Network pharmacology and experimental insights into STAT3 inhibition by novel isoxazole derivatives of piperic acid in triple negative breast cancer.

STAT3 is a crucial member within a family of seven essential transcription factors. Elevated STAT3 levels have been identified in various cancer types, notably in breast cancer (BC). Consequently, inhibiting STAT3 is recognized as a promising and effective strategy for therapeutic intervention against breast cancer. We herein synthesize a library of isoxazole (PAIs) from piperic acid [2E, 4E)-5-(2H-1,3-Benzodioxol-5-yl) penta-2,4-dienoic acid] on treatment with propargyl bromide followed by oxime under prescribed reaction conditions. Piperic acid was obtained by hydrolysis of piperine extracted from Piper nigrum. First, we checked the binding potential of isoxazole derivatives with breast cancer target proteins by network pharmacology, molecular docking, molecular dynamic (MD) simulation and cytotoxicity analysis as potential anti-breast cancer (BC) agents. The multi-source databases were used to identify possible targets for isoxazole derivatives. A network of protein-protein interactions (PPIs) was generated by obtaining 877 target genes that overlapped gene symbols associated with isoxazole derivatives and BC. Molecular docking and MD modelling demonstrated a strong affinity between isoxazole derivatives and essential target genes. Further, the cell viability studies of isoxazole derivatives on the human breast carcinoma cell lines showed toxicity in all breast cancer cell lines. In summary, our study indicated that the isoxazole derivative showed the significant anticancer activity. The results highlight the prospective utility of isoxazole derivatives as new drug candidates for anticancer chemotherapy, suggesting route for the continued exploration and development of drugs suitable for clinical applications.

Omeprazole as adjuvant therapy to endoscopic combination injection sclerotherapy for treating bleeding peptic ulcer.

BACKGROUND: Therapeutic endoscopy has provided a new means of treating bleeding peptic ulcers. Additional medical therapy may enhance the therapeutic benefit. Hemostasis is highly pH dependent and is severely impaired at low pH. Proton pump inhibitors, by achieving a significantly higher inhibition of gastric acidity, may improve the therapeutic outcomes after endoscopic treatment of ulcers. PATIENT AND METHODS: We enrolled 166 patients with hemorrhage from duodenal, gastric, or stomal ulcers and signs of recent hemorrhage, as confirmed by endoscopy. Twenty-six patients had ulcers with an arterial spurt, 41 patients had active ooze, 37 had a visible vessel, and 62 patients had an adherent clot. All patients received endoscopic injection sclerotherapy using 1:10,000 adrenaline and 1% polidocanol and were randomly assigned to receive omeprazole (40 mg orally) every 12 hours for 5 days or an identical-looking placebo. The outcome measures used were recurrent bleeding, surgery, blood transfusion, and hospital stay. RESULTS: Six (7%) of 82 patients in the omeprazole group had recurrent bleeding, as compared with 18 (21%) in the placebo group (P = 0.02). Two patients in the omeprazole group and 7 patients in the placebo group needed surgery to control their bleeding (P = 0.17). One patient in the omeprazole group and 2 patients in the placebo group died (P = 0.98). Twenty-nine patients (35%) in the omeprazole group and 61 patients (73%) in the placebo group received blood transfusions (P <0.001). The average hospital stay was 4.6 +/- 1.1 days in the omeprazole group and 6.0 +/- 0.7 days in the placebo group (P <0.001). CONCLUSION: The addition of oral omeprazole to combination injection sclerotherapy decreases the rate of recurrent bleeding, reduces the need for surgery and transfusion, and shortens the hospital stay for patients with stigmata of recent hemorrhage.