Aspergillus oryzae accelerates the conversion of ergosterol to ergosterol peroxide by efficiently utilizing cholesterol.

It is well-known that excessive cholesterol leads to hypercholesterolemia, arteriosclerosis, coronary heart disease, stroke, and other diseases, which seriously threatens human health. Lactobacillus, a prokaryote, is reported to utilize cholesterol in the environment. However, little research focuses on the cholesterol utilization by eukaryote. Hence, the objectives of the present study were to investigate the mechanism of cholesterol utilization by the eukaryote and determine the role of oxysterol binding protein in this process. Our results showed for the first time that Aspergillus oryzae, a food-safe filamentous fungus, can utilize cholesterol efficiently. Our results also demonstrated that cholesterol utilization by A. oryzae might promote the conversion of ergosterol to ergosterol peroxide. Osh3, an oxysterol binding protein, can bind sterols (e.g., cholesterol, ergosterol, and ergosterol peroxide) and plays an important role in sterols transportation. This research is of considerable significance for developing low-fat food and cholesterol-lowering probiotics.

Identification of prognostic metabolic genes in adrenocortical carcinoma and establishment of a prognostic nomogram: A bioinformatic study.

ABSTRACT: Adrenocortical carcinoma is an invasive malignancy with poor prognosis, high recurrence rate and limited therapeutic options. Therefore, it is necessary to establish an effective method to diagnose and evaluate the prognosis of patients, so as to realize individualized treatment and improve their survival rate.This study investigated metabolic genes that may be potential therapeutic targets for Adrenocortical carcinoma (ACC). Level 3 gene expression data from the ACC cohort and the relevant clinical information were obtained from The Cancer Genome Atlas (TCGA) database. To verify, other ACC datasets (GSE76021, GSE19750) were downloaded from the Gene Expression Omnibus (GEO) database. The ACC datasets from TCGA and GEO were used to screen metabolic genes through the Molecular Signatures Database using gene set enrichment analysis. Then, the overlapping metabolic genes of the 2 datasets were identified.A signature of five metabolic genes (CYP11B1, GSTM2, IRF9, RPL31, and UBE2C) was identified in patients with ACC. The signature could be used to divide the patients with ACC into high- and low-risk groups based on their median risk score. Multivariate Cox regression analysis was performed to determine the independent prognostic factors of ACC. Time-dependent receiver operating characteristic (ROC) curve analysis was conducted to assess the prediction accuracy of the prognostic signature. Last, a nomogram was established to assess the individualized prognosis prediction model.The results indicated that the signature of 5 metabolic genes had excellent predictive value for ACC. These findings might help improve personalized treatment and medical decisions.

Unique three-site compound heterozygous mutation in the WFS1 gene in Wolfram syndrome.

BACKGROUND: Wolfram syndrome (WFS) is a rare autosomal recessive genetic disease whose main cause is mutations in the WFS1 and CISD2 genes. Its characteristic clinical manifestations are diabetes insipidus, diabetes mellitus, optic atrophy and deafness. METHODS: In this study, two patients from this particular family underwent complete routine biochemical and ophthalmic tests. Blood, urine, routine stool test, visual acuity (VA) examination, visual field assessment, funduscope, optical coherence tomography and periorbital magnetic resonance imaging (MRI) scans were performed for each patient to evaluate whether the nerve fiber layer around the optic nerve head was atrophied and next-generation sequencing of target genes was performed in two patients. RESULTS: When the patients were diagnosed with Wolfram syndrome, their genetic analyses suggested unique three-site compound heterozygous mutations (c.2314C > T + c.2194C > T + c.2171C > T) in exon 8 of both patients' chromosome 4. One mutation (c.2314C > T) was a novel mutation in the known reports of Wolfram syndrome. As a degenerative genetic disease, the types of gene mutations in the Chinese population are generally homozygous mutations at the unit point or compound heterozygous mutations at two nucleotide change sites. However, the two patients reported in this study are the first known cases of compound heterozygous mutations with three mutation sites coexisting on the WFS1 gene in China or even globally. CONCLUSIONS: This study expands the phenotypic spectrum of Wolfram syndrome and may reveal a novel mutation pattern of pathogenesis of Wolfram syndrome. The implications of this discovery are valuable in the clinical diagnosis, prognosis, and treatment of patients with WFS1.

Role and mechanism of TXNIP in ageing-related renal fibrosis.

Kidney ageing, which is always accompanied by renal fibrosis, drives the progression of renal fibrosis. Thioredoxin-interacting protein (TXNIP) is an endogenous suppressor of the reactive oxygen species-scavenging protein thioredoxin, which has been implicated in the ageing of some organs and is involved in renal fibrosis. However, the expression of TXNIP in ageing kidneys has not been examined, and the relationship between TXNIP and ageing-related renal fibrosis is unclear. We found that TXNIP expression was upregulated in aged mouse kidneys, and this upregulation was accompanied by ageing-related renal fibrosis phenotypes. We demonstrated that the ageing biomarkers were downregulated in TXNIP-knockout mice, and these effects resulted in the alleviation of renal fibrosis and impairments in kidney function. TXNIP overexpression in tubular cells upregulated senescence markers, promoted a profibrotic response and activated STAT3 signalling, and these parameters were inhibited by the silencing of TXNIP. Similarly, the TXNIP-mediated profibrotic response was significantly suppressed by a STAT3 inhibitor. By coimmunoprecipitation, we verified that TXNIP directly bound to STAT3, which suggested that TXNIP exacerbates renal tubular epithelial fibrosis by activating the STAT3 pathway. In summary, TXNIP plays an important role in age-related renal fibrosis and might be a therapeutic target for preventing ageing-associated renal fibrosis.

The relationship of mesencephalic astrocyte-derived neurotrophic factor with hyperlipidemia in patients with or without type 2 diabetes mellitus.

PURPOSE: This study was conducted to determine the relationship between mesencephalic astrocyte-derived neurotrophic factor (MANF) and lipid metabolism with or without type 2 diabetes mellitus (T2DM). METHODS: Human serum samples were collected from 58 normal controls (NC), 40 subjects with hyperlipidemia (HLD) without T2DM, and 42 subjects with HLD and T2DM. Their MANF levels were detected using an enzyme-linked immunosorbent assay (ELISA). Subgroup analysis was performed in the group with HLD and T2DM based on fasting blood glucose (FBG) > 8.22 vs. FBG ≤ 8.22. Furthermore, the relationship between MANF levels and lipid indices was analyzed. RESULTS: Serum MANF levels were found to be significantly higher in the HLD group, both with and without T2DM (5.62 (3.59-7.11) and 4.21 (2.87-6.11)), both P < 0.001, than in the NC (2.81(1.81-4.01). MANF levels were higher in those with FBG > 8.22 than that in those with FBG ≤ 8.22. In addition, in the HLD without T2DM group, MANF levels were negatively correlated with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and age, while LDL-C and age were independently related to MANF levels. The area under the curve (AUC) in the ROC analysis of MANF for the diagnosis of HLD without T2DM and HLD with T2DM was 0.709 and 0.841, respectively (P < 0.001). CONCLUSION: Serum MANF levels increased in the HLD with or without T2DM groups and was associated with lipid and glucose metabolism. MANF may be a useful marker for predicting the development of dyslipidemia in T2DM.

Effects on Gene Transcription Profile and Fatty Acid Composition by Genetic Modification of Mevalonate Diphosphate Decarboxylase MVD/Erg19 in Aspergillus Oryzae.

Mevalonate diphosphate decarboxylase MVD/Erg19 is required for ergosterol biosynthesis, growth, sporulation, and stress tolerance in Aspergillus oryzae. In this study, RNA-seq was used to analyze the gene transcription profile in AoErg19 overexpression (OE) and RNAi strains. There were 256 and 74 differentially expressed genes (DEGs) in AoErg19 OE and RNAi strains, respectively, compared with the control strain (CK). The most common DEGs were transport- and metabolism-related genes. Only 22 DEGs were obtained that were regulated in both OE and RNAi strains. The transcriptomic comparison between CK and AoErg19 overexpression strain (CK vs. OE), and between CK and AoErg19 RNAi strain (CK vs. RNAi) revealed that the greatest difference existed in the number of genes belonging to the cytochrome P450 family; 12 were found in CK vs. OE, whereas 1 was found in CK vs. RNAi. The expression patterns of lipid biosynthesis and metabolism related genes were altered in OE and RNAi strains, either by gene induction or suppression. Moreover, the total fatty acid content in the RNAi strain was 12.1% greater than the control strain, but no difference in total acid content was found between the overexpression strain and the control strain. Therefore, this study highlights the gene expression regulation within mevalonate (MVA), ergosterol biosynthesis, and fatty acid biosynthesis pathways.