Search Results (1,055)

Advanced gastric (GAC) or gastroesophageal junction (GEJAC) adenocarcinoma continues to carry a poor prognosis. Understanding GAC/GEJAC at the molecular level has provided a new understanding and the basis for individualized approaches to treatment. The current biomarker-driven therapy focuses on four areas: microsatellite instability (MSI), human epidermal growth factor receptor-2 (HER2), programmed death ligand-1 (PD-L1) combined positive score, and claudin 18.2 (CLDN18.2). However, because of improving technology, the focus has shifted to cancer cell-surface proteins and peptides. Each of these GAC/GEJAC subgroups provides a different treatment pathway. The agents utilized to treat advanced GAC/GEJAC include immune checkpoint inhibitors (ICIs), chemotherapy, monoclonal antibodies (mAbs), and antibody–drug conjugate (ADC) therapy, as well as bispecific antibodies (BsAbs), but they are certainly not limited to the above. Drug development has shifted in recent years to establish different mechanisms that are attempting more sophisticated and targeted approaches, such as BsAbs and ADCs. Meanwhile, the development of cytotoxics has tapered off. Along with these developments in drug therapy, more therapies directed at CLDN18.2, HER2, MSI, EGFR, HER3 and trophoblast cell-surface antigen 2 (TROP2) are underway. Here we review future areas in advanced GAC, including zanidatamab’s potential role in HER2-positive advanced GAC and deciphering the abundance of anti-CLDN18.2, extending beyond investigative therapies. Full article

Uridine diphosphate glucuronosyltransferases (UGTs) are critical phase II detoxification enzymes; however, their mutational landscape and protective roles against chemical carcinogenesis in hepatocellular carcinoma (HCC) remain poorly defined. Here, targeted sequencing of ten liver-enriched UGT genes in 38 paired tissues from a Chinese HCC cohort revealed striking mutation frequencies in UGT2B15 (44.74%), UGT2B10 (36.84%), and UGT2B17 (26.32%). This genomic instability was accompanied by a profound downregulation of UGT2B15 mRNA (9.02-fold decrease, p < 0.001) and protein levels (Z-score = 2.32, p = 0.0093) in tumors, with higher UGT2B15 expression correlating with improved overall survival in TCGA cohorts (HR = 1.724, p = 0.012). Mechanistically, we identified the androgen receptor (AR) as a direct transcriptional regulator of UGT2B15 and UGT2B17, with dihydrotestosterone (DHT) inducing dose-dependent increases in their expression, thereby linking endocrine signaling to hepatic detoxification. Transcriptomic profiling following UGT2B15 knockdown in HCC cells revealed a significant enrichment in chemical carcinogenesis-related pathways. Crucially, UGT2B15 deficiency severely exacerbated carbon tetrachloride (CCl₄)- and ethanol-induced hepatotoxicity both in vitro and in vivo. Our study uncovers a profound impairment of UGT-mediated detoxification in HCC and establishes the AR–UGT2B15 axis as a critical barrier against chemical-induced liver injury, highlighting its potential as a chemopreventive target in carcinogen-exposed populations. Full article

Background/Objectives: Duchenne muscular dystrophy (DMD) is a fatal, progressive neuromuscular disorder caused by mutations in the dystrophin gene, leading to the absence of functional dystrophin protein. As the largest gene in the human genome, the DMD locus is highly susceptible to mutations, contributing to a prevalence of approximately 1 in 3800–6300 live male births worldwide. This review aims to provide a comprehensive and critical synthesis of current and emerging therapeutic strategies for DMD. Methods: We conducted a narrative review of the literature, integrating findings from clinical trials, regulatory approvals, and preclinical studies. We categorized therapeutic approaches into mutation-agnostic and mutation-specific strategies, with emphasis on the mechanism of action, clinical progress, and translational limitations. Results: Current standards of care, including corticosteroids and supportive interventions, remain foundational in disease management. Mutation-specific approaches such as exon skipping and adeno-associated virus (AAV)-mediated gene replacement can restore dystrophin expression, although clinical benefit remains variable and is influenced by factors such as mutation type, delivery efficiency, and durability. Emerging genome editing strategies offer the potential for permanent correction but face significant challenges related to delivery, safety, and scalability. Emerging mutation-agnostic therapies targeting inflammation, fibrosis, and membrane instability provide broader applicability but do not directly address the underlying genetic defect. Across modalities, key limitations include modest functional outcomes, safety concerns, and variability in clinical trial endpoints. Conclusions: The DMD therapeutic landscape is rapidly evolving, and future progress will likely depend on optimizing delivery platforms, improving durability, and integrating combination strategies to address the multifaceted nature of disease progression. Full article

Background: Arginine and related amino acids are widely used to suppress protein aggregation, thereby affecting stability, manufacturability, and therapeutic performance. However, their effectiveness remains limited, necessitating the exploration of alternative strategies. Previous studies have shown that N-acetyl-L-arginine (NA-Arg) can improve protein stability; however, the potential of other N-acetylated amino acids has not been fully explored. Methods: This study aimed to investigate the effects of multiple N-acetylated amino acids as alternative excipients on aggregation, colloidal stability, and viscosity in intravenous immunoglobulin (IVIG) formulations. Dynamic light scattering (DLS) was used to evaluate diffusion behavior and aggregation tendencies, while complementary analyses were performed using size-exclusion chromatography (SEC) and flow-imaging microscopy (FI). Results: Overall, N-acetylation of amino acids improved colloidal stability, shifting the kD values from −5.87 to 6.83 mL/g for arginine and from −8.17 to 16.22 mL/g for histidine, and increased the aggregation onset temperature (Tagg) to above 60 °C. Among the tested compounds, N-acetyl-L-histidine (NA-His) showed the most favorable results, increasing the monomer proportion by approximately 4%, reducing high-molecular-weight species to below 2%, and producing a greater than 10-fold decrease in subvisible particles relative to histidine hydrochloride after 5 days of agitation. At 50 mM, both NA-His and NA-Arg reduced the viscosity of highly concentrated 200 mg/mL IVIG formulations, with NA-His exhibiting the lowest viscosity (7.24 ± 0.12 mPa·s). Protein–protein interaction and surface charge analyses indicated improved colloidal stability relative to parent amino acids, attributable to the presence of the acetyl group. Conclusions: These findings support the potential of N-acetylation as a strategy to modulate interaction-driven instability and suggest NA-His as a promising candidate excipient for stabilizing highly concentrated therapeutic proteins at acidic pH. Full article

Objectives: The aim of this study is to investigate the relationship between the lactate/albumin ratio (LAR) and 28-day mortality in gastric cancer patients undergoing monitoring in a postoperative intensive care unit due to reasons such as haemodynamic instability, need for vasopressor support, or intraoperative bleeding. Methods: This retrospective study included patients followed up at the tertiary surgical intensive care unit of Kastamonu University Faculty of Medicine between January 2020 and October 2025 who were diagnosed with histologically confirmed gastric adenocarcinoma and underwent total open surgery or subtotal gastrectomy + D2 lymphadenectomy. The patients were categorized into two groups: non-survivors within 28 days (n: 45) and survivors within 28 days (n: 139). Results: A total of 184 critically ill patients (110 males, 74 females) who underwent gastric adenocarcinoma surgery and were followed up in the surgical intensive care unit were included in this study. The mean age of the patients was 72.2 ± 11.3 years. Of these patients, 139 (75.5%) were survivors, and 45 (24.5%) were non-survivors. Albumin, the C-reactive protein (CRP)/albumin ratio, lactate, and the lactate/albumin ratio were associated with 28-day mortality. Receiver operating characteristic (ROC) analysis showed that the LAR (area under the curve (AUC): 0.839) was superior to the serum albumin (AUC: 0.736) and lactate levels (AUC: 0.796) for predicting 28-day mortality. The optimal cut-off value of the LAR was 0.82, and an LAR of ≥ 0.82 was shown to be a significant and independent prognostic factor for 28-day mortality in patients with stomach cancer in a critical postoperative condition (odds ratio (OR): 4.78, confidence interval (CI): 1.09–21.08, p = 0.0386). Conclusions: The lactate/albumin ratio is a prognostic parameter for 28-day mortality in critically ill postoperative gastric cancer patients. The optimal cut-off value for the lactate/albumin ratio is 0.82. Full article

The heat shock transcription factor (HSF) family is a core regulatory component for plants in response to adversity stress and plays a pivotal role in regulating plant reactions to abiotic stress. Lanzhou lily (Lilium davidii var. unicolor) is an economically and horticulturally important bulbous crop widely cultivated in Northwest China, and its growth and yield are severely threatened by high-temperature stress during the growing season. Although HSF genes have been extensively and thoroughly investigated in other plant species, their functional characterization in lilies remains elusive. In this study, a total of 41 LdHSF genes were identified from the genome of Lilium davidii var. unicolor using bioinformatics approaches. The proteins encoded by these genes exhibited considerable variations in the number of amino acids (aa), as well as distinct isoelectric points (pI) and instability indices. Phylogenetic analysis classified these 41 LdHSF genes into three subfamilies (A, B and C). Promoter analysis revealed that the promoters of most LdHSF genes were rich in light-responsive cis-elements. Meanwhile, the promoters of some genes were highly abundant in hormone-responsive cis-elements, whereas those of other genes were enriched in stress-responsive cis-elements. Gene expression heatmaps and transcriptomic data demonstrated that the expression patterns of LdHSF genes showed significant differences in various tissues and under heat treatment. Based on transcriptomic and RT-qPCR data, we further screened out LdHSF10 and LdHSF40 as the major genes responding to heat stress. Functional experiments verified that these two genes encoded nuclear-localized proteins with transcriptional activity. Collectively, these findings lay a solid foundation for elucidating the molecular mechanisms underlying the regulation of heat tolerance by HSF transcription factors (TFs) in lilies in future research. Full article

Cardiac surgery represents a cornerstone of modern cardiovascular medicine, yet it is intrinsically linked to significant systemic stress responses that can compromise remote organ function. Among postoperative complications, cardiac surgery-associated acute kidney injury (CSA-AKI) remains a significant clinical challenge characterized by high morbidity and complex pathophysiology. While hemodynamic instability and ischemia–reperfusion injury are established risk factors, renal dysfunction frequently persists despite optimal perfusion. This observation suggests the involvement of potent circulating mediators in cellular injury. Extracellular vesicles (EVs) are essential for intercellular communication and serve as central hubs for transporting bioactive lipids, proteins, and genetic material. Accumulating evidence indicates that the mechanical and oxidative stress inherent to cardiopulmonary bypass triggers substantial release of EVs from platelets, erythrocytes, and injured vascular tissues. These vesicles may function as vectors that traffic oxidized mitochondrial components and pro-inflammatory cargo to the renal parenchyma. This signaling cascade appears to disrupt renal homeostasis through a proposed “dual-hit” mechanism involving the induction of endothelial dysfunction and endothelial-to-mesenchymal transition (EndMT), followed by tubular epithelial injury via mitochondrial fragmentation, redox imbalance, and downregulation of anti-aging factors. The complexity of these EV-mediated interactions may contribute to an incomplete understanding of why specific patient phenotypes fail to recover. This narrative review examines the mechanisms of surgery-induced EV biogenesis, the molecular pathogenesis of endothelial and tubular damage, and the role of intercellular crosstalk. Additionally, we discuss future perspectives on targeting the “EV vector” through therapeutic apheresis and mitochondrial pharmacotherapy to potentially improve clinical outcomes in high-risk surgical patients. Full article

Porcine epidemic diarrhea virus (PEDV) causes lethal enteritis in neonatal piglets, yet the mechanisms underlying rapid intestinal injury remain unclear. In particular, it is unknown whether different regulated cell death pathways act separately or cooperatively to worsen mucosal damage. To address this question, we performed multi-omics analyses of infected intestinal tissues and found concurrent activation of pyroptosis and ferroptosis during PEDV infection. PEDV infection activated the Caspa-se-1/GSDMD pathway in the duodenum and jejunum, as shown by generation of the Caspase-1 p20 fragment and cleavage of GSDMD into its active N-terminal form, indicating pyroptosis. At the same time, infected tissues displayed key features of ferroptosis, including weakened antioxidant defenses, increased lipid peroxidation, iron accumulation, lipid remodeling, and dysregulated ACSL4 and GPX4 expression. These two processes were closely linked and together contributed to tight junction disruption and barrier instability. Molecular docking further suggested that PEDV NSP1 and S proteins may interact with Caspase-1, providing a possible explanation for pyroptosis induction. Correlation analysis also showed strong associations between pyroptosis-related genes and ferroptosis-associated metabolites. Overall, our findings indicate that pyroptosis and ferroptosis cooperate to drive PEDV-induced intestinal inflammation and barrier damage, highlighting their joint inhibition as a potential strategy to reduce PEDV pathogenicity. Full article

Fanconi anemia (FA) is a rare inherited disorder classically defined by defective DNA interstrand crosslink repair, leading to bone marrow failure and cancer predisposition. Increasing evidence indicates that FA pathophysiology extends beyond genomic instability to include mitochondrial dysfunction, oxidative stress, and impaired antioxidant responses. Across multiple cellular models and patient-derived samples, FA cells display altered mitochondrial bioenergetics, increased reactive oxygen species (ROS) production, and defective activation of redox-adaptive pathways, contributing to cumulative damage to DNA, lipids, and proteins. These alterations are particularly relevant in hematopoietic stem and progenitor cells, where metabolic stress and redox imbalance amplify stem cell exhaustion. Current data support a bidirectional interplay in which mitochondrial dysfunction and oxidative stress act mainly as secondary but amplifying factors of the primary DNA repair defect, establishing pathogenic feedback loops. Preclinical studies suggest that modulation of redox balance and mitochondrial function may improve cellular homeostasis, and early clinical investigations of antioxidant strategies indicate acceptable safety and measurable effects on oxidative biomarkers. However, clinical evidence remains limited and heterogeneous, with uncertain impact on long-term disease progression. Moreover, most mechanistic insights derive from in vitro or patient-derived models, while animal models and longitudinal clinical studies remain insufficient. Overall, a more integrated and translational framework is needed to clarify causality, validate biomarkers, and define the therapeutic potential of targeting metabolic and redox pathways in FA. Full article

Chronic diseases increasingly reflect a shared biological origin: persistent cellular stress. This review summarizes the biochemical mechanisms that normally preserve cellular homeostasis, namely redox regulation, endoplasmic reticulum proteostasis, mitochondrial quality control, autophagy, and DNA damage response, and explains how they fail under sustained lifestyle-related overload. Repeated exposure to psychological stress, sleep disruption, hypercaloric intake, and physical inactivity shifts adaptive signaling toward maladaptation, promoting oxidative damage, protein misfolding, mitochondrial dysfunction, low-grade inflammation, and genomic instability. These interconnected processes contribute to the development and progression of major chronic non-communicable diseases, including obesity, type 2 diabetes, cardiovascular disease, neurodegeneration, and cancer. Particular emphasis is placed on circadian and neuroendocrine regulation, especially overactivation of the hypothalamic–pituitary–adrenal axis and impaired nocturnal regenerative pathways such as glymphatic clearance and DNA repair. Together, the evidence supports a unifying model in which chronic pathology emerges from cumulative failure of cellular resilience systems rather than isolated organ-specific defects. This perspective highlights sleep optimization, stress reduction, and metabolic regulation as mechanistically grounded strategies for prevention and supportive interventions for chronic disease. Full article

Myofibrillar protein microgel particles (MMP) are promising Pickering stabilisers due to their structure and delivery potential. However, their fibrous, irregular shape promotes aggregation, limiting practical use. This study investigated the effect of xanthan gum (XG) concentration (0.025–0.4%) on MMP dispersion in water and its role in stabilising Pickering emulsions. FTIR and interaction analysis revealed that hydrophobic interactions dominate between XG and MMP, followed by hydrogen bonding and electrostatic forces. At higher XG concentrations (0.2–0.4%), complex particle size decreased from 5.21 μm to 4.49 μm, the contact angle increased from 57.67° to 77.33°, and a uniform dispersed state was achieved. Although increasing XG gradually reduced the emulsifying activity of MMP, it significantly improved the emulsion stability. Microstructure analysis showed that at low XG concentrations, emulsions exhibited phase separation. Rheological measurements indicated that XG-MMP complexes increased continuous-phase viscosity and shear resistance, enhancing macroscopic stability. In summary, at a critical XG concentration of 0.2%, the emulsion undergoes a transition from aggregation-driven instability to network-mediated stabilisation, achieved through the interfacial layer with spatial confinement by a weak aqueous-phase network. This work provides a theoretical foundation and a practical design strategy for fabricating highly stable, tuneable Pickering emulsions based on protein microgel particles. Full article

Background. Cardiometabolic diseases (CMDs) have become a major health concern among adults living with HIV (ALWH) as antiretroviral therapy (ART) extends life expectancy. Metabolic syndrome (MetS)—a cluster of abdominal obesity, hypertension, hyperglycemia, hypertriglyceridemia, and hypoalphalipoproteinemia—is a key predictor of CMD risk. Despite high HIV prevalence in Panama, data on MetS among ALWH are scarce. Thus, the Colón C3 Study aimed to estimate the prevalence of MetS and its criteria in a large cohort of ALWH in Colón, Panama. Methods. Between April–December 2024, 659 ALWH aged ≥18 years were enrolled at the province’s sole ART Clinic (78.1% of active patients). Participants completed a computer-assisted survey on demographics and social determinants of health (SDoH), underwent anthropometry and body composition assessment, and provided ≥8 h fasting blood samples for glucose, lipid profiles, HbA1c, and high-sensitivity C-reactive protein (hsCRP). MetS was defined using NCEP-R ATP-III criteria, and analyses were stratified by sex. Results. Mean age was 43.9 (range 18–79) years; 55% were female, and 51% identified as Black/Afro-Caribbean. The overall prevalence of MetS was 38.6% (binomial 95% CI 34.5%, 42.9%), exceeding pooled estimates for ALWH in the Americas (30.4%). Among individual criteria, hypoalphalipoproteinemia (59.6%) and hypertension (52.6%) were most prevalent, followed by abdominal obesity (45.2%), hyperglycemia (33.5%), and hypertriglyceridemia (22.5%). Women exhibited significantly higher body fat mass and BMI than men. Mean hsCRP was 7.2 mg/L, indicating persistent inflammation despite virologic suppression. Socioeconomic vulnerabilities, food insecurity (30%), and housing instability (>40%) were common. Conclusions. Findings reveal a substantial cardiometabolic burden among ALWH in Colón and underscore the need for integrated HIV–CMD care models, earlier screening, and natal sex–responsive interventions. The results provide foundational evidence for improving long-term, equitable cardiometabolic outcomes in HIV care across Panama and the broader Latin American region. Full article

Background/Objectives: In-hospital critical outcome among palliative inpatients remains high, often driven by acute physiological instability rather than chronic comorbidities. Although diabetes mellitus (DM) is common in this population, its independent impact on critical outcome is unclear. This study aimed to determine whether acute metabolic and inflammatory markers—specifically glucose, C-reactive protein (CRP), albumin, and oxygen requirement—better predict short-term outcomes, defined as in-hospital critical outcome or ICU transfer during the same hospitalization period, than DM status alone. Methods: This retrospective study included 200 palliative inpatients admitted to the Internal Medicine Clinic of Kestel State Hospital, Bursa, Turkey, between January 2024 and January 2025. Demographic, clinical, and laboratory data were obtained from electronic records. The primary outcome was in-hospital critical outcome or ICU transfer (“critical outcome”). Logistic regression and receiver-operating characteristic (ROC) analyses identified independent predictors. The study was approved by the Bursa Yüksek İhtisas Training and Research Hospital Ethics Committee (ethics approval: protocol code 2024-TBEK 2025/05-12). Results: The mean age was 77.7 ± 12.3 years, and 47% were male. DM was present in 30.5% but did not independently predict critical outcome (p = 0.904). In contrast, oxygen requirement (OR = 4.08, p = 0.002), mean glucose (OR = 1.01, p = 0.001), and cancer (OR = 3.28, p = 0.016) were significant predictors. ROC analysis identified CRP > 64.1 mg/L and albumin < 25 g/L as optimal thresholds, and these two markers formed the basis of the low-, intermediate-, and high-risk stratification, with critical-outcome rates of 39.0%, 45.1%, and 85.4% (p < 0.001). Conclusions: Acute metabolic and inflammatory disturbances—particularly hyperglycemia, elevated CRP, hypoalbuminemia, and oxygen requirement—are stronger prognostic indicators than DM. A simple bedside model incorporating these parameters may improve prognostic accuracy and communication in palliative care. Full article

The practical application of protein hydrolysates as functional food ingredients is frequently obstructed by their inherent structural instability. To circumvent this limitation, liposomal encapsulation has emerged as a sophisticated strategy to bolster the bioactivity and integrity of cricket-derived proteins. In this study, varying concentrations (1–4% w/v) of defatted cricket protein hydrolysate (DCPH) were integrated into vesicles composed of soy lecithin and cholesterol. The highest encapsulation efficiency (EE) was observed at a 2% DCPH loading capacity, yielding a significant result of 88.18% (p < 0.05). Subsequent coating with sodium alginate (SA) at 0.1–0.3% (w/v) resulted in an increase in particle size and a more pronounced negative surface charge. When maintained at 4 °C over a 24-day duration, the SA-coated liposome (SA-L-2%DCPH) exhibited superior stability compared to its uncoated (L-2%DCPH) counterpart. Also, the digest derived from the SA-L-2%DCPH exhibited significantly enhanced transepithelial permeability across the Caco-2 cell monolayer, indicated by the higher protein content and ABTS radical scavenging activity. Thus, sodium alginate-coated liposomes serve as a promising delivery system for encapsulating DCPH both during storage stability and in the gastrointestinal digestion system. Full article

Aflatoxin B1 (AFB1) poses a serious threat to global food and feed safety. Laccase-based enzymatic degradation represents a promising green strategy for AFB1 removal; however, its industrial application is severely limited by the rapid thermal inactivation of wild-type enzymes under high-temperature processing conditions (>70 °C). Here, we engineered the thermal stability of a laccase from Bacillus amyloliquefaciens B10 through an integrated strategy combining computational structural biology with semi-rational design. By coupling molecular dynamics (MD) simulations with folding free-energy (ΔΔG) calculations, we identified key flexible regions associated with thermal instability and subsequently implemented iterative saturation mutagenesis. The best single mutant, R196C, retained more than 96% relative activity after heat treatment at 80 °C for 10 min. Further iterative mutational stacking progressively enhanced thermostability: the R90E/R196C double mutant showed 1.25-fold higher activity at 80 °C than R196C, and the R90E/R196C/H54F triple mutant showed a further 1.16-fold increase over the double mutant. The final quadruple mutant, R90E/R196C/H54F/R253I, achieved 86.9% AFB1 degradation at 80 °C after 24 h. High-temperature MD simulations (100 ns at 353.15 K) indicated that the enhanced thermostability was associated with reduced conformational flexibility, lower radius of gyration (Rg) and solvent-accessible surface area (SASA), and a coil-to-β-sheet transition that contributed to stabilization of the protein core. In addition, efficient secretory expression of the engineered enzyme was achieved in Pichia pastoris, reaching 3.0 U/mL, while the crude enzyme maintained more than 70% activity at 80 °C. Collectively, these results provide a practical basis for the rational engineering and scalable production of thermostable biocatalysts for AFB1 detoxification-related applications of AFB1 control, and offer broader insights into the targeted enhancement of thermal stability in industrial enzymes. Full article