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The membranes surrounding the eukaryotic cell and its organelles are continuously invaginating, budding, and undergoing membrane fusion–fission events, which enable them to perform functions not found in prokaryotic cells. In addition, organelles come into close contact with each other at membrane contact sites (MCSs), which involve many types of proteins, and which regulate the signaling and transport of various molecules. Vesicle-associated membrane protein (VAMP)-associated protein (VAP) is an important factor involved in the tethering and contact of various organelles at MCSs in almost all eukaryotes and has attracted attention for its association with various diseases, mainly neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, the detailed mechanism of its functional expression remains unclear. In this review, we quantitatively discuss the structural dynamics of the entire molecule, including intrinsically disordered regions and intramolecular and intermolecular interactions, focusing on the vertebrate VAP paralogs VAPA and VAPB. Molecular phylogenetic and biophysical considerations are the basis of the work. Full article

Background and Objectives: Neurotrophic receptor tyrosine kinase 3 (NTRK3) is a member of the tropomyosin receptor kinase family of receptor tyrosine kinases, which play a crucial role in neural development. However, owing to the limited number of studies about NTRK3 and cancer, we aimed to investigate NTRK3 as a potential prognostic marker for breast cancer (BC). Materials and Methods: We conducted a comprehensive analysis of NTRK3 expression in BC using the Tumor Immune Estimation Resource, Gene Expression Profiling Interactive Analysis 2, and Kaplan–Meier Plotter databases. We also explored the association between NTRK3 expression and tumor-infiltrating immune cells. Results: Low NTRK3 expression showed poorer prognosis in BC, as well as with T stage, pathology, and the Luminal subtype. In BC (BRCA), NTRK3 was positively correlated with CD4+ T cell, CD8+ T cell, macrophage, and neutrophil infiltration. Conclusions: These results suggest that NTRK3 may serve as a prognostic biomarker and provide novel insights into tumor immunology in BC. Therefore, NTRK3 represents a potential diagnostic and therapeutic target for BC treatment. Full article

Transforming growth factor-beta (TGF-β) plays a dual role in hepatocellular carcinoma (HCC), acting as a tumor suppressor in early stages by inducing cell cycle arrest and apoptosis, and as a promoter in advanced stages by fostering tumor progression, epithelial–mesenchymal transition (EMT), and metastasis. Understanding TGF-β’s role in HCC progression, particularly its impact on tumor–stroma interactions, is crucial for developing personalized therapies. This study aims to clarify TGF-β function in HCC using patient-derived cell lines and advanced 2D and 3D culture models. Three new cell lines (HLC21, HLC19 tumoral, and HLC19 metastatic) were isolated from HCC patient biopsies, characterizing their phenotypic markers and responses to TGF-β and its inhibitor, galunisertib. HLC21 cells displayed a mixed epithelial–mesenchymal phenotype, responding to TGF-β suppressing growth and undergoing EMT, which were inhibited by galunisertib. Conversely, HLC19 tumoral and metastatic cells exhibited mesenchymal phenotypes and were resistant to both TGF-β suppression and galunisertib effects. In 3D co-cultures with hepatic fibroblasts, TGF-β inhibitory effects were diminished for responsive cell lines, while resistant lines maintained their non-responsiveness. These findings highlight TGF-β’s dual role in HCC and its influence on tumor–stroma crosstalk, offering valuable models for exploring personalized anti-TGF-β therapies based on tumor characteristics. Full article

Cardiovascular diseases are one of the leading causes of mortality and morbidity worldwide. The pathogenesis of this group of disorders is highly complex and involves interactions between various cell types and substances, among others, catestatin (CTS). In recent years, numerous researchers have expanded our knowledge about CTS’s role in development and its potential for the treatment of a variety of diseases. In this review, the authors discuss CTS’s importance in the pathogenesis of arterial hypertension, coronary artery disease, and heart failure. Moreover, we present CTS’s influence on heart and vessel function. Full article

Aging is often a choice between developing cancer or autoimmune disorders, often due in part to loss of self-tolerance or loss of immunological recognition of rogue-acting tumor cells. Self-tolerance and cell recognition by the immune system are processes very much dependent on the specific signatures of glycans and glycosylated factors present on the cell plasma membrane or in the stromal components of tissue. Glycosylated factors are generated in nearly innumerable variations in nature, allowing for the immensely diverse role of these factors in aging and flexibility necessary for cellular interactions in tissue functionality. In previous studies, we showed that differential expression of TMEM230, an endoplasmic reticulum (ER) protein was associated with specific signatures of enzymes regulating glycan synthesis and processing and glycosylation in rheumatoid arthritis synovial tissue using single-cell transcript sequencing. In this current study, we characterize the genes and pathways co-modulated in all cell types of the synovial tissue with the enzymes regulating glycan synthesis and processing, as well as glycosylation. Genes and biological and molecular pathways associated with hallmarks of aging were in mitochondria-dependent oxidative phosphorylation and reactive oxygen species synthesis, ER-dependent stress and unfolded protein response, DNA repair (UV response and P53 signaling pathways), and senescence, glycolysis and apoptosis regulation through PI3K-AKT-mTOR signaling have been shown to play important roles in aging or neurodegeneration (such as Parkinson’s and Alzheimer’s disease). We propose that the downregulation of TMEM230 and RNASET2 may represent a paradigm for the study of age-dependent autoimmune disorders due to their role in regulating glycosylation, unfolded protein response, and PI3K-AKT-mTOR signaling. Full article

A novel series of oleanolic acid (OA, 1) derivatives incorporating phenolic and coumarin moieties were synthesized. This acid was extracted from olive pomace (Olea europaea L.) using an ultrasound-assisted method. The structures of these novel derivatives of OA were characterized through the utilization of ¹H-NMR, ¹³C-NMR and ESI-HRMS analyses. An evaluation of some biological activities of the prepared derivatives was conducted. The evaluation focused principally on the capacity of these structures to inhibit 15-lipoxygenase and α-glucosidase, as well as their anticancer properties when tested against tumour cell lines (HCT-116 and LS-174T) and a non-tumour cell line (HEK-293). In terms of their cytotoxic activity, the majority of the compounds exhibited notable inhibitory effects compared to the starting molecule, OA. Derivatives 4d, 4k and 4m exhibited particularly strong inhibitory effects against the HCT-116 cell line, with IC₅₀ values of 38.5, 39.3, 40.0 µM, respectively. Derivatives 4l, 4e and 5d demonstrated the most effective inhibition against the LS-174T cell line, with IC₅₀ values of 44.0, 44.3, 38.0 µM, respectively. However, compound 2a was the most effective, exhibiting the most potent inhibition of 15-lipoxygenase and α-glucosidase, with IC₅₀ values of 52.4 and 59.5 µM, respectively. Furthermore, molecular docking studies supported in vitro cytotoxic activity, revealing that the most potent compounds exhibited low binding energies and interacted effectively within the EGFR enzyme’s active pocket (PDB: 1M17). These findings highlight the potential of these derivatives as anticancer agents and enzymatic inhibitors, warranting further investigation. Full article

Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) are highly prevalent chronic conditions, frequently coexisting due to their shared pathophysiological mechanisms and risk factors. Epidemiological studies estimate that up to 30% of COPD patients have comorbid T2DM, contributing to worsened disease progression, more hospitalizations, and higher mortality rates. Systemic inflammation in COPD contributes to insulin resistance by increasing pro-inflammatory cytokines (TNF-α, IL-6, and CRP), which impair glucose metabolism and beta-cell function. Conversely, hyperglycemia in T2DM exacerbates oxidative stress, leading to endothelial dysfunction, reduced lung function, and impaired pulmonary repair mechanisms. A comprehensive narrative review was conducted to evaluate the interplay between COPD and T2DM, examining shared pathophysiological mechanisms, clinical consequences, and management strategies. The co-occurrence of COPD and T2DM accelerates disease development, elevates hospitalization rates, and deteriorates overall prognosis. Pharmacological interactions complicate illness treatment, requiring a multidisciplinary therapy strategy. Recent data underscore the need to integrate palliative care, facilitate shared decision-making, and provide psychological support to enhance patient outcomes. Efficient therapy of COPD-T2DM comorbidity necessitates a customized, interdisciplinary strategy that targets both respiratory and metabolic health. Preliminary prognostic dialogues, palliative care, and holistic lifestyle modifications can improve patient quality of life and clinical results. Full article

Diabetic peripheral neuropathy (DPN) is a prevalent and disabling complication of diabetes, with painful diabetic peripheral neuropathy (PDPN) being its most severe subtype due to chronic pain and resistance to treatment. Satellite glial cells (SGCs), critical for maintaining dorsal root ganglion (DRG) homeostasis, undergo significant structural and functional changes under pathological conditions. This study investigated the role of galactosylceramide (GalCer), a key sphingolipid, in SGC dysfunction and neuron–glia interactions during DPN progression. Using a rat model of PDPN, we employed single-cell RNA sequencing (scRNA-seq), targeted mass spectrometry, and immunofluorescence analysis. The PDPN group exhibited transcriptional activation and structural reorganization of SGCs, characterized by increased SGC abundance and glial activation, evidenced by elevated Gfap expression. Functional enrichment analyses revealed disruptions in sphingolipid metabolism, including marked reductions in GalCer levels. Subclustering identified vulnerable SGC subsets, such as Cluster a, with dysregulated lipid metabolism. The depletion of GalCer impaired SGC-neuron communication, destabilizing DRG homeostasis and amplifying neurodegeneration and neuropathic pain. These findings demonstrate that GalCer depletion is a central mediator of SGC dysfunction in PDPN, disrupting neuron–glia interactions and exacerbating neuropathic pain. This study provides novel insights into the molecular mechanisms of DPN progression and identifies GalCer metabolism as a potential therapeutic target. Full article

Allergic contact dermatitis (ACD) is a skin condition characterized by inflammation resulting from hypersensitivity upon contact with certain allergens. Although ACD is characterized by an immune-mediated pathomechanism, the involvement of the nervous system in this condition has increasingly been considered, particularly in the amplification and persistence of inflammation. This paper aims to present a comprehensive overview of the mechanisms involved in neurogenic inflammation in ACD, focusing on the role of sensory neurons, the release of neuropeptides, their interaction with immune cells, and the potential therapeutic implications related to neurogenic pathways, diversified by age and gender. Innovative therapies for ACD, including topical formulations, may target the mass-bound X2 G-protein-coupled receptor (MRGPRX2) and endocannabinoid systems. Full article

High-grade gliomas are aggressive, primary, central nervous system tumors with low survival rates due to recurrence and resistance to current therapy models. Recent studies have highlighted the importance between the interaction of glioma cancer cells and cells of the tumor microenvironment (TME). Cancer stem cells and immune cells play a critical role in the TME of gliomas. TMEs in glioma include the perivascular TME, hypoxic TME, and invasive TME, each of which have evolved as our understanding of the involved cellular players has improved. This review discusses the multidimensional aspects of the current targeted therapies and interactions between glioma cells and the TME with specific focus on targeted immunotherapies. Understanding the complexities of the TME and elucidating the various tumor-cell interactions will be critical for facilitating the development of novel precision strategies, ultimately enabling better patient outcomes. Full article

The BH3-interacting domain death agonist (Bid), a proapoptotic signaling molecule of the B-cell lymphoma 2 (Bcl-2) family, is a key regulator of mitochondrial outer membrane (MOM) permeability. Uniquely positioned at the intersection of extrinsic and intrinsic apoptosis pathways, Bid links death receptor signaling to the mitochondria-dependent cascade and can also be activated by endoplasmic reticulum (ER) stress. In its active forms, cleaved Bid (cBid) and truncated Bid (tBid), it disrupts MOM integrity via Bax/Bak-dependent and independent mechanisms. Apoptosis plays a dual role in viral infections, either promoting or counteracting viral propagation. Consequently, viruses modulate Bid signaling to favor their replication. The deregulation of Bid activity contributes to oncogenic transformation, inflammation, immunosuppression, neurotoxicity, and pathogen propagation during various viral infections. In this work, we explore Bid’s structure, function, activation processes, and mitochondrial targeting. We describe its role in apoptosis induction and its involvement in infections with multiple viruses. Additionally, we discuss the therapeutic potential of Bid in antiviral strategies. Understanding Bid’s signaling pathways offers valuable insights into host–virus interactions and the pathogenesis of infections. This knowledge may facilitate the development of novel therapeutic approaches to combat virus-associated diseases effectively. Full article

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular condition in the world, affecting around 1 in 500 people. HCM is characterized by ventricular wall thickening, decreased ventricular chamber volume, and diastolic dysfunction. Inherited HCM is most commonly caused by sarcomere gene mutations; however, approximately 50% of patients do not present with a known mutation, highlighting the need for further research into additional pathological mutations. The alpha-B crystallin (CRYAB) mutation CRYAB^R123W was previously identified as a novel sarcomere-independent mutation causing HCM associated with pathological NFAT signaling in the setting of pressure overload. We generated stable H9C2 cell lines expressing FLAG-tagged wild-type and mutant CRYAB, which demonstrated that CRYAB^R123W increases calcineurin activity. Using AlphaFold to predict structural and interaction changes, we generated a model where CRYAB^R123W uniquely binds to the autoinhibitory domain of calcineurin. Co-immunoprecipitation using the CRYAB FLAG tag followed by mass spectrometry showed novel and distinct changes in the protein interaction patterns of CRYAB^R123W. Finally, mouse heart extracts from our wild-type CRYAB and CRYAB^R123W models with and without pressure overload caused by transverse aortic constriction (TAC) were used in global proteomic and phosphoproteomic mass spectrometry analysis, which showed dysregulation in cytoskeletal, metabolomic, cardiac, and immune function. Our data illustrate how CRYAB^R123W drives calcineurin activation and exhibits distinct changes in protein interaction and cellular pathways during the development of HCM and pathological cardiac hypertrophy. Full article

Alginate hydrogels are integral to many cell-based models in tissue engineering and regenerative medicine. As a natural biomaterial, the properties of alginates can vary and be widely adjusted through the gelation process, making them versatile additives or bulk materials for scaffolds, microcarriers or encapsulation matrices in tissue engineering and regenerative medicine. The requirements for alginates used in biomedical applications differ significantly from those for technical applications. Particularly, the generation of novel niches for stem cells requires reliable and predictable properties of the resulting hydrogel. Ultra-high viscosity (UHV) alginates possess alginates with special physicochemical properties, and thus far, numerical simulations for the gelation process are currently lacking but highly relevant for future designs of stem cell niches and cell-based models. In this article, the gelation of UHV alginates is studied using a microscopic approach for disc- and sphere-shaped hydrogels. Based on the collected data, a multiphase continuum model was implemented to describe the cross-linking process of UHV alginate polysaccharides. The model utilizes four coupled kinetic equations based on mixture theory, which are solved using finite element software. A good agreement between simulation results and experimental data was found, establishing a foundation for future refinements in the development of an interactive tool for cell biologists and material scientists. Full article

Background: Pancreatic ductal adenocarcinoma is an aggressive neoplasm with a complex carcinogenesis process that must be understood through the interactions between tumor cells and tumor microenvironment cells. Methods: This study was retrospective with a chronological extension period of 16 years and included 56 cases of pancreatic ductal adenocarcinoma. This study identified, quantified, and correlated the cells of the tumor immune microenvironment in pancreatic ductal adenocarcinoma with major prognostic factors as well as overall survival, using an extensive panel of immunohistochemical markers. Results: Three tumor immunotypes were identified: subtype A (hot immunotype), subtype B (intermediate immunotype), and subtype C (cold immunotype). Patients with immunotype C exhibit considerably higher rates of both pancreatic fistulas and acute pancreatitis. Immunotypes B and C significantly increased the risk of this complication by factors of 3.68 (p = 0.002) and 3.94 (p = 0.001), respectively. The estimated probabilities of fistula formation for each immunotype are as follows: 2.5% for immunotype A, 25% for immunotype B, and 28% for immunotype C. There was a statistically significant difference in median survival times according to tumor immunotype (p < 0.001). Specifically, patients with immunotype C tumors had a median survival time of only 120.5 days, compared to 553.5 days for those with immunotype A and 331.5 for immunotype B tumors. Conclusions: The identification of the immunotype of pancreatic ductal adenocarcinoma can be a predictive factor for the occurrence of complications such as pancreatic fistula as well as for overall survival. Full article

Solar supergranulation is a large-scale convective structure on the solar surface, whose formation mechanism and dynamical properties are closely related to key physical processes such as solar magnetic field evolution, coronal heating, and solar wind acceleration. This paper reviews recent research progress on solar supergranulation, focusing on the latest achievements in high-resolution observations, theoretical models, and numerical simulations. By analyzing the flow field structure, magnetic field distribution, and their relationship with the solar activity cycle, the crucial role of supergranulation in solar physics is revealed. Studies indicate that supergranulation is not only a crucial component of the solar convection zone but also drives coronal heating and solar wind acceleration through mechanisms such as magnetic reconnection and Alfvén wave propagation. Furthermore, the interaction between supergranulation and larger-scale convective patterns (e.g., giant cells) provides new insights into the dynamics of the solar interior. Despite significant progress in recent years, the formation mechanism and dynamical nature of supergranulation remain unresolved. Future research should combine high-resolution observations, theoretical modeling, and numerical simulations to further elucidate the complex dynamical processes and the central role of supergranulation in solar physics. Full article