Inflammation is often a rapid coordinated response generated in the host against evading microbial infections or tissue injury. Microorganisms like bacteria and viruses instigate inflammation mediated by pro-inflammatory cytokines and activate cascade of signaling events leading to the recruitment of inflammatory cells (neutrophils and macrophages). Although the main function of inflammation is the resolution of infection, several viruses, including the hepatitis C viruses (HCV) have evolved to utilize this host response and make the cellular environments conducive to infection. In majority of infected individuals, HCV causes persistent chronic liver inflammation leading to development of liver cirrhosis and hepatocellular carcinoma. HCV induces reactive oxygen species (ROS) and activates nuclear factor-κB (NF-κB) leading to the activation of cyclooxygenase-2 (Cox-2) that ultimately produces prostaglandin-E2 (PGE2), thus enhancing inflammatory process. Interestingly, HCV further activates NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome (a multiprotein complex) by recruiting adaptor protein apoptosis-associated speck-like protein containing a carboxy-terminal CARD (ASC) which are involved in activation of caspase-1 leading to production of interleukin-1beta (IL-1β) and interleukin-18 (IL-18). In this chapter we have highlighted the recent advancements in HCV-induced inflammatory responses and discussed potential future directions to understand the role of inflammation during HCV infection.
Part of the book: Hepatitis C
Small molecule chemotherapeutic agents such as Imatinib, Gefitinib, and Erlotinib have played a significant role in the treatment of cancer. Although the unprecedented progress has been achieved in cancer treatment with these targeted agents, there is a strong demand for the development of selective and highly efficacious cancer drugs. V-ATPases are emerging as important target for the identification of novel therapeutic agents for cancer. Our screening and drug discovery processes have identified the bisbenzimidazole derivative (RP-15) as a potent anticancer V-ATPase inhibitor. In the present study, bisbenzimidazoles (compound-25, RP-11 and RP-15) have been tested for proton-pump inhibition activity in human hepatoma cell line (Huh7.5). RP-15 displayed comparable proton-pump inhibition activity to the standard Bafilomycin A1. We examined the antiproliferative activity of these analogs in two highly invasive and metastatic inflammatory breast cancer (IBC) cell lines (SUM 149PT and SUM190PT) along with Huh7.5. The compound-25 (SUM190PT: IC50 = 0.43±0.11 μM) and its structural analog RP-11 (SUM190PT: IC50 = 0.49±0.09 μM) have shown significant inhibition toward IBC cell lines. Additionally, RP-11 and RP-15 have demonstrated very good cytotoxicity toward the majority of cancer cell lines in the NCI 60 cell line panel.
Part of the book: Chemistry and Applications of Benzimidazole and its Derivatives