SEARCH · PubMed Health

Results for “Kinase signaling”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2026

Opposing kinase signaling may underlie the inverse relationship between cancer and Alzheimer's disease.

Cancer and Alzheimer's disease (AD) are leading causes of mortality and exhibit an inverse relationship, where AD patients have reduced cancer risk and vice versa. However, the molecular basis of this relationship remains poorly understood. We reanalyzed published proteomic and phosphoproteomic datasets to investigate this relationship. Differentially abundant proteins were identified in lung adenocarcinoma and glioblastoma samples relative to controls and compared with proteins altered in AD brains, revealing 37 proteins with opposing abundance patterns. Protein-protein interaction and pathway analyses revealed enrichment in kinase signaling and phosphorylation pathways. Phosphoproteomic analysis identified 52 differentially phosphorylated sites with opposing patterns, while kinase-substrate enrichment analysis identified 44 kinases with opposing inferred activity profiles. Integration of kinase activity and phosphosite data identified 29 kinase-phosphosite pairs, including 4 prioritized pairs with opposing patterns relevant to both diseases. Across seven independent cancer cohorts, 17 of 20 statistically significant phosphosite-cohort comparisons (85%) were concordant with the discovery findings, supporting reproducibility of the prioritized phosphosites. Together, these findings highlight opposing kinase signaling as a prominent feature of the inverse relationship and suggest potential biomarkers and therapeutic targets. This study provides a novel systems-level framework for investigating inverse relationships, supported by an R Shiny application for data exploration (https://advscancer.shinyapps.io/advscancer/). SIGNIFICANCE: This study presents an integrated proteomic and phosphoproteomic framework for investigating the inverse relationship between cancer and Alzheimer's disease (AD). By integrating differential protein abundance, phosphosite phosphorylation, inferred kinase activity, and curated kinase-substrate relationships, we identified opposing signaling patterns and prioritized four kinase-phosphosite pairs. Independent evaluation across seven CPTAC cancer cohorts supported the reproducibility of the prioritized phosphosite patterns. These findings provide insight into molecular processes potentially associated with the inverse relationship between cancer and AD, identify candidate biomarkers and therapeutic targets, and demonstrate the value of systems-level, data-driven approaches for investigating shared and opposing disease processes.

Humans↗

PubMed2026

Elevated mitochondrial superoxide promotes longevity through a mitochondria-to-nucleus kinase signaling pathway.

The reactive oxygen species superoxide is generated by mitochondria during the process of producing energy. While superoxide can cause oxidative damage to the cell, we and others have shown that a mild increase in mitochondrial superoxide extends longevity in multiple model organisms. To elucidate the molecular mechanisms involved, we identified transcriptional changes in mitochondrial superoxide dismutase deletion mutants (sod-2 worms) using RNA sequencing. sod-2 mutants exhibit a number of changes in nuclear gene expression resulting from elevated mitochondrial superoxide suggesting that mitochondria-to-nucleus signaling is contributing to their longevity. Gene ontology enrichment analysis demonstrated that genes involved in innate immunity and cuticle formation are significantly upregulated in sod-2 worms. To identify kinases involved in this lifespan-extending pathway, we completed a targeted RNA interference screen to examine the contribution of selected kinases to sod-2 longevity. From this screen, we found 25 kinases which are required for the long lifespan of sod-2 mutants including mak-2, which has a role in a kinase signaling pathway involved in axon regeneration. Disruption of mak-2 specifically reduces sod-2 lifespan but not wild-type longevity and also decreases resistance to multiple exogenous stressors. In examining other genes that act with mak-2 in established signaling pathways, we identified a SEK-3/PMK-3/MAK-2/CEBP-1 signaling pathway that is specifically required for sod-2 longevity but not wild-type lifespan. Combined these results suggest a novel role for kinases with established roles in axon regeneration in promoting longevity through a mitochondria-to-nucleus signaling pathway.

Aging↗

PubMed2026

Development of receptor and oncogene-responsive luciferase reporter vectors that are activated via kinase signaling to AP-1.

This study aimed to generate lentiviral vectors carrying an array of AP-1 motifs driving luciferase gene expression as reporters of mitogen-activated protein kinase (MAPK) activity. We created a series of vectors based on LeGO-iG that were used to generate stably transduced leukemia cell lines. A vector termed LEGO-AP1×6-GM55 containing an array of 6 AP-1 sites linked to the minimal CSF2 promoter was sufficient to support high levels of MAPK-inducible luciferase activity in leukemic cell lines that was suppressed by MAPK inhibitors. The inclusion of a putative chromatin priming element encompassing RUNX and ETS motifs increased the activity of these vectors. The additional inclusion of the full-length mouse CSF2 promoter, or the human DUSP5 promoter further increased the MAPK-dependent activity of these vectors in leukemic cells. These vectors support moderate levels of constitutive activity in cells carrying mutations that activate the RAS/RAF/MEK MAPK signaling pathway, and high-level activity after direct activation of MAPK signaling. They also respond to T-cell receptor activation via MAPK and Ca2+ signaling pathways. This resource will now make it easier to track receptor or oncogene-inducible MAPK activity in cultured cells, and potentially in tumors, close to real-time.

Humans↗

PubMed2025

Restraint of inflammasome-driven cytokine responses through the mRNA stability protein TTP.

Activation of the NLRP3 inflammasome causes extensive disturbance of cellular homeostasis, with Golgi disruption, mitochondrial dysfunction, and changes in intracellular ion concentration occurring rapidly upon stimulation. Given this, it would seem near certain that these changes might also globally affect cellular signaling pathways, yet few, if any, studies have explored this possibility. Here, we combine genomics and phosphoproteomics to identify inhibition of the ERK1/2 MAP kinase signaling cascade upon inflammasome stimulation. This loss of ERK1/2 activity results in rapid inactivation of the mRNA decay-promoting protein tristetraprolin (TTP), with loss of TTP promoting subsequent increased release of cytokines upon pyroptosis. Further, we observe significantly increased levels of TTP expression in patients with inflammatory bowel disease, a disease for which altered cytokine expression is a key driver of pathogenesis. Inflammasome activation thus rapidly inactivates a pathway designed to suppress cytokine release, potentially exacerbating hyperinflammatory states, including those involved in autoinflammatory disease.

Inflammasomes↗

PubMed2026

Human biopsy-defined ischemia-reperfusion injury-selective reperfusion signature prioritizes reperfusion-timed mitogen-activated protein kinase kinase inhibition after donation after circulatory death liver transplantation.

Early post-liver transplant ischemia-reperfusion injury (IRI) in donation after circulatory death grafts lacks therapies targeted to the immediate postreperfusion window, in part because generic reperfusion transcription obscures IRI-selective amplification. We analyzed paired prereperfusion/postreperfusion liver biopsies from 2 cohorts (GSE151648 and GSE87487) using a difference-in-differences interaction estimand (ΔΔ = [Post-Pre]IRI+ - [Post-Pre]IRI-) to define an IRI-selective early reperfusion program. Genome-wide ΔΔ effects were summarized using pathway-responsive genes, and pathway concordance was tested using permutation (B = 5000). The reproducible ΔΔ footprint highlighted epidermal growth factor receptor-mitogen-activated protein kinase signaling (Spearman ρ = 0.811; P = .001). Directional ΔΔ gene sets (interaction P < .05) were submitted to the L1000 characteristic direction signature search engine2; cross-cohort overlap identified 8 shared perturbagens, including 3 mitogen-activated protein kinase kinase (MEK)1/2 inhibitors. In a hepatic ischemia/reperfusion time course (GSE117915), epidermal growth factor receptor and mitogen-activated protein kinase activities increased within 0.5 hours of reperfusion, and transplant single-cell RNA sequencing (GSE189539) localized MEK/extracellular signal-regulated kinase pathway engagement predominantly to parenchymal cells. A representative MEK inhibitor, PD-0325901, reduced hepatocyte oxygen-glucose deprivation/reoxygenation injury and, when administered at reperfusion in a rat donation after circulatory death liver transplantation model (5-20 mg/kg), attenuated histologic and biochemical injury, apoptosis, and redox-inflammatory readouts and improved 7-day survival. Collectively, this biopsy-anchored ΔΔ interaction-phenotype framework, with cross-cohort concordance as a prespecified robustness gate, nominates reperfusion-timed MEK inhibition as a mechanism- and window-aligned strategy to blunt early post-liver transplant IRI.

difference-in-differences (time × IRI interac↗

PubMed2026

Phosphoproteomic analysis in a mouse model reveals ERK signaling as a key modulator of inflammatory response in nasal mucosa associated with childhood allergic rhinitis.

Childhood allergic rhinitis (AR) is a multifactorial condition arising from the interplay between genetic predisposition and environmental exposures. Although protein phosphorylation is widely recognized as a key regulator of gene expression across various physiological and pathological states, its global alterations in the nasal mucosa of pediatric patients with AR and their subsequent impact on mucosal function and inflammatory pathways remain incompletely characterized. Our study aimed to elucidate the molecular mechanisms underlying nasal mucosa dysfunction induced by pediatric AR. Our analysis revealed 3,861 proteins encompassing a total of 15,491 phosphorylation sites. Specifically, we detected 441 downregulated phosphorylation sites on 584 proteins and 531 upregulated phosphorylation sites on 722 proteins in the nasal mucosa of the AR group. Our proteomics findings suggest that the dysregulation of immune activation and metabolic regulation may contribute to AR pathophysiology. Through pathway analysis of the identified phosphorylation sites, we found Extracellular Signal-Regulated Kinase (ERK) signaling emerged as an important pathway; notably, upregulation of ERK1/2 phosphorylation was observed as a significant marker associated with AR. Importantly, targeting ERK inhibitors presents a potential therapeutic strategy for modulating key inflammatory response signaling pathways in the context of AR, although this finding is derived from preclinical mouse models and requires rigorous validation in human pediatric nasal mucosal tissues before any clinical translation can be considered. Collectively, these findings highlight that elucidating the molecular mechanisms underlying AR-induced nasal mucosal dysfunction in the mouse model may inform the novel therapeutic targets for pediatric allergy-related diseases. Overall, elucidating these mechanisms has substantial implications for developing targeted interventions aimed at mitigating inflammation associated with allergic rhinitis.

Animals↗

PubMed2025

Tofacitinib Mitigates the Increased SARS-CoV-2 Infection Susceptibility Caused by an IBD Risk Variant in the PTPN2 Gene.

BACKGROUND & AIMS: Coronavirus disease (COVID-19), caused by severe acquired respiratory syndrome-Coronavirus-2 (SARS-CoV-2), triggered a global pandemic with severe medical and socioeconomic consequences. Although fatality rates are higher among the elderly and those with underlying comorbidities, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases. The aim of our study was to investigate whether the autoimmunity risk gene, PTPN2, which also confers elevated risk to develop inflammatory bowel disease, affects susceptibility to SARS-CoV-2 viral uptake. METHODS: Using samples from PTPN2 genotyped patients with inflammatory bowel disease, PTPN2-deficient mice, and human intestinal and lung epithelial cell lines, we investigated how PTPN2 affects expression of the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2), and uptake of virus-like particles expressing the SARS-CoV2 spike protein and live SARS-CoV-2 virus. RESULTS: We report that the autoimmune PTPN2 loss-of-function risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry of SARS-CoV-2 spike protein and live virus. Elevated ACE2 expression and viral entry were mediated by increased Janus kinase-signal transducers and activators of transcription signaling and were reversed by the Janus kinase inhibitor, tofacitinib. CONCLUSION: Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk.

Humans↗

PubMed2026

CTSG Suppresses Breast Cancer Progression by Inhibiting the EGFR/ERK Signaling Pathway and Enhancing CD8⁺ T Cell Activation.

BACKGROUND: Breast cancer (BC), the most common female malignancy, has metastasis as its main cause of mortality. Cathepsin G (CTSG) is involved in tumorigenesis and immunity. This study explores the role of CTSG in BC progression and CD8 + T cell regulation. METHODS: Differentially expressed genes and proteins (DEGs/DEPs) were analyzed using Limma, and core genes were screened using Random Forest (RF) and Least absolute shrinkage and selection operator (LASSO). CTSG expression was analyzed using GSE36295, the Cancer Genome Atlas (TCGA), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blot. Cell viability, proliferation, cell cycle, migration, and invasion were detected using Cell Counting Kit-8 (CCK8), 5‑Ethynyl‑2'‑deoxyuridine (EdU), flow cytometry, and Transwell assays, respectively. Sphere diameter was analyzed via sphere formation assay. Downstream mechanisms were examined using western blot, CCK8, flow cytometry, and Transwell assays. CD8 + T cell activity was examined using EdU, western blot, and flow cytometry. RESULTS: A total of 177 genes overlapped between GSE36295 DEGs and PDC000173 DEPs. CTSG was the hub gene identified by RF and LASSO. CTSG expression was significantly reduced in BC (P < 0.01). CTSG overexpression suppressed cell viability, proliferation, migration, invasion, sphere formation, and CD44 and CD133 expression (P < 0.01). CTSG up-regulation inhibited epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) signaling axis and reduced cancer cell malignancy (P < 0.01). CTSG overexpression activated CD8 + T cells via EGFR/ERK inhibition, enhancing their cytotoxic effect on cancer cells (P < 0.01). CONCLUSION: CTSG inhibits BC malignancy and enhances CD8 + T cell function via EGFR/ERK inhibition.

Humans↗

PubMed2026

Shared genetic architecture and therapeutic targets across paediatric immune-mediated diseases.

OBJECTIVES: Paediatric-onset immune-mediated inflammatory diseases (IMIDs), including juvenile idiopathic arthritis and related rheumatic diseases, remain genetically undercharacterised. We aimed to define shared and category-specific genetic architecture across paediatric IMIDs, compare signals with adult IMIDs, and identify therapeutic opportunities. METHODS: We analysed 24 paediatric IMIDs classified as autoimmune, polygenic-autoinflammatory, mixed-pattern, or allergic. Genome-wide association analyses included 18,086 cases and 131,019 controls of European ancestry. We estimated single nucleotide polymorphism (SNP)-based heritability, genetic correlations, and polygenic overlap; performed subset-based meta-analysis; and conducted functional annotation, gene prioritisation, pathway and protein network analyses, adult-IMID comparison, and drug-target prioritisation. RESULTS: SNP-based heritability ranged from 28.9% for allergic IMIDs to 61.9% for autoimmune IMIDs. Genetic correlation and polygenic modelling supported partial sharing across categories with category-specific components. Meta-analysis identified 39 genome-wide significant loci outside the Major Histocompatibility Complex (MHC) region, including 15 previously unreported loci; 19 loci were shared between categories. Gene-prioritisation and protein interaction analyses identified a core MHC-centred antigen-presentation network, with category-enriched modules involving complement, innate/barrier pathways, epithelial biology, and type 2 immunity. Enriched pathways included nuclear factor κB signalling, T helper 17 related pathways, Janus kinase-signal transducer and activator of transcription signalling, programmed cell death protein 1/programmed death‑ligand 1, cytotoxic T‑lymphocyte associated protein 4 regulation, and osteoclast differentiation, several of which are relevant to rheumatic diseases. Paediatric IMIDs shared broad polygenic architecture with adult IMIDs, whereas top-ranked genes converged strongly with adult rheumatic diseases. Priority Index analysis identified 178 high-scoring genes, including 43 approved or investigational IMID drug targets. CONCLUSIONS: Paediatric-onset IMIDs share core pathways with adult forms but exhibit distinct genetic architecture shaped by age-specific immune and neurodevelopmental biology. These findings provide a genomic framework for paediatric precision medicine, guiding classification, risk prediction, and therapeutic development.

Humans↗

PubMed2026

Host Proteome Remodeling During Group A Streptococcus Skin Infection.

Group A Streptococcus (Streptococcus pyogenes, GAS) is a bacterial pathogen that commonly causes local infections in humans and can lead to invasive diseases. GAS infections trigger complex host immune and tissue responses, yet how these processes are coordinated over time and across different tissues remains poorly understood. To explore the spectrum of GAS infection, we examined responses in a skin infection model at multiple proteome levels, characterizing local and distant tissues with variable infection responses. We map changes in canonical innate and adaptive immune signaling while uncovering new mechanisms in the context of skin infection. We uncover the robust and time-dependent expression of one family of proteins, chitinase-like proteins, that coincides with immune cell infiltration of local tissues. Because immunomodulatory networks are tightly regulated through post-translational modifications, we integrated global proteomic data with cytokine signaling and key phosphoproteome changes. This analysis revealed correlations between mTOR and kinase signaling pathways that diverge at local and systemic tissues. Our systems-based approach provides a rigorous evaluation of a GAS skin infection, characterizing host proteome remodeling across experimental groups and individual mice.

Animals↗

PubMed2025

Weifuchun ( ) exerts therapeutic effects on gastric fundic gland polyps by promoting ferroptosis.

OBJECTIVE: To investigate the therapeutic effects of Chinese medicine Weifuchun (WFC, ) on gastric fundic gland polyps (FGPs). METHODS: FGPs organoids were constructed with patients-derived samples. The morphology and size of FGPs organoids were detected using bright-field imaging. Effective components and corresponding potential targets of WFC were screened using multiple open-source databases and research on Traditional Chinese Medicine or compound formulas. Core genes were identified through protein-protein interaction networks. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses of the core genes were conducted. The interactions between main components and core targets were analyzed through the FerrDb database. The expressions of core targets were detected by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: After WFC treatment, the number and size of FGPs organoids were significantly reduced. Twenty nine active drug components and 162 candidate targets of WFC for treating FGPs were identified, including 37 targets related to ferroptosis. Quercetin, Glaucocalyxin B, Melissoidesin U, Melissoidesin O, Hesperetin, Glaucocalyxin A, Angustifolin, Melissoidesin M, Di-n-octyl phthalate, and beta-sitosterol were identified as the main active compounds. SRC proto-oncogene, non-receptor tyrosine kinase, signal transducer and activator of transcription 3, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta, phosphoinositide-3-kinase regulatory subunit 1, and AKT serine/threonine kinase 1 were identified as the primary targets. KEGG pathways related to carcinogenesis, cell proliferation and metabolism, and oxidative stress. WFC promoted FGPs organoids' death and could be reversed by ferroptosis inhibitor of Erastin. The qRT-PCR results showed that WFC treatment could regulate the mRNA expression levels of solute carrier family 7 member 11, acyl-CoA synthetase long chain family member 4, and arachidonate 15-lipoxygenase, type B. CONCLUSION: WFC may exert its therapeutic effects by inducing ferroptosis in FGPs cells.

Humans↗

PubMed2025

Mathematical modeling suggests 14-3-3 proteins modulate RAF paradoxical activation.

RAF inhibitor "paradoxical activation" (PA) is a phenomenon where RAF kinase inhibitors increase RAF kinase signaling. Through mathematical modeling and experimental data analysis, we recently demonstrated that the combination of conformational autoinhibition (CA) with the disruption of CA by RAF inhibitors plays an important role in PA. 14-3-3 proteins are known to modulate RAF CA and RAF dimerization. We here extend our mathematical model to include both roles of 14-3-3 proteins, and we derive rigorous analytical expressions of RAF signal regulation as modulated by 14-3-3 proteins. We then use the model to investigate how 14-3-3 proteins may modulate PA. We mathematically show 14-3-3 protein stabilization of the autoinhibited form of RAF should potentiate PA, while 14-3-3 protein stabilization of the active RAF dimer should reduce PA. Our analysis suggests that the net-effect will often be a potentiation of PA, and that 14-3-3 proteins may be capable of inducing PA for RAF inhibitors that normally show little to no PA. We test model-based insights experimentally with two different approaches: forced increases in 14-3-3 expression (which we find amplifies PA) and evolved resistance assays (which suggest increased 14-3-3 expression may contribute to resistance to RAF inhibitors). Overall, this work supports a role for 14-3-3 in modulating RAF-inhibitor mediated paradoxical activation.

14-3-3 Proteins↗

PubMed2026

Alternative splicing of toll-like receptor pathway mRNAs in lung immune cells from patients with ARDS.

Acute respiratory distress syndrome (ARDS) is characterized by robust inflammation in the lungs and systemic circulation. In this context, the toll-like receptor (TLR) signaling pathway plays a major role, driving inflammation that promotes host defense but also causing pathological tissue damage. To limit excessive inflammation, TLR signaling must be tightly controlled. One mechanism that modulates TLR signaling is alternative splicing of TLR pathway pre-mRNAs, which balances production of positively acting inflammatory mediators with alternative splice forms that terminate inflammation. To determine whether altered TLR pathway splicing contributes to pathological inflammation in ARDS, we evaluated two central mediators of the TLR signaling pathway, the MyD88 signaling adapter and the IRAK1 signaling kinase, in leukocytes isolated from bronchoalveolar lavage (BAL) of patients with ARDS. We found that MyD88 gene expression was decreased in BAL immune cells, whereas IRAK1 gene expression was increased. In parallel, we monitored long proinflammatory (MyD88-L and IRAK1) and shorter anti-inflammatory (MyD88-S and IRAK1c) splice forms and determined that IRAK1 splicing was shifted in a proinflammatory direction in patients with ARDS. Finally, we evaluated relationships between MyD88 isoform levels in BAL leukocytes and clinical outcomes. We conclude that pre-mRNA splicing of TLR pathway genes is altered in lung immune cells in patients with ARDS, that monitoring splicing of these genes may provide important prognostic information, and that manipulating splicing of these genes may be a useful novel therapeutic approach that needs further investigation.NEW & NOTEWORTHY We found that MyD88 expression is decreased, that IRAK1 expression is increased, and that IRAK1 splicing is shifted in a proinflammatory direction, in lung immune cells in patients with ARDS. We also find that MyD88 expression levels may correlate with survival in patients with ARDS. Thus, changes in expression and splicing of these two genes offer potential novel prognostic and therapeutic targets for ARDS.

Humans↗

PubMed2026

Multimodal analysis of CD38 in T-cell Acute Lymphoblastic Leukemia Identifies Combinatorial Therapeutic Strategies.

Outcomes for pediatric patients with refractory or relapsed T-cell acute lymphoblastic leukemia (T-ALL) are poor, underscoring the need for improved therapeutic strategies. CD38, a type II transmembrane glycoprotein, is a promising target in T-ALL, with clinical trials evaluating CD38-targeting immunotherapies in frontline and relapsed settings. However, the biological role of CD38 in T-ALL has not been systematically defined. We interrogated CD38 biology through multimodal profiling of pediatric T-ALL samples. Bulk RNA sequencing of 1,335 primary tumors revealed that CD38 expression varies across genomic and immunophenotypic subtypes in T-ALL. Flow cytometry of 150 primary samples and CITE-sequencing of 40 cases demonstrated broad surface expression of CD38. A transcription factor CRISPR-screen identified RUNX1, RUNX3, and TP53 as candidate positive regulators of CD38. Metabolomic profiling of cell lines further revealed disruption of the polyamine pathway following CD38 perturbation. Supporting this finding, co-targeting CD38 with difluoromethylornithine (DFMO), a polyamine metabolism disruptor, improved survival in preclinical models. Across transcriptomic datasets, including primary tumors, cell lines, and patient-derived xenograft models, IL32 expression consistently decreased following CD38 loss or negativity, supporting an association between CD38 and inflammatory signaling pathways. Additionally, CD38 and LCK expression were positively correlated across majority of genomic subtypes, implicating SRC kinase signaling. Consistent with this, daratumumab in cell lines increased LCK phosphorylation, and combination therapy with dasatinib improved survival compared to monotherapy. Collectively, these findings define previously unrecognized interactions between CD38 and targetable pathways and genes in T-ALL and identify rational combinatorial strategies to enhance CD38-directed therapies and reduce relapse risk.

Journal Article↗

PubMed2025

Effect of acupuncture on brain microenvironment in rats with post-stroke limb spasticity based on single-cell transcriptome sequencing technology.

OBJECTIVE: To investigate the possible mechanisms by which acupuncture improves post-stroke limb spasticity using single-cell sequencing technology. METHODS: Thirty-two rats were randomly assigned to four groups: Control, Sham, Model, and Acupuncture. The middle cerebral artery occlusion (MCAO) model was established, and the acupuncture groups received acupuncture treatment. After treatment, brain morphological changes and the degree of neurological impairment were assessed. The effect of acupuncture on the proportion of brain cell types in the ischemic penumbra of MCAO rats was analyzed using single-cell transcriptomics, and the expression and enrichment of differentially expressed genes were examined. Finally, selected differential genes were validated by Western blot and quantitative real-time polymerase chain reaction. RESULTS: Triphenyltetrazolium chloride staining showed that the infarct area in MCAO rats was significantly reduced after acupuncture. Garcia scoring, hematoxylin-eosin staining, Nissl staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling demonstrated that acupuncture reduced brain damage. Enzyme-linked immunosorbent assay results showed that acupuncture significantly decreased serum inflammatory factors, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Single-cell transcriptome analysis revealed marked changes in cell type proportions between the Acupuncture and Model groups. A total of 207 differential genes were identified, including 157 upregulated and 50 downregulated genes. Analysis of macrophage-specific differential genes in the ischemic penumbra showed enrichment in Gene Ontology terms such as Ras protein signal transduction and regulation of GTPase activity, and Kyoto Encyclopedia of Genes and Genomes pathways including lysosome, axon guidance, and mitogen-activated protein kinase signaling. S100a8 and leukocyte specific transcript 1 (LST1) were identified as key differential genes. CONCLUSION: These findings suggest that the key differential genes S100a8 and LST1 may alleviate post-stroke limb spasticity by regulating the inflammatory response in the ischemic penumbra.

Animals↗

PubMed2025

Lipidomic profiling of mouse brain and human neuron cultures reveals a role for Mboat7 in mTOR-dependent neuronal migration.

Mutations in lipid regulator genes are a frequent cause of autism spectrum disorder, including those regulating phosphatidylinositol (PI) and phosphoinositide 3-kinase signaling. MBOAT7 encodes a key acyltransferase in PI synthesis and is mutated in an autism-related condition with neurodevelopmental delay and epilepsy. Using liquid chromatography-tandem mass spectrometry, we analyzed the PI-associated glycerolipidome in mice and humans during neurodevelopment and found dynamic regulation at times corresponding to neural apoptosis in the brains of Mboat7 knockout mice. Mboat7 function was necessary for polyunsaturated lipid synthesis and cortical neural migration, and loss resulted in massive accumulation of the precursor lysophosphatidylinositol and hyperactive mTOR signaling. Inhibiting mTOR signaling rescued migration defects. Our findings demonstrate roles for lipid remodeling during neurodevelopment and implicate lipid regulation in neuronal migration, revealing potential paths to treatment for MBOAT7 deficiency.

Animals↗

PubMed2026

Tumor-derived antioxidants suppress immunity by depriving T cells of reactive oxygen species.

Reactive oxygen species (ROS) promote genomic instability and fuel oncogenic signaling in cancer, but antioxidant therapies have so far failed to improve, or worsen, cancer outcomes. Emerging data suggest that T cells depend on ROS for signal transduction. In this study, we show that tumors exploit this dependency, releasing antioxidant enzymes into the tumor environment to suppress T cell-mediated antitumor immunity. The interstitial fluid of tumors possesses potent antioxidant activity, associated with enrichment of the antioxidant enzyme peroxiredoxin 1 (PRDX1). Extracellular PRDX1 deprives T cells of ROS, preventing oxidative inactivation of phosphatases required for T cell receptor-driven kinase signaling and effector function. Prdx1 is up-regulated upon cancer immunoediting, and loss of PRDX1 within tumors enhances antitumor immunity and immunotherapy responses. These findings define a redox-dependent mechanism of tumor immunosuppression that is potentially amenable to therapeutic intervention.

Animals↗

PubMed2025

Phylogeny, chromosomal mapping and expression analyses of wheat CLAVATA pathway components suggest differential selection on receptor-like kinases, CLEs and T3 WOXes.

Ensuring continuous global food security is a major challenge of the 21st century. Wheat contributes approximately 20% of the total calories consumed by humans, and an estimated 60% increase in production will be required by 2050 to meet forecast global demand. In cereals like wheat, inflorescence (ear) size and branching patterns determine the number of flowers (florets) and grains produced, and these aspects of plant architecture are regulated by the activity of stem cells in the growing shoot tips. CLAVATA peptide and receptor-like kinase signalling regulates angiosperm stem cell activity, and as changes in CLAVATA function can improve crop yields, CLAVATA is a key target for reverse engineering. Here, we identify components of the wheat CLAVATA pathway using genome searches against Triticum aestivum and its wild relatives Triticum turgidum ssp. durum, Triticum turgidum ssp. dicoccoides, Triticum urartu and Aegilops tauschii. Using phylogenetic and synteny analysis, we determine the relationship between homoeologues and infer patterns of gene family evolution. Whilst CLAVATA1, BARELY ANY MERISTEM, RECEPTOR-LIKE PROTEIN KINASE 2, CORYNE and CLAVATA2 receptor-like kinase homologues are mainly present as single genome copies as in other grasses, CLAVATA3-like but not TRACHEARY ELEMENT DIFFERENTIATION FACTOR (TDIF)-like peptide encoding genes and WUSCHEL-LIKE HOMEOBOX (WOX) genes have expanded copy numbers with many gene gains and losses during evolution. Our results highlight wheat CLAVATA pathway components for reverse genetic analysis and indicate potential differential selection on wheat receptor-like kinases, their peptide ligands and WOXes.

Triticum↗