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Unsaturated fatty acids (UFAs) play a crucial physiological role in human body. However, the concentration-related changes and prognostic significance of UFAs in epilepsyremain unclear. An optimized ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) approach was developed to measure six key UFAs: oleic acid (OA), linoleic acid (LA), arachidonic acid (AA), α-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). Subsequently, the levels of these six UFAs were determined in 40 healthy individuals and 49 epilepsy patients. The diagnostic value of UFAs and clinical examination indicators were assessed using statistical analysis and the support vector machine (SVM) algorithm. The results showed that the UPLC-MS/MS method successfully quantified the levels of OA, LA, AA, ALA, EPA, and DHA in both the healthy individuals and epilepsy patients. Compared with the healthy group, the levels of ALA, AA, and DHA were significantly elevated in the epilepsy group (P < 0.05). Pearson correlation analysis revealed a strong positive correlation among the UFAs in the epilepsy group. The orthogonal partial least squares-discriminant analysis (OPLS-DA) model showed that DHA and EPA were more important than cholesterol in distinguishing between two groups, although the separation was not complete. The SVM model achieved better separation, with an area under the curve (AUC) of 0.95 when including the six UFAs. The EPA/DHA ratio was identified as a key feature, with a significant contribution to the model's performance. Removing the six UFAs from the model reduced the AUC to 0.91, highlighting the predictive value of UFAs for epilepsy. In conclusion, ALA, AA, and DHA, are altered in epilepsy patients. The EPA/DHA ratio was found to be a key predictive indicator for epilepsy. The use of UFAs in conjunction with clinical examination data improved the predictive power of the SVM model, suggesting that UFAs have potential as biomarkers for epilepsy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier B.V. All rights reserved.) more...

Type 2 diabetes (T2D) is often accompanied by non-alcoholic fatty liver disease (NAFLD), both of which are related to brain damage and cognitive impairment. However, cortical structural alteration and its relationship with metabolism and cognition in T2D with NAFLD (T2NAFLD) and without NAFLD (T2noNAFLD) remain unclear. The brain MRI scans, clinical measures and neuropsychological test were evaluated in 50 normal controls (NC), 73 T2noNAFLD, and 58 T2NAFLD. The cortical thickness and graph theory properties of structural covariance network was calculated. Statistical analyses included one-way analysis of covariance with post hoc, partial correlation and mediation analysis. The nonparametric permutation test was performed to evaluate differences in topological properties of structural covariance network. We found T2NAFLD group had worse glucose and lipid profiles, more obesity and more severe insulin resistance, and poorer working memory compared to T2noNAFLD and NC. T2D patients demonstrated increase in cortical thickness compared to NC, but no difference between the two T2D groups. The structural covariance network integration decreased in T2D patients, with T2NAFLD exhibiting more obvious network reconfiguration at node level. Cortical thickness mediated the relationship between post-prandial glucose, waist-hip ratio, and working memory. The findings suggest that cortical thickening may be a compensatory response to reduced network integration, with NAFLD exacerbating regional structural network changes in T2D. This research advances our understanding of how these metabolic comorbidities contribute to cognitive decline, potentially guiding future therapeutic strategies for T2D patients with and without NAFLD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Caffeine is an FDA-approved drug for preventing and treating apnea in preterm infants. However, the pharmacokinetic (PK) characteristics of caffeine in preterm infants differ significantly from those in adults. Several population pharmacokinetic (PopPK) models have been developed to investigate potential covariates influencing PK parameters. This review aimed to summarize PopPK studies of caffeine in preterm infants and explore the identified influencing covariates. It has been observed that most caffeine pharmacokinetics followed a one-compartment model (1-CMT), although one study utilized a three-compartment model (3-CMT). Various covariates including birth weight, current weight, genetic polymorphism, combination medications, feeding patterns, and pathological conditions have been identified to affect caffeine PK parameters in preterm infants. Developing an individualized dosing regimen for preterm infants is essential for safe and effective treatment. Future PopPK studies of caffeine in preterm infants should focus on sampling and feeding patterns and further explore the effects of other covariates like gestational and postnatal age on caffeine PK parameters, which should be taken into account in the individualized dosing regimen of caffeine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.) more...

Cadmium (Cd 2+ ), a non-essential heavy metal for plant, adversely effects on crop productivity and food safety. Cotton, predominantly cultivated as a non-food crop, offers the advantage of not transferring Cd 2+ into the food chain, making it an effective option for remediating Cd 2+ contaminated soils. While previous researches have extensively examined the gene expression responses of cotton to Cd 2+ stress, insights at the post-transcriptional level remain limited. In this study, a comprehensive methodology was employed, incorporating miRNA sequencing, degradomics, and RNA sequencing, to investigate the responses of the Cd 2+ -tolerant cotton cultivar XM and the Cd 2+ -sensitive cotton cultivar ZM24 under Cd 2+ exposure. The analysis revealed that these the identified miRNA-target gene pairs predominantly influence various biological processes, including light signaling, cell wall biogenesis, abiotic stress responses, transportation, and hormone signaling pathways in response to Cd 2+ stress. Overall, our findings suggest that newly identified miRNAs and their corresponding target genes in cotton may contribute to enhance tolerance to Cd 2+ stress through multiple mechanisms, facilitating the breeding of superior cotton cultivars with enhanced tolerance to Cd 2+ toxicity., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2025 Elsevier Masson SAS. All rights reserved.) more...

Patients experiencing severe hemiplegia following a stroke struggle to rehabilitate their affected limbs. Cross-education (CE) training emerges as a promising rehabilitation method due to its safety, simplicity, low risk, and ability to effectively improve muscle strength in the affected limb. However, controversy surrounds the neural mechanisms and clinical applications of CE. To address this, we employed functional near-infrared spectroscopy to monitor the response of regions of interest (ROI) and functional connectivity in patients with stroke experiencing severe hemiplegia during one session of 50% maximal voluntary contraction (MVC) strength training with less-affected hand in both subacute and convalescent phases. Our objective was to compare the two stroke groups to gain insight into the potential utility for unilateral training of the less-affected limb as an effective rehabilitation approach during different phases post of stroke. The findings revealed varying degrees of activation in the ROIs within the affected hemisphere across both groups during the task. Additionally, we found that the subacute stroke patients with severe hemiplegia (SPS) had higher blood oxygen levels in the ipsilesional primary motor (iM1), ipsilesional pre-motor and supplementary motor area (iP-SMA) and contralesional P-SMA (cP-SMA). Functional connectivity strength between the iM1 and contralesional brain regions, as well as between the iP-SMA and ipsilesional ROIs, showed statistically significant differences in SPS compared to convalescent stroke patients with severe hemiplegia (CPS) during a 50% MVC strength training session using the less-affected hand. SIGNIFICANCE STATEMENT: Exploring the neural mechanisms underlying one session of 50% MVC strength training with less-affected hand sheds light on a safe therapy. The study enhances our understanding of less-affected hand training and investigates the feasibility as a future rehabilitation approach. Analyzing how one session of 50% MVC strength training with less-affected hand affects brain activation and connectivity could lead to more tailored and effective rehabilitation strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.) more...

Background and Aim: The acute pulmonary infectious disease caused by influenza viruses is known as influenza virus pneumonia (IVP). In recent years, Gegen Qinlian Decoction (GQD) has been widely used to treat pulmonary inflammation; however, the underlying mechanism of action of GQD in IVP remains unclear. This study aimed to elucidate the molecular mechanism through which GQD improved IVP., Materials and Methods: The efficacy of GQD was evaluated using classical pharmacodynamic indicators in a murine model of H1N1-induced IVP. Network pharmacology predicted the material basis of GQD in improving IVP, while metabonomics and 16 s rDNA sequencing assessed its regulation on small molecule metabolites and intestinal flora. Additionally, molecular biology techniques were used to investigate the molecular mechanism underlying the improvement of IVP by GQD., Results: The study results demonstrated that GQD exhibited a significant ameliorative effect on the inflammatory response in lung tissue of IVP mice. The potential pharmacological substances of GQD for improving IVP were identified by network pharmacology combined with ultra-high performance liquid chromatography/high-resolution time-of-flight mass spectrometry (UHPLC-HR-TOFMS) analysis, including puerarin, baicalin, berberine, and glycyrrhizin. Further analysis of biological processes and mechanisms of action predicted that GQD could improve IVP by inhibiting activation of inflammasomes, regulating the body's immune system, and intestinal microecology. Metabolomics and microbiomics findings revealed that GQD could bi-directionally regulate lipid and amino acid metabolites by increasing the abundance of beneficial bacteria like Akkermansia and Acetobacter, thereby maintaining host metabolic balance and immune homeostasis. RT-qPCR and immunohistochemistry results indicated that GQD improved IVP by inhibiting the complement C3/NLRP3 inflammasome pathway., Conclusion: The findings of this study confirmed that GQD effectively inhibited IVP by modulating the "gut microbiota-metabolomics-immune/inflammation" axis in the host, thereby establishing a solid immunological foundation for the clinical application of GQD., (Copyright © 2024 Elsevier B.V. All rights reserved.) more...

Empathy is central to individual and societal well-being. Numerous studies have examined how trait of empathy affects prosocial behavior. However, little studies explored the psychological and neural mechanisms by which different dimensions of trait empathy influence prosocial behavior. Addressing this knowledge gap is important to understand empathy-driven prosocial behavior. We employed an EEG experiment combined with interpretable machine learning methods to probe these questions. We found that empathic concern (EC) played the most pivotal role in donation decision. Behaviorally, EC negatively moderates the effect of perceived closeness and deservedness of charity projects on the willingness to donate. The machine learning results indicate that EC significantly predicts late positive potential (LPP) and beta-band activity during donation information processing. Further regression analysis results indicate that EC, rather than other dimensions of trait empathy, can positively predict LPP amplitude and negatively predict beta-band activity. These results indicated that participants with higher EC scores may experience heightened emotional arousal and the vicarious experience of others' emotions while processing donation information. Our work adds weight to understanding the relationship between trait empathy and prosocial behavior and provides electrophysiological evidence., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.) more...

Burn induced-pain (BIP) is one of the most common pain symptoms, which seriously affects the quality of sufferer life. Researches show that multi-targeted drug therapies offer superior efficacy and fewer side effects compared to single-target drug therapies. Consequently, in this study, we developed G(1-5)-EM2, a multi-targeted peptide designed to target μ-opioid receptor and the growth hormone secretagogue receptor 1α (GHS-R1α), and explored its antinociceptive effects on burn injury pain. Calcium mobilization experiments revealed that G(1-5)-EM2 demonstrated weak multi-agonist activities to μ-opioid receptor and κ-opioid receptor as well as GHS-R1α in vitro. Near-infrared fluorescence imaging experiments demonstrated that G(1-5)-EM2 could penetrate the blood-brain barrier (BBB) and access the brain following intravenous injection. The enzymatic stability of G(1-5)-EM2 was significantly enhanced compared to EM2. Our results indicated that intrathecal administration of G(1-5)-EM2 mitigated mechanical allodynia and thermal hyperalgesia in BIP. These antinociceptive effects of G(1-5)-EM2 were partially mediated through μ-opioid receptor and GHS-R1α. Moreover, intrathecal administration of G(1-5)-EM2 significantly decreased burn-induced up-regulation of phosphorylated p38 MAPK, phosphorylated NF-κBp65 and TRPV1 in the ipsilateral spinal cord, reduced the levels of IL-1β, IL-6 and TNF-α in serum, and enhanced wound healing in burned skin. Repeated intrathecal administration of G(1-5)-EM2 produced a non-tolerance-forming antinociception in BIP. These results suggest that the multi-targeted peptide G(1-5)-EM2 exhibits a novel role in alleviating BIP with fewer side effects and may represent a promising strategy for developing new analgesic drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.) more...

Tissue engineering employs the use of bioactive materials to facilitate the filling and acceleration of bone defect healing, thereby introducing novel concepts to the field of in situ bone repair. Some studies have shown that periosteum plays an important role in bone regeneration and repair. In this study, biomimetic periosteum-bone scaffolds were prepared by depositing poly-L-lactic acid (PLLA) electrospun fibers on the surface of the gelatin/chitosan cryogel to mimic the bone and periosteum structure, respectively. To improve the bioactivity of the scaffold, bone morphogenetic protein-2 (BMP-2) was loaded into a loose porous mesh-like cryogel, while platelet-derived growth factor-BB (PDGF-BB) was encapsulated in the core of PLLA nanofibers with core-shell structure. Both of these two growth factors were released locally at the site of bone defect, where they exert a synergistic effect on osteogenesis, thereby greatly accelerating bone healing. The in vitro experiments demonstrated that the biomimetic periosteum-bone scaffolds exhibited favourable biocompatibility and osteogenesis ability. Furthermore, the in vivo experiments indicated that the composite scaffold repaired rat skull defects in a more rapid and effective manner. In conclusion, biomimetic periosteum-bone scaffolds with codelivery of BMP-2 and PDGF-BB shows significant potential for bone regeneration., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Background: Although there is increasing evidence that environmental exposures are associated with the risk of neurodegenerative conditions, there is still limited mechanistic evidence evaluating potential mediators in human populations., Methods: UK Biobank is a large long-term study of 500,000 adults enrolled from 2006 to 2010 age 40-69 years. ICD-10 classified reports of dementia cases up to 2022 (Alzheimer's disease, vascular dementia, dementia in other classified diseases, and unspecified dementia) were identified from health record linkage. Estimates of residential air pollution, traffic noise, and greenspace exposure have been modelled. Structural brain MRI was conducted from 2014 to 2022, with brain volumes relevant to dementia identified a priori. Associations between environmental exposures, brain volumes, and dementia cases (diagnosed post-MRI) were tested using linear and logistic regression and adjusted for age, sex, household income, ethnicity, education, smoking, and area-level deprivation. Mediation of exposure-outcome associations by plausible brain volumes (those associated with both environmental exposure and dementia outcomes) were modelled using the quasi-Bayesian Monte Carlo method (N = 34,817-39,772)., Results: Small but significant mediating effects (2%-8% of relationships mediated) were observed between PM 2.5abs exposure and dementia risk by reduced total brain volume, NOx and Alzheimer's disease risk by reduced peripheral cortical grey matter, PM 2.5abs and vascular dementia risk by reduced peripheral cortical grey matter, PM 2.5abs and other dementia risk by reduced total grey matter, and PM 10 and other dementia risk by reduced total grey matter. Greenspace and noise were not associated with dementia outcomes in the subset of the cohort providing brain imaging data., Conclusions: This study adds to existing evidence of associations between environmental exposures and dementia outcomes. Our findings provide novel evidence that differences in brain volume may mediate these relationships. Future research is required to prove this mechanism and establish the other mechanisms through which exposure to air pollution might increase dementia risk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...

Anxiety and problematic smartphone use (PSPU) are prevalent issues among college students, and traditional research has tended to focus on cross-sectional data and grounded only in overall levels, thereby ignoring the complex interactions between the two over time. The development of network analysis methods has provided a new perspective for in-depth exploration of the relationship. This study aimed to explore the complex longitudinal interactions and specific pathways between problematic smartphone use and anxiety among Chinese college students from an internal specific symptom perspective. This study constructed a cross-lagged network model using longitudinal data on problematic smartphone use and anxiety symptoms in two waves of college students collected from 2022 to 2023 (N=741, M age  = 18.49, SD=0.81, 45.6 % male). The study found that anxiety symptoms and problematic smartphone use interacted with each other and had a vicious cycle of symptoms over time, with the effects of anxiety symptoms being more pronounced. "Feeling afraid" and "Uncontrollable worrying" had the most significant effects on the other symptoms, with "Impatient without the phone" and "Can't stand not having a phone" were more likely to be influenced by other symptoms. "Feeling afraid" may be a bridge symptom in the network to connect the anxiety and problematic smartphone use communities. The findings suggest that accurately intervening in the intrinsic link between problematic smartphone use and anxiety symptoms can combat the exacerbation of both problems simultaneously, resulting in more effective and comprehensive treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.) more...

MiR-30c and fatty acid synthase (fas) both play important roles in physiological processes such as lipid synthesis and fat metabolism. Predictive analysis revealed that fas is a target gene of miR-30c with multiple seed sites. Seed sites are useful to predict miRNA targeting relationships; however, detailed analyses of seed sites in fish genomes remain poorly studied. In this study, the regulatory relationship between miR-30c and fas, number and effect of seed regions, and mechanism by which miR-30c regulates lipid metabolism were evaluated in blunt snout bream (Megalobrama amblycephala). Four miR-30c target sites for fas were identified using various prediction tools. miR-30c mimics were transfected into 293 T cells, and dual-luciferase reporter assays were used to evaluate the roles of different fas target sites. When a single target site was mutated, relative luciferase activity was higher than that in the control group, with different activity levels depending on the mutation site. When multiple target sites were mutated, relative luciferase activity increased significantly as the number of mutation sites increased and was the highest when the four sites were mutated simultaneously. The miR-30c agomir was injected into the abdominal cavity of M. amblycephala at various concentrations for analyses of physiological and biochemical parameters in the liver and blood and the expression of genes related to lipid metabolism in the liver. Total cholesterol, free fatty acid, triglyceride, and low density lipoprotein levels were significantly lower after miR-30c agomir injection comparing to the control (P < 0.05). Additionally, the expression levels of genes related to lipid metabolism were significantly lower after miR-30c agomir injection than in the control (P < 0.05). In summary, this study identified four specific miR-30c target sites in the 3' UTR of fas mRNA; the effects of these sites are cumulative, and the redundancy ensures the accurate regulation of fas during evolution. In addition, miR-30c has a negative regulatory effect on fas and regulates lipid metabolism via various genes related to this process. Therefore, the regulation of miR-30c can effectively ameliorate the side effects of a high-fat diet on liver function in M. amblycephala., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.) more...

Historically, antibodies have been divided into two functionally independent domains, the variable (V) region for antigen binding and the constant (C) region for mediating effector functions. However, this classical view of antibody function has been severely challenged by a large and growing number of studies, which reveal long-range conformational interactions and allosteric links between the V and C regions. This review comprehensively summarizes the existing studies on antibody allostery, including allosteric conformational changes induced by covalent modifications or noncovalent ligand binding. In addition, we discuss how intramolecular allosteric signals are transmitted from the V to C regions and vice versa. This review argues that there is sufficient evidence to revisit the structure-function relationship of antibodies. These advances in antibody allostery will provide a blueprint for regulating antibody functions in a simple and highly predictable manner. More focus on antibody allostery will definitely benefit antibody engineering and vaccine design in the field of biotechnology., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial or personal interests influencing the work reported in this review paper., (Copyright © 2024 Elsevier Inc. All rights reserved.) more...

Aristolochic Acid I (AAI) is widely present in traditional Chinese medicines derived from the Aristolochia genus and is known to cause significant damage to renal tubular epithelial cells. Genome-wide screening has proven to be a powerful tool in identifying critical genes associated with the toxicity of exogenous substances. To identify undiscovered key genes involved in AAI-induced renal toxicity, a genome-wide CRISPR library screen was conducted in the human kidney-2 (HK-2) cell line. Among the altered sgRNAs, a significant enrichment of those targeting the E2F transcription factor 1 (E2F1) gene was observed in surviving HK-2 cells in the AAI-treated group. Interestingly, the role of E2F1 had not been previously explored in studies of AAI nephrotoxicity. Further investigations revealed that E2F1 promotes apoptosis by activating the p53 signaling pathway and upregulating pro-apoptotic genes, such as BAK and BAX. Additionally, using the high-throughput experiment- and reference-guided database of traditional Chinese medicine (HERB), cannabidiol (CBD) was identified as an inhibitor of E2F1 by suppressing the activity of NF-κB pathway. In vitro and in vivo models confirmed that CBD inhibits AAI-induced upregulation of E2F1, thereby suppressing p53-mediated apoptosis. In conclusion, this study highlights the crucial role of E2F1 in AAI-induced renal cell apoptosis and identifies CBD as a novel therapeutic candidate for mitigating AAI nephrotoxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...

Background: The goal is to identify methylation sites linked to transmission and their impact on host gene expression and HBV spread, aiming to uncover new molecular targets for preventing and treating intrauterine HBV infection., Methods: This study recruited 1205 infants born to HBsAg-positive mothers in Liuzhou City, China, between July 2023 and January 2024. Infants were followed up at 7-12 months of age and classified as HBsAg-positive (case, n = 5) or HBsAg-negative (control, n = 14) based on serological testing. Peripheral blood samples were collected for DNA extraction. DNA methylation profiling was performed using the Illumina Infinium MethylationEPIC BeadChip (850 K). Data were processed using the ChAMP package in R, including quality control, normalization, and identification of Differentially Methylated Positions (DMPs) and differentially methylated regions (DMRs). DMPs and DMRs were annotated using ANNOVAR 2018Apr16, and GO enrichment analysis was conducted using DAVID. The study was approved by the Guangxi University of Chinese Medicine Ethics Committee, and informed consent was obtained., Results: We identified 734,978 DMPs and 660 DMRs, with 1813 DMPs and 221 DMRs showing significant differences between groups. HBV-infected infants exhibited lower overall genomic methylation levels, with significant concentrations in gene body regions and CpG islands. GO enrichment analysis indicated that differentially methylated genes were enriched in processes related to cell adhesion and calcium ion binding., Conclusions: Prenatal HBV exposure was associated with significant infant hypomethylation, particularly in regulatory regions like TSS1500, TSS200, and CpG islands, potentially impacting gene expression. Enrichment of immune-related pathways among differentially methylated genes suggests that HBV may alter infant immune development through epigenetic modifications., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hai Li reports financial support was provided by Guangxi Natural Science Foundation. Hai Li reports financial support was provided by Chinese foundation for hepatitis prevention and control. Hai Li reports financial support was provided by Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis. Hai Li reports financial support was provided by Horizontal Research Project for Hepatitis B Prevention and Control in Guangxi. Hai Li reports financial support was provided by High-Level Public Health Talent Cultivation Innovation Team of Guangxi University of Chinese Medicine. Hai Li reports financial support was provided by Top Talent Program of Guangxi University of Chinese Medicine. Reports a relationship with that includes:. Has patent pending to. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.) more...

Background: Tumor metastasis is the main cause of death in lung adenocarcinoma (LAC) patients. It is known that the collagen triple helix repeats containing 1 (CTHRC1) protein is implicated in tissue remodeling and is tightly linked to the carcinogenesis and metastasis of solid tumors. However, the functional role of CTHRC1 and its potential mechanisms in LAC cell metastasis have not been fully explored., Methods: The expression level of CTHRC1 in LAC was measured by using bioinformatics analysis combined with quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB). Small interfering RNA and overexpression methods were employed to investigate the function and molecular mechanisms of CTHRC1 in LAC cells. Through bioinformatics analysis, qRT-PCR, WB, scratch healing assay, Transwell, assay kits, and flow cytometry, the downstream pathways and upstream regulatory genes of CTHRC1 in LAC cells were investigated. The binding sites were verified by using chromatin immunoprecipitation (ChIP) and dual luciferase reporter gene experiments., Results: In this project, CTHRC1 was found to be abnormally upregulated in LAC tissues and cells. CTHRC1 promoted the migration and invasion of LAC cells. The promoting effect of CTHRC1 overexpression on LAC cell migration was weakened after the addition of orlistat (a fatty acid synthase inhibitor). Mechanistically, TF AP-2α (TFAP2A) was directly bound to the upstream sequence of the CTHRC1 promoter and promoted CTHRC1 expression. The TFAP2A-CTHRC1 axis induced the migration of LAC cells by activating fatty acid metabolism., Conclusion: Our results indicated that TFAP2A activates fatty acid metabolism by positively modulating the expression of CTHRC1, thereby facilitating tumor cells' migration and invasion. These findings provided novel insights into LAC treatment and future research., Competing Interests: Declaration of Competing Interest The authors have no potential conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.) more...

Within cold seep environments, the Vesicomyidae clam emerges as a prevalent species, distinguished by its symbiotic relationship with microorganisms housed within its organ gill. Given the extreme conditions and the symbiotic nature of this association, investigating the host's immune genes, particularly immune recognition receptors, is essential for understanding their role in facilitating host-symbiotic interactions. Three short peptidoglycan recognition proteins (PGRPs) were identified in the clam. AmPGRP-S1, -S2, and -S3 were found to possess conserved amidase binding sites and Zn 2+ binding sites. Quantitative Real-time PCR (qRT-PCR) analysis revealed differential expression patterns among the PGRPs. AmPGRP-S1 and AmPGRP-S2 exhibited elevated expression levels in the gill, while AmPGRP-S3 displayed the highest expression in the adductor muscle. Functional experiments demonstrated that recombinant AmPGRP-S1, -S2, and -S3 (rAmPGRPs) exhibited binding capabilities to both L-PGN and D-PGN (peptidoglycan). Notably, rAmPGRP-S1 and -S2 possessed Zn 2+ -independent amidase activity, while rAmPGRP-S3 lacked this enzymatic function. rAmPGRPs were shown to bind to five different bacterial species. Among these, rAmPGRP-S1 inhibited Escherichia coli and Bacillus subtilis, while rAmPGRP-S2 and -S3 inhibited Bacillus subtilis in the absence of Zn 2+ . In the presence of Zn 2+ , rAmPGRP-S1 and -S2 exhibited enhanced inhibitory activity against Staphylococcus aureus or Bacillus subtilis. These findings suggest that AmPGRPs may play a pivotal role in mediating the interaction between the host and endosymbiotic bacteria, functioning as PGN and microbe receptors, antibacterial effectors, and regulators of host-microbe symbiosis. These results contribute to our understanding of the adaptive mechanisms of deep-sea organisms to the challenging cold seep environments., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...

Delivering nanoparticles to deep tumor tissues while maintaining high therapeutic efficacy and minimizing damage to surrounding tissues has long posed a significant challenge. To address this, we have developed innovative self-propelling bowl-shaped nanomotors MSLA@GOx-PDA composed of mesoporous silica loaded with l-arginine and polydopamine, along with glucose oxidase (GOx). These nanomotors facilitate the generation of hydrogen peroxide through GOx-catalyzed glucose oxidation, thereby initiating nitric oxide production from l-arginine. This dual mechanism equips MSLA@GOx-PDA with the robust motility required for deep tumor tissue penetration while depleting essential nutrients necessary for tumor growth, consequently impeding tumor progression. In addition, near-infrared lasers have the significant advantage of being depth-penetrating and non-invasive, allowing real-time fluorescence imaging and guiding dopamine-mediated mild photothermal therapy. Notably, starvation therapy depletes intracellular adenosine triphosphate and inhibits the synthesis of heat shock proteins, thus overcoming the Achilles' heel of mild photothermal therapy and significantly enhancing the efficacy of this therapy with encouraging synergistic anti-tumour effects. Overall, the integration of biochemical and optics strategies in this nanomotor platform represents a significant advancement in deep-tissue tumor therapy. It has substantial clinical translational value and is expected to have a transformative impact on future cancer treatments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.) more...

Low temperatures are a major abiotic stress factor that adversely affects the growth, development, and productivity of tea plants. Soluble sugars play a critical role in enhancing tea plants' resistance to cold stress. However, the mechanisms by which tea plants perceive and transmit sugar signals remain poorly understood. In this study, the transcription of CsHXK4, a type B hexokinase (HXK) gene in tea plants, was significantly upregulated by low temperatures and glucose signaling. CsHXK4 exhibited multiple subcellular localizations, particularly in the nucleus and mitochondria, and was ubiquitously expressed across various tissues, with predominant expression in younger organs. Hexose phosphorylation analysis using the HXK-deficient yeast triple mutant YSH7.4-3C demonstrated that CsHXK4 functions as a hexokinase with catalytic activity. Overexpression (OE) of CsHXK4 in Arabidopsis resulted in hypersensitivity to glucose, suggesting its role in sugar signal transduction. Furthermore, CsHXK4-OE Arabidopsis plants exhibited enhanced cold tolerance compared to wild-type plants, as evidenced by increased photosynthetic capacity, elevated sugar content, and stable cell membrane permeability. Transient induction of CsHXK4 expression in tea leaves improved freezing tolerance and activated the expression of cold-responsive marker genes, including CsCBF1/2/3/4, CsKIN2.2, CsCOR413, CsLEA14, and CsGOLS1, compared to the empty vector control. Overall, our findings reveal that CsHXK4 positively regulates cold resistance in tea plants by mediating sugar signaling and CBF signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Masson SAS. All rights reserved.) more...

Background: Ulcerative colitis (UC) is a common inflammatory bowel disease and a risk factor of colorectal cancer. Demethylzeylasteral (DZT), a bioactive component mainly isolated from Tripterygium wilfordii, has been shown to inhibit inflammation and cancer. However, its anti-UC function and molecular mechanisms have not been well characterized. This study aims to explore the therapeutic effect and functional targets of demethylzeylasteral against UC., Methods: RT-qPCR, Western blot and ELISA were used to detect the generation of pro-inflammatory cytokines and chemokines in murine macrophage cells. Luciferase reporter gene, Western blot, pull-down, CETSA, DARTS, and virtual docking were employed to detect the anti-inflammatory targets and molecular mechanisms of demethylzeylasteral. The anti-inflammatory and anti-colitis effects of demethylzeylasteral were further determined in DSS-challenged mice., Results: In vitro, demethylzeylasteral inhibited NO and PGE 2 production by suppressing the mRNA and protein expression of iNOS and COX-2, and suppressed the mRNA expression of TNF-α, IL-1β, IL-6, MCP-1, CXCL9, and CXCL10 in RAW264.7 macrophages stimulated by LPS/IFNγ. Furthermore, demethylzeylasteral was not only capable of inhibiting IKKα/β-NF-κB activation, but also able to block JAKs-STAT3/5 activation in LPS/INFγ-incubated RAW264.7 cells or DSS-exposed colon tissues of mice. Mechanistically, demethylzeylasteral was found to directly bind to IKKα/β and JAK2 kinases, leading to inactivation of pro-inflammatory signaling cascades and reduced generation of cytokines and chemokines. In vivo, oral administration of demethylzeylasteral significantly attenuated DSS-induced colitis, which was mainly manifested as mitigated symptoms of colitis, colonic mucosal barrier damage, and colonic inflammation., Conclusion: We demonstrated that demethylzeylasteral alleviated UC pathology by blocking NF-κB and STAT3/5 pathways via targeting IKKα/β and JAK2 kinases, raising the possibility that demethylzeylasteral could act as a candidate for the treatment of UC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.) more...

A significant amount of glycyrrhiza wastewater is generated in the cleaning process of glycyrrhiza. The wastewater contains polysaccharide, glycyrrhizic acid, liquiritin, and other polyphenols, which is expensive for cleanup and wastes medical resources. To reduce environmental pollution from glycyrrhiza wastewater and increase the resource usage efficiency of glycyrrhiza components. According to the physicochemical properties of the component in glycyrrhiza wastewater, the ultrasonic assisted membrane separation mode was adopted to regulate the micellar state of glycyrrhizic acid and enhance the differences in membrane separation of polysaccharides, saponins, and flavones, in order to achieve the classification and separation of polysaccharides, saponins, and flavones while removing organic matter in glycyrrhiza wastewater. However, the efficiency, application, and mechanism of ultrasonic-assisted membrane technology for the separation of polysaccharides, saponins, and flavonoids from glycyrrhiza wastewater remain unclear. This study presents a green and feasible technical strategy for glycyrrhiza wastewater treatment that was developed by adjusting the parameters of ultrasonic assisted membrane separation. In this study, the systematic separation mode of ultrasonic enhanced ultrafiltration combined with nanofiltration is provided. The SCQ-9200E ultrasonic system was provided for the study with adjustable ultrasonic power, and the ultrasonic frequency was 40 kHz. The glycyrrhizic acid micelle was changed using ultrasonic power, pH, and molecular weight cut off (MWCO), and the separation differences among polysaccharide, glycyrrhizic acid, and liquiritin were enhanced. The optimal polysaccharide separation parameters used in the first step: MWCO 30 kDa, ultrasonic power 500 W and pH 5.00, and the rejections of polysaccharide, glycyrrhizic acid, and liquiritin were 87.72 %, 8.01 %, and 6.57 %, respectively. The second step included the following parameters for the separation of liquiritin and glycyrrhizic acid: MWCO 10 kDa, ultrasonic power 100 W and pH 8.00, the rejections of liquiritin and glycyrrhizic acid were 9.22 % and 40.65 %, respectively. The third step is to remove the low molecular sugar in liquiritin by nanofiltration: MWCO 800 Da, pH 8.00, retention solution diluted and separated twice, the rejection of liquiritin and total sugar were 95.72 % and 3.70 %, respectively. Ultrasonic may regulate the microtopography of glycyrrhiza wastewater with the power intensity of 50 W/L, improving the mass transfer efficiency of glycyrrhizic acid and liquiritin in the ultrafiltration separation process. As the separation volume of wastewater increased from 2.00 L to 20.00 L, the concentrations of polysaccharide, glycyrrhizic acid, and liquiritin increased by 2.5-35.4 times, 0.6-15.2 times, and 2.4-32.8 times, respectively, significantly increasing the content of index components in wastewater and solving the problem of recycling and resource utilization in glycyrrhiza wastewater., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.) more...

Purpose: To investigate the relationship between visual prognosis and genotype in patients undergoing lens surgery for congenital ectopia lentis (EL)., Design: Prospective clinical cohort study., Methods: Patients with congenital EL who underwent lens removal and intraocular lens implantation received panel-based next-generation sequencing. Patients were grouped into children and adolescents/adults based on the age at surgery. The visual prognosis, including best-corrected visual acuity (BCVA) and amblyopia, was stratified into short-term and medium to long-term., Results: This study included 329 probands with congenital EL, with a median age at lens surgery of 7.00 years (interquartile range [IQR] = 5.00, 12.50 years). Children with the non-FBN1 mutation exhibited inferior medium to long-term postoperative BCVA (0.26 [IQR: 0.14, 0.33] vs 0.15 [IQR: 0.10, 0.22], P = .034) and a higher prevalence of amblyopia (44.4% vs 16.8%, P = .012) compared to those with FBN1 mutation. Multivariable analysis showed that genotype (FBN1 vs non-FBN1 mutation) was significantly associated with medium to long-term postoperative BCVA (b = -0.128, 95% CI -0.214 to -0.042, P = .004) and amblyopia (OR = 0.20, 95% CI 0.05-0.78, P = .020) in children. Further classification of FBN1 genotype did not yield significant correlations with visual prognosis. However, no significant correlation was observed between genotype and short-term visual prognosis in the children. Children with less severe EL (OR = 0.13, 95% CI 0.02-0.85, P = .033) had lower risks of amblyopia in the short-term follow-up. For adolescent and adult patients with congenital EL, those with poor preoperative BCVA and long axial length should be informed of suboptimal visual prognosis., Conclusions: Genotype significantly influences the medium to long-term visual prognosis in children with congenital EL. Genotype, along with preoperative BCVA, may assist in establishing reasonable expectations for patients regarding their visual outcomes after the lens surgery., (Copyright © 2024 Elsevier Inc. All rights reserved.) more...

This paper reports the antitumor activity and possible mechanism of anthraquinone derivatives containing substituted bisbenzyloxy groups. Series of anthraquinone derivatives containing substituted bisbenzyloxy groups were designed and synthesized by etherification and esterification. The antitumor activities of the synthesized substituted bisbenzyloxy anthraquinone derivatives on liver cancer cell Huh7, triple negative breast cancer cell line MDA-MB-231 and lung cancer cell A549 were in the order of methoxy substitution > methyl substitution > chloral substitution. Among these, the Compound KA-MO-g showed strong antitumor activity, especially against liver cancer Huh7 cells. Further studies on the antitumor mechanism showed that the Compound KA-MO-g simultaneously activated three pathways of endoplasmic reticulum stress (ERS), also caused impairment of endoplasmic reticulum (ER) functions, such as glycoprotein synthesis and disulfide bond formation are impeded and caused calcium overload, then increased mitochondrial ROS, damaged of mitochondria, changed of apoptosis-related protein levels, activated Caspase 3, induced the apoptosis of Huh7 cells. Because KA-MO-g showed strong antitumor activity, it is expected to be a new candidate drug for treating liver cancer and is worth further study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.) more...

Acute lung injury (ALI) is currently a global health concern. Nicandra physalodes (L.) Gaertn. (NP) holds an important position in traditional Chinese medicine and nutrition. The potential protective mechanisms of NP against ALI remain unknown. The purpose of this study was to investigate the protective effects and molecular mechanisms of NP extract (NPE) on lipopolysaccharide (LPS)-induced ALI in mice. By utilizing network pharmacology to forecast the active ingredients in NP as well as possible signaling pathways. The composition of the NPE was analyzed using UPLC-Q-TOF-MS/MS. In addition, 1 H-NMR immunometabolomics was employed to identify alterations in primary metabolic pathways and metabolites in the lung, serum, and fecal tissues. Finally, the protein and gene expression of key pathways were verified by IHC, IF, RT-qPCR, and ELISA. It was found that the main ingredients of NPE were revealed to be nicandrenone, withanolide A, and baicalin. NPE significantly improved lung injury, pulmonary edema, and inflammatory cell infiltration in mice with ALI. In addition, NPE improved autophagic activity and alleviated Th1 and Th17 cell-induced lung inflammation by suppressing the PI3K/Akt/mTOR signaling pathway. Importantly, immunometabolomic analysis of fecal, serum, and lung tissues revealed that NPE reversed ALI-induced leucine resistance by remodeling immunometabolism. We confirmed NPE prevents ALI by remodeling immunometabolism, regulating the Leucine/PI3K/Akt/mTOR signaling pathway, inhibiting Th1/Th17 cell differentiation, and providing a scientific immunological basis for the clinical application of NPE., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.) more...

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common causes of respiratory failure in critically ill patients. There is still a lack of definitive and effective treatment options, and the mortality rate remains as high as 30% to 40%. Effective therapeutics for ALI/ARDS are greatly hindered by the side effects resulting from inefficient delivery to the disease lesions and off-targeting biodistribution of drugs. Macrophages play an integral role in maintaining the steady state of the immune system and are involved in inflammation processes. Thus, nanodrug to accurately target macrophages have the potential to transform disease treatment. Here, we developed an mannosylated drug delivery system to target and deliver celastrol (Cel) to the alveolar macrophages for enhanced alleviating the cytokines in LPS-induce ALI mice. In vitro data demonstrated that the as-synthesized Man@Cel-NPs significantly improved the targeting of Cel into the inflammatory macrophages via mannose receptor-mediated phagocytosis. In vivo experiments further showed that intratracheal delivery of Man@Cel-NPs can improve the dysregulation of inflammatory response in LPS-induced mice by inhibiting the release of inflammatory cytokines and increasing autophagy and decreasing apoptosis in lungs. This work provides a potential NP platform for the locally tracheal delivery of herbal ingredients and exhibits promising clinical potential in the treatment of numerous respiratory diseases, including ALI/ARDS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.) more...

This study investigates the role of M2-exo-mediated HOXC13-AS in laryngeal squamous cell carcinoma (LSCC) by examining its transmission to tumor microenvironment (TME) macrophages. Exosomes from M2 macrophages were isolated and characterized using transmission electron microscopy, nanoparticle tracer analysis and western blot. Expression of HOXC13-AS, miR-485-5p, IGF2BP2, and PD-L1 was analyzed. Different interventions on LSCC cell function and immune escape were detected using molecular biological techniques. The study found that elevated HOXC13-AS were present in LSCC, and M2-exo expression was significantly increased in LSCC cells. Silencing HOXC13-AS in M2-exo inhibited LSCC malignant progression and immune escape in vivo and in vitro. M2-exo-mediated HOXC13-AS also regulated IGF2BP2 expression, impacting cellular biological function and immune escape process. The study concludes that M2-exo-mediated HOXC13-AS promotes LSCC malignancy and immune escape., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.) more...

Reduced glutathione (GSH) is an endogenous tripeptide antioxidant which plays a crucial role in a variety of physiological and pathological activities. Although GSH is not present in any FDA-approved drug product, GSH dietary supplement products and compounded GSH drugs are available to patients in the US. Several incidents of toxicity have occurred in recent years due to endotoxin or otherwise contaminated GSH in compounded drugs. Efficient and sensitive analytical methods are needed for assessing and ensuring the quality of GSH substance and associated drug or dietary supplement products. Impurities A (L-cysteinylglycine), B (cysteine), C (oxidized L-glutathione) and D (γ-L-glutamyl-L-cysteine) are the main related impurities for GSH drug substance which have been detected and quantified by capillary electrophoresis and qNMR analytical procedures. However, there are no reported HPLC methods for detecting or quantifying the three main related impurities A, B and D even though numerous HPLC analytical methods have been reported for analyzing GSH and impurity C. In this report, an isocratic HPLC-UV analytical procedure was developed and validated for separating and identifying GSH and related impurities A-D as well as a newly identified degradant, L-pyroglutamic acid (pGlu), within 10 minutes with resolution (R S ) more than 3. The LOD and LOQ were determined to be 0.02 % w/w and 0.05 % w/w, respectively, for impurities A-D and pGlu. Importantly, the optimized HPLC analytical procedure for GSH assay does not have interference from impurities A, B and D, providing highly specific results compared to the commonly used iodine titration method. The newly validated analytical procedure was applied to assess different commercial GSH bulk substance samples. The results suggest that the analytical procedure described in this work is suitable for quality assessment of GSH samples., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Qin Shu reports financial support was provided by US Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Qin Shu reports a relationship with US Food and Drug Administration that includes: employment and funding grants. Mary Schleiff, Jingfan Chen, Cynthia Sommers, Jingyue Yang, Xiaohui Shen, Jason D. Rodriguez, David A. Keire report a relationship with US Food and Drug Administration that includes: employment, (Published by Elsevier B.V.) more...

Endocrine-disrupting chemicals (EDCs) exhibited the detriment in female reproductive health. Our objective was to investigate the individual and mixture effects of EDCs present in follicular fluid, the environment in which oocytes grow and develop, on early reproductive outcomes. We recruited 188 women seeking reproduction examination from the Study of Exposure and Reproductive Health (SEARCH) cohort between December 2020 and November 2021. We assessed the concentrations of 7 categories of 64 EDCs in follicular fluid, and measured early reproductive outcomes, including retrieved oocytes, mature oocytes, normal fertilized oocytes, and high-quality embryos. In this study Monomethyl phthalate (MMP) (2.17 ng/ml) were the compounds found in the highest median concentrations in follicular fluid. After adjusting for multiple testing, multivariate regression showed that multiple EDCs were significantly negatively associated with early assisted reproduction outcomes. For example, MMP showed a significant negative correlation with the number of high quality embryos (β: -0.1, 95 % CI: -0.15, -0.04). Specifically, eight types of EDCs were significantly negatively associated with four early assisted reproductive outcomes (β range: -0.2 ∼ -0.03). In the mixed exposure model, we found that mixtures of EDC were significantly negatively correlated with all four outcomes. In the quantile g-computation (QGCOMP) model, for each interquartile range increase in the concentration of EDC mixtures, the number of oocytes retrieved, mature oocytes, normally fertilized oocytes, and high-quality embryos decreased by 0.46, 0.52, 0.77, and 1.2, respectively. Moreover, we identified that phthalates (PAEs) predominantly contributed to the negative effects. Future research should validate our findings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...

Soil salinization effects plant photosynthesis in a number of global ecosystems. In this study, photosynthetic and physiological parameters were used to elucidate the impacts of saline-alkaline stress on Cyperus esculentus L. (C. esculentus) seedling photosynthesis. The results demonstrate that salt stress, alkali stress and mixed salt and alkali stress treatments all have similar bell-shaped influences on photosynthesis. At low concentrations (0-100 mmol L -1 ), saline-alkaline stress promoted net photosynthetic rate, transpiration rate and water use efficiency in C. esculentus. However, as the treatments increased in intensity (100-200 mmol L -1 ), plant photosynthetic parameters began to decline. We interpreted this as the capacity of C. esculentus to improve osmoregulatory capacity in low saline-alkaline stress treatments by accumulating photosynthetic pigment, proline and malondialdehyde to counterbalance the induced stress - an adaptive mechanism that failed once concentrations reached a critical threshold (100 mmol L -1 ). Stomatal conductance, maximum photosynthetic rate and actual photosynthetic rate all decreased with increasing concentration of the stress treatments, and intercellular carbon dioxide showed a decreasing and then increasing trend. These results indicated that when the saline-alkaline stress concentrations were low, C. esculentus seedlings showed obvious adaptive ability, but when the concentration increased further, the physiological processes of C. esculentus seedlings were significantly affected, with an obvious decrease in photosynthetic efficiency. This study provides a new understanding of the photosynthetic adaptation strategies of C. esculentus seedlings to varying concentrations of saline-alkaline stress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.) more...

Multidrug resistance (MDR) Klebsiella pneumoniae (K. pneumoniae) is a major emerging threat to human health, and leads to very high mortality rate. The effectiveness of colistin, the last resort against MDR Gram-negative bacteria, is significantly compromised due to the widespread presence of plasmid- or chromosome-mediated resistance genes. In this study, o-cymen-5-ol has been found to greatly restore colistin sensitivity in MDR K. pneumoniae. Importantly, this compound does not impact bacterial viability, induce resistance, or cause any noticeable cell toxicity. Various routes disclosed the potential mechanism of o-cymen-5-ol potentiating colistin activity against MDR K. pneumoniae. These include inhibiting the activity of plasmid-mediated mobile colistin resistance gene (mcr-1), accelerating lipopolysaccharide (LPS) - mediated membrane damage, and promoting the ATP-binding cassette (ABC) transporter pathway. To enhance the administration and bioavailability of o-cymen-5-ol, a nanoemulsion has been designed, which significantly improves the loading efficiency and solubility of o-cymen-5-ol, resulting in antimicrobial potentiation of colistin against K. pneumoniae infection. This study has revealed a new understanding of the o-cymen-5-ol nanoemulsion as a means to enhance the effectiveness of colistin against resistant factors. The finding also suggests that o-cymen-5-ol nanoemulsion could be a promising approach in the development of potential treatments for multidrug-resistant Gram-negative bacterial infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.) more...

Background: Neutrophil extracellular traps (NETs) induce oxidative stress, which may initiate ferroptosis, an iron-dependent programmed cell death, during abdominal aortic aneurysm (AAA) formation. Mitochondria regulate the progression of ferroptosis, which is characterized by the depletion of mitochondrial glutathione (mitoGSH) levels. However, the mechanisms are poorly understood. This study examined the role of mitoGSH in regulating NET-induced ferroptosis of smooth muscle cells (SMCs) during AAA formation., Methods: Concentrations of NET markers were tested in plasma samples. Western blotting and immunofluorescent staining were performed to detect the expression and localization of NET and ferroptosis markers in tissue samples. The role of NETs and SMC ferroptosis during AAA formation was investigated using peptidyl arginine deiminase 4 gene (Padi4) knockout or treatment with a PAD4 inhibitor, ferroptosis inhibitor or activator in an angiotensin II-induced AAA mouse model. The regulatory effect of SLC25A11, a mitochondrial glutathione transporter, on mitoGSH and NET-induced ferroptosis of SMCs was investigated using in vitro and in vivo experiments. Transmission electron microscopy was used to detect mitochondrial damage. Blue native polyacrylamide gel electrophoresis was used to analyze the dimeric and monomeric forms of the protein., Results: Significantly elevated levels of NETosis and ferroptosis markers in aortic tissue samples were observed during AAA formation. Specifically, NETs promoted AAA formation by inducing ferroptosis of SMCs. Subsequently, SLC25A11 was identified as a potential biomarker for evaluating the clinical prognosis of patients with AAA. Furthermore, NETs decreased the stability and dimerization of SLC25A11, leading to the depletion of mitoGSH. This depletion induced the ferroptosis of SMCs and promoted AAA formation., Conclusion: During AAA formation, NETs regulate the stability of the mitochondrial carrier protein SLC25A11, leading to the depletion of mitoGSH and subsequent activation of NET-induced ferroptosis of SMCs. Preventing mitoGSH depletion and ferroptosis in SMCs is a potential strategy for treating AAA., Competing Interests: Conflict of interest The authors have declared no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.) more...

The transformation of salvianolic acid B brought on by heat treatment recovery of ethanol eluent, which is a difficult problem in pharmaceutical technology, affects the purity of raw material when the medicinal raw material salvianolic acid B is purified by resin. Ultrasonic-assisted nanofiltration separation (UANS) was first employed to improve efficiency of resource utilization by regulating rejection and separating salvianolic acid B and rosmarinic acid from organic pharmaceutical wastewater. The rejection was related to three variables: ultrasonic power, pH, and ethanol concentration. But there were differences in the effects of variables on the rejections of salvianolic acid B and rosmarinic acid. The rejections of rosmarinic acid and salvianolic acid B showed a decreasing trend with an increase in ultrasonic power or a decrease in pH; however, when the concentration of ethanol was increased from 5 % to 35 %, the salvianolic acid B rejection increased from 84.96 % to 96.60 % and the rosmarinic acid rejection decreased from 35.09 % to 17.51 %. On the basis of response surface methodology (RSM), the optimal UANS parameters for solution conditions involving different ethanol concentrations are as follows: 10 % ethanol solution (ultrasonic power 500 W and pH 6.15), 20 % ethanol solution (ultrasonic power 500 W and pH 6.54), and 30 % ethanol solution (ultrasonic power 460 W and pH 6.34). The molecular proportions of salvianolic acid B were 10.75 %, 7.13 %, and 8.27 % in 10 %, 20 %, and 30 % ethanol wastewater, while the molecular proportions of rosmarinic acid were 40.52 %, 33.83 %, and 69.87 %, respectively. And the recoveries of salvianolic acid B in 10 %, 20 %, and 30 % ethanol wastewater were 93.56 %, 95.04 %, and 97.30 %, respectively, while the recoveries of rosmarinic acid were 3.19 %, 2.27 %, and 0.56 %. The molecular proportion and the rejection are correlated exponentially. In comparison with conventional nanofiltration separation (CNS), UANS is able to resolve the conflict between rosmarinic acid and salvianolic acid B in pharmaceutical wastewater, as well as enhance resource recycling and separation efficiency to prevent pollution of the environment from pharmaceutical wastewater. Experiments using UANS at different power intensities suggest that the ultrasonic at a power intensity of 46-50 W/L and the power density of 0.92-1.00 W/cm 2 may resolve the separation conflict between rosmarinic acid and salvianolic acid B. This work suggests that UANS may be a significant advancement in the field of ultrasonic separation and has several potential uses in the water treatment industry., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.) more...

Bubble cluster dynamics in viscoelastic media is instructive for ultrasound diagnosis and therapy. In this paper, we propose a statistical model for bubble cluster dynamics in viscoelastic media considering the radius distribution of bubble nuclei. By investigating and comparing the response for a bubble in three conditions: single bubble; multi-bubble with the same radius; multi-bubble with different radius, the following rules are found: The promotion or suppression of the bubble cluster on the bubble vibration is not monotonous with the increase of the number of bubbles. The promotion or suppression of the bubble cluster on the bubble vibration varies alternately with the frequency. The effect of bubble cluster on bubble vibration is mostly suppressed when the driving acoustic pressure amplitude p a is high (5000 kPa). Usually, the bubble cluster promotes the vibration of the large bubbles (R 0  = 10 μm) more, or suppresses it less., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.) more...

This study aimed to investigate the effects of ultrasonic treatment at different powers on the physicochemical properties, microstructure and quercetin delivery capacity of fermentation-induced soy protein isolate emulsion gel (FSEG). The FSEG was prepared by subjecting soy protein isolate (SPI) emulsion to ultrasonic treatment at various powers (0, 100, 200, 300, and 400 W), followed by lactic acid bacteria fermentation. Compared with the control group (0 W), the FSEG treated with ultrasound had higher hardness, water holding capacity (WHC) and rheological parameters. Particularly, at an ultrasonic power of 300 W, the FSEG had the highest hardness (101.69 ± 4.67 g) and WHC (75.20 ± 1.07%) (p < 0.05). Analysis of frequency sweep and strain scanning revealed that the storage modulus (G') and yield strains of FSEG increased after 300 W ultrasonic treatment. Additionally, the recovery rate after creep recovery test significantly increased from 18.70 ± 0.49% (0 W) to 58.05 ± 0.54% (300 W) (p < 0.05). Ultrasound treatment also resulted in an increased β-sheet content and the formation of a more compact micro-network structure. This led to a more uniform distribution of oil droplets and reduced mobility of water within the gel. Moreover, ultrasonic treatment significantly enhanced the encapsulation efficiency of quercetin in FSEG from 81.25 ± 0.62 % (0 W) to 90.04 ± 1.54% (300 W). The bioaccessibility of quercetin also increased significantly from 28.90 ± 0.40% (0 W) to 42.58 ± 1.60% (300 W) (p < 0.05). This study enriches the induction method of soy protein emulsion gels and provides some references for the preparation of fermented emulsion gels loaded with active substances., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.) more...

The membrane-proximal external region (MPER) represents a highly conserved region of the Human Immunodeficiency Virus (HIV) envelope glycoprotein (env) targeted by several broadly neutralizing antibodies (bnAbs). In this study, we employed single genome amplification to amplify 34 full-length env sequences from the 2005 plasma sample of CBJC504, a chronic HIV-1 clade B infected individual. We identified three amino acid changes (N671S, D674N, and K677R) in the MPER. A longitudinal analysis revealed that the proportion of env sequences with MPER mutations increased from 26.5 % in 2005 to 56.0 % in 2009, and the sequences with the same mutation clustered together. Nine functional pseudoviruses were generated from the 34 env sequences to examine the effect of these mutations on neutralizing activity. Pseudoviruses carrying N674 or R677 mutations demonstrate increased sensitivity to autologous plasma and monoclonal antibodies 2F5, 4E10, and 10E8. Reverse mutations were performed in env including N674, R677, D659, and S671/N677 mutations, to validate the impact of the mutations on neutralizing sensitivity. Neutralization assays indicated that the N671S mutation increased neutralization sensitivity to 2F5 and 10E8. The amino acid R at position 677 increased viral resistance to 10E8, whereas N enhanced viral resistance to 4E10 and 10E8. It has been proposed that critical amino acids in the extra-MPER and the number of potential N-like glycosylation sites (PNGSs) in the V1 loop may have an impact on neutralizing activity. Understanding the mutations and evolution of MPER in chronically infected patients with HIV-1 is crucial for the design and development of vaccines that trigger bnAbs against MPER., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.) more...

Enzymes play a pivotal role in various industries by enabling efficient, eco-friendly, and sustainable chemical processes. However, the low turnover rates and poor substrate selectivity of enzymes limit their large-scale applications. Rational computational enzyme design, facilitated by computational algorithms, offers a more targeted and less labor-intensive approach. There has been notable advancement in employing rational computational protein engineering strategies to overcome these issues, it has not been comprehensively reviewed so far. This article reviews recent developments in rational computational enzyme design, categorizing them into three types: structure-based, sequence-based, and data-driven machine learning computational design. Case studies are presented to demonstrate successful enhancements in catalytic activity, stability, and substrate selectivity. Lastly, the article provides a thorough analysis of these approaches, highlights existing challenges and potential solutions, and offers insights into future development directions., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.) more...

Purpose: Human evidence on the association between oxidative stress and osteoporosis is inconsistent. Fluorescent Oxidation Products (FlOPs) are global biomarkers of oxidative stress. We examined the associations of FlOPs (excitation/emission wavelengths 320/420 nm for FlOP&#95;320, 360/420 nm for FlOP&#95;360, and 400/475 nm for FlOP&#95;400) with osteoporosis, bone microstructure, and bone turnover markers in humans and rats., Methods: In humans, we conducted a 1:2 age, sex, hospital, and specimen-matched case-control study to test the association between FlOPs and osteoporosis diagnosed from dual-energy X-ray absorptiometry. In eight-week-old male Wistar rats, we administrated D-galactose and 0.9 % saline for 90 days in treatment and control groups (n = 8/group); micro-CT was used to determine bone microstructure., Results: In humans, higher levels of FlOP&#95;320 (OR for per 1 SD increase = 1.49, 95 % CI: 1.01-2.20) and FlOP&#95;360 (OR for per 1 SD increase = 1.59, 95 % CI: 1.07-2.37) were associated with increased odds of osteoporosis. FlOP&#95;400 were not associated with osteoporosis. D-galactose treated rats, as compared with control rats, showed higher levels of FlOP&#95;320 and MDA, and lower P1NP levels during 90 days of experiment (all P < 0.05). The D-galactose group had lower trabecular bone volume fraction (0.07 ± 0.03 vs. 0.13 ± 0.05; P = 0.008) and volumetric BMD (225.4 ± 13.8 vs. 279.1 ± 33.2 mg HA/cm 3 ; P = 0.001) than the control group., Conclusion: In conclusion, higher FlOP&#95;320 levels were associated with increased odds of osteoporosis, impaired bone microstructure and decreased bone formation., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.) more...

The COMPASS-like complex, responsible for depositing H3K4 methylation, exhibits a conserved composition across yeast, plants, and animals, with functional analysis highlighting its crucial roles in plant development and stress response. In this study, we identified nine genes encoding four subunits of the COMPASS-like complex through homologous search. Phylogenetic analysis revealed the presence of two additional ASH2 genes in the sorghum genome, specifically expressed in endosperms, suggesting the formation of a unique COMPASS-like complex in sorghum endosperms. Y2H and BiFC protein-protein interaction tests demonstrated the interaction between SbRbBP5 and SbASH2A/B/C, while the association between other subunits appeared weak, possibly due to sequence variations in SbWDR5 or synergistic interactions among COMPASS-like complex subunits. The interaction between ATX1 and the C-Terminal Domain (CTD) of Pol II, reported in Arabidopsis, was not detected in sorghum. However, we made the novel discovery of transcriptional activation activity in RbBP5, which is conserved in sorghum, rice, and Arabidopsis, providing valuable insights into the mechanism by which the COMPASS-like complex regulates gene expression in plants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.) more...

Objectives: Skeletal muscle index (SMI) is insufficient for evaluating muscle in obesity, and muscle attenuation (MA) may be a preferred indicator. This study aimed to investigate whether MA has greater prognostic value than SMI in gastric cancer patients with overweight and obesity., Methods: Clinical parameters of 1312 patients with gastric cancer who underwent radical gastrectomy were prospectively collected between 2013 and 2019. MA and SMI were analyzed by computed tomography scan. Overweight/obesity was defined as body mass index (BMI) ≥24 kg/m 2 . The hazard ratio (HR) for death was calculated using Cox regression analysis., Results: Among all patients, 405 were identified as overweight and obese, and 907 were identified as normal and underweight. MA was inversely associated with BMI and visceral fat area. Among the 405 patients with overweight and obesity, 212 patients (52%) were diagnosed with low MA. In the overweight/obese group, MA was an independent predictor for overall survival (HR, 1.610; P = 0.021) in multivariate Cox regression analyses, whereas SMI did not remain in the model. In the normal/underweight group, both low MA (HR, 1.283; P = 0.039) and low SMI (HR, 1.369; P = 0.008) were independent factors of overall survival. Additionally, 318 patients were identified as having visceral obesity in the overweight/obese group, and low MA was also an independent prognostic factor for survival in these patients (HR, 1.765; P = 0.013)., Conclusion: MA had a higher prognostic value than SMI in overweight and obese patients with gastric cancer after radical gastrectomy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cheng-Le Zhuang reports financial support was provided by National Natural Science Foundation of China. Cheng-Le Zhuang reports financial support was provided by Shanghai Chongming Science and Technology Commission. Su-Lin Wang reports financial support was provided by Basic Scientific Research Project of Wenzhou City. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.) more...

In this study, an alternative method to compendial analytical procedures with enhanced detection and separation capabilities was validated for the quality assessment of glutathione (GSH) drug substance. The related impurities A, B, C, and D present in GSH drug substance were characterized using a one-dimension proton nuclear magnetic resonance (1D 1 H NMR) method on a 600 MHz spectrometer equipped with a liquid nitrogen cryoprobe. Two sample preparations at different pH were optimized to ensure the unambiguous identification of different impurities in the GSH samples. Specifically, impurities A and C in a GSH sample can be tested at pH 3.0, while pH 7.4 is more suitable for testing impurities B and D. The quantitative NMR (qNMR) method was validated following International Council for Harmonisation (ICH) guidelines. The limit of detection (LOD) was less than 0.1% wt for an individual impurity, and the limit of quantitation (LOQ) ranged from 0.14 to 0.24% wt, using about 14 min experimental time per spectrum. Following validation, the qNMR method was applied to assess different commercial GSH bulk substance samples, an in-house compounded GSH drug product, and a GSH dietary supplement product. The method was also applied to monitor GSH degradation (hydrolysis and oxidation) over time to provide quantitative information on GSH degradation and stability. The results suggest that the qNMR method can serve as a highly specific and efficient orthogonal tool for assessing the quality of GSH pharmaceuticals, providing both qualitative and quantitative information on GSH and its related impurities A-D., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Qin Shu reports financial support was provided by US Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Qin Shu reports a relationship with US Food and Drug Administration that includes: employment and funding grants. Mary Schleiff, Cynthia Sommers, Jingyue Yang, Xiaohui Shen, Jason D. Rodriguez, David A. Keire report a relationship with US Food and Drug Administration that includes: employment., (Published by Elsevier B.V.) more...

Dual oxidase (Duox) a member of the nicotinamide adenine dinucleotide phosphate oxidase (NOX) family can induce the production of reactive oxygen species (ROS). In vertebrates, the duox gene was indicated to be associated with the mucosal immunity. The roles of the duox gene in invertebrates were mainly studied in insects for the function of maintaining intestinal flora balance. In recent years, some studies have reported that Duox is involved in regulating the production of ROS and plays an important role in defending against the intestinal pathogen infection. However, the molecular mechanism has not been fully illuminated. In this study, a duox 2 involved in the production of H 2 O 2 was identified for the first time in P. clarkii. Mature Pc-Duox 2 is a 7-transmembrane protein molecule that includes PHD, FAD, and NAD domains. Pc-duox 2 was mainly expressed in hemocytes and intestinal tissue. Its expression levels were obviously upregulated after intramuscular or oral infection with V. harveyi. In the RNAi assay, the upregulated trends of H 2 O 2 and total ROS levels in crayfish intestine were significantly suppressed when Pc-duox 2 was knocked down. Compared with the slightly affected SOD activity, the upregulated CAT activity was suppressed more obviously in the crayfish intestine. Furthermore, Pc-duox 2 had an important effect on the maintenance of the structural stability of crayfish the intestine. Further research revealed that the knockdown of Pc-duox 2 could cause an obvious suppression in the upregulated levels of Toll signalling pathway-related genes, including Pc-toll 1, Pc-toll 3, Pc-dorsal, Pc-ALF 5, Pc-crustin 1, and Pc-lysozyme. Ultimately, these changes triggered the accelerated death of crayfish. Overall, we speculated that Pc-duox 2 played an important role in antibacterial innate immunity in the crayfish intestine by regulating the total ROS level., (Copyright © 2023 Elsevier Ltd. All rights reserved.) more...

Background: Microglia activation and oligodendrocyte maturation are critical for remyelination after cerebral ischemia. Studies have shown that enriched environment (EE) can effectively alleviate stroke-induced neurological deficits. However, little is known about the mechanism associated with glial cells underlying the neuroprotection of EE. Therefore, this study focuses on investigating the effect of EE on activated microglia polarization as well as oligodendrogenesis in the progress of remyelination following cerebral ischemia., Methods: The ischemia/reperfusion (I/R) injury model was established by middle cerebral artery occlusion (MCAO) in rats. Animals executed 4 weeks of environmental intervention after performing MCAO or sham surgery and were divided into sham, MCAO, and MCAO+EE groups. Cognitive function, myelin damage, microglia activation and polarization, inflammation, oligodendrogenesis, remyelination, and protein expression of the PI3K/AKT/GSK3β signaling pathway were determined., Results: The staining of NeuN indicated that the infarct size of MCAO rats was decreased under EE. EE intervention improved animal performance in the Morris water maze test and novel object recognition test, promoting the recovery of cognitive function after I/R injury. EE treatment alleviated myelin damage in MCAO rats, as evidenced by the lower fluorescence intensity ratio of SMI-32/MBP in MCAO+EE group. EE increased the fluorescence intensity ratio of NG2 + /Ki67 + /Olig2 + , MBP, and MOG, enhancing the proliferation and differentiation of OPCs and oligodendrogenesis after MCAO. In terms of remyelination, more myelinated axons and lower G/ratio were detected in MCAO+EE rats compared with MCAO group. Moreover, EE treatment decreased the number of Iba1 + /CD86 + M1 microglia, increased the number of Iba1 + /CD206 + M2 microglia, and suppressed the inflammation response after I/R injury, which could be attributed to the augmented expression of PI3K/AKT/GSK3β axis., Conclusion: EE improved long‑term recovery of cognitive function after cerebral I/R injury, at least in part by promoting M2 microglia transformation through activation of the PI3K/AKT/GSK3β signaling pathway, inhibiting inflammation to provide a favorable microenvironment for oligodendrocyte maturation and remyelination. The effect of the EE on myelin and inflammation could account for the neuroprotection provided by EE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Renal agenesis represents the most severe form of congenital anomalies of the kidney and urinary tract. Bilateral renal agenesis is almost invariably fatal at birth and has high genetic heterogeneity. Here we report on a Chinese family with two pregnancies affected by a prenatal form of bilateral renal agenesis. Trio-WES was conducted to explore the underlying genetic cause and identified a novel nonsense variant (c .2621G>A: p. Trp874Ter) in the GREB1L gene. Based on previous research, pathogenic mutations in GREB1L can cause renal hypodysplasia/aplasia-3 (RHDA3) with autosomal dominant inheritance. Sanger sequencing performed on the family members revealed that the variant was vertically transmitted from the maternal grandfather through the unaffected mother to the two affected fetuses, fully demonstrating the incomplete dominance of the disease. Our study extends the mutational spectrum associated with RHDA3 and contributes to a more general understanding for the complex genetic inheritance of GREB1L., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Isolated effects of single endocrine-disrupting chemicals (EDCs) on male reproductive health have been studied extensively, but their mixture effect remains unelucidated. Previous research has suggested that consuming diet enriched in omega-3 polyunsaturated fatty acids (PUFA) might be beneficial for reproductive health, whether omega-3 PUFA could moderate the effect of EDCs mixture on semen quality remains to be explored. In this study of 155 male recruited from a reproductive health center in China, we used targeted-exposomics to simultaneously measure 55 EDCs in the urine for exposure burden. Regression analyses were restricted to highly detected EDCs (≥55%, n = 34), and those with consistently elevated risk were further screened and brought into mixture effect models (Bisphenol A, ethyl paraben, methyl paraben [MeP], benzophenone-1 [BP1], benzophenone-3, mono(3-carboxypropyl) phthalate [MCPP]). Bayesian Kernel Machine Regression (BKMR) and quantile-based g-computation (QGC) models demonstrated that co-exposure to top-ranked EDCs was related to reduced sperm total (β = -0.18, 95%CI: -0.29 - -0.07, P = 0.002) and progressive motility (β = -0.27, 95%CI: -0.43 - -0.10, P = 0.002), but not to lower semen volume. BP1, MeP and MCPP were identified as the main effect driver for deteriorated sperm motion parameters using mixture model analyses. Seminal plasma fatty acid profiling showed that high omega-3 PUFA status, notably elevated docosapentaenoic acid (DPA, C22:5n-3) status, moderated the association between MCPP and sperm motion parameters (total motility: β = 0.26, 95%CI: 0.01 - -0.51, P interaction  = 0.047; progressive motility: β = 0.64, 95%CI: 0.23 - 1.05, P interaction  = 0.003). Co-exposure to a range of EDCs is mainly associated with deteriorated sperm quality, but to a lesser extent on sperm quantity, high seminal plasma DPA status might be protective against the effect. Our work emphasizes the importance of exposomic approach to assess chemical exposures and highlighted a new possible intervention target for mitigating the potential adverse effect of EDCs on semen quality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.) more...

Background: Spread of SARS-CoV-2 led to a global pandemic, and there remains unmet medical needs in the treatment of Omicron infections. VV116, an oral antiviral agent that has potent activity against SARS-CoV-2, was compared with a placebo in this phase 3 study to investigate its efficacy and safety in patients with mild-to-moderate COVID-19., Methods: This multicentre, double-blind, phase 3, randomised controlled study enrolled adults in hospitals for infectious diseases and tertiary general hospitals in China. Eligible patients were randomly assigned in a 1:1 ratio using permuted block randomisation to receive oral VV116 (0·6 g every 12 h on day 1 and 0·3 g every 12 h on days 2-5) or oral placebo (on the same schedule as VV116) for 5 days. Randomisation stratification factors included SARS-CoV-2 vaccination status and the presence of high-risk factors for progression to severe COVID-19. Inclusion criteria were a positive SARS-CoV-2 test, an initial onset of COVID-19 symptoms 3 days or less before the first study dose, and a score of 2 or more for any target COVID-19-related symptoms in the 24 h before the first dose. Patients who had severe or critical COVID-19 or who had taken any antiviral drugs were excluded from the study. The primary endpoint was the time to clinical symptom resolution for 2 consecutive days. Efficacy analyses were performed on a modified intention-to-treat population, comprising all patients who received at least one dose of VV116 or placebo, tested positive for SARS-CoV-2 nucleic acid, and did not test positive for influenza virus before the first dose. Safety analyses were done on all participants who received at least one dose of VV116 or placebo. This study was registered with ClinicalTrials.gov, NCT05582629, and has been completed., Findings: A total of 1369 patients were randomly assigned to treatment groups and 1347 received either VV116 (n=674) or placebo (n=673). At the interim analysis, VV116 was superior to placebo in reducing the time to sustained clinical symptom resolution among 1229 patients (hazard ratio [HR] 1·21, 95% CI 1·04-1·40; p=0·0023). At the final analysis, a substantial reduction in time to sustained clinical symptom resolution was observed for VV116 compared with placebo among 1296 patients (HR 1·17, 95% CI 1·04-1·33; p=0·0009), consistent with the interim analysis. The incidence of adverse events was similar between groups (242 [35·9%] of 674 patients vs 283 [42·1%] of 673 patients)., Interpretation: Among patients with mild-to-moderate COVID-19, VV116 significantly reduced the time to sustained clinical symptom resolution compared with placebo, with no observed safety concerns., Funding: Shanghai Vinnerna Biosciences, Shanghai Science and Technology Commission, and the National Key Research and Development Program of China., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests JM, BX, and KZ are employees of Shanghai Junshi Biosciences. Shanghai JunTop Biosciences is an affiliated company of Shanghai Junshi Biosciences; Shanghai Vinnerna Biosciences, the sponsor of this study, is the subsidiary of Shanghai JunTop Biosciences and Vigonvita Life Sciences. All aspects of this study were done by Shanghai Junshi Biosciences. The remaining authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.) more...

Cancer, as a prevalent cause of mortality, poses a substantial global health burden and hinders efforts to enhance life expectancy. Nevertheless, the prognosis of patients with malignant tumors remains discouraging, owing to the lack of specific diagnostic and therapeutic targets. Therefore, the development of early diagnostic indicators and novel therapeutic drugs for the prevention and treatment of cancer is essential. Transmembrane proteins (TMEMs) are a class of proteins that can span the phospholipid bilayer and are stably anchored. They are associated with fibrotic diseases, neurodegenerative diseases, autoimmune diseases, developmental disorders, and cancer. It has been found that the expression levels of TMEMs were elevated or reduced in cancer cells, exerting pro/anticancer effects. These aberrant expression levels have also been linked to the prognostic and clinicopathological features of diverse tumors. In this review, the structures, functions, and roles of TMEMs in cancer were discussed, and the scientific perspectives were described. This review also explored the potential of TMEMs as tumor drug candidates from the perspective of targeted therapies, and the challenges that need to be overcome in a wide range of preclinical and clinical anticancer research were summarized., Competing Interests: Declaration of competing interest None. There are no conflicts of interest among all authors., (Copyright © 2023 Elsevier B.V. All rights reserved.) more...

Immune dysfunction is one of the leading causes of death of sepsis. How to regulate host immune functions to improve prognoses of septic patients has always been a clinical focus. Here we elaborate on the efficacy and potential mechanism of a classical drug, thymopentin (TP5). TP5 could decrease peritoneal bacterial load, and reduce inflammatory cytokine levels both in the peritoneal lavage fluid (PLF) and serum, alleviate pathological injuries in tissue and organ, coaxed by cecal ligation and perforation (CLP) in mice, ultimately improve the prognosis of septic mice. Regarding the mechanism, using RNA-seq and flow cytometry, we found that TP5 induced peptidoglycan recognition protein 1 (PGLYRP1) expression, increased phagocytosis and restored TNF-α expression of small peritoneal macrophage (SPM) in the septic mice. This may be increased SPM's ability to clear peritoneal bacteria, thereby attenuates the inflammatory response both in the peritoneal cavity and the serum. It was shown that TP5 plays a key role in restoring the function of peritoneal macrophages to alleviate the sepsis process. We reckon that this is closely relevant to SPM phagocytosis, which might involve increased PGLYRP1 expression and restored TNF-α secretion., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.) more...

It is well known that aortic dissection (AD) is a very aggressive class of vascular diseases. S-adenosylmethionine (SAM) is an autophagy inhibitor with anti-inflammatory and anti-oxidative stress effects; however, the role of SAM in AD is unknown. In this study, we constructed an animal model of AD using subcutaneous minipump continuous infusion of AngII-induced ApoE-/-mice and a cytopathic model using AngII-induced primary vascular smooth muscle cells (VSMCs) to investigate the possible role of SAM in AD. The results showed that mice in the AngII + SAM group had significantly lower AD incidence, significantly prolonged survival, and reduced vascular elastic fiber disruption compared with mice in the AngII group. In addition, SAM significantly inhibited autophagy in vivo and in vitro. Meanwhile, SAM also inhibited the cellular phenotypic switch, mainly by up regulating the expression levels of contractile marker proteins [α-smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α)] and down regulating the expression levels of synthetic marker proteins [osteoblast protein (OPN), matrix metalloproteinase-2 (MMP2), and matrix metalloproteinase-9 (MMP9)]. Molecularly, SAM inhibited AD formation mainly by activating the PI3K/AKT/mTOR signaling pathway. Using a PI3K inhibitor (LY294002) significantly reversed the protective effect of SAM in AngII-induced mice and VSMCs.Our study demonstrates the protective effect of SAM on mice under AngII-induced AD for the first time. SAM prevented AD formation mainly by inhibiting cellular phenotypic switch and autophagy, and activation of the PI3K/AKT/mTOR signaling pathway is a possible molecular mechanism. Thus, SAM may be a novel strategy for the treatment of AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Evidence has demonstrated that oxidative stress plays a crucial role in regulating cellular glucose metabolism. In previous studies, wheat germ peptide (WGP) was found to effectively mitigate oxidative stress induced by high glucose. Based on the information provided, we hypothesized that WGP could exhibit antihyperglycemic and anti-insulin-resistant effects in cells. The insulin-resistant cell model was established by insulin stimulation. The glucose consumption, glycogen content, and the activities of hexokinase and pyruvate kinase following WGP treatment were measured. The protein expression of SOCS3, phosphorylated insulin receptor substrate-1 (p-IRS1), IRS1, phosphorylated protein kinase B (p-Akt), Akt, glucose transporter 2 (GLUT2), phosphorylated GSK 3β, GSK 3β, FOXO1, G6P, and phosphoenolpyruvate carboxykinase were assessed by western blot analysis. Our results demonstrated that WGP treatment increased cellular glucose consumption and glycogen synthesis and enhanced hexokinase and pyruvate kinase activities. Additionally, WGP treatment was observed to cause a significant reduction in the expression of SOCS3, FOXO1, G6P, and phosphoenolpyruvate carboxykinase, as well as in the ratio of p-IRS1/IRS1. Conversely, the expression of GLUT2 and the ratios of p-Akt/Akt and p-GSK3β/GSK3β were upregulated by WGP. These findings suggested that WGP can activate the SOCS3/IRS1/Akt signaling pathway, thus promoting the phosphorylation of GSK-3β and increasing the expression of FOXO1 and GLUT2, which contribute to enhancing glycogen synthesis, inhibiting gluconeogenesis, and promoting glucose transport in insulin-resistant HepG2 cells., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.) more...