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At least 379 records · Page 21Linked to original sources
PubMed2026

Progressive salinity drives flavonoid branch reprogramming in Anoectochilus roxburghii.

Flavonoids play critical roles in plant adaptation to abiotic stress; however, how salt stress modulates metabolic flux distribution within flavonoid branches remains poorly understood, particularly in non-model medicinal plants. Here, we integrated targeted metabolomics, transcriptomics, and proteomics to examine flavonoid regulation in Anoectochilus roxburghii under 0, 50, 100, and 200 mmol·L- 1 NaCl. Metabolite profiling showed that salinity reshaped flavonoid composition rather than uniformly increasing flavonoid abundance. A metabolite-derived branch bias index (MI), representing the balance between reductive branch metabolites and flavonol products, increased under salt treatment, peaked at 100 mmol·L- 1 NaCl, and declined at 200 mmol·L- 1, indicating maximal branch bias under moderate stress followed by partial rebalancing under severe stress. Transcriptomic analysis showed induction of upstream phenylpropanoid and flavonoid entry genes, including PAL, 4CL, and CHS, whereas F3H was suppressed and FLS showed no induction. Furthermore, several short-chain dehydrogenase/reductase homologs (IFR-like SDR homologs) were upregulated, and the transcript-derived reductive branch index (EI) increased progressively across the salt gradient. EI was positively associated with MI, although the relationship was not strictly proportional under severe stress (200 mmol·L- 1 NaCl). Proteomic profiling further provided supportive evidence for sustained activation of upstream flavonoid biosynthesis, such as salt-induced accumulation of chalcone synthase (CHS) protein, complementing the transcriptomic and metabolomic datasets. Together, these results indicate that salt stress reorganizes flavonoid metabolism in A. roxburghii through persistent upstream activation and branch-specific regulation, favoring the reductive branch under moderate salinity.

Orchidaceae↗
PubMed2026

Epigenetic alterations of AKT1 orchestrate a metabolic reprogramming in advanced lipedema: translational insights from an integrated multi-omics study.

BACKGROUND: lipedema is a chronic, progressive adipose disorder predominantly affecting women, characterized by painful, symmetrical subcutaneous fat accumulation, and typically resistant to lifestyle interventions. The pathophysiology of advanced-stage lipedema remains poorly defined, and no validated biomarkers or targeted therapies are currently available. METHODS: in this observational study, we applied a comprehensive multi-omics approach to dissect the molecular and metabolic alterations underlying late-stage lipedema. RESULTS: Genome-wide DNA methylation profiling identified over 5,000 differentially methylated CpG sites affecting genes involved in receptor tyrosine kinase signaling, phospho-metabolism, and immune pathways. Transcriptomic analysis revealed profound downregulation of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and fatty acid β-oxidation, alongside disruption of the sirtuin pathway and extracellular matrix remodeling. Integrative analysis pinpointed AKT1 as a central regulatory node: its promoter region was hypomethylated, correlating with increased gene expression and protein phosphorylation. Metabolomic profiling confirmed AKT1-linked metabolic dysregulation, including altered levels of L-arginine, NADP+, ATP, guanosine, glycerol, and glutamate, indicating impaired redox balance and energy metabolism. Trans-omic network analysis positioned AKT1 at the intersection of multiple dysregulated pathways, suggesting its key role in advanced-stage lipedema. CONCLUSIONS: the consistent enhancing of AKT pathway signaling across omic layers highlights its potential not only as a biomarker for disease stratification but also as a putative druggable target for therapeutic intervention. These findings offer new mechanistic insights into lipedema pathophysiology and provide a rationale for future personalized treatment strategies guided by AKT1-centric molecular profiling.

Proto-Oncogene Proteins c-akt↗
PubMed1996

Growth retardation of tumors by adoptive transfer of cytotoxic T lymphocytes reprogrammed by CD44v6-specific scFv:zeta-chimera.

Variants of the CD44 protein family containing sequences encoded by variant exon 6 (v6) are involved in the metastatic spread of rat and human tumors. The rat-specific antibody 1.1ASML, which recognizes a v6 epitope, interferes with metastatic dissemination of a rat pancreatic carcinoma. The single-chain antigen-binding fragment of this monoclonal antibody was fused to the zeta-chain of the T-cell receptor complex. The appropriate fusion gene was incorporated into a retroviral gene transfer vector. Murine cytotoxic T lymphocytes (CTLs) were infected, and cellular clones which express the single-chain zeta-chain fusion protein on their cell surface were selected. These CTLs are not MHC-restricted in their CD44v6 recognition and exhibit in vitro lytic activity toward cells expressing CD44 variants comprising exon v6. Tumor cell xenografts grown in athymic nude mice are suppressed in their growth upon infusion of the genetically manipulated CTLs. Our data indicate that the CD44v6 epitope is an effective target for immune tumor therapy and demonstrate the efficacy of genetically engineered CTLs in targeting tumors expressing such epitopes.

Adoptive Transfer↗
PubMed2001

Transcriptional reprogramming of dendritic cells by differentiation stimuli.

Immature and mature dendritic cells (DC) have been well characterized functionally and phenotypically. Microorganisms or bacterial products such as lipopolysaccharide (LPS) and inflammatory molecules, including tumor necrosis factor (TNF-alpha), are both believed to activate the DC maturation program which allows DC to initiate and amplify innate and adaptive immune responses. However, there is increasing evidence that the functional state of DC, induced by different stimuli, may be relevant for the immune response outcome. Thus, we compared the transcriptional program of mature, transitional and immature DC, after either LPS or TNF-alpha stimulation. GeneChip oligonucleotide microarrays, representing approximately 6,500 murine genes and ESTs, were used for this analysis. A very diverse modulation of gene expression was observed with the two stimuli. Only LPS-treated cells showed a pattern of expression of genes compatible with a definitive growth arrest and with a suitable activation and control of the immune response.

Animals↗
PubMed1993

Sensory nerves only temporarily protect the unstable canine knee joint from osteoarthritis. Evidence that sensory nerves reprogram the central nervous system after cruciate ligament transection.

OBJECTIVE: The slow rate at which articular cartilage degrades in dogs after transection of the anterior cruciate ligament (ACLT) has been attributed to capsular thickening and buttressing by osteophytes. We investigated the roles of the peripheral and central nervous systems in protecting knee joints with chronic ACL deficiency from breakdown. METHODS: Five groups of dogs were studied; all were killed 72 weeks after left knee surgery. Group A had ACLT, group B had ACLT followed 52 weeks later by ipsilateral L4-S1 dorsal root ganglionectomy (DRG), group C had DRG followed 2 weeks later by ACLT, group D had sham DRG followed 2 weeks later by ACLT, and group E had DRG followed 2 weeks later by sham ACTL. RESULTS: Group E dogs did not develop knee pathology. All cruciate-deficient knees were lax at the end of the study. The osteoarthritis (OA) that developed in groups A, B, and D was comparable (P > 0.05), and was significantly greater than that in group E (P < 0.05). Group C developed much more severe OA than any of the other groups (P < 0.05). CONCLUSION: Ipsilateral sensory input is temporarily important in protecting the unstable joint from rapid breakdown. Over time, the central nervous system apparently acquires the ability to protect the unstable joint without continued ipsilateral sensory input.

Animals↗
PubMed2004

Exogenous cadherin microdisplay can interfere with endogenous signaling and reprogram gene expression in cultured hepatocytes.

We recently found that the basal micro substrate presentation of E-cadherin, a key cell-cell adhesion molecule in the liver, can modulate hepatocellular proliferative potential and differentiated function (Brieva and Moghe, in press). In the current study, we established a similar experimental model involving rat hepatocytes cultured on collagen and incorporated 5 microm polystyrene microbeads functionalized with Protein A-anchored E-cadherin/human lgG Fc chimeric fusion constructs. We investigated the cadherin governed dose-response of cell proliferative potential and quantified the underlying changes in intracellular gene signaling processes. Hepatocellular proliferative potential was found to be intensified with an increase in the microdisplay of acellular cadherins and this effect was offset by increased cell seeding density. Notably, we report that following overnight exposure to acellular cadherins, the expression of genes known to mediate the control of cell proliferation, cyclin D1 and c-myc, was upregulated, while the expression of differentiation-related genes, namely albumin and cytochrome p450 II B1, was reduced. The exposure of cell cultures to exogenous cadherins was found to markedly disrupt the localization of endogenous E-cadherin and beta-catenin to junctions at cell-cell contacts and cause a quantitative decrease in the endogenous cadherin protein levels. Based on all of our observations, we propose that the acellular presentation of E-cadherin chimeras competitively disrupts endogenous cadherin containing complexes at cell-cell junctions and increases intracellular cadherin turnover, thereby promoting beta-catenin mediated signaling, which ultimately engenders an increase in cell proliferative potential and a decrease in differentiated function.

Animals↗
PubMed1990

Reprogramming of gene expression in postischemic rat liver: induction of proto-oncogenes and hsp 70 gene family.

Steady-state levels of messenger RNA (mRNA) for different members of the heat-shock protein 70 gene family were studied in rat livers reperfused after non-necrogenic ischemia. The expression of constitutive hsc 73 gene decreases during ischemia, returns to normal upon reperfusion, and increases 4 hr after restoration of blood flow. Reperfusion induces the expression of another hsp 70 gene family member (the so-called inducible hsp 70 gene), which remains at high levels for at least 7 hr. The induction of hsp 70 family genes is preceded by activation of the cellular oncogene c-fos, the most prompt change in gene expression detected in reperfused liver. Run-on experiments demonstrate that the increased expression of these genes is largely dependent on activation of transcription. Changes in the amount of c-myc and ornithine decarboxylase mRNA are not evident, while the level of the mRNA for glucose-regulated protein GRP 78 increases later, concurrent with the onset of the acute phase response to surgical trauma. Analysis of polysomal and nonpolysomal fractions from sucrose gradients indicates that in postischemic liver, hsp 70 and hsc 73 mRNA are rapidly engaged on light polysomal or nonpolysomal complexes and are later shifted to polysomes. Albumin mRNA displays the same behavior, indicating that hsp 70 mRNA are not preferentially translated and that increased transcription is the major mechanism for enhanced hsp synthesis in postischemic liver. Damage by active oxygen species, pressure overload, and derangements of protein synthesis is likely to include the causative factors of increased expression of c-fos and the hsp 70 gene family in postischemic reperfused liver.

Animals↗
PubMed1986

Reprograming of murine blastocoele formation.

The present study shows that there is communication between reaggregated asynchronous cleavage stage blastomeres that regulates blastocoele formation. Individual blastomeres from eight-cell murine embryos were transferred to empty zonae pellucidae, intact two-cell embryos, or enucleated two-cell embryos, and were examined over a period of 75 hours for development of cavitation. It was found that the isolated blastomeres cavitated concurrently with intact control eight-cell embryos, while intact control two-cell embryos cavitated 24 hours later. However, the embryos resulting from combining a two-cell embryo and a blastomere from an eight-cell embryo cavitated at a time in between the eight- and two-cell controls.

Animals↗
PubMed2002

Genomic imprinting and epigenetic reprogramming: unearthing the garden of forking paths.

Genomic imprinting, an epigenetic form of gene regulation, determines the parent-dependent gene expression of marked or imprinted genes during gametogenesis and embryonic development. Imprinting involves differential allele DNA methylation in one sex cell lineage but not in the other. Egg and sperm each contributes the same DNA sequences to the zygote but epigenetic imprinting of a subset of genes determines that only one of the parent alleles are expressed relative to the parental origin. Primordial germ cells inherit biallelically imprinted genes from maternal and paternal origin and erase their imprints to start de novo monoallelic imprinting during gametogenesis. Epigenetic paternalization is an ongoing process in the mitotically-dividing spermatogonial stem cell and derived meiotically-dividing spermatocyte progeny to endow sperm with imprinted alleles. Epigenetic maternalization is restricted to the oocyte growth phase of folliculogenesis and is unrelated to DNA replication since it takes place while the oocyte remains in the diplotene stage of meiotic prophase I. Sperm and oocyte genomic methylation patterns depend on the activity of DNA methyltransferases (Dnmt). A variant of Dnmt1, designated Dnmt1o, accumulates in oocyte nuclei during the follicular growth phase. Dnmt3L, an isoform of Dnmt3a and Dnmt3b, but lacking enzymatic activity, interacts with Dnmt2a and Dnmt3b and is required for spermatogenesis. In the mouse early zygote, the male pronucleus is demethylated within 4 h of fertilization. Global demethylation takes place gradually up to the morula stage. In the blastocyst, de novo methylation is reestablished in the inner cell mass but not in the trophectoderm. Both the significance of genomic imprinting and the severe developmental defects caused by disrupted Dnmt activity, point to a need for a better understanding of the causes of low cloning efficiency by somatic nuclear transfer to enucleated ovulated oocyte.

Animals↗
PubMed1998

Analysis of hematopoietic stem cell reprogramming with toxigenicity.

The molecular mechanisms by which a stem cell is committed to individual lineage are largely unknown. Two different models, though not mutually exclusive, are currently debated. The first describes the temporal and hierarchical coordination of lineage-specific transcriptional programs. The second suggests that multilineage genes are expressed in a self-renewing and undifferentiated cell prior to lineage commitment. To challenge these two models in in vivo-appropriate conditions, the expression of an exogenous toxigene was used to create transgenic animals in which an inducible, reversible cell knock-out at a specific stage of differentiation could be achieved. Both additional transgenesis using the megakaryocyte specific alphaIIb promoter and targeted transgenesis were used to express the herpes virus thymidine kinase (tk) gene in the megakaryocytic lineage. When the tk gene was targeted to the locus of the megakaryocyte-specific alphaIIb gene, a typical Glanzman thrombasthenic syndrome was created. Despite this bleeding disorder, the lack of expression of the alphaIIb gene did not affect the development of the mice. In both transgenic and targeted animals, all progenitor cells were sensitive to the effect of the gancyclovir (GCV), both in vivo and ex vivo. Long-term bone marrow cell cultures on stromal layers indicated that most of the very early progenitor cells expressed the enzyme. All the results obtained with this inducible toxic phenotype indicated that genetic programs that are in control of the expression of lineage-specific genes are operative in a totipotent stem cell prior to lineage commitment and strongly support the concept that stem cells express a multilineage transcriptome.

Animals↗
PubMed2000

Defined nuclear changes accompany the reprogramming of the microspore to embryogenesis.

The switch of the gametophytic developmental program toward pollen embryogenesis to form a haploid plant represents an important alternative for plant breeding. In the present study, the switch of the gametophytic developmental program toward a sporophytic pathway, "embryogenesis," has been studied in three different plant species, Brassica, tobacco, and pepper. The switch has been induced by stress (heat shock) at the very responsive stage of the microspore, which is the vacuolate period. As a result, the cell nucleus undergoes striking structural changes with regard to late gametophytic development, including alterations of biosynthetic activities and proliferative activity. An enrichment in HSP70 heat-shock protein and in the presence of Ntf6-MAP kinase was observed after inductive treatment in the nuclei during early embryogenesis. This apparently reflected the possible roles of these proteins, specifically the protective role of HSP70 for the nuclear machinery, and signal transduction of Ntf6-MAPK for the entry of cells into proliferation. Importantly, the observed nuclear changes were similar in the three species investigated and represented convenient markers for early monitoring of embryogenesis and selection purposes for obtaining double-haploid plants in plant breeding.

Brassica↗
PubMed1995

Reprogramming of muscle activation patterns at the wrist in compensation for elbow reaction torques during planar two-joint arm movements.

The relationship between wrist kinematics, dynamics and the pattern of muscle activation were examined during a two-joint planar movement in which the two joints moved in opposite directions, i.e. elbow flexion/wrist extension and elbow extension/wrist flexion. Elbow movements (ranging from 10 to 70 deg) and wrist movements (ranging from 10 to 50 deg) were performed during a visual, step-tracking task in which subjects were required to attend to the initial and final angles at each joint. As the elbow amplitude increased, wrist movement duration increased and the wrist movement trajectories became quite variable. Analysis of the torques acting at the wrist joint showed that elbow movements produced reaction torques acting in the same direction as the intended wrist movement. Distinct patterns of muscle activation were observed at the wrist joint that were dependent on the relative magnitude of the elbow reaction torque in relation to the net wrist torque. When the magnitude of the elbow reaction torque was quite small, the wrist agonist was activated first. As the magnitude of the elbow reaction torque increased, activity in the wrist agonist decreased significantly. In conditions where the elbow reaction torque was much larger than the net wrist torque, the wrist muscle torque reversed direction to oppose the intended movement. This reversal of wrist muscle torque was directly associated with a change in the pattern of muscle activation where the wrist antagonist was activated prior to the wrist agonist. Our findings indicate that motion of the elbow joint is an important consideration in planning wrist movement. Specifically, the selection of muscle activation patterns at the wrist is dependent on the relative magnitude and direction of the elbow reaction torque in relation to the direction of wrist motion.

Animals↗
PubMed1999

Receptor editing: genetic reprogramming of autoreactive lymphocytes.

The clonal selection theory postulates that immune tolerance mediated selection occurs at the level of the cell. The receptor editing model, instead, suggests that selection occurs at the level of the B-cell receptor, so that self-reactive receptors that encounter autoantigen in the bone marrow are altered through secondary rearrangement. Recent studies in transgenic model systems and normal B cells, both in vivo and in vitro, have demonstrated that receptor editing is a major mechanism for inducing B-cell tolerance.

Alleles↗