Orally administered drugs must overcome several barriers before reaching their target site. Such barriers depend largely upon specific membrane transport systems and intracellular drug-metabolizing enzymes. For the first time, the P-glycoprotein (P-gp) and cytochrome P450s, the main line of defense by limiting the oral bioavailability (OB) of drugs, were brought into construction of QSAR modeling for human OB based on 805 structurally diverse drug and drug-like molecules. The linear (multiple linear regression: MLR, and partial least squares regression: PLS) and nonlinear (support-vector machine regression: SVR) methods are used to construct the models with their predictivity verified with five-fold cross-validation and independent external tests. The performance of SVR is slightly better than that of MLR and PLS, as indicated by its determination coefficient (R2) of 0.80 and standard error of estimate (SEE) of 0.31 for test sets. For the MLR and PLS, they are relatively weak, showing prediction abilities of 0.60 and 0.64 for the training set with SEE of 0.40 and 0.31, respectively. Our study indicates that the MLR, PLS and SVR-based in silico models have good potential in facilitating the prediction of oral bioavailability and can be applied in future drug design.

Compound Danshen Formula (CDF) is a widely used Traditional Chinese Medicine (TCM) which has been extensively applied in clinical treatment of cardiovascular diseases (CVDs). However, the underlying mechanism of clinical administrating CDF on CVDs is not clear. In this study, the pharmacological effect of CDF on CVDs was analyzed at a systemic point of view. A systems-pharmacological model based on chemical, chemogenomics and pharmacological data is developed via network reconstruction approach. By using this model, we performed a high-throughput in silico screen and obtained a group of compounds from CDF which possess desirable pharmacodynamical and pharmacological characteristics. These compounds and the corresponding protein targets are further used to search against biological databases, such as the compound-target associations, compound-pathway connections and disease-target interactions for reconstructing the biologically meaningful networks for a TCM formula. This study not only made a contribution to a better understanding of the mechanisms of CDF, but also proposed a strategy to develop novel TCM candidates at a network pharmacology level.

Bladder cancer is one of the concerning malignancies worldwide, which is lacking effective targeted therapy. Gene therapy is a potential approach for bladder cancer treatment. While, a safe and effective targeted gene delivery system is urgently needed for prompting the bladder cancer treatment in vivo . In this study, we confirmed that the bladder cancer had CD44 overexpression and small interfering RNAs (siRNA) with high interfere to Bcl2 oncogene were designed and screened. Then hyaluronic acid dialdehyde (HAD) was prepared in an ethanol-water mixture and covalently conjugated to the chitosan nanoparticles (CS-HAD NPs) to achieve CD44 targeted siRNA delivery. The in vitro and in vivo evaluations indicated that the siRNA-loaded CS-HAD NPs (siRNA@CS-HAD NPs) were approximately 100 nm in size, with improved stability, high siRNA encapsulation efficiency and low cytotoxicity. CS-HAD NPs could target to CD44 receptor and deliver the therapeutic siRNA into T24 bladder cancer cells through a ligand-receptor-mediated targeting mechanism and had a specific accumulation capacity in vivo to interfere the targeted oncogene Bcl2 in bladder cancer. Overall, a CD44 targeted gene delivery system based on natural macromolecules was developed for effective bladder cancer treatment, which could be more conducive to clinical application due to its simple preparation and high biological safety.

Penile squamous cell carcinoma (PSCC) is a malignancy that affects the skin and tissues of the penis, but the knowledge of pathogenesis and carcinogenesis is limited. Here, we characterize the PSCC genomic landscape using whole‐exome sequencing. Of the 30 paired blood and tumor samples, we identified recurrent mutations in 11 genes; confirmed previous findings for FAT1 (4/30), HRAS (4/30), NOTCH1 (4/30), TP53 (3/30) and PIK3CA (3/30); and revealed novel candidate driver genes [CASP8 (4/30), SLITRK2 (3/30), FLG (3/30) and TRRAP (3/30)]. Our in vitro experiments suggested CASP8 was involved in mediating TRAIL‐induced apoptosis of penile cancer cell lines. We also observed the frequently altered pathways for potential therapeutic implications: alterations in the Notch (30% of sample altered), RTK–RAS (26.7% altered) and Hippo (23.3% altered) pathways accounted for over 50% of tumors. The frequently altered genes (>10%) in these pathways were proved to be expressed in penile tumors by immunohistochemistry assay. These findings provide new insight into the mutational and pathway landscapes of PSCC and suggest potential novel therapeutic opportunities for this malignancy.

The generation of reactive oxygen species (ROS) is a major cause of heart injury induced by ischemia-reperfusion. The left ventricular developed pressure (LVDP) and the maximum up/down rate of left ventricular pressure (±dp/dt max⁡) were documented by a physiological recorder. Myocardial infarct size was estimated macroscopically using 2,3,5-triphenyltetrazolium chloride staining. Coronary effluent was analyzed for lactate dehydrogenase (LDH) and creatine kinase (CK) release to assess the degree of cardiac injury. The levels of C-reactive protein (CRP), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were analyzed to determine the inflammation status of the myocardial tissue. Cardiomyocyte apoptosis analysis was performed using the In Situ Cell Death Detection Kit, POD. Accordingly, licochalcone B pretreatment improved the heart rate (HR), increased LVDP, and decreased CK and LDH levels in coronary flow. SOD level and GSH/GSSG ratio increased, whereas the levels of MDA, TNF-α, and CRP and activities of IL-8 and IL-6 decreased in licochalcone B-treated groups. The infarct size and cell apoptosis in hearts from licochalcone B-treated group were lower than those in hearts from the I/R control group. Therefore, the cardioprotective effects of licochalcone B may be attributed to its antioxidant, antiapoptotic, and anti-inflammatory activities.