Cu(OTf)2-catalyzed C3 aza-Friedel-Crafts alkylation of indoles with N,O-acetals.

An efficient approach to access functionalized indole derivatives has been developed through Cu(OTf)2-catalyzed C3 aza-Friedel-Crafts alkylation of substituted indoles 5a-5m, N-methyl-pyrrole with linear N,O-acetals 4a-4l. As a result, a series of C3 amide aza-alkylated indole derivatives 6a-6ag and 7 were synthesized in moderate to excellent yields.

Screening of a Small Molecule Compound Library Identifies Potential Drugs that Synergize with PARP Inhibitors against Ovarian Cancer Cells / 中国生物化学与分子生物学报

PARP inhibitors are a new class of drugs that target cancer cells with defective DNA repair. Early trials have shown that PARP inhibitors have achieved satisfactory results, but the mechanism of resistance after drug treatment has not been fully revealed. Therefore, it is necessary to find more targeted drugs in combination with PARP inhibitors to kill tumor cells. In this paper, several potential drugs that can synergistically kill ovarian cancer cells with PARP inhibitors were identified based on the combined drug screening of 379 small molecule compound libraries and PARP inhibitor Niraparib through cell proliferation experiments, colony-formation survival experiments and immunofluorescence staining experiments. The results showed that there are eight small molecule compounds with good combination effects, including two small molecule inhibitors STF-118804 and Disulfiram that have been reported to have combined effects with PARP inhibitors. We selected GW441756, an inhibitor of tropomyosin receptor kinase A (TrKA), to verify a variety of tumor cells and explore the preliminary mechanism. The combined therapeutic effects of the Niraparib and the TrKA inhibitor increased the sensitivity of tumor cells to PARP inhibitors (P < 0. 05). Mechanistically, the number of γH2AX foci in the combined treatment group was significantly increased (P<0. 05), indicating that the TrKA inhibitor hindered the DNA damage repair ability. Moreover, combination therapy significantly reduced the formation of RAD51 foci (P<0. 05), a marker of homologous recombination repair (HRR), suggesting that TrKA inhibitors may inhibit DNA damage repair by inhibiting HRR efficiency. Overall, these results suggest that TrKA inhibitor can be used as a potential drug to kill ovarian cancer cells in combination with PARP inhibitors.

Nickel-Catalyzed Regioselective Hydroamination of Ynamides with Secondary Amines.

The first Ni(OTf)2-catalyzed hydroamination of ynamides 2 was developed by reacting with secondary amines (1 and 4). This protocol features excellent regioselectivity, a broad substrate scope of secondary aryl amines, and good functional group tolerance for ynamides. Using this method, a variety of substituted ethene-1,1-diamine compounds were prepared in moderate to excellent yields with high regioselectivities.

[Diagnostic Application of Invasive Cardiopulmonary Exercise Test in Patients with Unexplained Dyspnea].

OBJECTIVE: To explore the clinical diagnostic application of invasive cardiopulmonary exercise test (iCPET) in patients with unexplained dyspnea. METHODS: A retrospective analysis was conducted, covering patients with a chief complaint of exertional dyspnea between May 5, 2017 and October 1, 2020. Right cardiac catheterization examination was performed on patients whose cause had not been identified through routine examination, and further iCPET was performed on patients if no clear etiology was identified through right cardiac catheterization. According to the results and the diagnostic criteria of iCPET, patients showing no obvious abnormalities in the right cardiac catheterization examination were divided into four subgroups: exercise-induced pulmonary arterial hypertension (eiPAH), exercise-induced heart failure with preserved ejection fraction (eiHFpEF), preload failure, and oxidative myopathy. By comparing the lab test, echocardiography, right heart catheter and iCPET peak exercise data of the subgroups, the disease distribution and exercise hemodynamic characteristics of patients with unexplained dyspnea examined by iCPET were described. RESULTS: Of the 1 046 patients with exertional dyspnea, 771 were diagnosed with routine examination, while among the remaining 275 patients, 131 (47.6%) were diagnosed with right cardiac catheterization and 144 (52.4%) showed no clear etiology after routine examination and right cardiac catheterization. Of these 144 patients, 49 (34.0%) received iCPET with a median exercise time of 375 s. A total of 47 patients completed the examination, with a male-to-female ratio of 0.27∶1 and an average age of (47.9±14.4) years old. Among the 47 patients, 76.6% (36/47) aged between 20 and 59 and 78.7% (36/47) lived in urban areas. The preload failure group ( n=27) showed low right atrium pressure at peak exercise intensity. The eiHFpEF group ( n=9) showed high wedge pressure of pulmonary capillaries at peak of exercise intensity. The eiPAH group ( n=8) showed high average pulmonary artery pressure at peak exercise intensity. The oxidative myopathy group ( n=3) was characterized by impairment of tissue uptake and/or utilization of oxygen during exercise. According to the comparison among the three subgroups of the preload failure, eiHFpEF and eiPAH, the eiPAH group had the highest blood K + level in routine examination, while the preload failure group had the lowest blood K + level ( P=0.014). The iCPET of the three subgroups showed statistically significant ( P=0.001) difference in right atrial pressure increase during exercise. Among the three, the eiHFpEF group had the highest increase and the preload failure group had the lowest increase. Conclusion 　In unexplained dyspnea patients showing no abnormal results in right cardiac catheterization examination, the main cause was preload failure, which manifested as low right atrial pressure at peak exercise intensity. The study showed that iCPET was of important value for dyspnea cases when the cause of the condition was not revealed with right cardiac catheterization.

Sc(OTf)3-catalyzed [3 + 2]-cycloaddition of nitrones with ynones.

An efficient approach to access functionalized (2,3-dihydroisoxazol-4-yl) ketones has been developed by reacting nitrones 4 with ynones 7 or terminal ynones 10 in a one-pot fashion. The reaction went through a formal Sc(OTf)3-catalyzed [3 + 2]-cycloaddition process to generate a number of functionalized (2,3-dihydroisoxazol-4-yl) ketones 11aa-11aw, 11ba-11la and 12aa-12ae in moderate to good yields.

Synthesis of a 3,4-Dihydro-1,3-oxazin-2-ones Skeleton via an Intermolecular [4 + 2] Process of N-Acyliminium Ions with Ynamides/Terminal Alkynes.

An approach to access functionalized 3,4-dihydro-1,3-oxazin-2-ones has been developed by reacting semicyclic N,O-acetals 5 and 6 with ynamides 7 or terminal alkynes 8 in a one-pot fashion. The reaction went through a formal [4 + 2] cycloaddition process to generate a number of functionalized 3,4-dihydro-1,3-oxazin-2-ones 9a-9ak and 10a-10bc in yields of 34-97%. In addition, the utility of this transformation was demonstrated by the synthesis of (±)-sedamine 13.

The influence of reward motivation on emotion regulation / 生理学报

The influence of reward on behavior is one of the hottest research subjects in psychological research. Reward-induced motivation promotes the performance of the participants. In the field of emotional processing, the reward can influence the individual's processing of emotional information, but previous studies have not directly discussed the effect of reward on emotional regulation. The present study focused on whether emotional regulation ability would be improved under the reward condition. Experiment 1 and 2 investigated the effect of reward on negative emotional down-regulation and positive emotional up-regulation respectively. In experiment 1, monetary reward stimulation was introduced on the basis of the classic emotion regulation paradigm, and the subjects were asked to regulate their negative emotion under the condition of reward or non-reward, and evaluate their current affective state subsequently. Similar to experiment 1, experiment 2 required subjects to up-regulate positive emotions under the condition of reward or non-reward. The results of experiment 1 showed that under the reward condition, the negative emotional regulation effect was significantly higher than that under the non-reward condition (P < 0.05). Experiment 2 also showed that compared to non-reward condition, the positive emotion regulation effect was significantly increased under the reward condition (P < 0.05). These results suggested that compared to non-reward condition, participants can regulate their emotion better under the condition of the reward. It is worth noting that the results of Experiment 1 and 2 may be caused by the incentive motivation induced by monetary stimulus, or the positive emotion caused by positive value of money information. Therefore, we carried out experiment 3 and 4 to explore whether the positive emotions induced by money itself can influence the emotional regulation of individuals. In experiment 3, the money pictures were used to induce the positive emotions of subjects, and the subjects were asked to regulate their negative emotion after the presence of money pictures or non-monetary picture, and evaluate their current affective state subsequently. Similarly, experiment 4 required subjects to regulate their positive emotion after the presence of money pictures. The results of experiment 3 and 4 showed that there was no significant difference in the subjects' scores of emotional pleasantness after the presence of money pictures or non-monetary picture (P < 0.05). The results of experiment 3 and 4 excluded the possibility that the positive emotions induced by simple money stimulus pictures could improve individual's emotional regulation ability. To sum up, the improvement of individual's emotional regulation ability was indeed driven by reward motivation in this study, that is, the motivation induced by reward can effectively promote individual's emotional regulation ability.

The effect of early versus late initiation of renal replacement therapy in patients with acute kidney injury: A meta-analysis with trial sequential analysis of randomized controlled trials.

BACKGROUND: The optimal timing for initiating renal replacement therapy (RRT) in patients with acute kidney injury (AKI) remains controversial. METHODS: We conducted a meta-analysis with trial sequential analysis (TSA) of randomized controlled trials (RCTs) using PUBMED, Cochrane Library databases, and Web of Science (from January 1, 1985, to August 21, 2016). Adult patients with AKI who received RRT with different timing were included. The primary outcome was mortality. The secondary outcomes were intensive care unit (ICU) length of stay (LOS) and hospital LOS. RESULTS: We included 9 RCTs with a total of 1636 participants. No differences between the early RRT group and the late RRT group were found with respect to mortality (38% vs 41.4%; relative risk, 0.93; 95% confidence interval [CI], 0.74-1.18). However, TSA showed that the cumulative Z-curve did not cross either the conventional boundary for benefit or the trial sequential monitoring boundary, indicating insufficient evidence. Similarity, there were no findings of benefits in terms of reduction in the ICU LOS (standard difference in the means, -0.32 days; 95% CI, -0.71 to 0.07 days) and hospital LOS (standard difference in the means, -1.11 days; 95% CI, -2.28 to 0.06 days). Meanwhile, the results of TSA did not confirm this conclusion. CONCLUSIONS: Although conventional meta-analysis showed that early initiation of RRT in patients with AKI was not associated with decreased mortality, ICU LOS and hospital LOS, TSA indicated that the data were far too sparse to make any conclusions. Therefore, well-designed, large RCTs are needed.

Effects of bone marrow-derived mesenchymal stem cells transfected with survivin on pulmonary fibrosis in mice.

The aim of the present study was to investigate the effects of bone marrow-derived mesenchymal stem cells (BMSCs) transfected with survivin on lung fibrosis in mice. Mice with bleomycin-induced pulmonary fibrosis were allocated at random to group A, B or C, and injected with 1×106 survivin gene-expressing BMSCs, 1×106 BMSCs or normal saline, respectively. A total of 6 mice were sacrificed from each group on days 7, 14 and 28 after treatment. The extent of alveolitis and pulmonary fibrosis was assessed and the apoptotic rates of the BMSCs and survivin-expressing BMSCs were detected. The content of surfactant protein A (SP-A) in the lung and hydroxyproline (Hyp) in the serum was measured. The mRNA expression levels of transforming growth factor (TGF)-ß1 and matrix metalloproteinase (MMP)-9 in the lung tissue of the mice was detected. Furthermore, the protein expression levels of caspase-3 and -9 were detected. The apoptotic rates of the BMSCs (group B) and survivin-expressing BMSCs (group A) were 14.466±1.953 and 7.718±0.493%, respectively. The degree of lung fibrosis in groups A and B was reduced compared with that in group C. The hydroxyproline content in groups A and B was reduced compared with that in group C, and the SP-A content in groups A and B was increased compared with that in group C. The mRNA expression levels of TGF-ß1 in group A were reduced compared with those in group B, and the levels in group B were reduced compared with those in group C. By contrast, the mRNA expression levels of MMP-9 in group A were increased compared with those in groups B and C, and the levels in group B were increased compared with those in group A. The expression levels of caspase-3 and -9 in group A were elevated compared with those in groups B and C. In conclusion, BMSCs are effective in preventing bleomycin-induced lung fibrosis, and survivin may enhance the protective effects of BMSCs.

[Statistical analysis of residues of heavy metals in Chinese crude drugs].

OBJECTIVE: To analyze the residues of heavy metals in Chinese crude drugs. METHOD: The SPSS 13.0 software was used to analyze the data of Cu, Pb, As, Cd, Hg collected in literatures. And, Green Trade Standards of Importing & Exporting Medicinal Plants & Preparations was used as the standard to evaluate the pollution condition of Cu, Pb, As, Cd, Hg in Chinese crude drugs. RESULT: Chinese crude drugs were contaminated by heavy metals in different levels. The content of Cu, Pb, As, Cd, Hg exceeded the limit of the standard and the percentage was 21.0%, 12.0%, 9.7%, 28.5%, 6.9%, respectively; the phenomena of two, three and four metals exceeding limited standard simultaneity in a drug were also found and the percentage was 4.6%, 1.5%, 0.7%, respectively; the content of heavy metals in Radix Platycodi, Radix Asari and Rhizoma Coptidis was higher among the thirty-six Chinese crude drugs; All of the content of five heavy metals in Barbary Fructus Lycii Rhizoma Anemones Raddeanae, Radix Panacis Quiquefolii and Fructus Aurantii were below the limit; The pollution levels of heavy metals in different locality were different; The content of Cu, Pb in cultivated Chinese crude drugs was higher than that in wild Chinese crude drugs, while the content of As in wild Chinese crude drugs was higher than that in cultivated Chinese crude drugs. CONCLUSION: The pollution levels of heavy metals in Chinese crude drugs were detailed reported in this paper. And it provided ways for the further study of heavy metals in Chinese crude drugs.

[Study on the prognostic factors of colorectal cancer after radical resection and on suggested model for prediction].

OBJECTIVE: To study the factors of colorectal cancer (CRC) after radical resection to provide data predicting the prognosis of the patients. METHODS: 120 cases of CRC were collected in this study. Medical clinical records and 5-year follow-up data were reviewed. Streptavidin-peroxidase immunohistochemical technique was used to detect the expression of p53, C-erbB-2, nm23-H(1) and Ras on formalin-fixed, paraffin embedded sections of CRC from the 120 patients. RESULTS: Results showed that the rates of positive expression of p53, C-erbB-2, Ras and nm23-H(1) were 62.5% (75/120), 25.8% (31/120), 80.0% (96/120) and 60.8% (73/120) respectively in the CRC tissue. All pathological variables and biological markers were analyzed with Cox regression model (alpha = 0.05). Eight distinguished prognostic factors were identified in the univariate analysis as: macroscopic configuration, histology grade, depth of invasion of intestinal, lymph nodes metastasis, Dukes' classification, p53, Ras and nm23-H(1). The results of multivariate analysis (alpha = 0.05) indicated that the independent prognostic factors were Dukes' classification, p53 and nm23-H(1) (P = 0.000), with relative risk of 3.06, 6.02 and 0.40, respectively. A prognostic model: h(t, x) = h(0)(t)exp (-0.9269X(14) + 1.1197X(10) + 1.7948X(11)) was established. Sensitivity, specificity agreement and reliability of the model and Kappa were 79.1%, 83.0%, 80.8% and 0.62, respectively. CONCLUSION: Dukes' classification, p53 and nm23-H(1)seemed to be independent and important prognostic factors. This prognostic model could be used to evaluate the prognosis of patients with CRC by clinicians.