BACKGROUND:Although epidemiological evidence links phthalate exposure to hyperuricemia development, the mediating role of obesity in this association remains unclear. METHODS:We performed a cross-sectional study of 9194 eligible participants from the National Health and Nutrition Examination Survey (NHANES) 2005-2018 cycles. Multivariate linear, logistic regression and restricted cubic splines were employed to assess dose-response relationships between ten phthalate metabolites (including monocarboxyoctyl phthalate (MCOP), monocarboxynonyl phthalate (MCNP), monobutyl phthalate(MBP), monoethyl phthalate(MEP), mono-isobutyl phthalate(MiBP), monobenzyl phthalate(MBzP), mono(3-carboxypropyl) phthalate (MCPP),mono(2-ethyl-5-hydroxyhexyl) phthalate(MEHHP),mono(2-ethyl-5-oxohexyl) phthalate(MEOHP), mono(2-ethyl-5-carboxypentyl) phthalate(MECPP)) and both serum uric acid/ hyperuricemia risk. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) models evaluated mixture effects, while causal mediation analysis quantified body mass index (BMI) 's mediating role. Interaction effects were examined through cross-product terms in linear regression models. RESULTS:All phthalate metabolites except MEP demonstrated positive dose-response associations with uric acid elevation and hyperuricemia. WQS and BKMR models identified significant mixture effects, MBzP being the primary contributor. BMI mediated 37.45%-62.67% of the total effect in the associations of individual phthalate metabolites and uric acid levels/hyperuricemia risk. Significant interaction was observed between BMI and MBzP. CONCLUSION:Our findings substantiate that both single and mixed phthalate metabolites exhibit significant uric acid dysregulation effects, mediated substantially through adiposity. This evidence highlights the clinical relevance of weight control strategies in phthalate-exposed populations.

BackgroundDespite advances in immunosuppressive therapies, lupus nephritis (LN) continues to be a major contributor to morbidity and mortality. The scarcity of reliable biomarkers for predicting renal outcomes further complicates clinical management. While Cordyceps is recognized for its immunomodulatory properties as a medicinal fungus, its therapeutic potential in LN remains underexplored. Moreover, it is unclear whether its molecular targets identified through screening constitute viable therapeutic interventions for this disease.MethodsNetwork pharmacology was integrated with LN-associated databases and transcriptomic analysis of GSE200306. Protein–protein interaction, Gene Ontology, and pathway-enrichment analyses were performed to identify candidate targets and biological processes. Molecular docking was used to evaluate predicted interactions between Cordyceps constituents and selected proteins. MAPK1 and CFB expression was further assessed using Nephroseq, an independent transcriptomic cohort (GSE112943), and immunohistochemistry in renal tissues from 30 patients with LN and 10 controls. A multivariable model incorporating age, sex, estimated glomerular filtration rate, MAPK1, and CFB was evaluated using receiver-operating-characteristic, calibration, and decision-curve analyses.ResultsSeven active constituents and 111 putative Cordyceps targets were identified. Intersection with 707 LN-associated genes yielded 26 candidate therapeutic targets enriched in apoptosis, inflammatory responses, complement activation, and NF-κB and PI3K–Akt signaling. Analysis of GSE200306 identified 89 differentially expressed genes, among which MAPK1 and CFB intersected with the Cordyceps–LN target network. Both genes were upregulated in LN kidneys, enriched in the tubulointerstitial compartment, inversely associated with renal function, and supported by immunohistochemistry. The combined model achieved an area under the curve of 0.954 and showed potential clinical utility. In GSE112943, MAPK1 was significantly upregulated, whereas CFB showed a concordant but nonsignificant increase. Docking suggested plausible interactions between peroxyergosterol and MAPK1/CFB but did not establish direct target engagement.ConclusionsCollectively, these findings identify MAPK1 as a reproducible candidate biomarker and CFB as a compartment-sensitive candidate biomarker in LN. Both molecules represent hypothesis-generating intervention nodes through which Cordyceps-derived constituents may act; direct target-engagement and functional studies are required before they can be considered actionable therapeutic targets.

Sepsis, a condition with substantial global morbidity and mortality, frequently leads to sepsis-associated acute kidney injury (SA-AKI). While glycemic variability (GV) correlates with adverse outcomes in critically ill populations, its prognostic value in SA-AKI remains underexplored. Using the MIMIC-IV database, this large-scale machine learning cohort study examined SA-AKI patients. Restricted cubic spline, Kaplan-Meier analysis, and Cox regression analyses were conducted to evaluate associations between GV, measured by glycemic coefficient of variation (CV) and 28- and 90-day mortality. Subgroup analyses stratified by age, sex, and diabetes status were performed. Prognostic models were developed using Cox proportional hazards (CoxPH), Least absolute shrinkage and selection operator (LASSO), and random survival forests (RSF). Among 12,268 eligible SA-AKI patients, the Boruta algorithm identified glycemic CV as a key prognostic determinant. When stratified by CV quartiles, higher CV quartiles exhibited significantly increased 28-day and 90-day mortality. Subgroup analyses revealed consistent associations except in diabetic patients, where increases in CV showed no correlation with mortality. Machine learning models exhibited strong predictive performance, with 28-day area under the curves (AUCs) of 0.822 (CoxPH), 0.822 (LASSO), and 0.845 (RSF), and 90-day AUCs of 0.819 (CoxPH), 0.820 (LASSO), and 0.837 (RSF). Elevated GV is associated with increased short- and long-term mortality in SA-AKI. Beyond prognostication, these findings position GV as a real-time, modifiable digital biomarker that may underpin a mechanistic Glycemic Oscillation-Induced Renal Injury (GO-RI) Axis. This framework supports future development of machine learning-enabled precision ICU nephrology strategies for dynamic risk stratification and phenotype-specific glycemic modulation in SA-AKI.

BACKGROUND:This study analyzed global, regional, and national trends in the burden of Type 1 diabetes mellitus (T1DM)-related chronic kidney disease (CKD) from 1990 to 2021, stratified by sociodemographic development level. METHODS:Data on T1DM-related CKD incidence, prevalence, disability-adjusted life years (DALYs), and mortality were obtained from the Global Burden of Disease, Injury, and Risk Factor Study (GBD) 2021 system. Joinpoint regression analysis, health inequalities, frontier analysis, decomposition analysis, age-period-cohort modeling, and Bayesian age-period-cohort (BAPC) modeling were applied to assess disease burden trends and their associations with the sociodemographic index (SDI). RESULTS:From 1990 to 2021, the incidence and prevalence of T1DM-related CKD increased, mortality changed little, and DALYs declined. The burden was consistently higher in men than in women. Age-standardized mortality rates (ASMR) and age-standardized DALYs rates (ASDR) were highest in middle SDI countries. Across SDI levels, absolute inequality increased whereas relative inequality decreased. Frontier analysis indicated widening effective disparities with sociodemographic development. Population aging was a major driver of the rising burden. BAPC projections suggested a future decline in both mortality and DALYs. CONCLUSION:The global burden of T1DM-related CKD increased between 1990 and 2021, with men disproportionately affected. Absolute inequality across regions rose, while relative inequality decreased. Disparities became more pronounced with higher sociodemographic development. Projections indicate that mortality and DALYs may decline by 2050.

Objective: This study aimed to elucidate the role of the IAH1 gene across multiple cancer types. Methods: Using multi-omics data from public databases including TCGA, GTEx, TIMER, and cBioPortal, we analyzed the expression patterns of IAH1 and their correlations with prognostic outcomes, immune cell infiltration, immune checkpoint markers, tumor mutational burden (TMB), microsatellite instability (MSI), response to immunotherapy, and drug sensitivity through bioinformatic tools and R software. Results: IAH1 expression was significantly upregulated in most cancers and associated with adverse prognosis. Elevated IAH1 levels correlated strongly with immune-related gene expression, immune checkpoint levels, TMB, MSI, and immune infiltration. Moreover, IAH1 expression was linked to sensitivity to anticancer drugs and survival outcomes following immune checkpoint inhibitor (ICI) treatment. Conclusions: IAH1 may serve as a promising immunoregulatory target and potential biomarker for diagnosis and prognosis in specific cancers.

BACKGROUND:Di (2-ethylhexyl) phthalate (DEHP) is a common plasticizer known to cause liver injury. Green tea is reported to exert therapeutic effects on heavy metal exposure-induced organ damage. However, limited studies have examined the therapeutic effects of green tea polyphenols (GTPs) on DEHP-induced liver damage. AIM:To evaluate the molecular mechanism underlying the therapeutic effects of GTPs on DEHP-induced liver damage. METHODS:C57BL/6J mice were divided into the following five groups: Control, model [DEHP (1500 mg/kg bodyweight)], treatment [DEHP (1500 mg/kg bodyweight) + GTP (70 mg/kg bodyweight), oil, and GTP (70 mg/kg bodyweight)] groups. After 8 wk, the liver function, blood lipid profile, and liver histopathology were examined. Differentially expressed micro RNAs (miRNAs) and mRNAs in the liver tissues were examined using high-throughput sequencing. Additionally, functional enrichment analysis and immune infiltration prediction were performed. The miRNA-mRNA regulatory axis was elucidated using the starBase database. Protein expression was evaluated using immunohistochemistry. RESULTS:GTPs alleviated DHEP-induced liver dysfunction, blood lipid dysregulation, fatty liver disease, liver fibrosis, and mitochondrial and endoplasmic reticulum lesions in mice. The infiltration of macrophages, mast cells, and natural killer cells varied between the model and treatment groups. mmu-miR-141-3p (a differentially expressed miRNA), Zcchc24 (a differentially expressed mRNA), and Zcchc24 (a differentially expressed protein) constituted the miRNA-mRNA-protein regulatory axis involved in mediating the therapeutic effects of GTPs on DEHP-induced liver damage in mice. CONCLUSION:This study demonstrated that GTPs mitigate DEHP-induced liver dysfunction, blood lipid dysregulation, fatty liver disease, and partial liver fibrosis, and regulate immune cell infiltration. Additionally, an important miRNA-mRNA-protein molecular regulatory axis involved in mediating the therapeutic effects of GTPs on DEHP-induced liver damage was elucidated.

BackgroundKidney fibrosis (KF) represents a critical pathological alteration in the end stage of chronic kidney disease (CKD) and is the ultimate cause of mortality. Lipid metabolism plays a significant role in the pathogenesis of KF. Therefore, biomarkers associated with lipid metabolism will be identified to guide the treatment and management of CKD.MethodsThree datasets obtained from the GEO database, along with 760 lipid metabolism-related genes sourced from two databases, were utilized to identify lipid metabolism-associated differentially expressed genes (LMDEGs) in KF. Subsequently, we performed GO, KEGG and ssGSEA enrichment analysis to elucidate the characteristics of LMDEGs. Then, machine learning was applied to identify core LMDEGs, Least Absolute Shrinkage and Selection Operator (LASSO) was utilized to construct a diagnostic model, and Receiver Operation Curve (ROC) was operated to evaluate the diagnostic performance. We used unsupervised hierarchical clustering to identify subtypes of KF associated with lipid metabolism and employed Gene Set Variation Analysis (GSVA) to examine differences among clusters. Finally, transcription factor and miRNA regulatory networks upstream of core LMDEGs were constructed using Cytoscape software.ResultsWe identified 54 LMDEGs and constructed a six core LMDEGs (UGCG, SFRP1A6, OSBPL6, INPP5J, PNPLA3, and GK) predictive model by LASSO regression, achieving area under the curve (AUC) values ranging from 0.723 to 0.774. ssGSEA confirmed that these six core LMDEGs exhibited significant positive or negative correlations with immune cell infiltration. Based on the expression profiles of these core LMDEGs, KF samples were categorized into three distinct subtypes. One subtype is predominantly characterized by enhanced lipid and energy metabolism, another exhibits features of inflammation and immune response activation, while the third displays an intermediate pattern between the two extremes. Moreover, the regulatory network of these core LMDEGs shared several common transcription factors, suggesting a potential interplay between lipid metabolism and immune responses in the pathogenesis of KF.ConclusionWe have identified six core LMDEGs that are significantly associated with KF. Based on this, we have established three distinct clusters related to lipid metabolism in KF, which may provide valuable insights into the treatment and management of CKD.

INTRODUCTION:Contrast-induced nephropathy (CIN) is a potential complication associated with the administration of intravenous contrast agents. The objective of this study was to evaluate the effectiveness of remote ischemic preconditioning (RIPC) and two pharmacological interventions in preventing CIN. METHODS:Randomized controlled trials (RCTs) examining the efficacy of RIPC, nicorandil, and trimetazidine in treating CIN were searched within databases such as PubMed, Cochrane Library, Embase, and Web of Science. The primary outcome was the incidence of CIN. The consistency model was used to address heterogeneity and enhance model fit. The assessment of consistency between direct and indirect evidence was conducted through the node-splitting method. Posterior probability estimates and surface under the cumulative ranking area (SUCRA) ranked interventions based on their effectiveness in preventing CIN. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework was used to grade the quality of evidence. RESULTS:Based on hydration therapy, RIPC, nicorandil, and trimetazidine all showed prophylactic effects on CIN compared to control groups. The SUCRA results showed that RIPC (SUCRA = 37.7%, PrBest = 0.4%), nicorandil (SUCRA = 91.2%, PrBest = 74.7%), and trimetazidine (SUCRA = 71.0%, PrBest = 24.9%). However, there were no significant differences between the nicorandil, RIPC, and trimetazidine groups. Subgroup analysis suggested that there was still a protective effect in populations with mean estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 or with a high prevalence of diabetes mellitus. CONCLUSIONS:Nicorandil, trimetazidine, and RIPC all showed renal protective effects. Based on hydration, nicorandil, trimetazidine, and RIPC may show better prophylaxis against CIN than hydration alone after intravenous contrast administration.

Purpose: This study aimed to examine the impact of APS on acute kidney injury induced by rhabdomyolysis (RIAKI), exploring its association with macrophage M1 polarization and elucidating the underlying mechanisms. Methods: C57BL/6J mice were randomly assigned to one of three groups: a normal control group, a RIAKI model group, and an APS treatment group. Techniques such as flow cytometry and immunofluorescence were employed to demonstrate that APS can inhibit the transition of renal macrophages to the M1 phenotype in RIAKI. Furthermore, the raw264.7 macrophage cell line was chosen and induced into the M1 phenotype to further examine the impact of APS on this model and elucidate the underlying mechanism. Results: Administration of APS led to a significant decrease in UREA levels by 25.2% and CREA levels by 60.9% within the model group. Also, APS exhibited an inhibitory effect on the infiltration of M1 macrophages and the cGAS-STING pathway in kidneys within the RIAKI, subsequently leading to decreased serum concentrations of IL-1 beta, IL-6 and TNF-alpha by 44.5%, 12.9%, and 10.3%, respectively, consistent with the results of in vitro experiments. Furthermore, APS exhibited an anti-apoptotic effect on MPC5 cells when co-cultured with M1 macrophages. Conclusion: Astragalus polysaccharide (APS) potentially mitigated rhabdomyolysis-induced renal damage by impeding the M1 polarization of macrophages. This inherent mechanism might involve the suppression of the cGAS-STING pathway activation within macrophages. Furthermore, APS could endow protective effects on podocytes through the inhibition of apoptosis.

The activation of the cGAS-STING pathway is associated with many sterile inflammatory and inflammatory conditions, including acute kidney injury. As a cytoplasmic DNA sensor, sensitization of the cGAS-STING pathway can ignite the innate immune response in vivo and trigger a series of biological effects. In recent years, there is increasing evidence showing that the cGAS-STING pathway plays a vital role in acute kidney injury, a non-inflammatory disease induced by activation of innate immune cells, and closely related to intracellular reactive oxygen species, mitochondrial DNA, and the cGAS-STING pathway. This review provides a prospect of the cGAS-STING pathway and its relationship to acute kidney injury.

Introduction: Di(2-ethylhexyl) phthalate (DEHP) is a common plasticizer. Studies have revealed that DEHP exposure can cause kidney damage. Green tea is among the most popular beverages in China. Green tea polyphenols (GTPs) have been proven to have therapeutic effects on organ damage induced by heavy metal exposure. However, few studies have reported on GTP-relieving DEHP-induced kidney damage. Methods: C57BL/6J male mice aged 6–8 weeks were treated with distilled water (control group), 1,500 mg/kg/d DEHP + corn oil (model group), 1,500 mg/kg/d DEHP + corn oil + 70 mg/kg GTP (treatment group), corn oil (oil group), and 70 mg/kg GTP (GTP group) by gavage for 8 weeks, respectively. The renal function of mice and renal tissue histopathology of each group were evaluated. The renal tissues of mice in the model, treatment, and control groups were analyzed using high-throughput sequencing. We calculated the differentially expressed microRNAs (miRNAs) and messenger RNAs (mRNAs) using the limma R package, the CIBERSORT algorithm was used to predict immune infiltration, the starBase database was used to screen the miRNA-mRNA regulatory axis, and immunohistochemical analyses were performed to verify protein expression. Results: GTP alleviated the deterioration of renal function, renal inflammation and fibrosis, and mitochondrial and endoplasmic reticulum lesions induced by DEHP in mice. Differential immune infiltrations of plasma, dendritic, T, and B cells were noted between the model and treatment groups. We found that three differentially expressed miRNAs (mmu-miR-383-5p, mmu-miR-152-3p, and mmu-miR-144-3p), three differentially expressed mRNAs (Ddit4, Dusp1, and Snx18), and three differentially expressed proteins (Ddit4, Dusp1, and Snx18) played crucial roles in the miRNA-mRNA-protein regulatory axes when GTPs mitigate DEHP-induced kidney damage in mice. Conclusion: GTP can alleviate DEHP-induced kidney damage and regulate immune cell infiltration. We screened four important miRNA-mRNA-protein regulatory axes of GTP, mitigating DEHP-induced kidney damage in mice.

脾与肾一司后天,一主先天,互为根本,共同参于水液的代谢、精微的封藏和精血的生化等.在生理上协调互济,病理上相互影响.多年来,从脾论治肾脏病成为临床上最受重视的治疗方法.故本期肾海探骊论坛特邀国内肾病领域的中医、中西医结合肾病专家李顺民、孙升云、占永立、刘伟敬和刘玉宁教授就脾之生理、病理及其治疗思路多角度探讨肾脏病从脾论治.本期论坛由论坛主席刘玉宁教授主持.

PURPOSE:The efficacy of the antioxidants vitamin E (VitE) and vitamin C (VitC) on male infertility is uncertain. Therefore, this research systematically assessed the influences of VitE and VitC on male infertility.METHODS:We did a meta-analysis of randomized controlled trials (RCTs) to analyze semen parameters, pregnancy rate, and adverse effects (AEs) between VitE and VitC groups and control groups by searching Cochrane Library, Excerpta Medica Database (Embase), PubMed, China Biology Medicine disc (CBMdisc), and Web of Science up to June 2020.RESULTS:We screened 11 studies (832 patients) that met the inclusion criteria. The evidence quality ranged from moderate to low. The pregnancy rate was obviously better in the VitE group than in the control group (relative risk (RR) 1.86, 95% confidence interval (CI) 1.02-3.41). Compared with the control group, VitE and VitC significantly improved progressive motility (standardized mean difference (SMD) 0.38, 95% CI 0.22-0.55), sperm concentration (SMD 0.21, 95% CI 0.09-0.34), sperm morphology (SMD 0.32, 95% CI 0.09-0.55), and total sperm number (SMD 0.28, 95% CI 0.12-0.43) without AEs.CONCLUSION:This study suggests that VitC and VitE can improve the spousal pregnancy rate and semen parameters in infertile men without AEs.

目的 观察慢肾康宁对肾间质纤维化大鼠肾组织Smad2、P-smad2及SARA蛋白表达的影响.方法 选用健康雄性Wistar大鼠60只,腺嘌呤灌胃21 d建立肾间质纤维化模型,将其随机分为正常模型组和(按1 ml/100 g体质量给予生理盐水经口灌服)氯沙坦组,慢肾康宁高、中、低剂量组.于治疗第30天大鼠腹主动脉取血.生化检测血清肌酐、尿素氮、24 h尿蛋白定量.行HE染色观察实验大鼠肾脏组织形态学改变并用Western blot检测Smad2、P-smad2及SARA表达水平.结果 模型组Scr、BUN和24 h MTP均明显高于正常组(P<0.05);各治疗组Scr、BUN和24 h MTP均明显低于模型组(P<0.05);慢肾康宁高剂量组与氯沙坦组Scr、BUN和24 h MTP差异均无统计学意义(P>0.05);各治疗组与模型组比较,Smad2、P-smad2蛋白显著下降,SARA蛋白显著升高;慢肾康宁高剂量组SARA蛋白显著高于氯沙坦组(P<0.05).结论 慢肾康宁可降低肾间质纤维化大鼠的Scr、BUN,减少24 h MTP,具有肾功能保护作用,其机制可能与下调Smad2、P-smad2及上调SARA蛋白表达水平而发挥抗间质纤维化的作用有关.

目的:观察慢肾康宁对腺嘌呤致肾间质纤维化(RIF)大鼠肾组织中转化生长因子-β1(TGF-β1)、Smad3、Snaill、E-钙黏着蛋白(E-cadherin)、α-平滑肌肌动蛋白(α-SMA)表达水平的影响.方法:将60只Wistar大鼠随机分为对照组、模型组、氯沙坦组及慢肾康宁高、中、低剂量组,每组10只.除对照组外,其余各组制备腺嘌呤致RIF大鼠模型.模型制备成功后,对照组及模型组灌胃蒸馏水,氯沙坦组按10 mg/(kg·d)的剂量灌胃氯沙坦混悬液,高、中、低剂量组分别按30、15、7.5 mg/(kg·d)的剂量灌胃慢肾康宁混悬液,均灌胃30 d.采用HE染色和Massan染色观察肾组织病理变化;免疫组织化学法测定E-cadherin、α-SMA、TGF-β1蛋白表达水平;采用蛋白质免疫印迹法检测肾组织中Smad3、Snail1蛋白表达水平;采用全自动生化分析仪检测血肌酐(SCr)、尿素氮(BUN)、24小时尿蛋白定量(24hMTP)、肾小球滤过率(eGFR)水平.结果:与模型组比较,氯沙坦及慢肾康宁组SCr、BUN、24hMTP水平均显著下降,eGFR上升;病理观察,模型组可见肾小管萎缩或扩张,炎症细胞浸润明显,肾小球及肾间质内可见腺嘌呤代谢产物聚集及蓝染胶原纤维聚集,氯沙坦及慢肾康宁各组中病理表现相对较轻;与模型组比较,各给药组α-SMA、TGF-β1、Snail1蛋白表达水平下降、E-cadherin蛋白表达水平升高,氯沙坦及慢肾康宁中、高剂量组中Smad3蛋白表达水平明显下降.结论:慢肾康宁能够抑制RIF大鼠TGF-β1/Smad3/Snail1信号传导,增加E-cadherin、拮抗α-SMA蛋白的表达,具有肾脏保护作用,这可能是其抗RIF的作用机制之一.

目的 探讨中医药治疗肾性贫血的用药规律.方法 检索中国知网相关文献材料,利用Excel 2003、SPSS statistic 26.0、Clementine 12.0统计数据,建立数据库并分析特点.结果 建立了147首中药汤剂的数据库.治疗肾性贫血的高频药物(≥20次)共有19味,以补虚药为主.通过对高频药物进行关联规则和聚类分析,得出9个药物和4个聚类法.结论 临床常用补虚药治疗肾性贫血,可配伍活血化瘀药、理气药,分析所得的9个药对和4个聚类方供临床运用参考.

Di(2-ethylhexyl) phthalate (DEHP) is a common environmental pollutant with renal and reproductive toxicity. Lycium barbarum glycopeptide (LbGp) is the main active component of Lycium barbarum, which can protect the kidney and promote reproduction. Autophagy and apoptosis are the regulatory mechanisms of cell adaptation to external stress. This study investigated whether DEHP and LbGp affect kidney and testis by regulating autophagy and apoptosis. DEHP induced apoptosis in human embryonic kidney-293 (HEK-293) cells and human kidney-2 (HK-2) cells, as well as glomerular enlargement, enhanced renal autophagy and inflammation, decreased testicular germ cells, and enhanced testicular autophagy. LbGp reduced apoptosis in HEK-293 cells and HK-2 cells, reduced glomerular enlargement and renal inflammation, enhanced renal autophagy, increased testicular germ cells, and alleviated testicular autophagy. These results suggested that DEHP induced inflammation to cause kidney injury, mildly enhanced renal autophagy, and also induced excessive autophagy, leading to testicular injury. LbGp reduced inflammation and appropriately enhanced autophagy to alleviate renal injury and also reduced excessive autophagy to alleviate testicular injury. Silent information regulator 1 (SIRT1)/forkhead box O3a (FoxO3a)-mediated autophagy and p38 mitogen-activated protein kinase (p38 MAPK)-mediated inflammation played important roles.

Pancreatic cancer (PCa) is a highly lethal and aggressive disease, characterized by high mortality rates. Although necroptosis plays a vital role in tumor progression, cancer metastasis, prognosis of cancer patients, necroptosis-related gene (NRG) sets have rarely been analyzed in PCa. Therefore, definition of novel necroptosis-related prognostic markers for PCa patients is urgently needed. Here, we screened 159 NRGs and identified 132 differentially expressed NRGs in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) cohorts. Next, we employed univariate and multivariate Cox proportional regression models to establish a prognostic-related NRG signature comprising five NRGs that could stratify patients into high-risk and low-risk groups. Results from survival analysis showed that patients in the high-risk had dramatically shorter overall survival (OS) rates compared with their low-risk counterparts. Results from univariate and multivariate Cox regression analysis further confirmed the independent prognostic value of the established necroptosis-related signature, and the area under receiver (AUC) of the operating curve (ROC) for 1-, 3-, 5-years was 0.72, 0.74, and 0.75, respectively. Finally, we validated the signature efficacy using an independent cohort from the Gene Expression Omnibus (GEO) database. The ROC curve confirmed the predictive capacity of the five-gene signature. Furthermore, we validated expression of the signature proteins using the Human Protein Atlas (HPA) database. In conclusion, we successfully constructed a novel necroptosis-related signature for prognosis of patients with pancreatic cancer.

Background: Extensive evidence has shown that immune cell infiltration is associated with the pathogenesis of Crohn’s disease (CD). Methods: Differentially expressed genes (DEGs) from the GSE179285 dataset in the intestinal mucosa of CD patients and healthy individuals were then identified. The infiltration pattern of 22 immune cell types was assessed using the CIBERSORT algorithm. The DEGs and 22 immune cell types were combined to find the key gene network using weighted gene co-expression network analysis (WGCNA). A linear regression model for the relationship between the expression of the hub genes in CD patients and infiltration of immune cells was also developed. The utility and accuracy of the hub genes for CD diagnosis were assessed using receiver operating characteristic (ROC) analysis. The accuracy of the model was validated using the GSE20881 dataset. Results: There were 1135 DEGs between the intestinal mucosal tissue of CD patients and healthy individuals. Of these DEGs, 711 genes were upregulated, whereas 424 of them were downregulated. There was also a significant difference in the infiltration of immune cells to the intestinal mucosal between the CD patients and healthy individuals. WGCNA revealed that the turquoise module genes were strongly correlated with the infiltration of M1 macrophages (cor =0.68, p = 10−16). Finally, the expression of GBP4, the identified hub gene, strongly correlated with the infiltration of M1 macrophages (adjusted r-squared =0.661, p < 2×10−16), and is a relatively good marker for CD diagnostic prediction (AUC =0.736). The relationship between GBP4 expression and infiltration of M1 macrophages (adjusted r-squared =0.435, p < 2×10−16) and diagnostic value of the gene (AUC =0.702) were verified using the GSE20881 validation dataset. Conclusion: The expression of GBP4 is associated with the infiltration of M1 macrophages to the intestinal mucosa of CD patients.