Search Results (103)

DNA damage is a hallmark of the fatal process of neurodegeneration in the central nervous system (CNS). As neurons are terminally differentiated, they accumulate metabolic and oxidative burdens over their whole life span. Unrepaired DNA develops into DNA double-strand breaks (DSBs), which are repaired through homologous recombination (HR) or non-homologous end joining (NHEJ). Being post-mitotic and unable to normally undergo HR, damage and defective repair is especially burdensome to CNS neurons. Current research has not produced treatment to prevent and halt progression of neurodegeneration. Hence, novel targeting strategies are desperately needed. Recent investigations in histone post-translational modifications (PTMs) reveal new mechanistic insight and highlight unexplored targets to ameliorate neurodegeneration. As various histone PTMs dictate and facilitate DSB repair, they represent an underexploited area in investigating DNA damage and incorrect repair aiding neurodegeneration. Here, we review the histone PTM alterations in several neurodegenerative diseases: Amyotrophic Lateral Sclerosis/Frontotemporal Dementia, Parkinson’s Disease, Alzheimer’s Diseases, Multiple Sclerosis, and Huntington’s Disease. These findings emphasize that histone PTM alterations can enable an aberrant DNA damage response (DDR) leading to neurodegeneration. Further research into the connections between histone PTMs and DNA damage in decaying neurons will illuminate novel targets to dampen the aberrant DDR and promote neuronal survival. Full article

Background/Objectives: Monoclonal antibody (mAb) stability is critical not only during manufacturing but also at the point of clinical administration. For therapies like tislelizumab (Tevimbra), a programmed death-1 (PD-1) targeting IgG mAb, delays in dosing often result in prepared infusions being discarded, contributing to substantial drug waste despite being engineered for improved stability. Methods: To evaluate the physicochemical in-use stability of tislelizumab in a ready-to-administer format, we mapped degradation pathways, including post-translational modifications (PTMs); peptide alterations; pH and solution characteristics—under 12-month storage (ultra-long), under 1-month storage (0, 7, 14, 21, 28 and 31 days), and under exposure-related forced degradation conditions including room temperature, elevated temperature, pH (acidic/basic), oxidation and UV exposure. Structural analysis was contextualised to the known PD-1 binding site, making stability assessment relevant to tislelizumab’s mechanism-of-action in blocking PD-1. To assess solution stability, a validated size-exclusion chromatography (SEC) assay was applied to all conditions. Results: Aggregation was identified as the primary degradation pathway during ultra-long-term storage. SEC and chemical assessment revealed no measurable changes in protein quantity, aggregation, peptide integrity, or PTM profile over 31 days at 2–8 °C in polyolefin intravenous bags (1.6 mg/mL). Conclusions: These results support the structural and physicochemical stability of tislelizumab under refrigerated conditions. Full article

Tau protein, a neuron-enriched microtubule-associated protein encoded by the MAPT gene, plays pivotal roles in microtubule stabilisation, axonal transport, and synaptic plasticity. Aberrant post-translational modifications (PTMs), hyperphosphorylation, acetylation, ubiquitination, oxidative stress and neuroinflammation disrupt tau’s normal functions, drive its mislocalization, and promote aggregation into neurofibrillary tangles, a hallmark of Alzheimer’s disease (AD) and related tauopathies. Over the past two decades, tau-targeted therapies have advanced into clinical development, yet most have failed to demonstrate efficacy in human trials. This review synthesises mechanistic insights into tau biology and pathology, highlighting phosphorylation and acetylation pathways, aggregation-prone motifs, and immune-mediated propagation. We analyse the current therapeutic landscape, including kinase and phosphatase modulators, O-GlcNAcase inhibitors, aggregation blockers, immunotherapies, and microtubule-stabilising agents, while examining representative clinical programs and the reasons underlying their limited success. By combining mechanistic understanding with clinical experience, this review outlines emerging opportunities for rational treatment development, aiming to inform future tau-targeted strategies for AD and other tauopathies. Full article

Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular disease (CVD) that cannot be fully explained by traditional cardiometabolic risk factors. The observed ‘lipid paradox’, where RA patients with lower total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels exhibit higher CVD risk, may be attributed to post-translational modifications (PTMs). These lipoprotein PTMs likely arise from inflammatory pathways. While PTMs like citrullination and carbamylation are well recognized in RA joint pathology, their occurrence in other protein compartments and their role in CVD have been less well explored. This scoping review summarizes the current literature on PTMs of lipoproteins, including oxidation, nitration, carbamylation, and citrullination, and their impacts on CVD in RA. We also discuss immune responses to these PTMs, their interactions with scavenger receptors, and the effects of disease-modifying antirheumatic drugs. Further research on PTMs may uncover new pathways linking autoimmunity, inflammation, and vascular damage, offering novel diagnostic and therapeutic opportunities for RA-associated CVD. Full article

Schizophrenia (SCZ) is a complex psychiatric disorder with heterogeneous molecular underpinnings that remain poorly resolved by conventional single-omics approaches, limiting biomarker discovery and mechanistic insights. To address this gap, we applied an artificial intelligence (AI)-driven multi-omics framework to an open access dataset comprising plasma proteomics, post-translational modifications (PTMs), and metabolomics to systematically dissect SCZ pathophysiology. In a cohort of 104 individuals, comparative analysis of 17 machine learning models revealed that multi-omics integration significantly enhanced classification performance, reaching a maximum AUC of 0.9727 (95% CI: 0.8889–1.000) using LightGBMXT, compared to 0.9636 (95% CI: 0.8636–1.0000) with CNNBiLSTM for proteomics alone. Interpretable feature prioritization identified carbamylation at immunoglobulin-constant region sites IGKC_K20 and IGHG1_K8, alongside oxidation of coagulation factor F10 at residue M8, as key discriminative molecular events. Functional analyses identified significantly enriched pathways including complement activation, platelet signaling, and gut microbiota-associated metabolism. Protein interaction networks further implicated coagulation factors F2, F10, and PLG, as well as complement regulators CFI and C9, as central molecular hubs. The clustering of these molecules highlights a potential axis linking immune activation, blood coagulation, and tissue homeostasis, biological domains increasingly recognized in psychiatric disorders. These results implicate immune–thrombotic dysregulation as a critical component of SCZ pathology, with PTMs of immune proteins serving as quantifiable disease indicators. Our work delineates a robust computational strategy for multi-omics integration into psychiatric research, offering biomarker candidates that warrant further validation for diagnostic and therapeutic applications. Full article

Redox signaling is central to plant adaptation, influencing metabolic regulation, stress responses, and developmental processes through thiol-based oxidative post-translational modifications (oxiPTMs) of redox-sensitive proteins. These modifications, particularly those involving cysteine (Cys) residues, act as molecular switches that alter protein function, structure, and interactions. Advances in mass spectrometry-based redox proteomics have greatly enhanced the identification and quantification of oxiPTMs, enabling a more refined understanding of redox dynamics in plant cells. In parallel, the emergence of computational modeling, artificial intelligence (AI), and machine learning (ML) has revolutionized the ability to predict redox-sensitive residues and characterize redox-dependent signaling networks. This review provides a comprehensive synthesis of methodological advancements in redox proteomics, including enrichment strategies, quantification techniques, and real-time redox sensing technologies. It also explores the integration of computational tools for predicting S-nitrosation, sulfenylation, S-glutathionylation, persulfidation, and disulfide bond formation, highlighting key models such as CysQuant, BiGRUD-SA, DLF-Sul, and Plant PTM Viewer. Furthermore, the functional significance of redox modifications is examined in plant development, seed germination, fruit ripening, and pathogen responses. By bridging experimental proteomics with AI-driven prediction platforms, this review underscores the future potential of integrated redox systems biology and emphasizes the importance of validating computational predictions, through experimental proteomics, for enhancing crop resilience, metabolic efficiency, and precision agriculture under climate variability. Full article

Reactive nitrogen species (RNS), particularly peroxynitrite (ONOO⁻), play a central role in post-translational modifications (PTMs) of proteins, including fibrinogen, a key component of the coagulation cascade. This review explores the structural and functional consequences of fibrinogen nitration, with a focus on its impact on clot formation, morphology, mechanical stability, and fibrinolysis. Nitration, primarily targeting tyrosine residues within functional domains of the Aα, Bβ, and γ chains, induces conformational changes, dityrosine crosslinking, and aggregation into high molecular weight species. These modifications result in altered fibrin polymerization, the formation of porous and disorganized clot networks, reduced mechanical resilience, and variable susceptibility to fibrinolysis. Moreover, nitrated fibrinogen may affect interactions with platelets and endothelial cells, although current evidence remains limited. Emerging clinical studies support its role as both a prothrombotic mediator and a potential biomarker of oxidative stress in cardiovascular and inflammatory diseases. Finally, we explore both pharmacological interventions, such as NOX inhibitors, and natural antioxidant strategies at counteracting fibrinogen nitration. Overall, fibrinogen nitration emerges as a critical molecular event linking oxidative stress to thrombotic risk. Full article

Autophagy is a highly conserved cellular process that plays a crucial role in maintaining cellular homeostasis by degrading damaged organelles, misfolded proteins, and other cellular components. p62/SQSTM1 functions as a selective autophagy receptor by binding polyubiquitinated cargo through its UBA domain and linking it to microtubule-associated protein light chain 3 (LC3)-decorated autophagosomes. Moreover, p62 acts as a signaling hub and is essential in response to various stressors, including nutrient deprivation and oxidative stress. Post-translational modifications (PTMs) critically regulate p62’s multifaceted roles, controlling p62’s phase separation, cargo recruitment, signaling interactions, and autophagic degradation efficiency. The dysregulation of p62 PTMs is closely related to the occurrence and development of human diseases, particularly neurodegenerative disorders and certain cancers. This review summarizes the main PTM events of p62 discovered to date that influence the autophagy process, including phosphorylation, acetylation, ubiquitination, and S-acylation, as well as their known contributions to protein aggregation and disease. The PTMs of p62 dynamically regulate autophagy, protein aggregation, and cellular signaling, underscoring its importance as a potential therapeutic target and biomarker for these diseases. Full article

Peroxiredoxins (Prxs; EC 1.11.1.15) are a group of thiol peroxidases that catalyze the detoxification of H₂O₂ and other organic hydroperoxides. The ripening of pepper (Capsicum annuum L.) fruit involves significant phenotypic, physiological, and biochemical changes. Based on the available pepper plant genome, eight PRX genes were identified and named CaPRX1, CaPRX1-Cys, CaPRX2B, CaPRX2E, CaPRX2F, CaPRX2-CysBAS1, CaPRX2-CysBAS2, and CaPRX Q. Among these, only CaPRX1-Cys was not detected in the transcriptome (RNA-Seq) of sweet pepper fruits reported previously. This study analyzes the modulation of these seven CaPRX genes during ripening and after treating fruits with nitric oxide (NO) gas. A time-course expression analysis of sweet pepper fruit during ripening revealed that two genes were upregulated (CaPRX1 and CaPRX2E), two were downregulated (CaPRX2B and PRX Q), and three were unaffected (CaPRX2F, CaPRX2-CysBAS1, and CaPRX2-CysBAS2). Gene expression was also studied in three hot pepper varieties with varying capsaicin contents (Piquillo < Padrón < Alegría riojana), showing a differential expression pattern during ripening. Furthermore, NO treatment of sweet pepper fruits triggered the upregulation of CaPRX2B and CaPRXQ genes and the downregulation of CaPRX1 and CaPRX2-CysBAS1 genes, while the other three remained unaffected. Among the CaPrx proteins, four (CaPrx2B, CaPrx2-CysBAS1, CaPrx2-CysBAS2, and CaPrx2E) were identified as susceptible to S-nitrosation, as determined by immunoprecipitation assays with an antibody against S-nitrocysteine and further mass spectrometry analyses. These findings indicate the diversification of PRX genes in pepper fruits and how some of them are regulated by NO, either at the level of gene expression or through protein S-nitrosation, a NO-promoting post-translational modification (PTM). Given that Prxs play a crucial role in stress tolerance, these data suggest that Prxs are vital components of the antioxidant system during pepper fruit ripening, an event that is accompanied by physiological nitro-oxidative stress. Full article

Superoxide dismutases (SODs) maintain redox homeostasis through the catalytic dismutation of superoxide anions, thereby affording protection to organisms against oxidative damage. The SOD family, encompassing Cu/Zn-SOD, Mn-SOD, Fe-SOD, and Ni-SOD, exhibits structural diversity and constitutes a multilevel antioxidant defense system with discrete subcellular localizations. Beyond their antioxidant functions, SODs also function as immunomodulatory proteins, regulating the maturation, proliferation, and differentiation of immune cells. They further fulfill a crucial role in host responses to parasitic infections. The current review synthesizes and critically evaluates extant research to comprehensively delineate the molecular architecture of SODs, their intricate post-translational modification (PTM) networks, and their dual regulatory mechanisms at the interface of immunomodulation and pathological processes. This review establishes a critical framework for elucidating the biological significance of redox homeostasis maintenance. Full article

Zinc (Zn) is a crucial trace element in vertebrates, fulfilling a range of physiological functions, whose metabolism and homeostasis are manipulated by Zn transporter proteins. SUMOylation, a reversible post-translational modification (PTM), extensively participates in various biological processes in the body, yet its underlying mechanism in regulating Zn transporters remains unexplored. Our findings indicate that high dietary Zn substantially elevated intestinal Zn content and modulated the expression profiles of Zn transporter-related genes and proteins, including ZIP8 transporter. In addition, high Zn diet tended to inhibit the SUMOylation modification and upregulate deSUMOylation modification in the intestine and intestinal epithelial cells. Furthermore, we found that the ZIP8 protein undergoes SUMOylation modification; UBC9 upregulated but SENP1 and Zn downregulated the SUMOylation level of ZIP8, and the K24 and K222 positions are the primary SUMOylation modification sites of ZIP8 protein in yellow catfish. Mechanistically, SENP1 modulates the deSUMOylation modification of ZIP8 by sensing Zn-induced oxidative stress. In summary, for the first time, we have uncovered a unique regulatory mechanism of ZIP8 mediated by SUMOylation modification in vertebrates and demonstrate that SENP1 is capable of sensing oxidative stress to reduce the SUMOylation modification of ZIP8 at K24 and K222 sites. Full article

Nitric oxide (NO) can perform its physiological role through protein S-nitrosylation, a redox-based post-translational modification (PTM). This review details the specific molecular mechanisms and current detection technologies of S-nitrosylation. It also comprehensively synthesizes emerging evidence of S-nitrosylation roles in plant biological processes, including growth and development, immune signaling, stress responses and symbiotic nitrogen fixation. Furthermore, the review analyzes research progress on the crosstalk between S-nitrosylation and other protein PTMs. Finally, unresolved issues such as the spatio-temporal resolution of SNO-proteome mapping and standardized protocols for reproducibility are pointed out. In summary, this work proposes a roadmap for future research. Full article

Metabolic diseases, including cardiovascular diseases, type 2 diabetes mellitus (T2DM), osteoporosis, and non-alcoholic fatty liver disease (NAFLD), constitute a major global health burden associated with chronic morbidity and mortality. Lactate, once considered as a metabolic byproduct, has emerged as a key regulator of cellular reprogramming through lactylation, a novel post-translational modification (PTM) that dynamically couples metabolic flux to chromatin remodeling. Lactylation exerts dual regulatory roles as a signaling molecule via GPR81/GPR4-mediated pathways and as a substrate for the covalent modification of histones and metabolic enzymes. Pathologically, chronic hyperlactatemia suppresses mitochondrial biogenesis, driving metabolic cardiomyopathy through the epigenetic silencing of oxidative metabolism genes. Conversely, exercise-induced lactate surges transiently enhance insulin sensitivity via AMPK/PGC-1α/GLUT4 signaling, resolve inflammation through GPR81-mediated M2 macrophage polarization, and restore mitochondrial function via lactylation-dependent pathways. This review delineates lactylation as a spatiotemporal rheostat: chronic dysregulation perpetuates metabolic disorders, whereas acute exercise-mediated lactylation remodels transcriptional networks to restore metabolic homeostasis. Future research should integrate multiomics to clarify lactylation’s spatiotemporal dynamics, tissue-specific thresholds, metabolism–immunity interactions, and metabolic–epigenetic crosstalk for the precision management of metabolic diseases. Full article

Oxidative stress, which is characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, has critical roles in the initiation, progression, and treatment of gastric cancer. On the one hand, an excessive ROS accumulation induces oxidative damage and cancer cell death. On the other hand, moderate levels of ROS cause genetic mutations and dysregulation of signaling pathways to promote proliferation, inflammation, angiogenesis, and metastasis in gastric cancer. Notably, emerging evidence has revealed that ROS also mediate oxidative post-translational modifications (oxPTMs) of redox-sensitive proteins, which can directly affect protein functions and regulate redox signaling in cancer cells. Therefore, elucidating the regulatory mechanisms of oxidative stress and redox signaling in gastric cancer holds great promise to identify novel therapeutic targets or redox-targeting strategies. This review will summarize the mechanisms of oxidative stress in regulating the hallmarks of gastric cancer and highlight the roles of ROS-mediated oxPTMs in gastric cancer. In addition, we will discuss emerging strategies targeting oxidative stress for the treatment of gastric cancer, with an emphasis on the use of bioactive natural products and nanomaterials. Full article

Plants are subjected to various stresses during the growth process, including biotic stresses, as well as abiotic stresses such as temperature, drought, salt, and heavy metals. To cope with these biotic and abiotic adversities, plants have evolved complex regulatory mechanisms during their long-term environmental adaptations. In a suddenly changing environment, protein modifiers target other proteins to induce post-translational modification (PTM) in order to maintain cell homeostasis and protein biological activity in plants. PTMs modulate the activity of enzymes and transcription factors in their respective metabolic pathways, enabling plants to produce essential compounds for their survival under stress conditions. Examples of post-translational mechanisms include phosphorylation, ubiquitination, glycosylation, acetylation, protein–protein interactions, and targeted protein degradation. Furthermore, the role of histone modifications in regulating secondary metabolism deserves attention due to its potential impact on heritability and its contribution to stress tolerance. Understanding the epigenetic aspect of these modifications can provide valuable insights into the mechanisms underlying stress response. In this context, also examining PTMs that impact the biosynthesis of secondary metabolites is meaningful. Secondary metabolites encompass a wide range of compounds such as flavonoids, alkaloids, and terpenoids. These secondary metabolites play a crucial role in plant defense against herbivores, pathogens, and oxidative stress. In this context, it is imperative to understand the contribution of secondary metabolism to plant tolerance to abiotic stresses and how this understanding can be leveraged to improve long-term survival. While many studies have focused on the transcriptional regulation of these metabolites, there is a growing interest in understanding various changes in PTMs, such as acetylation, glycosylation, and phosphorylation, that are able to modulate plants’ response to environmental conditions. In conclusion, a comprehensive exploration of post-translational mechanisms in secondary metabolism can enhance our understanding of plant responses to abiotic stress. This knowledge holds promise for future applications in genetic improvement and breeding strategies aimed at increasing plant resilience to environmental challenges. Full article