Ring finger protein 31-mediated atypical ubiquitination stabilizes forkhead box P3 and thereby stimulates regulatory T-cell function.

The CD4+CD25+FOXP3+ regulatory T (Treg) cells are critical for maintaining immune tolerance in healthy individuals and are reported to restrict anti-inflammatory responses and thereby promote tumor progression, suggesting them as a target in the development of antitumor immunotherapy. Forkhead box P3 (FOXP3) is a key transcription factor governing Treg lineage differentiation and their immune-suppressive function. Here, using Treg cells, as well as HEK-293T and Jurkat T cells, we report that the stability of FOXP3 is directly and positively regulated by the E3 ubiquitin ligase ring finger protein 31 (RNF31), which catalyzes the conjugation of atypical ubiquitin chains to the FOXP3 protein. We observed that shRNA-mediated RNF31 knockdown in human Treg cells decreases FOXP3 protein levels and increases levels of interferon-γ, resulting in a Th1 helper cell-like phenotype. Human Treg cells that ectopically expressed RNF31 displayed stronger immune-suppressive capacity, suggesting that RNF31 positively regulates both FOXP3 stability and Treg cell function. Moreover, we found that RNF31 is up-regulated in Treg cells that infiltrate human gastric tumor tissues compared with their counterparts residing in peripheral and normal tissue. We also found that elevated RNF31 expression in intratumoral Treg cells is associated with poor survival of gastric cancer patients, suggesting that RNF31 supports the immune-suppressive functions of Treg cells. Our results suggest that RNF31 could be a potential therapeutic target in immunity-based interventions against human gastric cancer.

Dysregulation of microRNA-181b and TIMP3 is functionally involved in the pathogenesis of diabetic nephropathy.

This study aimed to study the roleof microRNA (miR)-181b and its target TIMP3 in the development of diabetic nephropathy (DMN) via inhibiting the apoptosis of mesangial cells. Real-time polymerase chain reaction (RT-PCR) was adopted to compare the miR-181b expression between subjects with diabetic nephropathy (DN) and normal control. In addition, luciferase assays were utilized to explore the regulatory relationship between TIMP3 and miR-181b. Real-time PCR and densitometry analysis were conducted to measure the levels of TIMP3 mRNA/protein in DMN or in cells treated by miR-181b inhibitors, miR-181b mimics, and TIMP3 siRNA. And the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was adopted to study the effect of miR-181b on cell survival and apoptosis. miR-181b expression was much higher in the DN group, and the results of computational analysis identified TIMP3 as a miR-181b target. The luciferase activity of cells transfected with wild-type TIMP3 and mutant2 TIMP3 was significantly reduced, whereas the luciferase activity of cells transfected with mutant1 TIMP3 was evidently higher. Furthermore, a negative regulatory relationship was established between TIMP3 and miR-181b expression with a correlation efficient of -0.5351. The levels of TIMP3 mRNA/protein expression were apparently increased in the DN group. In addition, the treatment of cells with miR-181b mimics and TIMP3 siRNA remarkably lowered the levels of TIMP3 mRNA/protein, whereas the transfection of cells with miR-181b inhibitors notably elevated the expression of TIMP3 mRNA/protein. miR-181b promoted the survival of cells and inhibited their apoptosis. The miR-181b expression was related to the development of DMN and could be used as a prognosis biomarker of DMN in the patients with DM.

Aquaporin 11 rs2276415 variant and progression of chronic kidney disease.

BACKGROUND: The Aquaporin 11 (AQP11) rs2276415 variant has been implicated in kidney disease in Type 2 diabetes. Association of the AQP11 variant with chronic kidney disease (CKD) beyond diabetic nephropathy is unknown, with no studies reported in the Chinese population. We explored the risk of CKD progression associated with the AQP11 rs2276415 variant in a population-based study in China. METHODS: We conducted a prospective cohort study of 620 participants with CKD (Stages 2-5 and who were not receiving dialysis) at the Nephrology Center of First Affiliated Hospital of Jiaxing University between July 2011 and December 2014 and followed up for 3 years. Incident CKD progression, defined as an increase in creatinine levels of at least 0.4 mg/dL (35 µmol/L) above baseline or maintenance dialysis initiation or transplantation, was examined by AQP11 genotypes. RESULTS: During the follow-up period, CKD progression developed in 170 individuals. Cumulative events-free survival was significantly dependent on AQP11 genotypes with an apparent gene-dose effect (log-rank P < 0.001). Adjusting for sex, age and major CKD risk factors, the A allele of AQP11 gene (GA + AA) increased the risk of CKD progression by 1.92 (95% confidence interval 1.31- 2.84). CONCLUSIONS: The AQP11 rs2276415 variant predicts CKD progression in the Chinese population, independent of traditional risk factors. Exploring the pathways mediating the association may shed light on novel therapeutic targets in the pathophysiology of CKD.

Regulation of Metabolism Across Different Subsets of T Cells in Cancer.

T cells play a critical role to defend against tumor and maintain immune homeostasis. The diverse functions of T cells require precise regulation of metabolic pathways. Recent studies reveal that metabolic changes are tightly linked to the activation and function of T cells. Given the importance of these cells in tumor progression, it is important to understand how the tumor microenvironment regulates metabolism of T cells and how the metabolic reprogramming of T cells affects tumor growth. Here, we review new findings and discuss how metabolic reprogramming of different types of T cells affects the immune response in tumors.

Adipose Tissue-Resident Regulatory T Cells.

Tissue-resident immune cells play critical roles in regulating tissue function and homeostasis. Obesity-associated visceral adipose tissue inflammation is attributed to the accumulation of M1 macrophages which produce inflammatory cytokines like TNF-α, IL-6, and expansion of effector T cells like Th1 cells, CD8+ cytotoxic T cells which produce interferon-γ to further add to the severity of inflammation in the visceral adipose tissue. Regulatory T cells have been reported to exert key roles in suppressing inflammation, thus maintaining the homeostasis of immune responses, and visceral adipose Tregs exert critical roles in defending against obesity-associated metabolic disorders. They inhibit the infiltration of effector T cells and facilitate the reconstitution of adipose tissue macrophages from M1 to M2 phenotype. What is more, they can take up lipids from the adipocytes through CD36 which is driven by PPARγ. Here we review the recent progress in adipose tissue-resident regulatory T cells (Tregs), a subpopulation of CD4+ T cells which suppress adipose tissue inflammation.

Protective effect of regular physical activity on major depressive episodes in patients with early stages of chronic kidney disease.

Previous studies have demonstrated an association between physical activity (PA) and depression in diverse population. The purpose of our study is to examine if PA within the recommended level over time is associated with major depressive episode (MDE) in patients with early stages of chronic kidney disease (CKD) in Mainland China. Patients with stages 2-5 CKD not receiving dialysis were enrolled from a nephrology outpatient clinic between May 2014 and February 2016. Based on the patterns of PA over time, all patients were divided into four groups: persistently active, from inactive to active, from active to inactive, and persistently inactive. An MDE was diagnosed by using the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition)-based the Mini International Neuropsychiatric Interview. Among 150 patients, 34 had a current MDE (22.7%) and 116 did not (77.3%). After multivariable adjustment, patients being persistently active had significantly lower odds of having an MDE (odds ratio 0.102, 95% confidence interval, 0.022-0.467, p = .003) compared with those who were persistently inactive. Additionally, patients with diabetes mellitus had significantly higher odds of having an MDE (odds ratio 4.287, 95% confidence interval, 1.473-12.483, p = .008) compared with those without diabetes mellitus. Our results suggest a protective effect of regular PA on MDE in patients with early stages of CKD in Mainland China.

Molecular Characterization of the Complete Genome of Three Basal-BR Isolates of Turnip mosaic virus Infecting Raphanus sativus in China.

Turnip mosaic virus (TuMV) infects crops of plant species in the family Brassicaceae worldwide. TuMV isolates were clustered to five lineages corresponding to basal-B, basal-BR, Asian-BR, world-B and OMs. Here, we determined the complete genome sequences of three TuMV basal-BR isolates infecting radish from Shandong and Jilin Provinces in China. Their genomes were all composed of 9833 nucleotides, excluding the 3'-terminal poly(A) tail. They contained two open reading frames (ORFs), with the large one encoding a polyprotein of 3164 amino acids and the small overlapping ORF encoding a PIPO protein of 61 amino acids, which contained the typically conserved motifs found in members of the genus Potyvirus. In pairwise comparison with 30 other TuMV genome sequences, these three isolates shared their highest identities with isolates from Eurasian countries (Germany, Italy, Turkey and China). Recombination analysis showed that the three isolates in this study had no "clear" recombination. The analyses of conserved amino acids changed between groups showed that the codons in the TuMV out group (OGp) and OMs group were the same at three codon sites (852, 1006, 1548), and the other TuMV groups (basal-B, basal-BR, Asian-BR, world-B) were different. This pattern suggests that the codon in the OMs progenitor did not change but that in the other TuMV groups the progenitor sequence did change at divergence. Genetic diversity analyses indicate that the PIPO gene was under the highest selection pressure and the selection pressure on P3N-PIPO and P3 was almost the same. It suggests that most of the selection pressure on P3 was probably imposed through P3N-PIPO.

Development and Validation of a Nomogram Model for Accurately Predicting Depression in Maintenance Hemodialysis Patients: A Multicenter Cross-Sectional Study in China.

Purpose: Depression is a major concern in maintenance hemodialysis. However, given the elusive nature of its risk factors and the redundant nature of existing assessment forms for judging depression, further research is necessary. Therefore, this study was devoted to exploring the risk factors for depression in maintenance hemodialysis patients and to developing and validating a predictive model for assessing depression in maintenance hemodialysis patients. Patients and Methods: This cross-sectional study was conducted from May 2022 to December 2022, and we recruited maintenance hemodialysis patients from a multicentre hemodialysis centre. Risk factors were identified by Lasso regression analysis and a Nomogram model was developed to predict depressed patients on maintenance hemodialysis. The predictive accuracy of the model was assessed by ROC curves, area under the ROC (AUC), consistency index (C-index), and calibration curves, and its applicability in clinical practice was evaluated using decision curves (DCA). Results: A total of 175 maintenance hemodialysis patients were included in this study, and cases were randomised into a training set of 148 and a validation set of 27 (split ratio 8.5:1.5), with a depression prevalence of 29.1%. Based on age, employment, albumin, and blood uric acid, a predictive map of depression was created, and in the training set, the nomogram had an AUC of 0.7918, a sensitivity of 61.9%, and a specificity of 89.2%. In the validation set, the nomogram had an AUC of 0.810, a sensitivity of 100%, and a specificity of 61.1%. The bootstrap-based internal validation showed a c-index of 0.792, while the calibration curve showed a strong correlation between actual and predicted depression risk. Decision curve analysis (DCA) results indicated that the predictive model was clinically useful. Conclusion: The nomogram constructed in this study can be used to identify depression conditions in vulnerable groups quickly, practically and reliably.

Development and validation of a nomogram model for accurately predicting severe fatigue in maintenance hemodialysis patients: A multicenter cross-sectional study in China.

INTRODUCTION: This study aims to analyze the risk factors for severe fatigue in maintenance hemodialysis (MHD) patients and develop a clinical prediction model to help doctors and patients prevent severe fatigue. METHODS: Multicentre MHD patients were included in this study. The objective was to investigate the risk factors for severe fatigue in MHD patients and develop a prediction model. RESULTS: A total of 243 MHD patients were included in the study, and the incidence of severe fatigue was found to be 20.99%. Using age, body mass index, total cholesterol, and albumin levels, a predictive nomogram for fatigue was constructed. In the training set, the nomogram had an area under the curve of 0.851, sensitivity of 82.86%, specificity of 81.76%, and c-index of 0.851. The nomogram was accurate in calibration and proved to be clinically useful. CONCLUSION: The nomogram developed in this study is a practical and reliable tool for quickly identifying severe fatigue in MHD patients.

Clinical and pathological features of advanced rectal cancer with submesenteric root lymph node metastasis: Meta-analysis.

BACKGROUND: Advanced rectal cancer with submesenteric lymph node metastasis is a common complication of advanced rectal cancer, which has an important impact on the treatment and prognosis of patients. AIM: To investigate the clinical and pathological characteristics of inferior mesenteric artery (IMA) root lymph node metastases in patients with rectal cancer. The findings of this study provided us with fresh medical information that assisted us in determining the appropriate treatment for these patients. METHODS: Our study searched PubMed, Google Scholar, and other databases and searched the relevant studies and reports on the risk factors of IMA root lymph node metastasis of rectal cancer published in the self-built database until December 31, 2023. After data extraction, the Newcastle-Ottawa scale was used to evaluate the quality of the included literature, and RevMan5.3 software was used for meta-analysis and heterogeneity testing. The fixed effect modules without heterogeneity were selected to combine the effect size, and the random effect modules with heterogeneity were selected to combine the effect size. The cause of heterogeneity was found through sensitivity analysis, and the data of various risk factors were combined to obtain the final effect size, odds ratio (OR) value, and 95% confidence interval (CI). Publication bias was tested by drawing funnel plots. RESULTS: A total of seven literature were included in this study. By combining the OR value of logistic multivariate regression and the 95%CI of various risk factors, we concluded that the risk factors for lymph node metastasis in the IMA region of rectal cancer were as follows: Preoperative carcinoembryonic antigen (CEA) > 5 ng/mL (OR = 0.32, 95%CI: 0.18-0.55, P < 0.05), tumor located above peritoneal reflexive (OR = 3.10, 95%CI: 1.78-5.42, P < 0.05), tumor size ≥ 5 cm (OR = 0.36, 95%CI: 0.22-0.57, P < 0.05), pathological type (mucinous adenocarcinoma/sig-ring cell carcinoma) (OR = 0.23, 95%CI: 0.13-0.41, P < 0.05), degree of tumor differentiation (low differentiation) (OR = 0.17, 95%CI: 0.10-0.31, P < 0.05), tumor stage (T3-4 stage) (OR = 0.11, 95%CI: 0.04-0.26, P < 0.05), gender and age were not risk factors for IMA root lymph node metastasis in rectal cancer (P > 0.05). CONCLUSION: Preoperative CEA level, tumor location, tumor size, tumor pathologic type, tumor differentiation, and T stage were correlated with IMA root lymph node metastasis.