Search Results (47)

Background: Chronic heart failure (CHF) is a major cause of morbidity and mortality worldwide, with limited therapeutic options. Floating wheat (Fu Xiao Mai), used in traditional Chinese medicine for CHF, contains linoleic acid (LA) and α-linolenic acid (ALA) as major bioactive components, but their therapeutic mechanisms remain unclear. Objective: this study aimed to investigate the cardioprotective effects of LA and ALA in CHF, focusing on their interactions with aquaporin-1 (AQP1) and gut microbiota. Methods: LA and ALA were identified in floating wheat via LC-MS/MS. Molecular docking and dynamics simulations assessed their binding to AQP1. In vivo studies used C57BL/6 and AQP1⁻/⁻ mice with isoproterenol-induced CHF. Cardiac function was assessed through echocardiography; myocardial ultrastructure through transmission electron microscopy (TEM); inflammatory markers (TNF-α, NO, VEGF, VCAM-1) through ELISA; and gut microbiota through 16S rRNA sequencing. Results: Molecular docking revealed a strong binding affinity of LA and ALA to AQP1, with binding energies of −8.532 kcal/mol and −8.835 kcal/mol, respectively. In C57 mice, LA and ALA administration significantly improved cardiac function (p < 0.05, the high-dose group compared to the model group) while reducing myocardial edema. They also downregulated AQP1 expression and decreased levels of inflammatory markers (p < 0.05, the high-dose group compared to the model group). These functional improvements were significantly attenuated in AQP1⁻/⁻ mice. However, the reduction in inflammatory markers persisted, indicating AQP1-independent anti-inflammatory effects. Furthermore, high-dose LA/ALA treatment in AQP1⁻/⁻ mice markedly altered gut microbiota. Conclusion: LA and ALA alleviate CHF through an AQP1-dependent reduction in myocardial edema and AQP1-independent anti-inflammatory and gut microbiota-modulating effects. These findings highlight their potential as a multi-target therapeutic complex for CHF. Full article

Bypass graft is widely used, especially in cardiovascular diseases, to detour clogged blood vessels, alleviating and correcting the manifestation of the symptoms of damaged blood vessels. Bypass grafting is also used in hemodialysis treatment, specifically an arteriovenous bypass graft, considering the repeated withdrawal of blood, for the dialysis machine to filter the blood and return it to the body to circulate. Nonetheless, bypass grafts are susceptible to failure due to the abnormal hemodynamic performance of the blood flowing to the graft, leading to complications such as thrombosis, intimal hyperplasia, and atherosclerosis. Multiple bypass graft designs are continuously developed to optimize the desirable hemodynamics of the blood, which is essential to avoid complications. This study examines helical arteriovenous bypass graft (AVG) hemodynamic performance using Computational Fluid Dynamics (CFD) simulations to identify enhanced blood flow characteristics. The analysis concentrated on area-weighted average wall shear stress (AWA-WSS), helicity, pressure drop, time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), and relative residence time (RRT) from twenty-seven graft models changing anastomosis angles, helical diameters, and helical pitches. Model 25-13-30 (25-degree anastomosis angle, 13 mm helical diameter, 30 mm helical pitch) demonstrated the most favorable overall hemodynamic performance based on the variables considered. The results indicate that integrating helical shape into bypass grafts improves hemodynamic performance, reduces intimal hyperplasia risk, and may prolong graft durability. These findings provide valuable insights and suggestions for enhancing AVG designs to support patient outcomes. Full article

Advanced Gastric Signet Ring Cell Carcinoma (SRCC) is characterized by aggressive behavior, high metastatic potential, and extremely poor prognosis. There is an urgent need for effective imaging modalities to evaluate systemic metastatic lesions and to dynamically monitor disease progression during treatment. We report a rare case of a 26-year-old female with advanced SRCC presenting with extensive systemic metastases, clinically staged as IV (cT4N3M1). High-frequency and conventional ultrasound imaging revealed metastatic lesions involving the scalp soft tissues, cervical lymph nodes, intercostal soft tissues, pancreatic-splenic hilum region, pelvic cavity, peritoneum and omentum. The ultrasonographic findings were highly consistent with contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) results. The patient received seven cycles of a modified BEMA regimen (oxaliplatin, leucovorin and 5-fluorouracil) combined with nivolumab. Serial ultrasound monitoring indicated continuous disease progression. Due to poor therapeutic response, the patient succumbed to acute obstructive renal failure caused by tumor progression seven months after diagnosis. This report provided a comprehensive ultrasonographic assessment of widespread and rare metastatic sites in advanced SRCC, a scenario seldom documented. The combination of high-frequency ultrasound and Super Microvascular Imaging (SMI) offered precise, radiation-free, and repeatable evaluation of both superficial and deep lesions, proving particularly valuable for real-time monitoring of treatment response in critically ill patients. These findings underscore the unique role of systemic ultrasound in enhancing metastatic detection and therapeutic evaluation for advanced SRCC. Full article

Background: Osteosarcoma (OS) is a fast-growing malignant bone tumor that occurs most often in children and teenagers. Development of pulmonary metastasis is the primary cause of treatment failure and mortality. Our previous studies demonstrated that cytoplasmic p27 interacts with PAK1, enhancing PAK1 phosphorylation and promoting OS pulmonary metastasis. However, the cellular functions of p27 and PAK1 are primarily regulated by phosphorylation, and the roles of specific phosphorylation residues in modulating OS metastatic potential remain unclear. Methods: To study tumor invasiveness and lung metastasis, we employed a CRISPR-based knock-in method to introduce specific mutations—p27-T157A, p27-T157D, PAK1-T423E, and PAK1-K299R—into the 143B OS cell line, followed by in vitro invasion and orthotopic xenograft mouse experiments. These residues were selected for their therapeutic potential, as T157 regulates p27 nuclear–cytoplasmic shuttling, while T423 and K299 modulate PAK1 kinase activity. Results: No significant differences in pulmonary metastasis were observed across p27 mutants compared to parental controls. However, the p27-T157D mutant exhibited increased cytoplasmic mislocalization, elevated PAK1-S144 phosphorylation, and enhanced in vitro invasiveness compared to the p27-T157A mutant and parental 143B cells. The PAK1-K299R mutant, designed to be kinase-dead, showed negligible S144 phosphorylation, consistent with loss of kinase activity. Unexpectedly, this mutant displayed increased T423 phosphorylation and in vitro invasiveness, and significantly enhanced pulmonary metastasis in vivo compared to the PAK1-T423E mutant and parental controls. Conclusions: These findings highlight the complexity of targeting specific p27 and PAK1 phosphorylation sites as an anti-metastatic strategy for OS. While p27-T157 phosphorylation influences cytoplasmic localization and invasiveness, it does not significantly alter metastatic outcomes. Conversely, PAK1-T423 phosphorylation is critical in driving OS metastatic potential, and the kinase-dead K299R mutant’s unexpected pro-metastatic effect suggests that kinase-independent mechanisms or compensatory pathways may contribute to metastasis. Our findings suggest the necessity for a more comprehensive understanding of the phosphorylation dynamics of p27 and PAK1 in metastatic OS. They also indicate that conventional kinase inhibition may be insufficient and underscore the potential benefits of alternative or combinatorial therapeutic strategies, such as targeting kinase-independent functions or other upstream kinases involved in these regulatory pathways. Full article

Despite aesthetic trends, metal–ceramic restorations continue to be widely accepted due to their durability, and variations in surface preparation process can significantly influence bond strength outcomes. The purpose of this study was to determine whether there are differences in the bond strength depending on three surface treatment protocols for veneering ceramics on Ni-Cr alloys. The following surface treatments were used: (1) control (C) (no treatment), (2) airborne-particle abrasion (APA) with 50 µm Al₂O₃ (G1-APA), (3) APA followed by oxidation (G2-APA-O), and (4) APA-O, with a second APA (G3-APA-O-APA). Subsequently surface roughness (R_a and R_z) was evaluated using profilometry, hardness was measured through Leeb’s hardness dynamic test (HLD), morphology was investigated through scanning electron microscopy (SEM), and the chemical composition of the alloy surface was evaluated using energy-dispersive spectroscopy (EDS). After surface treatments, veneering ceramic was applied, the debonding crack initiation strength (DCIS) was investigated through the three-point bending test, failure mode was classified using a stereoscopic microscope, and chemical characterization of the fractured surfaces was performed using Raman spectroscopy (RS). For DCIS, G2-APA-O demonstrated the highest value 63.97 ± 44.40 (MPa) (p < 0.05). The results of this study indicate that oxidation treatment has a positive effect on the bonding strength between veneering ceramic and Ni-Cr alloys. Full article

Cardiovascular diseases (CVD), such as myocardial hypertrophy, heart failure, atherosclerosis, and myocardial ischemia/reperfusion (I/R) injury, are among the major threats to human health worldwide. Post-translational modifications alter the function of proteins through dynamic chemical modification after synthesis. This mechanism not only plays an important role in maintaining homeostasis and plays a crucial role in maintaining normal cardiovascular function, but is also closely related to the pathological state of various diseases. Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression, and play important roles in post-translational modification by catalyzing the deacetylation of key lysine residues in nucleosomal histones, which are closely associated with the occurrence and development of cardiovascular diseases. Recent studies indicate that HDAC inhibitors (HDACis) may represent a new class of drugs for the treatment of cardiovascular diseases by influencing post-translational modifications. In this review, we systematically summarize the mechanism of action of HDACs and HDACis in post-translational modifications related to common cardiovascular diseases, providing new ideas for the treatment of CVD, and explore possible future research directions on the relationship between HDAC and HDACi in post-translational modifications and cardiovascular diseases. Full article

Targeting fibrosis in Duchenne muscular dystrophy (DMD)-associated cardiomyopathy is a critical outstanding clinical issue, as cardiac failure remains a leading cause of death despite advances in supportive care. This study evaluates the therapeutic efficacy of CSPG4-targeted chimeric antigen receptor (CAR) T cells in reducing cardiac fibrosis and improving heart function in a preclinical model of the disease. DMD is a progressive genetic disorder characterized by degeneration of skeletal and cardiac muscle. Cardiomyopathy, driven by fibrosis and chronic inflammation, is a leading contributor to mortality in affected patients. Proteoglycans such as CSPG4, critical regulators of extracellular matrix dynamics, are markedly overexpressed in dystrophic hearts and promote pathological remodeling. Current treatments do not adequately target the fibrotic and inflammatory processes underlying cardiac dysfunction. CSPG4-specific CAR-T cells were engineered and administered to dystrophic mice. Therapeutic efficacy was assessed through histological, molecular, and echocardiographic analyses evaluating cardiac fibrosis, inflammation, innervation, and overall function. Treatment with CSPG4 CAR-T cells preserved myocardial integrity, improved cardiac performance, and reduced both fibrosis and inflammatory markers. The therapy also restored cardiac innervation, indicating a reversal of neural remodeling commonly seen in muscular dystrophy-related cardiomyopathy. CSPG4-targeted CAR-T therapy offers a novel, cell-based strategy to mitigate cardiac remodeling in dystrophic hearts. By addressing core fibrotic and inflammatory drivers of disease, this approach represents a significant advancement in the development of precision immune therapies for muscular dystrophies and cardiovascular conditions. Full article

Concrete materials exposed to sulfate-rich geological environments are prone to structural durability degradation due to chemical erosion. Silane-based protective materials can enhance the durability of concrete structures under harsh environmental conditions. This study investigates the evolution of acoustic emission (AE) precursor characteristics in silane-protected, sulfate-eroded concrete specimens during uniaxial compression failure. Unlike existing research focused primarily on protective material properties, this work establishes a novel framework linking “silane treatment–AE parameters–failure precursor identification”, thereby bridging the research gap in damage evolution analysis of sulfate-eroded concrete under silane protection. Uniaxial compressive strength tests and AE monitoring were conducted on both silane-protected and unprotected sulfate-eroded concrete specimens. A diagnostic system integrating dynamic analysis of the acoustic emission b-value, mutation detection of energy concentration index ρ, and multifractal detrended fluctuation analysis (MF-DFA) was developed. The results demonstrate that silane-protected specimens exhibited a distinct b-value escalation followed by an abrupt decline prior to peak load, whereas unprotected specimens showed disordered fluctuations. The mutation point of energy concentration ρ for silane-protected specimens occurred at 0.83 σc, representing a 9.2% threshold elevation compared to 0.76 σc for unprotected specimens, confirming delayed damage accumulation in protected specimens. MF-DFA revealed narrowing spectrum width ($∆\alpha$) in unprotected specimens, indicating reduced heterogeneity in AE signals, while protected specimens maintained significant multifractal divergence. $∆f\left(\alpha \right)$ peak localization revealed that weak AE signals dominated during early loading stages in both groups, with crack evolution primarily involving sliding and friction. During the mid-late elastic phase, crack propagation became the predominant failure mode. Experimental evidence confirms the engineering significance of silane protection in extending service life of concrete structures in sulfate environments. The proposed multi-parameter AE diagnostic methodology provides quantitative criteria for the safety monitoring of protected concrete structures in sulfate-rich conditions. Full article

Stress-induced demyelination resulting from oligodendrocyte (OLG) dysfunction is one of the key pathological mechanisms of depression, yet its dynamic regulatory network remains unclear. This study integrates single-cell transcriptomics, lineage tracing, and functional interventions to uncover a temporally disordered OLG cholesterol metabolism in a restraint stress mouse model: After 3 days of stress, upregulation of efflux genes Abca1/Abcg1 triggers a compensatory response; however, by day 14, persistent suppression of transport genes (Apoe, Apod) and homeostatic regulatory genes (Dhcr24, Srebf2, etc.) leads to intracellular accumulation of “ineffective cholesterol”, with compensatory activation of the AMPK pathway unable to restore cholesterol conversion into myelin. Pseudotime analysis further reveals that stress alters OLG differentiation trajectories, decreasing the proportion of mature OLGs and causing immature precursors to abnormally stall at the late pre-differentiation stage, resulting in myelin regeneration failure. Moreover, an immune OLG_C10 subpopulation expressing complement component C3 and P2ry12 is identified, indicating that OLGs may contribute to neuroinflammatory cascades through immune reprogramming. In summary, these findings reveal a novel mechanism from the dynamic perspective of OLGs, in which the interplay of “metabolic imbalance, differentiation blockade, and immune activation” collaboratively drives stress-induced demyelination, providing a theoretical foundation for depression treatment targeting OLG functional restoration. Full article

Botulinum toxin A (BoNT-A) is widely used in both therapeutic and aesthetic settings; however, the formation of neutralizing antibodies (NAbs) remains a critical concern, leading to treatment failure. Immunogenic responses are known to vary between individuals due to HLA polymorphisms. Although some claim that neurotoxin-associated proteins (NAPs) shield BoNT-A from immune detection or are themselves immunogenic, there is limited molecular evidence supporting either view. This study applies computational immunogenetics to explore BoNT-A immunogenicity, focusing on HLA binding and the influence of accessory proteins. Epitope mapping, molecular docking, and HLA binding predictions were used to evaluate interactions between BoNT-A epitopes and selected class II HLA alleles (HLA-DQA1*01:02, HLA-DQA1*03:03, HLA-DQB1*06:04, HLA-DQB1*03:01, and HLA-DRB1*15:01). To assess the potential immunomodulatory role of NAPs, molecular dynamics (MD) simulations, solvent-accessible surface area (SASA) analysis, and electrostatic potential mapping were also conducted. Key epitopes—L11, N25, and C10—showed strong binding affinities to HLA-DQA1*01:02, HLA-DQB1*06:04, and HLA-DQA1*03:03, indicating a potential immunodominant role. NAPs did not obstruct these epitopes but slightly increased their exposure and appeared to stabilize the toxin structure. Electrostatic mapping and binding free energy calculations suggested no significant immunogenic shift in the presence of NAPs. BoNT-A immunogenicity appears to be influenced by HLA allele variability, reinforcing the value of patient-specific genetic profiling. The presumed immunogenic role of NAPs remains unsubstantiated at the molecular level, underscoring the need for evidence-based evaluation over commercial rhetoric. While these findings provide valuable molecular insight, it is important to acknowledge that they are derived entirely from in silico analyses. As such, experimental validation remains essential to confirm the immunological relevance of these predicted interactions. Nonetheless, this computational framework offers a rational basis for guiding future clinical research and the development of HLA-informed BoNT-A therapies. Full article

Drug delivery systems enhance drug efficacy while minimizing side effects. Liposomes, as well-studied and clinically approved carriers, offer biodegradability, biocompatibility, and low toxicity, making them suitable for delivering various pharmacological agents. Granulocyte colony-stimulating factor (G-CSF), a key growth factor, has shown therapeutic potential, particularly in infertility treatment. It effectively manages chronic and refractory endometritis by improving endometrial receptivity and increasing embryo implantation success. Studies indicate that G-CSF promotes endometrial growth and enhances the uterine microenvironment, benefiting patients with recurrent implantation failures and chronic endometritis. Encapsulation of G-CSF in liposomes enhances its stability, bioavailability, and controlled release. G-CSF-loaded liposomes were prepared using passive loading via the thin-film hydration method. The size of the liposomes, polydispersity index (PDI), and zeta potential were determined using dynamic and electrophoretic light scattering methods, and the encapsulation efficiency was measured using high-performance liquid chromatography. The morphology of the liposomes was established and confirmed using cryogenic transmission electron microscopy. The cytocompatibility of the G-CSF-loaded liposomes was evaluated on human dermal fibroblasts using an MTT assay. The G-CSF-loaded liposomes had an average particle size of 161.9 ± 9.9 nm, a PDI of 0.261 ± 0.03, and a zeta potential of +2.09 ± 0.10 mV, exhibiting high physical stability during long-term storage at +4 °C and 60% humidity. The passive loading method resulted in a 52.37 ± 3.64% encapsulation efficiency of the active substance. The analysis of cell viability revealed no cytotoxicity toward liposomes loaded with G-CSF and demonstrated a dose-dependent effect on the viability of human dermal fibroblasts. Thus, the obtained data confirm the successful preparation of G-CSF-loaded liposomes. However, to fully understand their effectiveness in biomedical applications, further research is needed, including an evaluation of their effectiveness in vivo. Such studies will help in determining the potential of these formulations for specific biomedical purposes and evaluating their safety and efficacy in living systems. Full article

Capsid assembly modulators (CAMs) are a novel class of antiviral agents in clinical development for the treatment of chronic hepatitis B. CAMs inhibit hepatitis B virus (HBV) replication by binding to a hydrophobic pocket, i.e., HAP pocket, between HBV capsid protein (Cp) dimer–dimer interfaces to misdirect its assembly into empty capsids or aberrant structures and designated as CAM-E and CAM-A, respectively. Because the emergence of CAM-resistant variants results in the failure of antiviral therapy, it is important to rationally design CAMs with a high barrier of resistance for development. To establish computational approaches for the prediction of Cp mutations that confer resistance to CAMs, we investigated the interaction of representative CAM-A and CAM-E compounds, BAY 41-4109 and JNJ-56136379, with wild-type and 35 naturally occurring mutations of Cp residues at the HAP pocket using molecular docking, prime molecular mechanics with generalized Born and surface area solvation (MM/GBSA) and molecular dynamics (MD) simulation methods. Out of nine publicly available HBV capsid or CpY132A hexamer structures in the protein database, molecular docking correctly predicted the resistance and sensitivity of more than 50% Cp mutations to JNJ-56136379 with structures 5D7Y and 5T2P-FA. MM/GBSA correctly predicted the resistance and sensitivity of more than 50% Cp mutations to BAY41-4109 with the structures 5E0I-BC and 5WRE-FA, and to JNJ-56136379 with the 5E0I-FA structure. Our work indicates that only the capsid or CpY132A hexamer structure bound with a CAM with similar chemical scaffold can be used for more accurately predicting the resistance and sensitivity of Cp mutations to a CAM molecule under investigation by molecular docking and/or MM/GBSA methods. Full article

High-energy thermal treatments, such as electron beam irradiation, are crucial for enhancing the performance of tungsten carbide–cobalt (WC-Co) composites in cutting tools and wear-resistant coatings. This study utilizes molecular dynamics simulations to analyze the nanoscale effects of such treatments on WC-Co surfaces, focusing on cobalt evaporation and linear scratching phenomena. The results demonstrate that electron beam irradiation significantly accelerates cobalt evaporation, with rates depending on energy flux and local atomic environments. Embedded cobalt atoms within WC grains exhibit higher resistance to evaporation due to stronger bonding, while pure cobalt surfaces show greater susceptibility to material loss. Under high energy flux, WC-Co surfaces experience an interplay of thermal expansion, density reduction, and evaporation, resulting in accelerated degradation. Linear scratching simulations reveal that thermally treated WC-Co surfaces exhibit increased structural instability, as indicated by broader distributions of local entropy and von Mises stress, reflecting heightened susceptibility to deformation and failure. Stress concentrations from indentation and scratching are more pronounced in thermally treated samples, highlighting the influence of thermal history on mechanical behavior. Molecular dynamics simulations enable detailed insights into atomic-scale phenomena, allowing precise quantification of the effects of energy flux, material composition, and thermal treatment on structural and mechanical responses. These findings emphasize the need to optimize thermal treatment protocols to enhance the durability and performance of WC-Co composites, providing valuable guidance for the development of robust materials for industrial applications. Full article

In this study, changes in the basic physical properties, mineral composition, mass, and microstructure of layered sandstone were evaluated following heat treatment at 200–800 °C. Dynamic impact compression tests were performed using a split-Hopkinson pressure bar test system (SHPB), and digital image correlation (DIC) was used to monitor the dynamic failure processes of the involved specimens. Results indicate that high-temperature treatment reduces the mass, wave velocity and peak stress of layered sandstone; increases the porosity, pore length, and pore aperture. The rates of decrease in the wave velocity and peak stress considerably increase with increasing temperature above a threshold of 400 °C. This is because at temperatures above 400 °C, thermal cracks will form both between and within particles. As the number of cracks increases, they will propagate and connect with each other, forming a network of cracks. DIC results show that as the heat treatment temperature rises, the range of the strain-concentration areas, which are formed by sandstone failures, substantially expands. However, the increase in the heat treatment temperature only negligibly influences the propagation direction of primary sandstone cracks, which mainly propagate along the weak bedding planes. Full article

We have previously reported that the calcineurin inhibitor macrolide immunosuppressant Tacrolimus (TAC, FK506) can promote the migration and invasion of the human-derived extravillous trophoblast cells conducive to preventing implantation failure in immune-complicated gestations manifesting recurrent implantation failure. Although the exact mode of action of TAC in promoting implantation has yet to be elucidated, the integral association of its binding protein FKBP12 with the inositol triphosphate receptor (IP3R) regulated intracellular calcium [Ca²⁺]i channels in the endoplasmic reticulum (ER), suggesting that TAC can mediate its action through ER release of [Ca²⁺]i. Using the immortalized human-derived first-trimester extravillous trophoblast cells HTR8/SVneo, our data indicated that TAC can increase [Ca²⁺]I, as measured by fluorescent live-cell imaging using Fluo-4. Concomitantly, the treatment of HTR8/SVneo with TAC resulted in a major dynamic reorganization in the actin cytoskeleton, favoring a predominant distribution of cortical F-actin networks in these trophoblasts. Notably, the findings that TAC was unable to recover [Ca²⁺]i in the presence of the IP3R inhibitor 2-APB indicate that this receptor may play a crucial role in the mechanism of action of TAC. Taken together, our results suggest that TAC has the potential to influence trophoblast migration through downstream [Ca²⁺]i-mediated intracellular events and mechanisms involved in trophoblast migration, such as F-actin redistribution. Further research into the mono-therapeutic use of TAC in promoting trophoblast growth and differentiation in clinical settings of assisted reproduction is warranted. Full article