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Current antiplatelet therapies have several clinical complications and are mostly irreversible in terms of suppressing platelet activity; hence, there is a need to develop improved therapeutic agents. Previous studies have implicated RhoA in platelet activation. Here, we further characterized the lead RhoA inhibitor, Rhosin/G04, in platelet function and present structure–activity relationship (SAR) analysis. A screening for Rhosin/G04 analogs in our chemical library by similarity and substructure searches revealed compounds that showed enhanced antiplatelet activity and suppressed RhoA activity and signaling. A screening for Rhosin/G04 analogs in our chemical library using similarity and substructure searches revealed compounds that showed enhanced antiplatelet activity and suppressed RhoA activity and signaling. SAR analysis revealed that the active compounds have a quinoline group optimally attached to the hydrazine at the 4-position and halogen substituents at the 7- or 8-position. Having indole, methylphenyl, or dichloro-phenyl substituents led to better potency. Rhosin/G04 contains a pair of enantiomers, and S-G04 is significantly more potent than R-G04 in inhibiting RhoA activation and platelet aggregation. Furthermore, the inhibitory effect is reversible, and S-G04 is capable of inhibiting diverse-agonist-stimulated platelet activation. This study identified a new generation of small-molecule RhoA inhibitors, including an enantiomer capable of broadly and reversibly modulating platelet activity.

Background: The association of dietary patterns representing multiple dietary components and breast cancer risk is not clearly understood. This systematic review presents a novel way of assessing the healthfulness of dietary patterns using a scoring matrix based on the American Cancer Society dietary guidelines. The objective of this review was to comprehensively and systematically evaluate articles that examined the association between breast cancer risk and dietary patterns.Methods: The literature search was carried out using PubMed and EMBASE databases and included original articles published between January 2013 and May 2017. Included articles reported risk estimates of breast cancer, compared the highest to the lowest categories of dietary intake, and had measures of variability in examining the association between dietary patterns (determined by posteriori or a priori approaches) and breast cancer risk.Results: 17 articles met the inclusion criteria; studies were conducted in diverse populations across different countries. Case-control and nested case-control studies were retrieved, which identified 15 healthy dietary patterns and 10 unhealthy dietary patterns determined posteriori and 7 dietary indices determined a priori. Six of 15 healthy dietary patterns were related to lower risk of breast cancer with greater adherence, and 5 of 10 unhealthy dietary patterns were related to greater risk of breast cancer with greater adherence. Out of the 7 a priori dietary indices, greater adherence to the Healthy Eating Index was related to lower risk of breast cancer. Vegetables were consistently found in cancer-protective patterns whereas saturated fat and red and processed meats were consistently found in cancer-promoting patterns. Conclusions: Findings suggest that dietary patterns that include vegetables and limit saturated fat and red and processed meats may be conducive to lowering breast cancer risk.