Diabetic cardiomyopathy (DCM) is a major complication of diabetes, but its underlying mechanisms still remain unclear. The multifunctional protein Y-box binding protein-1 (YB-1) plays an important role in cardiac pathogenesis by regulating cardiac apoptosis, cardiac fibrosis, and pathological remodeling, whereas its role in chronic DCM requires further investigation. Here, we report that the phosphorylation of YB-1 at serine102 (S102) was markedly elevated in streptozotocin-induced diabetic mouse hearts and in high glucose-treated cardiomyocytes, whereas total YB-1 protein levels were significantly reduced. Coimmunoprecipitation experiments showed that YB-1 interacts with the deubiquitinase otubain-1, but hyperglycemia-induced phosphorylation of YB-1 at S102 diminished this homeostatic interaction, resulting in ubiquitination and degradation of YB-1. Mechanistically, the high glucose-induced phosphorylation of YB-1 at S102 is dependent on the upstream extracellular signal-regulated kinase (ERK)/Ras/mitogen-activated protein kinase (p90 ribosomal S6 kinase [RSK]) signaling pathway. Accordingly, pharmacological inhibition of the ERK pathway using the upstream kinase inhibitor U0126 ameliorated features of DCM compared with vehicle-treated diabetic mice. We demonstrate that ERK inhibition with U0126 also suppressed the phosphorylation of the downstream RSK and YB-1 (S102), which stabilized the interaction between YB-1 and otubain-1 and thereby preserved YB-1 protein expression in diabetic hearts. Taken together, we propose that targeting the ERK/RSK/YB-1 pathway could be a potential therapeutic approach for treating DCM.

Background: Clinical presentations of paraneoplastic syndromes in neuroblastoma may multiply. Review of the clinical data and the literature on this syndrome may help in the diagnosis of neuroblastoma. Objectives: In order to make more accurate diagnosis, we reviewed the clinical data and the literature on this syndrome. Patients and Methods: Between April 2007 and April 2012, 68 children were diagnosed with neuroblastoma or ganglioneuroblastoma in our institution, 9 of which presented exclusively with paraneoplastic syndromes and were not treated with chemotherapy prior to diagnosis. After the diagnosis, all patients received chemotherapy and operation on NB97 protocol. Results: Among 68 pediatric patients with neuroblastoma or ganglioneuroblastoma, 4 (5.9%) patients suffered from neurological complications at diagnosis, 2 (2.9%) patients had digestive tract disorders, 2 (2.9%) patients had immune diseases, and 1 (1.5%) suffered from hematological disorder (without bone marrow involvement). All paraneoplastic syndrome patients achieved complete remission on paraneoplastic syndrome before completion of chemotherapy. Conclusions: Neuroblastoma may present with a range of non-specific neurologic symptoms in addition to the well-known opsoclonus-myoclonus syndrome and cerebellar ataxia. In any case, the presence of unexplained neurologic manifestations and other common clinical presentations such as rash, constipation, diarrhea, and especially immune disorders in an otherwise healthy child had raised the possibility of paraneoplastic syndrome due to the presence of an undiagnosed tumor. Keywords: Paraneoplastic Syndromes; Neuroblastoma; Child; Ganglioneuroblastoma; Nervous System Diseases

Panvascular disease, defined by the systemic involvement of multiple vascular beds, poses a growing challenge to contemporary diagnostic and therapeutic paradigms. Despite organ-specific manifestations, these conditions share a convergent pathological basis driven by chronic low-grade inflammation, immune dysregulation, and maladaptive vascular remodeling. Within this immunovascular interface, complement C3 (C3) has emerged as a pivotal regulator. Positioned at the convergence of the classical, lectin, and alternative complement pathways, C3 integrates systemic immune cues with microenvironmental stimuli to orchestrate endothelial activation, smooth muscle cell phenotypic switching, immune cell recruitment, platelet activation, and fibroinflammatory remodeling. This review provides a comprehensive analysis of C3 biology, including its structural domains, activation cascades, and downstream effector functions. We examine the role of C3 across major vascular cell types, endothelial cells, vascular smooth muscle cells, innate and adaptive immune cells, platelets, and fibroblasts, highlighting how C3 signaling dynamically shapes both acute injury responses and chronic vascular adaptation. In disease-specific contexts, we delineate how C3 contributes to the pathogenesis of atherosclerosis, coronary artery disease, aortic aneurysm and dissection, hypertension, pulmonary arterial hypertension, peripheral vascular disease, stroke, and autoimmune- associated vasculitides. Special emphasis is placed on the dual-phase roles of C3, such as its injuryexacerbating effects in the acute phase of stroke versus its reparative functions in neuroregeneration. Finally, we review emerging therapeutic strategies targeting C3, with a focus on compstatin-based inhibitors, their pharmacological profiles, clinical trial progress, and immunological safety considerations. Collectively, this review reframes C3 as a master orchestrator of panvascular pathology and a promising target for precision immunomodulation across vascular systems.

BACKGROUND: The long isoform of the Wnk1 (with-no-lysine [K] kinase 1) is a ubiquitous serine/threonine kinase, but its role in vascular smooth muscle cells (VSMCs) pathophysiology remains unknown. METHODS: AngII (angiotensin II) was infused in Apoe ^−/− to induce experimental aortic aneurysm. Mice carrying an Sm22-Cre allele were cross-bred with mice carrying a floxed Wnk1 allele to specifically investigate the functional role of Wnk1 in VSMCs. RESULTS: Single-cell RNA-sequencing of the aneurysmal abdominal aorta from AngII-infused Apoe ^−/− mice revealed that VSMCs that did not express Wnk1 showed lower expression of contractile phenotype markers and increased inflammatory activity. Interestingly, WNK1 gene expression in VSMCs was decreased in human abdominal aortic aneurysm. Wnk1 -deficient VSMCs lost their contractile function and exhibited a proinflammatory phenotype, characterized by the production of matrix metalloproteases, as well as cytokines and chemokines, which contributed to local accumulation of inflammatory macrophages, Ly6C ^hi monocytes, and γδ T cells. Sm22Cre+Wnk1 ^lox/lox mice spontaneously developed aortitis in the infrarenal abdominal aorta, which extended to the thoracic area over time without any negative effect on long-term survival. AngII infusion in Sm22Cre+Wnk1 ^lox/lox mice aggravated the aortic disease, with the formation of lethal abdominal aortic aneurysms. Pharmacological blockade of γδ T-cell recruitment using neutralizing anti-CXCL9 (anti-CXC motif chemokine ligand 9) antibody treatment, or of monocyte/macrophage using Ki20227, a selective inhibitor of CSF1 receptor, attenuated aortitis. Wnk1 deletion in VSMCs led to aortic wall remodeling with destruction of elastin layers, increased collagen content, and enhanced local TGF-β (transforming growth factor-beta) 1 expression. Finally, in vivo TGF-β blockade using neutralizing anti-TGF-β antibody promoted saccular aneurysm formation and aorta rupture in Sm22 Cre+ Wnk1 ^lox/lox mice but not in control animals. CONCLUSION: Wnk1 is a key regulator of VSMC function. Wnk1 deletion promotes VSMC phenotype switch toward a pathogenic proinflammatory phenotype, orchestrating deleterious vascular remodeling and spontaneous severe aortitis in mice.

Cardiovascular diseases (CVDs) remain a significant public health burden, characterized by escalating morbidity and mortality rates and demanding novel therapeutic approaches. Cold shock protein Y-box binding protein 1 (YB-1), a highly conserved RNA/DNA-binding protein, has emerged as a pivotal regulator in various pathophysiological processes, including CVDs. YB-1 exerts pleiotropic functions by modulating gene transcription, pre-mRNA splicing, mRNA translation, and stability. The expression and function of YB-1 are intricately regulated by its subcellular localization, post-translational modifications, upstream regulatory signals. YB-1 plays a multifaceted role in CVDs, influencing inflammation, oxidative stress, cell proliferation, apoptosis, phenotypic switching of smooth muscle cells, and mitochondrial dysfunction. However, the regulation of YB-1 expression and function in CVDs is complex and context-dependent, exhibiting divergent effects even in the same disease across different cell types or at disease stages. This review comprehensively explores the structure, regulation, and functional significance of YB-1 in CVDs. We delve into the transcriptional and translational control mechanisms of YB-1, as well as its post-translational modifications. Furthermore, we elucidate the upstream signaling pathways that influence YB-1 expression, with a particular emphasis on non-coding RNAs and specific upstream molecules. Finally, we systematically examine the role of YB-1 in CVDs, summarizing its expression patterns, regulatory mechanisms, and therapeutic potential as a promising target for novel therapeutic interventions. By providing a comprehensive overview of YB-1's involvement in CVDs, this review aims to stimulate further research and facilitate the development of targeted therapies to improve cardiovascular health.