Colon-targeted S100A8/A9-specific peptide systems ameliorate colitis and colitis-associated colorectal cancer in mouse models.

The link between chronic inflammation and cancer development is well acknowledged. Inflammatory bowel disease including ulcerative colitis and Crohn's disease frequently promotes colon cancer development. Thus, control of intestinal inflammation is a therapeutic strategy to prevent and manage colitis-associated colorectal cancer (CRC). Recently, gut mucosal damage-associated molecular patterns S100A8 and S100A9, acting via interactions with their pattern recognition receptors (PRRs), especially TLR4 and RAGE, have emerged as key players in the pathogenesis of colonic inflammation. We found elevated serum levels of S100A8 and S100A9 in both colitis and colitis-associated CRC mouse models along with significant increases in their binding with PRR, TLR4, and RAGE. In this study we developed a dual PRR-inhibiting peptide system (rCT-S100A8/A9) that consisted of TLR4- and RAGE-inhibiting motifs derived from S100A8 and S100A9, and conjugated with a CT peptide (TWYKIAFQRNRK) for colon-specific delivery. In human monocyte THP-1 and mouse BMDMs, S100A8/A9-derived peptide comprising TLR4- and RAGE-interacting motif (0.01, 0.1, 1 µM) dose-dependently inhibited the binding of S100 to TLR4 or RAGE, and effectively inhibited NLRP3 inflammasome activation. We demonstrated that rCT-S100A8/A9 had appropriate drug-like properties including in vitro stabilities and PK properties as well as pharmacological activities. In mouse models of DSS-induced acute and chronic colitis, injection of rCT-S100A8/A9 (50 µg·kg-1·d-1, i.p. for certain consecutive days) significantly increased the survival rates and alleviated the pathological injuries of the colon. In AOM/DSS-induced colitis-associated colorectal cancer (CAC) mouse model, injection of rCT-S100A8/A9 (50 µg·kg-1·d-1, i.p.) increased the body weight, decreased tumor burden in the distal colon, and significantly alleviated histological colonic damage. In mice bearing oxaliplatin-resistant CRC xenografts, injection of rCT-S100A8/A9 (20 µg/kg, i.p., every 3 days for 24-30 days) significantly inhibited the tumor growth with reduced EMT-associated markers in tumor tissues. Our results demonstrate that targeting the S100-PRR axis improves colonic inflammation and thus highlight this axis as a potential therapeutic target for colitis and CRC.

Exploring the potential of Toxoplasma gondii in drug development and as a delivery system.

Immune-mediated inflammatory diseases are various groups of conditions that result in immune system disorders and increased cancer risk. Despite the identification of causative cytokines and pathways, current clinical treatment for immune-mediated inflammatory diseases is limited. In addition, immune-mediated inflammatory disease treatment can increase the risk of cancer. Several previous studies have demonstrated that Toxoplasma gondii manipulates the immune response by inhibiting or stimulating cytokines, suggesting the potential for controlling and maintaining a balanced immune system. Additionally, T. gondii also has the unique characteristic of being a so-called "Trojan horse" bacterium that can be used as a drug delivery system to treat regions that have been resistant to previous drug delivery therapies. In this study, we reviewed the potential of T. gondii in drug development and as a delivery system through current research on inflammation-regulating mechanisms in immune-mediated inflammatory diseases.

Tumor-targeted liposomes with platycodin D2 promote apoptosis in colorectal cancer.

Conventional chemotherapy for colorectal cancer (CRC), though efficacious, is discouraging due to its limited targeting capability, lack of selectivity, and chemotherapy-associated side effects. With the advent of nanomedicines, a liposomal delivery system making use of a combination of anticancer phytochemicals is fast gaining popularity as one of the most promising nanoplatforms for CRC treatment. Rising evidence supports phytochemicals such as platycosides for their anticancer potency. To this end, a combination therapy including tumor-targeted liposomes along with phytochemicals might have a greater therapeutic potential against cancer. In this study, we developed acidity-triggered rational membrane (ATRAM) along with conjugated platycodin D2 (PCD2) and liposomes (PCD2-Lipo-ATRAM) as a tumor-targeting therapy. The PCD2-Lipo-ATRAM treatment demonstrated a successful tumor-targeting ability in the CRC xenografts, in which PCD2 not only exerted a potent antitumor effect by inducing apoptotic cell death and but also functioned as a liposome membrane stabilizer. Moreover, PCD2-Lipo-ATRAM suppressed antiapoptotic BCL-2 family proteins, resulting in enhanced cytotoxicity toward CRC cells by inducing intrinsic caspase-9/-3 mediated apoptosis. Thus, our data has shown that tumor-targeting PCD2-based liposomal systems represent a promising strategy for CRC therapy, since they directly target the tumors, unlike other therapies that can miss the target.

The strategies of NLRP3 inflammasome to combat Toxoplasma gondii.

Infection with the protozoan parasite Toxoplasma gondii (T. gondii) results in the activation of nucleotide-binding domain leucine-rich repeat containing receptors (NLRs), which in turn leads to inflammasome assembly and the subsequent activation of caspase-1, secretion of proinflammatory cytokines, and pyroptotic cell death. Several recent studies have addressed the role of the NLRP3 inflammasome in T. gondii infection without reaching a consensus on its roles. Moreover, the mechanisms of NLRP3 inflammasome activation in different cell types remain unknown. Here we review current research on the activation and specific role of the NLRP3 inflammasome in T. gondii infection.