Associations of vitamin D receptor polymorphisms with risk of Alzheimer's disease, Parkinson's disease, and mild cognitive impairment: a systematic review and meta-analysis.

Vitamin D is a lipid soluble steroid hormone, which plays a critical role in the calcium homeostasis, neuronal development, cellular differentiation, and growth by binding to vitamin D receptor (VDR). Associations between VDR gene polymorphism and Alzheimer's disease (AD), Parkinson's disease (PD), and mild cognitive impairment (MCI) risk has been investigated extensively, but the results remain ambiguous. The aim of this study was to comprehensively assess the correlations between four VDR polymorphisms (FokI, BsmI, TaqI, and ApaI) and susceptibility to AD, PD, and MCI. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to determine the relationship of interest. Pooled analyses suggested that the ApaI polymorphism decreased the overall AD risk, and the TaqI increased the overall PD susceptibility. In addition, the BsmI and ApaI polymorphisms were significantly correlated with the overall MCI risk. Stratified analysis by ethnicity further showed that the TaqI and ApaI genotypes reduced the AD predisposition among Caucasians, while the TaqI polymorphism enhanced the PD risk among Asians. Intriguingly, carriers with the BB genotype significantly decreased the MCI risk in Asian descents, and the ApaI variant elevated the predisposition to MCI in Caucasians and Asians. Further studies are need to identify the role of VDR polymorphisms in AD, PD, and MCI susceptibility.

Reduced Proteolipid Protein 2 promotes endoplasmic reticulum stress-related apoptosis and increases drug sensitivity in acute myeloid leukemia.

BACKGROUND: The Proteolipid Protein 2 (PLP2), a protein in the Endoplasmic Reticulum (ER) membrane, has been reported to be highly expressed in various tumors. Previous studies have demonstrated that the reduced PLP2 can induce apoptosis and autophagy through ER stress-related pathways, leading to a decreased proliferation and aggressiveness. However, there is no research literature on the role of PLP2 in Acute Myeloid Leukemia (AML). METHODS: PLP2 expression, clinical data, genetic mutations, and karyotype changes from GEO, TCGA, and timer2.0 databases were analyzed through the R packages. The possible functions and pathways of cells were explored through GO, KEGG, and GSEA enrichment analysis using the clusterProfiler R package. Immuno-infiltration analysis was conducted using the Cibersort algorithm and the Xcell R package. RT-PCR and western blot techniques were employed to identify the PLP2 expression, examine the knockdown effects in THP-1 cells, and assess the expression of genes associated with endoplasmic reticulum stress and apoptosis. Flow cytometry was utilized to determine the apoptosis and survival rates of different groups. RESULTS: PLP2 expression was observed in different subsets of AML and other cancers. Enrichment analyses revealed that PLP2 was involved in various tumor-related biological processes, primarily apoptosis and lysosomal functions. Additionally, PLP2 expression showed a strong association with immune cell infiltration, particularly monocytes. In vitro, the knockdown of PLP2 enhanced endoplasmic reticulum stress-related apoptosis and increased drug sensitivity in THP-1 cells. CONCLUSIONS: PLP2 could be a novel therapeutic target in AML, in addition, PLP2 is a potential endoplasmic reticulum stress regulatory gene in AML.

Combination of genetic engineering and random mutagenesis for improving production of raw-starch-degrading enzymes in Penicillium oxalicum.

BACKGROUND: Raw starch-degrading enzyme (RSDE) is applied in biorefining of starch to produce biofuels efficiently and economically. At present, RSDE is obtained via secretion by filamentous fungi such as Penicillium oxalicum. However, high production cost is a barrier to large-scale industrial application. Genetic engineering is a potentially efficient approach for improving production of RSDE. In this study, we combined genetic engineering and random mutagenesis of P. oxalicum to enhance RSDE production. RESULTS: A total of 3619 mutated P. oxalicum colonies were isolated after six rounds of ethyl methanesulfonate and Co60-γ-ray mutagenesis with the strain A2-13 as the parent strain. Mutant TE4-10 achieved the highest RSDE production of 218.6 ± 3.8 U/mL with raw cassava flour as substrate, a 23.2% compared with A2-13. Simultaneous deletion of transcription repressor gene PoxCxrC and overexpression of activator gene PoxAmyR in TE4-10 resulted in engineered strain GXUR001 with an RSDE yield of 252.6 U/mL, an increase of 15.6% relative to TE4-10. Comparative transcriptomics and real-time quantitative reverse transcription PCR revealed that transcriptional levels of major amylase genes, including raw starch-degrading glucoamylase gene PoxGA15A, were markedly increased in GXUR001. The hydrolysis efficiency of raw flour from cassava and corn by crude RSDE of GXUR001 reached 93.0% and 100%, respectively, after 120 h and 84 h with loading of 150 g/L of corresponding substrate. CONCLUSIONS: Combining genetic engineering and random mutagenesis efficiently enhanced production of RSDE by P. oxalicum. The RSDE-hyperproducing mutant GXUR001 was generated, and its crude RSDE could efficiently degrade raw starch. This strain has great potential for enzyme preparation and further genetic engineering.

EPS8 supports pancreatic cancer growth by inhibiting BMI1 mediated proteasomal degradation of ALDH7A1.

Aldehyde dehydrogenase 7 family member A1 (ALDH7A1) is an enzyme catalyzing lipid peroxidation of fatty aldehydes. It plays a critical role in sustaining high oxygen consumption rate (OCR) and ATP production in pancreatic ductal adenocarcinoma (PADC). However, why PADC cells maintain a relatively high level of ALDH7A1 concentration is still not well understood. In the current study, we explored the interplay between epidermal growth factor receptor kinase substrate 8 (EPS8) and ALDH7A1 in PADC cells. PADC cell lines MIA PaCa-2 and AsPANC-1 were used for in vitro and in vivo studies. The co-IP assay showed mutual interactions between Flag-EPS8 and Myc-ALDH7A1 in both MIA PaCa-2 and AsPANC-1 cells. EPS8 knockdown resulted in decreased ALDH7A1 protein levels and increased poly-ubiquitination. An interaction was observed between ALDH7A1 and BMI1 but not between BMI1 and EPS8. BMI1 knockdown reduced ALDH7A1 poly-ubiquitination and degradation caused by EPS8 knockdown. Dual EPS8 and ALDH7A1 knockdown had a synergistic effect on suppressing PADC cell proliferation in vitro and in vivo. In conclusion, this study revealed that EPS8 supports PADC growth by interacting with ALDH7A1 and inhibiting BMI1 mediated proteasomal degradation of ALDH7A1.

LncRNA LINC00680 promotes lung adenocarcinoma growth via binding to GATA6 and canceling GATA6-mediated suppression of SOX12 expression.

Lung adenocarcinoma (LUAD) is a major subtype of non-small-cell lung cancers (NSCLC). LINC00680 has been characterized as a novel oncogenic lncRNA in LUAD, but its regulatory mechanisms remain largely unclear. This study aimed to explore the subcellular localization of LINC00680 in LUAD and its regulation on the transcriptional process. LUAD cell lines (A549, H1650, and H1299) were used for in vitro and in vivo studies. Results showed LINC00680 depletion resulted in G0/G1 phase arrest of LUAD cells and reduced CDK4 and cyclin D1 expression in H1650 and H1299 cells. LINC00680 overexpression promoted A549 cell proliferation and increased CDK4 and cyclin D1 expression. RNA-fluorescence in situ hybridization (FISH) assay showed that LINC00680 has both cytoplasmic and nuclear distribution in LUAD cells. RNA pulldown and western blotting assays confirmed a physical interaction between LINC00680 and GATA6. In LUAD cells, GATA6 overexpression only slightly suppressed SOX12 transcription. ChIP-qPCR and dual-luciferase assay showed that GATA6 only weakly bound to the SOX12 promoter and decreased its activity. However, when LINC00680 was depleted, these transcriptional suppressive effects were significantly enhanced. These findings suggested that LINC00680 forms a complex with GATA6 and weakens its transcriptional suppressive effect on SOX12 expression. In the nude mice model, LINC00680 overexpression partly abrogated the growth-suppressive effects of GATA6 on A549 derived tumors. In summary, this study revealed a novel LINC00680-GATA6-SOX12 axis in promoting LUAD cell cycle progression and proliferation. Future studies should be conducted for a better understanding of the complex networking of LINC00680 in LUAD.

ARTP/EMS-combined multiple mutagenesis efficiently improved production of raw starch-degrading enzymes in Penicillium oxalicum and characterization of the enzyme-hyperproducing mutant.

BACKGROUND: Application of raw starch-degrading enzymes (RSDEs) in starch processing for biofuel production can effectively reduce energy consumption and processing costs. RSDEs are generally produced by filamentous fungi, such as Penicillium oxalicum, but with very low yields, which seriously hampers industrialization of raw starch processing. Breeding assisted by random mutagenesis is an efficient way to improve fungal enzyme production. RESULTS: A total of 3532 P. oxalicum colonies were generated after multiple rounds of mutagenesis, by atmospheric and room-temperature plasma (ARTP) and/or ethyl methanesulfonate (EMS). Of these, one mutant A2-13 had the highest RSDE activity of 162.7 U/mL, using raw cassava flour as substrate, a yield increase of 61.1%, compared with that of the starting strain, OXPoxGA15A. RSDE activity of A2-13 further increased to 191.0 U/mL, through optimization of culture conditions. Increased expression of major amylase genes, including the raw starch-degrading glucoamylase gene, PoxGA15A, and its regulatory gene, PoxAmyR, as well as several single-nucleotide polymorphisms in the A2-13 genome, were detected by real-time reverse transcription quantitative PCR and genomic re-sequencing, respectively. In addition, crude RSDEs produced by A2-13, combined with commercial α-amylase, could efficiently digest raw corn flour and cassava flour at 40 °C. CONCLUSIONS: Overall, ARTP/EMS-combined mutagenesis effectively improved fungal RSDE yield. An RSDE-hyperproducing mutant, A2-13, was obtained, and its RSDEs could efficiently hydrolyze raw starch, in combination with commercial α-amylase at low temperature, which provides a useful RSDE resource for future starch processing.