisher, GeneCards and OMIM databases, targets of drug compositions and AMI-related genes were obtained, and the differential expression genes between AMI and normal tissues were extracted through the GEO database. Then, through an online mapping tool, the intersection genes were obtained to predict the possible effective components of T. maculata that can be used to treat AMI. The top five targets were selected for molecular docking via the protein-protein interaction (PPI) network to verify the binding activity between key compounds and target proteins. GO and KEGG enrichment analyses of the intersection genes were carried out with the program R to further screen key genes and effective compositions. On this basis, the compound with more optimal activity was screened and validated in vitro.In this study, 40 known monomer components were selected, and 1112 predicted genes, 1655 disease genes, 1425 differentially expressed genes, 1206 GO functions and 127 KEGG pathways were obtained. The results of molecular docking showed that the binding of MMP9 with drug components is stable. Through the comprehensive research of network pharmacology and experimental pharmacology, it was shown that T. maculata intervenes in the process of AMI through multicomponent, multitarget, and multichannel synergistic effects. It is speculated that the anti-AMI effect may be related to the regulation of the Akt/FoxO/BCl signaling pathway. Cellular experiments showed that nicotiflorin has satisfactory anti-inflammatory activity and endothelial protection and can reduce the release of nitric oxide (NO), an inflammatory medium after endothelial cell damage.This study reveals the therapeutic effect and relative mechanism of extract of T. maculata extract on AMI. Analysis revealed that nicotiflorin from T. maculata is a compound with satisfactory anti-inflammatory activity and endothelial protection, which provides a new direction and treatment basis for further experimental exploration and clinical treatment.
BACKGROUND: The interest in plasma biomarkers has increased recently. Plasma exosome-derived microRNA-532 is aberrantly expressed in a variety of human cancers and has the prognostic value in many solid tumors. However, the prognostic impact of the expression value on AML remains unclear. OBJECTIVE : The aim of this study is to investigate the prognostic value of exosome-derived microRNA-532 in AML patients. METHODS: We performed the real-time PCR to quantify exosome-derived microRNA-532 in plasma of 198 AML patients. To assess the prognostic value, we performed Cox regression analyses in the context of well-established clinical and molecular markers. Cellular metabolic profile was conducted to help us understand the biological insight of its expression. RESULTS: The expression level was not associated with white blood cell counts, age, FAB subtypes, cytogenetic risk groups and genes of FLT3-ITD, NPM1, CEBPA and DNMT3A mutations. Interestingly, high expressers had a favorable overall survival in the univariate analysis. This prognostic value was testified in the multivariate analysis. Moreover, up-regulation of miR-532 was negatively associated with cellular energy like fructose and glutamine. CONCLUSION: We found plasma exosome-derived microRNA-532 can be used as a novel survival predictor for acute myeloid leukemia.
Two precocious walnut varieties, Lvling and Lvzao were used as materials in this study, the kernel fat contents and 3 related enzyme activities in different development periods after flowe-ring 50 days were analyzed. The key enzymes affecting walnut fat in different periods were illumina-ted. The results showed that the kernel fat accumulation trends of the two varieties were basically the same. The kernel began to solidify 50 days after flowering, and the increase in kernel fat content was rapid 60-90 days after flowering, slowed down 90-120 days after flowering, and stopped 120-130 days after flowering. The Logistic model was used to fit the fat accumulation (P<0.01). Fat content rapid accumulation period was 57.8-85.8 days after flowering for Lvling, and 67.4-92.1 days after flowering for Lvzao. The activities of acetyl-CoA carboxylase (ACCase), 6-phosphate dextrose dehydrogenase (G6PDH) and pyruvate kinase (PK) increased from 50 to 100 days after flowering, and then the activities of enzymes began to decrease. The kernel fat content was positively correlated with the activity of ACCase. The kernel fat accumulation rate was positively correlated with PK enzyme activity. The correlation between fat content and enzyme activity was different at different development stages. The 50-100 days after flowering was the exuberant period of walnut kernel fat synthesis, and at this time the fat content could be improved by strengthening the field cultivation management measures. At the early stage of the walnut fat synthesis, G6PDH was the major enzyme to affect fat content, and PK activity influenced the formation of pyruvic acid, so as to indirectly affect the synthesis of fat. ACCase activity affected the final fat content and ACCase played an important regulating role in every period of fat synthesis. It was speculated that ACCase might be a key enzyme to affect the fat synthesis of walnut kernel.以绿岭和绿早2个早实核桃品种为试材,对开花50 d后不同发育时期核仁的脂肪含量与3种相关的酶活性动态进行研究,分析不同发育时期影响核桃脂肪含量的关键酶.结果表明: 2个品种的核仁脂肪积累动态一致,核仁在开花后50 d开始固化,花后60～90 d核仁脂肪含量迅速增加,花后90～120 d增长幅度变缓,花后120～130 d脂肪含量停止增长.利用Logistic模型对核桃脂肪积累进程进行拟合(P<0.01),绿岭脂肪积累盛期为开花后57.8～85.8 d,绿早为开花后67.4～92.1 d.乙酰辅酶A羧化酶(ACCase)、6-磷酸葡萄糖脱氢酶(G6PDH)和丙酮酸激酶(PK)活性均在花后50～100 d呈上升趋势,随后酶活性呈下降趋势.核仁脂肪含量与ACCase活性呈显著正相关;脂肪积累速率与PK活性呈显著正相关;不同发育时期脂肪含量与酶活性的相关性不同.花后50～100 d是核桃核仁脂肪合成旺盛的时期,此时加强田间栽培管理可以提高脂肪含量.在核桃脂肪合成前期G6PDH是影响脂肪含量的主要酶,PK活性影响丙酮酸形成,从而间接影响脂肪的合成.ACCase活性影响了最终的脂肪含量,并在脂肪合成的各个时期均起到重要的调节作用,是影响核桃脂肪合成的关键酶.
FFAR2 (GPR43) is a receptor for short‐chain fatty acids (SCFAs), acetate and propionate. In the current study, we investigate the molecular determinants contributing to receptor activation by endogenous ligands. Mutational analysis revealed several important residues located in transmembrane domains (TM) 3, 4, 5, 6, and 7 for acetate binding. Interestingly, mutations that abolished acetate activity, including the mutation in the well‐conserved D(E)RY motif, could be rescued by a recently identified synthetic allosteric agonist. These findings provide additional insight into agonist binding and activation which may aid in designing allosteric ligands for targeting receptor function in various diseases.
Activation of FFA1 (GPR40), a member of G protein-coupling receptor family A, is mediated by medium- and long-chain fatty acids and leads to amplification of glucose-stimulated insulin secretion, suggesting a potential role for free fatty acid 1 (FFA1) as a target for type 2 diabetes. It was assumed previously that there is a single binding site for fatty acids and synthetic FFA1 agonists. However, using members of two chemical series of partial and full agonists that have been identified, radioligand binding interaction studies revealed that the full agonists do not bind to the same site as the partial agonists but exhibit positive heterotropic cooperativity. Analysis of functional data reveals positive functional cooperativity between the full agonists and partial agonists in various functional assays (in vitro and ex vivo) and also in vivo. Furthermore, the endogenous fatty acid docosahexaenoic acid (DHA) shows negative or neutral cooperativity with members of both series of agonists in binding assays but displays positive cooperativity in functional assays. Another synthetic agonist is allosteric with members of both agonist series, but apparently competitive with DHA. Therefore, there appear to be three allosterically linked binding sites on FFA1 with agonists specific for each of these sites. Activation of free fatty acid 1 receptor (FFAR1) by each of these agonists is differentially affected by mutations of two arginine residues, previously found to be important for FFAR1 binding and activation. These ligands with their high potencies and strong positive functional cooperativity with endogenous fatty acids, demonstrated in vitro and in vivo, have the potential to deliver therapeutic benefits.
We recently reported the discovery of a potent GPR40 full agonist AM-1638 (1). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties. Compound 8 and 20 also showed potent in vivo efficacy in oral glucose tolerance tests in mice in addition to the improvement in properties.
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