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Results for “Metabolic Reprogramming”

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At least 343 records · Page 19Linked to original sources

PubMed2006

Regulation of fat storage via suppressed thermogenesis: a thrifty phenotype that predisposes individuals with catch-up growth to insulin resistance and obesity.

Catch-up growth during infancy and childhood is increasingly recognized as a major risk factor for later development of insulin-related complications and chronic diseases, namely abdominal obesity, type 2 diabetes and cardiovascular disease. As catch-up growth per se is characterized by insulin resistance, hyperinsulinaemia and an accelerated rate of fat storage (i.e., catch-up fat) even in the absence of hyperphagia, the possibility arises that suppressed thermogenesis in certain organs/tissues - for the purpose of enhancing the efficiency of catch-up fat - also plays a role in the pathophysiological consequences of catch-up growth. Here, the evidence for the existence of an adipose-specific control of thermogenesis, the suppression of which contributes to catch-up fat, is reviewed. Recent findings suggest that such suppression of thermogenesis is accompanied by hyperinsulinaemia, insulin resistance in skeletal muscle and insulin hyperresponsiveness in adipose tissue, all of which precede the appearance of excess body fat, central fat distribution and elevations in intramyocellular triglyceride or circulating lipid concentrations. These findings underscore a role for suppressed thermogenesis per se as an early event in the pathophysiology of catch-up growth. It is proposed that, in its evolutionary adaptive role to spare glucose for the rapid rebuilding of an adequate fat reserve (for optimal survival capacity during intermittent famine), suppressed thermogenesis in skeletal muscle constitutes a thrifty phenotype that confers to the phase of catch-up growth its high sensitivity to the development of insulin resistance and hyperinsulinaemia. In the context of the complex interactions between earlier reprogramming and a modern lifestyle characterized by nutritional abundance and low physical activity, this thrifty 'catch-up fat phenotype' is a central event that predisposes individuals with catch-up growth to abdominal obesity, type 2 diabetes and cardiovascular disease.

Adipose Tissue↗

PubMed2001

Directed inhibition of nuclear import in cellular hypertrophy.

Each nuclear pore is responsible for both nuclear import and export with a finite capacity for bidirectional transport across the nuclear envelope. It remains poorly understood how the nuclear transport pathway responds to increased demands for nucleocytoplasmic communication. A case in point is cellular hypertrophy in which increased amounts of genetic material need to be transported from the nucleus to the cytosol. Here, we report an adaptive down-regulation of nuclear import supporting such an increased demand for nuclear export. The induction of cardiac cell hypertrophy by phenylephrine or angiotensin II inhibited the nuclear translocation of H1 histones. The removal of hypertrophic stimuli reversed the hypertrophic phenotype and restored nuclear import. Moreover, the inhibition of nuclear export by leptomycin B rescued import. Hypertrophic reprogramming increased the intracellular GTP/GDP ratio and promoted the nuclear redistribution of the GTP-binding transport factor Ran, favoring export over import. Further, in hypertrophy, the reduced creatine kinase and adenylate kinase activities limited energy delivery to the nuclear pore. The reduction of activities was associated with the closure of the cytoplasmic phase of the nuclear pore preventing import at the translocation step. Thus, to overcome the limited capacity for nucleocytoplasmic transport, cells requiring increased nuclear export regulate the nuclear transport pathway by undergoing a metabolic and structural restriction of nuclear import.

Animals↗

PubMed2026

Tissue-Level Transcriptomic Entropy Reveals Organ-Specific Aging Patterns and Predicts Cancer Progression.

Although aging and cancer share complex molecular mechanisms, distinguishing causative factors from byproducts remains challenging. Here, we investigated the role of tissue transcriptomic entropy-a measure of transcriptional disorder-in aging and cancer processes by analyzing RNA-sequencing data from over 25,000 samples from human and mouse tissues. We found that entropy changes during aging are highly tissue-specific, with some tissues showing increased entropy while others exhibit decreased or stable entropy levels. Moreover, transcriptomic entropy strongly correlates with age-related processes, showing positive associations with proliferation, cellular senescence, somatic mutation burden, and cellular reprogramming, whereas it negatively correlates with stemness. In cancer, we observed that primary tumors generally display higher entropy than normal tissue, with its levels further increasing in metastatic stages. Cancer treatment modulated entropy patterns in multiple contexts, with changes suggesting a role for transcriptional complexity in tumor plasticity and therapy resistance. Elevated entropy levels predicted poor survival outcomes in multiple cancer types, suggesting its potential as a prognostic marker. Furthermore, differential expression analysis revealed that entropy-associated genes are enriched in developmental processes and depleted in metabolic pathways, indicating a possible link to cellular dedifferentiation. Finally, we found increased entropy in various age-related disorders beyond cancer, suggesting that transcriptomic entropy may be a common feature in age-related diseases. Our findings establish transcriptomic entropy as a fundamental parameter in aging and cancer progression, offering new insights into disease mechanisms.

Humans↗

PubMed1993

Cellular tolerance as a dynamic state of the adaptable lymphocyte.

The regulation of immunological tolerance is considered from the perspective of contextual discrimination, rather than self-nonself discrimination. According to the adaptive lymphocyte hypothesis, the scale of immune aggression versus tolerance can be regulated at the cell population level, but individual cells also tune and update their responsiveness under the influence of recurrent signals. The generation of a sizeable conventional immune response, which is transient and aggressive, depends critically on the perturbation to the system, which is related to the rate of appearance of the immunizing agent. These characteristics are explained in quantitative terms by the "balance of growth and differentiation model". Strong perturbations are typically associated, physiologically, with acute infections. Full activation of individual lymphocytes also requires strong metabolic perturbations, where the perturbation is defined as a measure of variation in the intensity of stimulation. Cells that fail to be activated in this way may be driven into a state which formally conforms to the operational definition of anergy. This state is characterized by a variable degree of resistance to the stereotypic mode of activation for which the cell has been programmed before. While in this state, the cell interacts with its environment: these interactions promote its viability, update its activation thresholds and its excitability, and may reprogram the cell for a different mode of response when activated later. In addition, cells engaged in such interactions may mediate context-dependent immunological functions. The characteristics of the interactions involving such anergic cells are discussed in semi-quantitative terms with the help of the "tunable activation-thresholds model". Several aspects of immunological tolerance are interpreted in a unifying way based on this conceptual framework. It is suggested that progress in our ability to evaluate and manipulate the regulation of immunological tolerance would require a methodology to conjoin many pieces of data together and to look for patterns.

Adaptation, Physiological↗

PubMed2026

Hepatocyte-Specific Deficiency of Endoplasmic Reticulum-Associated Degradation Induces Coordinated Innate-Adaptive Immune Responses.

Hepatic inflammation is a defining feature of Metabolic Dysfunction-Associated Steatohepatitis (MASH), yet the specific contributions of individual immune cell populations and their reciprocal interactions remain incompletely understood. In this study, we combined flow cytometry with single-cell transcriptomic profiling to characterize the hepatic immune landscape in a novel model of spontaneous MASH caused by hepatocyte-specific deficiency of endoplasmic reticulum-associated degradation (ERAD). Hepatic ERAD deficiency led to the expansion of multiple immune cell populations in the liver, including CD8+ T cells, macrophages, monocytes, and dendritic cells, accompanied by extensive functional reprogramming of both innate and adaptive immune compartments. Myeloid cells exhibited enhanced phagocytic activity and increased antigen processing and presentation, whereas CD8+ T cells displayed elevated proliferation capacity, DNA repair activity and cytotoxicity. Notably, two functionally distinct triggering receptor expressed on myeloid cells 2 (TREM2)-expressing macrophage subsets emerged during the progression of ERAD deficiency-induced MASH. Depletion of CD8+ T cells increased monocyte infiltration and aggravated liver injury, suggesting that CD8+ T cells exert a previously unrecognized protective role by restraining monocyte recruitment. Collectively, these findings reveal highly coordinated interactions between innate and adaptive cells during MASH progression and identify CD8+ T cells as potential regulators of monocyte infiltration and hepatic injury.

Animals↗

PubMed2006

Linking the nutritional status of Streptococcus pyogenes to alteration of transcriptional gene expression: the action of CodY and RelA.

In this investigation, we identify the CodY protein from Streptococcus pyogenes as a pleiotropic transcription regulator with global features. The notion that acquisition of nutrients by this polyauxotrophic organism is the primary event occurring during the establishment of infection and that virulence expression is a result of this quest, led us to study the action of codY and relA genes on transcriptional gene expression under different nutritional conditions using complex and chemically defined media. Real-time reverse transcription PCR was used to determine the extent to which inactivation of codY and relA affects the mRNA levels of selected transcription factors, virulence genes, transporters, and genes encoding metabolic enzymes. The results show that CodY and RelA did not affect the expression of each other but that both exhibited strong negative autoregulatory properties. Genes negatively controlled by the relA-directed stringent response to amino acid starvation included, besides relA itself, transporters, metabolic enzymes, and at least two virulence genes (graB and speH). The expression of many genes of all four groups studied proved to be subject to direct or indirect control by CodY, often in a nutritional status-dependent fashion. One of the most important results implicates CodY in growth phase-dependent positive transcriptional regulation of pel/sagA and mga, loci that themselves positively affect the expression of numerous virulence factors. Increasing the cellular activity of nicotinamidase in both a codY mutant and wild-type background induced extensive transcriptional reprogramming, altering, among others, the growth phase-dependent transcription pattern of the genes for cysteine protease (speB) and several transporters. Inasmuch as CodY influenced the expression of other regulators (pel/sagA, mga, covRS, ropB, pyrR), its action is amplified and expands the complex regulatory network that governs gene expression in S. pyogenes.

Adaptation, Physiological↗

PubMedDate not supplied

Biochemical strategy of hepatomas.

An insight into the ordered pattern of enzymatic and biochemical imbalance of cancer cells was made possible, at least in part, by the molecular correlation concept, the concept of key enzymes, and the use of biological model systems. With these approaches the pattern of gene expression in neoplasia can be studied in terms of the activities of key enzymes and their linking with neoplastic transformation and progression. An ordered pattern of biochemical imbalance was recognized in carbohydrate, pentose phosphate, purine, pyrimidine, DNA, and polyamine metabolism and in other biochemical areas. Current work is directed to clarifying the enzymology and metabolic pattern of thymidine metabolism and CTP biosynthesis since these areas are of particular importance in selective chemotherapy and rescue. The activities of key enzymes in thymidine metabolism have been correlated with the growth rates in a spectrum of hepatomas. Increases in the activities of four key enzymes in CTP biosynthesis appear to be specific to neoplasia because no similar pattern was observed in the normal adult resting or regenerating liver or in the fetal and developing liver. The overall pattern discovered in transplantable rat hepatomas applies to other rodent tumors. It is of particular importance that the pattern of biochemical imbalance is also applicable to human hepatocellular carcinomas. With the recognition of the ordered pattern of reprogramming of gene expression in hepatomas, the path is open for the development of sensitive assays for biochemical diagnosis of liver tumors and for a rational design of selective chemotherapy and rescue.

Animals↗

PubMed2000

Understanding the growth phenotype of the yeast gcr1 mutant in terms of global genomic expression patterns.

The phenotype of an organism is the manifestation of its expressed genome. The gcr1 mutant of yeast grows at near wild-type rates on nonfermentable carbon sources but exhibits a severe growth defect when grown in the presence of glucose, even when nonfermentable carbon sources are available. Using DNA microarrays, the genomic expression patterns of wild-type and gcr1 mutant yeast growing on various media, with and without glucose, were compared. A total of 53 open reading frames (ORFs) were identified as GCR1 dependent based on the criterion that their expression was reduced twofold or greater in mutant versus wild-type cultures grown in permissive medium consisting of YP supplemented with glycerol and lactate. The GCR1-dependent genes, so defined, fell into three classes: (i) glycolytic enzyme genes, (ii) ORFs carried by Ty elements, and (iii) genes not previously known to be GCR1 dependent. In wild-type cultures, GCR1-dependent genes accounted for 27% of the total hybridization signal, whereas in mutant cultures, they accounted for 6% of the total. Glucose addition to the growth medium resulted in a reprogramming of gene expression in both wild-type and mutant yeasts. In both strains, glycolytic enzyme gene expression was induced by the addition of glucose, although the expression of these genes was still impaired in the mutant compared to the wild type. By contrast, glucose resulted in a strong induction of Ty-borne genes in the mutant background but did not greatly affect their already high expression in the wild-type background. Both strains responded to glucose by repressing the expression of genes involved in respiration and the metabolism of alternative carbon sources. Thus, the severe growth inhibition observed in gcr1 mutants in the presence of glucose is the result of normal signal transduction pathways and glucose repression mechanisms operating without sufficient glycolytic enzyme gene expression to support growth via glycolysis alone.

DNA-Binding Proteins↗

PubMed2006

Host cell responses induced by hepatitis C virus binding.

Initiation of hepatitis C virus (HCV) infection is mediated by docking of the viral envelope to the hepatocyte cell surface membrane followed by entry of the virus into the host cell. Aiming to elucidate the impact of this interaction on host cell biology, we performed a genomic analysis of the host cell response following binding of HCV to cell surface proteins. As ligands for HCV-host cell surface interaction, we used recombinant envelope glycoproteins and HCV-like particles (HCV-LPs) recently shown to bind or enter hepatocytes and human hepatoma cells. Gene expression profiling of HepG2 hepatoma cells following binding of E1/E2, HCV-LPs, and liver tissue samples from HCV-infected individuals was performed using a 7.5-kd human cDNA microarray. Cellular binding of HCV-LPs to hepatoma cells resulted in differential expression of 565 out of 7,419 host cell genes. Examination of transcriptional changes revealed a broad and complex transcriptional program induced by ligand binding to target cells. Expression of several genes important for innate immune responses and lipid metabolism was significantly modulated by ligand-cell surface interaction. To assess the functional relevance and biological significance of these findings for viral infection in vivo, transcriptional changes were compared with gene expression profiles in liver tissue samples from HCV-infected patients or controls. Side-by-side analysis revealed that the expression of 27 genes was similarly altered following HCV-LP binding in hepatoma cells and viral infection in vivo. In conclusion, HCV binding results in a cascade of intracellular signals modulating target gene expression and contributing to host cell responses in vivo. Reprogramming of cellular gene expression induced by HCV-cell surface interaction may be part of the viral strategy to condition viral entry and replication and escape from innate host cell responses.

Antigens, Viral↗

PubMed1996

High cAMP levels antagonize the reprogramming of gene expression that occurs at the diauxic shift in Saccharomyces cerevisiae.

In order to analyse the involvement of the cAMP pathway in the regulation of gene expression in Saccharomyces cerevisiae, we have examined the effect of cAMP on protein synthesis by using two-dimensional gel electrophoresis. cAMP had only a minor effect on the protein pattern of cells growing exponentially on glucose. However, it interfered with the changes in gene expression normally occurring upon glucose exhaustion in yeast cultures, maintaining a protein pattern typical of cells growing on glucose. This effect was accompanied by a delay before growth recovery on ethanol. We propose a model in which the cAMP-signalling pathway has a role in the maintenance of gene expression, rather than in the determination of a specific programme. A decrease of cAMP would then be required for metabolic transitions such as the diauxic phase.

Cyclic AMP↗

PubMed2006

Phenotypic plasticity of adult myocardium: molecular mechanisms.

Cardiac phenotypic plasticity (so-called cardiac remodelling, CR) is characterized by changes in myocardial structure that happen in response to either mechanical overload or a loss of substance such as that occurring after myocardial infarction. Mechanosensation is a widespread biological process and is inextricably mixed with other transduction systems from hormones and vasopeptides, which ultimately produce post-translational modifications of transcription factors. The expression of the four main transcription factors during cardiogenesis is also enhanced as a link to foetal reprogramming. CR results from re-expression of the foetal programme, which is mostly adaptive, but also from several other phenotypic modifications that are not usually adaptive, such as fibrosis. (i) The initial determinant is mechanical, and re-expression of the foetal programme includes a global increase in genetic expression with cardiac hypertrophy, re-expression of genes that are normally not expressed in the adult ventricles, repression of genes not expressed during the foetal life, and activation of pre-exisiting stem cells. Microarray technology has revealed a coordinated change in expression of genes pertaining to signal transduction, metabolic function, structure and motility, and cell organism defence. The physiological consequence is a better adapted muscle. (ii) During clinical conditions, the effects of mechanics are modified by several interfering determinants that modify CR, including senescence, obesity, diabetes, ischemia and the neurohormonal reaction. Each of these factors can alter myocardial gene expression and modify molecular remodelling of mechanical origin. Finally, as compared to evolutionary phenotypic plasticity described in plants and insects in response to variations in environmental conditions, in CR, the environmental factor is internal, plasticity is primarily adaptive, and it involves coordinated changes in over 1400 genes. Study of reaction norms showed that the genotypes from different animal species are similarly plastic, but there are transgenic models in which adaptation to mechanics is not caused by hypertrophy but by qualitative changes in gene expression.

Adaptation, Physiological↗

PubMed2003

Two operative concepts for the post-genomic era: the "mémoire vive" of the cell and a molecular algebra.

The first successes in cloning experiments and stem cell "reprogramming" have already demonstrated the primordial role of cellular working-space memory and regulatory mechanisms, which use the knowledge stored in the DNA database in read mode. We present an analogy between living systems and informatics systems by considering: 1) the cell cytoplasm as a memory device accessible as read/write; 2) the mechanisms of regulation as a programming language defined by a grammar, a molecular algebra; 3) biological processes as volatile programs which are executed without being written; 4) DNA as a database in read only mode. We also present applications to two biological algorithms: the immune response and glycogen metabolism.

Biomimetics↗

PubMed2005

Reprogramming of the human atrial transcriptome in permanent atrial fibrillation: expression of a ventricular-like genomic signature.

Atrial fibrillation is associated with increased expression of ventricular myosin isoforms in atrial myocardium, regarded as part of a dedifferentiation process. Whether reexpression of ventricular isoforms in atrial fibrillation is restricted to transcripts encoding for contractile proteins is unknown. Therefore, this study compares atrial mRNA expression in patients with permanent atrial fibrillation to atrial mRNA expression in patients with sinus rhythm and to ventricular gene expression using Affymetrix U133 arrays. In atrial myocardium, we identified 1434 genes deregulated in atrial fibrillation, the majority of which, including key elements of calcium-dependent signaling pathways, displayed downregulation. Functional classification based on Gene Ontology provided the specific gene sets of the interdependent processes of structural, contractile, and electrophysiological remodeling. In addition, we demonstrate for the first time a prominent upregulation of transcripts involved in metabolic activities, suggesting an adaptive response to increased metabolic demand in fibrillating atrial myocardium. Ventricular-predominant genes were 5 times more likely to be upregulated in atrial fibrillation (174 genes upregulated, 35 genes downregulated), whereas atrial-specific transcripts were predominantly downregulated (56 genes upregulated, 564 genes downregulated). Overall, in fibrillating atrial myocardium, functional classes of genes characteristic of ventricular myocardium were found to be upregulated (eg, metabolic processes), whereas functional classes predominantly expressed in atrial myocardium were downregulated (eg, signal transduction and cell communication). Therefore, dedifferentiation with adoption of a ventricular-like signature is a general feature of the fibrillating atrium.

Atrial Fibrillation↗

PubMed2002

A gene expression profile that defines colon cell maturation in vitro.

Colonic epithelial cells undergo cell cycle arrest, lineage specific differentiation, and apoptosis, as they migrate along the crypt axis toward the lumenal surface. The Caco-2 colon carcinoma cell line models many of these phenotypic changes, in vitro. We used this model system and cDNA microarray analysis to characterize the genetic reprogramming that accompanies colon cell differentiation. The analyses revealed extensive yet functionally coordinated alterations in gene expression during the differentiation program. Consistent with cell differentiation reflecting a more specialized phenotype, the majority of changes (70%) were down-regulations of gene expression. Specifically, Caco-2 cell differentiation was accompanied by the coordinate down-regulation of genes involved in cell cycle progression and DNA synthesis, which reflected the concomitant reduction in cell proliferation. Simultaneously, genes involved in RNA splicing and transport, protein translation, folding, and degradation, were coordinately down-regulated, paralleled by a reduction in protein synthesis. Conversely, genes involved in xenobiotic and drug metabolism were up-regulated, which was linked to increased resistance of differentiated cells to chemotherapeutic agents. Increased expression of genes involved in extracellular matrix deposition, lipid transport, and lipid metabolism were also evident. Underlying these altered profiles of expression, components of signal transduction pathways, and several transcription factors were altered in expression.

Alternative Splicing↗

PubMed2026

Deconstructing the Alternative Lengthening of Telomeres: Integromics Prioritizes Five Master Hubs Dictating Clinical Survival and Therapeutic Vulnerabilities.

The Alternative Lengthening of Telomeres (ALT) pathway drives replicative immortality in aggressive malignancies, particularly sarcomas and gliomas. Clinical ALT stratification has relied on screening for structural ATRX and DAXX mutations. However, this genotypic approach fails to capture the dynamic macro-reprogramming required to sustain ALT. Here, we established and validated a 28-gene transcriptomic signature that captures the ALT-associated transcriptomic phenotype of the ALT phenotype. Using multivariate Cox proportional hazards models and time-dependent ROC analyses, we demonstrate that this signature is a robust, independent predictor of poor overall survival in Sarcoma (SARC) and Lower Grade Glioma (LGG) cohorts, outperforming the prognostic value of traditional ATRX/DAXX mutational status. Genomic mapping revealed this transcriptional synchrony is structurally facilitated by non-random focal clustering on Chromosome 8. To deconstruct the machinery driving this lethal phenotype, we employed an integromic approach, synthesizing protein-protein and metabolic flux networks. Topological algorithms prioritized five indispensable hubs: TP53, ATM, ATR, PCNA, and UBE2I. Gene-metabolite profiling identified PCNA as a bottleneck funneling extreme deoxyribonucleotide (dNTP) demand to sustain break-induced telomeric recombination. To translate these vulnerabilities into actionable treatments, we mapped these hubs to a precision pharmacological network. We propose a multi-targeted strategy combining FDA-approved PARP inhibitors to exploit ATR-mediated synthetic lethality, alongside antimetabolites to induce nucleotide starvation. This study redefines ALT risk stratification and provides a data-driven framework to target and treat resistant ALT-positive tumors.

Alternative Lengthening of Telomeres↗

PubMed2026

Functional and Proteomic Profiles of CD3(+) Plasma-Derived Small Extracellular Vesicles Differentiate Cancer Patients From Healthy Donors.

Small extracellular vesicles (sEV) released by T cells play a key role in immune regulation. Immune capture with anti-CD3 antibodies was used to isolate and study T cell-derived CD3(+)sEV from the plasma of patients with melanoma (MPs) or healthy donors (HDs). Functional responses induced in recipient target cells by CD3(+)sEV of MPs differed from responses induced by CD3(+)sEV of HDs. Approximating functions mediated by melanoma cell-derived sEV (MTEX), CD3(+)sEV of MPs reduced metabolic activity and proliferation of T cells while promoting activity in Mel526 cell targets. Proteomics profiling confirmed functional differences between CD3(+)sEV of MPs and HDs. Of 294 sEV-specific proteins identified in CD3(+)sEV, 226 were detected in the parent T cell proteome, confirming that the CD3(+)sEV proteome mimics that of the parent T lymphocytes. Among them were 66 differentially expressed proteins (DEPs) that differentiated vesicles from MPs and HDs. These DEPs were associated with processes linked to cancer-related functions. DEPs upregulated in CD3(+)sEV of MPs were associated with RHO-GTPase, cytokine, and MAPK signaling pathways. Thus, T cells of MPs were reprogrammed by MTEX to produce CD3(+)sEV that functionally resembled MTEX, partly recapitulated features of the tumor proteome, and differed from CD3(+)sEV of HDs. In cancer, the TEX-rewired T cells produce CD3(+)sEV that potentially could serve as a liquid biopsy of patients' T cells.

Humans↗

PubMed2026

Multi-omics integration uncovers adaptive responses of stomach and pyloric ceca to artificial feed in mandarin fish (Siniperca chuatsi).

The mandarin fish, as an obligate piscivore, is highly dependent on live bait, which restricts its intensive aquaculture. Although domestication has enabled it to partially accept formulated diets, the tissue-specific molecular adaptation mechanisms of its digestive tract to artificial feed remain unclear. In this study, we conducted an integrated analysis of mandarin fish fed with live bait or artificial diet for three weeks, combining growth performance evaluation, gastric histology, and paired transcriptomic and metabolomic analyses of the stomach and pyloric ceca. AD feeding significantly improved growth performance, while histological examination revealed marked hyperplasia of the gastric mucosa and disorganized fold structures. Transcriptomic analysis identified 5065 and 3381 differentially expressed genes in the stomach and pyloric ceca, respectively. In the stomach, the artificial diet induced a glutathione-dependent antioxidant response, accompanied by glycolytic reprogramming and coordinated upregulation of genes in the extracellular matrix (ECM)-receptor interaction signaling pathway, including those encoding collagen, laminin, and integrin. In the pyloric ceca, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation were broadly suppressed, whereas glycosaminoglycan degradation and lysosomal pathways were activated. Metabolomic analysis showed that gastric metabolites were enriched in vascular and inflammatory mediator pathways, while metabolites in the pyloric ceca were enriched in peroxisome proliferator-activated receptor (PPAR) signaling, sphingolipid signaling, and steroid hormone biosynthesis pathways. Following artificial diet feeding, integrated multi-omics analysis of the stomach revealed significant enrichment of pathways such as phospholipase D signaling, sphingolipid signaling, and arachidonic acid metabolism, accompanied by the accumulation of key metabolites including sphingosine-1-phosphate, 20-hydroxyeicosatetraenoic acid, and cellobiose. Integrated analysis of the pyloric ceca identified significantly altered pathways, including sphingolipid metabolism, alpha-linolenic acid metabolism, and glutathione metabolism, along with elevated levels of sphingosine-1-phosphate, sphingosine galactoside, and 9-hydroxy-12-oxo-10,15-octadecadienoic acid, as well as decreased glutathionylspermidine. These findings systematically unveil the tissue-specific molecular adaptation characteristics of the mandarin fish digestive tract in response to artificial feed, providing an important basis for understanding the molecular mechanisms of dietary adaptation in carnivorous fish and for optimizing artificial feed formulations.

Animals↗

PubMed2001

Silencing of Wnt signaling and activation of multiple metabolic pathways in response to thyroid hormone-stimulated cell proliferation.

To investigate the transcriptional program underlying thyroid hormone (T3)-induced cell proliferation, cDNA microarrays were used to survey the temporal expression profiles of 4,400 genes. Of 358 responsive genes identified, 88% had not previously been reported to be transcriptionally or functionally modulated by T3. Partitioning the genes into functional classes revealed the activation of multiple pathways, including glucose metabolism, biosynthesis, transcriptional regulation, protein degradation, and detoxification in T3-induced cell proliferation. Clustering the genes by temporal expression patterns provided further insight into the dynamics of T3 response pathways. Of particular significance was the finding that T3 rapidly repressed the expression of key regulators of the Wnt signaling pathway and suppressed the transcriptional downstream elements of the beta-catenin-T-cell factor complex. This was confirmed biochemically, as beta-catenin protein levels also decreased, leading to a decrease in the transcriptional activity of a beta-catenin-responsive promoter. These results indicate that T3-induced cell proliferation is accompanied by a complex coordinated transcriptional reprogramming of many genes in different pathways and that early silencing of the Wnt pathway may be critical to this event.

Animals↗