activator

摘要： BACKGROUND Study shows that signal transducer and activator of transcription 3(STAT3) can increase the Warburg effect by stimulating hexokinase 2 in breast cancer and upregulate lactate dehydrogenase A and pyruvate dehydrogenase kinase 1 in myeloma. STAT3 and pyruvate kinase M2(PKM2) can also be activated and enhance the Warburg effect in hepatocellular carcinoma. Precancerous lesions are critical to human and rodent hepatocarcinogenesis. However, the underlying molecular mechanism for the development of liver precancerous lesions remains unknown. We hypothesized that STAT3 promotes the Warburg effect possibly by upregulating p-PKM2 in liver precancerous lesions in rats.AIM To investigate the mechanism of the Warburg effect in liver precancerous lesions in rats.METHODS A model of liver precancerous lesions was established by a modified Solt-Farber method. The liver pathological changes were observed by HE staining and immunohistochemistry. The transformation of WB-F344 cells induced with Nmethyl-N'-nitro-N-nitrosoguanidine and hydrogen peroxide was evaluated by the soft agar assay and aneuploidy. The levels of glucose and lactate in the tissue and culture medium were detected with a spectrophotometer. The protein levels of glutathione S-transferase-π, proliferating cell nuclear antigen(PCNA), STAT3,and PKM2 were examined by Western blot and immunofluorescence.RESULTS We found that the Warburg effect was increased in liver precancerous lesions in rats. PKM2 and p-STAT3 were upregulated in activated oval cells in liverprecancerous lesions in rats. The Warburg effect, p-PKM2, and p-STAT3 expression were also increased in transformed WB-F344 cells. STAT3 activation promoted the clonal formation rate, aneuploidy, alpha-fetoprotein expression,PCNA expression, G1/S phase transition, the Warburg effect, PKM2 phosphorylation, and nuclear translocation in transformed WB-F344 cells.Moreover, the Warburg effect was inhibited by stattic, a specific inhibitor of STAT3, and further reduced in transformed WB-F344 cells after the intervention for PKM2.CONCLUSION The Warburg effect is initiated in liver precancerous lesions in rats. STAT3 activation promotes the Warburg effect by enhancing the phosphorylation of PKM2 in transformed WB-F344 cells.

摘要： A new class of potential antibacterial agents has been synthesized on a new molecular scaffold of cyclohexane carboxylate. We have tagged this new class of compounds TACCs (Trisubstituted Aryl Cyclohexanecarboxylate). These new molecules are structural analogues of an Activators of Self-Compartmentalizing Proteases 4 and 5 (ACP 4 and 5), and were synthesized to circumvent the drug-like property (drug-ability) challenges and liability noted in ACP 4 and 5. A pseudo-Robinson annulation protocol was used to furnish this new class of potential antibiotics. Structure-activity relationship (SAR) study was done to identify the pharmacophore(s) in this molecular scaffold. A selection of these compounds was used in our preliminary antibacterial inhibitory activities’ studies on Bacillus mycoides and Bacillus subtilis. These preliminary studies show that the TACCs exhibited equal, and in some cases better, antibacterial activity than ACP 4 and 5.

摘要： Proton pump inhibitors(PPIs) are one of the most frequently used medications for upper gastrointestinal diseases. However, a number of physicians have raised concern about the serious side effects of long-term use of PPIs, including the development of gastric cancer. Recent epidemiological studies have reported a significant association between long-term PPI intake and the risk of gastric cancer, even after successful Helicobacter pylori eradication. However, the effects of PPIs on the development of pre-malignant conditions such as atrophic gastritis or intestinal metaplasia are not fully known, suggesting the need for comprehensive and confirmative studies are needed in the future. Meanwhile,several experimental studies have demonstrated the effects of PPIs in reducing chemoresistance in gastric cancer cells by modulating the acidic microenvironment, cancer stemness and signal transducer and activator of transcription 3(STAT3) signaling pathway. The inhibitory effects of PPIs on STAT3 activity may overcome drug resistance and enhance the efficacy of conventional or targeted chemotherapeutic agents. Taken together, PPIs may"play dual role" in gastric carcinogenesis and treatment of gastric cancer.

摘要： 缺血性脑卒中是目前我国最主要的致死致残病因之一,而其中颅内外大血管急性闭塞是病情严重、预后不良的亚型,导致了巨大的社会和经济负担。4.5 h内静脉应用重组组织型纤溶酶原激活剂(recombinant human tissue type plasminogen activator,rt-PA)作为处理急性缺血性脑卒中证据最充分的治疗方式,已在世界范围内广泛开展,但限于其相对严格的时间窗和适应证、禁忌证要求,接受溶栓治疗的患者比例较低[1-3]。另外,相当部分的大血管闭塞性脑卒中对rt-PA并不敏感,仅5%~30%能够实现闭塞血管再通,患者获益程度有限[2-4]。近年来,多项国外随机对照研究结果证实,在颅内大血管闭塞性病变中,早期施行以支架型取栓装置为代表的血管内介入治疗能够显著改善患者预后[5-10]。在国内,2015年国家卫计委发布了《中国缺血性脑卒中血管内治疗指导规范》,中华医学会神经病学分会发布了《急性缺血性卒中血管内治疗中国指南2015》,对急性缺血性脑卒中急诊救治中的临床、检验、影像评估,以及静脉溶栓和血管内治疗的技术与时间管理均提出了明确的要求[2,11]。

摘要： Concomitantly with the increase in the prevalences of overweight/obesity, nonalcoholic fatty liver disease(NAFLD) has worldwide become the main cause of chronic liver disease in both adults and children. Patients with fatty liver display features of metabolic syndrome(Met S), like insulin resistance(IR), glucose intolerance, hypertension and dyslipidemia. Recently, epidemiological studies have linked obesity, Met S, and NAFLD to decreased bone mineral density and osteoporosis, highlighting an intricate interplay among bone, adipose tissue, and liver. Osteoprotegerin(OPG), an important symbol of the receptor activator of nuclear factor-B ligand/receptor activator of nuclear factor kappa B/OPG system activation, typically considered for its role in bone metabolism, may also play critical roles in the initiation and perpetuation of obesityrelated comorbidities. Clinical data have indicated that OPG concentrations are associated with hypertension, left ventricular hypertrophy, vascular calcification, endothelial dysfunction, and severity of liver damage in chronic hepatitis C. Nonetheless, the relationship between circulating OPG and IR as a key feature of Met S as well as between OPG and NAFLD remains uncertain. Thus, the aims of the present review are to provide the existent knowledge on these associations and to discuss briefly the underlying mechanisms linking OPG and NAFLD.

摘要： Background: PAI-1 (plasminogen activator inhibitor-1) is a powerful regulator of fibrinolysis and plasma level is high in type 2 diabetes and cardio-vascular disease, which is determined by genetic polymorphisms in PAI-1 gene and environmental factors. The aim of the study was to examine the determinants of plasma PAI-1 Ag level among type 2 diabetes patients. Methods: 491 Tunisian type 2 diabetes patients had clinical evaluation (weight, high, BMI, Waist Circumference), laboratory investigations including FBG Hb1Ac, cholesterol, triglyceride;HDL-cholesterol was done;plasma PAI-1 antigen level was done with ELISA;?675 4G/5G and ?844 G/A polymorphisms of PAI-1 gene was done by PCR-ASA and PCR-RFLP respectively. Results: The mean age for our patients was 58.3 ± 10.5 years;sex-ratio = 0.92;mean PAI-1 level was 34.6 ± 21.3 ng/ml. We didn’t find correlation between PAI-1 level and BMI, but we have found significant correlation between PAI-1 and waist circumference (p = 0.032), most enhanced in men (P = 0.002), T2D patients who have FBG > 11 mmol/l had PAI-1 Ag level higher than those who have FBG P = 0.034), but no difference found between T2D with high Hb1Ac > 8% and those with Hb1Ac < 8%, significant correlation was seen between PAI-1 level and LDL-cholesterol (P = 0.05), high correlation between PAI-1 Ag level and ?675 4G/5G polymorphism genotype was seen, 4G/4G carriers had the highest PAI-1 level, 4G/5G had intermediary level and 5G/5G had the lowest level (P ?844G/A polymorphism genotypes. Using multiple variable linear regression analysis, the independent factor associated with plasma PAI-1 level was ?675 4G/5G polymorphism (regression coefficient β = 4.6, P Conclusion: the present study identifies ?675 4G/5G not ?844 G/A polymorphism of PAI gene as the principal determinant of plasma PAI-1 level in Tunisian T2D patients, the android fat distribution, dyslipidemia and hyperglycemia play a modest role in this variation.

摘要： AIM: To investigate the dynamic expression of p-signal transducer and activator of transcription 3(STAT3) and vascular endothelial growth factor(VEGF) in the formation of gastric tumors induced by drinking water containing N-methyl-N'-nitro-N-nitrosoguanidine(MNNG) in Wistar rats.METHODS: One hundred and twenty Wistar rats were randomly divided into two groups(60 in each group): Control group and Model group. The rats in each group were then randomly divided into three groups(20 in each group): C/M15, C/M25 and C/M40(15, 25 and 40 represent the number of feeding weeks from termination). Rats in the control group received normal drinking water and rats in the model group received drinking water containing 100 μg/m L MNNG. Stomach tissues were collected at the end of the 15 th, 25 th and 40 th week, respectively, for microscopic measurement using hematoxylin and eosin staining. The expression of p-STAT3 and VEGF in different pathological types of gastric tissue, including normal, inflammation, atrophy, hyperplasia and gastric stromal tumor, was observed by immunohistochemistry and Western blot, and the corelation between p-STAT3 and VEGF was analyzed. RESULTS:(1) The expression of p-STAT3 in tissue with gastritis, atrophy, dysplasia and gastric stromal tumor were significantly increased in the model group compared with the control group(2.5 ± 1.0, 2.75 ±0.36, 6.2 ± 0.45, 5.67 ± 0.55 vs 0.75 ± 0.36, P = 0.026, 0.035, 0.001, 0.002, respectively); the expression of p-STAT3 in tissue with dysplasia was higher than that in samples with gastritis or atrophy(6.2 ± 0.45 vs 2.5 ± 1.0, P = 0.006; 6.2 ± 0.45 vs 2.75 ± 0.36, P = 0.005, respectively); however, the expression of p-STAT3 in gastritis and atrophy was not significantly different(P > 0.05);(2) the expression of VEGF in tissue with gastritis, atrophy, dysplasia and gastric stromal tumor was significantly increased in the model group compared with normal gastric mucosa; and the expression of VEGF in tissue with dysplasia was higher than that in tissue with inflammation and atrophy(10.8 ± 1.96 vs 7.62 ± 0.25, P = 0.029; 10.8 ± 1.96 vs 6.26 ± 0.76, P = 0.033, respectively); similarly, the expression of VEGF in tissue with gastritis and atrophy was not significantly different(P > 0.05); and(3) the expression of VEGF was positively correlated with p-STAT3. CONCLUSION: p-STAT3 plays an important role in gastric cancer formation by regulating the expression of VEGF to promote the progression of gastric tumor from gastritis.

摘要： AIM: To evaluate the therapeutic effects of bone marrow-derived mesenchymal stem cells(BMSCs) with human urokinase-type plasminogen activator(u PA) on liver fibrosis, and to investigate the mechanism of gene therapy.METHODS: BMSCs transfected with adenovirusmediated human urokinase plasminogen activator(Adu PA) were transplanted into rats with CCl4-induced liver fibrosis. All rats were sacrificed after 8 wk, and their serum and liver tissue were collected for biochemical, histopathologic, and molecular analyzes. The degree of liver fibrosis was assessed by hematoxylin and eosin or Masson's staining. Western blot and quantitative reverse transcription-polymerase chain reaction were used to determine protein and m RNA expression levels.RESULTS: Serum levels of alanine aminotransferase, aminotransferase, total bilirubin, hyaluronic acid, laminin, and procollagen type Ⅲ were markedly decreased, whereas the levels of serum albumin were increased by u PA gene modified BMSCs treatment. Histopathology revealed that chronic CCl4-treatment resulted in significant fibrosis while u PA gene modified BMSCs treatment significantly reversed fibrosis. By quantitatively analysing the fibrosis area of liver tissue using Masson staining in different groups of animals, we found that model animals with CCl4-induced liver fibrosis had the largest fibrotic area(16.69% ± 1.30%), while fibrotic area was significantly decreased by BMSCs treatment(12.38% ± 2.27%) and was further reduced by u PA-BMSCs treatment(8.31% ± 1.21%). Both protein and m RNA expression of β-catenin, Wnt4 and Wnt5 a was down-regulated in liver tissues following u PA gene modified BMSCs treatment when compared with the model animals.CONCLUSION: Transplantation of u PA gene modified BMSCs suppressed liver fibrosis and ameliorated liver function and may be a new approach to treating liver fibrosis. Furthermore, treatment with u PA gene modified BMSCs also resulted in a decrease in expression of molecules of the Wnt signaling pathway.

摘要： Gene editing has recently emerged as a promising technology to engineer genetic modifications precisely in the genome to achieve long-term relief from corneal disorders.Recent advances in the molecular biology leading to the development of clustered regularly interspaced short palindromic repeats(CRISPRs) and CRISPR-associated systems,zinc finger nucleases and transcription activator like effector nucleases have ushered in a new era for high throughput in vitro and in vivo genome engineering.Genome editing can be successfully used to decipher complex molecular mechanisms underlying disease pathophysiology,develop innovative next generation gene therapy,stem cell-based regenerative therapy,and personalized medicine for corneal and other ocular diseases.In this review we describe latest developments in the field of genome editing,current challenges,and future prospects for the development of personalized genebased medicine for corneal diseases.The gene editing approach is expected to revolutionize current diagnostic and treatment practices for curing blindness.

摘要： Signal transducers and activators of transcription(STATs) mediate essential signals for various biological processes,including immune responses,hematopoiesis,and neurogenesis. STAT3,for example,is involved in the pathogenesis of various human diseases,including cancers,autoimmune and inflammatory disorders. STAT3 activation is therefore tightly regulated at multiple levels to prevent these pathological conditions. A number of proteins have been reported to associate with STAT3 and regulate its activity. These STAT3-interacting proteins function to modulate STAT3-mediated signaling at various steps and mediate the crosstalk of STAT3 with other cellular signaling pathways. This article reviews the roles of novel STAT3 binding partners such as DAXX,zipperinteracting protein kinase,Krüppel-associated box-associated protein 1,Y14,PDZ and LIM domain 2 and signal transducing adaptor protein-2,in the regulation of STAT3-mediated signaling.

摘要： 本发明公开了一种真空成型改良式Activator矫治器，包括由透明胶粘接成一体的上颌牙弓膜板和下颌牙舌侧牙弓膜板，上颌牙弓膜板与上颌牙冠紧贴并与牙颈缘平齐，且两侧的下颌后牙合面为平面导板；下颌牙舌侧牙弓膜板带有延伸至牙颈缘下5mm～10mm的翼板，且翼板让开倒凹；下颌牙舌侧牙弓膜板两侧的下颌颊侧后牙弓处开窗，保留前牙唇侧弓膜板；上颌牙弓膜板和下颌牙舌侧牙弓膜板的牙合面部分通过透明胶粘接成一体。其结构合理，患者易合作，由于采用了透明材料制作，无毒、无味，佩戴舒适且具有隐形效果，并且解决了制作过程的苯和粉尘的污染。经临床试验，可以提高临床治疗效果，缩短治疗时间。

摘要： 本发明公开了一种真空成型改良式Activator矫治器，包括由透明胶粘接成一体的上颌牙弓膜板和下颌牙舌侧牙弓膜板，上颌牙弓膜板与上颌牙冠紧贴并与牙颈缘平齐，且两侧的下颌后牙合面为平面导板；下颌牙舌侧牙弓膜板带有延伸至牙颈缘下5mm～10mm的翼板，且翼板让开倒凹；下颌牙舌侧牙弓膜板两侧的下颌颊侧后牙弓处开窗，保留前牙唇侧弓膜板；上颌牙弓膜板和下颌牙舌侧牙弓膜板的牙合面部分通过透明胶粘接成一体。其结构合理，患者易合作，由于采用了透明材料制作，无毒、无味，佩戴舒适且具有隐形效果，并且解决了制作过程的苯和粉尘的污染。经临床试验，可以提高临床治疗效果，缩短治疗时间。