OBJECTIVE:This study investigated the effects of electroacupuncture (EA) on mast cell activation and transient receptor potential vanilloid 1 (TRPV1)-related signaling in skin tissue using a rat model of passive cutaneous anaphylaxis (PCA)-like urticaria. METHODS:An immunoglobulin E (IgE)/high-affinity Fc receptor for IgE (FcεRI)-mediated PCA-like urticaria model was established in rats by anti-ovalbumin serum injection followed by ovalbumin challenge. Rats were randomly divided into negative control, model, EA, Cap (capsaicin + model), and Cap + EA groups. Capsaicin was administered subcutaneously in the Cap and Cap + EA groups to activate cutaneous TRPV1. After model establishment, rats in the EA and Cap + EA groups underwent EA stimulation at LI11 (Quchi) and SP10 (Xuehai) for seven consecutive days. Urticarial responses were assessed using Evans blue dye extravasation, wheal area, and scratching bouts. Histopathological changes were assessed using hematoxylin-eosin staining, and mast cell numbers were quantified by toluidine blue staining. Mast cell-derived mediators in sensitized skin and serum cytokine levels were quantified using enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry, immunofluorescence, and Western blot analyses were performed to assess TRPV1-related protein expression. RESULTS:EA significantly alleviated inflammatory responses and pruritic behavior in rats in the ovalbumin-induced PCA-like urticaria model. Histopathological examination revealed marked attenuation of skin lesions and reduced mast cell-associated pathological changes following EA. ELISA demonstrated decreased levels of mast cell-derived mediators in sensitized skin, accompanied by reduced serum inflammatory cytokine levels. Immunohistochemistry, immunofluorescence, and Western blot analyses further showed that EA suppressed TRPV1-related protein expression and mast cell-mediated inflammatory responses. CONCLUSION:EA at LI11 and SP10 alleviates local inflammation and pruritus in a PCA-like urticaria model, with effects associated with mast cell regulation and modulation of TRPV1-related signaling. Please cite this article as: Zhao Y, You LX, Zhang JY, Wang W, Li SJ, Li JQ. Electroacupuncture at LI11 and SP10 attenuates inflammation and pruritus in a rat model of passive cutaneous anaphylaxis-like urticaria via mast cell modulation related to transient receptor potential vanilloid 1. J Integr Med. 2026; Epub ahead of print.

Acute pancreatitis (AP) concurrent with acute kidney injury (AKI) remarkably elevates the risk of adverse outcomes in affected individuals. Abnormal serum magnesium concentrations have been linked to AKI development across diverse patient populations; however, the prognostic significance of serum magnesium levels at multiple time points (60 days, 90 days, 180 days, and 365 days) remains inadequately explored in AP patients with AKI admitted to the intensive care unit (ICU). This study aimed to assess the dynamic prognostic value of serum magnesium at the aforementioned key time points, clarify its clinical utility for risk stratification in this specific cohort, and investigate prognostic disparities among patients stratified by gender, as well as the presence or absence of diabetes mellitus, congestive heart failure, and pre-existing kidney disease. Study data were extracted from the MIMIC-IV database, which was made publicly available in October 2024. Adult patients (≥ 18 years) diagnosed with AP, who had an ICU length of stay (LOS) exceeding 24 h and complete mortality data, were enrolled. Exclusion criteria included missing serum magnesium measurements, ICU LOS < 24 h, incomplete clinical records, and aberrant survival data. Finally, 492 data samples meeting the inclusion criteria were enrolled in the present study. Serum magnesium levels were stratified into three grades using X-tile software, with stratification thresholds determined based on 60-day survival outcomes. Clinical data were retrieved using SQL and PostgreSQL. Intergroup comparisons were performed using statistical methods including the Wilcoxon rank-sum test, chi-square test, and t-test. Survival analyses were conducted to evaluate the association between serum magnesium levels and prognosis. Univariate Cox regression models were used to initially assess the relationship, and multivariate Cox regression models were constructed to adjust for confounding factors based on key patient characteristics. Among the 492 enrolled patients, males accounted for 53.25%. No statistically significant differences were noted in gender distribution or age across the three groups stratified by serum magnesium levels (P > 0.05). The hypermagnesemia group had the longest median ICU length of stay (LOS) (145 h, interquartile range [IQR]: 62-274 h), with intergroup differences approaching statistical significance (H = 5.112, P = 0.078). The incidence rates of sepsis and hypertension increased significantly with elevated serum magnesium levels (sepsis: χ² = 11.496, P = 0.003; hypertension: χ² = 6.065, P = 0.048). Additionally, the utilization rate of continuous renal replacement therapy (CRRT) in the hypermagnesemia group (20.75%) was significantly higher than that in the hypomagnesemia group (9.15%) and normomagnesemia group (11.48%) (χ² = 6.302, P = 0.043). In the hypermagnesemia group, serum creatinine, potassium, sodium, and chloride levels were significantly elevated, while serum calcium levels were markedly decreased (all P < 0.05). Disease severity scores, including the Sequential Organ Failure Assessment (SOFA) score, Simplified Acute Physiology Score II (SAPS II), and Logistic Organ Dysfunction System (LODS) score, were significantly higher in the hypermagnesemia group compared to the other two groups (all P < 0.05). Regarding prognostic outcomes, the hypermagnesemia group had the shortest median survival times at 60, 180, and 365 days, with statistically significant intergroup differences (H-values: 6.75, 6.033, 9.235; all P < 0.049). Its 365-day mortality rate (37.74%) was more than twice that of the hypomagnesemia group (18.61%). Kaplan-Meier analysis revealed that the hypermagnesemia group had significantly lower survival rates at all time points compared to the hypomagnesemia group (log-rank test, P < 0.05). Multivariate Cox regression analysis indicated that the risk of death gradually increased with rising serum magnesium levels, and hypermagnesemia was associated with a 54% higher risk of 365-day mortality (HR = 1.54, 95% CI: 0.54-4.43). Restricted cubic spline (RCS) analysis demonstrated a significant increase in mortality risk when serum magnesium levels exceeded 1.9 mg/dL. Subgroup analysis confirmed that the association between serum magnesium levels and prognosis was consistent across different subgroups. Furthermore, during the 365-day follow-up, the hypermagnesemia-related mortality risk was significantly elevated in obese patients and those with sepsis (P < 0.05). Elevated serum magnesium levels upon ICU admission are closely correlated with increased risks of adverse events and medium- and long-term mortality in patients with acute pancreatitis complicated by acute kidney injury, and can serve as a valuable early clinical indicator for evaluating disease severity and predicting patient prognosis. Abnormally elevated serum magnesium levels effectively reflect the status of severe concomitant organ dysfunction and possess favorable clinical value for disease assessment and prognostic prediction. The stratified cut-off values of serum magnesium established in this study can be applied to early clinical risk stratification and early warning for such patients. Routine dynamic monitoring of serum magnesium is recommended to facilitate early clinical evaluation and risk assessment. Furthermore, it provides a reliable reference for subsequent mechanistic investigations and prospective clinical trials to explore targeted interventions for improving patient outcomes.

Per- and polyfluoroalkyl substances (PFAS), particularly perfluorooctane sulfonate (PFOS), persist in humans and have been associated with cardiovascular outcomes, but cardiac-specific molecular responses remain incompletely characterized. We integrated transcriptomic screening, ensemble machine learning, molecular docking and 100-ns molecular dynamics, cross-species cardiac single-cell atlases with virtual knockout, and a time-stratified mouse exposure study (approximately 5 μg/kg/d for 4-8 weeks) to prioritize candidate molecular nodes associated with PFOS-related cardiac remodeling. Robustness analyses supported the stability of the machine-learning prioritization, and MYH6 was repeatedly selected and enriched in cardiomyocytes across human and mouse atlases. Docking and simulation supported a structurally plausible modeled PFOS-MYH6 complex. In exposed mice, Myh6 expression declined over time as septal asymmetry and interstitial fibrosis increased. Batch docking revealed 11 of 26 PFAS with scores at least as favorable as PFOS, indicating compound-level variation in modeled MYH6 compatibility. Together, the data prioritize MYH6 as a candidate molecular node associated with PFOS-related HCM-like remodeling and integrate these multiscale observations into a testable putative AOP-like hypothesis.

OBJECTIVES:The effectiveness of prolonged infusion of meropenem in treating sepsis remains debated. This meta-analysis aims to compare the clinical effectiveness and safety of prolonged infusion versus short-term infusion of meropenem in sepsis patients. METHODS:A systematic search was conducted in PubMed, Web of Science, ClinicalTrials.gov, and the Cochrane Library for randomized controlled trials (RCTs) and observational studies published from database inception up to February 2025. Studies meeting the inclusion and exclusion criteria were included. Data were extracted in prespecified forms, and fixed-effect or random-effects models were used based on I2 values. This meta-analysis is registered with the PROSPERO database and follows the Preferred Reporting Items for Systematic and Meta-Analyses reporting guidelines. RESULTS:A total of 1597 articles were identified and screened, leading to the inclusion of 18 studies (3703 patients) in the meta-analysis. Prolonged infusion of the meropenem was associated with a reduced risk of mortality compared to short-term infusion (risk ratio [RR] = 0.85, 95% confidence interval [CI] = 0.76-0.95). No significant heterogeneity was observed ( P = 0.24, I2  = 19%). Furthermore, prolonged infusion is associated with a higher rate of clinical cure (RR = 1.35, 95% CI = 1.25-1.47). Additionally, the group receiving prolonged infusions demonstrated a higher microbiological eradication rate (RR = 1.13, 95% CI = 1.04-1.22). CONCLUSIONS:Administering meropenem via prolonged infusion to sepsis patients is associated with short-term survival benefits, an increased likelihood of clinical cure, and greater microbiological eradication. Further high-quality RCTs are needed to determine the potential long-term survival benefits of prolonged meropenem infusion in sepsis patients.

Objective:To evaluate the real-world efficacy and safety of eculizumab in atypical hemolytic uremic syndrome (aHUS) within a Western Chinese cohort, with emphasis on treatment initiation timing and renal outcomes. Methods:We conducted a retrospective analysis of 17 aHUS patients treated at Sichuan Provincial People's Hospital, focusing on the relationship between treatment timing and clinical prognosis. To evaluate timing effects, patients were categorized as Early Initiators (treatment within 7 days of symptom onset, n=9) versus Delayed Initiators (treatment beyond 7 days, n=8) The main outcome measures included hematological parameters, renal function, and adverse events. Results:The cohort (n=17, 76.5% female, mean age 43.2 ± 20.0 years) demonstrated significant improvements post-eculizumab: creatinine decreased from 647.0 (439.0, 915.0) to 198.5 (86.5, 749.5) μmol/L, eGFR increased from 8.0 (5.0, 11.0) to 22.1 (6.4, 55.1) mL/min/1.73m², platelets rose from 75 ± 11 to 143 ± 33×109/L, and LDH declined from 787.5±908.0 to 232.8 ± 70.0 U/L (all P<0.001). Early treatment initiation (≤7 days, n=9) yielded superior outcomes versus delayed (>7 days, n=8): higher renal remission (88.9% vs 12.5%, P=0.003), hematological remission (100% vs 12.5%, P<0.001), and reduced dialysis dependence (0% vs 87.5%, P<0.001), with greater ΔeGFR (+(19.5 ± 3.1) vs +(2.3 ± 1.7 )mL/min/1.73m2, P=0.016) and Δplatelets (+(67.8 ± 9.8) vs +(19.3 ± 7.2)×109/L, P=0.007). Renal survival favored early treatment (log-rank P<0.001), though residual renal impairment persisted. Two non-meningococcal bloodstream infections resolved with antibiotics. Conclusion:Our findings provide the first Chinese evidence supporting early eculizumab initiation (≤7 days post-symptom onset) significantly improves hematological/renal outcomes and reduces dialysis dependence in Chinese aHUS patients. Despite residual renal impairment, prompt complement blockade mitigates ESRD risk, supporting time-sensitive intervention in resource-limited settings.

BACKGROUND:Type 2 diabetes mellitus is characterized by pancreatic β-cell dysfunction and insulin resistance. Studies have suggested that β-cell dedifferentiation is one of the pathogeneses of β-cell dysfunction, but the detailed mechanism is still unclear. Most studies of β-cell dedifferentiation rely on rodent models and human pathological specimens. The development of in vitro systems can facilitate the exploration of β-cell dedifferentiation. AIM:To investigate the molecular mechanism of β-cell dedifferentiation. Hence, an in vitro model of β-cell dedifferentiation induced by palmitic acid and high glucose was established using the INS-1 832/13 cell line. METHODS:The study was further analyzed using RNA-sequencing, transmission electron microscopy, quantitative real-time polymerase chain reaction and Western blot. RESULTS:Results showed that the treatment of palmitic acid and high glucose significantly up-regulated β-cell forbidden genes and endocrine precursor cell marker genes, and down-regulated the expression of β-cell specific markers. Data showed that dedifferentiated INS-1 cells up-regulated the expression of endoplasmic reticulum (ER) stress-related genes. Moreover, the results also showed that forkhead box O1 (Foxo1) inhibition potentiated genetic changes in β-cell dedifferentiation induced by palmitic acid and high glucose. CONCLUSION:ER stress is sufficient to trigger β-cell dedifferentiation and is necessary for palmitic acid and high glucose-induced β-cell dedifferentiation. Foxo1 inhibition can further enhance these phenomena.

The neutrophil percentage-to-albumin ratio (NPAR) emerges as a novel inflammation marker, demonstrating prognostic ability in a variety of cardiovascular diseases. However, its impact on mortality among patients undergoing maintenance hemodialysis (MHD) remains uncertain. Our research aims to determine whether NPAR is a reliable predictor of mortality in MHD patients. A total of 1803 MHD patients were recruited in this prospective cohort. Patients were stratified into three groups based on baseline NPAR levels. The association between NPAR and all-cause and cardiovascular mortality was evaluated using multivariate Cox proportional risk model and sensitivity analysis. NPAR’s predictive performance was assessed using the receiver operating characteristic (ROC) curve, compared to several conventional biomarkers, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), neutrophil count, and serum albumin. The area under the curve (AUC) values of NPAR and these biomarkers were compared using the DeLong’s test. Throughout a median follow-up period of 28 months, 239 (13.3

BackgroundTo summarize current evidence on kidney related adverse events (AEs) following targeted therapies in lung cancer from trial settings.MethodsA systematic search was conducted in MEDLINE, EMBASE, and Cochrane Central Library. Randomized controlled trials that had reported kidney related AEs following targeted therapies in lung cancer were eligible. Outcomes included renal dysfunction as reported, increased serum creatinine, proteinuria, urinary tract infection (UTI), and electrolyte disorders. The risk of bias was assessed using the Cochrane guidelines. The incidence of the examined outcomes, along with their corresponding 95% confidence intervals (CIs), were combined using a random-effects model. Network analysis was applied if the comparisons had passed the consistency test. Publication bias was assessed using Funnel plot analysis.Results57 studies encompassing 11,497 patients were included. The pooled incidences (95% CI) of acute kidney injury (AKI), increased serum creatinine, proteinuria, and UTI following targeted therapies in lung cancer were 1% (0%, 2%), 4% (1%, 8%), 9% (6%, 13%), and 6% (2%, 12%), respectively. Targeted therapies did not increase the risk of AKI, yet were associated with higher incidence of proteinuria, particularly vascular endothelial growth factor inhibitors containing therapies. Multiple electrolyte disorders could be observed following targeted treatments, with the pooled incidences ranging from 4% to 21%; however, most electrolytes disorders had limited number of reports. Most of the reported kidney related AEs were of Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or 2. Publication bias was present for kidney related AEs excluding AKI.ConclusionKidney related adverse events are not uncommon following targeted therapies in lung cancer in trial settings. In comparison to chemotherapy alone, targeted therapies did not increase the risk of AKI, yet were associated with higher risk of proteinuria. Proteinuria and electrolytes disorders are more often observed than renal dysfunction and UTI. All types of AEs were mostly mild in severity.Systematic Review RegistrationPROSPERO CRD42023441979.

BackgroundThe objective of our retrospective multicenter analysis was to identify risk factors and construct a statistical model for predicting acute kidney injury (AKI) among elderly patients with severe pneumonia requiring mechanical ventilation (SPRMV) in elderly patients in different intensive care units (ICU).MethodsWe aimed to utilize a multi-center retrospective analysis, including 353 cases of SPRMV patients diagnosed and treated in the ICU of the Hefei Second People’s Hospital between May 2018 and February 2025 as a training dataset, and 151 participants were admitted to the ICU of the First Affiliated Hospital of Anhui Medical University between June 2020 and March 2025, considered as a validation dataset. Both univariate and multivariate logistic regression analyses were utilized to investigate the risk factors of SPRMV with AKI. After that, our predictive model was evaluated using a nomogram, a receiver operating characteristic (ROC) curve for discrimination, calibration curves, and decision curve analysis (DCA) curves for clinical validity.ResultsOur multivariate logistic regression analysis indicated that CREA, SOFA, APACHE II, driving pressure, mechanical kinetic energy, CRP/ALB, and MAP are independent risk factors of SPRMV in the elderly patients with AKI. A nomogram of SPRMV in elderly patients with AKI was constructed. The ROC curve revealed that our predictive model showed good predictive efficacy with an area under curve (AUC) of 0.920 (95% confidence intervals (CI) = 0.892–0.948) with a specificity of 0.993 and sensitivity of 0.763 in the training dataset and an AUC value of 0.938 (95%CI = 0.899–0.977) with a specificity of 0.952 and sensitivity of 0.854 in the validation dataset. Moreover, calibration and DCA curves demonstrated that our predictive model had a good fit, better net benefit, and higher predictive efficiency for SPRMV in the elderly patients with AKI.ConclusionOur predictive model demonstrated that CREA, SOFA, APACHE II, driving pressure, mechanical kinetic energy, CRP/ALB, and MAP were the independent risk factors of AKI in SPRMV in the elderly patients with high accuracy and good calibration.

Erythropoiesis is precisely regulated by multilayered networks. It is crucial for maintaining steady-state hemoglobin levels and ensuring effective oxygen transport. Alternative polyadenylation (APA) is a post-transcriptional regulatory mechanism generating multiple mRNA isoforms from a single gene based on specific 3'-untranslated region sequences. While APA plays a vital role in various cellular processes, the underlying mechanism in erythropoiesis remains largely unexplored. In this study, we employed an integrative approach, combining bioinformatics analyses and experimental validations, to systematically investigate the role of APA in erythropoiesis. We mapped the APA landscape during erythroid differentiation and identified significant APA shifts essential for the differentiation of erythroid cells from burst-forming unit erythroid (BFU–E) to colony-forming unit erythroid (CFU–E). Notably, our findings highlighted polyadenylate-binding protein cytoplasmic 1 (PABPC1) as the primary regulator of APA during these stages. Functional analyses have revealed that knockdown of PABPC1 disrupts erythroid progenitor cell proliferation and differentiation. These results implicate an essential role of PABPC1 in modulating cell fate through APA regulation. Furthermore, we found that decreased PABPC1 levels increased the usage of the proximal polyadenylation sites in the TSC22D1 gene. This shift led to elevated expression of TSC22D1, uncovering a novel mechanism by which APA influences erythroid progenitor expansion and differentiation. Our findings provide novel insights into APA regulation in early erythropoiesis and suggest potential therapeutic strategies for diseases associated with erythropoietic disorders.

BACKGROUND:The aim of this study is to investigate the clinicopathologic characteristics, treatment and prognosis of crescentic glomerulonephritis (Crescentic GN) in patients with normal renal function at diagnosis, and compare to those with impaired renal function. METHODS:We conducted a retrospective review of patients with renal biopsy proven Crescentic GN at our center and divided them into normal eGFR group (eGFR≥60 ml/min/1.73 m2) and low eGFR group (eGFR <60 ml/min/1.73 m2). Clinical and renal pathological findings at diagnosis and renal outcomes were compared between the two groups using t-test, Wilcoxon rank sum test or Kruskal-Wallis H test. RESULTS:From Jan 2010 to Dec 2021, 90 Crescentic GN patients with normal eGFR were included, in which clinicopathological diagnoses were LN (lupus nephritis) (60 cases, 66.77 %), IgAN (IgA nephropathy) (9 cases, 10 %), HSPN (Henoch-Schnlein purpura nephritis) (14 cases, 15.6 %) and AAV (ANCA-associated GN) (7 cases, 7.8 %). Compared with the low eGFR group (n = 300), the following characteristics were observed in the normal eGFR group: younger age (p < 0.001), female predominance (p < 0.001), longer time from onset to biopsy (p < 0.001), lower hypertension rate (p < 0.001), lower rate of oliguria (p < 0.001), and anemia (p < 0.001), lower levels of C3 (p < 0.001), C4 (p < 0.001) and Urine RBC (p < 0.001), higher titers of ANA (p < 0.001) and ds-DNA (p = 0.002), lower positive rate of ANCA (<0.001) and GBM (p = 0.02), less extra-renal involvement (p < 0.05), lower proportions of crescents (56.3(51.8-62.7) % vs 66.7 (56.3-81.3) %, p < 0.001) and glomerular sclerosis (p < 0.001), less severe tubulointerstitial lesion (p < 0.001) and interstitial inflammation (p < 0.001), higher degree of immune complex deposition of IgA, IgM, C3, C4 and C1q by Immunofluorescence. Normal eGFR group received lower frequency of intravenous methylprednisolone pulse therapy (71.2 % vs 89 %, p = 0.044) and dialysis treatment (0 % vs 53.7 %, p < 0.001). The 5- and 10-year cumulative renal survival rates from ESRD were 90.7 % vs 45.5 % and 58.3 % vs 43.7 %, respectively in normal and low eGFR group. CONCLUSION:Crescentic GN may present with normal renal function, which has poor renal outcomes and may benefit from intensive immunosuppressive treatment. This often occurs in patients with abnormal immunological indicators and systemic autoimmune disease. Shorter time from onset to biopsy may help better management and improve long-term outcomes in these cases. Renal biopsy remains the diagnostic gold standard when urinary abnormalities are present in nephritis.

OBJECTIVES:Long-term elevated blood pressure may lead to kidney damage, yet the pathogenesis of hypertensive kidney damage is still unclear. This study aims to explore the role and significance of leucine-rich alpha-2-glycoprotein-1 (LRG-1) in hypertensive renal damage through detecting the levels of LRG-1 in the serum and kidney of mice with hypertensive renal damage and its relationship with related indexes.METHODS:C57BL/6 mice were used in this study and randomly divided into a control group, an angiotensin II (Ang II) group, and an Ang II+irbesartan group. The control group was gavaged with physiological saline. The Ang II group was pumped subcutaneously at a rate of 1.5 mg/(kg·d) for 28 days to establish the hypertensive renal damage model in mice, and then gavaged with equivalent physiological saline. The Ang II+irbesartan group used the same method to establish the hypertensive renal damage model, and then was gavaged with irbesartan. Immunohistochemistry and Western blotting were used to detect the expression of LRG-1 and fibrosis-related indicators (collagen I and fibronectin) in renal tissues. ELISA was used to evaluate the level of serum LRG-1 and inflammatory cytokines in mice. The urinary protein-creatinine ratio and renal function were determined, and correlation analysis was conducted.RESULTS:Compared with the control group, the levels of serum LRG-1, the expression of LRG-1 protein, collagen I, and fibronectin in kidney in the Ang II group were increased (all P<0.01). After treating with irbesartan, renal damage of hypertensive mice was alleviated, while the levels of LRG-1 in serum and kidney were decreased, and the expression of collagen I and fibronectin was down-regulated (all P<0.01). Correlation analysis showed that the level of serum LRG-1 was positively correlated with urinary protein-creatinine ratio, blood urea nitrogen, and blood creatinine level in hypertensive kidney damage mice. Serum level of LRG-1 was also positively correlated with serum inflammatory factors including TNF-α, IL-1β, and IL-6.CONCLUSIONS:Hypertensive renal damage mice display elevated expression of LRG-1 in serum and kidney, and irbesartan can reduce the expression of LRG-1 while alleviating renal damage. The level of serum LRG-1 is positively correlated with the degree of hypertensive renal damage, suggesting that it may participate in the occurrence and development of hypertensive renal damage.

BackgroundSepsis-associated acute kidney injury (S-AKI) is considered to be associated with high morbidity and mortality, a commonly accepted model to predict mortality is urged consequently. This study used a machine learning model to identify vital variables associated with mortality in S-AKI patients in the hospital and predict the risk of death in the hospital. We hope that this model can help identify high-risk patients early and reasonably allocate medical resources in the intensive care unit (ICU).MethodsA total of 16,154 S-AKI patients from the Medical Information Mart for Intensive Care IV database were examined as the training set (80%) and the validation set (20%). Variables (129 in total) were collected, including basic patient information, diagnosis, clinical data, and medication records. We developed and validated machine learning models using 11 different algorithms and selected the one that performed the best. Afterward, recursive feature elimination was used to select key variables. Different indicators were used to compare the prediction performance of each model. The SHapley Additive exPlanations package was applied to interpret the best machine learning model in a web tool for clinicians to use. Finally, we collected clinical data of S-AKI patients from two hospitals for external validation.ResultsIn this study, 15 critical variables were finally selected, namely, urine output, maximum blood urea nitrogen, rate of injection of norepinephrine, maximum anion gap, maximum creatinine, maximum red blood cell volume distribution width, minimum international normalized ratio, maximum heart rate, maximum temperature, maximum respiratory rate, minimum fraction of inspired O2, minimum creatinine, minimum Glasgow Coma Scale, and diagnosis of diabetes and stroke. The categorical boosting algorithm model presented significantly better predictive performance [receiver operating characteristic (ROC): 0.83] than other models [accuracy (ACC): 75%, Youden index: 50%, sensitivity: 75%, specificity: 75%, F1 score: 0.56, positive predictive value (PPV): 44%, and negative predictive value (NPV): 92%]. External validation data from two hospitals in China were also well validated (ROC: 0.75).ConclusionsAfter selecting 15 crucial variables, a machine learning-based model for predicting the mortality of S-AKI patients was successfully established and the CatBoost model demonstrated best predictive performance.

Insulin resistance (IR) promotes atherosclerosis and increases the risk of diabetes and cardiovascular diseases. Our previous studies have demonstrated that high uric acid (HUA) increased oxidative stress, leading to IR in cardiomyocytes and pancreatic β cells. However, whether HUA can induce IR in monocytes/macrophages, which play critical roles in all stages of atherosclerosis, is unclear. Recent findings revealed that thioredoxin-interacting protein (TXNIP) negatively regulates insulin signaling; however, the roles and mechanisms of TXNIP in HUA-induced IR remain unclear. Therefore, in this study, we investigated the function of TXNIP in macrophages treated with UA. Transcriptomic profiling revealed TXNIP as one of the most upregulated genes, and subsequent RT-PCR and Western blot analyses confirmed that TXNIP was upregulated by HUA. HUA treatment significantly increased mitochondrial reactive oxygen species (MtROS) levels and decreased insulin-stimulated glucose uptake. Silencing TXNIP by RNA interference significantly diminished HUA-induced oxidative stress and IR. Mechanistically, silencing TXNIP reversed the inhibition of the phosphorylation of insulin receptor substrate 2 (IRS2)/protein kinase B (AKT) pathway induced by HUA. Additional study revealed that HUA induced the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway, but silencing TXNIP abolished it. Moreover, Nrf2 inhibitor (ML385) ameliorated HUA-induced IR independent of IRS2/AKT signaling. Probenecid, a well-known UA-lowering drug, significantly suppressed the activation of TXNIP and Nrf2/HO-1 signaling. Furthermore, RNA-seq revealed that activation of the TXNIP-related redox pathway may be a key regulator in patients with asymptomatic hyperuricemia. These data suggest that silencing TXNIP could ameliorate HUA-induced IR via the IRS2/AKT and Nrf2/HO-1 pathways in macrophages. Additionally, TXNIP might be a promising therapeutic target for preventing and treating oxidative stress and IR induced by HUA.

Hypertensive renal injury (HRI) is a main cause of end-stage renal diseases, and CD4+ T cells and the secreted inflammatory cytokines contribute to the progress of HRI. However, the exact mechanisms remain unidentified in HRI, and there is still a shortage of effective treatments. Here, we aim to explore the role of interleukin-22 (IL22) and its underlying mechanism in HRI. Serum IL-22 level and peripheral Th22 cells frequency in patients with HRI were detected by ELISA and flow cytometry respectively. Angiotension II (Ang II) was infused subcutaneously to C57BL/6 mice for 28 days. Hypertensive mice were treated with recombinant IL-22 (rIL-22), anti-IL-22 antibody, or JAK2/STAT3 pathway blocker AG-490 respectively. Blood pressure (BP), urinary albumin/creatinine ratio (UACR), serum creatinine (Scr) and renal histopathology were measured; renal Th22 cells proportion were evaluated; inflammatory factors were evaluated by ELISA; JAK2/STAT3 pathway and fibrosis related factors expression in kidney were detected by Western blot. Serum IL-22 and Th22 cells proportion in kidney of mice were elevated after Ang II infusion. Compared to Ang II-infused mice, treatment with rIL-22 resulted in further increased UACR, Scr, renal pathological damage, inflammation and renal fibrosis, accompanied by elevated BP and JAK2/STAT3 pathway activation. Conversely, anti-IL-22 antibody reduced inflammation, renal fibrosis and BP in Ang II treated mice. AG490 could compromised the above effects of rIL-22. Taken together, recombinant IL-22 may aggravate hypertensive renal damage mediated by Ang II in mice, which may be through promoting JAK2/STAT3 pathway activation. Anti-IL-22 antibody exerts the opposite effects. These data suggest the IL-22 signaling maybe a novel therapeutic target for the treatment of hypertensive renal injury.

Angiotensin II (Ang II) as an important pathogenic factor, has been implicated in the pathogenesis of hypertension and associated renal injury, and inhibition of Ang II can reduce renal inflammation and exert renal protective effects. In the present study, we determine the infiltration of Th22 cells in kidney and serum IL-22 level in hypertensive renal injury, and explore the effects and mechanisms of a widely used angiotensin II type 1 receptor blocker irbesartan on Th22 cells infiltration and related renal injury. Hypertension was induced by administering 1.5 mg/kg Ang II subcutaneously daily in C57BL/6 mice for 28 days. The mice were additionally treated by irbesartan or amlodipine. Renal Th22 lymphocytes frequency was evaluated through flow cytometry, serum IL-22 was detected by ELISA, and renal histopathological changes were also detected. The levels of renal chemokines (CCL20, CCL22, CCL27) and serum proinflammatory factors (IL-1 beta, IL-6, TNF-alpha) were measured by ELISA. Renal expression of alpha-smooth muscle actin (alpha-SMA), Fibronectin (FN) and collagen I (Col I) were evaluated by western blot. Chemotaxis assay and co-culture assay were conducted to clarify the effect of irbesartan on Th22 cells chemotaxis and differentiation in vitro. Our results showed in Ang II-infused hypertension mice, irbesartan suppressed renal Th22 cells accumulation as well as CCL20, CCL22, CCL27 expression. Serum IL-22, IL-1 beta, IL-6 and TNF-alpha concentrations wasere also reduced, in addition to inhibited renal expression of alpha-SMA, FN and Col I. Irbesartan treatment lowered blood pressure, urinary protein and renal pathological damage. In vitro, irbesartan could abrogate the Th22 cells chemotaxis and differentiation, compared to control and amlodipine groups. Our study reveals a new pharmacological mechanism that irbesartan ameliorates inflammation and fibrosis in hypertensive renal injury induced by Ang II, maybe through inhibiting Th22 cells chemotaxis and infiltration, which provides a new theoretical basis and therapeutic target for hypertensive renal injury.

Recent evidence indicates that elevated placental adenosine signaling contributes to preeclampsia (PE). However, the molecular basis for the chronically enhanced placental adenosine signaling in PE remains unclear. Here, we report that hypoxia-inducible factor-1α (HIF-1α) is crucial for the enhancement of placental adenosine signaling. Utilizing a pharmacologic approach to reduce placental adenosine levels, we found that enhanced adenosine underlies increased placental HIF-1α in an angiotensin receptor type 1 receptor agonistic autoantibody (AT1 -AA)-induced mouse model of PE. Knockdown of placental HIF-1α in vivo suppressed the accumulation of adenosine and increased ecto-5'-nucleotidase (CD73) and adenosine A2B receptor (ADORA2B) in the placentas of PE mouse models induced by AT1 -AA or LIGHT, a TNF superfamily cytokine (TNFSF14). Human in vitro studies using placental villous explants demonstrated that increased HIF-1α resulting from ADORA2B activation facilitates the induction of CD73, ADORA2B, and FLT-1 expression. Overall, we demonstrated that (a) elevated placental HIF-1α by AT1 -AA or LIGHT upregulates CD73 and ADORA2B expression and (b) enhanced adenosine signaling through upregulated ADORA2B induces placental HIF-1α expression, which creates a positive feedback loop that promotes FLT-1 expression leading to disease development. Our results suggest that adenosine-based therapy targeting the malicious cycle of placental adenosine signaling may elicit therapeutic effects on PE.

Chronic obstructive pulmonary disease (COPD) is a progressive condition of chronic bronchitis, small airway obstruction, and emphysema that represents a leading cause of death worldwide. While inflammation, fibrosis, mucus hypersecretion, and metaplastic epithelial lesions are hallmarks of this disease, their origins and dependent relationships remain unclear. Here we apply single-cell cloning technologies to lung tissue of patients with and without COPD. Unlike control lungs, which were dominated by normal distal airway progenitor cells, COPD lungs were inundated by three variant progenitors epigenetically committed to distinct metaplastic lesions. When transplanted to immunodeficient mice, these variant clones induced pathology akin to the mucous and squamous metaplasia, neutrophilic inflammation, and fibrosis seen in COPD. Remarkably, similar variants pre-exist as minor constituents of control and fetal lung and conceivably act in normal processes of immune surveillance. However, these same variants likely catalyze the pathologic and progressive features of COPD when expanded to high numbers.

BACKGROUND Recent guidelines recommend that patients with immunoglobulin A nephropathy (IgAN) and proteinuria 0.5-1 g/d and >1 g/d be treated with long-term renin-angiotensin system blockade (RASB). This study investigated whether patients with IgAN and persistent hematuria, but without proteinuria, can benefit from RASB. MATERIAL AND METHODS IgAN patients with persistent hematuria at four centers were recruited from January 2013 to December 2018. Patients were divided into those who did and did not receive long-term RASB. The primary outcome was the appearance of proteinuria, and the secondary outcomes were the decreased percentage of hematuria, rate of decline in estimated glomerular filtration rate (eGFR) and final blood pressure. The effects of RASB on these outcomes were assessed by multivariate Cox regression models and propensity score matching. RESULTS Of the 110 eligible patients, 44 (40.0%) received RASB and 66 (60.0%) did not. Treated patients had higher diastolic pressure. The unadjusted primary outcome, the appearance of proteinuria, was significantly less frequent in individuals who were than who were not treated with RASB. Multivariate Cox regression showed that RASB reduced the risk of the primary outcome and the levels of hematuria. The rate of eGFR decline and final blood pressure did not differ in the two groups. CONCLUSIONS RASB reduced the risk of proteinuria development and increased the remission of hematuria in patients with IgAN who presented with persistent hematuria alone. RASB, however, did not affect blood pressure in patients without hypertension and did not affect the rate of eGFR decline.