Discovery of 2-(isoxazol-5-yl)phenyl 3,4-dihydroxybenzoate as a potential inhibitor for the Wnt/ß-catenin pathway.

Carnosic acid could disrupt the ß-catenin/BCL9 protein-protein interaction and inhibit ß-catenin dependent transcription, thereby reduce the incidence of colorectal cancer induced by abnormal activation of Wnt/ß-catenin signalling pathway. However, its activity was weak (IC50 for SW480: 28.2 ± 2.05 µM) and total synthesis was difficult. During the structural simplification of natural products, S0 was revealed to be the basic pharmacophore of carnosic acid. Subsequent structural optimization of S0 led to the discovery of S11 as a possible anticancer agent with prominent proliferation inhibition effect (IC50 for SW480: 9.56 ± 0.91 µM) and best selectivity index (SI = 3.0) against Wnt hyperactive cancer cells. Futher mechanism investigation through TOP/FOP dual luciferase reporter assay, immunofluorescence, co-immunoprecipitation, microscale thermophoresis, downstream oncoprotein expression and cell apoptosis showed that compound S11 could significantly inhibit the proliferation of SW480 cells via obvioudsly decreasing the nucleus translocation of ß-catenin and effectively disrupting ß-catenin/BCL9 protein-protein interaction. Additionally, cell migration, molecule docking, in vitro stability and solubility assays were also conducted. Overall, S11 was worthy of in-depth study as a potential inhibitor for the Wnt/ß-catenin pathway and its discovery also proved that the structural simplification of natural products was still one of the effective methods to find new lead compounds or candidate drugs.

Hybrid molecules of scutellarein and tertramethylpyrazine's active metabolites for ischemic stroke.

A series of hybrid molecules of scutellarein and tertramethylpyrazine's active metabolites have been synthesized. Compared to the original compound, these prepared compounds exhibited higher water solubility, more appropriate logP and better stability. Importantly, compounds 11b, 11d and 11e showed improved neuroprotective activity against the H2O2-induced cell death in PC12 cells, and better antithrombosis activity. The optimized compound 11b was further evaluated by cerebral ischemia/ reperfusion in the middle cerebral artery occlusion (MCAO) model, the results showed that the compound could significantly reduce the infarct area and decrease the neuronal cell damage in CA1 pyramidal neurons. Overall, we demonstrated that the twin drug strategy could be applied in the development of agents for the treatment of ischemic stroke.

Assessing Awareness of College Student Startup Entrepreneurs Toward Mass Entrepreneurship and Innovation From the Perspective of Educational Psychology.

Against the background of economic globalization, the awareness of college student startup entrepreneurs toward mass entrepreneurship and innovation is analyzed from the perspective of educational psychology, thus responding to national development strategies. First, the status quo of innovation and entrepreneurship education is understood by literature analysis. Second, the existing innovation and entrepreneurship education in colleges and universities is investigated with a questionnaire survey (QS) and interviews to discover the challenges that college students face during innovation and entrepreneurship. The QS results provide a data basis for subsequent strategies. The results demonstrate that 19.86% of the students have a complete understanding of innovation and entrepreneurship, while only 9.93% of the students are interested in innovation and entrepreneurship activities. The technical significance of innovation and entrepreneurship activities only accounts for 41.84%. Moreover, the vast majority of students (79.67%) believe that the curriculum of innovation and entrepreneurship education is single, simple, and irrelevant to their majors. Meanwhile, some problems have been found: for example, the teaching faculty is insufficient, and there is not a sound entrepreneurial atmosphere. As per the survey results, an innovation and entrepreneurship education strategy for core stakeholders, namely, universities, society, government, university teachers, and students, is formulated to promote the sound development of innovation and entrepreneurship education in colleges and universities. Besides, a training strategy in line with the awareness of college students toward mass entrepreneurship and innovation is formulated based on the current situation of innovation and entrepreneurship education, which can serve as a reference and has practical significance for enriching and perfecting the innovation and entrepreneurship education system for college students.

Relationship Between Human Capital and Technological Innovation Growth of Regional Economy and Psychology of New Entrepreneurs in Northeast China.

The economic restructuring and rapid rise of the economy in Northeast China have resulted in a proliferation of new ventures. Studying the psychology of new entrepreneurs is conducive to understanding the relationship between human capital and economic growth. The work reported here aims to explore the impact of human capital on economic growth in Northeast China and the influencing factors of psychological capital of new entrepreneurs in the entrepreneurial process. Based on Cobb-Douglas production function, the relationship between labor, physical capital, or human capital and economic growth in Northeast China is analyzed by econometric methods, and a model of human capital and economic growth in Northeast China is constructed. Besides, a psychological capital intervention (PCI) model is proposed to develop the psychological capital of new entrepreneurs, and the psychological quality structure model of entrepreneurial entrepreneurs and its operation mechanism. The results of the empirical analysis demonstrate that the elasticity coefficient of human capital in Northeast China is 0.15902, five times smaller than that of labor and physical capital. Moreover, 70% of new ventures are willing to accept higher education. The fitting degree of using the PCI model to develop the psychological capital of new ventures is only 0.3%. In addition, the modified external environment PCI instead of the external environment PCI model has a huge operating potential in the macro-entrepreneurial environment. In conclusion, the impact of human capital on economic growth in the northeast is smaller than the impact of labor and material capital investment on regional economic growth. The development of human capital and research on the composition and mechanism of psychological quality of entrepreneurial entrepreneurs are of significant theoretical and practical values to promote the economic growth in the northeast.

Intermediary Management and Employee Corporate Culture Identification Mediation and Mediation Effect Verification.

This exploration is mainly performed to study the role of corporate culture accepted by employees in enterprise development and its impact on employees themselves. First, the influence of employee participation, cross-cultural management, and corporate culture on the enterprise is realized through the relevant literature. Then, investigation and analysis are carried out with American I Industrial Group as the research object to determine the impact of cross-cultural management on mergers and acquisitions and organizational performance. The results show that the total impact of trust on reuse is 0.264 before mergers and acquisitions; the difference is not statistically significant, and so is the overall impact of mergers and acquisitions. This means that there is no correlation between trust and reuse. However, when the merger is done, the total effect of trust on reuse rises to 1.594, indicating that the difference and the total effect are statistically significant. The data calculation and analysis for the direct impact of trust on reuse and the indirect impact of trust on reuse are 0.667 and 0.926, respectively, which means that the difference is statistically significant. This proves the role of satisfaction in the impact of trust on reuse once mergers and acquisitions are completed. Therefore, in the process of mergers and acquisitions in the future, enterprises must consider the different cultures of employees and company locations and employee participation, which will further affect the organizational performance of enterprises.

Rhizoma Bletillae polysaccharide elicits hemostatic effects in platelet-rich plasma by activating adenosine diphosphate receptor signaling pathway.

Rhizoma Bletillae, the tubes of Bletilla striata, has been traditionally used in China as a hemostatic agent. In preliminary studies, the major active fraction responsible for its hemostatic effect have been confirmed to be Rhizoma Bletillae polysaccharide (RBp), but the hemostatic mechanism of action of RBp is still unknown.The main aim of this study was to clarify its mechanism of hemostatic effect. RBp was prepared by 80 % ethanol precipitation of the water extract of Rhizoma Bletillae followed by the Sevag method to remove proteins. The average molecular weight (Mw) of the crude RBp maintained at a range of 30.06-200 KDa. The hemostatic effects of RBp were evaluated by testing its effect on the platelet aggregation of rat platelet-rich plasma (PRP). PRP was dealt with different concentrations of RBp and platelet aggregation was measured by the turbidimetric method. The hemostatic mechanism of RBp was investigated by examining its effect on platelet shape, platelet secretion, and activation of related receptors (P2Y1, P2Y12 and TXA2) by electron microscopy and the turbidimetric method. RBp significantly enhanced the platelet aggregations at concentrations of 50-200 mg/L in a concentration-dependent manner. The inhibitory rate of platelet aggregation was significantly increased by apyrase and Ro31-8220 in a concentration-dependent manner, while RBp-induced platelet aggregation was completely inhibited by P2Y1, P2Y12 and the PKC receptor antagonists. However, the aggregation was not sensitive to TXA2. RBp, the active ingredients of Rhizoma Bletillae responsible for its hemostatic effect, could significantly accelerate the platelet aggregation and shape change. The hemostatic mechanism may involve activation of the P2Y1, P2Y12, and PKC receptors in the adenosine diphosphate (ADP) receptor signaling pathway.

[Thymidine phosphorylase expressed in monocyte-macrophages enhanced anticancer effect of 5'-deoxy-5-fluorouridine on colorectal carcinoma cells].

OBJECTIVE: To detect the thymidine phosphorylase (dThdPase) expression in colorectal carcinoma tissue, and clarify whether dThdPase expressed in macrophage-like cell lines, and monocytes from human peripheral blood can modulate the anticancer effect of 5'-deoxy-5-fluorouridine (5'-DFUR) on colorectal carcinoma cells. METHODS: Forty specimens resected from 40 patients with colorectal carcinoma were immunohistochemically stained by the monoclonal antibodies 654-1 (anti-dThdPase) and PG-M1 (anti-macrophage marker CD68). Then morphometrical analysis and positive cell counting were performed. In 27 of 40 specimens, dThdPase activity analysis was assayed by HPLC. The dThdPase level were also measured by ELISA in 4 colorectal cancer cell lines, LS174T, Clone A, Colo320, MIP101, and 2 macrophage-like cell lines, THP-1, U937. After estimated the drug sensitivities of each colorectal carcinoma cell both to 5'-DFUR and 5-Fu by MTT assay, THP-1, U937, or monocytes isolated from human blood were incubated in the medium containing 5-Fu or 5'-DFUR for 24 hours, respectively. Then the supernatant was collected and 2-fold serially diluted with the medium, in which the macrophage-like cells, or monocytes were also cultivated for 24 h without anticancer agents. Using the serially diluted medium, MTT assay were also carried out on 4 colorectal carcinoma cell lines. Each experiment was repeated six times and the means of IC50 value +/- standard errors (mean +/- S.E.M.) were calculated. Finally, THP-1 or U937 cells were cultured in medium containing 400 micro mol/L of 5'-DFUR for 24 hours, then the supernatants were collected and the amount of generated 5-Fu was measured by HPLC. RESULTS: dThdPase activities was significantly increased (139.7 micro g x 5-Fu x h(-1) x ml(-1) +/- 61.5 micro g x 5-Fu x h(-1) x ml(-1)) in colorectal carcinoma tissues compared with adjacent normal tissues (42.2 micro g x 5-Fu x h(-1) x ml(-1) +/- 21.4 micro g x 5-Fu x h(-1) x ml(-1)), P < 0.001. In immunohistochemical analysis, it was confirmed that most cells expressed dThdPase-positive cells were the stromal cells, especially macrophages, which surrounding cancer nests, or along the invasive margin of cancer. The distribution patterns of dThdPase-positive stromal cells are similar to that of the CD68-positive cells. The number of dThdPase positive cells was correlated with the number of macrophages in the cancerous tissues, r = 0.76. The dThdPase protein were detected at the levels of 18.2 unit/mg in THP-1, 19.3 unit/mg in U937, and 0.5 unit/mg in LS174T, however, not detected in other 3 colorectal carcinoma cells. The values of IC50 of 5'-DFUR on the 4 colorectal carcinoma cell lines were 11.5 approximately 84.8 times higher than those of 5-Fu (all P < 0.01). It was showed that no inhibiting effect for 5'-DFUR on the growth rates of THP-1, U937, and monocyte cells. After incubated with THP-1 or U937, 5'-DFUR expressed a significant enhanced antitumor effect (P < 0.0001), while almost no change is observed to 5-Fu (P > 0.05). Same conclusion was also demonstrated in using the monocytes instead of THP-1 or U937. 40.2 micro mol/L and 29.5 micro mol/L of 5-Fu were detected in the medium containing 400 micro mol/L of 5'-DFUR treated with THP-1 and U937 cells, respectively. CONCLUSION: 5'-DFUR cannot be converted into 5-Fu in colorectal carcinoma cells in vitro because no dThdPase is expressed in those cells. After being incubated with macrophage-like cell, THP-1, U937, or human monocytes, the anticancer effect of 5'-DFUR is significantly increased due to the activation by dThdPase expressed in above cells.