Network pharmacology, molecular docking and experimental verification help unravel chelerythrine's potential mechanism in the treatment of gastric cancer.

Gastric cancer (GC) is a deadly malignant tumor with a high fatality rate and limited curative options. A growing body of research suggests that network pharmacology can replace traditional methods for determining the precise mechanism of action of medicinal substances in conditions such as cancer. The goal of this study was to clarify the biological mechanism of chelerythrine (CHE) and develop a prediction target for CHE against GC using network pharmacology. First, the genes related to GC were identified from the databases Genecards, Disgenet, Online Mendelian Inheritance in Man, Therapeutic Target Database, and Drugbank, and the targets of CHE were obtained from the SwissTargetPrediction database. Fifty linked targets were identified as anti-GC targets of CHE. Functional enrichment and pathway analyses revealed important biological mechanisms mediated by these targets. The core target PIK3CA of CHE anti-GC was obtained using the protein-protein interaction network, CytoHubba plug-in, and Human Protein Atlas. Molecular docking studies revealed that CHE has a strong affinity for PIK3CA (-10.5 kcal/mol). In addition, we used MTT, colony formation, wound-healing, Transwell®, and flow cytometry experiments to confirm that CHE inhibited the proliferation and migration of GC cells and induced cell cycle arrest and apoptosis. Finally, western blotting results showed that CHE downregulated the expression of the PIK3CA protein and inhibited the activation of the PI3K/AKT signaling pathway. Therefore, we concluded that CHE inhibited GC cell proliferation and migration and induced cell cycle arrest and apoptosis by targeting the PIK3CA protein to inhibit the PI3K/AKT pathway activity.

Biosynthesis of a novel recombinant peptide derived from hPTH(1-34).

A recombinant human parathyroid hormone fragment, Pro-Pro-[Arg(11)]hPTH(1-34)-Pro-Pro (MW=4550 Da), was developed by substituting Arg for Leu at position 11 and adding Pro-Pro at the carboxyl terminus. Following a single injection (0.5-13.5 µg/bird) of the rhPTH fragment, the serum calcium level in chickens increased 12-42% (P<0.05) after 1h as determined by the Parson's Chicken Assay. The functional activity of Pro-Pro-[Arg(11)]hPTH(1-34)-Pro-Pro may be due to removal of the N-terminus Pro-Pro- by X-prolyl dipeptidyl peptidase IV (DPPIV) in vivo, increasing its activity compared to Pro-Pro-hPTH(1-34). This artificial rhPTH fragment could be used to increase calcium mobilization and potentially improve bone health.

[Analysis of risk factors for prognosis of patients with acute paraquat intoxication].

OBJECTIVE: To explore the risk factors influencing the prognosis by analyzing clinical data of patients with acute paraquat intoxication, and to assess the prognostic values of acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score, and Acute Kidney Injury Network (AKIN) stage. METHODS: The clinical data of patients with acute paraquat intoxication admitted into the First People's Hospital of Xianyang City during October 2005 to May 2015 were retrospectively analyzed. The patients were divided into death group and survival group according to 28-day outcome after poisoning. The gender, age, body weight index, toxin dose, time elapsed from poisoning to gastric lavage, time elapsed from poisoning to hemoperfusion (HP), times of HP treatment, white blood cell count (WBC), alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TBil), serum creatinine (SCr), blood urea nitrogen (BUN), creatine kinase (CK) were determined at admission. Arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), arterial lactate (Lac), and APACHE II score, SOFA score and AKIN stage were recorded and compared between two groups. The receiver operating characteristic (ROC) curve was plotted for APACHE II score, SOFA score and AKIN stage to analyze the prognostic value for patients with acute paraquat intoxication. RESULTS: There were 118 cases in total, with 64 survivors and 54 deaths in 28 days, and the fatality rate was 45.76%. Compared with survival group, the toxic dose (mL: 66.29 ± 27.40 vs. 29.16 ± 19.40), time elapsed from poisoning to gastric lavage (minutes: 60.37 26.68 vs. 41.17 ± 14.82), WBC count ( X 109/L: 16.86 ± 2.77 vs. 10.25 ± 2.60), ALT (U/L: 53.94 ± 10.85 vs. 36.40 ± 9.21), SCr (µmol/L: 159.69 ± 42.85 vs. 81.73 ± 34.40) at admission as well as Lac (mmol/L: 3.06 ± 1.33 vs. 1.71 ± 0.88), APACHE II score (6.46 ± 2.38 vs. 3.31 ± 1.51), SOFA score (3.31 ± 1.06 vs. 2.21 ± 0.76) 48 hours after admission were significantly higher in the death group (all P < 0.01). PaO2 and PaCO2 48 hours after admission were significantly lower in death group than those in the survival group [PaO2 (mmHg, 1 mmHg = 0.133 kPa): 64.07 ± 13.04 vs. 75.40 ± 13.27, PaCO2 (mmHg): 26.20 ± 8.89 vs. 31.25 ± 6.29, both P < 0.01]. There were 18, 15, 11 and 10 patients in AKIN 0, 1, 2, 3 stage 48 hours after admission respectively in death group, and 38, 15, 7, 4 in survival group. The difference between two groups was statistically significant (P < 0.01). There were no statistically significant differences in gender, age, body mass index, time elapsed from poisoning to HP, levels of HP, and AST, TBil, BUN and CK at admission between the two groups. At 48 hours after admission, the area under the ROC curve (AUC) of APACHE II score predicting the prognosis of patients with acute paraquat poisoning was 0.875 [95% confidence interval (95%CI) = 0.814-0.935, P = 0.000]. When the cut-off point of APACHE II score was 4, the sensitivity and specificity were 79.6% and 79.7%, and the best Youden index was 0.593. The AUC of SOFA score was 0.776 (95% CI = 0.692-0.859, P = 0.000). When the cut-off point of FOFA score was 3, the sensitivity was 72.2%, the specificity 67.2%, and the best Youden index 0.394. The AKIN stage of ROC curve had an area of 0.656 (95% CI = 0.556-0.755, P = 0.004). When the cut-off point of AKIN stage was 1, the sensitivity was 66.7%, the specificity was 59.4%, and the best Youden index was 0.261. CONCLUSIONS: Amount of the poison, time elapsed from poisoning to gastric lavage, and WBC, ALT, SCr at admission as well as PaO2, PaCO2 and Lac 48 hours after admission are the risk factors for prediction of the prognosis of acute paraquat intoxication. APACHE II score, SOFA score and AKIN stage can be used to assess the prognosis of acute paraquat poisoning, and APACHE II score is better than SOFA score and AKIN stage.