Dataset Information

Exploring the effect of estrogen on Candida albicans hyphal cell wall glycans and ergosterol synthesis

ABSTRACT: Increased levels of 17-β estradiol (E2) due to pregnancy in young women or to hormonal replacement therapy in postmenopausal women have long been associated with an increased risk of yeast infections. Nevertheless, the effect underlying the role of E2 in Candida albicans infections is not well understood. To address this issue, functional, transcriptomic, and metabolomic analyses were performed on C. albicans cells subjected to temperature and serum induction in the presence or absence of E2. Increased filament formation was observed in E2 treated cells. Surprisingly, cells treated with a combination of E2 and serum showed decreased filament formation. Furthermore, the transcriptomic analysis revealed that serum and E2 treatment is associated with downregulated expression of genes involved in filamentation, including HWP1, ECE1, IHD1, MEP1, SOD5, and ALS3, in comparison with cells treated with serum or estrogen alone. Moreover, glucose transporter genes HGT20 and GCV2 were downregulated in cells receiving both serum and E2. Functional pathway enrichment analysis of the differentially expressed genes (DEGs) suggested major involvement of E2 signaling in several metabolic pathways and the biosynthesis of secondary metabolites. The metabolomic analysis determined differential secretion of 36 metabolites based on the different treatments' conditions, including structural carbohydrates and fatty acids important for hyphal cell wall formation such as arabinonic acid, organicsugar acids, oleic acid, octadecanoic acid, 2-keto-D-gluconic acid, palmitic acid, and steriacstearic acid with an intriguing negative correlation between D-turanose and ergosterol under E2 treatment. In conclusion, these findings suggest that E2 signaling impacts the expression of several genes and the secretion of several metabolites that help regulate C. albicans morphogenesis and virulence.

INSTRUMENT(S): Gas Chromatography MS - positive

PROVIDER: MTBLS5821 | MetaboLights | 2025-09-11

REPOSITORIES: MetaboLights

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			Action	DRS
	Metabolites.xlsx	Xlsx
	a_MTBLS5821_GC-MS_positive__metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS5821_GC-MS_positive__metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS5821.txt	Txt

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Exploring the effect of estrogen on Candida albicans hyphal cell wall glycans and ergosterol synthesis.

Bataineh Mohammad Tahseen Al MTA Cacciatore Stefano S Semreen Mohammad Harb MH Dash Nihar Ranjan NR Soares Nelson C NC Zhu Xiaolong X Mousa Muath Khairi MK Salam Jasmin Shafarin Abdul JSA Zerbini Luiz F LF Hajjo Rima R Hamad Mawieh M

Frontiers in cellular and infection microbiology 20220921

Increased levels of 17-β estradiol (E2) due to pregnancy in young women or to hormonal replacement therapy in postmenopausal women have long been associated with an increased risk of yeast infections. Nevertheless, the effect underlying the role of E2 in Candida albicans infections is not well understood. To address this issue, functional, transcriptomic, and metabolomic analyses were performed on C. albicans cells subjected to temperature and serum induction in the presence or abs ...[more]

PMID: 36268228

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Project description:Use of long-acting progestin-only contraceptives (LAPCs) offers a discrete and highly effective family planning method. Abnormal uterine bleeding (AUB) is the major side effect of, and cause for, discontinuation of LAPCs. The endometria of LAPC-treated women display abnormally enlarged, fragile blood vessels, decreased endometrial blood flow and oxidative stress. To understand the mechanisms underlying AUB, we propose to identify LAPC-modulated unique gene cluster(s) in human endometrial stromal cells (HESCs). Protein and RNA isolated from cultured HESCs treated 7 days with estradiol (E2) or E2+medroxyprogesterone acetate (MPA) or E2+ etonogestrel (ETO) or E2+progesterone (P4) were analyzed by q-PCR and immunoblotting. HSCORES were determined for immunostained-paired endometria of pre-and 3 months post-Depo-Provera (Depo) treated women (n=6) and ovariectomized guinea pigs (GPs; n=12) treated with placebo or E2 or MPA or E2+MPA for 21 days. In HESCs, whole genome analysis identified a 67-gene group regulated by all three progestins, whereas a 235-gene group was regulated by E2+ETO and E2+MPA, but not E2+P4. Ingenuity pathway analysis identified glucocorticoid receptor (GR) activation as an upstream regulator of the 235 LAPCMPA and ETO-specific genes. Among these, microarray results demonstrated significant enhancement of FKBP51, a repressor of PR/GR transcriptional activity, by both LAPCsMPA and ETO. q-PCR and immunoblot analysis confirmed the microarray results. In endometria of post-Depo versus pre-Depo administered women, FKBP51 expression was significantly increased in endometrial stromal and glandular cells. In GPs, E2+MPA or MPA significantly increased FKBP51 immunoreactivity in endometrial stromal and glandular cells versus placebo- and E2-administered groups. LAPC MPA or ETO administration activates GR signaling and increases endometrial FKBP51 expression, which could be one of the mechanisms causing AUB by inhibiting feeds back to inhibit PR- and GR-mediated transcription. The resultant PR- and/or GR-mediated functional withdrawal may contribute to associated endometrial inflammation, aberrant angiogenesis, and bleeding.

Project description:The role of Group IVA cytosolic phospholipase A2 (cPLA2M-NM-1) activation in regulating macrophage transcriptional responses to Candida albicans infection was investigated. cPLA2M-NM-1 releases arachidonic acid for the production of eicosanoids. In mouse resident peritoneal macrophages, prostacyclin, prostaglandin E2 and leukotriene C4 were produced within minutes of C. albicans addition before cyclooxygenase 2 expression. The production of TNFa was lower in C. albicans-stimulated cPLA2a+/+ than cPLA2a-/- macrophages due to an autocrine effect of prostaglandins that increased cAMP to a greater extent in cPLA2a+/+ than cPLA2a-/- macrophages. For global insight, differential gene expression in C. albicans-stimulated cPLA2a+/+ and cPLA2a-/- macrophages (3 h) was compared by microarray. cPLA2M-NM-1+/+ macrophages expressed 86 genes at lower levels and 181 genes at higher levels than cPLA2M-NM-1-/- macrophages (M-bM-^IM-%2-fold, p<0.05 ). Several pro-inflammatory genes were expressed at lower levels (Tnfa, Cx3cl1, Cd40, Ifng, several IFNg-inducible GTPases, Ccl5, Csf1, Edn1, CxCr7, Irf1, Irf4, Akna). Genes that dampen inflammation (Socs3, Il10, Crem, Stat3, Thbd, Thbs1, Abca1) and genes involved in host defense (Gja1, Csf3, Trem1, Hdc) were expressed at higher levels in cPLA2a+/+ macrophages. Representative genes expressed lower in cPLA2a+/+ macrophages (Tnfa and Csf1) were increased by treatment with a prostacyclin receptor antagonist and protein kinase A inhibitor, whereas genes expressed at higher levels (Crem, Nr4a2, Il10, Csf3) were suppressed. The results suggest that C. albicans stimulates an autocrine loop in macrophages involving cPLA2a, cyclooxygenase 1-derived prostaglandins and increased cAMP that globally effects expression of genes involved in host defense and inflammation. Resident peritoneal macrophages from Group IVA cytosolic phospholipase A2 (cPLA2a) +/+ and -/- mice were stimulated with Candida albicans (m.o.i. 2) for 3 hours and RNA isolated to evaluate the role of cPLA2a-derived lipid mediators on gene expression. Three independent experiments were analyzed.

Project description:6-Nonadecynoic acid (6-NDA), a plant-derived acetylenic acid, exhibits strong inhibitory activity against the human fungal pathogens Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model organism Saccharomyces cerevisiae to investigate the mechanism of action of this compound. 6-NDA elicited a transcriptome response indicative of fatty acid stress, altering the expression of genes known to be affected when yeast cells are grown in the presence of oleate. Mutants of S. cerevisiae lacking transcription factors that regulate fatty acid ?-oxidation showed increased sensitivity to 6-NDA. Fatty acid profile analysis indicated that 6-NDA inhibited the formation of fatty acids longer than 14 carbons in length. In addition, the growth inhibitory effect of 6-NDA was rescued in the presence of exogenously supplied oleate. To investigate the response of a pathogenic fungal species to 6-NDA, transcriptional profiling and biochemical analyses were also conducted in C. albicans. The transcriptional response and fatty acid profile of C. albicans were comparable to those obtained in S. cerevisiae, and the rescue of growth inhibition with exogenous oleate was also observed in C. albicans. In addition, 6-NDA enhanced the potency of the antifungal drug fluconazole in a fluconazole-resistant clinical isolate of C. albicans. Collectively, our results indicate that the antifungal activity of 6-NDA is mediated by a disruption in fatty acid homeostasis, and that this compound has potential utility in combination therapy in the treatment of drug-resistant fungal infections. Cultures of S. cerevisiae strain S288C were started at OD600 of 0.1, allowed to grow to OD600 of 0.2, then treated with either DMSO (0.25%) or 6-NDA at the IC50 concentration (2.2 ug/ml). When OD600 of 0.5 was reached, cells were harvested and frozen. Two biological replicate cultures were grown for each treatment, and RNA from each replicate was hybridized to 2 independent arrays, resulting in 4 hybridizations for each treatment. Cultures of C. albicans strain SC5314 were started at OD600 of 0.1, allowed to grow to OD600 of 0.2, then treated with either DMSO (0.25%) or 6-NDA at the IC50 concentration (4 ug/ml). When OD600 of 0.5 was reached, cells were harvested and frozen. Three biological replicate cultures were grown for each treatment, and RNA from each replicate was hybridized as dye-swap pairs, resulting in 6 hybridizations for each treatment.

Dataset Information

Exploring the effect of estrogen on Candida albicans hyphal cell wall glycans and ergosterol synthesis

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Publications

Exploring the effect of estrogen on <i>Candida albicans</i> hyphal cell wall glycans and ergosterol synthesis.

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