Hostile Takeover: How Viruses Reprogram Prokaryotic Metabolism.

To reproduce, prokaryotic viruses must hijack the cellular machinery of their hosts and redirect it toward the production of viral particles. While takeover of the host replication and protein synthesis apparatus has long been considered an essential feature of infection, recent studies indicate that extensive reprogramming of host primary metabolism is a widespread phenomenon among prokaryotic viruses that is required to fulfill the biosynthetic needs of virion production. In this review we provide an overview of the most significant recent findings regarding virus-induced reprogramming of prokaryotic metabolism and suggest how quantitative systems biology approaches may be used to provide a holistic understanding of metabolic remodeling during lytic viral infection.

Novel phages of Pseudomonas syringae unveil numerous potential auxiliary metabolic genes.

Relatively few phages that infect plant pathogens have been isolated and investigated. The Pseudomonas syringae species complex is present in various environments, including plants. It can cause major crop diseases, such as bacterial canker on apricot trees. This study presents a collection of 25 unique phage genomes that infect P. syringae. These phages were isolated from apricot orchards with bacterial canker symptoms after enrichment with 21 strains of P. syringae. This collection comprises mostly virulent phages, with only three being temperate. They belong to 14 genera, 11 of which are newly discovered, and 18 new species, revealing great genetic diversity within this collection. Novel DNA packaging systems have been identified bioinformatically in one of the new phage species, but experimental confirmation is required to define the precise mechanism. Additionally, many phage genomes contain numerous potential auxiliary metabolic genes with diversified putative functions. At least three phages encode genes involved in bacterial tellurite resistance, a toxic metalloid. This suggests that viruses could play a role in bacterial stress tolerance. This research emphasizes the significance of continuing the search for new phages in the agricultural ecosystem to unravel novel ecological diversity and new gene functions. This work contributes to the foundation for future fundamental and applied research on phages infecting phytopathogenic bacteria.

Molecular subtypes based on metabolic genes are potential biomarkers for predicting prognosis and immune responses of clear cell renal cell carcinoma.

Due to the existence of tumor molecular heterogeneity, even patients having similar clinicopathological features could have vastly different survival rates. Hence, we aimed to explore novel metabolism-associated genes (MAGs) related molecular subtypes for clear cell renal cell carcinoma (ccRCC) and their immune landscapes for predicting prognosis and immune responses. Gene matrices and clinical information were downloaded from TCGA and ICGC datasets. Consensus clustering was conducted by the R "ConsensusClusterPlus" package. ccRCC patients were successfully divided into three clusters (MC1, MC2, and MC3) based on MAGs in both TCGA and ICGC datasets. Our established three MAGs were significantly associated with chemokine/chemokine receptor, IFN, CYT, angiogenesis, immune checkpoint molecules, tumor-infiltrating immune cells, oncogenic pathways, pan-cancer immune subtypes, and tumor microenvironment (TME) scores or expressions. Moreover, these three metabolic ccRCC subtypes could predict immunotherapeutic responses. We further constructed a characteristic index (LDAscore) in three metabolic ccRCC subtypes and identified LDAscore-related modules by WGCNA. After deep data mining, 10 hub genes were obtained and seven genes (ATRX, BPTF, DHX9, EP300, POLR2B, SIN3A, UBE3A) were finally validated by qRT-PCR. Our results successfully established a novel ccRCC subtype based on MAGs, providing novel insights into metabolism-related ccRCC tumor heterogeneity and facilitating individualized therapy for future work.

Viral communities in a pH>10 serpentinite-like environment: insight into diversity and potential roles in modulating the microbiomes by bioactive vitamin B9 synthesis.

Viral communities exist in a variety of ecosystems and play significant roles in mediating biogeochemical processes, whereas viruses inhabiting strongly alkaline geochemical systems remain underexplored. In this study, the viral diversity, potential functionalities, and virus-host interactions in a strongly alkaline environment (pH = 10.4-12.4) exposed to the leachates derived from the serpentinization-like reactions of smelting slags were investigated. The viral populations (e.g., Herelleviridae, Queuovirinae, and Inoviridae) were closely associated with the dominating prokaryotic hosts (e.g., Meiothermus, Trueperaceae, and Serpentinomonas) in this ultrabasic environment. Auxiliary metabolic genes (AMGs) suggested that viruses may enhance hosts' fitness by facilitating cofactor biosynthesis, hydrogen metabolism, and carbon cycling. To evaluate the activity of synthesis of essential cofactor vitamin B9 by the viruses, a viral folA (vfolA) gene encoding dihydrofolate reductase (DHFR) was introduced into a thymidine-auxotrophic strain Escherichia coli MG1655 ΔfolA mutant, which restored the growth of the latter in the absence of thymidine. Notably, the homologs of the validated vDHFR were globally distributed in the viromes across various ecosystems. The present study sheds new light on the unique viral communities in hyperalkaline ecosystems and their potential beneficial impacts on the coexisting microbial consortia by supplying essential cofactors. IMPORTANCE: This study presents a comprehensive investigation into the diversity, potential functionalities, and virus-microbe interactions in an artificially induced strongly alkaline environment. Functional validation of the detected viral folA genes encoding dihydrofolate reductase substantiated the synthesis of essential cofactors by viruses, which may be ubiquitous, considering the broad distribution of the viral genes associated with folate cycling.

Improved biohydrogen production by co-fermentation of corn straw and excess sludge: Insights into biochemical process, microbial community and metabolic genes.

The global climate change mainly caused by fossil fuels combustion promotes that zero-carbon hydrogen production through eco-friendly methods has attracted attention in recent years. This investigation explored the biohydrogen production by co-fermentation of corn straw (CS) and excess sludge (ES), as well as comprehensively analyzed the internal mechanism. The results showed that the optimal ratio of CS to ES was 9:1 (TS) with the biohydrogen yield of 101.8 mL/g VS, which was higher than that from the mono-fermentation of CS by 1.0-fold. The pattern of volatile fatty acids (VFAs) indicated that the acetate was the most preponderant by-product in all fermentation systems during the biohydrogen production process, and its yield was improved by adding appropriate dosage of ES. In addition, the content of soluble COD (SCOD) was reduced as increasing ES, while concentration of NH4+-N showed an opposite tendency. Microbial community analysis revealed that the microbial composition in different samples showed a significant divergence. Trichococcus was the most dominant bacterial genus in the optimal ratio of 9:1 (CS/ES) fermentation system and its abundance was as high as 41.8%. The functional genes prediction found that the dominant metabolic genes and hydrogen-producing related genes had not been significantly increased in co-fermentation system (CS/ES = 9:1) compared to that in the mono-fermentation of CS, implying that enhancement of biohydrogen production by adding ES mainly relied on balancing nutrients and adjusting microbial community in this study. Further redundancy analysis (RDA) confirmed that biohydrogen yield was closely correlated with the enrichment of Trichococcus.

Habitat- and lifestyle-dependent structural and functional characteristics of viruses in mangrove wetlands of different functional zonings.

Mangrove wetlands, as one of the natural ecosystems with the most ecological services, have garnered widespread attention about their microbial driven biogeochemical cycling. Urbanization have led to different spatial patterns of environmental conditions and microbial communities in mangroves. However, viruses, as the pivotal drivers of biogeochemical cycling in mangroves, remain inadequately explored in terms of how their ecological potential and complex interactions with host respond to functional zonings. To address this knowledge gap, we conducted a comprehensive investigation on the structural and functional properties of temperate and lytic viruses in mangrove wetlands from different functional zonings by jointly using high-throughput sequencing, prokaryotic and viral metagenomics. Multiple environmental factors were found to significantly influence the taxonomic and functional composition, as well as lysogen-lysis decision-making of mangrove viruses. Furthermore, enriched auxiliary metabolic genes (AMGs) involved in methane, nitrogen and sulfur metabolism, and heavy metal resistance were unveiled in mangrove viruses, whose community composition was closely related to lifestyle and host. The virus-host pairs with different lifestyles were also discovered to react to environmental changes in different ways, which provided an empirical evidence for how virus and bacteria dynamics were specific to viral lifestyles in nature. This study expands our comprehension of the intricate interactions among virus, prokaryotic host and the environment in mangrove wetlands from multiple perspectives, including viral lifestyles, virus-host interactions, and habitat dependence. Importantly, it provides a new ecological perspective on how mangrove viruses are adapted to the stress posed by urbanization.

Awaking the dormant virome in the rhizosphere.

The rhizosphere is a vital soil compartment providing key plant-beneficial functions. However, little is known about the mechanisms driving viral diversity in the rhizosphere. Viruses can establish lytic or lysogenic interactions with their bacterial hosts. In the latter, they assume a dormant state integrated in the host genome and can be awakened by different perturbations that impact host cell physiology, triggering a viral bloom, which is potentially a fundamental mechanism driving soil viral diversity, as 22%-68% of soil bacteria are predicted to harbour dormant viruses. Here we assessed the viral bloom response in rhizospheric viromes by exposing them to three contrasting soil perturbation agents: earthworms, herbicide and antibiotic pollutant. The viromes were next screened for rhizosphere-relevant genes and also used as inoculant on microcosms incubations to test their impacts on pristine microbiomes. Our results show that while post-perturbation viromes diverged from control conditions, viral communities exposed to both herbicide and antibiotic pollutant were more similar to each other than those influenced by earthworms. The latter also favoured an increase in viral populations harbouring genes involved in plant-beneficial functions. Post-perturbation viromes inoculated on soil microcosms changed the diversity of pristine microbiomes, suggesting that viromes are important components of the soil ecological memory driving eco-evolutionary processes that determine future microbiome trajectories according to past events. Our findings demonstrate that viromes are active players in the rhizosphere and need to be considered in efforts to understand and control the microbial processes towards sustainable crop production.

Function and distribution of nitrogen-cycling microbial communities in the Napahai plateau wetland.

Nitrogen is an essential component of living organisms and a major nutrient that limits life on Earth. Until now, freely available nitrogen mainly comes from atmospheric nitrogen, but most organisms rely on bioavailable forms of nitrogen, which depends on the complex network of microorganisms with a wide variety of metabolic functions. Microbial-mediated nitrogen cycling contributes to the biogeochemical cycling of wetlands, but its specific microbial abundance, composition, and distribution need to be studied. Based on the metagenomic data, we described the composition and functional characteristics of microbial nitrogen cycle-related genes in the Napahai plateau wetland. Six nitrogen cycling pathways existed, such as dissimilatory nitrate reduction, denitrification, nitrogen fixation, nitrification, anammox, and nitrate assimilation. Most genes related to the nitrogen cycling in this region come from bacteria, mainly from Proteobacteria and Acidobacteria. Habitat types and nitrogen cycle-related genes largely explained the relative abundance of total nitrogen pathways. Phylogenetic trees were constructed based on nitrogen cycle-related genes from different habitats and sources, combined with PCoA analysis, most of them clustered separately, indicating richness and uniqueness. Some microbial groups seemed to be special or general in the nitrogen cycling. In conclusion, it suggested that microorganisms regulated the N cycling process, and may lead to N loss throughout the wetland, thus providing a basis for further elucidation of the microbial regulation of N cycling processes and the Earth's elemental cycles.

Potential Auxiliary Metabolic Capabilities and Activities Reveal Biochemical Impacts of Viruses in Municipal Wastewater Treatment Plants.

Viruses influence biogeochemical cycles in oceans, freshwater, soil, and human gut through infection and by modulating virocell metabolism through virus-encoded auxiliary metabolic genes (vAMGs). However, the geographical distribution, potential metabolic function, and engineering significance of vAMGs in wastewater treatment plants (WWTPs) remain to be explored. Here, 752 single-contig viral genomes with high confidence, 510 of which belonged to Caudovirales, were recovered from the activated sludge metagenomes of 32 geographically distributed WWTPs. A total of 101 vAMGs involved in various metabolic pathways were identified, the most common of which were the queuosine biosynthesis genes folE, queD, and queE and the sulfur metabolism gene cysH. Phylogenetic analysis and virus-host relationship prediction revealed the probable evolutionary histories of vAMGs involved in carbon (acpP and prsA), nitrogen (amoC), sulfur (cysH), and phosphate (phoH) metabolism, which potentially mediate microbial carbon and nutrient cycling. Notably, 11 of the 38 (28.3%) vAMGs identified in the metagenomes with corresponding metatranscriptomes were transcriptionally expressed, implying an active functional state. This meta-analysis provides the first broad catalog of vAMGs in municipal WWTPs and how they may assist in the basic physiological reactions of their microbial hosts or nutrient cycling in the WWTPs, and therefore, may have important effects on the engineering of wastewater treatment processes.

Enhanced Bacterium-Phage Symbiosis in Attached Microbial Aggregates on a Membrane Surface Facing Elevated Hydraulic Stress.

Phages are increasingly recognized for their importance in microbial aggregates, including their influence on microbial ecosystem services and biotechnology applications. However, the adaptive strategies and ecological functions of phages in different aggregates remain largely unexplored. Herein, we used membrane bioreactors to investigate bacterium-phage interactions and related microbial functions within suspended and attached microbial aggregates (SMA vs AMA). SMA and AMA represent distinct microbial habitats where bacterial communities display distinct patterns in terms of dominant species, keystone species, and bacterial networks. However, bacteria and phages in both aggregates exhibited high lysogenicity, with 60% lysogenic phages in the virome and 70% lysogenic metagenome-assembled genomes of bacteria. Moreover, substantial phages exhibited broad host ranges (34% in SMA and 42% in AMA) and closely interacted with habitat generalist species (43% in SMA and 49% in AMA) as adaptive strategies in stressful operation environments. Following a mutualistic pattern, phage-carried auxiliary metabolic genes (pAMGs; 238 types in total) presumably contributed to the bacterial survival and aggregate stability. The SMA-pAMGs were mainly associated with energy metabolism, while the AMA-pAMGs were mainly associated with antioxidant biosynthesis and the synthesis of extracellular polymeric substances, representing habitat-dependent patterns. Overall, this study advanced our understanding of phage adaptive strategies in microbial aggregate habitats and emphasized the importance of bacterium-phage symbiosis in the stability of microbial aggregates.

Revealing viral diversity in the Napahai plateau wetland based on metagenomics.

We focused on exploring the diversity of viruses in the Napahai plateau wetland, a unique ecosystem located in Yunnan, China. While viruses in marine environments have been extensively studied for their influence on microbial metabolism and biogeochemical cycles, little is known about their composition and function in plateau wetlands. Metagenomic analysis was employed to investigate the viral diversity and biogeochemical impacts in the Napahai wetland. It revealed that the Caudoviricetes and Malgrandaviricetes class level was the most abundant viral category based on phylogenetic analysis. Additionally, a gene-sharing network highlighted the presence of numerous unexplored viruses and demonstrated their unique characteristics and significant variation within the viral community of the Napahai wetland. Furthermore, the study identified the auxiliary metabolic genes (AMGs). AMGs provide phages with additional functions, such as protection against host degradation and involvement in metabolic pathways, such as the pentose phosphate pathway and DNA biosynthesis. The viruses in the Napahai wetland were found to influence carbon, nitrogen, sulfur, and amino acid metabolism, indirectly contributing to biogeochemical cycling through these AMGs. Overall, the research sheds light on the diverse and unique viral communities in the Napahai plateau wetland and emphasizes the significant roles of viruses in microbial ecology. The findings contribute to a deeper understanding of the characteristics and ecological functions of viral communities in plateau wetland ecosystems.

Prognostic value of metabolic genes in lung adenocarcinoma via integrative analyses.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common malignant lung tumor. Metabolic pathway reprogramming is an important hallmark of physiologic changes in cancers. However, the mechanisms through which these metabolic genes and pathways function in LUAD as well as their prognostic values have not been fully established. METHODS: Four publicly available datasets from GEO and TCGA were used to identify differentially expressed genes (DEGs) in LUAD, which were then subjected to GO and KEGG pathway enrichment analysis. Associations between metabolic gene expressions with overall survival, tumor stage, TP53 mutation status, and infiltrated immune cells were investigated. Protein-protein interactions were evaluated using GeneMANIA and Metascape. RESULTS: By integrating four public datasets, 247 DEGs were identified in LUAD. These DEGs were significantly enriched in regulation of chromosome segregation, centromeric region, and histone kinase activity GO terms, as well as in cell cycle, p53 signaling pathway, metabolic pathways, and other KEGG pathways. Elevated expressions of ten metabolic genes in LUAD were significantly associated with poor survival outcomes. These metabolic genes were highly expressed in more advanced tumor stage and TP53 mutated patients. Moreover, expression levels were significantly correlated with tumor-infiltrating immune cells. PPI interaction analysis revealed that the top 20 genes interacting with each metabolic gene were significantly enriched in DNA replication, response to radiation, and central carbon metabolism in cancer. CONCLUSION: This study elucidates on molecular changes in metabolic genes in LUAD, which may inform the development of genetically oriented diagnostic approaches and effective treatment options.

Climate-Endangered Arctic Epishelf Lake Harbors Viral Assemblages with Distinct Genetic Repertoires.

Milne Fiord, located on the coastal margin of the Last Ice Area (LIA) in the High Arctic (82°N, Canada), harbors an epishelf lake, a rare type of ice-dependent ecosystem in which a layer of freshwater overlies marine water connected to the open ocean. This microbe-dominated ecosystem faces catastrophic change due to the deterioration of its ice environment related to warming temperatures. We produced the first assessment of viral abundance, diversity, and distribution in this vulnerable ecosystem and explored the niches available for viral taxa and the functional genes underlying their distribution. We found that the viral community in the freshwater layer was distinct from, and more diverse than, the community in the underlying seawater and contained a different set of putative auxiliary metabolic genes, including the sulfur starvation-linked gene tauD and the gene coding for patatin-like phospholipase. The halocline community resembled the freshwater more than the marine community, but harbored viral taxa unique to this layer. We observed distinct viral assemblages immediately below the halocline, at a depth that was associated with a peak of prasinophyte algae and the viral family Phycodnaviridae. We also assembled 15 complete circular genomes, including a putative Pelagibacter phage with a marine distribution. It appears that despite its isolated and precarious situation, the varied niches in this epishelf lake support a diverse viral community, highlighting the importance of characterizing underexplored microbiota in the Last Ice Area before these ecosystems undergo irreversible change. IMPORTANCE Viruses are key to understanding polar aquatic ecosystems, which are dominated by microorganisms. However, studies of viral communities are challenging to interpret because the vast majority of viruses are known only from sequence fragments, and their taxonomy, hosts, and genetic repertoires are unknown. Our study establishes a basis for comparison that will advance understanding of viral ecology in diverse global environments, particularly in the High Arctic. Rising temperatures in this region mean that researchers have limited time remaining to understand the biodiversity and biogeochemical cycles of ice-dependent environments and the consequences of these rapid, irreversible changes. The case of the Milne Fiord epishelf lake has special urgency because of the rarity of this type of "floating lake" ecosystem and its location in the Last Ice Area, a region of thick sea ice with global importance for conservation efforts.

Phosphoserine phosphatase as a prognostic biomarker in patients with gastric cancer and its potential association with immune cells.

BACKGROUND: Because of dismal prognosis in gastric cancer, identifying relevant prognostic factors is necessary. Phosphoserine phosphatase (PSPH) exhibits different expression patterns in many cancers and has been reported to affect the prognosis of patients with cancer. In this study, we examined the prognostic role of metabolic gene PSPH in gastric cancer based on the TCGA dataset and our hospital-based cohort cases. METHODS: We collected and analysed RNA-seq data of Pan-cancer and gastric cancer in the TCGA dataset and PSPH expression data obtained from immunohistochemical analysis of 243 patients with gastric cancer from Sun Yat-sen University cancer center. Further, Kaplan-Meier survival analysis and Cox analysis were used to assess the effect of PSPH on prognosis. The ESTIMATE and Cibersort algorithms were used to elucidate the relationship between PSPH and the abundance of immune cells using the TCGA dataset. RESULTS: We observed that PSPH expression displayed considerably high in gastric cancer and it was significantly associated with inferior prognosis (P = 0.043). Surprisingly, there was a significant relationship between lower immune scores and high expression of PSPH (P < 0.05). Furthermore, patients with a low amount of immune cells exhibited poor prognosis (P = 0.046). The expression of PSPH significantly increased in activated memory CD4 T cells, resting NK cells and M0 macrophages (P = 0.037, < 0.001, and 0.005, respectively). CONCLUSIONS: This study highlighted that PSPH influences the prognosis of patients with gastric cancer, and this is associated with the infiltration of tumour immune cells, indicating that PSPH may be a new immune-related target for treating gastric cancer.

Viral diversity and biogeochemical potential revealed in different prawn-culture sediments by virus-enriched metagenome analysis.

As the most numerous biological entities on Earth, viruses affect the microbial dynamics, metabolism and biogeochemical cycles in the aquatic ecosystems. Viral diversity and functions in ocean have been relatively well studied, but our understanding of viruses in mariculture systems is limited. To fill this knowledge gap, we studied viral diversity and potential biogeochemical impacts of sediments from four different prawn-mariculture ecosystems (mono-culture of prawn and poly-culture of prawn with jellyfish, sea cucumber, and clam) using a metagenomic approach with prior virus-like particles (VLPs) separation. We found that the order Caudovirales was the predominant viral category and accounted for the most volume (78.39% of classified viruses). Sediment viruses were verified to have a high diversity by using the construct phylogenetic tree of terL gene, with three potential novel clades being identified. Meanwhile, compared with viruses inhabiting other ecosystems based on gene-sharing network, our results revealed that mariculture sediments harbored considerable unexplored viral diversity and that maricultural species were potentially important drivers of the viral community structure. Notably, viral auxiliary metabolic genes were identified and suggested that viruses influence carbon and sulfur cycling, as well as cofactors/vitamins and amino acid metabolism, which indirectly participate in biogeochemical cycling. Overall, our findings revealed the genomic diversity and ecological function of viral communities in prawn mariculture sediments, and suggested the role of viruses in microbial ecology and biogeochemistry.

In Silico Analysis of CatSper Family Genes and APOB Gene Regulation in Male Infertility.

Sperm concentration and sperm motility are the two major causes of male infertility. Having spermatozoa in semen without motility or flagellum tail defect is a major concern needed to be investigated. The CatSper genes are the novel family of four sperm-specific Ca2+-permeable channels which plays an important role in sperm motility, acrosome reaction, sperm, and oocyte fusion. CatSper1, CatSper2, and CatSper3 are very well-studied genes for their role in asthenozoospermia, but the association of these genes with metabolic genes is still unstudied. Another unrevealed aspect is how ROS alter the function of CatSper genes. Among the Catsper family genes, the role of CatSper4 gene must be explored more. In this study, we have used the in silico approach to find the connection between the CatSper family gene with glycolytic genes and also the involvement of CATSPER4 protein in sperm flagellum using the STRING database. Connection of CATSPER1 protein with lipid metabolic gene is also found in Reactome database, and after that gene ontology of these genes was done by using DAVID and Enrichr databases. This analysis showed a strong interaction between CATSPER1, CATSPER2, and CATSPER3 protein with glycolytic protein (i.e., GAPDHS and PGK2), and CATSPER4 protein shows strong relation in the function of sperm flagellum. We also found a novel gene, i.e., APOB contributing to sperm motility. Gene ontology showed the role of APOB and glycolytic proteins in sperm motility. Enrichr analysis showed the association of APOB and glycolytic proteins in asthenozoospermia and CATSPER4 protein with sperm flagellum. Elsevier Pathway Collection also showed proteins involved in male infertility (i.e., GAPDHS). Therefore, we report the role of the CatSper4 gene in sperm tail function and the APOB novel gene involved in sperm motility. Understanding the molecular mechanism(s) of regulations of the CatSper family gene will help us to develop new therapeutic approaches in infertile males.

Benzo(a)pyrene affects proliferation with reference to metabolic genes and ROS/HIF-1α/HO-1 signaling in A549 and MCF-7 cancer cells.

Benzo(a)pyrene (BaP) is a representative polycyclic aromatic hydrocarbon (PAH) compound, which has been implicated in cancer initiation and promotion. Although BaP is one of the most extensively studied pollutants, the underlying mechanisms through which BaP affects reactive oxygen species (ROS)/hypoxia-inducible factor 1α (HIF-1α)/heme oxygenase 1(HO-1) signaling during lung or breast carcinogenesis are not yet fully understood. In this study, we analyzed the effects of 0 (control), 1, 5, or 25 µM BaP exposure on A549 and MCF-7 cancer cells, by evaluating cell viability, cell cycle, and regulatory protein expression, metabolic gene expression, and ROS/HIF-1α/HO-1 signaling. Cell viability increased following exposure to 1 and 5 µM BaP in A549 cells but decreased following exposure to all concentrations of BaP in MCF-7 cells. BaP significantly increased the proportions of cells in S and G2/M phases, with concomitant reductions in the proportions of cells in G0/G1 phase, following 5 and 25 µM exposure, which was accompanied by the upregulation of the regulatory proteins cyclin A, cyclin B, cyclin-dependent kinase (CDK)1, and CDK2. The subsequent upregulation of cytochrome p450 (CYP)1A1, CYP1B1, CYP3A4, epoxide hydrolase (EH), aldo-keto reductase (AKRC1) expression, and the attenuation of multi-drug resistance protein 4 (MRP4), glutathione-S-transferase (GST)1A1, and GST1B1 were also observed in both cell lines. Moreover, the induction of ROS and the modulation of HIF-1α and HO-1 were observed after BaP exposure. Taken together, these findings suggest that BaP affects proliferation with reference to metabolic genes and ROS/HIF-1α/HO-1 signaling in A549 and MCF-7 cancer cells.

Genome-Wide Comprehensive Analysis of the Nitrogen Metabolism Toolbox Reveals Its Evolution and Abiotic Stress Responsiveness in Rice (Oryza sativa L.).

Nitrogen metabolism (NM) plays an essential role in response to abiotic stresses for plants. Enzyme activities have been extensively studied for nitrogen metabolism-associated pathways, but the knowledge of nitrogen metabolism-associated genes involved in stress response is still limited, especially for rice. In this study, we performed the genome-wide characterization of the genes putatively involved in nitrogen metabolism. A total of 1110 potential genes were obtained to be involved in nitrogen metabolism from eight species (Arabidopsis thaliana (L.) Heynh., Glycine max (L.) Merr., Brassica napus L., Triticum aestivum L., Sorghum bicolor L., Zea mays L., Oryza sativa L. and Amborella trichopoda Baill.), especially 104 genes in rice. The comparative phylogenetic analysis of the superfamily revealed the complicated divergence of different NM genes. The expression analysis among different tissues in rice indicates the NM genes showed diverse functions in the pathway of nitrogen absorption and assimilation. Distinct expression patterns of NM genes were observed in rice under drought stress, heat stress, and salt stress, indicating that the NM genes play a curial role in response to abiotic stress. Most NM genes showed a down-regulated pattern under heat stress, while complicated expression patterns were observed for different genes under salt stress and drought stress. The function of four representative NM genes (OsGS2, OsGLU, OsGDH2, and OsAMT1;1) was further validated by using qRT-PCR analysis to confirm their responses to these abiotic stresses. Based on the predicted transcription factor binding sites (TFBSs), we built a co-expression regulatory network containing transcription factors (TFs) and NM genes, of which the constructed ERF and Dof genes may act as the core genes to respond to abiotic stresses. This study provides novel sights to the interaction between nitrogen metabolism and the response to abiotic stresses.

Identification of metabolism-associated molecular subtype in ovarian cancer.

Ovarian cancer (OC) is the most lethal gynaecological cancer with genomic complexity and extensive heterogeneity. This study aimed to characterize the molecular features of OC based on the gene expression profile of 2752 previously characterized metabolism-relevant genes and provide new strategies to improve the clinical status of patients with OC. Finally, three molecular subtypes (C1, C2 and C3) were identified. The C2 subtype displayed the worst prognosis, upregulated immune-cell infiltration status and expression level of immune checkpoint genes, lower burden of copy number gains and losses and suboptimal response to targeted drug bevacizumab. The C1 subtype showed downregulated immune-cell infiltration status and expression level of immune checkpoint genes, the lowest incidence of BRCA mutation and optimal response to targeted drug bevacizumab. The C3 subtype had an intermediate immune status, the highest incidence of BRCA mutation and a secondary optimal response to bevacizumab. Gene signatures of C1 and C2 subtypes with an opposite expression level were mainly enriched in proteolysis and immune-related biological process. The C3 subtype was mainly enriched in the T cell-related biological process. The prognostic and immune status of subtypes were validated in the Gene Expression Omnibus (GEO) dataset, which was predicted with a 45-gene classifier. These findings might improve the understanding of the diversity and therapeutic strategies for OC.

Specific activation of glycolytic enzyme enolase 2 in BRAF V600E-mutated colorectal cancer.

The BRAF V600E mutation occurs in approximately 10% of patients with metastatic colorectal cancer (CRC) and constitutes a distinct subtype of the disease with extremely poor prognosis. To address this refractory disease, we investigated the unique metabolic gene profile of BRAF V600E-mutated tumors via in silico analysis using a large-scale clinical database. We found that BRAF V600E-mutated tumors exhibited a specific metabolic gene expression signature, including some genes that are associated with poor prognosis in CRC. We discovered that BRAF V600E-mutated tumors expressed high levels of glycolytic enzyme enolase 2 (ENO2), which is mainly expressed in neuronal tissues under physiological conditions. In vitro experiments using CRC cells demonstrated that BRAF V600E-mutated cells exhibited enhanced dependency on ENO2 compared to BRAF wild-type cancer cells and that knockdown of ENO2 led to the inhibition of proliferation and migration of BRAF V600E-mutated cancer cells. Moreover, inhibition of ENO2 resulted in enhanced sensitivity to vemurafenib, a selective inhibitor of BRAF V600E. We identified AP-1 transcription factor subunit (FOSL1) as being involved in the transcription of ENO2 in CRC cells. In addition, both MAPK and PI3K/Akt signaling were suppressed upon inhibition of ENO2, implying an additional oncogenic role of ENO2. These results suggest the crucial role of ENO2 in the progression of BRAF V600E-mutated CRC and indicate the therapeutic implications of targeting this gene.