Use of multibranched stent-grafts in the treatment of TAAAs and PRAAs appears to be feasible and safe based on satisfactory early outcomes in the limited literature available to date. Long-term surveillance and further studies are essential to determine the durability of this technique.
Worldwide research efforts in drug discovery involving HIV integrase have produced only one compound, raltegravir, that has been approved for clinical use in HIV/AIDS. As resistance, toxicity and drug-drug interactions are recurring issues with all classes of anti-HIV drugs, the discovery of novel integrase inhibitors remains a significant scientific challenge. We have designed a lead HIV-1 strand transfer (ST) inhibitor (IC50 70 nM), strategically assembled on a pyridinone scaffold. A focused structure-activity investigation of this parent compound led to a significantly more potent ST inhibitor, 2 (IC50 6 ± 3 nM). Compound 2 exhibits good stability in pooled human liver microsomes. It also displays a notably favorable profile with respect to key human cytochrome P450 (CYP) isozymes and human UDP glucuronosyl transferases (UGTs). The prodrug of inhibitor 2, i.e., compound 10, was found to possess remarkable anti-HIV-1 activity in cell culture (EC50 9 ± 4 nM, CC50 135 ± 7 μM, therapeutic index = 15,000).
Biomechanical factors play an extremely important role in regulating the function of articular chondrocytes. Understanding the mechanical factors that drive chondrocyte biological responses is at the heart of our interpretation of cascade events leading to changes in articular cartilage osteoarthritis. The mechanism by which mechanical load is transduced into intracellular signals that can regulate chondrocyte gene expression remains largely unknown. The mechanically sensitive ion channel (MSC) may be one of its specific mechanisms. This review focuses on four ion channels involved in the mechanotransduction of chondrocytes, exploring their properties and the main factors that activate the associated pathways. The upstream and downstream potential relationships between the protein pathways were also explored. The specific biophysical mechanism of the chondrocyte mechanical microenvironment is becoming the focus of research. Elucidating the mechanotransduction mechanism of MSC is essential for the research of biophysical pathogenesis and targeted drugs in cartilage injury-related diseases.
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