Elucidating the distinctive regulatory effects and mechanisms of active compounds in Salvia miltiorrhiza Bunge via network pharmacology: Unveiling their roles in the modulation of platelet activation and thrombus formation.

Salvia miltiorrhiza Bunge. (DS), as an important traditional Chinese medicine (TCM), has a long history of usage for promoting blood circulation and removing blood stasis. Modern studies have shown that the chemical components of DS have many biological activities such as cardiovascular protection, anti-arrhythmia, anti-atherosclerosis, improvement of microcirculation, protection of myocardium, inhibition and removal of platelet aggregation. Nevertheless, the action mechanism of DS as well its active compounds on platelet activation has not been fully uncovered. This study aimed to find out the potential targets and mechanisms of DS in the modulation of platelet activation and thrombosis, using network pharmacology and biological experimental. These compounds with anti-thrombotic activity in DS, cryptotanshinone (CPT), isoeugenol (ISO) and tanshinone IIA (TSA), together with the corresponding targets being Src, Akt and RhoA are screened by network pharmacology. We confirmed that ISO, CPT and TSA dose-dependently inhibited platelet activation in vitro, mainly by inhibiting agonist-induced clot retraction, aggregation and P-selectin and ATP release. The western blot findings indicated that ISO, CPT, and TSA led to reduced levels of p-Akt and p-ERK in activated platelets. Additionally, ISO and TSA were observed to decrease p-cSrc expression while increasing RhoA expression. ISO, CPT, and TSA demonstrated a potential to restrict the advancement of carotid arterial thrombosis in vivo. We confirm that ISO, CPT and TSA are the key anti-thrombotic active compounds in DS. These active compounds exhibit unique inhibitory effects on platelet activation and thrombus formation by modulating the Akt/ERK and cSrc/RhoA signaling pathways.

Development of Membrane-Active Honokiol/Magnolol Amphiphiles as Potent Antibacterial Agents against Methicillin-Resistant Staphylococcus aureus (MRSA).

Currently, infections caused by drug-resistant bacteria have become a new challenge in anti-infective treatment, seriously endangering public health. In our continuous effort to develop new antimicrobials, a series of novel honokiol/magnolol amphiphiles were prepared by mimicking the chemical structures and antibacterial properties of cationic antimicrobial peptides. Among them, compound 5i showed excellent antibacterial activity against Gram-positive bacteria and clinical MRSA isolates (minimum inhibitory concentrations (MICs) = 0.5-2 µg/mL) with low hemolytic and cytotoxic activities and high membrane selectivity. Moreover, 5i exhibited rapid bactericidal properties, low resistance frequency, and good capabilities of disrupting bacterial biofilms. Mechanism studies revealed that 5i destroyed bacterial cell membranes, resulting in bacterial death. Additionally, 5i displayed high biosafety and potent in vivo anti-infective potency in a murine sepsis model. Our study indicates that these honokiol/magnolol amphiphiles shed light on developing novel antibacterial agents, and 5i is a potential antibacterial candidate for combating MRSA infections.

Efficacy of sequential therapies with sorafenib-sunitinib versus sunitinib-sorafenib in metastatic renal cell carcinoma: A systematic review and meta-analysis.

The most efficient sequence of targeted agents for metastatic renal cell carcinoma patients has yet to be identified. Whether the sequence of sorafenib and sunitinib really matters is controversial and not answered clearly until now. This meta-analysis aims to estimate the efficacy of receptor tyrosine kinase inhibitors sorafenib-sunitinib and sunitinib-sorafenib for metastatic renal cell carcinoma, on the outcome of first-line progression-free survival, second-line progression-free survival, total progression-free survival and overall survival.We searched PubMed, Embase, Cochrane Library and ClinicalTrails.gov for eligible studies. Data were analyzed using random or fixed effects model depending on the heterogeneity of the eligible studies. Heterogeneity across studies were analyzed using Q and I2 statistics.Of 902 identified studies, ten were qualified in our analysis (N = 1732 patients). Sorafenib-sunitinib yielded no statistically significant benefit in first-line progression-free survival (fixed effects; HR = 0.95; 95%CI 0.75-1.21; p = 0.702), total progression-free survival (random effects; HR = 0.92; 95%CI 0.71-1.19; p = 0.531) and overall survival (fixed effects; HR = 0.89; 95%CI 0.72-1.09; p = 0.257), compared with sunitinib-sorafenib. Second-line progression-free survival was longer for sorafenib-sunitinib than sunitinib-sorafenib (fixed effects; HR = 0.55; 95%CI 0.44-0.68; p = 0.000).Sequential therapies with sorafenib and sunitinib is well tolerated and efficient in mRCC. However, there are no evidence supported that sorafenib-sunitinib has the superiority to sunitinib-sorafenib in sequence. The ideal sequence of targeted agents requires further elucidation.