Inhibiting CD44-ICD Attenuates LPS-Induced Initiation of Hepatic Inflammation in Septic Mice.

Sepsis is a severe condition induced by microbial infection. It elicits a systemic inflammatory response, leading to multi-organ failure, and the liver, as a scavenger, plays a significant role in this process. Controlling hepatic inflammation and maintaining liver function is crucial in managing sepsis. CD44-ICD, as a CD44 signal transductor, is involved in multiple inflammatory responses. However, the role of CD44-ICD in lipopolysaccharide (LPS)-induced hepatic inflammation has not been investigated. Therefore, we aimed to examine whether CD44-ICD initiates hepatic inflammation in septic mice. We induced hepatic inflammation in mice by administering LPS. DAPT, a CD44-ICD inhibitor, was given to mice or Chang cells 30 min or 1 h before LPS administration (10 mg/kg, i.p., or 100 ng/mL, respectively). Inhibition of CD44-ICD decreased the level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), hepatic necrosis, inflammatory cell infiltration, interleukin (IL)-1ß, inducible NO synthase (iNOS), nitric oxide (NO) production, nuclear factor (NF)κB signaling pathway proteins, and CD44 expression in mice. CD44-ICD inhibition also decreased IL-1ß and CD44 expression levels in Chang cells. CD44-ICD may be a primary regulatory function in CD44-associated LPS-induced initiation of hepatic inflammation in mice.

Dehydroxyhispolon Methyl Ether, A Hispolon Derivative, Inhibits WNT/ß-Catenin Signaling to Elicit Human Colorectal Carcinoma Cell Apoptosis.

Colorectal cancer (CRC) is the fourth leading cause of cancer mortality worldwide. Aberrant activation of WNT/ß-catenin signaling present in the vast majority of CRC cases is indispensable for CRC initiation and progression, and thus is a promising target for CRC therapeutics. Hispolon is a fungal-derived polyphenol with a pronounced anticancer effect. Several hispolon derivatives, including dehydroxyhispolon methyl ether (DHME), have been chemically synthesized for developing lead molecules with stronger anticancer activity. Herein, a DHME-elicited anti-CRC effect with the underlying mechanism is reported for the first time. Specifically, DHME was found to be more cytotoxic than hispolon against a panel of human CRC cell lines, while exerting limited toxicity to normal human colon cell line CCD 841 CoN. Additionally, the cytotoxic effect of DHME appeared to rely on inducing apoptosis. This notion was evidenced by DHME-elicited upregulation of poly (ADP-ribose) polymerase (PARP) cleavage and a cell population positively stained by annexin V, alongside the downregulation of antiapoptotic B-cell lymphoma 2 (BCL-2), whereas the blockade of apoptosis by the pan-caspase inhibitor z-VAD-fmk attenuated DHME-induced cytotoxicity. Further mechanistic inquiry revealed the inhibitory action of DHME on ß-catenin-mediated, T-cell factor (TCF)-dependent transcription activity, suggesting that DHME thwarted the aberrantly active WNT/ß-catenin signaling in CRC cells. Notably, ectopic expression of a dominant-active ß-catenin mutant (∆N90-ß-catenin) abolished DHME-induced apoptosis while also restoring BCL-2 expression. Collectively, we identified DHME as a selective proapoptotic agent against CRC cells, exerting more potent cytotoxicity than hispolon, and provoking CRC cell apoptosis via suppression of the WNT/ß-catenin signaling axis.