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PubMed2005

Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro.

INTRODUCTION: Mitochondrial biogenesis is a complex process, and several factors and signaling pathways regulate this process in muscle or brown adipocytes. The aim of the study was to explore pathways affecting mitochondrial biogenesis and fatty acid oxidation (FAO) in human white adipocytes. METHODS: Human preadipocytes obtained from liposuction samples were differentiated in vitro. On the 10th day of differentiation, 4 microM forskolin and 1 microM peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist (pioglitazone, rosiglitazone, or GW 929) or 10 microM PPARalpha agonist (WY-14,643) were added to the media for 96 h. Quantitative real-time PCR was used to determine gene expression/mitochondrial copy number and 14C-labeled palmitate to measure direct energy dissipation. RESULTS: The treatment of adipocytes with forskolin increased mitochondrial copy number and the expression of genes involved in mitochondrial biogenesis (PPARgamma coactivator 1alpha and transcriptional factor A) and fatty acid oxidation (PPARalpha and medium-chain acyl-coenzyme A dehydrogenase). The end (CO2) and intermediate products (14C-labeled acid-soluble products) of FAO were also increased after forskolin treatment. PPARgamma and PPARalpha agonists increased mitochondrial copy number, uncoupling protein 1, medium-chain acyl-coenzyme A dehydrogenase, and carnitine palmitoyltransferase 1, but did not change PPARalpha, PPARgamma coactivator 1alpha, or transcriptional factor A mRNA levels. FAO was higher after rosiglitazone, GW 929, and WY-14,643 but not after pioglitazone treatment. CONCLUSIONS: Pharmacological activation of the cAMP or PPARgamma pathway pushes the white adipocyte down the oxidative continuum. The direct energy-dissipating effects could be significant tools to treat obesity and to improve insulin resistance in type 2 diabetic patients by reduction of fat accumulation in adipocytes or by reprogramming fatty acid metabolism.

Adipocytes↗
PubMed2026

Genome-wide transcriptional landscape of Mycobacterium tuberculosis during acute lung infection.

Tuberculosis (TB) remains a major global health burden, yet the mechanisms by which Mycobacterium tuberculosis (Mtb) adapts to host environments to drive disease pathology are incompletely defined. A key limitation has been reliance on axenic culture systems that fail to recapitulate the complex, host-imposed stresses encountered by Mtb in vivo. Here, we report the first microarray-based genome-wide transcriptomic profiling of Mtb in rabbit lungs with active TB, which closely mirrors human disease features, including granuloma heterogeneity, necrosis, and cavitation. Using Mtb RNA isolated from infected lung homogenates or broth-culture, we capture bacterial transcriptional states shaped by the host microenvironments. The transcriptional data analyses reveal extensive, context-dependent reprogramming of Mtb metabolic, respiratory, and stress-response networks that diverges markedly from in vitro expression profiles, including activation of stress adaptation, lipid catabolism, nucleic acid metabolism, and transcriptional regulation pathways. These data uncover pathways and networks that are selectively engaged in vivo and likely critical for Mtb survival within granulomatous lesions. Our findings demonstrate that transcriptional states most relevant to TB pathogenesis are underrepresented in standard lab-grown Mtb models and highlight the importance of in vivo bacterial profiling. By characterizing Mtb gene expression within diseased lungs, this study provides a systems-level framework for understanding TB pathogenesis and reveals in vivo-essential pathways, offering potential targets for translational drug discovery and the development of more effective anti-TB therapies.

Animals↗
PubMed1995

Chronic effects of smokeless tobacco extract on rat liver histopathology and production of HSP-90.

Tobacco consumption is a worldwide problem. The recent increase in the consumption of the smokeless tobacco products (snuff and chewing tobacco) has stimulated interest into the carcinogenic effects of these forms of tobacco. The use of smokeless tobacco products has increased in popularity as the use of cigarettes has become less socially acceptable. For most individuals the use of tobacco is a chronic process. Therefore, the effects of an aqueous extract of smokeless tobacco (STE) in rats following low-dose exposure were examined. Female Sprague-Dawley rats were treated orally with 25 mg STE/kg every other day for 90 days. In order to obtain information regarding the cytotoxicity of STE, the ultrastructural changes occurring in livers of rats following administration of STE were examined under light and electron microscopy. Electron microscopy revealed that in the perisinusoidal spaces an accumulation of indistinct filamentous material occurred following 60 days of treatment, occupying most of the sinusoids. Moreover, the lipids were in a state of disintegration. Significant increases in 90 kDa protein expression were also observed due to chronic treatment with STE. Western blot analysis using a polyclonal mouse antibody against heat shock/stress protein 90 (HSP90) confirmed that the overexpressed proteins were heat shock/stress proteins (HSPs). The HSPs are believed to serve as adaptive or survival functions involving a rapid but transient reprogramming of cellular metabolic activity to protect cells from oxidative damage.

Animals↗
PubMed2026

Spatial niche remodeling of senescent liver-resident immune cells and its role in chronic liver diseases.

The liver serves the triple functions of metabolism, detoxification, and immune surveillance. Its unique immune microenvironment is shaped by continuous exposure to gut-derived antigens, pathogen-associated molecular patterns (PAMPs), and metabolites arriving via the portal vein, necessitating a delicate equilibrium between immune tolerance and effector activation. This equilibrium relies on the coordinated activities of diverse liver-resident immune cell populations-including Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), dendritic cells (DCs), tissue-resident memory T cells (TRM), innate-like T cells, including mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, and γδ T cells, innate lymphoid cells (ILCs, encompassing conventional NK cells and helper ILC subsets), and neutrophils. With advancing age and chronic injury, these resident immune cell populations undergo profound senescence-associated phenotypic reprogramming that is spatially organized along the portal-to-central axis of the hepatic lobule. Key mechanisms include: telomere dysfunction and DNA damage accumulation driving persistent activation of p53/p21 and p16/Rb pathways; mitochondrial dysfunction with mitochondrial DNA (mtDNA) leakage fueling the senescence-associated secretory phenotype (SASP) via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway; epigenetic age acceleration, including genome-wide H3K27me3 heterochromatinization; and metabolic reprogramming toward glycolysis and lipid accumulation. This review proposes a "spatial niche remodeling" framework to integrate these cell-intrinsic senescence programs with their lobular context, intercellular communication network rewiring, and pathogenic roles across the spectrum of chronic liver disease-from steatosis through steatohepatitis, fibrosis, cirrhosis, to hepatocellular carcinoma. We critically evaluate emerging senotherapeutic strategies targeting specific liver-resident immune cell subsets, discuss the barriers to clinical translation, and identify priority areas for future investigation, including the application of spatial multi-omics, humanized models, and epigenetic clock-guided clinical trials.

Kupffer cells↗
PubMed2026

Glycerophospholipid remodeling under osmotic stress in grass carp gills.

Salinity fluctuations represent a pervasive environmental challenge for freshwater fishes, yet the cellular and metabolic programs governing early osmoregulatory responses remain understudied. Here, we investigated the time-dependent gill responses of juvenile grass carp (Ctenopharyngodon idella) subjected to an acute, sublethal salinity increase 9 parts per thousand (ppt). Histological and biochemical analyses revealed progressive gill lesions accompanied by elevated lactate dehydrogenase (LDH) activity and lipid peroxidation, indicating rapid tissue injury under osmotic stress. Integrative metabolomic and transcriptomic profiling uncovered pronounced temporal reprogramming, consistently highlighting glycerophospholipid metabolism as a central axis of response. In particular, phosphatidylcholine (PC) species exhibited dynamic remodeling, coupled with transcriptional enrichment of lipid turnover, membrane transport, and innate immune pathways. Network-based integration identified a PC-centered remodeling module characterized by accelerated PC headgroup turnover, disruption of the PLA2-LPCAT2 lyso-PC reacylation cycle, and enhanced ABC transporter-associated lipid and sterol export, reflected by cholesteryl sulfate accumulation and a shifted n-6 polyunsaturated fatty acid-derived oxylipin signature. Functional assays further demonstrated that PC and linoleic acid (LA) supplementation improved cell viability and alleviated oxidative stress and pro-inflammatory signaling in grass carp cells under salinity challenge. Collectively, these findings reveal phospholipid-centered membrane remodeling as an early, integrative mechanism linking osmotic stress to gill injury and immune activation in freshwater fish, providing insights into potential strategies of environmental stress adaptation.

Animals↗
PubMed1999

Nitrate regulation of metabolism and growth.

Recent research shows that signals derived from nitrate are involved in triggering widespread changes in gene expression, resulting in a reprogramming of nitrogen and carbon metabolism to facilitate the uptake and assimilation of nitrate, and to initiate accompanying changes in carbon metabolism. These nitrate-derived signals interact with signals generated further downstream in nitrogen metabolism, and in carbon metabolism. Signals derived from internal and external nitrate also adjust root growth and architecture to the physiological state of the plant, and the distribution of nitrate in the environment.

Fungi↗
PubMed2025

Immune dysfunction in Alzheimer disease.

Emerging evidence highlights the crucial role of peripheral immune cells in maintaining brain homeostasis and their influence on the pathology of Alzheimer disease (AD). Genome-wide association studies have identified numerous AD risk variants in genes expressed by immune cells, implicating innate and adaptive immune pathways in disease progression. Advances in neuroimmunology have revealed that immune cell crosstalk involving T cells, B cells, monocytes and/or macrophages and neutrophils can modulate the hallmark features of AD, including amyloid plaque accumulation, tau pathology and chronic neuroinflammation. Mechanistic insights suggest that chronic peripheral inflammation, immune exhaustion, metabolic dysfunction and epigenetic reprogramming exacerbate neurodegeneration in AD by promoting toxic inflammation and impairing protein clearance in the brain. These findings may catalyse the development of novel immunomodulatory strategies, such as immune checkpoint inhibition and cytokine targeting, among others, for AD. This Review examines peripheral immune alterations in AD, evaluates related therapeutic opportunities and highlights key knowledge gaps, particularly the need for human-derived data to advance translational progress. Future research should prioritize personalized approaches that integrate genetic risk, immune profiling and ageing to inform next-generation therapies for AD.

Humans↗
PubMed1995

Collagen and collagenase gene expression in three-dimensional collagen lattices are differentially regulated by alpha 1 beta 1 and alpha 2 beta 1 integrins.

The reorganization of extracellular matrix (ECM) is an important function in many biological and pathophysiological processes. Culture of fibroblasts in a three-dimensional collagenous environment represents a suitable system to study the underlying mechanisms resulting from cell-ECM interaction, which leads to reprogramming of fibroblast biosynthetic capacity. The aim of this study was to identify receptors that transduce ECM signals into cellular events, resulting in reprogramming of connective tissue metabolism. Our data demonstrate that in human skin fibroblasts alpha 1 beta 1 and alpha 2 beta 1 integrins are the major receptors responsible for regulating ECM remodeling: alpha 1 beta 1 mediates the signals inducing downregulation of collagen gene expression, whereas the alpha 2 beta 1 integrin mediates induction of collagenase (MMP-1). Applying mAb directed against different integrin subunits resulted in triggering the heterodimeric receptors and enhancing the normal biochemical response to receptor ligation. Different signal transduction inhibitors were tested for their influence on gel contraction, expression of alpha 1(I) collagen and MMP-1 in fibroblasts within collagen gels. Ortho-vanadate and herbimycin A displayed no significant effect on any of these three processes. In contrast, genistein reduced lattice contraction, and completely inhibited induction of MMP-1, whereas type I collagen down-regulation was unaltered. Calphostin C inhibited only lattice contraction. Taken together, these data indicate a role of tyrosine-specific protein kinases in mediating gel contraction and induction of MMP-1, as well as an involvement of protein kinase C in the contraction process. The data presented here indicate that different signaling pathways exist leading to the three events discussed here, and that these pathways do not per se depend upon each other.

Antibodies, Monoclonal↗
PubMed2026

IL17 signaling promotes oocyte developmental competence acquisition during maturation.

BACKGROUND: Defects in the acquisition of oocyte developmental competence during the maturation process causes subfertility or infertility in animals and humans. Understanding the regulatory mechanisms of oocyte maturation is essential for reproductive biology and medicine. Follicular fluid (FF) is an important microenvironment governing oocyte maturation. METHODS: A tandem mass tags (TMT)-based comparative FF proteomic analysis was employed to identify FF proteins that are potentially crucial for oocyte maturation. A very large number of pig and mouse oocytes (approximately 20,000) and embryos (over 13,000, including somatic cell nuclear transfer, parthenogenetic activation, and in vitro fertilization embryos) were used to investigate the effects of identified FF proteins on in vitro oocyte maturation and subsequent in vitro and in vivo embryo development. RNA sequencing, quantitative PCR, enzyme-linked immunosorbent assays, and immunofluorescence were used to study the expression patterns and action mechanisms of identified FF proteins in oocytes. In addition, intra-oocyte levels of glutathione and reactive oxygen species were measured to assess redox homeostasis. RESULTS: Interleukin 17D (IL17D) was identified as an important FF protein and it is significantly upregulated in porcine FF during oocyte maturation. IL17D promotes oocyte maturation by enhancing bidirectional communication between oocytes and cumulus cells, via upregulating CX43 expression and transzonal projections, which helps to maintain oocyte redox homeostasis and nuclear-cytoplasmic synchrony. IL17D treatment of oocytes enhances subsequent in vitro and in vivo full-term embryo development by modulating lipid metabolism and histone modification reprogramming. IL17D exerts its function via activating IL17 signaling through binding to CD93. Two other IL17 family members, IL17A and IL17F, also enhance oocyte maturation quality. IL17D displays a conserved expression pattern and function in pig and mouse oocytes. CONCLUSIONS: This study reveals the critical roles of IL17D in regulating oocyte developmental competence acquisition during maturation by activating IL17 signaling. The findings provide valuable insights into the molecular mechanisms underlining oocyte developmental potential acquisition and may help to develop methods for efficient production of oocytes for assisted reproduction.

Animals↗
PubMed2026

Japanese encephalitis virus hijacks the host purine biosynthetic network to promote viral replication in neurons.

Japanese encephalitis virus (JEV) is an important neurotropic orthoflavivirus that poses a threat to both human and animal health. However, the mechanism underlying its rapid replication in the central nervous system (CNS) remains poorly understood. In this study, we conducted metabolomic profiling of JEV-infected mouse brains and neurons, revealing a profound reprogramming of central carbon metabolism, particularly an enhancement in nucleotide synthesis. Integrated multi-omics analyses confirmed that JEV infection transcriptionally upregulates key enzymes involved in de novo purine biosynthesis (DNPB), one-carbon (1C) metabolism, and the pentose phosphate pathway (PPP) in neurons. Pharmacological inhibition of the core DNPB enzymes potently suppressed JEV replication in neurons and reduced both viral loads and neuroinflammation in JEV-infected mice, suggesting the essential role of DNPB in JEV replication within CNS. Mechanistically, we delineated the critical functions of both the non-oxidative PPP and MTHFD2-mediated 1C metabolism, which jointly supply essential precursors, such as ribose-5-phosphate and formyl groups, for the de novo biosynthesis of purines required for viral RNA replication. These findings unveil a strategy by which JEV co-opts the host's purine biosynthetic machinery to fulfill the nucleotide demands for its genomic replication, establishing DNPB and its supporting pathways as promising therapeutic targets for infections caused by JEV and other neurotropic viruses.

Animals↗
PubMed2026

Epigenetic regulation of fatty acid chain elongation in MAFLD and its implications in the liver-brain axis dysfunction.

Lipid metabolism plays a crucial role in cellular health and physiology by acting as an energy storehouse, cell membrane component, brain development and signaling molecules. Crucial steps to metabolize dietary fat take place within the hepatic tissue. Any abnormalities in the hepatic fatty metabolic pathways cause abnormal accumulation of lipid inside the liver, causing MAFLD, ranging from simple steatosis to more complex steatohepatitis and fibrosis. During high-fat-diet-induced hepatic inflammation, systemic proinflammatory cytokines disrupt the blood-brain barrier, resulting in neuroinflammation, cognitive impairment, brain damage and even neurodegeneration. Further, during this altered metabolic scenario, circulating metabolites pass through the impaired BBR and deregulate the epigenetic landscape of the central nervous system. Thus, it becomes crucial to understand the epi-metabolic crosstalk between two crucial organs of our body: the liver and the brain. Here in this chapter, we demonstrate the approach that we are using in our laboratory to study the epigenetic reprogramming in the context of metabolic gene expression in the liver, which is the causal for life style disorders like MAFLD. Remarkably, we intend to understand how liver dysfunction can have an implication in the brain function. Here, we discuss the concept of developing a diet-induced steatosis and steatohepatitis mouse model to understand the disease progression and its interconnection with brain physiology. Further, we also demonstrate 2D and 3D cell culture models to study the liver-brain cross-talk in greater molecular detail. Collectively, these approaches can provide a template for studying the role of epi-metabolic cross-talk in liver-guided brain dysfunction upon MAFLD.

Animals↗
PubMed2003

Molecular basis of skeletal muscle plasticity--from gene to form and function.

Skeletal muscle shows an enormous plasticity to adapt to stimuli such as contractile activity (endurance exercise, electrical stimulation, denervation), loading conditions (resistance training, microgravity), substrate supply (nutritional interventions) or environmental factors (hypoxia). The presented data show that adaptive structural events occur in both muscle fibres (myofibrils, mitochondria) and associated structures (motoneurons and capillaries). Functional adaptations appear to involve alterations in regulatory mechanisms (neuronal, endocrine and intracellular signalling), contractile properties and metabolic capacities. With the appropriate molecular techniques it has been demonstrated over the past 10 years that rapid changes in skeletal muscle mRNA expression occur with exercise in human and rodent species. Recently, gene expression profiling analysis has demonstrated that transcriptional adaptations in skeletal muscle due to changes in loading involve a broad range of genes and that mRNA changes often run parallel for genes in the same functional categories. These changes can be matched to the structural/functional adaptations known to occur with corresponding stimuli. Several signalling pathways involving cytoplasmic protein kinases and nuclear-encoded transcription factors are recognized as potential master regulators that transduce physiological stress into transcriptional adaptations of batteries of metabolic and contractile genes. Nuclear reprogramming is recognized as an important event in muscle plasticity and may be related to the adaptations in the myosin type, protein turnover, and the cytoplasma-to-myonucleus ratio. The accessibility of muscle tissue to biopsies in conjunction with the advent of high-throughput gene expression analysis technology points to skeletal muscle plasticity as a particularly useful paradigm for studying gene regulatory phenomena in humans.

Animals↗
PubMed2026

Molecular mechanisms of natural de novo shoot organogenesis and their applications.

Natural de novo shoot organogenesis (DNSO) is the spontaneous regeneration of shoots from wound sites outside the shoot apical region through endogenous developmental programs. This regenerative capacity enables plants to recover from severe tissue damage by re-establishing the shoot-root axis. Here, we review current knowledge about the molecular mechanisms of natural DNSO, focusing on transcriptomic and physiological studies in model plants. Accumulating evidence suggests that natural DNSO proceeds through three sequential phases: (i) early wound responses, characterized by the activation of the WIND1-ESR1 module and the establishment of apical-basal auxin asymmetry; (ii) cellular proliferation driven by metabolic and cell-cycle reprogramming; and (iii) cytokinin-mediated establishment of shoot apical meristem identity. We also discuss how these mechanistic insights have been harnessed for practical applications, including tissue culture-free transformation systems such as the cut-dip-budding (CDB) method, and developmental reprogramming strategies that employ ectopic expression of developmental regulator (DR) genes to induce DNSO in otherwise recalcitrant species. Together, these advances illustrate how understanding natural regeneration can guide the development of simplified, broadly applicable plant transformation technologies.

Plant Shoots↗
PubMed2026

Activation of mTOR pathway by human cytomegalovirus promoting host ribosomal protein expression by coordinated transcriptional and translational controls.

Human cytomegalovirus (HCMV) profoundly reprograms host transcription and RNA metabolism, yet its impact on transcription start site (TSS) regulation of host genes remains poorly understood. Here, we employed NanoCap Analysis of Gene Expression sequencing (NanoCAGE-seq) to investigate HCMV-driven changes in alternative TSS usage across the host transcriptome. We identified widespread TSS switching, with ribosomal protein genes (RPGs) emerging as a highly enriched category. Alternative TSS usage produced isoforms with distinct 5'untranslated regions (UTRs), thereby altering cis-regulatory elements that shape translational efficiency. Integrative transcriptomic and proteomic analyses revealed a paradoxical accumulation of RPG proteins despite transcriptional downregulation during infection. Using 5' Rapid Amplification of cDNA Ends (5'RACE), we characterized four RPGs of RPL4, RPS11, RPS23, and RPS24 that generated 5'UTR variants through alternative TSS usage. Notably, isoforms containing a 5'terminal oligopyrimidine (5'TOP) motif were significantly enriched, correlating with mTOR activation induced by HCMV. Functional assays with bicistronic reporter constructs in HEK293 cells and infection models in human embryonic lung fibroblasts demonstrated that the RPL4 5'TOP isoform exhibited enhanced mTORC1-driven translation compared with non-5'TOP counterparts. Importantly, RPL4 upregulation facilitated viral protein synthesis and boosted production of infectious virions. Together, our findings reveal that dynamic TSS switching of RPGs provides a simple, yet effective, mechanism for fine-tuning mTORC1-responsive translation. By co-opting host transcriptional and translational programs, HCMV enhances ribosome function to optimize the cellular environment for productive viral replication.

Humans↗
PubMed2005

Sensing and signalling in response to oxygen deprivation in plants and other organisms.

AIMS AND SCOPE: All aerobic organisms require molecular di-oxygen (O2) for efficient production of ATP though oxidative phosphorylation. Cellular depletion of oxygen results in rapid molecular and physiological acclimation. The purpose of this review is to consider the processes of low oxygen sensing and response in diverse organisms, with special consideration of plant cells. CONCLUSIONS: The sensing of oxygen deprivation in bacteria, fungi, metazoa and plants involves multiple sensors and signal transduction pathways. Cellular responses result in a reprogramming of gene expression and metabolic processes that enhance transient survival and can enable long-term tolerance to sub-optimal oxygen levels. The mechanism of sensing can involve molecules that directly bind or react with oxygen (direct sensing), or recognition of altered cellular homeostasis (indirect sensing). The growing knowledge of the activation of genes in response to oxygen deprivation has provided additional information on the response and acclimation processes. Conservation of calcium fluxes and reactive oxygen species as second messengers in signal transduction pathways in metazoa and plants may reflect the elemental importance of rapid sensing of cellular restriction in oxygen by aerobic organisms.

Bacterial Physiological Phenomena↗
PubMed1999

The maternal, fetal and postnatal somatotrophic axes in intrauterine growth retardation.

Both the maternal and fetal somatotrophic axes are closely linked to fetal substrate supply. Nutritional insults at critical stages of fetal development may lead to permanent reprogramming of the relationships between these factors. The consequences of reprogramming during fetal life may be harmful to metabolic, endocrine and cardiovascular homoeostatic mechanisms in postnatal life. The exact mechanisms that lead to reprogramming during fetal life need thorough investigation before effective strategies to deal with this problem can be devised.

Amniotic Fluid↗
PubMed2026

Reprogramming of TLR-Ferroptosis Signaling and Immunometabolic Pathways Overcomes Myeloid Suppression to Improve Checkpoint Blockade in Prostate Cancer.

UNLABELLED: The limited efficacy of immunotherapies in advanced prostate cancer stems from a tumor microenvironment (TME) in which myeloid-driven immune suppression, stromal remodeling, and metabolic barriers converge to limit antitumor immunity. In this study, we characterized the immunometabolic properties of an ultrasmall prostate-specific membrane antigen-targeting silica particle therapy as a first-in-class strategy to reprogram the Toll-like receptor (TLR)-ferroptosis axis in MYC-driven prostate cancer. As single agents, these particles suppressed lipid and steroid biosynthesis, disrupted lipid peroxidation control, and impaired nutrient flux, sensitizing tumors to ferroptosis. Coordinated redox remodeling, stromal reprogramming, and innate immune activation reversed myeloid suppression and promoted CD8+ T-cell infiltration. When combined with CSF-1R inhibition and immune checkpoint blockade, the particles suppressed tumor growth, extended survival beyond 100 days, and achieved up to 50% complete remission in MYC-overexpressing models. These findings position TLR-ferroptosis axis remodeling as a mechanistic blueprint for rational, particle-driven immunotherapies with broad translational potential in prostate cancer and other immunologically refractory malignancies. SIGNIFICANCE: Clinically validated, PSMA-targeted ultrasmall core-shell silica particles reprogram immunometabolic pathways via a TLR-ferroptosis axis, enabling tumor microenvironment remodeling and potentiating checkpoint blockade in prostate cancer, with translational implications for treatment-resistant disease.

Male↗
PubMed2003

Transcriptional adaptations of lipid metabolism in tibialis anterior muscle of endurance-trained athletes.

It was hypothesized that transcriptional reprogramming is involved in the structural and functional adaptations of lipid metabolism in human tibialis anterior muscle (TA) from endurance-trained male subjects. RT-PCR experiments demonstrated a significant upregulation of the mRNA level of key enzymes involved in 1) lipolytic mobilization of fatty acids (FA) from intramyocellular lipid (IMCL) stores via hormone-sensitive lipase (LIPE), 2) intramyocellular FA transport via muscle fatty acid binding protein (FABP3), and 3) oxidative phosphorylation (cytochrome c oxidase I, COI), in TA of endurance-trained vs. untrained subjects. In contrast, mRNAs for factors involved in glycolysis (muscle 6-phosphofructokinase, PFKM), intramyocellular storage of FA (diacylglycerol O-acyltransferase 1, DGAT), and beta-oxidation (long-chain acyl-coenzyme A dehydrogenase, ACADL) were invariant between TA of trained and untrained subjects. Correlation analysis identified an association of LIPE with FABP3 and LPL (lipoprotein lipase) mRNA levels and indicated coregulation of the transcript level for LIPE, FABP3, and COI with the level of mRNA encoding peroxisome proliferator-activated receptor-alpha (PPAR-alpha), the master regulator of lipid metabolism. Moreover, a significant correlation existed between LPL mRNA and the absolute rate of IMCL repletion determined by magnetic resonance spectroscopy after exhaustive exercise. Additionally, the LIPE mRNA level correlated with ultrastructurally determined IMCL content and mitochondrial volume density. The present data point to a training-induced, selective increase in mRNA levels of enzymes which are involved in metabolization of intramuscular FA, and these data confirm the well-established phenomenon of enhanced lipid utilization during exercise at moderate intensity in muscles of endurance-trained subjects.

Adaptation, Physiological↗