Iron Effects on Clostridioides difficile Toxin Production and Antimicrobial Susceptibilities.

Despite the benefits of red blood cell (RBC) transfusion therapy, it can render patients vulnerable to iron overload. The excess iron deposits in various body tissues cause severe complications and organ damage such as cardiotoxicity and mold infections. Clostridioides difficile infection (CDI) is the most common cause of nosocomial diarrhea among cancer patients and is associated with significant morbidity and mortality. Our study aims to determine the role of iron overload and the effects of iron chelators on CDI. Our results demonstrated that iron (Fe3+) stimulated the growth of C. difficile with increased colony formation units (CFU) in a dose-dependent manner. Exposure to excess iron also increased the gene expression levels of tcdA and tcdB. The production of C. difficile toxin A, necessary for the pathogenesis of C. difficile, was also elevated after iron treatment. In the presence of excess iron, C. difficile becomes less susceptible to metronidazole with significantly elevated minimum inhibitory concentration (MIC) but remains susceptible to vancomycin. Iron-stimulated colony formation and production of C. difficile toxins were effectively diminished by iron chelator deferoxamine co-treatment. Incorporating iron overload status as a potential factor in developing a risk prediction model of CDI and antibiotic treatment response may aid clinical practitioners in optimizing CDI management in oncology patients.

Bis-Cinnamamide Derivatives as APE/Ref-1 Inhibitors for the Treatment of Human Melanoma.

Human malignant melanoma exhibits imbalances in redox status, leading to activation of many redox-sensitive signaling pathways. APE/Ref-1 is a multifunctional protein that serves as a redox chaperone that regulates many nuclear transcription factors and is an important mechanism in cancer cell survival of oxidative stress. Previous studies showed that APE/Ref-1 is a potential druggable target for melanoma therapy. In this study, we synthesized a novel APE/Ref-1 inhibitor, bis-cinnamoyl-1,12-dodecamethylenediamine (2). In a xenograft mouse model, compound 2 treatment (5 mg/kg) significantly inhibited tumor growth compared to the control group, with no significant systemic toxicity observed. We further synthesized compound 2 analogs to determine the structure-activity relationship based on their anti-melanoma activities. Among those, 4-hydroxyphenyl derivative (11) exhibited potent anti-melanoma activities and improved water solubility compared to its parental compound 2. The IC50 of compound 11 was found to be less than 0.1 µM. Compared to other known APE/Ref-1 inhibitors, compound 11 exhibited increased potency in inhibiting melanoma proliferation. As determined by luciferase reporter analyses, compound 2 was shown to effectively inhibit H2O2-activated AP-1 transcription activities. Targeting APE/Ref-1-mediated signaling using pharmaceutical inhibitors is a novel and effective strategy for melanoma treatment with potentially high impact.