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PubMed2026

AKR7A3 rs1738023 association with susceptibility to female hepatocellular carcinoma and its role in AFB1 metabolism and tumor.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancer worldwide. In this study, we performed a two-stage exome-chip association analysis and found that the aldo-keto reductase family7 member A3 (AKR7A3) rs1738023 may be a potential susceptibility locus for HCC in females. We aimed to explore its role and mechanism. METHODS: The association between genotype and phenotype was analyzed through GWAS method. The expression of AKR7A3 in cancer tissue and blood analysis by qRT-PCR. The relationship of AKR7A3 and aflatoxin B1 (AFB1) was also analyzed. The effect of AKR7A3 on the biological behavior of HCC cell line was investigated on proliferation and invasion. The potential mechanism was analyzed by transcriptome analysis and western blot. RESULTS: Through genome-wide association analysis (GWAS), AKR7A3 (rs1738023), KIF2C (rs4342887), and CYP3A5 (rs6977165 and rs4646450) were found to be associated with susceptibility to hepatocellular carcinoma (HCC) in women. Further expression quantitative trait loci (eQTL) analysis showed that only AKR7A3 (rs1738023) was significantly associated with gene expression. The expression of AKR7A3 was significantly lower in HCC than adjacent non-tumorous tissues (P < 0.001). The genotype of rs1738023 was significantly associated with AKR7A3 expression (P = 0.0085). Rs1738023[C] genotype had a low AKR7A3 expression level and limited detoxification ability of AFB1. Literature data showed that AKR7A3 is involved in the metabolism of aflatoxin B1 (AFB1). Functional experimental results showed that overexpression of AKR7A3 in the normal liver cell line HL-7702 could significantly reduce AFB1-induced ROS levels and DNA adduct formation, suggesting that it plays a protective role in AFB1 metabolic detoxification. Cell function test showed that overexpression of AKR7A3 inhibit the proliferation, migration and invasion of HCC cells, and block the cell cycle. Transcriptome sequencing and KEGG pathway enrichment analysis revealed that overexpression of AKR7A3 affected the PI3K signaling pathway and led to downregulation of HIF1A and its downstream VEGFA protein expression. The validation results were confirmed in HCC cell lines Huh-7 and SUN-387. CONCLUSION: Overexpression of AKR7A3 contributes to inhibition of HCC progression and reduction of aflatoxin toxicity. AKR7A3 may serve as a potential prognostic and therapeutic target for HCC patients, although further validation is needed.

AKR7A3↗

PubMed1992

Glucose repression in the yeast Saccharomyces cerevisiae.

Understanding the mechanism of glucose repression in yeast has proved to be a difficult and challenging problem. A multitude of genes in different pathways are repressed by glucose at the level of transcription. The SUC2 gene, which encodes invertase, is an excellent reporter gene for glucose repression, since its expression is controlled exclusively by this pathway. Genetic analysis has identified numerous regulatory mutations which can either prevent derepression of SUC2 or render its expression insensitive to glucose repression. These mutations allow us to sketch the outlines of a pathway for general glucose repression, which has several key elements: hexokinase PII, encoded by HXK2, which seems to play a role in the sensing of glucose levels; the protein kinase encoded by SNF1, whose activity is required for derepression of many glucose-repressible genes; and the MIG1 repressor protein, which binds to the upstream regions of SUC2 and other glucose-repressible genes. Repression by MIG1 requires the activity of the CYC8 and TUP1 proteins. Glucose repression of other sets of genes seems to be controlled by the general glucose repression pathway acting in concert with other mechanisms. In the cases of the GAL genes and possibly CYC1, regulation is mediated by a cascade in which the general pathway represses expression of a positive transcriptional activator.

Cytochrome c Group↗

PubMed2005

Multiplicity of different cell- and organ-specific import routes for the NADPH-protochlorophyllide oxidoreductases A and B in plastids of Arabidopsis seedlings.

The NADPH-dependent protochlorophyllide (Pchlide) oxidoreductase (POR) is a photoenzyme that requires light for its catalytic activity and uses Pchlide itself as a photoreceptor. In Arabidopsis there are three PORs denoted PORA, PORB and PORC. The PORA and PORB genes are strongly expressed early in seedling development. In contrast to PORB the import of PORA into plastids of cotyledons is substrate-dependent and organ-specific. These differences in the import reactions between PORA and PORB most likely are due to different import mechanisms that are responsible for the uptake of these proteins. The two major core constituents of the translocon of the outer plastid envelope, Toc159 and Toc34, have been implicated in the binding and recognition of precursors of nuclear-encoded plastid proteins. Their involvement in conferring substrate dependency and organ specificity of PORA import was analyzed in intact Arabidopsis seedlings of wild type and the three mutants ppi3, ppi1 and ppi2 that are deficient in atToc34, atToc33, a closely related isoform of atToc34, and atToc159. Whereas none of these three Toc constituents is required for maintaining the organ specificity and substrate dependency of PORA import, atToc33 is indispensable for the import of PORB in cotyledons and true leaves suggesting that in these parts of the plant translocation of PORA and PORB occurs via two distinct import pathways. The analysis of PORA and PORB import into plastids of intact seedlings revealed an unexpected multiplicity of import routes that differed by their substrate, cell, tissue and organ specificities. This versatility of pathways for protein targeting to plastids suggests that in intact seedlings not only the constituents of the core complex of import channels but also other factors are involved in mediating the import of nuclear-encoded plastid proteins.

Arabidopsis↗

PubMed2026

Integrated Genome-Wide Association Studies and Selection Signature Analysis Reveal the Genetic Architecture of the Wattle Trait in Goats.

Wattles are finger-like appendages on the ventral neck of goats, serving as a distinctive morphological marker for breed identification that serves potential implications for production performance. However, their genetic basis remains incompletely characterized. Here, we integrated a genome-wide association study (GWAS) and selection signature analysis to identify candidate genes and genomic regions associated with the wattle trait in goats. Using a linear mixed model, GWAS on 463 goats (23 wattled and 440 non-wattled) identified 385 quantitative trait loci (QTLs) at a 5% false discovery rate, yielding 346 candidate genes. The most significant association signal was observed on chromosome 10 (72.61-73.48 Mb), where the lead SNP (rs636481767) is located within a region containing GJD2, GREM1, and FMN1, showing strong linkage disequilibrium (r2 > 0.6) with surrounding loci. Subsequent selection signature analysis (23 wattled and 23 non-wattled) identified 83 genomic regions harboring 119 candidate genes. The strongest signals were detected at MFSD14B on chromosome 8 (FST = 0.154, log2π-ratio = 2.611) and PDLIM7 on chromosome 7 (FST = 0.144, log2π-ratio = 0.806). KEGG pathway enrichment analysis revealed that GWAS-associated genes were involved in glycosylation and immune responses, whereas selection-signature genes were enriched in DNA repair and the Hippo, Notch, and Wnt pathways. Furthermore, cross-species PheWAS revealed that human FMN1 is associated with dermatological, skeletal, and metabolic phenotypes, while porcine FMN1 is associated with backfat thickness and loin muscle depth. Overall, this study provides molecular markers of potential value for goat breeding and pinpoints key candidate genes for future functional validation of wattle development.

Animals↗

PubMed1984

Transposon mutagenesis analysis of meta-cleavage pathway operon genes of the TOL plasmid of Pseudomonas putida mt-2.

Hybrid plasmids containing the regulated meta-cleavage pathway operon of TOL plasmid pWWO were mutagenized with transposon Tn1000 or Tn5. The resulting insertion mutant plasmids were examined for their ability to express eight of the catabolic enzymes in Escherichia coli. The physical locations of the insertions in each of 28 Tn1000 and 5 Tn5 derivative plasmids were determined by restriction endonuclease cleavage analysis. This information permitted the construction of a precise physical and genetic map of the meta-cleavage pathway operon. The gene order xylD (toluate dioxygenase), L (dihydroxycyclohexidiene carboxylate dehydrogenase), E (catechol 2,3-dioxygenase), G (hydroxymuconic semialdehyde dehydrogenase), F (hydroxymuconic semialdehyde hydrolase), J (2-oxopent-4-enoate hydratase), I (4-oxalocrotonate decarboxylase), and H (4-oxalocrotonate tautomerase) was established, and gene sizes were estimated. Tn1000 insertions within catabolic genes exerted polar effects on distal structural genes of the operon, but not on an adjacent regulatory gene xylS.

DNA Restriction Enzymes↗

PubMed2026

In silico screening of anti-atherosclerotic compounds from Morus alba leaves by machine learning and network pharmacology.

OBJECTIVE: This study integrates machine learning with network pharmacology, molecular docking, and molecular dynamics simulations to screen bioactive compounds from Mulberry leaves and elucidate their potential mechanisms against atherosclerosis (AS). METHODS: A training dataset of anti-AS active compounds was compiled and encoded as Morgan fingerprints. Three machine learning classifiers, specifically Random Forest (RF), Support Vector Machine (SVM), and Extreme Gradient Boosting (XG-Boost), were constructed and evaluated using multiple performance metrics. Potential active components from Mulberry leaves and AS-related targets were retrieved, followed by protein-protein interaction network construction and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Molecular docking was then performed to evaluate binding affinities between core targets and candidate compounds, and the most stable complex was subjected to molecular dynamics simulations using GROMACS (2025). RESULTS: The RF model achieved superior performance (accuracy= 0.8354, F1 = 0.8408, AUC = 0.9119) with 100% external validation accuracy. Thirteen anti-AS candidates were prioritized from mulberry leaves, four of which have been previously documented. Network pharmacology revealed AKT1 and IL6 as core targets, enriched in pathways such as endocrine resistance. Molecular docking and dynamics simulations confirmed strong binding between oxysanguinarine and AKT1, with the complex exhibiting high stability. CONCLUSION: The RF model provides a reliable computational tool for prioritizing anti-AS compounds from Mulberry leaves. The integrated analysis reveals that Mulberry leaves exert anti-atherosclerotic effects through multi-target (e.g., AKT1, IL6) and multi-pathway (e.g., PI3K-Akt) mechanisms, offering a framework for further experimental validation.

Morus↗

PubMed2006

Phylophenetic properties of metabolic pathway topologies as revealed by global analysis.

BACKGROUND: As phenotypic features derived from heritable characters, the topologies of metabolic pathways contain both phylogenetic and phenetic components. In the post-genomic era, it is possible to measure the "phylophenetic" contents of different pathways topologies from a global perspective. RESULTS: We reconstructed phylophenetic trees for all available metabolic pathways based on topological similarities, and compared them to the corresponding 16S rRNA-based trees. Similarity values for each pair of trees ranged from 0.044 to 0.297. Using the quartet method, single pathways trees were merged into a comprehensive tree containing information from a large part of the entire metabolic networks. This tree showed considerably higher similarity (0.386) to the corresponding 16S rRNA-based tree than any tree based on a single pathway, but was, on the other hand, sufficiently distinct to preserve unique phylogenetic information not reflected by the 16S rRNA tree. CONCLUSION: We observed that the topology of different metabolic pathways provided different phylogenetic and phenetic information, depicting the compromise between phylogenetic information and varying evolutionary pressures forming metabolic pathway topologies in different organisms. The phylogenetic information content of the comprehensive tree is substantially higher than that of any tree based on a single pathway, which also gave clues to constraints working on the topology of the global metabolic networks, information that is only partly reflected by the topologies of individual metabolic pathways.

Chromosome Mapping↗

PubMed1997

Vagal afferent and efferent contributions to the inhibition of food intake by cholecystokinin.

To assess the role of subdiaphragmatic vagal afferent and efferent fibers in the mediation of the inhibition of food intake by cholecystokinin (CCK), we compared the ability of a dose range (1-16 microg/kg), of CCK to affect 30-min liquid glucose (0.125 g/ml) intake in rats with either total subdiaphragmatic vagotomy, selective subdiaphragmatic vagal deafferentation, selective subdiaphragmatic vagal deefferentation, or sham surgery. Selective vagal deafferentation and deefferentations were produced by combinations of unilateral subdiaphragmatic vagotomy and contralateral afferent or efferent rootlet transection as fibers enter the caudal medulla. CCK produced a dose-related suppression of glucose intake in sham animals, and this action was eliminated in rats with total subdiaphragmatic vagotomy. CCK suppression of intake was attenuated in rats with vagal deafferentation, such that there was a loss of sensitivity to CCK. Vagal deefferentation resulted in lower levels of baseline intake and a truncation of the feeding-inhibitory actions of CCK. These data demonstrate that CCK's suppression of intake depends on actions of both vagal afferent and efferent fibers. We interpret these data as suggesting that 1) the actions of low doses of CCK depend on activation of vagal afferent CCK receptors and 2) the greater efficacy of higher CCK doses is the result of the potentiation of these vagal afferent actions due to local physiological gastrointestinal effects of the peptide that rely on vagal efferent input.

Afferent Pathways↗

PubMed2003

Genome-wide analysis of nuclear mRNA export pathways in Drosophila.

NXF1, p15 and UAP56 are essential nuclear mRNA export factors. The fraction of mRNAs exported by these proteins or via alternative pathways is unknown. We have analyzed the relative abundance of nearly half of the Drosophila transcriptome in the cytoplasm of cells treated with the CRM1 inhibitor leptomycin-B (LMB) or depleted of export factors by RNA interference. While the vast majority of mRNAs were unaffected by LMB, the levels of most mRNAs were significantly reduced in cells depleted of NXF1, p15 or UAP56. The striking similarities of the mRNA expression profiles in NXF1, p15 and UAP56 knockdowns show that these proteins act in the same pathway. The broad effect on mRNA levels observed in these cells indicates that the functioning of this pathway is required for export of most mRNAs. Nonetheless, a set of mRNAs whose export was unaffected by the depletions and some requiring NXF1:p15 but not UAP56 were identified. In addition, our analysis revealed a feedback loop by which a block to mRNA export triggers the upregulation of genes involved in this process.

Active Transport, Cell Nucleus↗

PubMed2005

The Sho1 adaptor protein links oxidative stress to morphogenesis and cell wall biosynthesis in the fungal pathogen Candida albicans.

The Sho1 adaptor protein is an important element of one of the two upstream branches of the high-osmolarity glycerol (HOG) mitogen-activated protein (MAP) kinase pathway in Saccharomyces cerevisiae, a signal transduction cascade involved in adaptation to stress. In the present work, we describe its role in the pathogenic yeast Candida albicans by the construction of mutants altered in this gene. We report here that sho1 mutants are sensitive to oxidative stress but that Sho1 has a minor role in the transmission of the phosphorylation signal to the Hog1 MAP kinase in response to oxidative stress, which mainly occurs through a putative Sln1-Ssk1 branch of the HOG pathway. Genetic analysis revealed that double ssk1 sho1 mutants were still able to grow on high-osmolarity media and activate Hog1 in response to this stress, indicating the existence of alternative inputs of the pathway. We also demonstrate that the Cek1 MAP kinase is constitutively active in hog1 and ssk1 mutants, a phenotypic trait that correlates with their resistance to the cell wall inhibitor Congo red, and that Sho1 is essential for the activation of the Cek1 MAP kinase under different conditions that require active cell growth and/or cell wall remodeling, such as the resumption of growth upon exit from the stationary phase. sho1 mutants are also sensitive to certain cell wall interfering compounds (Congo red, calcofluor white), presenting an altered cell wall structure (as shown by the ability to aggregate), and are defective in morphogenesis on different media, such as SLAD and Spider, that stimulate hyphal growth. These results reveal a role for the Sho1 protein in linking oxidative stress, cell wall biogenesis, and morphogenesis in this important human fungal pathogen.

Candida albicans↗

PubMed2026

Comparative Analysis of Volatile Compounds, Amino Acids, Fatty Acids, and Lipidomic Profiles in Thigh Muscles of Commercial Arbor Acres (AA) Broilers and Indigenous Chengkou and Langshan Chickens.

Flavor-related compounds and nutritional components of chicken meat vary among different breeds, but comprehensive comparisons of these characteristics between commercial and indigenous chickens remain insufficiently characterized. In this study, three chicken breeds (Arbor Acres, Chengkou, and Langshan) were slaughtered at their respective market ages, and the volatile flavor compounds, amino acids, fatty acids, and lipidomic profiles of thigh muscle were analyzed to investigate breed-associated differences in flavor-related and nutritional characteristics. Langshan chickens exhibited the highest total volatile compound content and also had the highest total amino acid levels, with significantly higher contents of umami and sweet amino acids. In addition, both indigenous breeds showed higher levels of arachidonic acid (C20:4n6) than Arbor Acres broilers, while Chengkou chickens had the highest content of docosahexaenoic acid (DHA, C22:6n3). Lipidomic analysis identified 787 lipids, with glycerophospholipids and sphingolipids as the predominant classes. Differential lipid analysis revealed that Langshan chickens had 38 upregulated lipids compared with Arbor Acres chickens, while Chengkou chickens exhibited 258 differential lipids relative to Arbor Acres chickens. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis indicated that these differential lipids were mainly associated with glycerolipid, sphingolipid, and glycerophospholipid metabolism. Correlation analysis further revealed significant associations between specific lipids and flavor-related compounds, amino acids, and fatty acids, suggesting their potential roles in breed-associated differences. Overall, this study demonstrates that indigenous chicken breeds possess distinct flavor-related and nutritional profiles compared with commercial Arbor Acres broilers and provides valuable insights into breed-associated differences in chicken meat characteristics.

amino acids↗

PubMed2000

Orchestrated transcription of key pathways in Arabidopsis by the circadian clock.

Like most organisms, plants have endogenous biological clocks that coordinate internal events with the external environment. We used high-density oligonucleotide microarrays to examine gene expression in Arabidopsis and found that 6% of the more than 8000 genes on the array exhibited circadian changes in steady-state messenger RNA levels. Clusters of circadian-regulated genes were found in pathways involved in plant responses to light and other key metabolic pathways. Computational analysis of cycling genes allowed the identification of a highly conserved promoter motif that we found to be required for circadian control of gene expression. Our study presents a comprehensive view of the temporal compartmentalization of physiological pathways by the circadian clock in a eukaryote.

Arabidopsis↗

PubMed2006

Biosynthetic analysis of the petrobactin siderophore pathway from Bacillus anthracis.

The asbABCDEF gene cluster from Bacillus anthracis is responsible for biosynthesis of petrobactin, a catecholate siderophore that functions in both iron acquisition and virulence in a murine model of anthrax. We initiated studies to determine the biosynthetic details of petrobactin assembly based on mutational analysis of the asb operon, identification of accumulated intermediates, and addition of exogenous siderophores to asb mutant strains. As a starting point, in-frame deletions of each of the genes in the asb locus (asbABCDEF) were constructed. The individual mutations resulted in complete abrogation of petrobactin biosynthesis when strains were grown on iron-depleted medium. However, in vitro analysis showed that each asb mutant grew to a very limited extent as vegetative cells in iron-depleted medium. In contrast, none of the B. anthracis asb mutant strains were able to outgrow from spores under the same culture conditions. Provision of exogenous petrobactin was able to rescue the growth defect in each asb mutant strain. Taken together, these data provide compelling evidence that AsbA performs the penultimate step in the biosynthesis of petrobactin, involving condensation of 3,4-dihydroxybenzoyl spermidine with citrate to form 3,4-dihydroxybenzoyl spermidinyl citrate. As a final step, the data reveal that AsbB catalyzes condensation of a second molecule of 3,4-dihydroxybenzoyl spermidine with 3,4-dihydroxybenzoyl spermidinyl citrate to form the mature siderophore. This work sets the stage for detailed biochemical studies with this unique acyl carrier protein-dependent, nonribosomal peptide synthetase-independent biosynthetic system.

Bacillus anthracis↗

PubMed2026

An integrated proteomics and transcriptomics analysis highlights concordance between protein turnover and carbohydrate transport and metabolism as key functional categories during the growth of Trichophyton rubrum.

Dermatophytes are a class of keratinophilic skin fungi that invade host skin, hair, and nails to acquire nutrients. An integrated multi-omics approach utilizing liquid chromatography-tandem mass spectrometry and RNA-seq after growth in a protein-rich soy medium was employed to capture the major subset of secreted protein families of Trichophyton rubrum. The secretome consisted mainly of proteases and cell wall-degrading enzymes, with subtilisins (Sub6 and Sub7), metallopeptidase (LAP2), and chitinase having the most abundant peptides. Transcriptional profiling indicated fungal adaptation in protein-rich media to process the protein nutrients through modulation of metabolism and general cellular function pathways. Correlation analysis between proteomics and transcriptomics data using functional KOG categories shows high concordance of KOG categories O (posttranslational modification, protein turnover, and chaperones), P (inorganic ion transport and metabolism), and G (carbohydrate transport and metabolism), as per cosine similarity analysis.IMPORTANCEDermatophytes are keratinophilic skin fungal pathogens that invade host skin, hair, and nails to acquire nutrients. There is an epidemic-like increase in infections, as well as an increase in antimicrobial resistance among dermatophytes, as witnessed over the last decade. There is hence a need to understand the key pathways and virulence factors required during growth and infection. We present an integrated multi-omics analysis (proteomics and transcriptomics data) using a vector-based similarity approach to show high concordance of KOG functional categories belonging to posttranslational modification, protein turnover, carbohydrate transport, and metabolism.

Proteomics↗

PubMed1993

Lipopolysaccharide nonresponder cells: the C3H/HeJ defect.

Since its initial discovery as endotoxin resistant, the C3H/HeJ mouse has been extensively studied and used as a comparative model to help reveal the mechanism under genetic control which governs host responses to endotoxin. Most of the research has focused on the B lymphocyte and macrophage of this strain which fail to be activated by LPS. Recently, specific LPS binding proteins have been isolated on lymphocytes and other cells; however a receptor which transduces an activation signal has not been isolated as yet from responder cells which is missing or altered on C3H/HeJ nonresponder cells. Investigations into the signal transduction pathways used by C3H/HeJ B cells when they are activated by a protein mitogen have been found to be similar to those used by LPS responder cells when activated by LPS. Protein kinase C and tyrosine kinase, which phosphorylate signal proteins in cells have been found to be operative in C3H/HeJ and C3H/OuJ B cells. In both cases, DNA synthesis is shut off by either PKC or PTK blockade; however, PTK inhibition will also block activation of PKC stimulated DNA synthesis, indicating tyrosine kinase initiated phosphorylation may regulate the PKC signal pathway. Further analysis of the proteins that are phosphorylated in LPS responder and LPS nonresponder B cells is needed before conclusions can be drawn as to whether the defect in C3H/HeJ cells resides in the signal pathway leading to gene activation and proliferation. Nevertheless, the notion of a missing or defective signal receptor still remains as a working hypothesis to explain C3H/HeJ cell hyporesponsiveness to LPS. Isolation of the Lpsn gene and its product will provide the evidence needed for a clearer understanding of how LPS reacts with cells.

Animals↗

PubMed2003

PACAP and gastrin regulate the histidine decarboxylase promoter via distinct mechanisms.

The enterochromaffin-like (ECL) cell controls gastric acid secretion via histamine, generated by l-histidine decarboxylase (HDC). HDC expression is regulated by gastrin. However, gastrin is not alone in controlling ECL cell function. For example, the neural peptide pituitary adenylate cyclase-activating polypeptide (PACAP) also increases ECL cell proliferation. To investigate a potential role of PACAP in regulating HDC expression, we generated a series of HDC promoter-luciferase reporter constructs and transiently transfected them into PC12 cells (stably expressing the gastrin-CCK-2 receptor). We found that PACAP regulates HDC promoter activity. This is temporally biphasic, involving both adenyl cyclase and phospholipase C-dependent pathways. Deletional analysis, block mutation, and EMSA demonstrated a PACAP-response element at -177 to -170, wholly necessary for the effects of PACAP and discrete from known gastrin-responsive elements. Discrete neural and endocrine pathways regulate ECL cells through different patterns of postreceptor signaling and promoter activation, which may be appropriate to their functions in vivo.

Adenylyl Cyclases↗

PubMed2025

Novel insights into hypoxia-driven transcriptomic and epigenetic landscapes in grade 3 meningioma.

BACKGROUND: Meningiomas are among the most prevalent central nervous system (CNS) tumors, with up to 20% of cases exhibiting recurrence or aggressive behavior. Hypoxia is a key driver of malignant transformation and therapeutic resistance, yet its molecular basis in meningioma remains poorly understood. METHODS: We conducted integrative transcriptomic and epigenomic profiling of IOMM-Lee cells (grade 3 meningioma) cultured under hypoxic (0.2% O₂) and normoxic conditions. RNA-sequencing and Illumina MethylationEPIC v2.0 data were analyzed in R using DESeq2 and minfi, respectively. Functional enrichment, transcription-factor binding analysis, and pathway mapping (clusterProfiler, enrichR) were performed. Findings were cross-validated in public meningioma datasets, in Indian meningioma patient cohort and cell line via RT-qPCR, and azacytidine-based demethylation assay. Functional role of the candidate gene was elucidated in vitro via cellular assays. RESULTS: Hypoxia triggered a canonical HIF1A-driven transcriptional program activating glycolytic and angiogenic pathways while downregulating genes associated with DNA repair and replication in meningioma. Several differentially expressed genes (DEGs) were identified as known oncogenes, tumor-suppressors, or associated with immune regulation and stemness. Promoter motif analysis identified HIF1, SP1, TP53, BRCA1, and E2F1 as enriched transcriptional regulators. We validated hypoxia and HIF1-mediated regulation of some of the top DEGs. DNA-methylation analysis revealed epigenetic silencing of RTN4IP1 and ZBTB7C under hypoxia, reversible upon azacytidine treatment. Integrative comparison with patient datasets highlighted SLITRK2, PDE4C, SGCD, and LRP1B as hypoxia-responsive genes associated with poor prognosis. Several hypoxia-regulated genes also showed significant correlation with known hypoxia biomarkers, VEGFA and CA9. IGFBP3 and NDRG1 were among the top hypoxia-associated upregulated genes, and IGFBP3 expression was linked to advanced meningioma grades. Knockdown of IGFBP3 via siRNA in hypoxia-treated IOMM-Lee cells was associated with reduced cell proliferation and migration. CONCLUSIONS: This study presents the first integrated transcriptomic–epigenomic landscape of hypoxia in grade 3 meningioma, uncovering regulatory networks and candidate biomarkers with prognostic and therapeutic potential. These findings provide a foundation for future translational studies targeting hypoxia-driven tumor progression in meningioma.

Humans↗

PubMed2026

Remodeling of host lipid metabolism by Wolbachia strain wAlbB is associated with lipid accumulation and cardiolipin dysregulation in the Aedes aegypti fat body.

BACKGROUND: The intracellular symbiont Wolbachia, particularly the wAlbB strain, is a promising biocontrol agent against mosquito-borne diseases. Although Wolbachia infection is known to perturb host metabolism, the underlying mechanisms, especially those related to lipid metabolism, remain poorly understood. METHODS: We performed an integrated multi-level analysis of the Aedes aegypti fat body in uninfected and wAlbB-infected mosquitoes, combining histology, biochemistry, untargeted liquid chromatography-mass spectrometry (LC-MS) lipidomics, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis, reverse transcription quantitative PCR of key metabolic genes, and quantification of acetyl-coenzyme A (acetyl-CoA) and reduced nicotinamide adenine dinucleotide (NADH) levels. RESULTS: wAlbB infection increased fat body wet weight and thickness, accompanied by accumulation of triglyceride and of lipid droplets. Lipidomic analysis further revealed extensive lipidome remodeling, with elevated free fatty acid, diglyceride, and triglyceride, but broad depletion of glycerophospholipids, particularly cardiolipin. These changes were supported by transcriptional alterations: upregulation of fatty acid synthase 1 and glycerol-3-phosphate acyltransferase 1, and downregulation of adipose triglyceride lipase and carnitine palmitoyltransferase 1. Cardiolipin depletion correlated with downregulation of genes involved in its synthesis and remodeling, including phosphatidylglycerophosphate synthase and calcium-independent phospholipase A2γ. These lipid changes were also associated with accumulation of acetyl-CoA and NADH. CONCLUSIONS: Our findings suggest that wAlbB infection is associated with extensive lipid metabolic remodeling in the Aedes aegypti fat body, characterized by accumulation of neutral lipids and cardiolipin depletion, accompanied by transcriptional remodeling of key metabolic enzymes. This study establishes the fat body as a primary tissue-level hub for Wolbachia-associated lipid remodeling and provides a foundational framework for future mechanistic investigations into host-symbiont metabolic interactions.

Animals↗