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Results for “reprogramming”

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PubMed2025

Baculovirus enhances arginine uptake and induces mitochondrial autophagy to promote viral proliferation.

As obligatory intracellular parasites, viruses must rely on metabolic reprogramming of host cells to meet their replication needs. Baculovirus is an important biopesticide and a vector for the preparation of biological products. In addition, one of its representative species, Bombyx mori nucleopolyhedrovirus (BmNPV-Baculoviridae), also causes huge losses to the insect industry. In our previous study, amino acid metabolism has been found to play a crucial role in the BmNPV infection process. However, the mechanisms by which BmNPV reprograms host amino acid metabolism remains unclear. In fact, current insights in the importance of amino acid metabolism are limited to the impact of glutamine on viral infection. Therefore, unraveling the mechanism of amino acid metabolism reprogramming induced by baculovirus would advance this field of research to a great extent. In this study, targeted metabolomics revealed that the preferred amino acids of BmNPV budded virus (BV) include arginine, lysine, proline, isoleucine, histidine and others. In addition, most of the viral amino acids were found to be increased in the hemolymph of BmNPV infected silkworms at the later stage of infection, especially arginine, valine, phenylalanine and others. Furthermore, the importance of arginine for BmNPV proliferation was validated. Next, we confirmed that the expression of the arginine transporter Slc7a6 was strongly induced by BmNPV infection and that Slc7a6 could promote arginine uptake to support BmNPV proliferation in host cells. Moreover, using Slc7a6 knockout cells which eliminate extracellular arginine uptake, we confirmed that BmNPV could induce mitochondrial autophagy, thereby supplementing intracellular arginine and providing necessary amino acids for BmNPV proliferation. Overall, these findings support a model in which baculovirus (BmNPV) enhances the uptake of exogenous amino acids by inducing the expression of amino acid transporters and activating autophagy of organelles to maintain intracellular amino acid levels, thereby facilitating virus proliferation.

Animals↗

PubMed1988

Physiologic pacing in the elderly. Effects on exercise capacity and exercise-induced arrhythmias.

It is not clear whether hemodynamic and other benefits from dual-chamber pacing also exist in elderly patients. We studied a group of 18 elderly patients (mean age 74 +/- 4 yrs) with exercise testing in DDD and VVI modes in a randomized way to compare the effects of these pacing modes on exercise capacity, atrial rate and exercise-induced arrhythmias. Patients were selected when complete heart block was present without clinical evidence of sinus node dysfunction. Significant differences were observed: atrial rate was lower during exercise in DDD-mode (p less than 0.01); exercise time and cumulative load increased (p less than 0.05); maximal oxygen uptake was improved (p less than 0.05). Some of these differences were less clear in a subgroup with replacement of a VVI-device by DDD-stimulation. No differences could be observed in severity of exercise-induced arrhythmias. No evidence of sinus node dysfunction was found during exercise. Reprogramming of atrial sensitivity was required in 3 patients, with reprogramming to DVI because of paroxysmal atrial fibrillation once. Two patients died within a mean follow-up period of 13 months. Sinus rhythm was present at the most recent evaluation in all patients, including the patient stimulated in the DVI mode. Physiologic stimulation is of value for elderly patients with an active life style and complete heart block. Reprogramming to another pacing mode is only seldom necessary.

Aged↗

PubMed2026

Genome agnostic, multi-level non-oncogene addiction-based systems pharmacology for rescuing metastatic relapsed/refractory neoplasias.

Rescue therapies for relapsed/refractory (r/r) metastatic neoplasias present significant unmet needs. Tumor tissue editing regimen for 13 r/r tumor types, carcinomas, sarcomas and hematologic neoplasias, included in 15 phase I/II trials, nuclear/cytokine receptor agonists, pioglitazone, plus/minus dexamethasone or all-trans retinoic acid or interferon-α to counterbalance tumor tissue homeostasis and reprogramming of cancer hallmarks, stress response inhibitors, COX-2 inhibitor, everolimus, lenalidomide, or clarithromycin, and a stress response inducer, low-dose metronomic chemotherapy with treosulfan, trofosfamide, capecitabine, or azacitidine. CR in three, cCR in another five r/r neoplasias, as the best response occurred after transcriptional reprogramming of cancer hallmarks, inflammation control or differentiation induction. Receptor agonist combinations for cCR induction can be identical among quite different tumor types and diversified within the same tumor histology. Data reveal ubiquitous, differential transcriptional access to non-oncogene addiction (NOA) networks that cope with cancer hallmarks/stress responses and three levels of therapeutic NOA targeting. (1) Agonists of nuclear/cytokine receptor NOAs critically target tumor identity and viability, while (2) transcriptional reprogramming of NOA networks that contribute to tumor tissue addiction, thereby genome-agnostically counteracting oncogene addictions. (3) Targeting edited NOAs may improve long-term outcome with CR/cCR (everolimus, IMiD). Transcriptionally accessible NOA targets offer high specificity, modest toxicity profile, low cost of therapy and outpatient treatment, independent of comorbidities. Adaptive targeting of the transcriptomic landscapes of tumor cell compartments breaks tumor tissue addiction and overcomes M-CRAC, post-therapy metastasis, cancer cell recolonization, acquired resistance and genetic heterogeneity. Thus, editing approaches provide a template for controlling metastatic r/r tumors. In the future, diagnostics of NOA networks and transcription factors involved in tumor tissue addiction may be as valuable for therapy selection as histological/molecular genetic tumor typing for the establishment of personalized hematology/oncology.

Hodgkin’s lymphoma↗

PubMed2026

Extravascular coagulation stabilizes pro-fibrotic stromal states via tumor-intrinsic PAR1 signaling in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) exhibits a desmoplastic stroma with context-dependent tumor-restraining and tumor-promoting functions, highlighting the need to selectively reprogram stromal states. Extravascular coagulation is a prominent feature of the PDAC tumor microenvironment, yet whether it functions as an upstream regulator of fibrotic stromal states, rather than merely a byproduct of tumor-associated vascular dysfunction, has remained unclear. Here, we identify extravascular coagulation as a tumor-amplified regulatory module that stabilizes pro-fibrotic stromal states via tumor-intrinsic protease-activated receptor-1 (PAR1) signaling. To interrogate this axis mechanistically, we integrated human tumor bioinformatics with microphysiological tumor-stroma (MPTS) models that reconstruct tumor-stroma interactions under controlled coagulation exposure, followed by cross-scale validation in vivo. Analysis of The Cancer Genome Atlas (TCGA) revealed heterogeneous F2R (PAR1) expression across tumors, with elevated expression associated with fibrotic transcriptional programs and reduced survival. Consistently, thrombin induced coordinated pro-fibrotic programs in tumor cells and cancer-associated fibroblasts (CAFs), which were recapitulated in MPTS where tumor-intrinsic PAR1 was required for amplification of extracellular matrix deposition and CAF activation. Mechanistically, PAR1 signaling amplified tumor-stroma communication, in part through induction of TGF-β1-dependent pathways, establishing a reinforcing feedback loop that stabilizes fibrotic remodeling. Pharmacologic inhibition of PAR1 selectively suppressed the fibrotic transcriptional program within myofibroblastic CAFs while reducing the abundance of other CAF subtypes, reprogramming stromal states and attenuating tumor progression across MPTS and in vivo models. These findings establish a coagulation-PAR1 axis as an upstream organizer of PDAC stromal architecture and identify pharmacologic PAR1 inhibition as a mechanistically grounded strategy for selectively reprogramming the tumor-promoting stroma.

Journal Article↗

PubMedDate not supplied

[Aging and limited capacity for division of normal, diploid amphibian fibroblasts in vitro in relation to cell nucleus transplantations in amphibia].

In many experiments Hayflick had proved the limited division capacity of lung fibroblasts derived from different mammalian species, chicken and tortoise. Gurdon transplanted the nuclei of differentiated Xenopus cells into enucleated eggs yielding a complete development of the hybrid individuals. These results arise the question about a reprogramming of cell nuclei concerning their division capacity. On the other hand, amphibian cells may not show any proliferative limit. Thus, primary cultures were established from tadpoles, recently metamorphosed frogs and adult animals, respectively. The latent period of the tissue explants proved to be dependent on donor age. The cell strain I401 showed the characteristic degeneration phenomena after six subcultivations and ceased to proliferate. These results lead to the conclusion that nuclear transplantation into an enucleated egg yields reprogramming of the nucleus, including the reprogramming of the division capacity as much as the biological age of the nucleus.

Animals↗

PubMed1983

Early experience with a universal (DDD) pacing device.

To assess the advantages and complications of a new universal (DDD) pacemaker, we studied retrospectively the initial 38 patients who received such a pacing device. This group consisted of 27 men and 11 women whose ages ranged from 23 to 89 years. The pacemaker was the initial one for 32 patients and was the replacement unit for 6. Indications for dual-chamber pacing included a need to maintain atrioventricular synchrony, the previous occurrence of the pacemaker syndrome or the presence of intact ventriculoatrial conduction, and previous success with atrioventricular sequential pacing. Pacemaker-mediated tachycardia developed in six patients during the follow-up period. All six were successfully treated by a change in pacing mode. Eighteen pacemakers remained in the DDD mode, 17 were reprogrammed to the DVI mode, and 3 were reprogrammed to the VVI mode. Seven patients experienced difficulties with loss of capture or undersensing, the most common problem being failure of atrial sensing. This was corrected in four of five patients by noninvasive reprogramming. Pacemaker-mediated tachycardia is a frequent complication that can be avoided by assessing ventriculoatrial conduction before implantation of the pacemaker. Use of the DDD device should be considered in patients in whom atrioventricular synchrony must be maintained or who have previously had the pacemaker syndrome with VVI pacing.

Adult↗

PubMedDate not supplied

Long term performance of atrial leads.

Long term performance of 163 atrial leads implanted in 158 patients between July 1981 and June 1993 was evaluated. There were 122 DDD and 36 AAI units, with 125 (77%) polyurethane and 38 (23%) silicone leads. One hundred and nine (67%) unipolar and 54 (33%) bipolar leads were used. Patients were followed in the Pacemaker Clinic for 6 to 124 months (mean 50 +/- 39 months). Five patients were lost to follow up. Transient malfunction was observed in 18 cases (sensing 13, pacing 5) within the first 2 weeks. In 13 cases failure to sense subsided spontaneously and in 4 pacing malfunction could be corrected by reprogramming. Lead dislodgement occurred in 4 patients (2.5%), all within the first week. After the 1st month malfunction was uncommon. Between 1 and 12 months undersensing occurred in 4 (2.5%). In 3 cases it could be corrected by reprogramming. In the first year, reoperation was performed in 5 cases for lead related problems (3 dislodgements, 2 insulation failures). Beyond 12 months complications were as follows: failure to sense-8 (5%), failure to pace-3 (2%), insulation break -1 (0.6%). Majority of these problems could be managed by reprogramming. Reoperation was performed in 1 case with insulation break. The pacing mode had to be changed in 5 (3%) patients with dual chamber units who had loss of P wave sensing. During follow-up 98%, 98%, 96%, 95% and 83% of the leads were working satisfactorily at 1,2,3,4 and 9 years respectively. Thus atrial leads have excellent long term performance and an acceptable rate of late malfunction.

Adolescent↗

PubMed2026

Proteomic signatures of adipocyte recruitment in breast cancer.

The tumor microenvironment (TME) is increasingly recognized as a dynamic regulator of breast cancer progression, with adipocytes functioning as active contributors rather than passive bystanders. Here, we investigated the proteomic and morphologic reprogramming of breast cancer-associated adipocytes (BrCAAs) in response to triple-negative breast cancer (TNBC). Using conditioned medium from HCC1143 cells, we established an in vitro BrCAA model and performed mass spectrometry-based proteomics. Comparative profiling revealed 256 differentially expressed proteins, enriched for pathways including fatty acid degradation, carbon metabolism, and glycogen turnover, consistent with a metabolic shift from energy storage to energy supply. Gene ontology and protein-protein interaction analyses further identified cytoskeletal remodeling, adhesion dynamics, and secretory pathway activation, supporting BrCAA-driven microenvironmental remodeling. In the MMTV-PyMT mouse model, morphometric analysis demonstrated progressive size reduction and increased contour irregularity of adipocytes adjacent to tumors, correlating with proteomic evidence of metabolic stress. Importantly, BrCAAs localized at tumor interfaces were associated with increased microvessel density and CD105+ endothelial activation compared to desmoplastic zones. Proteomic enrichment highlighted pro-angiogenic remodeling, with validation of basigin (BSG), integrin αV (ITGAV), and 2,4-dienoyl-CoA reductase 1 (DECR1). Collectively, our findings establish BrCAAs as metabolically and structurally reprogrammed stromal components that promote tumor metabolism and localized angiogenesis, representing potential therapeutic targets in aggressive breast cancer.

Female↗

PubMed2026

Efferocytosis regulatory factors in atherosclerosis: A preclinical systematic review.

BACKGROUND: Impaired efferocytosis is a key driver of plaque instability during atherosclerosis progression. Efficient clearance of apoptotic cells through efferocytosis relies on the coordinated action of multiple regulatory factors. METHODS: PubMed, Web of Science, ScienceDirect, OVID MEDLINE, and Scopus were searched for studies published up to February 7, 2026. Eligible preclinical studies were systematically reviewed to identify endogenous factors that regulate efferocytosis in atherosclerosis. Clinical evidence was also incorporated to enable a preliminary translational assessment of these regulatory factors. RESULTS: Thirty-five endogenous regulatory factors were identified from 36 included studies, and their functional roles across distinct stages of efferocytosis were characterized. Notably, metabolic regulators such as PKM2, PFKFB3, GLS1, and Drp1 were involved in distinct efferocytosis stages. This suggests that metabolic reprogramming may provide the metabolic support require for efficient efferocytosis and inflammation resolution. Ten factors were supported by preliminary clinical evidence consistent with preclinical data. PKM2 was the only candidate biomarker with prospective observational data. However, its independent predictive value still requires validation in multicenter prospective studies. CONCLUSIONS: This review provides a systematic synthesis of 35 endogenous efferocytosis regulators and elucidates their regulatory network in atherosclerosis based on a functional stage framework. Metabolic reprogramming is identified as a central hub linking efferocytosis efficiency to inflammation resolution. This review offers a new theoretical basis for efferocytosis-targeted intervention strategies.

Animals↗

PubMed2026

Maternal transfer of nonylphenol drives oxidative, immune, and epigenetic dysregulation in zebrafish offspring.

Nonylphenol (NP), a widespread surfactant and endocrine-disrupting pollutant, poses significant ecological and public health risks globally; however, its transgenerational effects remain poorly understood. Using zebrafish (Danio rerio), we compared chronic maternal NP exposure (50 and 100 µg/L, 28 days) with acute embryonic exposure (0.22 µmol/L) during 0-3 days post-fertilization (dpf) to delineate mechanistic differences in toxicity. Maternal NP exposure produced severe developmental defects in offspring, including edema, axial curvature, impaired swim bladder inflation, reduced growth, cardiac dysfunction, and decreased viability. These phenotypes were accompanied by systemic molecular disruptions including oxidative stress, altered estrogen receptor (ER) expression, dysregulated mitogen-activated protein kinase (MAPK) signaling, and suppressed innate immune response characterized by attenuated neutrophil/macrophage density, reduced CD68 and complement protein C3 expression, diminished nitrite load, and downregulation of pro-inflammatory mediators at both transcript and protein levels. Maternal exposure further induced apoptosis and persistent epigenetic reprogramming (alterations in DNA methylation and histone-modifying enzymes), hallmarks of transgenerational toxicity. In contrast, direct embryonic NP exposure elicited morphological abnormalities without significant lethality, accompanied by induction of pro-inflammatory cytokines, nitric oxide (NO) synthesis, and MAPK activation, reflecting an augmented inflammatory response. These mechanistic contrasts reveal that maternal NP exposure is a potent driver of systemic, heritable molecular reprogramming, whereas embryonic exposure triggers acute inflammatory pathways. Together, our findings underscore the global relevance of NP as a transgenerational toxicant, advocating for its urgent inclusion in ecotoxicological risk assessments and regulatory frameworks.

Animals↗

PubMed2026

Matrix Mechanics Governs Mechano-Metabolic Adaptation across Cancer Grades in Bladder Spheroids.

Extracellular matrix (ECM) mechanics is pivotal regulators of tumor progression, yet how viscoelasticity and matrix architecture converge to shape metabolic and invasive adaptation remains insufficiently defined. We postulate that mechanical stimuli from the ECM induce coordinated changes in adhesive and metabolic pathways, and that the nature of this independent mechano-metabolic pathway is conserved across benign, low-invasive, and high-invasive bladder cancer phenotypes. Therefore, we engineered collagen-hyaluronan hydrogels with tunable stiffness to recapitulate soft and rigid tumor microenvironments and profiled bladder cancer spheroids representing benign, low-invasive, and highly invasive states. Integrating hydraulic force spectroscopy, rheology, and molecular phenotyping, we show that matrix stiffening differentially reprograms spheroid architecture, motility, and adhesion- and metabolism-related gene expression. Spheroid behavior emerged from the interplay between intrinsic mechanical properties, matrix rheology, and molecular adaptation. HCV29 spheroids formed rigid, compact structures, relying on cell-matrix adhesion rather than metabolic or proteolytic remodeling. HT1376 spheroids activated glycolysis (HK2) and MMP-2-dependent ECM remodeling in soft matrices, but remained largely nonmigratory, indicating decoupling of invasive priming from motility. T24 spheroids were soft, deformable, and highly migratory in compliant matrices, integrating metabolic reprogramming, adhesion remodeling (E-/N-cadherin, SDC4), and radial collagen fiber alignment to drive invasion. Notably, canonical FAK/AKT/mTOR signaling was absent across all spheroids, while pS6 ribosomal protein and ILK indicated noncanonical, SDC4/integrin-ILK-dependent mechanotransduction supporting cytoskeletal dynamics, metabolism, and ECM remodeling. Collagen organization further differed across spheroid types, with dense, radially aligned fibers in HT1376, intermediate architecture in HCV29, and loose, disorganized networks in T24, closely matching their distinct migratory behaviors and cell-ECM interactions. These findings reveal stage-specific mechanometabolic strategies in bladder cancer, demonstrating how ECM mechanics and architecture jointly guide invasion, metabolic adaptation, and local immune modulation, including the regulation of immune cell infiltration and tumor immune evasion.

Humans↗

PubMed2026

Multimodal Analysis Reveals Aberrant Expression of SUMO2 and Its Significant Association With Key Mechanisms of Metabolic Pathways in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. However, the role of small ubiquitin-like modifier 2 (SUMO2), a core member of the small ubiquitin-like modifier (SUMO) family, regarding its expression patterns and metabolism-related functions in HCC remains inadequately understood. METHODS: A multidimensional analytical framework was applied, integrating immunohistochemistry (153 HCC vs. 21 non-HCC samples), proteomics (159 paired samples), bulk transcriptomics (3240 HCC vs. 2267 non-HCC samples), single-cell RNA sequencing (RNA-seq) (10 HCC vs. 8 non-HCC samples), spatial transcriptomics, and external CRISPR/Cas9 functional genomics data. Systematic analyses included standardized mean difference (SMD), pathway enrichment, pseudotime trajectory inference, in silico knockout, cell-cell communication, metabolic flux scoring, immune infiltration, clinical correlation, drug sensitivity prediction, and molecular docking. RESULTS: At the protein level, immunohistochemistry (nuclear positivity) and external proteomic data collectively demonstrated consistent SUMO2 overexpression in HCC. Consistent upregulation was also observed at the mRNA level across large-scale cohorts. Single-cell RNA-seq and spatial transcriptomics localized SUMO2 enrichment to malignant hepatocytes and tumor-dominant regions. CRISPR-mediated SUMO2 knockout suppressed proliferation in multiple HCC cell lines. Mechanistically, high SUMO2 expression was significantly associated with metabolic reprogramming involving glycolysis/gluconeogenesis, pyruvate metabolism, and the tricarboxylic acid cycle. SUMO2-high malignant hepatocyte subpopulations exhibited enhanced activity of the macrophage migration inhibitory factor signaling axis and enhanced iron-sensor interactions. Further, the immune infiltration analysis revealed a negative correlation between SUMO2 expression and M1 macrophages and a positive correlation between follicular helper T cells and regulatory T cells. Clinically, elevated SUMO2 levels were found to be associated with adverse prognostic features. Furthermore, high SUMO2 expression was associated with increased sensitivity to dasatinib, and molecular docking simulations predicted potential binding between SUMO2 and dasatinib, with a Vina score of -8.5 kcal/mol. CONCLUSIONS: SUMO2 is aberrantly expressed at the protein, mRNA, single-cell, and spatial transcriptomic levels in HCC and is significantly associated with metabolic reprogramming and altered migration inhibitory factor (MIF)-mediated intercellular communication, suggesting its potential as a novel biomarker for diagnosis and treatment.

Humans↗

PubMed2026

Induced Pluripotent Stem Cells in Non-Model Species: Applications and Challenges.

Induced pluripotent stem cells have revolutionized biomedical research-yet the vast majority of life on Earth remains beyond their reach. Non-model species lack the annotated genomes, validated reagents, and species-specific culture infrastructure that make iPSC technology routine in humans and mice, and this infrastructure deficit, compounded by genuine biological differences in pluripotency network architecture across taxa, is what has kept the field narrow. The deep conservation of the core pluripotency network across vertebrates suggests that reprogramming may, in principle, be achievable across a far broader range of species than currently demonstrated-though the extent to which this holds across more divergent taxa remains to be established. This review consolidates current progress and future potential of iPSC technology across five domains: technical reprogramming challenges and advances; conservation applications including genetic rescue, in vitro gametogenesis, and de-extinction; medical applications within a one medicine framework; agricultural applications spanning disease resistance, climate resilience, and cultured meat; and species-specific iPSC-derived systems in ecotoxicology. Throughout, we distinguish what has been demonstrated from what remains aspirational and identify the priorities that will determine whether the iPSC revolution can be extended-rigorously and at scale-beyond model organism research.

Induced Pluripotent Stem Cells↗

PubMed2026

Enzyme-Metabolite Network Analysis of Endometrial Cancer-Derived Extracellular Vesicles Through Integrated Proteomics and Metabolomics.

Endometrial cancer (EC) is the most common gynecological malignancy in high-income countries. Extracellular vesicles (EVs) are key mediators of intercellular communication and metabolic reprogramming, but their molecular cargo in EC remains poorly characterized. EVs were isolated from four EC cell lines representing Type I and Type II subtypes (AN3CA, ISHIKAWA, HEC1A, and KLE). Untargeted metabolomics was performed by HILIC-LC-MS/MS, proteomics by data-independent acquisition (DIA) mass spectrometry, and multi-omics integration using MetaboAnalyst and OmicsNet. Metabolomic profiling identified 1463 annotated features and revealed significant differences among EC cell lines (PERMANOVA, p = 0.002). Twenty-eight differentially abundant metabolites, including lactic acid, succinic acid, and uric acid, were identified. Proteomic analysis quantified 8513 proteins with subtype-specific expression patterns. Integrated analysis revealed seven significantly enriched pathways, including glycolysis/gluconeogenesis, central carbon metabolism in cancer, and the pentose phosphate pathway. Increased LDHA abundance in metastatic AN3CA-derived EVs was confirmed by Western blot (p = 0.047). EC-derived EVs display subtype- and metastatic-status-specific metabolo-proteomic signatures, with glycolysis, TCA cycle remodeling, and central carbon metabolism as convergent pathway signatures of molecular reprogramming. These findings establish a multi-omics framework for characterizing EV cargo in EC and identify candidate enzyme-metabolite nodes for future biomarker validation in patient-derived specimens.

Female↗

PubMed1989

Transfer of dorsoventral information from mesoderm to ectoderm at the onset of limb development.

Control of dorsoventral patterns in the chick at the prelimb stages resides in the limb mesoderm. Recombination experiments at stage 14, with dorsoventrally reversed ectoderm, result in wings with mesodermal dorsoventral polarity. Similar recombinations at stage 16 show that the ectoderm has acquired dorsoventral information and can impose this polarity on the patterns of mesodermal differentiation in the distal regions of the wing. The dorsoventral information in the ectoderm comes from the mesoderm, which transfers this information to the overlying ectoderm between stages 14 and 16. The initial dorsoventral overlying ectoderm between stages 14 and 16. The initial dorsoventral information in the ectoderm is not stable and can be reprogrammed by stage 14 mesoderm. Subsequently, there is a gradual stabilization of the ectodermal information. At the same time the mesoderm loses its capacity to reprogram dorsoventral information in the ectoderm.

Animals↗

PubMed1990

Nuclear transplantation in the pig embryo: nuclear swelling.

The transfer of nuclei from cleavage stage embryos to enucleated activated meiotic metaphase II oocytes results in a reprogramming of the transferred nucleus such that it behaves as a zygotic nucleus. One estimator of nuclear reprogramming is nuclear swelling after nuclear transfer. The diameter of nuclei after nuclear transfer was not found to be dependent upon the amount of cytoplasm transferred with the donor cell or the amount of cytoplasm in the recipient cell. Nuclei from 4-, 8-, and 16-cell stage embryos swelled to a similar diameter after nuclear transfer (26.9, 27.3, and 27.2 microns, respectively) and this was significantly different from the diameter of contemporary donor embryos (18.3, 14.3, and 13.0 microns, respectively). This is a swelling of 47, 91, and 109%, respectively. Since the degree of nuclear swelling does not appear to be related to cytoplasmic volume it is concluded that the components mediating nuclear swelling are not in a limiting supply.

Animals↗

PubMed1996

Heat-shock induced protein modifications and modulation of enzyme activities.

Upon heat stress, the cell physiology is profoundly altered. The extent of the alterations depends on the severity of the stress and may lead to cell death. The heat shock response is an array of metabolic changes characterized by the impairment of major cellular functions and by an adaptative reprogramming of the cell metabolism. The enhanced synthesis of the HSPs is a spectacular manifestation of this reprogramming. Numerous post translational modifications of proteins occur in response to heat stress and can be related to altered cellular functions. Some proteins are heat-denatured and temporarily inactivated. Heat-denaturation is reversible, chaperones may contribute to the repair. The extent of heat-denaturation depends on the cell metabolism: (a) it is attenuated in thermotolerant cells or in cells overexpressing the appropriate chaperones (b) it is enhanced in energy-deprived cells. Covalent modifications may also rapidly alter protein function. Changes in protein glycosylation, methylation, acetylation, farnesylation, ubiquitination have been found to occur during stress. But protein phosphorylation is the most studied modification. Several protein kinase cascades are activated, among which the various mitogen activated protein kinase (MAP kinase) cascades which are also triggered by a wide range of stimuli. As a possible consequence, stress modifies the phosphorylation status and the activity of components from the transcriptional and translational apparatuses. The same kinases also target key enzymes of the cellular metabolism. Protein denaturation results in constitutive hsp titration, this titration is a signal to trigger the heat-shock gene transcription and to activate some of the protein kinase cascades.

Animals↗

PubMed2026

NFS1 activates PI3K/AKT/mTOR signaling to upregulate GPX4 expression and enhance ferroptosis resistance in osteosarcoma.

Osteosarcoma continues to exhibit poor survival outcomes due to chemoresistance and metastasis, with metabolic reprogramming and ferroptosis resistance being key features of tumor heterogeneity, yet their upstream regulators remain poorly defined. NFS1, a cysteine desulfurase essential for iron-sulfur cluster biogenesis, protects multiple cancers from ferroptosis, but its role in osteosarcoma is unknown. In this study, we performed a transcriptomic meta-analysis and found that NFS1 expression was significantly upregulated in osteosarcoma tissues, with further elevation in metastatic lesions, and high NFS1 expression correlated with poor overall survival. Genome‑wide CRISPR screening data revealed a marked NFS1 dependency in osteosarcoma cell lines. Functionally, NFS1 promoted cell proliferation, migration, and invasion, whereas its knockdown suppressed these phenotypes. Using single‑cell RNA sequencing data from 27 osteosarcoma specimens, we applied a multi‑algorithm glycolytic scoring framework and observed NFS1 enrichment in highly glycolytic malignant cells, along with an association with PI3K/AKT/mTOR pathway activation. Mechanistically, NFS1 selectively enhanced PI3K, AKT, and mTOR phosphorylation without altering total protein levels, and upregulated GPX4, a central ferroptosis suppressor, leading to elevated ferroptosis resistance scores in NFS1‑high malignant cells. Collectively, these findings identify a previously unrecognized NFS1-PI3K/AKT/mTOR-GPX4 regulatory axis in osteosarcoma, linking metabolic reprogramming to ferroptosis resistance, and suggest that NFS1 functions as an oncogenic driver, as well as a promising prognostic biomarker and therapeutic target in osteosarcoma.

Humans↗