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Integrating personalized gene expression profiles into predictive disease-associated gene pools.

Sertaconazole (Dermofix, Ertaczo, Ginedermofix, Monazol, Mykosert or Zalain), an imidazole antifungal agent, inhibits the synthesis of ergosterol, an essential cell wall component of fungi. It is indicated in the EU for the treatment of superficial skin mycoses such as dermatophytosis (including tinea corporis, tinea cruris, tinea manus, tinea barbae and tinea pedis), cutaneous candidiasis, pityriasis versicolor and seborrhoeic dermatitis of the scalp, and in the US for tinea pedis only. Sertaconazole has broad-spectrum antifungal activity against dermatophytes of the Trichophyton, Epidermophy…

Cwh8 moonlights as a farnesyl pyrophosphate phosphatase and is essential for farnesol biosynthesis in Candida albicans.

In the opportunistic pathogen Candida albicans, hyphal growth and virulence factor expression are regulated by environmental and chemical cues. Farnesol is a secreted autoregulatory molecule that represses filamentation. It is derived from farnesyl pyrophosphate (FPP), an ergosterol biosynthesis pathway intermediate. Although Dpp1, Dpp2, and Dpp3 were proposed to synthesize farnesol, a mutant lacking all three had only a modest reduction in farnesol. To identify other farnesol biosynthesis genes, we employed transcription factor mutants that underproduced or overproduced farnesol in a screen a…

Core histones govern echinocandin susceptibility in Candida glabrata.

UNLABELLED: The dynamic chromatin structure regulates many biological processes including gene expression, DNA repair, and genome stability … Nakaseomyces) glabrata is increasingly being reported to exhibit co-resistance to echinocandins and ergosterol biosynthesis-inhibitory azole drugs in hospitals worldwide. However, the role of histones, protein-building blocks of the nucleosome, in governing echinocandin resistance in C. glabrata is not understood. Herein, we show that the reduced gene dosage …

Mitochondrial targeting of Candida albicans SPFH proteins and requirement of stomatins for SDS-induced stress tolerance.

UNLABELLED: The SPFH (stomatin, prohibitin, flotillin, and HflK/HflC) protein superfamily is conserved across all domains of life. Fungal SP … presence of 0.08% SDS, accumulated intracellular reactive oxidative species, and displayed aberrant ergosterol distribution in the plasma membrane. These phenotypes were not observed in slp2Δ/Δ or slp3Δ/Δ single mutants, indicating a possible indirect genetic interaction between SLP2 and SLP3. In addition, slp2Δ/Δ and slp2Δ/Δ/slp3Δ/Δ mutant strains were slig …

TMT-based quantitative proteomic analysis of the effects of novel antimicrobial peptide AMP-17 against Candida albicans.

Candida albicans is the most common human fungal pathogen in immunocompromised individuals. With the emergence of clinical fungal resistance … ith the cell wall, RNA and oxidative stress were significantly up-regulated, while DEPs involved in ergosterol metabolism and membrane were significantly down-regulated in the AMP-17/control. KEGG pathway enrichment revealed that DEPs involved seven significant metabolic pathways, mainly involved oxidative phosphorylation, RNA degradation, propanoate metabol …

On a Countable Sequence of Homoclinic Orbits Arising Near a Saddle-Center Point.

BACKGROUND: Treatment failures and relapses are not uncommon in onychomycosis. Therefore, it is worthwhile to consider the combination of sy … SIONS: The combination of amorolfine and oral itraconazole, which interfere with different steps of ergosterol synthesis, exhibited substantial synergy. Compared with oral itraconazole alone, the combination achieved greater mycological cure and increased total cure rate. However, no statistically significant difference was documented for this number of obse …

Vitamin D: part II; cod liver oil, ultraviolet radiation, and eradication of rickets.

PURPOSE: After Glisson's description of rickets, it took two centuries to realize that rickets was due to the absence of antirachitic nutrie … to 1935. A public health campaign of the 1930s was a success to eradicate rickets, using irradiated ergosterol from yeast to enrich milk and other foods with vitamin D, ensuring that the general population was consuming sufficient vitamin D. CONCLUSION: Rickets therefore provides an excellent window into the early politics of preventive health and the promo …

New Sulfur Organic Polymer-Concrete Composites Containing Waste Materials: Mechanical Characteristics and Resistance to Biocorrosion.

The aim of this study was to develop new sulfur-copolymer concrete composites using waste compounds that have good mechanical characteristic … to microbiological corrosion, based on the metabolic activity of the bacteria and the production of ergosterol by the molds after eight weeks of incubation. It was found that Thiobacillus thioparus was the first of the acidifying bacteria to colonize the sulfur concrete, decreasing the pH of the environment. The molds Penicillium chrysogenum, Aspergillus ver …

Vitamin D for skeletal and non-skeletal health: What we should know.

Vitamin D plays an essential role in regulating calcium and phosphate metabolism and maintaining a healthy mineralized skeleton. Humans obtain vitamin D from sunlight exposure, dietary foods and supplements. There are two forms of vitamin D: vitamin D3 and vitamin D2. Vitamin D3 is synthesized endogenously in the skin and found naturally in oily fish and cod liver oil. Vitamin D2 is synthesized from ergosterol and found in yeast and mushrooms. Once vitamin D enters the circulation it is converted by 25-hydroxylase in the liver to 25-hydroxyvitamin D [25(OH)D], which is further converted by the…

Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols.

Using LC/qTOF-MS we detected lumisterol, 20-hydroxylumisterol, 22-hydroxylumisterol, 24-hydroxylumisterol, 20,22-dihydroxylumisterol, pregnalumisterol, 17-hydroxypregnalumisterol and 17,20-dihydroxypregnalumisterol in human serum and epidermis, and the porcine adrenal gland. The hydroxylumisterols inhibited proliferation of human skin cells in a cell type-dependent fashion with predominant effects on epidermal keratinocytes. They also inhibited melanoma proliferation in both monolayer and soft agar. 20-Hydroxylumisterol stimulated the expression of several genes, including those associated wit

Withania somnifera inhibits NF-kappaB and AP-1 transcription factors in human peripheral blood and synovial fluid mononuclear cells.

Withania somnifera (WS) is an important herb with known antiinflammatory activity. Its molecular mechanism of action has not been investigated. The effect of a WS crude ethanol extract was studied on peripheral blood mononuclear cells of normal individuals and rheumatoid arthritis (RA) patients and synovial fluid mononuclear cells of RA patients in vitro. The WS extract significantly suppressed lipopolysaccharide (LPS) induced production of proinflammatory cytokines TNF-alpha, IL-1beta and IL-12p40 in normal individuals and RA patients, but had no effect on IL-6 production at the protein and t

The genome of the African trypanosome Trypanosoma brucei.

African trypanosomes cause human sleeping sickness and livestock trypanosomiasis in sub-Saharan Africa. We present the sequence and analysis of the 11 megabase-sized chromosomes of Trypanosoma brucei. The 26-megabase genome contains 9068 predicted genes, including approximately 900 pseudogenes and approximately 1700 T. brucei-specific genes. Large subtelomeric arrays contain an archive of 806 variant surface glycoprotein (VSG) genes used by the parasite to evade the mammalian immune system. Most VSG genes are pseudogenes, which may be used to generate expressed mosaic genes by ectopic recombin

The JAK inhibitor antcin H exhibits direct anticancer activity while enhancing chemotherapy against LMP1-expressed lymphoma.

Epstein-Barr virus (EBV) infection is associated with B cell lymphomas in humans. The latent membrane protein 1 (LMP-1) of EBV constitutively activates the JAK/STAT signaling pathway and contributes to the proliferation of EBV-infected primary human B lymphocytes. Thus, targeting LMP1-induced JAK/STAT signaling may prove effective in treating B-cell lymphomas. The extract of the fruiting body of Antrodia cinnamomea, has been reported to have cytotoxicity on blood cancer cells. Here, we report that the bioactivity of antcin H, an analog of the JAK2 inhibitor zhankuic acid A (ZAA), inhibits LMP1

Molecular characterization of the Aspergillus fumigatus NCS-1 homologue, NcsA.

Here, we characterize the Aspergillus fumigatus homologue ncsA Neuronal Calcium Sensor. We showed that ncsA is not an essential gene and ncsA growth was decreased in the presence of EGTA and SDS. Furthermore, the ncsA mutant is more resistant to calcium chloride. NcsA:mRFP localizes to the cytoplasm and its cellular localization is not affected by the cellular response to either calcium chloride or EGTA. The ncsA mutant strain is more sensitive to voriconazole, itraconazole, and amphotericin. Polar growth in the DeltancsA mutant was also considerably more affected by lovastatin than in the wil

Genomic insights into a clade-specific Candida tropicalis lineage with resistance to azoles and immune evasion traits.

Candida tropicalis is a leading cause of invasive candidiasis in the Asia-Pacific region with reported crude mortality rates exceeding 50%. … ot mutations (Y132F) in the ERG11 gene along with its duplication, overexpression, and twofold high ergosterol content. Comparative transcriptomics of two clinical isolates exhibiting >512 fold difference in fluconazole susceptibility identified upregulation of virulence-associated genes, ALS7 gene (eightfold), SAP7 and SAP9 (1.6- and 2-fold, respectively) i …

A Preclinical Evaluation of the Antitumor Activities of Edible and Medicinal Mushrooms: A Molecular Insight.

Cancer is the leading cause of morbidity and mortality around the globe. For certain types of cancer, chemotherapy drugs have been extensively used for treatment. However, severe side effects and the development of resistance are the drawbacks of these agents. Therefore, development of new agents with no or minimal side effects is of utmost importance. In this regard, natural compounds are well recognized as drugs in several human ailments, including cancer. One class of fungi, "mushrooms," contains numerous compounds that exhibit interesting biological activities, including antitumor activity

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… The tremendous therapeutic potential of edible and medicinal mushrooms is because of the lectin, arginine, ergosterol, β-glucan, and other bioactive substances in mushrooms. … According to the findings, ergosterol peroxide inhibited the nuclear β-catenin level, which resulted in the down-regulation of downstream genes. …

Antioxidant and immunostimulating activities of the fruiting bodies of Paecilomyces japonica, a new type of Cordyceps sp.

Cordyceps is negative for its many biological activities and a tonic for restoring vital functions in traditional Chinese medicine. In an effort to evaluate the pharmacological effects, including the antiaging effect of the fruiting bodies of the cultivated Paecilomyces japonica fungus, a new type of Cordyceps sp. was investigated. This investigation was focused on ultimately revealing its biologically active principles, its effects on free-radical scavenging enzymes, lipid peroxidation, as well as its immunological functions. As a result, both water and methanol extracts were found to cause n

A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of orally administered VT-1161 in the treatment of recurrent vulvovaginal candidiasis.

BACKGROUND: Lanosterol demethylase is an enzyme that is essential for fungal growth and catalyzes an early step in the biosynthetic pathway of ergosterol, which is a sterol that is required for fungal cell membrane formation and integrity. Lanosterol demethylase is the molecular target of the class of drugs referred to as "azole antifungals." VT-1161 is a novel, oral, selective inhibitor of fungal lanosterol demethylase and is being developed for the treatment of recurrent vulvovaginal candidiasis. OBJECTIVE: We evaluated the efficacy and safety of 4 dosing regimens of oral VT-1161 compared w…

Essential gene discovery in the basidiomycete Cryptococcus neoformans for antifungal drug target prioritization.

UNLABELLED: Fungal diseases represent a major burden to health care globally. As with other pathogenic microbes, there is a limited number o … be required for viability in C. neoformans. These genes are involved in mitochondrial translation, ergosterol biosynthesis, and RNA-related functions. The heterozygous diploid mutants were evaluated for haploinsufficiency on a number of perturbing agents and drugs, revealing phenotypes due to the loss of one copy of an essential gene in C. neoformans. This …

Proteome-level evidence that tebuconazole, both alone and in interaction with thiacloprid, affects epigenetic events in bumblebee heads.

Tebuconazole, a widely used ergosterol biosynthesis-inhibiting fungicide, can affect nontargets, especially when combined with insecticides. We employed label-free quantitative proteomics to investigate the effects of long-term exposure to sublethal concentrations (100 μg/L) of tebuconazole, either by itself or alongside the neonicotinoid thiacloprid (100 μg/L), on the heads of Bombus terrestris workers. A Bayesian factor power analysis revealed that the experiment produced conclusive proteomic results. Tebuconazole treatment revealed eleven differentially abundant proteins, which increased el…