Discovery of Aldehyde Dehydrogenase as a Potential Fungicide Target and Screening of its Natural Inhibitors against Fusarium verticillioides.

Fusarium verticillioides is the primary pathogen causing ear rot and stalk rot in corn (Zea mays). It not only affects yields but also produces mycotoxins endangering both human and animal health. Aldehyde dehydrogenase (ALDH) is essential for the oxidation of aldehydes in living organisms, making it a potential target for human drug design. However, there are limited reports on its function in plant pathogenic fungus. In this study, we analyzed the expression levels and gene knockout mutants, revealing that ALDH genes FvALDH-43 and FvALDH-96 in F. verticillioides played significant roles in pathogenicity and resistance to low-temperature stress by affecting antioxidant capacity. Virtual screening for natural product inhibitors and molecular docking were performed targeting FvALDH-43 and FvALDH-96. Following the biological activity analysis, three natural flavonoid compounds featuring a 2-hydroxyphenol chromene were identified. Among these, Taxifolin exhibited the highest biological activity and low toxicity. Both in vitro and in vivo biological evaluations confirmed that Taxifolin targeted ALDH and inhibited its activity. These findings indicate that aldehyde dehydrogenase may serve as a promising target for the design of novel fungicides.

Impacts of monosaccharide composition on immunomodulation by cello-pentaose, manno-pentaose, and xylo-pentaose: Unraveling the underlying molecular mechanisms.

Different types of functional oligosaccharides exhibit varying degrees of immune-enhancing effects, which might be attributable to differences in their glycosyl structures. The differences in the immunomodulatory action of three functional oligosaccharides with distinct glycosyl compositions: cello-oligosaccharides (COS), manno-oligosaccharides (MOS), and xylo-oligosaccharides (XOS), were investigated in mouse-derived macrophage RAW264.7. Moreover, the immune enhancement mechanism of oligosaccharides with diverse glycosyl compositions was investigated from a molecular interaction perspective. The TLR4-dependent immunoregulatory effect of functional oligosaccharides was shown by measuring the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in RAW264.7 cells treated with different functional oligosaccharides, both with and without Resatorvid [TAK-242] (a Toll-like receptor 4 [TLR4] inhibitor). Western blot analysis showed that binding of the three oligosaccharides to TLR4 activated the downstream signaling pathway and consequently enhanced the immune response. The fluorescence spectra and molecular docking results revealed that the main mechanisms by which these oligosaccharides attach to the TLR4 active pocket are hydrogen bonds and van der Waals forces. Functional oligosaccharides were ranked according to their affinity for TLR4, as follows: MOS > COS > XOS, indicating that oligosaccharides or polysaccharides containing mannose units may confer significant advantages for immune enhancement.

Association of Plasma Anion Gap with 28-Day Inhospital Mortality and 1-Year Mortality of Patients with Alcohol Use Disorder at ICU Admission: A Retrospective Cohort Study.

Background: Alcohol use disorder (AUD) is common in critically ill patients. Plasma anion gap (AG) was known as a feasible parameter and was associated with outcomes of various diseases. This study is intended to explore whether AG is related to 28-day inhospital mortality and 1-year mortality of critically ill patients with AUD. Method: We extracted data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The association of plasma AG with 28-day inhospital mortality and 1-year mortality of critically ill AUD patients was assessed using Cox proportional hazard regression models and stratification analyses, allowing AG as a time-varying covariate in the models. To evaluate the accuracy of AG in predicting different endpoints, receiver operator characteristic (ROC) curves were used. Result: Among the 3993 critically ill patients with AUD, AG was positively associated with 28-day inhospital mortality and 1-year mortality after adjusting confounders (p < 0.001 for all). Compared with lower AG (<12 mmol/L), patients in different groups (12 ≤ AG < 14 mmol/L, 14 ≤ AG < 17 mmol/L, 17 ≤ AG < 20 mmol/L, and AG ≥ 20 mmol/L) had different HRs (95% CIs) for 28-day inhospital mortality (1.105, (0.906, 1.347); 1.171, (0.981, 1.398); 1.320, (1.108, 1.573); and 1.487, (1.254, 1.763), respectively) and 1-year mortality (1.037 (0.898, 1.196); 1.091 (0.955, 1.246); 1.201 (1.052, 1.371); and 1.3093 (1.149, 1.492), respectively). Conclusion: Increased AG is associated with greater 28-day inhospital mortality and 1-year mortality. The effect of AG on all-cause mortality is linear in critically ill AUD patients.