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Integrated Proteomic and Phosphoproteomic Profiling Reveals Dysregulated Inflammatory Signaling Networks in Rheumatoid Arthritis.

Aberrant protein phosphorylation orchestrates sustained inflammatory immune signaling in rheumatoid arthritis (RA), yet the coordinated remodeling of proteomic and phosphoproteomic landscapes in peripheral blood mononuclear cells (PBMCs) remains poorly resolved via system-level multi-omics integration. In this article, we integrated quantitative proteomics, phosphoproteomics, and public transcriptomic datasets from PBMCs of RA patients and healthy controls to unravel multilayered molecular circuits driving RA autoimmune pathology. Differentially expressed proteins were enriched in perturbed fa…

Altered gene expression associated with Alzheimer's disease in the SH-SY5Y neuroblastoma cell model: Enhanced intracellular GSK3β and Cyclophilin A, as key neuropathology-inducing factors.

Glycogen synthase kinase 3β (GSK3β) has been shown to play a role in the pathophysiology of Alzheimer's disease (AD). Another important factor in the pathophysiology of AD is Cyclophilin A (CypA). The objective of this study is to evaluate the impact of enhanced intracellular levels of these two macromolecules on the expression of genes associated with AD and Tau protein phosphorylation in SH-SY5Y cells. According to RT-qPCR results, GSK3β and CypA significantly affect the mRNA expression of genes involved in AD development, including those associated with multiple signaling pathways, such as …

Mdivi-1 regulates mitochondrial fission and function via the CaMK2/Drp1 pathway in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive motor neuron loss. Given the high energy reli … rial content, loss of mitochondrial membrane potential, enhanced apoptotic signaling, and increased phosphorylation of CaMK2 and Drp1. Mdivi-1 treatment improved cell viability, reduced oxidative stress, restored mitochondrial integrity and membrane potential, and suppressed apoptosis. In addition, Mdivi-1 decreased Drp1 phosphorylation, whereas co-treatment with …

Coordinated Developmental Remodeling of IGF/FGF-MAPK Signaling and Cytoskeletal Plasticity Coincides with the Loss of Cardiac Regenerative Capacity.

Postnatal loss of cardiac regenerative capacity coincides with profound remodeling of signaling, structural, and metabolic programs in the d … strong decreases in B-Raf, MEK1, and MEK2, together with pronounced loss of MEK1/2 activation-loop phosphorylation. MEK1 Thr292 phosphorylation also declined markedly, identifying a previously unrecognized developmental phosphorylation pattern. Structural maturation was accompanied by stable Actn2 expression, downregulation of immature cytoskeletal markers, incr …

A Tel1-Rad9 axis links DNA double-strand break end-tethering to repair pathway choice.

In eukaryotes, DNA double-strand breaks (DSBs) activate Tel1/ATM- and Mec1/ATR-dependent checkpoint signaling and can be repaired by homologous recombination (HR), which requires DNA end resection, typically initiated by the MRX/MRN complex. In budding yeast, Sae2/CtIP promotes MRX-dependent end processing, limits Tel1-Rad53 signaling, and contributes to DSB end-tethering. Here, we identify a Tel1 FAT-domain variant, Tel1-400, that increases the DNA damage resistance of sae2Δ cells by suppressing their DSB end-tethering defect through Rad9 phosphorylation-dependent oligomerization. Tel1-400 ac…

A Phosphoproteomic Platform Identifies Erythrocyte Membrane Protein Band 4.1-Like 3-Mediated Lipid Droplet Remodeling Linked to Liver Cancer Invasion and Migration.

Aberrant lipid metabolism is a hallmark of hepatocellular carcinoma (HCC), yet the regulatory mechanisms governing lipid droplet (LD) dynamics and their contribution to tumor progression remain poorly understood. Here, we developed an ultrasensitive phosphoproteomic platform using high-affinity HPDA@Ti4+ nanospheres to map LD-associated phosphorylation events across six HCC cell lines. By correlating phosphoproteomic signatures with LD morphology, we identified distinct regulatory signatures associated with LD size and abundance. Functional perturbation screens identified two distinct phosphop…

Hyperbaric Oxygen Attenuates Cerebral Ischemia-Reperfusion Injury Through ROS-Dependent Remodeling of Microglial Mitochondrial Dynamics.

Hyperbaric oxygen (HBO) shows neuroprotective potential in cerebral ischemia-reperfusion (CIR) injury, but its variable efficacy suggests th … ochondrial membrane potential, maintained mitofusin 2 (MFN2) protein level, and reduced DRP1 Ser616 phosphorylation without altering total DRP1 or FIS1 expression. MitoTEMPOL abolished HBO-mediated protection against mitochondrial fragmentation, MFN2 reduction, and DRP1 Ser616 phosphorylation in vitro. Edaravone, when combined with HBO, attenuated HBO-mediated ne …

Вирус Pseudorabies pUL40 вызывает подстрекательские сигналы через конкурентный захват ЭФА2 из взаимодействия Akt-EphA2.

Герпесвирусная инфекция вызывает чрезмерное воспаление, что ведет к повреждению тканей и серьезному болезням, однако основные водители остаются неясными. Здесь мы идентифицируем EfA2 в качестве важнейшего посредника в возбудительской реакции, вызванной псевдорабочими вирусами (ППВ). Генетическое или фармакологическое ингибирование ЭФА2 привело к сокращению производства ТНФ-α в инфицированных ПРВ клетках и мышах, уменьшило повреждения печени и легких и улучшило выживаемость мышей. Механистически инфекция PRV стимулировала фосфориляцию EfA2 в Ser-897, которая активировала каналы NF-K и MAPK для

Совпадение в аннотации оригинала
Herpesvirus infection triggers excessive inflammation, contributing to tissue injury and disease severity, but the underlying drivers remain … ed liver and lung damage, and improved mice survival. Mechanistically, PRV infection promoted EphA2 phosphorylation at Ser-897, which activated NF-κB and MAPK pathways to drive TNF-α production. The PRV tegument protein UL40 directly bound the EphA2 kinase domain (residues 697-901), a region that also interacts with Akt. Unexpectedly, Akt acted as a negative regu …

Selective dependency of CALR-mutant myeloproliferative neoplasms on TYK2 signaling.

Myeloproliferative neoplasms (MPN) are driven by the oncoproteins JAK2V617F, mutant calreticulin (CALR), and mutant thrombopoietin receptor (TPOR; MPL), all of which activate JAK/STAT signaling. While JAK2 signaling is engaged in all MPNs, TYK2 is dispensable for JAK2V617F-driven disease. Here, we hypothesized a distinct role for TYK2 in CALR-mutant driven MPN. We found constitutive TYK2 phosphorylation in CALRdel52/ins5- and MPLW515K- but not JAK2V617F-expressing cells. Structural modeling predicted similar TPOR-binding affinities for JAK2 and TYK2, while micropatterning experiments demonstra…

The interplay between oxytocin receptor and YAP in regulating gastric cancer progression.

Gastric cancer (GC) remains a lethal malignancy with limited therapeutic targets, while recent studies revealed YAP could be a promising tar … OXTR leads to the formation of a complex with ARRB2, thereby outcompeting LATS1 and inhibiting its phosphorylation of YAP. This interaction increases YAP signaling activity, which in turn promotes the progression of gastric cancer. Furthermore, YAP can bind to the promoter region of OXTR, facilitating its expression and establishing a positive feedback loop. The …

Proteomic and phosphoproteomic signatures of aging mouse liver.

The liver is a metabolic powerhouse, crucial for regulating carbohydrates, fats, and protein metabolism. In this study, we conducted a compa … ns," and "biosynthesis of unsaturated fatty acids" were increased, while those linked to "oxidative phosphorylation," "steroid hormone biosynthesis," and "tryptophan metabolism" were decreased. Interestingly, aging was marked by a significant decrease in liver protein phosphorylation, with nearly 90% of significant phosphosites being downregulated. Pathway analys …

Fenbendazole Exhibits Antitumor Activity Against Cervical Cancer Through Dual Targeting of Cancer Cells and Cancer Stem Cells: Evidence from In Vitro and In Vivo Models.

Cervical cancer remains a major threat to women's health, with advanced cases often exhibiting recurrence and metastasis due to cancer stem … est, and triggered apoptosis in both CCCs and CCSCs. Mechanistically, FBZ upregulated cyclin B1 and phosphorylation of cdc25C-Ser198, while downregulating Wee1, phosphorylation of CDK1, and phosphorylation of cdc25C-Ser216, collectively enforcing G2/M blockade. In vivo, FBZ (100 mg/kg) significantly suppressed tumor growth in xenograft models without weight loss, …

Mechanosensitive Ca2+ channel TRPV1 activated by low-intensity pulsed ultrasound ameliorates acute kidney injury through Notch1-Akt-eNOS signaling.

Acute Kidney Injury (AKI) is a significant medical condition characterized by the abrupt decline in kidney function.Low-intensity pulsed ult … y TRPV1 knockdown. RNA sequencing analysis indicated LIPUS-induced activation of the Notch pathway, phosphorylation of Akt and eNOS. Furthermore, inhibition or genetic silencing of Notch1 abolished the beneficial effects of LIPUS on angiogenesis, renal function, and Akt-eNOS phosphorylation in both cells and AKI rats. These findings suggest that LIPUS-induced cal …

Resveratrol as a Potential Platelet Inhibitor in Aspirin-Resistant Diabetic Patients-A Novel Therapeutic Strategy Targeting F0F1-ATP Synthase Inhibition.

In Diabetes Mellitus (DM), a metabolic disorder characterized by elevated blood glucose due to impaired insulin action, platelet function is … atalysis. Platelet chemical energy demand during the activation phase is achieved through oxidative phosphorylation. Both mitochondrial and extra-mitochondrial oxidative phosphorylation drive aerobic energy production in activated platelets, utilizing fatty acids and glucose, respectively. Hyperglycemia can cause an overwork of the oxidative phosphorylation, prod …

DHCR24 knockdown-induced cellular cholesterol deficiency triggers tau hyperphosphorylation at Thr181, Ser199 and Ser202/Thr205 via p38 MAPK/JNK signaling.

Cholesterol deficiency is implicated in Alzheimer's disease (AD) pathogenesis, yet its regulatory role in tau phosphorylation remains unclear. We investigated whether the loss of 24-dehydrocholesterol reductase (DHCR24), a key enzyme in cholesterol biosynthesis, drives tau hyperphosphorylation via p38 MAPK and JNK signaling pathways in SH-SY5Y neuroblastoma cells. Using lentiviral vectors encoding DHCR24-cDNA or DHCR24-shRNA, we established stable DHCR24-overexpression and DHCR24-knockdown SH-SY5Y cell models. Filipin III staining and UPLC-MS/MS demonstrated that DHCR24 knockdown significantly…

The novel role of Kallistatin in linking metabolic syndromes and cognitive memory deterioration by inducing amyloid-β plaques accumulation and tau protein hyperphosphorylation.

Accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheim … er long-term potentiation in hippocampal CA1 neurons accompanied by increased Aβ deposition and tau phosphorylation. Mechanistically, Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPARγ signaling, resulting in Aβ cleavage and production. Besides, Kallistatin could promote the phosphorylation of tau by …

Single-nucleus analysis reveals oxidative stress in Down syndrome basal forebrain neurons at birth.

INTRODUCTION: Basal forebrain cholinergic neurons (BFCNs) are integral to learning, attention, and memory, and are prone to degeneration in … in life. Genes encoding proteins associated with energy metabolism pathways, specifically oxidative phosphorylation and glycolysis, and genes encoding antioxidant enzymes are upregulated in DS BFCNs. DISCUSSION: Multiomic analyses reveal that energy metabolism may be disrupted in DS BFCNs by birth. Increased oxidative phosphorylation and the accumulation of reac …

Evolution of growth factor signaling to the TSC complex to regulate mTORC1.

The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates signals from factors that both stimulate (exogenous growth factors) and are essential for (intracellular nutrients and energy) cellular growth. Activation of the protein kinase mTOR within mTORC1 results in the phosphorylation of downstream substrates that collectively stimulate biomass accumulation to drive cell growth. Many upstream signals, especially growth factors, regulate mTORC1 by inducing the phosphorylation of the tuberous sclerosis complex 2 (TSC2) subunit of the TSC protein complex, a conserved brake on mTORC1…

Synaptic and extrasynaptic distribution of NMDA receptors in the cortex of Alzheimer's disease patients.

BACKGROUND: Synaptic and extrasynaptic distribution of N-methyl-D-aspartate receptors (NMDARs) has not been addressed in the brain from Alzheimer´s disease (AD) subjects, despite their contribution to neurodegeneration. METHODS: We have developed a protocol to isolate synaptic and extrasynaptic membranes from controls and AD frontal cortex. We characterized the distribution of the NMDAR subunits GluN2B, GluN2A, GluN1, and GluN3A, as well as post-translational modifications, such as phosphorylation and glycosylation. RESULTS: Lower levels of synaptic GluN2B and GluN2A were found in AD fractio…

House dust mites stimulate thymic stromal lymphopoietin production in human bronchial epithelial cells and promote airway remodeling through activation of PAR2 and ERK signaling pathway.

House dust mites (HDM) are common aeroallergens linked to airway inflammation and remodeling in asthma. Protease-activated receptor 2 (PAR2) … r without the PAR2 antagonist FSLLRY-NH2 (FSL), and TSLP expression was measured by qPCR and ELISA. Phosphorylation of MAPKs was assessed by western blotting. Human lung fibroblasts (HLFs) were exposed to recombinant TSLP or conditioned medium (CM) from HDM-stimulated HBECs, with or without anti-TSLP antibodies. Fibroblast proliferation and collagen production we …