BHAFT: Bayesian heredity-constrained accelerated failure time models for detecting gene-environment interactions in survival analysis.

In addition to considering the main effects, understanding gene-environment (G × E) interactions is imperative for determining the etiology of diseases and the factors that affect their prognosis. In the existing statistical framework for censored survival outcomes, there are several challenges in detecting G × E interactions, such as handling high-dimensional omics data, diverse environmental factors, and algorithmic complications in survival analysis. The effect heredity principle has widely been used in studies involving interaction identification because it incorporates the dependence of the main and interaction effects. However, Bayesian survival models that incorporate the assumption of this principle have not been developed. Therefore, we propose Bayesian heredity-constrained accelerated failure time (BHAFT) models for identifying main and interaction (M-I) effects with novel spike-and-slab or regularized horseshoe priors to incorporate the assumption of effect heredity principle. The R package rstan was used to fit the proposed models. Extensive simulations demonstrated that BHAFT models had outperformed other existing models in terms of signal identification, coefficient estimation, and prognosis prediction. Biologically plausible G × E interactions associated with the prognosis of lung adenocarcinoma were identified using our proposed model. Notably, BHAFT models incorporating the effect heredity principle could identify both main and interaction effects, which are highly useful in exploring G × E interactions in high-dimensional survival analysis. The code and data used in our paper are available at https://github.com/SunNa-bayesian/BHAFT.

Biomimetic exosomal vesicles loaded with siRNA improves antitumor immune responses by inhibiting the secretion of tumor-derived exosome PD-L1.

Tumor-derived exosome PD-L1 exhaustsTcells and permits tumor cells to evade immune surveillance; thus, the inhibition of ExoPD-L1 secretion can significantly enhance the clinical efficacy of PD-L1 antibody. In this study, we combined exosome membrane, apoA1 and phospholipid into biomimetic exosome vesicles (apoA1-bExo) which were then incubated with cholesterol modified siRNA to generate apoA1-bExo containing siRNA (apoA1-bExo/siRNA). Thepreparedvesicleswere uniformandsphericalin size and could be loaded effectively with siRNA to protect from nuclease degradation. Compared with bExo/siRNA, apoA1-bExo/siRNA showed stronger tumor targeting, tissue permeability, intracellular accumulation efficiency and antitumor efficiency. A portion of apoA1-bExo/siRNA transport siRNA occurred through the endosome-Golgi-ER pathway similar to bExo/siRNA, but mostly occurred directly through selective uptake pathways mediated by the SR-B1 receptor. apoA1-bExo/siRNA successfully achieved silencing efficiency at the transcription and protein levels (96.78 % and 94.07 %, respectively) and reduced the secretion of ExoPD-L1 from HepG2 cells to 15.92 % of that in the PBS group, thus enhancing the killing activity of co-cultured T cells on HepG2 cells. In addition, relevant pharmacodynamic indices were positively correlated with delivery efficiency and the modification of apoA1 could significantly enhance the intracellular accumulation of siRNA, thus exhibiting stronger activity than bExo/siRNA. Moreover, in addition to curing mice of their implanted tumors, blocking ExoPD-L1 secretion in combination with αPD-1 promoted the infiltration of durable antitumor hCD8+ T cells and hCD45+ T cells into tumor in a immune system-tumor dual humanized mice.

Torreya grandis Kernel Oil Alleviates Loperamide-Induced Slow Transit Constipation via Up-Regulating the Colonic Expressions of Occludin/Claudin-1/ZO-1 and 5-HT3R/5-HT4R in BALB/c Mice.

SCOPE: Torreya grandis kernel has traditionally been used to remove intestinal parasites and increases intestinal motility. However, the effect of Torreya grandis kernel oil (TKO) on constipation has not yet been investigated. Therefore, mouse model is used to investigate the effect of TKO on slow transit constipation (STC) and its possible mechanism. METHODS AND RESULTS: The effects of TKO on intestinal motility of STC mice are evaluated by fecal weight, fecal water content, colon length, defecation test, and intestinal propulsion test. The mechanism of TKO alleviating STC is explored by detecting biochemical analysis, histological analysis, western blot, qRT-PCR, immunohistochemistry, and gut microbiota analysis. The results reveal that TKO effectively promotes defecation and intestinal motility, increases the level of endothelin-1, and restores the histopathological morphology of the colon under LOP pretreatment. The expression levels of occludin, claudin-1, and zonula occludens-1 (ZO-1) mRNA and protein are up-regulated in mice receiving TKO treatment. The colonic 5-hydroxytryptamine 3R/4R (5-HT3R/5-HT4R) expressions are also increased by TKO supplementation. Additionally, TKO rescues LOP-caused disorders of the gut microbiota. CONCLUSION: Consumption of TKO is beneficial to STC recovery, and it can alleviate LOP-induced STC by up-regulating the colonic expressions of Occludin/Claudin-1/ZO-1 and 5-HT3R/5-HT4R.

Bayesian Approaches in Exploring Gene-environment and Gene-gene Interactions: A Comprehensive Review.

Rapid advancements in high-throughput biological techniques have facilitated the generation of high-dimensional omics datasets, which have provided a solid foundation for precision medicine and prognosis prediction. Nonetheless, the problem of missing heritability persists. To solve this problem, it is essential to explain the genetic structure of disease incidence risk and prognosis by incorporating interactions. The development of the Bayesian theory has provided new approaches for developing models for interaction identification and estimation. Several Bayesian models have been developed to improve the accuracy of model and identify the main effect, gene-environment (G×E) and gene-gene (G×G) interactions. Studies based on single-nucleotide polymorphisms (SNPs) are significant for the exploration of rare and common variants. Models based on the effect heredity principle and group-based models are relatively flexible and do not require strict constraints when dealing with the hierarchical structure between the main effect and interactions (M-I). These models have a good interpretability of biological mechanisms. Machine learning-based Bayesian approaches are highly competitive in improving prediction accuracy. These models provide insights into the mechanisms underlying the occurrence and progression of complex diseases, identify more reliable biomarkers, and develop higher predictive accuracy. In this paper, we provide a comprehensive review of these Bayesian approaches.

Inulin Inhibits the Inflammatory Response through Modulating Enteric Glial Cell Function in Type 2 Diabetic Mellitus Mice by Reshaping Intestinal Flora.

Inulin, a commonly used dietary fiber supplement, is capable of modulating the gut microbiome. Chronic inflammation resulting from metabolic abnormalities and gut flora dysfunction plays a significant role in the development of type 2 diabetes mellitus (T2DM). Our research has demonstrated that inulin administration effectively reduced colonic inflammation in T2DM mice by inducing changes in the gut microbiota and increasing the concentration of butyric acid, which in turn modulated the function of enteric glial cells (EGCs). Experiments conducted on T2DM mice revealed that inulin administration led to an increase in the Bacteroidetes/Firmicutes ratio and the concentration of butyric acid in the colon. The anti-inflammatory effects of altered gastrointestinal flora and its metabolites were further confirmed through fecal microbiota transplantation. Butyric acid was found to inhibit the activation of the κB inhibitor kinase ß/nuclear factor κB pathway, regulate the expression levels of interleukin-6 and tumor necrosis factor-α, suppress the abnormal activation of EGCs, and prevent the release of inflammatory factors by EGCs. Similar results were observed in vitro experiments with butyric acid. Our findings demonstrate that inulin, by influencing the intestinal flora, modifies the activity of EGCs to effectively reduce colonic inflammation in T2DM mice.

Association between coffee and incident heart failure: A prospective cohort study from the UK Biobank.

BACKGROUND AND AIMS: The relationship between coffee consumption and heart failure (HF) incidence is inconclusive. This study aimed to explore the association between time-varying coffee consumption and incident HF using a longitudinal study design. METHODS AND RESULTS: Data were obtained from the UK Biobank, comprising 497,503 adults (age, 56.5 ± 8.1 years; 54.6% women) who were free from HF at baseline in 2006-2010. The median follow-up time for the HF incidence was 11.9 years. Marginal structural models (MSM) were employed to adjust for potential time-varying confounders and account for bias caused by loss of follow-up. Furthermore, we used a restricted cubic spline to test and describe the nonlinear relationship between coffee consumption and HF risk. At baseline, 70.5% of participants reported drinking ≥1 cups/d coffee and 2.7% participants developed HF. After adjusting for potential confounders, we identified a nonlinear J-shaped association between coffee consumption and HF risk (P < 0.001). Compared with drinking coffee <1 cups/d, 1-2 cups/d (HR = 0.878; 95% CI: 0.838-0.920), 3-4 cups/d (HR = 0.920; 95% CI: 0.869-0.974) may be associated with a reduced risk of HF, while >6 cups/d (HR = 1.209; 95% CI: 1.056-1.385) may be associated with a higher risk of HF. However, sensitive analyses stratified by gender and smoking status indicated that >6 cups/d does not significantly increase the risk of HF. Additionally, the type of coffee was found to significant impact on the incidence of HF (P < 0.05). CONCLUSION: In this large cohort of UK adults, moderate coffee consumption may reduce risk of HF incidence.

The synthesis and functionalization of metal organic frameworks and their applications for the selective separation of proteins/peptides.

Recently, proteins separation has drawn great interest for the full investigation of a proteome because the proteins separation is the precondition when conducting clinical research or proteomics research. Metal organic frameworks (MOFs) are fabricated via covalent connection between organic ligands and metal ions/clusters units. MOFs have attracted much attention due to the ultra-high specific surface area, tunable structure, more metal site or unsaturated site, and chemical stability. Over the past decade, different functionalization types of MOFs have been reported in combination with amino acids, nucleic acids, proteins, polymers, and nanoparticles for various applications. In this review, the synthesis and functionalization of MOFs have been thoroughly discussed, and we introduced the existing problems and development trends in these fields. Furthermore, MOFs as advanced adsorbents for selective separation of proteins/peptides are summarized. Additionally, we present a comprehensive prospects and challenges in the preparation of robust functional MOFs-based adsorbents and make a final outlook on their future development prospects in selective separation of proteins/peptides.

Significance of YAP1-MAML2 rearrangement and GTF2I mutation in the diagnosis and differential diagnosis of metaplastic thymoma.

BACKGROUND: Metaplastic thymoma (MT) is a very uncommon thymoma type, with biphasic differentiation as one of its histological characteristics. This histological pattern, however, can also be mistaken for type A thymoma and the A component in type AB thymoma. METHODS: Postoperative specimens were collected from five MT and four type A thymomas with a retrospective analysis involving immunohistochemistry, fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS). RESULTS: The histological morphology of the MT overlapped with that of the type A thymoma. With immunostains, the former's spindle cell components expressed vimentin and EMA, but not CD20. In MT, 3/5 cases had the nuclear expression of YAP1. The spindle cell component of the type A thymoma was found to express CD20. In all five cases of MT, FISH detection revealed YAP1-MAML2 fusion, which was not found in any type A thymoma cases. NGS sequencing confirmed YAP1-MAML2 rearrangement in all five cases of MT, and mutations in POLE and HRAS were also found in two cases, respectively. GTF2I c.74146970 T > A mutations were found in all cases of type A thymoma, and HRAS and NRAS mutations were found in two cases, but no YAP1-MAML2 rearrangement was evident. CONCLUSIONS: For the diagnosis and differential diagnosis of challenging cases, the YAP1-MAML2 rearrangement and GTF2I mutation were both significant molecular events specific to MT and type A thymoma, respectively.

Mechanism of the association between sleep quality and mortality in middle-aged and older adults: A prospective study analysis of the UK Biobank.

BACKGROUND: Although sleep quality is known to be associated with mortality, how poor sleep quality contributes to an increased risk of mortality is still unknown. We aimed to examine whether lifestyle, psychosocial and biological factors mediate the association. METHODS: 205,654 participants from UK Biobank were used for the analysis. The outcome was all-cause, cardiovascular disease (CVD) and cancer mortality by February 2022. Exposure was assessed by a sleep score consisting of five sleep behaviors at baseline. Lifestyle, psychosocial, and biological factors are regarded as potential mediators. Mediation analysis based on Cox proportional hazards models was performed. RESULTS: Poor sleep quality was associated with a higher risk of all-cause (Hazard Ratio [HR] = 1.098; 95% CI: 1.058-1.140), CVD (HR = 1.139; 95% CI: 1.045-1.243) and cancer mortality (HR = 1.095; 95% CI: 1.040-1.152). Lifestyle mediators (smoking, physical activity, sedentary, BMI and diet) could explain between 2.6% and 34.0% of the increased risk of all-cause mortality in individuals with poor sleep quality. Self-reported health, frailty, depression, and loneliness were significant psychosocial mediators of this association pathway. About one-fifth of the association can be explained by the biological role of CRP. Similar mediating patterns were observed for CVD and cancer mortality. LIMITATIONS: Both exposure and mediators were measured at baseline, so the possibility of reverse causality cannot be ruled out. CONCLUSIONS: Poor sleep quality is associated with an increased risk of death through a combination of lifestyle, psychosocial and biological pathways. Adopting healthy lifestyles and staying psychosocial well-being are cost-effective interventions to lower the risk of death.

Acupuncture for Crohn's disease: a protocol for systematic review and meta-analysis.

INTRODUCTION: Crohn's disease (CD) is a chronic inflammatory bowel disease that seriously affects the quality of life. While conventional medicines are of limitations, acupuncture has been shown to be a promising therapy. While no systematic review related has been published, the present study aimed to evaluate the efficacy and safety of acupuncture for CD. METHODS AND ANALYSIS: PubMed, the Cochrane Central Register of Controlled Trials and Chinese electronic databases, including China National Knowledge Infrastructure, Wan Fang database, VIP, SinoMed and the Chinese Clinical Trial Registry, will be searched from the establishment of the database until 31 December 2022. Randomised controlled trials evaluating the efficacy and safety of acupuncture/electroacupuncture on patients with CD, controlled by conventional therapies, were included. Outcomes include induction of clinical remission and response, maintenance of remission, and the incidence of adverse events. All articles will be screened and extracted by two reviewers independently. The risk of bias will be evaluated using the revised Cochrane Risk of Bias 2 tool. A fixed effect model or a random effects model will be used based on the assessment of heterogeneity. A subgroup analysis and sensitivity analysis will be carried out if necessary. Publication bias will be analysed, and the strength of the body of evidence for primary outcomes will be graded. ETHICS AND DISSEMINATION: There is no necessity for this study to acquire ethical approval, and this review will be disseminated in a peer-reviewed journal or conference presentation. TRIAL REGISTRATION NUMBER: CRD42022356967.

DIA-MS Based Proteomics Combined with RNA-Seq Data to Unveil the Mitochondrial Dysfunction in Human Glioblastoma.

Mitochondrial dysfunctions underlie the pathogenesis in glioblastoma multiforme (GBM). Comprehensive proteomic profiling of mitochondria-specific changes in human GBM is still insufficient. This study carried out a DIA-MS based proteomic analysis on the mitochondria isolated from human primary GBM and peritumoral tissue (as paired control), and further compared those findings with the transcriptomic datasets. A total of 538 mitochondrion-specific proteins were rigorously confirmed, among which 190 differentially expressed proteins were identified. Co-regulations of the mitochondrial dysfunction pathway networks were observed, including significant up-regulations of mitochondrial translation and apoptosis, as well as down-regulations of OXPHOS and mitochondrial dynamics. Proteins related to FA, AA metabolism and ROS also showed significant variations. Most of these alterations were consistent in trend when compared the proteomics findings with the RNA-Seq datasets, while the changes at protein levels appeared to be more dramatic. Potentially key proteins in GBM were identified, including up-regulated pro-apoptotic protein CASP3, BAX, fatty acid oxidation enzymes CPT1A, CPT2, ACADM, serine-glycine enzymes SHMT2, GATM, ROS-related protein SOD2, GPX1, and CAT; and down-regulated dynamin-related protein MFN1, MFN2, OPA1, and OXPHOS components; and also several differentially expressed ALDH isoforms. This study systematically profiled the mitochondrial dysfunctions by combining proteomic findings and mRNA datasets, which would be a valuable resource to the community for further thorough analyses.

Novel Engineered Carbon Cloth-Based Self-Cleaning Membrane for High-Efficiency Oil-Water Separation.

A novel engineered carbon cloth (CC)-based self-cleaning membrane containing a Cu:TiO2 and Ag coating has been created via hydrothermal and light deposition methods. The engineered membrane with chrysanthemum morphology has superhydrophilic and underwater superoleophilic performance. The cooperativity strategy of Cu doping and Ag coating to the TiO2 is found to be critical for engineering the separation efficiency and self-cleaning skill of the CC-based membrane under visible light due to the modulated bandgap structure and surface plasmon resonance. The CC-based membrane has excellent oil-water separation performance when Cu is fixed at 2.5 wt% and the Ag coating reaches a certain amount of 0.003 mol/L AgNO3. The contact angle of underwater oil and the separation efficiency are 156° and 99.76%, respectively. Furthermore, the membrane has such an outstanding self-cleaning ability that the above performance can be nearly completely restored after 30 min of visible light irradiation, and the separation efficiency can still reach 99.65% after 100 cycles. Notably, the membrane with exceptional wear resistance and durability can work in various oil-water mixtures and harsh environments, indicating its potential as a new platform of the industrial-level available membrane in dealing with oily wastewater.

Monounsaturated fatty acid-enriched olive oil exacerbates chronic alcohol-induced hepatic steatosis and liver injury in C57BL/6J mice.

Dietary oil composition determines the pathological processes of alcoholic fatty liver disease (AFLD). Oil rich in saturated fatty acids protects, whereas oil rich in polyunsaturated fatty acids aggravates the alcohol-induced liver injury. However, limited studies have been conducted to address how monounsaturated fatty acids (MUFAs) enriched oil controls the pathological development of AFLD. Therefore, this study was designed to evaluate the effect of MUFA-enriched extra virgin olive oil (OO) on AFLD. Twenty C57BL/6J mice were randomly allocated into four groups and fed modified Lieber-DeCarli liquid diets containing isocaloric maltose dextrin a non-alcohol or alcohol with corn oil and OO for four weeks. Dietary OO significantly exacerbated alcohol-induced liver dysfunction, evidenced by histological examinations and disturbed biochemical parameters. Dietary OO with alcohol decreased hormone-sensitive lipase (HSL), phosphorylated 5'-AMP-activated protein kinase (p-AMPK), and carnitine palmitoyltransferase-Iα (CPT1α) expression, and increased sterol regulatory element-binding protein-1c (SREBP-1c), diacylglycerol acyltransferase-2 (DGAT2), and very low-density lipoprotein receptor (VLDLR) expression in the liver. It also promoted the expression of hepatic interleukin-6 (IL-6) and hepatic tumour necrosis factor-alpha (TNF-α) at the transcriptional level. Additionally, adipose tissue lipolysis partially had an etiologic effect on alcohol-induced hepatic steatosis under OO pretreatment. In conclusion, MUFA-enriched OO exacerbated liver dysfunction in vivo. OO should be cautiously considered as a unique dietary oil source for individuals with AFLD.

Recent advances in development of functional magnetic adsorbents for selective separation of proteins/peptides.

Nowadays, proteins separation has attracted great attention in proteomics research. Because the proteins separation is helpful for making an early diagnosis of many diseases. Magnetic nanoparticles are an interesting and useful functional material, and have attracted extensive research interest during the past decades. Because of the excellent properties such as easy surface functionalization, tunable biocompatibility, high saturation magnetization etc, magnetic microspheres have been widely used in isolation of proteins/peptides. Notably, with the rapid development of surface decoration strategies, more and more functional magnetic adsorbents have been designed and fabricated to meet the growing demands of biological separation. In this review, we have collected recent information about magnetic adsorbents applications in selective separation of proteins/peptides. Furthermore, we present a comprehensive prospects and challenges in the field of protein separation relying on magnetic nanoparticles.

Metal-Polyphenol Network-Mediated Protein Encapsulation Strategy Facilitating the Separation of Proteins and Metabolites in Biospecimens.

Access to both protein and metabolite biomarker information in biospecimens from trace samples remains a significant challenge, and it is necessary to separate proteins and metabolites before analysis. In this work, the Fe3O4@SiO2@Proteins@Metal-polyphenol network (MPN) was successfully constructed and applied to separate metabolites and proteins. Tannic acid (TA) and Cu2+ were involved in the synthesis of MPN because of rapid degradation and maintaining the assay performance of proteins. There are a variety of interactions between TA and proteins, including hydrogen-bonding, hydrophobic, and ionic interactions. Moreover, benefiting from the small molecule permeability and surface adherence of MPN, proteins were encapsulated and immobilized on the surface of substrates with the growth of MPN. At the same time, endogenous metabolites remained dispersed in the supernatant. In the model sample and real biospecimen cases, the protein biomarkers (e.g., carcinoembryonic antigen and alanine aminotransferase) were encapsulated on the surface of Fe3O4@SiO2, which allowed the isolation of proteins from the original matrix, as well as release and analysis in a short time. Meanwhile, the metabolites in the produced supernatant were analyzed by LC-MS/MS. By the self-assembly and disassembly of MPN, the group differences of proteins and metabolites between physiological and pathological biospecimens are correctly characterized without multisampling. Overall, an MPN-mediated separation strategy of biomarkers was proposed, and MPN facilitated a "two birds with one stone" approach, where the proteins were encapsulated and immobilized in the precipitation while endogenous metabolites distributed in the produced supernatant, opening a new chapter in the application of MPNs.

BgNet: Classification of benign and malignant tumors with MRI multi-plane attention learning.

Objectives: To propose a deep learning-based classification framework, which can carry out patient-level benign and malignant tumors classification according to the patient's multi-plane images and clinical information. Methods: A total of 430 cases of spinal tumor, including axial and sagittal plane images by MRI, of which 297 cases for training (14072 images), and 133 cases for testing (6161 images) were included. Based on the bipartite graph and attention learning, this study proposed a multi-plane attention learning framework, BgNet, for benign and malignant tumor diagnosis. In a bipartite graph structure, the tumor area in each plane is used as the vertex of the graph, and the matching between different planes is used as the edge of the graph. The tumor areas from different plane images are spliced at the input layer. And based on the convolutional neural network ResNet and visual attention learning model Swin-Transformer, this study proposed a feature fusion model named ResNetST for combining both global and local information to extract the correlation features of multiple planes. The proposed BgNet consists of five modules including a multi-plane fusion module based on the bipartite graph, input layer fusion module, feature layer fusion module, decision layer fusion module, and output module. These modules are respectively used for multi-level fusion of patient multi-plane image data to realize the comprehensive diagnosis of benign and malignant tumors at the patient level. Results: The accuracy (ACC: 79.7%) of the proposed BgNet with multi-plane was higher than that with a single plane, and higher than or equal to the four doctors' ACC (D1: 70.7%, p=0.219; D2: 54.1%, p<0.005; D3: 79.7%, p=0.006; D4: 72.9%, p=0.178). Moreover, the diagnostic accuracy and speed of doctors can be further improved with the aid of BgNet, the ACC of D1, D2, D3, and D4 improved by 4.5%, 21.8%, 0.8%, and 3.8%, respectively. Conclusions: The proposed deep learning framework BgNet can classify benign and malignant tumors effectively, and can help doctors improve their diagnostic efficiency and accuracy. The code is available at https://github.com/research-med/BgNet.

PLEKHH2 binds ß-arrestin1 through its FERM domain, activates FAK/PI3K/AKT phosphorylation, and promotes the malignant phenotype of non-small cell lung cancer.

PLEKHH2 is an important FERM domain containing-protein. However, the role of PLEKHH2 in human solid tumors has not been reported yet. We report that PLEKHH2 showed enhanced cytoplasmic expression in non-small cell lung cancer (NSCLC). Its overexpression was positively correlated with high TNM stage, low differentiation, lymphatic node metastasis, and poor prognosis. In A549 and H1299 cells, high expression of PLEKHH2 significantly promoted cell proliferation, migration, invasion, and increased the expression of proliferation- and invasion-related proteins. It also enhanced the phosphorylation of FAK and promoted the activity of the PI3K/AKT pathway. Immunofluorescence and co-immunoprecipitation analyses were performed to elucidate the molecular mechanism underlying PLEKHH2-mediated regulation of proliferation and invasion in lung cancer cells. Upon transfection of full length PLEKHH2 or its FERM domain, we observed enhanced binding of PLEKHH2 to ß-arrestin1, whereas FAK- ß-arrestin1 binding was diminished and this led to an increase in FAK phosphorylation. PLEKHH2-mutant plasmids without the FERM domain could not effectively promote its binding to ß-arrestin1, activation of FAK phosphorylation, PI3K/AKT activation, or the malignant phenotype. Our findings suggested that PLEKHH2 is an important oncogene in NSCLC. PLEKHH2 binding to ß-arrestin1 through the FERM domain competitively inhibits ß-arrestin1 binding to FAK, which causes the dissociation of FAK from the FAK-ß-arrestin1 complex. Furthermore, the dissociation of FAK promotes its autophosphorylation, activates the PI3K/AKT signaling pathway, and subsequently promotes lung cancer cell proliferation, migration, and invasion. These results provide evidence for the potential use of PLEKHH2 inhibition as an anticancer therapy.

Dietary camellia seed oil attenuates liver injury in mice chronically exposed to alcohol.

Dietary fat composition is closely associated with the pathological development of alcoholic liver disease (ALD). Fat enriched with saturated fatty acids protects whereas with polyunsaturated fatty acids aggravates alcohol-induced liver injury. However, limited study has addressed how monounsaturated fatty acids (MUFAs) determines the pathological process of ALD. Our study was conducted to evaluate the effect of MUFAs-enriched-camellia seed oil (CSO) on alcohol-induced liver injury. The ALD model was established by feeding C57BL/6 mice with Lieber-DeCarli diet, and with either CSO or polyunsaturated fatty acids (PUFAs)-enriched-corn oil (CO) as fat source. After 4-week-intervention, CSO-feed rescued alcohol-induced liver injury compared to CO-feed, evidenced by measurements of plasma ALT activity, H&E stain, and hepatic cleaved-Caspase-3 expression. Besides, CSO-feed alleviated alcohol-induced oxidative stress, associated with NRF2 and Hif-1α expressions improvement. The reduction of F4/80 immunostaining and the decreased expressions of hepatic TNF-α and IL-6 suggested CSO-feed improved alcohol-induced inflammation. The mechanistic analysis showed that the inhibition of ASK1 and MAPKs might contribute to CSO-protected liver injury. Notably, we observed CSO-feed relieved the gut microbiota disturbance with the decreased Firmicutes and Turicibater, and the increased Bacteroidota, Alloprevotella, and Bacteroides, and reduced circulatory endotoxin level and lipolysis of adipose tissue, which are the known pathogenic factors in alcohol-induced liver injury. Unexpectedly, CSO induced more hepatic steatosis than CO-feed. In conclusion, CSO attenuated chronic alcohol consumption-induced liver injury but enhanced hepatic steatosis. CSO could be a potential dietary choice for alcoholic individuals with liver injury.

Association between the visceral adiposity index and risks of all-cause and cause-specific mortalities in a large cohort: Findings from the UK biobank.

BACKGROUND AND AIMS: The visceral adiposity index (VAI) has been recently established as a measure of visceral fat distribution and is shown to be associated with a wide range of adverse health events. However, the precise associations between the VAI score and all-cause and cause-specific mortalities in the general population remain undetermined. METHODS AND RESULTS: In this large-scale prospective epidemiological study, 357,457 participants (aged 38-73 years) were selected from the UK Biobank. We used Cox competing risk regression models to estimate the association between the VAI score and all-cause, cardiovascular disease (CVD), cancer, and other mortalities. The VAI score was significantly correlated with an increased risk of all-cause mortality (hazard ratio [HR], 1.200; 95% confidence interval [CI], 1.148-1.255; P < 0.0001), cancer mortality (HR, 1.224; 95% CI, 1.150-1.303; P < 0.0001), CVD mortality (HR, 1.459; 95% CI, 1.148-1.255; P < 0.0001), and other mortalities (HR, 1.200; 95% CI, 1.148-1.255; P < 0.0001) after adjusting for a series of confounders. In addition, the subgroup analyses showed that HRs were significantly higher in participants who were male, aged below 65 years, and body mass index less than 25. CONCLUSION: In summary, VAI was positively associated with an increased risk of all-cause and cause-specific mortalities in a nationwide, well-characterised population identified in a UK Biobank. The VAI score might be a complementary traditional predictive indicator for evaluating the risk of adverse health events in the population of Western adults aged 38 years and older.

Zizhu Ointment Accelerates Wound-Healing of Diabetic Ulcers through Promoting M2 Macrophage Polarization via Downregulating the Notch4 Signaling Pathway.

Objective: The long-term clinical practice shows that Zizhu ointment (ZZO) is an empirical formula for the treatment of diabetic ulcers (DUs). In this study, we investigated the underlying mechanism of ZZO in the treatment of DU mice. Methods: Through streptozotocin induction and high-fat diet, a DU mouse model was established and ZZO was given for treatment. The activation of Notch4 signaling was examined by immunofluorescence staining, RT-PCR, as well as Western blotting. Flow cytometry was performed to detect the counts of F4/80+ cells, M1 and M2 macrophages, as well as the expression of CD11c, CD206, etc. The role of Notch4 in wound healing in diabetic mice was verified by Notch4 inhibitors and agonists. Results: Accelerated wound healing and decreased expression levels of Notch4 and its target genes and ligands were observed in diabetic mice treated with ZZO. ZZO promoted M2 macrophage polarization, downregulated the expression of proinflammatory factors, and upregulated the levels of anti-inflammatory factors. The same tendency was observed in diabetic mice after treatment with Notch4 inhibitors. Knockout of Notch4 accelerated the wound healing rate as well. Conclusions: ZZO accelerates wound healing of diabetic mice through inhibiting the activation of Notch4 signaling, promoting M2 macrophage polarization, and alleviating inflammation.