Cai Ping Koh

Excessive oxidative stress can cause irreversible cytotoxic damage to both healthy and cancer cells through the induction of reactive oxygen species (ROS) mediated lipid peroxidation. Ferroptosis has recently been shown to promote lipid peroxidation due to the over-accumulation of iron. Although cancer cells possess elevated antioxidant capacity to neutralize chemotherapy-induced oxidative stress, the co-delivery of polyphenol compounds such as curcumin (CUR) can overwhelm these defenses by elevating intracellular ROS levels to a toxic threshold, thereby increasing anticancer efficacy. In this study, we evaluated the potential of CUR to chemosensitize doxorubicin (DOX) towards the DOX-resistant lung cell line (H69AR). Our results demonstrated that the combination of DOX and CUR resulted in a concentration-dependent behavior, where low-dose concentrations exhibited antagonistic effects, while high-dose IC₅₀-equivalent concentrations shifted towards synergism. The combination induced significantly greater mitochondrial dysfunction, ATP depletion, cytochrome C release, and caspase-3 activation. This also resulted in excessive ROS generation, intracellular iron overload, and lipid peroxidation, accompanied by a reduction in antioxidant enzymatic activities. Pretreatment with N-acetyl-L-cysteine (ROS inhibitor) and ferrostatin-1 (ferroptosis inhibitor) further supported the involvement of oxidative stress and ferroptosis in modulating apoptosis and DNA fragmentation. Molecular docking analyses supported the binding of CUR and DOX to key ferroptosis regulators. This study shows the potential of CUR to sensitize DOX-resistant cancer cells through ferroptosis-linked-oxidative stress targeting.

The RUNX3 gene is frequently involved in a variety of cancers and immunological diseases. Despite such widespread association with human diseases, the transcriptional regulation of RUNX3 remains elusive. Here we report the identification of an enhancer for Runx3 , eR3(−18m/−28h) , by employing a combination of in silico prediction and in vivo verification using zebrafish and mouse models. eR3 is active in CD8 ⁺ CD103 (integrin α _E ) ⁺ cytotoxic T lymphocytes (CTLs) that reside in the intestinal epithelium via their interaction with the CD103 ligand, E‐cadherin, on epithelial cells. Removal of eR3(−18m) specifically in CD8 T cells compromised the suppression of tumorigenesis in murine cancer models. In humans, single nucleotide polymorphisms (SNPs) in eR3(−28h) were overrepresented and were associated with weakened CTL activity in colorectal cancer patients. Together, our results indicate that eR3 plays a role in immune surveillance against gut‐associated tumors by upregulating RUNX3 expression in specific CTLs.

This study sought to assess the leaf extracts of matoa (Pometia pinnata) and pulasan (Nephelium ramboutan-ake) for antimicrobial, antifungal, antioxidant, and cytotoxic activities, besides phytochemical content. Four extracts (hexane, ethyl acetate, ethanol, and water) were obtained from each plant via sequential extraction. The antimicrobial activities were evaluated using colorimetric broth microdilution methods. The antioxidant activities were studied using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and ferric-reducing antioxidant power (FRAP) assays. The cytotoxicity was examined using mouse fibroblasts NIH/3T3 while the phytochemical content was detected using various chemical tests. Among the extracts, only the water extract of matoa and ethyl acetate extract of pulasan exerted bactericidal effects on Bacillus cereus (minimum bactericidal concentration (MBC): 0.63 mg/mL) and Staphylococcus aureus (MBC: 1.25 mg/mL), respectively. In contrast, all extracts, except hexane extract, of both plants exhibited fungicidal effects with minimum fungicidal concentrations of 0.31-1.25 mg/mL. All extracts of matoa leaves displayed higher DPPH radical scavenging activity and FRAP than the extracts of pulasan leaves. Notably, the water extract of matoa showed the lowest half-maximal inhibitory concentration (IC50) value of 9.88 ± 1.70 µg/mL and the highest FRAP value of 6.11 ± 0.51 mmol Fe2+ equivalent/g extract (n=3). These antioxidant activities were significantly correlated (p<0.01) with the amounts of phenolic compounds in the extracts. All extracts of both plants, except water extracts, showed significant toxicities (p<0.05) towards NIH/3T3 cells. Alkaloids, terpenoids, saponins, and glycosides were detected in the leaves of both plants. The matoa and pulasan leaves contained bioactive compounds with antibacterial, antifungal, and antioxidant activities.

A well-documented Achilles heel of current cancer immunotherapy approaches is T cell exhaustion within solid tumor tissues. The pro-inflammatory cytokine interleukin-23 (IL-23) has been utilised to augment chimeric antigen receptor (CAR)-T cells survival and tumor immunity. However, in-depth interrogation of molecular events downstream of IL-23/IL23R signaling is hampered by a paucity of suitable cell models. The current study investigates the differential contribution of IL-2 and IL-23 to the maintenance and differentiation of the IL-23 responsive Kit225 T-cell line. We observed that IL-23 enhanced cellular fitness and survival but was insufficient to drive proliferation. IL-23 rapidly induced phosphorylation of STAT1, 3 and 4, and mRNA expression of IL17A, the archetypal effector cytokine of Th17 cells, but not their lineage markers RORC and NCR1. These observations suggest that IL-23 endowed Th17/ILC3-like effector function but did not promote their differentiation. In contrast, spontaneous differentiation of Kit225 cells towards a Th17/ILC3-like phenotype was induced by prolonged IL-2 withdrawal. This was marked by strongly elevated basal IL17A and IL17F expression and the secretion of IL-17. Together, our data present Kit225 cells as a valuable model for studying the interplay between cytokines and their contribution to T cell survival, proliferation, and differentiation.