High‐fat diet (HFD) has been recognized as a primary factor in the risk of chronic disease. Obesity, diabetes, gastrointestinal diseases, neurodegenerative diseases, and cardiovascular diseases have long been known as chronic diseases with high worldwide incidence. In this review, the influences of gut microbiota and their corresponding bacterial metabolites on the mechanisms of HFD‐induced chronic diseases are systematically summarized. Gut microbiota imbalance is also known to increase susceptibility to diseases. Several studies have proven that HFD has a negative impact on gut microbiota, also exacerbating the course of many chronic diseases through increased populations of Erysipelotrichaceae, facultative anaerobic bacteria, and opportunistic pathogens. Since bile acids, lipopolysaccharide, short‐chain fatty acids, and trimethylamine N‐oxide have long been known as common features of bacterial metabolites, we will explore the possibility of synergistic mechanisms among those metabolites and gut microbiota in the context of HFD‐induced chronic diseases. Recent literature concerning the mechanistic actions of HFD‐mediated gut microbiota have been collected from PubMed, Google Scholar, and Scopus. The aim of this review is to provide new insights into those mechanisms and to point out the potential biomarkers of HFD‐mediated gut microbiota.

Ssk1p ofCandida albicansis a putative response regulator protein of the Hog1 two-component signal transduction system. InSaccharomyces cerevisiae, the phosphorylation state of Ssk1p determines whether genes that promote the adaptation of cells to osmotic stress are activated. We have previously shown thatC. albicans SSK1does not complement thessk1mutant ofS. cerevisiaeand that thessk1mutant ofC. albicansis not sensitive to sorbitol. In this study, we show that theC. albicans ssk1mutant is sensitive to several oxidants, including hydrogen peroxide,t-butyl hydroperoxide, menadione, and potassium superoxide when each is incorporated in yeast extract-peptone-dextrose (YPD) agar medium. We used DNA microarrays to identify genes whose regulation is affected by thessk1mutation. RNA from mutant cells (strain CSSK21) grown in YPD medium for 3 h at 30°C was reverse transcribed and then compared with similarly prepared RNA from wild-type cells (CAF2). We observed seven genes from mutant cells that were consistently up regulated (three-fold or greater compared to CAF2). InS. cerevisiae, three (AHP1,HSP12, andPYC2) of the seven genes that were up regulated provide cells with an adaptation function in response to oxidative stress; another gene (GPH1) is regulated under stress conditions by Hog1p. Three other genes that are up regulated encode a cell surface protein (FLO1), a mannosyl transferase (MNN4-4), and a putative two-component histidine kinase (CHK1) that regulates cell wall biosynthesis inC. albicans. Of the down-regulated genes,ALS1is a known cell adhesin inC. albicans. Verification of the microarray data was obtained by reverse transcription-PCR forHSP12,AHP1,CHK1,PYC2,GPH1,ALS1,MNN4-4, andFLO1. To further determine the function of Ssk1p in the Hog1p signal transduction pathway inC. albicans, we used Western blot analysis to measure phosphorylation of Hog1p in thessk1mutant ofC. albicanswhen grown under either osmotic or oxidative stress. We observed that Hog1p was phosphorylated in thessk1mutant ofC. albicanswhen grown in a hyperosmotic medium but was not phosphorylated in thessk1mutant when the latter was grown in the presence of hydrogen peroxide. These data indicate thatC. albicansutilizes the Ssk1p response regulator protein to adapt cells to oxidative stress, while its role in the adaptation to osmotic stress is less certain. Further,SSK1appears to have a regulatory function in some aspects of cell wall biosynthesis. Thus, the functions ofC. albicans SSK1differ from those ofS. cerevisiae SSK1.

The mitochondrion plays wide-ranging roles in eukaryotic cell physiology. In pathogenic fungi, this central metabolic organelle mediates a range of functions related to disease, from fitness of the pathogen to developmental and morphogenetic transitions to antifungal drug susceptibility. In this review, we present the latest findings in this area. We focus on likely mechanisms of mitochondrial impact on fungal virulence pathways through metabolism and stress responses, but also potentially via control over signaling pathways. We highlight fungal mitochondrial proteins that lack human homologs, and which could be inhibited as a novel approach to antifungal drug strategy.

Using a Tn 7 transposon library of Candida albicans , we have identified a mutant that exhibited sensitivity in drop plate assays to oxidants such as menadione and hydrogen peroxide. To verify the role of the mutated gene in stress adaptation, null mutants were constructed and phenotypically characterized. Because of its apparent functions in growth and oxidant adaptation, we have named the gene GOA1 . Goa1p appears to be unique to the CTG subclade of the Saccharomycotina , including C. albicans . Mutants of C. albicans lacking goa1 (strain GOA31) were more sensitive to 6 mM H ₂ O ₂ and 0.125 mM menadione than the wild type (wt) or a gene-reconstituted (GOA32) strain. The sensitivity to oxidants correlated with reduced survival of the GOA31 mutant in human neutrophils and avirulence compared to control strains. Other phenotypes of GOA31 include reduced growth and filamentation in 10% serum, Spider, and SLAD agar media and an inability to form chlamydospores. Since Goa1p has an N-terminal mitochondrion localization site, we also show that green fluorescent protein-tagged Goa1p shows a mitochondrionlike distribution during oxidant or osmotic stress. Further, the inability of GOA31 to grow in medium containing lactate, ethanol, or glycerol as the sole carbon source indicates that the mitochondria are defective in the mutant. To determine how Goa1p contributes to mitochondrial function, we compared the wt, GOA32, and GOA31 strains for mitochondrial electrical membrane potential, respiration, and oxidative phosphorylation. We now show that GOA31, but not the wt or GOA32, had decreased respiration and mitochondrial membrane potential such that mutant cells are unable to drive oxidative phosphorylation. This is the first report in C. albicans of a respiratory defect caused by a loss of mitochondrial membrane potential.

New data suggest that the global incidence of several types of fungal diseases have traditionally been under-documented. Of these, mortality caused by invasive fungal infections remains ...

We have previously shown that deletion ofGOA1(growth andoxidantadaptation) ofCandida albicansresults in a loss of mitochondrial membrane potential, ATP synthesis, increased sensitivity to oxidants and killing by human neutrophils, and avirulence in a systemic model of candidiasis. We established that translocation of Goa1p to mitochondria occurred during peroxide stress. In this report, we show that thegoa1Δ (GOA31), compared to the wild type (WT) and a gene-reconstituted (GOA32) strain, exhibits sensitivity to inhibitors of the classical respiratory chain (CRC), including especially rotenone (complex I [CI]) and salicylhydroxamic acid (SHAM), an inhibitor of the alternative oxidase pathway (AOX), while potassium cyanide (KCN; CIV) causes a partial inhibition of respiration. In the presence of SHAM, however, GOA31 has an enhanced respiration, which we attribute to the parallel respiratory (PAR) pathway and alternative NADH dehydrogenases. Interestingly, deletion ofGOA1also results in a decrease in transcription of the alternative oxidase geneAOX1in untreated cells as well as negligibleAOX1andAOX2transcription in peroxide-treated cells. To explain the rotenone sensitivity, we measured enzyme activities of complexes I to IV (CI to CIV) and observed a major loss of CI activity in GOA31 but not in control strains. Enzymatic data of CI were supported by blue native polyacrylamide gel electrophoresis (BN-PAGE) experiments which demonstrated less CI protein and reduced enzyme activity. The consequence of a defective CI in GOA31 is an increase in reactive oxidant species (ROS), loss of chronological aging, and programmed cell death ([PCD] apoptosis)in vitrocompared to control strains. The increase in PCD was indicated by an increase in caspase activity and DNA fragmentation in GOA31. Thus,GOA1is required for a functional CI and partially for the AOX pathway; loss ofGOA1compromises cell survival. Further, the loss of chronological aging is new to studies ofCandidaspecies and may offer an insight into therapies to control these pathogens. Our observation of increased ROS production associated with a defective CI and PCD is reminiscent of mitochondrial studies of patients with some types of neurodegenerative diseases where CI and/or CIII dysfunctions lead to increased ROS and apoptosis.