Single-cell Profiling of Intrahepatic Immune Cells Reveals an Expansion of Tissue-resident Cytotoxic CD4+ T Lymphocyte Subset Associated With Pathogenesis of Alcoholic-associated Liver Diseases.

BACKGROUND & AIMS: The immunological mechanisms underpinning the pathogenesis of alcoholic-associated liver disease (ALD) remain incompletely elucidated. This study aims to explore the transcriptomic profiles of hepatic immune cells in ALD compared with healthy individuals and those with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: We utilized single-cell RNA sequencing to analyze liver samples from healthy subjects and patients with MASLD and ALD, focusing on the immune cell landscapes within the liver. Key alterations in immune cell subsets were further validated using liver biopsy samples from additional patient cohorts. RESULTS: We observed a significant accumulation of CD4+ T cells in livers of patients with ALD, surpassing the prevalence of CD8+ T cells, in contrast to patients with MASLD and healthy counterparts, whereas natural killer (NK) cells and γδT cells exhibited reduced intrahepatic infiltration. In-depth transcriptional and developmental trajectory analyses unveiled that a distinct CD4+ subset characterized by granzyme K (GZMK) expression, displaying a tissue-resident signature and terminal effector state, prominently enriched among CD4+ T cells infiltrating the livers of patients with ALD. Subsequent examination of an independent ALD patient cohort corroborated the substantial enrichment of GZMK+CD4+ T lymphocytes, primarily within liver fibrotic zones, suggesting their potential involvement in disease progression. Additionally, we noted shifts in myeloid populations, with expanded APOE+ macrophage and FCGR3B+ monocyte subsets in ALD samples relative to MASLD and healthy tissues. CONCLUSIONS: In summary, this study unravels the intricate cellular diversity within hepatic immune cell populations, highlighting the pivotal immune pathogenic role of the GZMK+CD4+ T lymphocyte subset in ALD pathogenesis.

Causal inference and mechanism for unraveling the removal of four pesticides from lettuce (Lactuca sativa L.) via ultrasonic processing and various immersion solutions.

This study explores the reduction of carbamates (CAs) and pyrethroids (PYs) - commonly used pesticides - in lettuce using various immersion solutions and ultrasonic processing. It also examines the role of machine learning and molecular docking in understanding the mechanisms of pesticide reduction. The results revealed that the highest reduction of both CAs and PYs exceeded 80 % on lettuce leaves. In most samples, the reduction increased with the power of ultrasonic processing and processing time. The results of machine learning models (XGBoost and SHAP) showed that during the immersion cleaning of CAs and PYs, as well as during both immersion cleaning and ultrasonic processing of CAs + PYs, the reduction was most influenced by the initial pesticide levels and immersion time. Gas Chromatography-Mass Spectrometry (GC-MS) analysis of lettuce's wax layer identified 24 compounds, including fatty alcohols, fatty acids, fatty acid esters, and triterpenoids. Despite the absence of active sites, the lipophilic nature of long-chain aliphatic compounds aids in pesticide binding, while triterpenoids form strong hydrogen bonds with pesticides, indicating a robust adsorption on the lettuce surface. This study aims to offer insights into the efficient removal of chemical pesticide residues from fruits and vegetables, addressing critical concerns for food safety and human health.

Construction and Identification of a Human Colorectal Adenoma Epithelial Cell Line by SV40 Large T-Antigen Transfection.

BACKGROUND: Colorectal adenoma represents the critical step in the development of colorectal cancer. The establishment of an immortalized epithelial cell line of colorectal adenoma of human origin would provide a tool for studying the mechanism of precancerous lesions, screening the efficacy of novel drugs, and constructing in vivo disease models. Currently, there is no commercially available stable supply of epithelial cells from precancerous lesions. AIMS: This study aimed to establish a natural LHPP low-expressing precancerous epithelial cell line by SV40-LT antigen gene transfection. METHODS: Simian vacuolating virus 40(SV40), SV40-LT overexpressed lentivirus vector, was transfected into primary human colorectal adenomatous polyp epithelial cells. The transfected cells were screened, and the screened cells were amplified to obtain the epithelial cell line: IHCRA- CELL. The cells were identified by morphological observation, cell proliferation, Quantitative real-time PCR (qPCR), and Short Tandem Repeats (STR) experiments. Morphologically, the cells showed epithelial-like characteristics, such as polygon shape, desmosomes mitochondria, and strong positive keratin staining. There was no significant difference between the transfected cells and the primary cells. Through the STR identification experiment, no matching cell lines were found in the cell lines retrieval. CONCLUSION: We successfully established a natural LHPP low-expressing precancerous epithelial cell line by SV40-LT antigen gene transfection, which has been patented and is now preserved in the Chinese Typical Culture Preservation Center. It was verified that the transformed cells maintained the phenotype and biological characteristics of epithelial cells. This cell line can be used to study the mechanism of precancerous lesions, screen the efficacy of novel drugs, and construct in vivo disease models.

Optimization of polydimethylsiloxane (PDMS) surface chemical modification and formulation for improved T cell activation and expansion.

Adoptive T cell therapy has undergone remarkable advancements in recent decades; nevertheless, the rapid and effective ex vivo expansion of tumor-reactive T cells remains a formidable challenge, limiting their clinical application. Artificial antigen-presenting substrates represent a promising avenue for enhancing the efficiency of adoptive immunotherapy and fostering T cell expansion. These substrates offer significant potential by providing flexibility and modularity in the design of tailored stimulatory environments. Polydimethylsiloxane (PDMS) silicone elastomer stands as a widely utilized biomaterial for exploring the varying sensitivity of T cell activation to substrate properties. This paper explores the optimization of PDMS surface modification and formulation to create customized stimulatory surfaces with the goal of enhancing T cell expansion. By employing soft PDMS elastomer functionalized through silanization and activating agent, coupled with site-directed protein immobilization techniques, a novel T cell stimulatory platform is introduced, facilitating T cell activation and proliferation. Notably, our findings underscore that softer modified elastomers (Young' modulus E∼300 kPa) exhibit superior efficacy in stimulating and activating mouse CD4+ T cells compared to their stiffer counterparts (E∼3 MPa). Furthermore, softened modified PDMS substrates demonstrate enhanced capabilities in T cell expansion and Th1 differentiation, offering promising insights for the advancement of T cell-based immunotherapy.

DGPRI, a new liver fibrosis assessment index, predicts recurrence of AFP-negative hepatocellular carcinoma after hepatic resection: a single-center retrospective study.

Although patients with alpha-fetoprotein-negative hepatocellular carcinoma (AFPNHCC) have a favorable prognosis, a high risk of postoperative recurrence remains. We developed and validated a novel liver fibrosis assessment index, the direct bilirubin-gamma-glutamyl transpeptidase-to-platelet ratio (DGPRI). DGPRI was calculated for each of the 378 patients with AFPNHCC who underwent hepatic resection. The patients were divided into high- and low-score groups using the optimal cutoff value. The Lasso-Cox method was used to identify the characteristics of postoperative recurrence, followed by multivariate Cox regression analysis to determine the independent risk factors associated with recurrence. A nomogram model incorporating the DGPRI was developed and validated. High DGPRI was identified as an independent risk factor (hazard ratio = 2.086) for postoperative recurrence in patients with AFPNHCC. DGPRI exhibited better predictive ability for recurrence 1-5 years after surgery than direct bilirubin and the gamma-glutamyl transpeptidase-to-platelet ratio. The DGPRI-nomogram model demonstrated good predictive ability, with a C-index of 0.674 (95% CI 0.621-0.727). The calibration curves and clinical decision analysis demonstrated its clinical utility. The DGPRI nomogram model performed better than the TNM and BCLC staging systems for predicting recurrence-free survival. DGPRI is a novel and effective predictor of postoperative recurrence in patients with AFPNHCC and provides a superior assessment of preoperative liver fibrosis.

MiR-380 inhibits the proliferation and invasion of cholangiocarcinoma cells by silencing LIS1.

BACKGROUND: The objective of this study was to determine the role and regulatory mechanism of miR-380 in cholangiocarcinoma. METHODS: The TargetScan database and a dual-luciferase reporter assay system were used to determine if LIS1 was a target gene of miR-380. The Cell Counting Kit 8 assay, flow cytometry, and Transwell assay were used to detect the effects of miR-380 and LIS1 on the proliferation, S-phase ratio, and invasiveness of HCCC-9810/HuCCT1/QBC939 cells. Western blotting was used to determine the effect of miR-380 on MMP-2/p-AKT. Immunohistochemistry detected the regulatory effect of miR-380 on the expression of MMP-2/p-AKT/LIS1. RESULTS: Expression of miR-380 in cholangiocarcinoma was decreased but expression of LIS1 was increased. LIS1 was confirmed to be a target gene of miR-380. Transfection with miR-380 mimics inhibited the proliferation, S-phase arrest, and invasion of HCCC-9810/HuCCT1/QBC939 cells, and LIS1 reversed these inhibitory effects. miR-380 inhibitor promoted proliferation, S-phase ratio, and invasiveness of HCCC-9810/HuCCT1/QBC939 cells. si-LIS1 salvaged the promotive effect of miR-380 inhibitor. Overexpression of miR-380 inhibited expression of MMP-2/p-AKT/LIS1, but miR-380 inhibitor promoted their expression. CONCLUSION: An imbalance of miR-380 expression is closely related to cholangiocarcinoma, and overexpression of miR-380 inhibits the expression of MMP-2/p-AKT by directly targeting LIS1.

PLD2 deletion ameliorates sepsis-induced cardiomyopathy by suppressing cardiomyocyte pyroptosis via the NLRP3/caspase 1/GSDMD pathway.

OBJECTIVE: Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication. Phospholipase D2 (PLD2) is crucial in mediating inflammatory reactions and is associated with the prognosis of patients with sepsis. Whether PLD2 is involved in the pathophysiology of SICM remains unknown. This study aimed to investigate the effect of PLD2 knockout on SICM and to explore potential mechanisms. METHODS: The SICM model was established using cecal ligation and puncture in wild-type and PLD2-knockout mice and lipopolysaccharide (LPS)-induced H9C2 cardiomyocytes. Transfection with PLD2-shRNA lentivirus and a PLD2 overexpression plasmid were used to interfere with PLD2 expression in H9C2 cells. Cardiac pathological alterations, cardiac function, markers of myocardial injury, and inflammatory factors were used to evaluate the SICM model. The expression of pyroptosis-related proteins (NLRP3, cleaved caspase 1, and GSDMD-N) was assessed using western blotting, immunofluorescence, and immunohistochemistry. RESULTS: SICM mice had myocardial tissue damage, increased inflammatory response, and impaired heart function, accompanied by elevated PLD2 expression. PLD2 deletion improved cardiac histological changes, mitigated cTNI production, and enhanced the survival of the SICM mice. Compared with controls, PLD2-knockdown H9C2 exhibits a decrease in inflammatory markers and lactate dehydrogenase production, and scanning electron microscopy results suggest that pyroptosis may be involved. The overexpression of PLD2 increased the expression of NLRP3 in cardiomyocytes. In addition, PLD2 deletion decreased the expression of pyroptosis-related proteins in SICM mice and LPS-induced H9C2 cells. CONCLUSION: PLD2 deletion is involved in SICM pathogenesis and is associated with the inhibition of the myocardial inflammatory response and pyroptosis through the NLRP3/caspase 1/GSDMD pathway.

Postoperative adjuvant chemotherapy is important for improving long-term survival in patients with colorectal cancer liver metastases undergoing simultaneous resection.

BACKGROUND AND AIM: A growing number of studies have demonstrated that neoadjuvant chemotherapy can improve the prognosis of patients with resectable colorectal liver metastases (CRLM). However, the routine use of postoperative adjuvant chemotherapy (POAC) for patients with CRLM after simultaneous resection remains controversial. This retrospective study investigated the impact of POAC on outcomes in patients with CRLM who underwent simultaneous resection of colorectal cancer tumors and liver metastases using propensity score matching (PSM) analysis. METHODS: From January 2009 to November 2020, patients with CRLM who underwent simultaneous resection were retrospectively enrolled. The confounding factors and selection bias were adjusted by 2:1 PSM. Patients were stratified into the POAC and non-POAC groups. Kaplan-Meier curves were utilized to compare overall survival (OS) and progression-free survival (PFS) between the groups. Univariate and multivariate Cox regression analyses were used to identify independent clinicopathological factors before and after PSM analysis. The utility of the model was evaluated using receiver operating characteristic (ROC) and calibration curves after PSM analysis. RESULTS: In total, 478 patients with resectable CRLM were enrolled and assigned to the POAC (n = 212, 60.9%) or non-POAC group (n = 136, 39.1%). After 2:1 PSM, there was no significant bias between the groups. Kaplan-Meier survival analysis revealed a significant effect of POAC on OS (P < 0.001) but not PFS. Multivariate Cox regression analysis identified T stage (T3-T4), lymph node metastasis, radiofrequency ablation during surgery, operative time ≥ 325 min, and the receipt of postoperative adjuvant chemotherapy (hazard ratio = 0.447, 95% confidence interval = 0.312-0.638, P < 0.001) as independent prognostic factors for OS. The areas under the ROC curves for the nomogram model for predicting 1-, 3-, and 5-year survival were 0.653, 0.628, and 0.678, respectively. Subgroups analysis suggested that POAC can enhance OS in patients with resectable CRLM with either low (1-2, P < 0.001) or high clinical risk scores (3-5, P = 0.020). CONCLUSIONS: Overall, this study identified POAC as a prognostic factor to predict OS in patients with CRLM undergoing simultaneous resection.

Value of original and modified pathological scoring systems for prognostic prediction in paraffin-embedded donor kidney core biopsy.

BACKGROUND: No study has validated, compared and adapted scoring systems for prognosis prediction based on donor kidney core biopsy (CB), with less glomeruli than wedge biopsy. METHODS: A total of 185 donor kidney CB specimens were reviewed using seven scoring systems. The association between the total score, item scores, score-based grading, and allograft prognosis was investigated. In specimens with less than ten glomeruli (88/185, 47.6%), scoring systems were modified by adjusting weights of the item scores. RESULTS: The Maryland aggregate pathology index (MAPI) score-based grading and periglomerular fibrosis (PGF) associated with delayed graft function (DGF) (Grade: OR = 1.59, p < 0.001; PGF: OR = 1.06, p = 0.006). Total score, score-based grading and chronic lesion score in scoring systems associated with one-year and 3-year eGFR after transplantation. Total-score-based models had similar predictive capacities for eGFR in all scoring systems, except MAPI and Ugarte. Score of glomerulosclerosis (GS), interstitial fibrosis (IF), tubular atrophy (TA), and arteriolar hyalinosis (AH) had good eGFR predictive capacities. In specimens with less than ten glomeruli, modified scoring systems had better eGFR predictive capacities than original scoring systems. CONCLUSIONS: Scoring systems could predict allograft prognosis in paraffin-embedded CB with ten more glomeruli. A simple and pragmatic scoring system should include GS, IF, TA and AH, with weights assigned based on predictive capacity for prognosis. Replacing GS scores with tubulointerstitial scores could significantly improve the predictive capacity of eGFR. The conclusion should be further validated in frozen section.

Trametinib ameliorates aging-associated gut pathology in Drosophila females by reducing Pol III activity in intestinal stem cells.

Pharmacological therapies are promising interventions to slow down aging and reduce multimorbidity in the elderly. Studies in animal models are the first step toward translation of candidate molecules into human therapies, as they aim to elucidate the molecular pathways, cellular mechanisms, and tissue pathologies involved in the anti-aging effects. Trametinib, an allosteric inhibitor of MEK within the Ras/MAPK (Ras/Mitogen-Activated Protein Kinase) pathway and currently used as an anti-cancer treatment, emerged as a geroprotector candidate because it extended lifespan in the fruit fly Drosophila melanogaster. Here, we confirm that trametinib consistently and robustly extends female lifespan, and reduces intestinal stem cell (ISC) proliferation, tumor formation, tissue dysplasia, and barrier disruption in guts in aged flies. In contrast, pro-longevity effects of trametinib are weak and inconsistent in males, and it does not influence gut homeostasis. Inhibition of the Ras/MAPK pathway specifically in ISCs is sufficient to partially recapitulate the effects of trametinib. Moreover, in ISCs, trametinib decreases the activity of the RNA polymerase III (Pol III), a conserved enzyme synthesizing transfer RNAs and other short, non-coding RNAs, and whose inhibition also extends lifespan and reduces gut pathology. Finally, we show that the pro-longevity effect of trametinib in ISCs is partially mediated by Maf1, a repressor of Pol III, suggesting a life-limiting Ras/MAPK-Maf1-Pol III axis in these cells. The mechanism of action described in this work paves the way for further studies on the anti-aging effects of trametinib in mammals and shows its potential for clinical application in humans.

Identification and prediction of molecular subtypes of atherosclerosis based on m6A immune cell infiltration.

BACKGROUND: Atherosclerosis is a complex disease with multiple molecular subtypes that are not yet fully understood. Recent studies have suggested that N6-methyladenosine (m6A) alterations may play a role in the pathogenesis of atherosclerosis. However, the relationship between m6A regulators and atherosclerosis remains unclear. METHODS: In this study, we analyzed the expression levels of 25 m6A regulators in a cohort of atherosclerosis (AS) and non-AS patients using the R "limma" package. We also used machine learning models, including random forest (RF), support vector machine (SVM), generalized linear model (GLM), and extreme gradient boosting (XGB), to predict the molecular subtypes of atherosclerosis based on m6A immune cell infiltration. RESULTS: We found that METTL3, YTHDF2, IGFBP1, and IGF2BP1 were overexpressed in AS patients compared to non-AS patients, while the other significant m6A regulators showed no significant difference. Our machine learning models achieved high accuracy in predicting the molecular subtypes of atherosclerosis based on m6A immune cell infiltration. CONCLUSION: Our study suggests that m6A alterations may play a role in the pathogenesis of atherosclerosis, and that machine learning models can be used to predict molecular subtypes of atherosclerosis based on m6A immune cell infiltration. These findings may have important implications for the detection and management of atherosclerosis.

Bioinformatics analyses of infiltrating immune cell participation on pancreatic ductal adenocarcinoma progression and in vivo experiment of the therapeutic effect of Shuangshen granules.

ETHNOPHARMACOLOGICAL RELEVANCE: Shuangshen granules (SSG), a nationally patented Chinese medicinal formula, including Panax quinquefolium L., Panax notoginseng (Burkill) F. H. Chen, and Cordyceps sinensis (Berk.) Sacc., has demonstrated remarkable therapeutic effects on pancreatic cancer in clinical treatment for nearly 10 years. Previous pharmacological researches have found that its main components, including ginsenosides and cordycepin have anticancer or preventive effects on pancreatic ductal adenocarcinoma (PDAC), which may be associated with immune metabolism. However, the underlying pharmacological mechanism of SSG in the truncation effect of PDAC progression is still unclear. AIM OF THE STUDY: To comprehensively understand the infiltrating immune cells during the different stages of the PDAC development chain and search for immune-related biomarkers that could potentially serve as drug targets through bioinformatic analysis. Meanwhile, the truncation effect of SSG on PDAC progression was also investigated. MATERIALS AND METHODS: The gene expression profiles at different PDAC developmental stages, including normal pancreas, pancreatic intraepithelial neoplasia (PanIN), and PDAC, were retrieved from the GEO database. The GEO2R tool was used to identify differentially expressed genes among the three groups. Functional enrichment analysis was performed with the GSEA software and Metascape platform. The CIBERSORT algorithm evaluated immune cell infiltration in the three groups, and immune-related biomarkers were identified. Correlation analysis was employed to examine the association between immune cells and the biomarkers. One of these biomarkers was selected for immunohistochemistry validation in human samples. Lastly, the effectiveness of SSG against PDAC progression and the influence on the selected biomarker were validated in vivo. The underlying pharmacological mechanisms were also explored. RESULTS: One dataset was obtained, where the functional enrichment of DEGs primarily involved immune effector processes and cytokine production of immune cells. The differential immune cells reflected during the progression from PanIN to PDAC were B memory cells, monocytes, M2 macrophages, and activated dendritic cells. The upregulation of ACTA2 was closely associated with M2 macrophage regulation. The immunohistochemistry on human samples validated significant differences in ACTA2 expression levels as the PDAC progressed. Moreover, animal experiments revealed that the national patented drug SSG ameliorated the pathological changes, decreased the expression of ACTA2 and its functional protein α-smooth muscle actin during PDAC progression. The underlying pharmacological mechanism was related to the regulation of macrophage polarization and downregulation of TGF-ß/Smad signaling pathway. CONCLUSIONS: The immunosuppressive environment changes during the PDAC progression. ACTA2 is a potential immuned-target for drug prevention of PDAC, while SSG could be a promising drug candidate.

Leg disorders in broiler chickens: a review of current knowledge.

Ensuring improved leg health is an important prerequisite for broilers to achieve optimal production performance and welfare status. Broiler leg disease is characterized by leg muscle weakness, leg bone deformation, joint cysts, arthritis, femoral head necrosis, and other symptoms that result in lameness or paralysis. These conditions significantly affect movement, feeding and broiler growth performance. Nowadays, the high incidence of leg abnormalities in broiler chickens has become an important issue that hampers the development of broiler farming. Therefore, it is imperative to prevent leg diseases and improve the health of broiler legs. This review mainly discusses the current prevalence of broiler leg diseases and describes the risk factors, diagnosis, and prevention of leg diseases to provide a scientific basis for addressing broiler leg health problems.

Integrating network pharmacology with molecular docking for elucidation of molecular biological mechanisms of Jiedu Qingjin formula for non-small cell lung cancer.

Traditional Chinese medicine is an important part of complementary alternative medicine. Jiedu Qingjin formula (JDQJF) is an effective national invention patent for the treatment of non-small cell lung cancer (NSCLC). We investigated the molecular biological mechanisms based on network pharmacology, molecular docking, and molecular dynamics simulations. Compounds of JDQJF were screened through the TCMSP, ETCM, and literature. Targets were searched by DrugBank and predicted by SwissTargetPrediction. GEO database was applied for screening differentially expressed genes between cancerous tissues and healthy tissues of NSCLC. Subsequently, the protein-protein interaction between JDQJF and NSCLC were obtained by Cytoscape. Visual analyses were carried out to extract candidate genes, then subjected to Metascape for enrichment analyses. Finally, molecular docking was performed by AutoDock, and the best complexes were subjected to molecular dynamics simulation and binding energy calculations by MMPBSA. A total of 273 compounds, 390 targets, 3146 GO terms, and 174 KEGG pathways were obtained. Five potential compounds (quercetin, adenosine, apigenin, heptadecanoic acid, and luteolin) were notably modulated by key targets AKT1, MAPK3, and RAF1. Enrichment results included cell cycle process, growth transduction factor, immune response-activating transduction, and involved PI3K/AKT, MAPK, NF-κB and VEGF pathway. RAF1-quercetin showed the highest binding affinity (-9.1 kcal/mol), revealed stable interactions during the simulation, and the highest estimated relative binding energy of the RAF1-Heptadecanoic was -184.277 kcal/mol. This study suggested that EMT-related, inflammation-related, immune-related, and angiogenesis-related pathways may be associated with JDQJF, and involved in the advancement of NSCLC, which points out the research direction for subsequent utility mechanism validation.Communicated by Ramaswamy H. Sarma.

Polymerization force-regulated actin filament-Arp2/3 complex interaction dominates self-adaptive cell migrations.

Cells migrate by adapting their leading-edge behaviors to heterogeneous extracellular microenvironments (ECMs) during cancer invasions and immune responses. Yet it remains poorly understood how such complicated dynamic behaviors emerge from millisecond-scale assembling activities of protein molecules, which are hard to probe experimentally. To address this gap, we establish a spatiotemporal "resistance-adaptive propulsion" theory based on the interactions between Arp2/3 complexes and polymerizing actin filaments and a multiscale dynamic modeling system spanning from molecular proteins to the cell. We quantitatively find that cells can accurately self-adapt propulsive forces to overcome heterogeneous ECMs via a resistance-triggered positive feedback mechanism, dominated by polymerization-induced actin filament bending and the bending-regulated actin-Arp2/3 binding. However, for high resistance regions, resistance triggers a negative feedback, hindering branched filament assembly, which adapts cellular morphologies to circumnavigate the obstacles. Strikingly, the synergy of the two opposite feedbacks not only empowers the cell with both powerful and flexible migratory capabilities to deal with complex ECMs but also enables efficient utilization of intracellular proteins by the cell. In addition, we identify that the nature of cell migration velocity depending on ECM history stems from the inherent temporal hysteresis of cytoskeleton remodeling. We also show that directional cell migration is dictated by the competition between the local stiffness of ECMs and the local polymerizing rate of actin network caused by chemotactic cues. Our results reveal that it is the polymerization force-regulated actin filament-Arp2/3 complex binding interaction that dominates self-adaptive cell migrations in complex ECMs, and we provide a predictive theory and a spatiotemporal multiscale modeling system at the protein level.

Exploring the methylation status of CFTR and PKIA genes as potential biomarkers for lung adenocarcinoma.

BACKGROUND: One of the most prevalent cancers in the world is lung cancer, with adenocarcinoma (LUAD) making up a significant portion of cases. According to the National Cancer Institute (NCI), there are new cases and fatality rates per 100,000 individuals as follows: New instances of lung and bronchial cancer occur annually at a rate of 50.0 per 100,000 persons. The yearly death rate for men and women is 35.0 per 100,000. DNA methylation is one of the earliest discovered and widely studied epigenetic regulatory mechanisms, and its abnormality is closely related to the occurrence and development of cancer. However, the prognostic value of DNA methylation and LUAD needs to be further explored to improve the survival prediction of LUAD patients. METHODS: The transcriptome data and clinical data of LUAD were downloaded from TCGA and GEO databases, and the Illumina Human Methylation450 array (450k array) data were downloaded from the TCGA database. Firstly, the intersection of the expressed genes of the two databases is corrected, the differential analysis is performed, and the methylation data is evaluated by the MethylMix package to obtain differentially methylated genes. Independent prognostic genes were screened out using univariate and multivariate Cox regression analysis, and a methylation prognostic model was developed using univariate Cox analysis and validated with the GSE30219 dataset in the GEO database. Survival analysis between methylation high-risk and low-risk groups was performed and a methylation-based gene prognostic model was constructed. Finally, the prediction of potential drugs associated with the LUAD gene signature using Drug Sensitivity Genomics in Cancer (GDSC). RESULTS: In this study, a total of 555 samples from the TCGA database and 307 samples from GSE30219 were included, and a total of 24 differential methylation driver genes were identified. Univariate and multivariate Cox regression analyzes were used to screen out independent prognostic genes, involving 2 genes: CFTR, PKIA. Survival analysis was different between the methylation high-risk group and the low-risk group, the CFTR high methylation group and the low methylation group were poor, and the opposite was true for PKIA. CONCLUSIONS: Our study revealed that the methylation status of CFTR and PKIA can serve as potential prognostic biomarkers and therapeutic targets in lung cancer.

Cancer Nanomedicine: Emerging Strategies and Therapeutic Potentials.

Cancer continues to pose a severe threat to global health, making pursuing effective treatments more critical than ever. Traditional therapies, although pivotal in managing cancer, encounter considerable challenges, including drug resistance, poor drug solubility, and difficulties targeting tumors, specifically limiting their overall efficacy. Nanomedicine's application in cancer therapy signals a new epoch, distinguished by the improvement of the specificity, efficacy, and tolerability of cancer treatments. This review explores the mechanisms and advantages of nanoparticle-mediated drug delivery, highlighting passive and active targeting strategies. Furthermore, it explores the transformative potential of nanomedicine in tumor therapeutics, delving into its applications across various treatment modalities, including surgery, chemotherapy, immunotherapy, radiotherapy, photodynamic and photothermal therapy, gene therapy, as well as tumor diagnosis and imaging. Meanwhile, the outlook of nanomedicine in tumor therapeutics is discussed, emphasizing the need for addressing toxicity concerns, improving drug delivery strategies, enhancing carrier stability and controlled release, simplifying nano-design, and exploring novel manufacturing technologies. Overall, integrating nanomedicine in cancer treatment holds immense potential for revolutionizing cancer therapeutics and improving patient outcomes.

Effect of traditional Chinese medicine on postoperative depression of breast cancer: a systematic review and meta-analysis.

Background: Depression is one of the common complications in patients with postoperative breast cancer (BC). Conventional therapies for postoperative depression of BC always have modest treatment outcomes and undesirable side effects. Clinical practice and many studies have shown that traditional Chinese medicine (TCM) has a good effect on postoperative depression of BC. This meta-analysis aimed to assess the clinical effect of TCM as an add-on treatment for postoperative depression of BC. Methods: A systematic and thorough search was conducted on eight online electronic databases up to 20 July 2022. The control group received conventional therapies, and intervention groups received what control groups received plus TCM treatment. Review Manager 5.4.1 was used for statistical analysis. Results: Nine RCTs involved 789 participants who met the inclusion standards. The results showed the intervention group was better at decreasing the score of the Hamilton rating scale for depression (HAMD) (mean difference, MD = -4.21, 95% CI -5.54 to -2.88) and the self-rating depression scale (SDS) (MD = -12.03, 95% CI -15.94 to -8.13), improving clinical efficacy (RR = 1.25, 95% CI 1.14-1.37), increasing the levels of 5-hydroxytryptamine (5-HT) (MD = 0.27, 95% CI 0.20-0.34), dopamine (DA) (MD = 26.28, 95% CI 24.18-28.77), and norepinephrine (NE) (MD = 11.05, 95% CI 8.07-14.04), and influencing the immune index, including the levels of CD3+ (MD = 15.18, 95% CI 13.61-16.75), CD4+ (MD = 8.37, 95% CI 6.00-10.74), and CD4+/CD8+ (MD = 0.33, 95% CI 0.27-0.39). The level of CD8+ (MD = -4.04, 95% CI -11.98 to 3.99) had no obvious difference between the two groups. Conclusion: The meta-analysis stated that a therapeutic regimen involving TCM could better improve the depression status in postoperative BC.

The SGLT2 Inhibitor Canagliflozin Reduces Atherosclerosis by Enhancing Macrophage Autophagy.

It has been shown that SGLT2 suppresses atherosclerosis (AS). Recent studies indicate that autophagy widely participates in atherogenesis. This study aimed to assess the effect of canagliflozin (CAN) on atherogenesis via autophagy. Macrophages and ApoE - / - mice were used in this study. In macrophages, the results showed that CAN promoted LC3II expression and autophagosome formation. Furthermore, the cholesterol efflux assay demonstrated that CAN enhanced cholesterol efflux from macrophages via autophagy, resulting in lower lipid droplet concentrations in macrophages. The western blot revealed that CAN regulated autophagy via the AMPK/ULK1/Beclin1 signaling pathway. CAN resulted in increased macrophage autophagy in atherosclerotic plaques of ApoE - / - mice, confirming that CAN could inhibit the progression of AS via promoting macrophage autophagy. The current study found that CAN reduced the production of atherosclerotic lesions, which adds to our understanding of how SGLT2 inhibitors function to delay the progression of AS.

m6A modification-tuned sphingolipid metabolism regulates postnatal liver development in male mice.

Different organs undergo distinct transcriptional, epigenetic and physiological alterations that guarantee their functional maturation after birth. However, the roles of epitranscriptomic machineries in these processes have remained elusive. Here we demonstrate that expression of RNA methyltransferase enzymes Mettl3 and Mettl14 gradually declines during postnatal liver development in male mice. Liver-specific Mettl3 deficiency causes hepatocyte hypertrophy, liver injury and growth retardation. Transcriptomic and N6-methyl-adenosine (m6A) profiling identify the neutral sphingomyelinase, Smpd3, as a target of Mettl3. Decreased decay of Smpd3 transcripts due to Mettl3 deficiency results in sphingolipid metabolism rewiring, characterized by toxic ceramide accumulation and leading to mitochondrial damage and elevated endoplasmic reticulum stress. Pharmacological Smpd3 inhibition, Smpd3 knockdown or Sgms1 overexpression that counteracts Smpd3 can ameliorate the abnormality of Mettl3-deficent liver. Our findings demonstrate that Mettl3-N6-methyl-adenosine fine-tunes sphingolipid metabolism, highlighting the pivotal role of an epitranscriptomic machinery in coordination of organ growth and the timing of functional maturation during postnatal liver development.