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At least 109 records · Page 6Linked to original sources
PubMed2026

Metagenome-resolved evidence that soluble factors in granular activated carbon-amended reactor effluent reprogram propionate metabolism and methanogenic pathways.

Granular activated carbon (GAC) enhances anaerobic digestion performance, yet the mechanisms underlying reactor-scale improvements remain incompletely understood, particularly how GAC affects biomass not attached to its surface. Here, sludge from a non-GAC up-flow anaerobic sludge blanket reactor was incubated with 0.45-&#x3bc;m-filtered effluents from non-GAC and GAC-amended reactors under repeated propionate loading, followed by genome-resolved metagenomics. GAC-reactor effluent increased methane yield from 64&#x202f;&#xb1;&#x202f;3% to 76&#x202f;&#xb1;&#x202f;3% (p&#x202f;<&#x202f;0.01) in the absence of GAC particles. A non-redundant catalog of 170 quality-filtered metagenome-assembled genomes (MAGs) was recovered, enabling pathway- and gene-set quantification. Genomic potential for both major propionate-oxidation routes increased in the GAC-effluent group relative to the non-GAC group, with a larger increase for the methylmalonyl-CoA (MMC) route than for the dismutation route (1.289- versus 1.221-fold). Accordingly, the MMC-to-dismutation preference ratio was 5.60% higher in the GAC-effluent group, alongside a broader carrier base. Cobamide potential shifted toward remodeling and cobamide-dependent use rather than increased de novo corrin-ring synthesis. Candidate electron-transfer architectures were also rebalanced: PilA-associated carriers became less prominent, whereas maturation-supported multiheme cytochrome carriers increased from 22.96% to 34.90% of community abundance, although H2/formate-module carriers remained prevalent. Quorum-sensing systems underwent pathway- and carrier-specific redistribution, while all eight curated extracellular-polysaccharide modules showed higher mean gene abundance in the GAC-effluent composite. These findings show that a filter-passing effluent fraction can extend GAC-associated effects beyond direct particle contact and link enhanced methanogenesis to a broader, redistributed network of metabolic, redox, and coordination capacities. This expands the mechanistic framework of conductive-material-assisted anaerobic digestion and provides a basis for harnessing GAC-derived functions throughout the reactor.

Extracellular polymeric substances (EPS)↗
PubMed2026

Maternal high-fat diet modulates lupus nephritis through fetal Wnt-steroid hormone and epigenetic reprogramming in MRL/lpr mouse offspring.

We previously investigated whether maternal high-fat diet (HFD) exposure alters lupus nephritis (LN) progression in MRL/lpr offspring. Contrary to expectation, maternally HFD-exposed offspring showed delayed and attenuated nephritic progression compared with control diet offspring. The maternal HFD developmental impact on LN remains unclear. Here, integrated amniotic fluid metabolomics and fetal liver transcriptomics revealed that maternal HFD reshaped the intrauterine molecular environment, particularly involving steroid hormone biosynthesis and Wnt/&#x3b2;-catenin-associated regulatory networks. Methylome profiling further demonstrated broad CpG hypomethylation, immune-related differentially methylated region enrichment, and an inverse association between global CpG methylation and oxidative genomic DNA damage. Among candidate regulatory nodes, Axin2, a canonical Wnt/&#x3b2;-catenin target and feedback regulator, emerged as a potential link between fetal nutritional exposure, epigenetic remodeling, and persistent pathway modulation. Although whole-locus and gene body methylation of Axin2 were not markedly altered, promoter-region methylation showed an increasing tendency under maternal HFD exposure. In adult offspring, maternal HFD was associated with reduced Axin2 protein expression, decreased Wnt-responsive transcripts, increased peripheral corticosterone levels, and attenuation of LN progression. The inverse association between Axin2 expression and corticosterone further suggested coupling between suppressed Wnt pathway output and steroid hormone remodeling. Together, these findings support a developmental model in which maternal HFD reshapes the fetal intrauterine environment and establishes a persistent Wnt-steroid hormone-epigenetic regulatory axis that unexpectedly attenuates LN progression in genetically susceptible offspring.

Axin2↗
PubMed2026

Gene-environment interaction between perinatal oxytocin exposure and Pten mutation shapes epigenetic reprogramming of oxytocin signaling and behavior in mice.

Synthetic oxytocin (Pitocin) is the most commonly used pharmacologic agent for induction and augmentation of labor. Beyond its uterotonic effects, oxytocin plays a critical role in neurodevelopment and social behavior. Dysregulated oxytocin signaling has been implicated in autism spectrum disorder (ASD), raising concern that perinatal exposure to exogenous oxytocin may have lasting neurodevelopmental consequences. This study aimed to determine whether offspring harboring a genetic predisposition for ASD are differentially impacted by perinatal oxytocin exposures, with a focus on long-term oxytocin signaling and autism-like behavior. Pregnant mice carrying offspring with heterozygous mutations in phosphatase and tensin homolog deleted on chromosome ten (Pten), a well-established monogenic risk factor for ASD, received continuous oxytocin versus phosphate-buffered saline (PBS) control via micro-osmotic pumps during late gestation. Wild-type (WT) offspring exposed to each treatment served as a secondary control. Adult offspring were assessed for oxytocin receptor (Oxtr) methylation in the frontal cortex and hippocampus, oxytocin expression in the hypothalamus, serum oxytocin levels, and were subject to a battery of social and anxiety-related behavior tests. Perinatal oxytocin exposure produced genotype-dependent effects in offspring. Epigenetic analyses revealed bidirectional remodeling of Oxtr methylation in the frontal cortex and hippocampus, with increased exon 1 methylation in WT mice and decreased methylation in Pten-mutant mice, resulting in significant genotype-treatment interactions. Hypothalamic oxytocin expression increased following treatment regardless of genotype, though baseline levels were higher in Pten-mutant mice. Neither oxytocin treatment nor genotype impacted long-term serum oxytocin levels. Behavioral outcomes were modest but context-specific: repetitive behaviors and cognition performance were unchanged, but oxytocin-treated Pten-mutant mice exhibited increased anxiety-like behavior alongside improved social memory. In contrast, oxytocin-treated WT mice showed reduced social novelty preference. Exploratory analyses suggested potential sex-dependent trends. Our findings support a model in which genetic susceptibility shapes the epigenetic encoding of early-life hormonal signals, thereby recalibrating oxytocin system function and downstream behavioral outcomes. Together, these data highlight the context-dependent effects of perinatal oxytocin exposure and argue against uniformly beneficial or detrimental effects, emphasizing the importance of gene-environment interactions in neurodevelopmental trajectories.

Animals↗
PubMed2026

Temporal DIA-MS proteomics reveals coordinated metabolic reprogramming associated with oil accumulation in oil palm mesocarp.

Oil palm (Elaeis guineensis Jacq.) is the most productive oil-bearing crop globally, yet the molecular basis of mesocarp development and lipid accumulation remains poorly understood. Ultra-deep data-independent acquisition mass spectrometry (DIA-MS) was applied to characterize proteome dynamics in two contrasting genotypes, seedless (KS) and thin-shelled (TS), across five developmental stages (P1-P5) spanning fruit development to mature oil accumulation. Phenotypic analysis revealed higher mesocarp proportion and oil content in KS during late maturation. A total of 137,615 peptides corresponding to 12,163 protein groups were identified, providing a temporal proteomic landscape of mesocarp development. Multivariate analysis indicated that developmental progression was the primary contributor to proteomic variation, whereas genotype-associated differences increased during lipid accumulation. Differentially abundant proteins were mainly associated with carbohydrate metabolism, photosynthesis, proteolysis, antioxidant responses, and lipid biosynthesis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and KOG analyses suggested extensive remodeling of metabolic networks, including developmental changes in photosynthesis-associated proteins and increased representation of lipid-associated pathways during maturation. Weighted protein co-expression network analysis identified 17 modules associated with developmental progression and lipid accumulation, highlighting candidate proteins involved in carbon metabolism, energy production, and cellular protection. Genes encoding selected hub protein candidates were further examined by RT-qPCR. Biochemical analyses supported these proteomic patterns, showing increased acetyl-CoA availability, enhanced antioxidant enzyme activities (SOD, CAT, APX, and GR), improved GSH/GSSG balance, and reduced oxidative damage in KS. Together, these findings provide a temporal proteomic and biochemical framework for understanding genotype-associated differences in oil accumulation and identify candidate metabolic networks for functional studies.

Carbon metabolism↗
PubMed2026

Hypoxia reprograms VEGF signaling to differentially control ADAMTS2 and ADAMTS3 expression in endothelial cells.

ADAMTS2/-3, key metalloproteinases involved in collagen processing and extracellular matrix dynamics, remain insufficiently characterized in terms of their transcriptional regulation under hypoxic and pro-angiogenic conditions. In this study, we demonstrate that VEGF&#x2081;&#x2086;&#x2085; robustly enhances ADAMTS2/-3 expression in endothelial cells, with hypoxia providing a striking amplification of this response. Bioinformatic analyses revealed that hypoxia and VEGF induced HIF-mediated and time-varying expression responses in ADAMTS2/-3. Using HUVECs exposed to CoCl&#x2082;-induced hypoxia, VEGF stimulation led to substantial increases in ADAMTS2 (approximately 19-fold at 3&#x202f;h) and ADAMTS3 (approximately 46-fold at 3&#x202f;h) mRNA levels, accompanied by concordant protein upregulation. Promoter-reporter assays revealed strong VEGF responsiveness in defined ADAMTS2 (-658/+112) and ADAMTS3 (-131/+40; -1340/+40) promoter fragments, particularly under hypoxic conditions. Pharmacological inhibition showed that JNK, MAPK/ERK, p38, and PI3K pathways each contributed partially to VEGF-mediated transcription, indicating multi-pathway convergence rather than single-pathway dependency. This finding is consistent with RNA-seq analyses showing that VEGF-related signaling is extensively re-regulated under hypoxic conditions. Extension of these analyses to MG-63 and SAOS-2 cell lines revealed modest but consistent VEGF-induced upregulation, supporting a tissue-independent regulatory axis. Collectively, these findings position ADAMTS2/-3 as potent hypoxia- and VEGF-responsive genes, uncovering their integration into HIF-1&#x3b1;-dependent transcriptional networks and VEGF-activated signaling cascades. This work highlights the relevance of ADAMTS2/-3 in angiogenesis-associated extracellular matrix remodeling and identifies them as promising biomarkers and potential therapeutic targets in hypoxia-driven vascular pathology.

Humans↗
PubMed2026

Targeting Regnase-1 in B7-H3-CAR T cells reprograms the tumor microenvironment and enhances antitumor efficacy for osteosarcoma.

The microenvironment in solid tumors represents an immunosuppressive therapeutic barrier to CAR T cell therapy, and it is currently unknown whether it can be reshaped by the deletion of negative regulators in CAR T cells. To address this knowledge gap, we evaluated the intrinsic and extrinsic effects of deleting the negative regulator Regnase-1 (Reg-1) in B7-H3-CAR T cells for the immunotherapy of osteosarcoma. Reg-1 knockout (KO) improved the antitumor activity of human and murine B7-H3-CAR T cells in vivo. In immune-competent models, Reg-1 KO also endowed murine B7-H3-CAR T cells with the ability to create a proinflammatory landscape characterized by an influx of interferon gamma (IFN-&#x3b3;)-producing endogenous T cells and natural killer (NK) cells and a reduction of inhibitory myeloid cells, including M2-like macrophages. Thus, deleting Reg-1 has cell- and non-cell-autonomous benefits, nominating Reg-1 KO B7-H3-CAR T cells as a promising cell product for early-phase clinical testing in patients with solid tumors.

Animals↗
PubMed2026

Oxygen-dependent subcellular redistribution of PHD3 links the hypoxic microenvironment to mitochondrial metabolic reprogramming in ccRCC.

Clear cell renal cell carcinoma (ccRCC) is characterized by profound metabolic dysregulation, with both prolyl hydroxylase domain protein 3 (PHD3) and pyruvate carboxylase (PC) independently implicated in disease progression. Although each influences patient outcomes, a direct mechanistic interplay between these two regulators has remained elusive. Here, we uncover a novel regulatory axis involving PHD3 and PC by identifying an unexpected subcellular behavior of PHD3, namely, its dual localization to the cytosol and the mitochondrial matrix. We show that mitochondrial import of PHD3 is associated with its intracellular clustering, a process modulated by PHD3 hydroxylase activity and oxygen levels. Once in the matrix, PHD3 directly hydroxylates PC, suppressing its enzymatic activity. In ccRCC with elevated PHD3 expression, this modification restricts anaplerotic flux into the tricarboxylic acid cycle, leading to impaired proliferation, reduced metastasis, and enhanced apoptosis. Together, our findings provide a new framework for targeting cancer metabolism by establishing a previously unrecognized mechanistic link between PHD3-mediated oxygen sensing within the tumor microenvironment and the regulation of ccRCC mitochondrial metabolism through the subcellular re-localization of PHD3.

Journal Article↗
PubMed2026

The establishment of prostate-specific, SKP2 humanized mice by CRISPR knock-in method reveals neoplastic initiation and microenvironmental reprogramming.

Genetic inactivation of SKP2 has been shown to effectively prevent cancer initiation and block tumorigenesis. However, direct in vivo evidence for SKP2 on cancer initiation and prostatic microenvironment is still lacking and a SKP2 humanized mouse model is critical for developing prostate cancer immunoprevention approaches through targeting SKP2. We therefore have established a prostate-specific human SKP2 knock-in mouse model driven by an endogenous mouse probasin promoter. Overexpression of hSKP2 induces PIN and low-grade carcinoma. RNA-sequencing analysis revealed significant gene expression alterations in EMT, extracellular matrix, and interferon signaling. Single-cell deconvolution showed an increase of fibroblast population and a decrease of CD8+ T cell and B cell populations. Consistent with these results from the SKP2 humanized mouse, SKP2 protein is overexpressed in human prostatic hyperplasia, PIN and prostate adenocarcinoma compared to normal prostate tissues. Overexpression of SKP2 markedly increased cell migration and invasion and induced the gene expression of EMT and interferon pathways. Inhibition of SKP2 signaling by Flavokawain A and C1 reverses EMT and affects EMT and interferon-related gene expression. In addition, paired prostate organoids were derived from SKP2 humanized and wild-type mice for drug screening and validated by known SKP2 inhibitors, Flavokawain A and C1. Both of which selectively decreased viability and altered the morphologies of organoids of hSKP2 knock-in rather than wild-type mice. Our studies provide a well-characterized prostate-specific hSKP2 knock-in mouse model and offer new mechanistic insights for understanding the oncogenic role of SKP2 in shaping the prostatic microenvironment during early carcinogenesis.

Animals↗
PubMed2026

Single-cell multiomics reveals exosome-mediated reprogramming and clonotypic remodeling of T cells in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive and immunogenic subtype lacking targeted therapies. While tumor-derived exosomes are known to modulate immune function, their direct impact on human T cell plasticity and antigen specificity remains poorly defined. Here, we conducted a comprehensive single-cell multiomic analysis of primary human T cells exposed to exosomes derived from 17 genomically diverse TNBC cell lines and 35 patient samples. Integrating single-cell RNA-seq, V(D)J sequencing, non-coding RNA profiling, bulk and single-cell cytokine analyses, we uncovered conserved and subtype-specific immunomodulatory programs induced by TNBC exosomes. Exosome-treated T cells displayed skewing toward regulatory and dysfunctional phenotypes, including Th17-like, Treg, and PD-1&#x207a;/PD-L1&#x207a; Tfh cells. Functional profiling revealed suppression of early activation markers and cytokine responses, alongside selective preservation of cytotoxic features in &#x3b3;&#x3b4; T and NKT subsets. Transcriptomic and miRNA network analyses demonstrated widespread downregulation of immune effector genes (e.g., HBEGF and TNFSF9) mediated by exosome-delivered regulatory miRNAs (has-miR-98-5p). Notably, exosome-stimulated T cells displayed distinct clonotypic expansions, characterized by the emergence of five tumor-specific &#x3b3;&#x3b4; TCR clonotypes and 30 unique &#x3b1;&#x3b2; TCR CDR3 sequences that were absent in mock-treated controls, underscoring the role of exosomes in shaping TCR repertoire dynamics.

Humans↗
PubMed1988

Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload.

Hypertrophy, an increase in cell size without cell division, is a fundamental adaptive process employed by postmitotic cardiac and skeletal muscle cells. Cardiac myosins undergo an adult-to-fetal isoform transition in various models of hypertrophy. Using gene-specific cDNA probes, we show here that in the adult myocardium the mRNAs encoding the fetal (skeletal muscle type) isoforms of alpha-actin and sarcomeric tropomyosin are re-expressed within 2 days in response to pressure overload. In addition, atrial natriuretic factor mRNA, so far believed to be expressed primarily in the atria, was readily detectable in the ventricles of neonates and was induced to markedly high levels in pressure-overloaded adult ventricles. In contrast, cardiac hypertrophy produced by thyroid hormone excess was not associated with induction of the atrial natriuretic factor gene or fetal contractile protein isogenes. Furthermore, the c-fos and c-myc protooncogenes and a major heat shock protein gene (hsp70) are induced in the ventricular myocardium within 1 hr after imposition of pressure overload. These results suggest that induction of cellular protooncogenes and heat shock (stress) protein genes is an early response to pressure overload, whereas reinduction of the genes normally expressed only in perinatal life, such as fetal isoforms of contractile proteins and atrial natriuretic factor, is a later event. These two types of responses might represent the general pattern of growth induction to work overload by terminally differentiated cells that have lost the ability to undergo DNA replication.

Aging↗
PubMed2026

Circadian reprogramming of inflammation and metabolism in chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is driven by inflammation, fibrosis, and metabolic dysfunction. While circadian rhythm dysregulation is well documented in chronic disorders, its specific impact on CKD pathogenesis remains elusive. METHODS: We performed four-hour interval time-series RNA sequencing on renal tissues from control and CKD mice. We used the JTK_CYCLE algorithm to identify rhythmic genes and categorize them as lost, acquired, or sustained in CKD; we subsequently performed focused bioinformatic analyses. RESULTS: The renal circadian profile was substantially altered; acquired rhythmicity emerged as the dominant pattern, and core clock gene expression was disrupted. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that upregulated acquired-rhythmic genes in CKD were enriched in immune-inflammatory pathways; the expression of these genes peaked at Zeitgeber time (ZT) 12-16, consistent with a higher level of renal macrophage infiltration at ZT16 than at ZT0. Conversely, genes associated with nutrient and energy metabolism pathways were downregulated but acquired rhythmicity in CKD. Dapagliflozin improved renal function and restored the circadian expression rhythms of NR1D1 and p-BMAL1. CONCLUSIONS: CKD profoundly remodels the renal circadian transcriptome, driving immune-inflammatory and metabolic pathways into maladaptive rhythmicity. Furthermore, dapagliflozin can partially restore the expression of renal core clock genes.

Animals↗
PubMed2025

Conserved lipid metabolic reprogramming confers hypoxic and aging resilience.

The Arctic ground squirrel (AGS, Urocitellus parryii), an extreme hibernator, exhibits remarkable resilience to stressors like hypoxia and hypothermia, making it an ideal model for studying cellular metabolic adaptation. The underlying mechanisms of AGS resilience are largely unknown. Here, we use lipidomic and metabolomic profiling to discover specific downregulation of triglyceride lipids and upregulation of the lipid biosynthetic precursor malonic acid in AGS neural stem cells (NSC) versus murine NSCs. Inhibiting lipid biosynthesis recapitulates hypoxic resilience of squirrel NSCs. Extending this model, we find that acute exposure to hypoxia downregulates key lipid biosynthetic enzymes in C. elegans, while inhibiting lipid biosynthesis reduces mitochondrial fission and facilitates hypoxic survival. Moreover, inhibiting lipid biosynthesis protects against APOE4-induced pathologies and aging trajectories in C. elegans. These findings suggest triglyceride downregulation as a conserved metabolic resilience mechanism, offering insights into protective strategies for neural tissues under hypoxic or ischemic conditions, APOE4-induced pathologies and aging.

Journal Article↗
PubMed1990

Reprogramming cell fate in the developing Drosophila retina: transformation of R7 cells by ectopic expression of rough.

In the developing eye of Drosophila, the homeo box gene rough is required in the developing photoreceptor cells R2 and R5 for the correct development of the neighboring R3 and R4 cells. We have expressed rough ectopically in a limited subset of developing ommatidial cells using the sevenless enhancer. Expression of rough in the presumptive R7 cell transforms this cell into an R1-6 type photoreceptor. This transformation is cell autonomous in contrast to the apparent nonautonomy of the rough mutant phenotype and depends on the presence of the sevenless gene. We propose that in wild type, rough functions autonomously in the specification of R2/5 photoreceptor cell identity but by itself cannot initiate neural development.

Animals↗