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Colon adenocarcinoma (COAD) represents a major public health issue due to its high incidence and mortality. As different histological subtypes of COAD are related to various survival outcomes and different therapies, finding specific targets and treatments for different subtypes is one of the major demands of individual disease therapy. Interestingly, as these different subtypes show distinct metabolic profiles, it may be possible to find specific targets related to histological typing by targeting COAD metabolism. In this study, the differential expression patterns of metabolism-related genes between COAD ( n  = 289) and adjacent normal tissue ( n  = 41) were analyzed by one-way ANOVA. We then used weighted gene co-expression network analysis (WGCNA) to further identify metabolism-related gene connections. To determine the critical genes related to COAD metabolism, we obtained 2,114 significantly differentially expressed genes (DEGs) and 12 modules. Among them, we found the hub module to be significantly associated with histological typing, including non-mucin-producing colon adenocarcinoma and mucin-producing colon adenocarcinoma. Combining survival analysis, we identified glycerophosphodiester phosphodiesterase 1 (GDE1) as the most significant gene associated with histological typing and prognosis. This gene displayed significantly lower expression in COAD compared with normal tissues and was significantly correlated with the prognosis of non-mucin-producing colon adenocarcinoma ( p  = 0.0017). Taken together, our study showed that GDE1 exhibits considerable potential as a novel therapeutic target for non-mucin-producing colon adenocarcinoma.

CRISPR/Cas9-mediated genome editing technology enables researchers to efficiently generate and analyze genetically modified animals. We have taken advantage of this game-changing technology to uncover essential factors for fertility. In this study, we generated knockouts (KOs) of multiple male reproductive organ-specific genes and performed phenotypic screening of these null mutant mice to attempt to identify proteins essential for male fertility. We focused on making large deletions (dels) within 2 gene clusters encoding cystatin (CST) and prostate and testis expressed (PATE) proteins and individual gene mutations in 2 other gene families encoding glycerophosphodiester phosphodiesterase domain (GDPD) containing and lymphocyte antigen 6 (Ly6)/Plaur domain (LYPD) containing proteins. These gene families were chosen because many of the genes demonstrate male reproductive tract-specific expression. Although Gdpd1 and Gdpd4 mutant mice were fertile, disruptions of Cst and Pate gene clusters and Lypd4 resulted in male sterility or severe fertility defects secondary to impaired sperm migration through the oviduct. While absence of the epididymal protein families CST and PATE affect the localization of the sperm membrane protein A disintegrin and metallopeptidase domain 3 (ADAM3), the sperm acrosomal membrane protein LYPD4 regulates sperm fertilizing ability via an ADAM3-independent pathway. Thus, use of CRISPR/Cas9 technologies has allowed us to quickly rule in and rule out proteins required for male fertility and expand our list of male-specific proteins that function in sperm migration through the oviduct.

Reprogramming of host metabolism is a common strategy of viral evasion of host cells, and is essential for successful viral infection and induction of cancer in the context cancer viruses. Kaposi’s sarcoma (KS) is the most common AIDS-associated cancer caused by KS-associated herpesvirus (KSHV) infection. KSHV-encoded viral interferon regulatory factor 1 (vIRF1) regulates multiple signaling pathways and plays an important role in KSHV infection and oncogenesis. However, the role of vIRF1 in KSHV-induced metabolic reprogramming remains elusive. Here we show that vIRF1 increases glucose uptake, ATP production and lactate secretion by downregulating heterogeneous nuclear ribonuclear protein Q1 (hnRNP Q1). Mechanistically, vIRF1 upregulates and recruits E3 ubiquitin ligase Kelch-like 3 (KLHL3) to degrade hnRNP Q1 through a ubiquitin–proteasome pathway. Furthermore, hnRNP Q1 binds to and stabilizes the mRNA of glycerophosphodiester phosphodiesterase domain containing 1 (GDPD1). However, vIRF1 targets hnRNP Q1 for degradation, which destabilizes GDPD1 mRNA, resulting in induction of aerobic glycolysis. These results reveal a novel role of vIRF1 in KSHV metabolic reprogramming, and identifying a potential therapeutic target for KSHV infection and KSHV-induced cancers.

Blood biochemical indicators play a crucial role in assessing an individual’s overall health status and metabolic function. In this study, we measured five blood biochemical indicators, including total cholesterol (CHOL), low-density lipoprotein cholesterol (LDL-CH), triglycerides (TG), high-density lipoprotein cholesterol (HDL-CH), and blood glucose (BG), as well as 19 growth traits of 206 male chickens. By integrating host whole-genome information and 16S rRNA sequencing of the duodenum, jejunum, ileum, cecum, and feces microbiota, we assessed the contributions of host genetics and gut microbiota to blood biochemical indicators and their interrelationships. Our results demonstrated significant negative phenotypic and genetic correlations (r =  − 0.20 ~  − 0.67) between CHOL and LDL-CH with growth traits such as body weight, abdominal fat content, muscle content, and shin circumference. The results of heritability and microbiability indicated that blood biochemical indicators were jointly regulated by host genetics and gut microbiota. Notably, the heritability of HDL-CH was estimated to be 0.24, while the jejunal microbiability for BG and TG reached 0.45 and 0.23. Furthermore, by conducting genome-wide association study (GWAS) with the single-nucleotide polymorphism (SNPs), insertion/deletion (indels), and structural variation (SV), we identified RAP2C, member of the RAS oncogene family (RAP2C), dedicator of cytokinesis 11 (DOCK11), neurotensin (NTS) and BOP1 ribosomal biogenesis factor (BOP1) as regulators of HDL-CH, and glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5), dihydrodiol dehydrogenase (DHDH), and potassium voltage-gated channel interacting protein 1 (KCNIP1) as candidate genes of BG. Moreover, our findings suggest that cecal RF39 and Clostridia_UCG_014 may be linked to the regulation of CHOL, and jejunal Streptococcaceae may be involved in the regulation of TG. Additionally, microbial GWAS results indicated that the presence of gut microbiota was under host genetic regulation. Our findings provide valuable insights into the complex interaction between host genetics and microbiota in shaping the blood biochemical profile of chickens.Key points• Multiple candidate genes were identified for the regulation of CHOL, HDL-CH, and BG.• RF39, Clostridia_UCG_014, and Streptococcaceae were implicated in CHOL and TG modulation.• The composition of gut microbiota is influenced by host genetics.

The hydrolysis of deacylated glycerophospholipids into sn-glycerol 3-phosphate and alcohol is facilitated by evolutionarily conserved proteins known as glycerophosphodiester phosphodiesterases (GDPDs). These proteins are crucial for the pathogenicity of bacteria and for bioremediation processes aimed at degrading organophosphorus esters that pose a hazard to both humans and the environment. Additionally, GDPDs are enzymes that respond to multiple nutrients and could potentially serve as candidate genes for addressing deficiencies in zinc, iron, potassium, and especially phosphate in important plants like rice. In mammals, glycerophosphodiesterases (GDEs) play a role in regulating osmolytes, facilitating the biosynthesis of anandamine, contributing to the development of skeletal muscle, promoting the differentiation of neurons and osteoblasts, and influencing pathological states. Due to their capacity to enhance a plant's ability to tolerate various nutrient deficiencies and their potential as pharmaceutical targets in humans, GDPDs have received increased attention in recent times. This review provides an overview of the functions of GDPD families as vital and resilient enzymes that regulate various pathways in bacteria, plants, and humans.

Background Chemoresistance gradually develops during treatment of epithelial ovarian cancer (EOC). Metabolic alterations, especially in vivo easily detectable metabolites in paclitaxel (PTX)-resistant EOC remain unclear. Methods Xenograft models of the PTX-sensitive and PTX-resistant EOCs were built. Using a combination of in vivo proton-magnetic resonance spectroscopy ( 1 H-MRS), metabolomics and proteomics, we investigated the in vivo metabolites and dysregulated metabolic pathways in the PTX-resistant EOC. Furthermore, we analyzed the RNA expression to validate the key enzymes in the dysregulated metabolic pathway. Results On in vivo 1 H-MRS, the ratio of (glycerophosphocholine + phosphocholine) to (creatine + phosphocreatine) ((GPC + PC) to (Cr + PCr))(i.e. Cho/Cr) in the PTX-resistant tumors (1.64 [0.69, 4.18]) was significantly higher than that in the PTX-sensitive tumors (0.33 [0.10, 1.13]) ( P  = 0.04). Forty-five ex vivo metabolites were identified to be significantly different between the PTX-sensitive and PTX-resistant tumors, with the majority involved of lipids and lipid-like molecules. Spearman’s correlation coefficient analysis indicated in vivo and ex vivo metabolic characteristics were highly consistent, exhibiting the highest positive correlation between in vivo GPC + PC and ex vivo GPC (r = 0.885, P  < 0.001). These metabolic data suggested that abnormal choline concentrations were the results from the dysregulated glycerophospholipid metabolism, especially choline metabolism. The proteomics data indicated that the expressions of key enzymes glycerophosphocholine phosphodiesterase 1 (GPCPD1) and glycerophosphodiester phosphodiesterase 1 (GDE1) were significantly lower in the PTX-resistant tumors compared to the PTX-sensitive tumors (both P  < 0.01). Decreased expressions of GPCPD1 and GDE1 in choline metabolism led to an increased GPC levels in the PTX-resistant EOCs, which was observed as an elevated total choline (tCho) on in vivo 1 H-MRS. Conclusions These findings suggested that dysregulated choline metabolism was associated with PTX-resistance in EOCs and the elevated tCho on in vivo 1 H-MRS could be as an indicator for the PTX-resistance in EOCs.

Glycerophosphodiester phosphodiesterase (GDPD) catalyzes the hydrolysis of glycerophosphodiesters into sn-glycerol-3-phosphate (G-3-P) and corresponding alcohols, which is integral to various physiological processes in plants. However, our comprehension of the GDPD gene family in foxtail millet ( Setaria italica L.) remains limited and unclear. This study aimed to identify and predict the function of GDPD gene family members in foxtail millet through a comprehensive genome-wide analysis.14 SiGDPD genes were identified in the foxtail millet genome. Phylogenetic analysis categorized SiGDPD proteins into five groups. Promoter regions of SiGDPD genes contained multiple cis -acting elements related to light response, hormone regulation, and stress response. Phylogenetic and collinearity analyses demonstrated conservation of GDPD proteins among foxtail millet, sorghum, rice, and maize, with the SiGDPD gene family undergoing purifying selection during evolution.Tissue differential expression analysis revealed distinct expression patterns of SiGDPD genes across various tissues, showing spatiotemporal expression characteristics. Under low phosphorus stress, the expression levels of SiGDPD3 and SiGDPD14 significantly increased, while SiGDPD1 , SiGDPD5 , SiGDPD6 , and SiGDPD11 showed significant decreases.To identify the function of SiGDPD14 , an over-expressed transgenic Arabidopsis was generated. The results showed that transgenic Arabidopsis thaliana plants over-expressing SiGDPD14 exhibited enhanced tolerance to low phosphorus stress.Taken together, the results of this study provide valuable information for further studies on candidate SiGDPD genes involved in the phosphate deficiency response in foxtail millet.

To identify genetic and environmental factors contributing to the pathogenesis of non-alcoholic fatty liver disease, we examined liver steatosis and related clinical and molecular traits in more than 100 unique inbred mouse strains, which were fed a diet rich in fat and carbohydrates. A >30-fold variation in hepatic TG accumulation was observed among the strains. Genome-wide association studies revealed three loci associated with hepatic TG accumulation. Utilizing transcriptomic data from the liver and adipose tissue, we identified several high-confidence candidate genes for hepatic steatosis, including Gde1, a glycerophosphodiester phosphodiesterase not previously implicated in triglyceride metabolism. We confirmed the role of Gde1 by in vivo hepatic over-expression and shRNA knockdown studies. We hypothesize that Gde1 expression increases TG production by contributing to the production of glycerol-3-phosphate. Our multi-level data, including transcript levels, metabolite levels, and gut microbiota composition, provide a framework for understanding genetic and environmental interactions underlying hepatic steatosis. Non-alcoholic fatty liver disease is a major health problem worldwide and is caused by an abnormal build-up of fat molecules in liver cells that disrupts how the cells work. Although many people with the disease show only mild or no symptoms, if the disease progresses the consequences—such as organ damage and an increased risk of liver cancer—can be severe. Although non-alcoholic fatty liver disease has been linked with obesity and diabetes, how it develops is poorly understood. The most widely supported explanation suggests that the disease begins with an imbalance in the process that normally maintains the correct amount of fat molecules called triglycerides inside cells. As a result, triglycerides accumulate in the liver cells in a process known as steatosis, which is then thought to make the liver vulnerable to further problems. However, this theory has been questioned by genetic experiments that suggest triglyceride build-up actually protects cells from other kinds of damage. Hui et al. studied mice that had been fed a diet that was high in fat and sugar. The extent of liver steatosis varied considerably between the mice, with some mice accumulating 30 times more triglyceride in their liver than others. The underlying variation in the genes of the mice was then examined to investigate whether this can explain the differences in liver condition. This revealed at least three DNA stretches that appear to be linked to triglyceride accumulation in the liver, including several genes that appear to be active during steatosis. One of these genes, known as Gde1, had not previously been shown to have a role in controlling how cells make and use triglycerides. To confirm the role of Gde1, Hui et al. artificially turned the gene on in some mice and prevented it from turning on in others. Turning on Gde1 significantly increased the amount of triglyceride in the liver and keeping it turned off decreased triglyceride levels. Hui et al. suggest that this is because Gde1 helps to make a precursor molecule that is needed to build triglycerides. Certain gut bacteria also appear to be linked to steatosis. This study used a population-based approach in mice to examine genetic factors in the development of fatty liver disease. The challenge now is to find out how the genes work and to understand their interactions with each other and with the environment.

Psoriasis is immune-mediated skin disorder affecting thousands of people. Sphingolipids (SLs) are bioactive molecules present in the epidermis, involved in the following cellular processes: proliferation, differentiation, and apoptosis of keratinocytes. Alterations in SLs synthesis have been observed in psoriatic skin. To investigate if the imbalance in lipid skin metabolism could be related to psoriasis, we analyzed the gene expression in non-lesioned and lesioned skin of patients with psoriasis available in two datasets (GSE161683 and GSE136757) obtained from National Center for Biotechnology Information (NCBI). The differentially expressed genes (DEGs) were searched for using NCBI analysis, and Gene Ontology (GO) biological process analyses were performed using the Database of Annotation, Visualization, and Integrated Discovery (DAVID) platform. Venn diagrams were done with InteractiVenn tool and heatmaps were constructed using Morpheus software. We observed that the gene expression of cytoplasmic phospholipase A2 (PLA2G4D), glycerophosphodiester phosphodiesterase domain containing 3 (GDP3), arachidonate 12-lipoxygenase R type (ALOX12B), phospholipase B-like 1 (PLBD1), sphingomyelin phosphodiesterase 3 (SMPD3), ganglioside GM2 activator (GM2A), and serine palmitoyltransferase long chain subunit 2 (SPTLC2) was up-regulated in lesioned skin psoriasis when compared with the non-lesioned skin. These genes are related to lipid metabolism and more specifically to sphingolipids. So, in the present study, the role of sphingolipids in psoriasis pathogenesis is summarized. These genes could be used as prognostic biomarkers of psoriasis and could be targets for the treatment of patients who suffer from the disease.

In the last years, regional differences have been reported between the brain and spinal cord oligodendrocytes, which should be considered when designing therapeutic strategies for myelin repair. Promising targets to achieve myelin restoration are the different components of the endocannabinoid system (ECS) that modulate oligodendrocyte biology, but almost all studies have been focused on brain-derived cells. Therefore, we compared the ECS between the spinal cord and cerebral cortex-derived oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes (OLs). Cells from both regions express synthesizing and degrading enzymes for the endocannabinoid 2-arachidonoylglycerol, and degrading enzymes increase with maturation, more notably in the spinal cord (monoglyceride lipase-MGLL, alpha/beta hydrolase domain-containing 6-ABHD6, and alpha/beta hydrolase domain-containing 12-ABHD12). In addition, spinal cord OPCs express higher levels of the synthesizing enzymes diacylglycerol lipases alpha (DAGLA) and beta (DAGLB) than cortical ones, DAGLA reaching statistical significance. Cells from both the cortex and spinal cord express low levels of NAEs synthesizing enzymes, except for the glycerophosphodiester phosphodiesterase 1 (GDE-1) but high levels of the degrading enzyme fatty acid amidohydrolase (FAAH) that increases with maturation. Finally, cells from both regions show similar levels of CB 1 receptor and GPR55, but spinal cord-derived cells show significantly higher levels of transient receptor potential cation channel V1 (TRPV1) and CB 2 . Overall, our results show that the majority of the ECS components could be targeted in OPCs and OLs from both the spinal cord and brain, but regional heterogeneity has to be considered for DAGLA, MGLL, ABHD6, ABHD12, GDE1, CB 2 , or TRPV1.