Chronic stress is a common emotional disorder in cancer patients. Chronic stress promotes progression of gastric cancer (GC) and leads to poor outcomes. However, the underlying mechanisms remain not clear. Herein, we explored the possible mechanisms of chronic stress in GC progression. The Cancer Genome Atlas (TCGA) datasets were analyzed for differentially expressed genes. Clinical data of GC were evaluated for their association with PlexinA1 using TCGA and Kaplan-Meier-plotter databases. Chronic stress of GC patients was evaluated using the Self-Rating Anxiety Scale and Self-Rating Depression Scale. Chronic unpredictable mild stress (CUMS) was used to induce chronic stress in mice. Gastric xenograft tumor was constructed using the sewing method. Chronic stress-like behaviors were assessed using light/dark box and tail suspension tests. Protein expression was detected using immunohistochemistry and Western blot analysis. Analyses of TCGA and the Kaplan-Meier-plotter databases showed that patients with high levels of PlexinA1 in GC had worse overall survival than those with low levels of PlexinA1. A total of 36 GC patients were enrolled in the study, and about 33% of the patients had chronic stress. Compared with patients without chronic stress, higher expression levels of adrenoceptor beta 2 and PlexinA1 were observed in patients with chronic stress. The tumor size in mice under CUMS was significantly increased compared with the control mice. Adrenoceptor beta 2, PlexinA1, N-cadherin, and alpha-smooth muscle actin, as well as Ki67 were highly expressed in the tumors of CUMS group. However, E-cadherin was lowly expressed in the tumors of CUMS group. Importantly, chemical sympathectomy with 6-hydroxydopamine or treatment with a selective β2 adrenergic receptor antagonist (ICI118,551) could reverse these effects. Our findings suggest that chronic stress plays an important role in GC progression and there is a potential for blocking the epinephrine-β2AR/PlexinA1 pathway in the treatment of GC.

With the medical model shifting from a single biomedical model to a biopsychological-social model, the impact of psychosocial factors on cancer patients has attracted attention.Studies have shown that chronic stress caused by long-term psychological stress, such as anxiety and depression, can promote the malignant progression of tumors by acting on β2-adrenergic receptor (β2-AR).β2-AR can promote tumor migration by activating epithelial-mesenchymal transition (EMT).However, the underlying mechanisms in the regulation of EMT by β2-AR are still unclear.In this study, we established a chronic stress model by treating MGC-803 and SGC-7901 human gastric cancer cells with isoproterenol (ISO), a β2-AR agonist.EMT in the two gastric cancer cell lines was enhanced after ISO treatment.Thereafter, we found that the interaction between β2-AR and PlexinA1 was involved in the process by which chronic stress affects EMT in both MGC-803 and SGC-7901 cells.Moreover, the activation of β2-AR by ISO increased the expression of PlexinA1, activated JAK-STAT3 signaling and further promoted EMT in human gastric cancer cells.Importantly, the knockdown of PlexinA1 by small hairpin RNAs inhibited JAK-STAT3 signaling and abolished the EMT induced by β2-AR.In conclusion, PlexinA1 was an important downstream target of β2-AR, through which β2-AR promoted EMT in human gastric cancer cells by activating JAK-STAT3 signaling.

应激是机体内环境稳态被破坏,或者面临破坏威胁时产生的适应性反应;根据应激源的持续时间分为急性应激和慢性应激.急性应激是指机体面对紧急危险情况下产生的非特异性适应性改变,通常有积极的影响,比如可以提高记忆力,暂时改善大脑的功能.慢性应激则是机体长期处于失稳状态,如生活、社会、职场压力和逆境等持续产生的负面影响,不仅会产生抑郁、不安和焦虑等负面情绪,还会影响睡眠质量和食欲、胃肠道功能,更有极端者会对自己的躯体造成伤害籍此缓解应激情绪、逃避应激源;此外慢性应激还会增加动脉粥样硬化、心血管疾病、精神障碍和肿瘤的发病风险.

目的 探究异丙肾上腺素(ISO)模拟的慢性应激通过神经丛素A1-蛋白酪氨酸激酶2-信号转导与转录激活因子3(Plexin A1-JAK2-STAT3)通路对胃癌血管生成的影响.方法 利用慢病毒或通路抑制剂分别干扰MGC-803胃癌细胞中Plexin A1的表达或JAK2-STAT3信号通路,再联合利用20μmol/L浓度的ISO作用MGC-803细胞12 h后,收集细胞培养液,采用放射免疫法检测MGC-803细胞分泌血管内皮生长因子(VEGF)水平;用MGC-803细胞培养液进一步培养血管内皮细胞EA.hy926,分别利用CCK-8法、Transwell法、血管形成实验检测EA.hy926细胞的增殖、迁移和成管能力;Western印迹检测EA.hy926细胞中Plexin A1、VEGF受体2(VEGFR2)蛋白表达.结果 慢病毒干扰MGC-803细胞Plexin A1后,细胞VEGF分泌水平明显降低;干扰了Plexin A1表达的MGC-803细胞培养液培养EA.hy926细胞后,EA.hy926细胞中VEGFR2和Plexin A1表达明显减少,同时EA.hy926细胞增殖、迁移和成管能力显著降低;抑制MGC-803细胞中JAK2-STAT3信号通路,细胞VEGF分泌水平明显降低;利用MGC-803细胞培养液培养的血管内皮细胞EA.hy926的增殖、迁移和成管能力显著降低.结论 慢性应激通过胃癌细胞Plexin A1-JAK2-STAT3信号通路刺激VEGF分泌,促进胃癌血管生成.

ObjectiveWe investigated the clinical significance of preoperative pan-immune-inflammation value (PIV) in patients with colorectal cancer (CRC).MethodsIn this retrospective study, 366 cases who underwent surgery for CRC were enrolled. Their clinical data were collected. PIV was calculated with the formula PIV = [neutrophil count (109/L)× platelet count (109/L) × monocyte count (109/L) /lymphocyte count (109/L). Patients were divided into high PIV (> median PIV) and low PIV (< median PIV) groups. The relationship between PIV and clinicopathological features of CRC was investigated. Receiver operating characteristic (ROC) curve was plotted to indicate the value of immune-inflammatory biomarkers (IIBs) in predicting the TNM stage of CRC, and the area under the curve (AUC) was calculated to evaluate the actual clinical value of IIBs. AUC > 0.5 and closer to 1 indicated the better predictive efficacy. The influencing factors of PIV in CRC were analyzed.ResultsWe found that PIV was positively correlated with tumor size (r = 0.300, p < 0.05), carcinoembryonic antigen (CEA) (r = 0.214, p < 0.05) and carbohydrate antigen 125 (CA-125) (r = 0.249, p < 0.05), but negatively correlated with albumin (Alb) (r = −0.242, p < 0.05). PIV was significantly different in patients with different tumor locations (left or right), surgical methods (laparotomy versus laparoscopic surgery) (p < 0.05), and patients with different pathological T stages, N-stage and TNM stages (p < 0.05). ROC curve analysis of IIBs showed the AUC of PIV was greater than other markers when combined with CEA or carbohydrate antigen 19–9 (CA19–9). Multivariate regression analysis identified T stage, CEA, Alb, and tumor size as the independent influential factors of PIV in CRC.ConclusionPIV is associated with the tumor stage in patients with CRC, which may be useful in preoperative assessment of CRC.

Inflammatory bowel disease (IBD) is a chronic non-specific inflammatory disease that occurs in the intestinal tract. It is mainly divided into two subtypes, i.e., the Crohn's disease (CD) and ulcerative colitis (UC). At present, its pathogenesis has not been fully elucidated, but it has been generally believed that the environment, immune disorders, genetic susceptibility, and intestinal microbes are the main factors for the disease pathogenesis. With the development of the sequencing technology, microbial factors have received more and more attention. The gut microbiota is in a state of precise balance with the host, in which the host immune system is tolerant to immunogenic antigens produced by gut commensal microbes. In IBD patients, changes in the balance between pathogenic microorganisms and commensal microbes lead to changes in the composition and diversity of gut microbes, and the balance between microorganisms and the host would be disrupted. This new state is defined as dysbiosis. It has been confirmed, in both clinical and experimental settings, that dysbiosis plays an important role in the occurrence and development of IBD, but the causal relationship between dysbiosis and inflammation has not been elucidated. On the other hand, as a classic research method for pathogen identification, the Koch's postulates sets the standard for verifying the role of pathogens in disease. With the further acknowledgment of the disease pathogenesis, it is realized that the traditional Koch's postulates is not applicable to the etiology research (determination) of infectious diseases. Thus, many researchers have carried out more comprehensive and complex elaboration of Koch's postulates to help people better understand and explain disease pathogenesis through the improved Koch's postulates. Therefore, focusing on the new perspective of the improved Koch's postulates is of great significance for deeply understanding the relationship between dysbiosis and IBD. This article has reviewed the studies on dysbiosis in IBD, the use of microbial agents in the treatment of IBD, and their relationship to the modified Koch's postulates.

以2-（2-氯苯基）-2-{6,7-二氢噻吩并[3,2-c]吡啶5（4H）乙酸甲酯为原料,设计并合成了一系列新型的N-取代-2-（2-氯苯基）-2-{6,7-二氢噻吩并[3,2-c]吡啶-5（4H）-基}乙酰胺（4a～4o）,其结构经1H NMR和MS表征。体内初步生物活性测试结果表明,4a～4o均有一定的抗血小板聚集作用,其中4a,4l和4m对大鼠血小板聚集的抑制率分别为60.3%,63.0%和65.1%。

OBJECTIVE: To design and synthesize a novel series of 4, 5, 6, 7-tetrahydrothieno [3,2-c] pyridine containing substituted piperazine or piperidine derivatives and to test their in vivo anti-platelet aggregation activity in the rat. METHODS: Key intermediate 2 was synthesized by connecting compound 1 with chloroacetyl chloride. Title compounds 3-19 were produced by connecting intermediate 2 with a series of substituted piperazine or piperidine. RESULTS: 17 novel compounds were synthesized and structurally characterized by 1H NMR and MS. Their in vivo anti-platelet aggregation activities were evaluated in the rat. Compounds 10-14 exhibited more potent inhibitory activity than other compounds synthesized. CONCLUSION: These thienopyridine derivatives showed a certain anti-platelet aggregation activity, and were worth further developing as promising lead compounds.

A series of novel derivatives of 4, 5, 6, 7-tetrahydrothieno [3,2-c] pyridine were synthesized and structurally characterized by 1H NMR and MS. Their in vivo anti-platelet aggregation activities were evaluated. A 3D-QSAR was performed using the CoMFA and the CoMSIA. This model provided useful guidelines for novel anti-platelet thienopyridines design.

Two series of novel derivatives of 4,5,6,7-tetrahydrothieno [3,2-c]pyridine were synthesized and structurally characterized by 1H NMR and MS. Their in vivo antiplatelet aggregation activities were evaluated.

The invention discloses a thieno[3.2-c]pyridine containing acetyl hydrazine derivative or a salt chemically acceptable of the derivative; meanwhile, the invention also discloses a drug combination with the compounds as active-effective components and an application of the same as a medicine for treating platelet aggregation inhibitor, and particularly for preparing, preventing or curing diseases due to the platelet aggregation, such as coronary syndrome, myocardial infarction, myocardial ischemia and cardio-cerebrovascular diseases.

The title compound, C 13 H 16 O 3 , is an intermediate in the synthesis of the anti-ulcer agent sofalcone. The asymmetric unit contains two independent molecules. Intramolecular O—H...O hydrogen bonds are formed between the carbonyl and hydroxyl groups.

AIM:To study the relationship between quantitative structure and pharmacokinetics (QSPkR) of fluoroquinolone antibacterials.METHODS:The pharmacokinetic (PK) parameters of oral fluoroquinolones were collected from the literature. These pharmacokinetic data were averaged, 19 compounds were used as the training set, and 3 served as the test set. Genetic function approximation (GFA) module of Cerius(2) software was used in QSPkR analysis.RESULTS:A small volume and large polarizability and surface area of substituents at C-7 contribute to a large area under the curve (AUC) for fluoroquinolones. Large polarizability and small volume of substituents at N-1 contribute to a long half life elimination.CONCLUSION:QSPkR models can contribute to some fluoroquinolones antibacterials with excellent pharmacokinetic properties.

The title compound, C 13 H 16 O 3 , is an intermediate in the synthesis of the anti-ulcer agent sofalcone. The asymmetric unit contains two independent molecules. Intramolecular O—H...O hydrogen bonds are formed between the carbonyl and hydroxyl groups.

In recent years, correlation between genotype and phenotype of CYP450s is gradually paid attention. In the region of clinical rational use of drugs, we hope to know everyone's activity of CYP450s respectively by genotype analysis. Then we can not only improve therapeutical effect of drugs but also reduce their adverse reactions. In the region of new drug research and development, study of function of CYP450s can guide design, screening and optimization of new drugs. This paper summarized research development of genetic polymorphism of CYP450s in recent years, and introduced six main drug-metabolizing enzymes respectively; they are CYP2C19, CYP2C9, CYP3A4, CYP2D6, CYP1A2 and CYP2E1. Research on genetic polymorphism of CYP450s is significant to drug design, screening, evaluation and optimization.