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In recent years, a burgeoning body of research has revealed links between depression and the gut microbiota, leading to the therapeutic use of probiotics for stress-related disorders. In this study, we explored the potential antidepressant efficacy of a multi-strain probiotics treatment ( , , and ) in a chronic mild stress (CMS) mouse model of depression and determined its probable mechanism of action. Our findings revealed that mice subjected to CMS exhibited anxiety- and depressive-like behaviors in the sucrose preference test, elevated plus maze, and forced swim test, along with increased interferon-γ, tumor necrosis factor-α, and indoleamine 2,3-dioxygenase-1 levels in the hippocampus. Moreover, the microbiota distinctly changed from the non-stress group and was characterized by highly diverse bacterial communities associated with significant reductions in species. Probiotics attenuated CMS-induced anxiety- and depressive-like behaviors, significantly increased abundance, and reversed the CMS-induced immune changes in the hippocampus. Thus, the possible mechanism involved in the antidepressant-like activity of probiotics is correlated with species via the gut microbiota-inflammation-brain axis.

Background The Zhejiang University (ZJU) Index has emerged as a comprehensive metabolic indicator and demonstrated significant association with various diseases. The goal of this study was to investigate the potential relationship between ZJU index and kidney stones. Methods A cross-sectional study analyzed participants’ demographic, socioeconomic, and laboratory data from NHANES 2007–2018. Weighted multivariate logistic regression, restricted cubic spline (RCS) models, and stratified analysis were applied to validate the relationship between ZJU index and kidney stone. Machine learning based analysis was employed to further improve the predictive performance and identify key predictors. Results A total of 11,317 participants were enrolled in our study and 1,115 were classified as kidney stone former. Significant differences were observed between the kidney stone formers and non-kidney stone formers in variables such as gender, race, age, education, marital status, recreational activities, hypertension, diabetes mellitus and BMI. Weighted logistic regression analysis revealed a significant positive association between ZJU index and kidney stone risk (OR = 1.03, 95% CI: 1.01–1.04) after maximal adjustment for the covariates. Participants in the highest ZJU tertile faced a 74% higher odds of nephrolithiasis than those in the lowest tertile (OR = 1.74, 95% CI: 1.34–2.26). RCS analysis indicated ZJU index raise the risk of stone formation in a non-linear dose-response manner. In the stratified analysis, we observed that the positive association was maintained across most subgroups, except for individuals younger than 40 or from other race. A significant interaction between ZJU index and marital status was detected ( P interaction =0.042). Among the three machine learning models, XGBoost model exhibited the best predictive performance, with an area under the curve (AUC) of 0.638. SHAP analysis ranked ZJU index as the most influential predictor for nephrolithiasis. Conclusion Our study provided additional evidence supporting the role of ZJU index as an effective metabolic biomarker for kidney stone risk prediction. Further clinical and epidemiological study should be warranted to unveil a more precise cause-effect relationship between them.

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive and heterogeneous malignant tumor. Mast cells are one of the immune cells widely distributed in the tumor microenvironment (TME), and their immune response with various immune cells is essential in promoting or inhibiting tumor growth and metastasis. However, the role played by mast cells in HNSCC has yet to be fully clarified. We identified mast cell marker genes using single-cell RNA sequencing (scRNA-seq) from the GSE103322 of the GEO database. The HNSCC data from the TCGA databases was divided into training and validation groups. Cox regression and LASSO regression analyses were used to screen the prognostically relevant mast cell-related genes (MRGs) to construct a prognostic signature and differentiate risk groups. The receiver operating characteristic (ROC) and calibration curves were used to test the model's accuracy. We revealed the immune landscape of HNSCC by immune infiltration, immune checkpoint levels, ESTIMATE, and TIDE analyses. Drug sensitivity analyses were used to understand the sensitivity of different risk groups to drug therapy. The 14-MRGs prognostic signature classified patients into high- and low-risk groups, and the overall survival (OS) of the low-risk group was significantly higher than that of the high-risk group (p < 0.05). The areas under the ROC curves of the nomogram were 0.740, 0.737 and 0.707 at 1-, 3-, and 5-year, and they also showed better detection efficacy in the validation group than other independent predictors. The low-risk group had richer immune cell infiltration and higher immune scores. The lower TIDE score in the low-risk group demonstrates that patients in this group were less prone to have immune escape and more likely to benefit from immunotherapy. In addition, the low-risk group was more sensitive to a broader range of drugs than the high-risk group. We combined scRNA-seq data and bulk RNA-seq data to construct a 14-MRGs-based prognostic model capable of well predicting the prognosis of HNSCC patients. This model may also help identify patients who can benefit from immunotherapy.

Introduction During the last decades, the advent of flexible ureteroscopic lithotripsy has revolutionized the management of upper urinary tract stones. We designed a patented tip-bendable ureteral access sheath to facilitate stone clearance. Our current study reported our initial experience of 224 cases. Materials and methods The study is a descriptive, retrospective analysis. The initial 224 cases, operated consecutively by one surgeon during 16 months, were reviewed. The novel tip-bendable ureteral access sheath was applied in the procedure. Demographics, laboratory tests, and peri- and postoperative findings (operation duration, stone-free rate (SFR), utilization of flexible instruments and complications) were analyzed. Resutls The median age of the patients was 56 years and the mean stones size was 2.3 ± 1.3 cm. There were 63 cases of upper ureteral stone, 93cases of renal stone and 68 cases of ureteral-renal stones. The mean operative time was 69.2 ± 65.2 min. The immediate stone-free rate was 76.8% and the 1 month post-operative stone-free rate was 97.3%. Most cases(95.5%)were success in single session. Two patient experienced post-operative fever. There was no unplanned readmission. The frequency of post-operative complications was estimated at 0.89% (Clavien I). Conclusion Flexible ureteroscopic lithotripsy with tip-bendable ureteral access sheath is a safe and effective procedure, which can achieve excellent stone clearance.

BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or CDK6 significantly overcomes the resistance of luminal breast cancer cells to AKT inhibitors in vitro and in vivo. Our study reports the involvement of BRD4/FOXO3a/CDK6 axis in AKTi resistance and provides potential therapeutic strategies for treating resistant breast cancer. The molecular mechanism underlying the resistance of AKT inhibitors in breast cancer is still elusive. Here, the authors demonstrate that BRD4/FOXO3a axis upregulates CDK6 promoter activity to promote resistance to AKT inhibition in breast cancer cells and that blocking the action of CDK6 re-sensitizes resistant cancer cells to growth inhibition.

Background The association of hypertension and depression with mortality has not been fully understood. We aimed to explore the possible independent or joint association of hypertension and depression with mortality. Their interaction effects on mortality and possible mediating role were also investigated. Methods Associations of hypertension, depression, and their interaction with all-cause and cardiovascular disease (CVD) mortality were evaluated using multivariate Cox proportional hazards regression models. The mediation analysis was conducted with a Sobel test. Results A total of 35152 participants were included in the final analysis. Hypertension and depression were independently associated with increased risk of all-cause and CVD mortality. The co-existence of hypertension and depression resulted in a 1.7-fold [95% confidence interval (CI): 1.3-2.1] increase in all-cause mortality and a 2.3-fold (95% CI: 1.4-3.7) increase in CVD mortality compared to those with neither of them. Hypertension and depression showed no significant multiplicative (P for interaction, 0.587) and additive interaction (P for relative excess risk of interaction, 0.243; P for Interaction on additive scale, 0.654) on all-cause mortality, as well as on CVD mortality. Depression did not mediate the relationship between hypertension and all-cause (Z=1.704, P= 0.088) and CVD mortality (Z=1.547, P= 0.122). Hypertension did not mediate the relationship between all-cause and CVD mortality as well. Conclusion Hypertension and depression were related to all-cause and CVD mortality independently and the co-existence of them increased the risk of mortality. However, there is no interaction effect of them on mortality, and hypertension or depression did not mediate the association of each other with mortality.

Snail1, a key transcription factor of epithelial–mesenchymal transition (EMT), is subjected to ubiquitination and degradation, but the mechanism by which Snail1 is stabilized in tumours remains unclear. We identify Dub3 as a bona fide Snail1 deubiquitinase, which interacts with and stabilizes Snail1. Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis. These effects are rescued by ectopic Snail1 expression. IL-6 also stabilizes Snail1 by inducing Dub3 expression, the specific inhibitor WP1130 binds to Dub3 and inhibits the Dub3-mediating Snail1 stabilization in vitro and in vivo . Our study reveals a critical Dub3–Snail1 signalling axis in EMT and metastasis, and provides an effective therapeutic approach against breast cancer. Snail1 is a key factor controlling epithelial-to-mesenchymal transition and cancer metastasis. While the E3 ligases responsible for Snail1 ubiquitination and degradation have been defined, the deubiquitinating enzyme is unknown. Here Zhou and colleagues show that Dub3 stabilizes Snail1 by removing ubiquitin, thus impacting breast cancer cell metastasis.

Epithelial–mesenchymal transition (EMT) is a transdifferentiation programme. The mechanism underlying the epigenetic regulation of EMT remains unclear. In this study, we identified that Snail1 interacted with histone lysine‐specific demethylase 1 (LSD1). We demonstrated that the SNAG domain of Snail1 and the amine oxidase domain of LSD1 were required for their mutual interaction. Interestingly, the sequence of the SNAG domain is similar to that of the histone H3 tail, and the interaction of Snail1 with LSD1 can be blocked by LSD1 enzymatic inhibitors and a histone H3 peptide. We found that the formation of a Snail1–LSD1–CoREST ternary complex was critical for the stability and function of these proteins. The co‐expression of these molecules was found in cancer cell lines and breast tumour specimens. Furthermore, we showed that the SNAG domain of Snail1 was critical for recruiting LSD1 to its target gene promoters and resulted in suppression of cell migration and invasion. Our study suggests that the SNAG domain of Snail1 resembles a histone H3‐like structure and functions as a molecular hook for recruiting LSD1 to repress gene expression in metastasis.

Liver cirrhosis is a progressive chronic disease with high morbidity and mortality, thereby posing a major challenge to global health. Evidence suggests that thyroid dysfunction, particularly hypothyroidism, is linked to liver diseases. Hypothyroidism disrupts metabolism, immune homeostasis, and inflammatory pathways, processes central to cirrhosis pathophysiology. However, its causal role and molecular mechanisms remain unclear. The study initiated by analyzing the association between thyroid dysfunction and cirrhosis through retrospective analysis of longitudinal data obtained from the Medical Information Mart for Intensive Care clinical database. To assess genetic correlation, we applied linkage disequilibrium score regression, followed by bidirectional Mendelian randomization to explore potential causal relationships. Through transcriptome-wide association studies, we identified candidate genes, which were then prioritized using a combination of weighted gene co-expression network analysis and differential gene expression data integration. To interpret the biological relevance of these genes, we conducted functional enrichment analyses. We further explored gene function at the cellular level by leveraging single-cell RNA sequencing (scRNA) to map cell-specific expression patterns, analyze intercellular communication, and simulate gene knockouts. Finally, we performed molecular docking and phenome-wide Mendelian randomization to identify potential therapeutic compounds targeting the prioritized genes. Through a combination of observational and genetic insights, we established a causal relationship between hypothyroidism and cirrhosis, identifying hypothyroidism as a risk factor for cirrhosis. Subsequent multi-omics analyses highlighted HLA-DQA1 and CD27 as potential therapeutic targets. ScRNA revealed key roles of these molecules in macrophages and CD8 ⁺ T cells, and simulated knockouts confirmed their importance in T cell activation and lymphocyte proliferation. Finally, molecular docking analysis identified glycyrrhizic acid and levothyroxine sodium as candidate drugs targeting HLA-DQA1 and CD27, while phenome-wide Mendelian randomization analysis revealed potential adverse effects associated with these targets. This study is the first to reveal a causal relationship between hypothyroidism and cirrhosis, potentially driven by immune dysregulation mediated by HLA-DQA1 and CD27. These findings offer novel insights into disease progression and identify HLA-DQA1 and CD27 as potential therapeutic targets, with glycyrrhizic acid and levothyroxine sodium as promising candidate drugs.

Background Current evidence indicates that miR-608 is widely down-regulated in various malignant tumors including liver cancer, colon cancer, lung cancer and glioma, and acts as a tumor suppressor by inhibiting cell proliferation, invasion and migration or by promoting apoptosis. The specific biological function of miR-608 in bladder cancer is still unknown. Methods qRT-PCR and Chromogenic in Situ Hybridization (CISH) was conducted to assess the expression of miR-608 in paired BCa tissues and adjacent non-tumor bladder urothelial tissues. Bisulfite sequencing PCR was used for DNA methylation analysis. CCK-8, colony formation and flow cytometry assays were performed, and a xenograft model was studied. Immunohistochemistry staining was performed with peroxidase and DAB. The target of miR-608 was validated with a dual-luciferase reporter assay, quantitative RT-PCR, and Western blotting. Results miR-608 is frequently down-regulated in human BCa tissues. The methylation status of CpG islands is involved in the regulation of miR-608 expression. Overexpression of miR-608 inhibits the proliferation and tumorigenesis of BCa cells in vitro and in vivo. Additionally, up-regulation of miR-608 in BCa cells induces G1-phase arrest through AKT/FOXO3a signaling. In contrast, down-regulation of miR-608 promotes proliferation and cell cycle progression in BCa cells. Moreover, the expression of FLOT1 was directly inhibited by miR-608, the down-regulation of FLOT1 induced by siFLOT1 could be significantly reversed by miR-608 inhibitor. Similarly, the up-regulation of FLOT1 by FLOT1 overexpression plasmid (pFLOT1) could also reverse the suppressed cell proliferation caused by miR-608. Conclusions miR-608 is a potential tumor suppressor in BCa, and the restoration of miR-608 might be a promising therapeutic option for BCa.