Search Results (3,598)

High-risk neuroblastoma (HRNB) is an extracranial solid pediatric cancer. Despite the plethora of treatments available for HRNB, up to 65% of patients are refractory or exhibit an initial response to treatment that transitions to therapy-resistant relapse, which is invariably fatal. A key feature that promotes HRNB progression is aberrant calcium (Ca²⁺) signaling. Ca²⁺ signaling is regulated by several druggable channel proteins, offering tremendous therapeutic potential. Unfortunately, many of the Ca²⁺ channels in HRNB also perform fundamental functions in normal healthy cells, hence targeting them increases the potential for adverse effects. To overcome this challenge, we sought to identify novel Ca²⁺ signaling pathways that are observed in HRNB but not normal non-cancerous cells with the hypothesis that these novel pathways may serve as potential therapeutic targets. One Ca²⁺ signaling pathway that is deregulated in HRNB is store-operated Ca²⁺ entry (SOCE). SOCE relays the release of Ca²⁺ from the endoplasmic reticulum (ER) and Ca²⁺ influx via the plasma membrane and promotes cancer drug resistance by regulating transcriptional programming and the induction of mitochondrial Ca²⁺ (mtCa²⁺)-dependent signaling. mtCa²⁺ signaling is critical for cellular metabolism, reactive oxygen production, cell cycle, and proliferation and has a key role in the regulation of cell death. Therefore, a dynamic interplay between ER, SOCE, and mitochondria tightly regulates cell survival and apoptosis. From a library of synthesized novel molecules, we identified two structurally related compounds that uniquely disrupt the dynamic interplay between SOCE, ER, and mitochondrial signaling pathways and induce cell death in HRNB. Our results revealed that compounds 248 and 249 activate distinct aberrant Ca²⁺ signals that are unique to relapsed HRNB and could be exploited to induce mtCa⁺ overload, a novel calcium influx current, and subsequent cell death. These findings establish a potential new pathway of calcium-mediated cell death; targeting this pathway could be critical for the treatment of refractory and relapsed HRNB. Full article

Background: As an innovative approach to deep-sea aquaculture, fish farm vessels offer a dual benefit by alleviating the pressure on offshore fishing resources while providing an additional high-quality protein source. However, the potential impacts of vessel coatings on farmed fish remain poorly understood. Methods: In this study, to investigate the effects of vessel coatings on the large yellow croaker (Larimichthys crocea), we established four experimental groups with coating concentrations at 1-fold, 10-fold, 20-fold, and 80-fold levels. Antioxidant enzyme activities in kidney tissues were measured across all groups, while histological and transcriptome analyses were specifically conducted for the 1-fold and 80-fold concentration groups. Results: Firstly, significant alterations in antioxidant enzyme activity were observed in the 80-fold concentration group. Moreover, histological analysis demonstrated more severe pathological changes in kidney tissue at the higher concentration, including interstitial hemorrhage and tubular epithelial cell fatty degeneration. In addition, we identified 11,902 differentially expressed genes (DEGs) by high-throughput sequencing. KEGG pathway enrichment analysis revealed that the DEGs were predominantly involved in critical biological processes, including endoplasmic reticulum protein processing, oxidative phosphorylation, cytokine–cytokine receptor interactions, cell cycle regulation, DNA replication, and PPAR signaling pathways. Finally, the validation of nine selected DEGs through quantitative real-time PCR (qRT-PCR) showed significant correlation with RNA-Seq data, confirming the reliability of our transcriptome analysis. Conclusions: This study provides preliminary insights into the antioxidant stress response mechanisms of L. crocea to coating exposure and establishes a theoretical foundation for optimizing healthy fish farming practices in aquaculture vessels. Full article

Pore-forming peptides are promising antimicrobial and anticancer agents due to their membrane selectivity and biodegradability. Our prior work identified peptide M159, which permeabilized synthetic phosphatidylcholine liposomes without mammalian cell toxicity. Here, we report that the D-type variant (D-M159) induces apoptosis in HeLa cells under starvation. To explore its anticancer mechanism, we analyzed D-M159 cytotoxicity, intracellular uptake, and apoptotic pathways via flow cytometry, confocal microscopy, and Western blot. Calcium dynamics and mitochondrial function were examined via specific labeling and functional assays. Results revealed that D-M159 exhibited starvation-dependent, dose-responsive cytotoxicity and triggered apoptosis in HeLa cells. Mechanistic studies indicated that D-M159 entered the cells via caveolin-dependent and caveolae-dependent endocytosis pathways and induced endoplasmic reticulum stress in HeLa cells by up-regulating proteins such as ATF6, p-IRE1, PERK, GRP78, and CHOP. Meanwhile, D-M159 promoted the expression of IP3R1, GRP75, and VDAC1, which led to mitochondrial calcium iron overload, decreased mitochondrial membrane potential, and increased reactive oxygen species (ROS) generation, thereby activating the mitochondrial apoptotic pathway and inducing the aberrant expression of Bax, Bcl-2, Caspase-9, and Caspase-3. This study showed that D-M159 synergistically induced apoptosis in starved HeLa cells through endoplasmic reticulum stress and mitochondrial dysfunction, demonstrating its potential as a novel anticancer agent. Full article

Hypertension (HTN) is a complex disease with significant global health implications, driven by neural and oxidative mechanisms. Reactive oxygen species (ROS), once considered mere metabolic byproducts, are now recognized as one of the key contributors to dysfunction of the autonomic nerve system, which involves the onset and progression of HTN. This review highlights the dynamic roles of ROS in neuronal signaling, subcellular compartmentalization, and brain–immune interactions, focusing on their impacts on synaptic remodeling, neuroinflammation, and epigenetic modifications within key autonomic regions such as the paraventricular nucleus and rostral ventrolateral medulla. We discuss novel ROS sources, including microglia-derived and endoplasmic reticulum stress-related ROS, and their contributions to HTN. Subcellular dynamics, such as ROS signaling at mitochondria-associated membranes and neuronal microdomains, are explored as activators of the sympathetic nerve system. Emerging evidence has linked ROS to epigenetic regulation, including histone modifications and non-coding RNA expression, with sex-specific differences offering insights for the development of personalized therapies. Innovative therapeutic strategies targeting ROS involve precision delivery systems, subcellular modulators, and circadian-optimized antioxidants. We propose several priorities for future research, including the real-time imaging of brain ROS, translating preclinical findings into clinical applications, and leveraging precision medicine to develop tailored interventions based on ROS activity and genetic predisposition. Through emphasizing the spatial and temporal complexity of ROS in HTN, this review identifies novel therapeutic opportunities and establishes a foundation for targeted treatments to address this health challenge. Full article

Background: Endoplasmic reticulum (ER)-targeted phototherapy has emerged as a promising approach to amplify ER stress, induce immunogenic cell death (ICD), and enhance anti-tumor immunity. However, its impact on the antigenicity of dying tumor cells remains poorly understood. Methods: Laser activation of the ER-targeted photosensitizer ER-Cy-poNO₂ was performed to investigate its effects on tumor cell antigenicity. Transcriptomic analysis was carried out to assess gene expression changes. Immunopeptidomics profiling was used to identify high-affinity major histocompatibility complex class I (MHC-I) ligands. In vitro functional studies were conducted to evaluate dendritic cell maturation and T lymphocyte activation, while in vivo experiments were performed by combining the identified peptide with poly IC to evaluate anti-tumor immunity. Results: Laser activation of ER-Cy-poNO₂ significantly remodeled the antigenic landscape of 4T-1 tumor cells, enhancing their immunogenicity. Transcriptomic analysis revealed upregulation of antigen processing and presentation pathways. Immunopeptidomics profiling identified multiple high-affinity MHC-I ligands, with IF4G3_986–994 (QGPKTIEQI) showing exceptional immunogenicity. In vitro, IF4G3_986–994 promoted dendritic cell maturation and enhanced T lymphocytes activation. In vivo, the combination of IF4G3_986–994 with poly IC elicited robust anti-tumor immunity, characterized by increased CD8⁺ T lymphocytes infiltration, reduced regulatory T cells (Tregs) in the tumor microenvironment, elevated systemic Interferon-gamma (IFN-γ) levels, and significant tumor growth inhibition without systemic toxicity. Conclusions: These findings establish a mechanistic link between ER stress-driven ICD, immunopeptidome remodeling, and adaptive immune activation, highlighting the potential of ER-targeted phototherapy as a platform for identifying immunogenic peptides and advancing peptide-based cancer vaccines. Full article

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy that poses a significant therapeutic challenge due to its high recurrence rate and demanding treatment regimens. Increasing evidence suggests that endoplasmic reticulum (ER) stress and downstream activation of the unfolded protein response (UPR) pathway play a key role in the pathogenesis of AML. ER stress is triggered by the accumulation of misfolded or unfolded proteins within the ER. This causes activation of the UPR to restore cellular homeostasis. However, the UPR can shift from promoting survival to inducing apoptosis under prolonged or excessive stress conditions. AML cells can manipulate the UPR pathway to evade apoptosis, promoting tumor progression and resistance against various therapeutic strategies. This review provides the current knowledge on ER stress in AML and its prognostic and therapeutic implications. Full article

Hydroxytyrosol (HT), a principal bioactive phytochemical abundant in Mediterranean dietary sources, has emerged as a molecule of significant scientific interest owing to its multifaceted health-promoting properties. Accumulating evidence suggests that HT’s therapeutic potential in metabolic disorders extends beyond conventional antioxidant capacity to encompass mitochondrial regulatory networks. This review synthesizes contemporary evidence from our systematic investigations and the existing literature to delineate HT’s comprehensive modulatory effects on mitochondrial homeostasis. We systematically summarized the impact of HT on mitochondrial dynamics (fusion/fission equilibrium), biogenesis and energy metabolism, mitophagy, inter-organellar communication with the endoplasmic reticulum, and microbiota–mitochondria crosstalk. Through this multidimensional analysis, we established HT as a mitochondrial homeostasis modulator with potential therapeutic applications in metabolic syndrome (MetS) and its related pathologies including type 2 diabetes mellitus, obesity-related metabolic dysfunction, dyslipidemia, non-alcoholic steatohepatitis, and hypertension-related complications. Moreover, we further discussed translational challenges in HT research, emphasizing the imperative for direct target identification, mitochondrial-targeted delivery system development, and combinatorial therapeutic strategies. Collectively, this review provides a mechanistic framework for advancing HT research and accelerating its clinical implementation in MetS and its related diseases. Full article

The growing prevalence of diabetes highlights the urgent need to study diabetic cardiovascular complications, specifically diabetic cardiomyopathy, which is a diabetes-induced myocardial dysfunction independent of hypertension or coronary artery disease. This review examines the role of mitochondrial dysfunction in promoting diabetic cardiac dysfunction and highlights metabolic mechanisms such as hyperglycaemia-induced oxidative stress. Chronic hyperglycaemia and insulin resistance can activate harmful pathways, including advanced glycation end-products (AGEs), protein kinase C (PKC) and hexosamine signalling, uncontrolled reactive oxygen species (ROS) production and mishandling of Ca²⁺ transient. These processes lead to cardiomyocyte apoptosis, fibrosis and contractile dysfunction. Moreover, endoplasmic reticulum (ER) stress and dysregulated RNA-binding proteins (RBPs) and extracellular vesicles (EVs) contribute to tissue damage, which drives cardiac function towards heart failure (HF). Advanced patient-derived induced pluripotent stem cell (iPSC) cardiac organoids (iPS-COs) are transformative tools for modelling diabetic cardiomyopathy and capturing human disease’s genetic, epigenetic and metabolic hallmarks. iPS-COs may facilitate the precise examination of molecular pathways and therapeutic interventions. Future research directions encourage the integration of advanced models with mechanistic techniques to promote novel therapeutic strategies. Full article

Membrane contact sites (MCSs) between the endoplasmic reticulum and the plasma membrane enable the transport of lipids without membrane fusion. Extended Synaptotagmins (ESYTs) act at MCSs, functioning as tethers between two membrane compartments. In plants, ESYTs have been mainly investigated in A. thaliana and shown to maintain the integrity of the plasma membrane, especially during stress responses like cold acclimatization, mechanical trauma, and salt stress. ESYTs are present at the MCSs of plasmodesmata, where they regulate defense responses by modulating cell-to-cell transfer of pathogens. Here, the analysis of ESYTs was expanded to the bryophyte Physcomitrium patens, an extant representative of the earliest land plant lineages. P. patens was found to contain a large number of ESYTs, distributed over all previously established classes and an additional class not present in A. thaliana. Motif discovery identified regions in the Synaptotagmin-like mitochondrial (SMP) domain that may explain phylogenetic relationships as well as protein function. The adaptation mechanisms of P. patens necessary to conquer land and its simple tissue structure make it highly suitable as a model organism to study ESYT functions in tip growth, stress responses, and plasmodesmata-mediated transport, and open new directions of research regarding the function of MCSs in cellular processes and plant evolution. Full article

Background/Objectives: Endoplasmic reticulum (ER) stress occurs when ER homeostasis is disrupted, leading to the accumulation of misfolded or unfolded proteins. This condition activates the unfolded protein response (UPR), which aims to restore balance or trigger cell death if homeostasis cannot be achieved. In cancer, ER stress plays a key role due to the heightened metabolic demands of tumor cells. This review explores how metabolomics can provide insights into ER stress-related metabolic alterations and their implications for cancer therapy. Methods: A comprehensive literature review was conducted to analyze recent findings on ER stress, metabolomics, and cancer metabolism. Studies examining metabolic profiling of cancer cells under ER stress conditions were selected, with a focus on identifying potential biomarkers and therapeutic targets. Results: Metabolomic studies highlight significant shifts in lipid metabolism, protein synthesis, and oxidative stress management in response to ER stress. These metabolic alterations are crucial for tumor adaptation and survival. Additionally, targeting ER stress-related metabolic pathways has shown potential in preclinical models, suggesting new therapeutic strategies. Conclusions: Understanding the metabolic impact of ER stress in cancer provides valuable opportunities for drug development. Metabolomics-based approaches may help identify novel biomarkers and therapeutic targets, enhancing the effectiveness of antitumor therapies. Full article

Numerous factors are involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), which are responsible for its development and progression as an independent entity, but also thanks to their simultaneous action. This is explained by the hypothesis of multiple parallel hits. These factors are insulin resistance, lipid metabolism alteration, oxidative stress, endoplasmic reticulum stress, inflammatory cytokine liberation, gut microbiota dysbiosis or gut–liver axis activation. This is a systematic review which has an aim to show the connection between intestinal microbiota and the role of its disbalance in the development of NAFLD. The gut microbiota is made from a wide spectrum of microorganisms that has a systemic impact on human health, with a well-documented role in digestion, energy metabolism, the stimulation of the immune system, synthesis of essential nutrients, etc. It has been shown that dysbiosis is associated with all three stages of chronic liver disease. Thus, the modulation of the gut microbiota has attracted research interest as a novel therapeutic approach for the management of NAFLD patients. The modification of microbiota can be achieved by substantial diet modification and the application of probiotics or prebiotics, while the most radical effects are observed by fecal microbiota transplantation (FMT). Given the results of FMT in the context of metabolic syndrome (MetS) and NAFLD in animal models and scarce pilot studies on humans, FMT seems to be a promising treatment option that could reverse intestinal dysbiosis and thereby influence the course of NAFLD. Full article

As a prevalent metabolic disorder, the increasing incidence of diabetes imposes a significant burden on global healthcare. Flavonoids in natural phytochemical products exhibit notable hypoglycemic properties, making them potential alternatives for diabetes treatment. This article summarizes the hypoglycemic properties of flavonoid subcategories studied in recent years, including flavones, isoflavones, flavonols, flavanols, and others. The relevant targets and signal pathways, such as α-amylase, α-glucosidase, insulin receptor substrate (IRS)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), PKR-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2α (eIF2α)/activation transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP), etc., are also elaborated. Additionally, flavonoids have also been demonstrated to modulate the gut microbiota and its metabolites. Through the aforementioned mechanisms, flavonoids mainly suppress carbohydrate metabolism and gluconeogenesis; facilitate glucose uptake, glycogenesis, and insulin secretion; and mitigate insulin resistance, oxidative stress, inflammation, etc. Notably, several studies have indicated that certain flavonoids displayed synergistic hypoglycemic effects. In conclusion, this article provides a comprehensive review of the hypoglycemic effects of the flavonoids investigated in recent years, aiming to offer theoretical insights for their further exploration. Full article

Missense mutations are the most prevalent alterations in genetic disorders such as hemophilia A (HA), which results from coagulation factor VIII (FVIII) deficiencies. These mutations disrupt protein biosynthesis, folding, secretion, and function. Current treatments for HA are extremely expensive and inconvenient for patients. Small molecule drugs offer a promising alternative or adjunctive strategy due to their lower cost and ease of administration, enhancing accessibility and patient compliance. By screening drug/chemical libraries with cells stably expressing FVIII–Gaussia luciferase fusion proteins, we identified compounds that enhance FVIII secretion and activity. Among these, suberoylanilide hydroxamic acid (SAHA) improved the secretion and activity of wild-type FVIII and common HA-associated missense mutants, especially mild and moderate ones. SAHA increased FVIII interaction with the endoplasmic reticulum chaperone BiP/GRP78 but not with calreticulin. Lowering cellular BiP levels decreased SAHA-induced FVIII secretion and enhancing BiP expression increased FVIII secretion. SAHA also enhanced secretion and BiP interactions with individual domains of FVIII. In vivo, treating mice with SAHA or a BiP activator boosted endogenous FVIII activity. These findings suggest that SAHA serves as a proteostasis regulator, providing a novel therapeutic approach to improve the secretion and functionality of FVIII missense mutants prone to misfolding. Full article

The disruption of microglial homeostasis and cytokine release are critical for neuroinflammation post-injury and strongly implicated in retinal neurodegenerative diseases like glaucoma. This study examines microglial responses to chemical hypoxia induced by cobalt chloride (CoCl₂) in BV-2 murine microglial cells, focusing on signaling pathways and proteomic alterations. We assessed the protective effects of monoclonal antibodies against TNFα and IL-1β. CoCl₂ exposure led to decreased cell viability, reduced mitochondrial membrane potential, increased lactate dehydrogenase release, elevated reactive oxygen species generation, and activation of inflammatory pathways, including nitric oxide synthase (iNOS), STAT1, and NF-κB/NLRP3. These responses were significantly mitigated by treatment with anti-TNFα and anti-IL-1β, suggesting their dual role in reducing microglial damage and inhibiting inflammatory reactivity. Additionally, these treatments reduced apoptosis by modulating ATF4 and the p38 MAPK/caspase-3 pathways. Label-free quantitative mass spectrometry-based proteomics and Gene Ontology revealed that CoCl₂ exposure led to the upregulation of proteins primarily involved in endoplasmic reticulum and catabolic processes, while downregulated proteins are associated with biosynthesis. Anti-TNFα and anti-IL-1β treatments partially restored the proteomic profile toward normalcy, with network analysis identifying heat shock protein family A member 8 (HSPA8) as a central mediator in recovery. These findings offer insights into the pathogenesis of hypoxic microglial impairment and suggest potential therapeutic targets. Full article

Faba bean (Vicia faba L.) is a globally significant legume valued for its applications in food, vegetables, and green manure, yet its high outcrossing rate (30–80%) poses challenges for production development. A rare short-winged trait identified in Yunnan, China, offers promise for developing low-outcrossing varieties, reducing outcrossing rates to below 5%. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses revealed that the epidermal cells of normal wing petals are conical, while those of short-wing petals are tubular. This study examined 200 F₂ lines from crosses between ‘K0692’ (short-winged) and ‘Yundou 1183’, as well as ‘Yundoulvxin 1’ (short-winged) and ‘Yundou 1183’. The GWASs identified 10 SNP loci across chromosomes 2, 3, 4, and 5, with SNP_chr4::1013887633 explaining 22.20% of the wing trait variation. Key candidate genes were identified, such as VFH_III145120, which influences floral identity; and VFH_III149200, associated with epidermal differentiation. GO enrichment analysis demonstrated significant gene involvement in RNA localization, ribosome biogenesis, and preribosome metabolism, while KEGG analysis linked these genes to pathways in amino acid, nucleotide, and purine metabolism; ubiquitin-mediated proteolysis; and protein processing in the endoplasmic reticulum. These findings lay a foundation for breeding low-outcrossing faba bean varieties and enhancing sustainable faba bean cultivation. Full article