Antimicrobial peptides (AMPs) are expressed in various living organisms as first-line host defenses against potential harmful encounters in their surroundings. AMPs are short polycationic peptides exhibiting various antimicrobial activities. The principal antibacterial activity is attributed to the membrane-lytic mechanism which directly interferes with the integrity of the bacterial cell membrane and cell wall. In addition, a number of AMPs form a transmembrane channel in the membrane by self-aggregation or polymerization, leading to cytoplasm leakage and cell death. However, an increasing body of evidence has demonstrated that AMPs are able to exert intracellular inhibitory activities as the primary or supportive mechanisms to achieve efficient killing. In this review, we focus on the major intracellular targeting activities reported in AMPs, which include nucleic acids and protein biosynthesis and protein-folding, protease, cell division, cell wall biosynthesis, and lipopolysaccharide inhibition. These multifunctional AMPs could serve as the potential lead peptides for the future development of novel antibacterial agents with improved therapeutic profiles.

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IFN-regulatory factor 5 (IRF-5), a member of the IRF family, is a transcription factor that has a key role in the induction of the antiviral and inflammatory response. When compared with C57BL/6 mice, Irf5 −/− mice show higher susceptibility to viral infection and de- in Toll-like receptor (TLR) 7-and TLR9-induced IL-6 production, and the aged Irf5 −/− mice have decreased serum levels of natural antibodies; however, the antigen-specific IgG1 primary response was already dependent in IRF-5 in young mice, although the IgM response was not. Analysis of the profile of transcription factors associated with plasma cell differentiation shows down-regulation of Blimp-1 expression, a master regulator of plasma cell differentiation, which can be reconstituted with ectopic IRF-5. IRF-5 stimulates transcription of the Prdm1 gene encoding Blimp-1 and binds to the IRF site in the Prdm1 promoter. Collectively, these results reveal that the age-related splenomegaly in Irf5 he roles of IFN-regulatory factor (IRF) 3 and IRF-7 in the antiviral response have been well established, and their function in induction of type I Ifn genes has been extensively characterized (1, 2). The in vitro studies indicated that IRF-5 may also be involved in the antiviral response, but it was only recently that Irf5 −/− mice became available and the importance of IRF-5 in the antiviral and inflammatory response in vivo was clearly demonstrated (3, 4). Irf5 −/− mice exhibit high susceptibility to viral infection and show reductions in serum levels of type I IFN as well as inflammatory cytokines (4). Irf5−/− mice also show resistance to lethal shock induced by unmethylated CpG DNA and LPS (3). IRF-5 expression is induced by type I IFN and viral infection. In humans, IRF-5 is expressed in multiple spliced variants (5), and a distinct polymorphism in the IRF-5 gene is associated with autoimmune diseases such as systemic lupus erythematosus (6) and rheumatoid arthritis (7).The aim of this study was to examine the role of IRF-5 in B-cell development and differentiation, because we had observed that Irf5 −/− mice exhibit age-related splenomegaly associated with a large increase in CD19 + cells. Here, we demonstrate that Irf5 −/− mice show a dramatic increase in CD19 + B220− cells and attenuation of plasma cell development. Addressing the molecular mechanism responsible for this impairment, we show that IRF-5 regulates expression of the plasma cell maturation protein Blimp-1. Blimp-1 encoded by Prdm1 is required for the formation of Ig-secreted plasma cells (8). In mice, B cells specific for Blimp-1 deficiency result in attenuation of plasma cell development and a reduction in the humoral antigenic response (9). Thus, our results reveal the importance of IRF-5 in B-cell development and the commitment to terminal B-cell differentiation by stimulating expression of Blimp-1, the master regulator of plasma cell differentiation.

Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. Resistance to apoptosis is a hallmark of virtually all malignancies. Despite being a cause of pathological conditions, apoptosis could be a promising target in cancer treatment. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of TNF cytokine superfamily. It is a potent anti-cancer agent owing to its specific targeting towards cancerous cells, while sparing normal cells, to induce apoptosis. However, resistance occurs either intrinsically or after multiple treatments which may explain why cancer therapy fails. This review summarizes the apoptotic mechanisms via extrinsic and intrinsic apoptotic pathways, as well as the apoptotic resistance mechanisms. It also reviews the current clinically tested recombinant human TRAIL (rhTRAIL) and TRAIL receptor agonists (TRAs) against TRAIL-Receptors, TRAIL-R1 and TRAIL-R2, in which the outcomes of the clinical trials have not been satisfactory. Finally, this review discusses the current strategies in overcoming resistance to TRAIL-induced apoptosis in pre-clinical and clinical settings.

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