Effect of Nicotinamide Against Candida albicans

Nicotinamide (NAM) has a long history in clinical applications and can be safely used for treating various diseases. In recent years, NAM was found to exhibit antimicrobial activities, inhibiting the growth of Plasmodium falciparum, Mycobacterium tuberculosis, and human immunodeficiency virus (HIV). Here we investigated the activity of NAM against Candida albicans, one of the most prevalent human fungal pathogens. Our results showed that NAM exhibited significant antifungal activity against C. albicans, including fluconazole-resistant isolates. NAM could also effectively suppress biofilm formation. In addition, NAM exhibited antifungal activity against non-Candida albicans species and Cryptococcus neoformans. Combination of NAM and fluconazole showed an even strong antifungal activity. The antifungal activity of NAM was further confirmed in a mouse model of disseminated candidiasis. Confocal laser scanning microscopy revealed that NAM increased cell wall β-glucans exposure and chitin content while decreased mannan level. Furthermore, by screening the C. albicans homozygous deletion mutant library, the C. albicans mutant lacking GIN4, which encodes a septin regulatory protein kinase and is essential for the maintenance of cell wall integrity, was identified to be high sensitive to NAM. These findings suggested that NAM might exhibit antifungal activities through affecting cell wall organization

Macrophage-mediated trogocytosis contributes to destroying human schistosomes in a non-susceptible rodent host, Microtus fortis

Schistosoma parasites, causing schistosomiasis, exhibit typical host specificity in host preference. Many mammals, including humans, are susceptible to infection, while the widely distributed rodent, Microtus fortis, exhibits natural anti-schistosome characteristics. The mechanisms of host susceptibility remain poorly understood. Comparison of schistosome infection in M. fortis with the infection in laboratory mice (highly sensitive to infection) offers a good model system to investigate these mechanisms and to gain an insight into host specificity. In this study, we showed that large numbers of leukocytes attach to the surface of human schistosomes in M. fortis but not in mice. Single-cell RNA-sequencing analyses revealed that macrophages might be involved in the cell adhesion, and we further demonstrated that M. fortis macrophages could be mediated to attach and kill schistosomula with dependence on Complement component 3 (C3) and Complement receptor 3 (CR3). Importantly, we provided direct evidence that M. fortis macrophages could destroy schistosomula by trogocytosis, a previously undescribed mode for killing helminths. This process was regulated by Ca2+/NFAT signaling. These findings not only elucidate a novel anti-schistosome mechanism in M. fortis but also provide a better understanding of host parasite interactions, host specificity and the potential generation of novel strategies for schistosomiasis control

Metabonomics on Candida albicans

ABSTRACTDevelopment of antifungal agents with novel mechanism and low toxicity are essential due to the prevalence of the infectious diseases caused by Candida albicans. The current study employed a new research method, which combined the ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry and gas chromatography-mass spectrometry, to investigate the intrinsic mechanism of Shikonin (SK) against C. albicans. The levels of 27 metabolites, which mainly involved in histone deacetylation, amino acid synthesis, lipid synthesis, nitrogen metabolism, tricarboxylic acid cycle, oxidative stress and glycolysis, were remarkably changed upon SK treatment. Specially, the down-regulation of nicotinamide (NAM) upon SK treatment indicated the suppression of the deacetylation of the histone H3 on lysine 56 residue (H3K56). Further experiment confirmed that the level of H3K56 acetylation (H3K56ac) was dramatically increased upon SK treatment which was mediated by HST3, the gene encoding the H3K56 deacetylase (Hst3p). Our results demonstrated that SK is the first natural compound reported to execute antifungal activity directly via boosting H3K56ac mediated by HST3. Importantly, this finding shed new light on the mechanisms to relieve the side effects or reverse the drug tolerance, as well as the development of agents for antifungal therapies

Related metabolites and their metabolic pathway.

<p>Related metabolites and their metabolic pathway.</p

Metabolomic profiling for the identification of potential biomarkers involved in a laboratory azole resistance in <i>Candida albicans</i>

<div><p><i>Candida albicans</i>, one of the most common fungal pathogens, is responsible for several yeast infections in human hosts, being resistant to classically used antifungal drugs, such as azole drugs. Multifactorial and multistep alterations are involved in the azole resistance in <i>Candida albicans</i>. In this study, a FCZ-resistant <i>C</i>. <i>albicans</i> strain was obtained by serial cultures of a FCZ-susceptible <i>C</i>. <i>albicans</i> strain in incrementally increasing concentrations of FCZ. We performed an integrated profile of different classes of molecules related to azole resistance in <i>C</i>. <i>albicans</i> by combining several mass-spectrometry based methodologies. The comparative metabolomic study was performed with the sensitive and resistant strains of <i>C</i>.<i>albicans</i> to identify metabolites altered during the development of resistance to fluconazole, while the intervention strains and non-intervention strains of <i>C</i>.<i>albicans</i> to identify metabolites altered involved in cross-resistant to azole drugs. Our analysis of the different metabolites identified molecules mainly involved in metabolic processes such as amino acid metabolism, tricarboxylic acid cycle and phospholipid metabolism. We also compared the phospholipid composition of each group, revealing that the relative content of phospholipids significantly changed during the development of resistance to azole drugs. According with these results, we hypothesized that the metabolism shift might contribute to azole drugs resistance in <i>C</i>.<i>albicans</i> from multifactorial alterations. Our result paves the way to understand processes underlying the resistance to azole drugs in <i>C</i>. <i>albicans</i>, providing the basis for developing new antifungal drugs.</p></div

The result of total number of carbons in the fatty acid chains of phosphoglyceride.

<p>The result of total number of carbons in the fatty acid chains of phosphoglyceride.</p

PLS-DA scores plot of extracellular metabolites from LC-Q-TOF/MS.

<p>(A)S group vs R group; (B)S group vs S+KCZ group; (C)R group vs R+KCZ group; (D)S+KCZ group vs R+KCZ group.</p

HILIC-QQQ/MS scan parameters.

<p>HILIC-QQQ/MS scan parameters.</p