Activation of the IL-6/STAT3 pathway contributes to the pathogenesis of membranous nephropathy and is a target for Mahuang Fuzi and Shenzhuo Decoction (MFSD) to repair podocyte damage.

BACKGROUND: Primary membranous nephropathy (PMN) is an autoimmune glomerular disease. IL-6 is a potential therapeutic target for PMN. Previous clinical studies have demonstrated the effectiveness of Mahuang Fuzi and Shenzhuo Decoction (MFSD) in treating membranous nephropathy. However, the mechanism of action of MFSD remains unclear. METHODS: Serum IL-6 levels were measured in patients with PMN and healthy subjects. The passive Heymann nephritis (PHN) rat model was established, and high and low doses of MFSD were used for intervention to observe the repair effect of MFSD on renal pathological changes and podocyte injury. RNA-seq was used to screen the possible targets of MFSD, and the effect of MFSD targeting IL-6/STAT3 was further verified by combining the experimental results. Finally, the efficacy of tocilizumab in PHN rats was observed. RESULTS: Serum IL-6 levels were significantly higher in PMN patients than in healthy subjects. These levels significantly decreased in patients in remission after MFSD treatment. MFSD treatment improved laboratory indicators in PHN rats, as well as glomerular filtration barrier damage and podocyte marker protein expression. Renal transcriptome changes showed that MFSD-targeted differential genes were enriched in JAK/STAT and cytokine-related pathways. MFSD inhibits the IL6/STAT3 pathway in podocytes. Additionally, MFSD significantly reduced serum levels of IL-6 and other cytokines in PHN rats. However, treatment of PHN with tocilizumab did not achieve the expected effect. CONCLUSION: The IL-6/STAT3 signaling pathway is activated in podocytes of experimental membranous nephropathy. MFSD alleviates podocyte damage by inhibiting the IL-6/STAT3 pathway.

Efficacy and safety of Mahuang Fuzi and Shenzhuo Decoction for treatment of primary membranous nephropathy: a multicenter prospective trial.

BACKGROUND: This study aims to undertake a comprehensive assessment of the effectiveness and safety profile of Mahuang Fuzi and Shenzhuo Decoction (MFSD) in the management of primary membranous nephropathy (PMN), within the context of a prospective clinical investigation. METHODS: A multicenter, open-label clinical trial was executed on patients diagnosed with PMN. These individuals were subjected to MFSD therapy for a duration of at least 24 months, with primary outcome of clinical remission rates. The Cox regression analysis was employed to discern the pertinent risk factors exerting influence on the efficacy of MFSD treatment, with scrupulous monitoring of any adverse events. RESULTS: The study comprised 198 participants in total. Following 24 months of treatment, the remission rate was 58.6% (116/198). Among the subgroup of 130 participants subjected to a 36-month follow-up, the remission rate reached 70% (91/130). Subgroup analysis revealed that neither a history of immunosuppressive therapy (HIST) nor an age threshold of ≥60 years exhibited a statistically significant impact on the remission rate at the 24-month mark (p > .05). Multivariate Cox regression analyses elucidated HIST, nephrotic syndrome, or mass proteinuria, and a high-risk classification as noteworthy risk factors in the context of MFSD treatment. Remarkably, no fatalities resulting from side effects were documented throughout the study's duration. CONCLUSIONS: This trial establishes the efficacy of MFSD as a treatment modality for membranous nephropathy. MFSD demonstrates a favorable side effect profile, and remission rates are consistent across patients, irrespective of HIST and age categories.

Experimental models for elderly patients with membranous nephropathy: Application and advancements.

Membranous nephropathy (MN) occurs predominantly in middle-aged and elderly individuals and ranks among the most prevalent etiologies of elderly nephrotic syndrome. As an autoimmune glomerular disorder characterized by glomerular basement membrane thickening and immune complex deposition, conventional MN animal models, including the Heymann nephritis rat model and the c-BSA mouse model, have laid a foundation for MN pathogenesis research. However, differences in target antigens between rodents and humans have impeded this work. In recent years, researchers have created antigen-specific MN animal models, primarily centered on PLA2R1 and THSD7A, employing diverse techniques that provide innovative in vivo research platforms for MN. Furthermore, significant advancements have been made in the development of in vitro podocyte models relevant to MN. This review compiles recent antigen-specific MN animal models and podocyte models, elucidates their immune responses and pathological characteristics, and offers insights into the future of MN experimental model development. Our aim is to provide a comprehensive resource for research into the pathogenesis of MN and the development of targeted therapies for older patients with MN to prolong lifespan and improve quality of life.

Tandem Oxidative Ritter Reaction/Hydration/Aldol Condensation of α-Arylketones with Propiolonitriles for the Construction of 3-Acyl-3-pyrrolin-2-ones.

A novel tandem oxidative Ritter reaction/hydration/aldol condensation of α-arylketones with substituted propiolonitriles has been developed. This protocol conveniently affords a wide range of functionalized 3-acyl-3-pyrrolin-2-ones through the efficient construction of four chemical bonds, a C-N bond, a C═C bond, and two C═O bonds, and the formation of one ring bearing an aza-quaternary center, which is ascribed to the strategical introduction of functionalized nitriles to this transformation. A reaction mechanism was proposed based on some control experiments.

Corrigendum: MicroRNAs: Potential mediators between particulate matter 2.5 and Th17/Treg immune disorder in primary membranous nephropathy.

[This corrects the article DOI: 10.3389/fphar.2022.968256.].

Cytokines network in primary membranous nephropathy.

There have been extensive studies on the immunological mechanism of primary membranous nephropathy (PMN). Autoantibodies, being the end product of humoral auto-immunity, matter much in diagnosis, therapy and prediction. Although PMN has been thought of as oligoinflammatory glomerulopathy, autoimmune diseases usually involve inflammation and it may be long-lasting. Cytokines are key mediators and effector molecules of inflammatory and humoral immune responses. Their function and network are helpful to understand the immune mechanism of PMN, but there is a lack of systematic summary. Accordingly, this review explores the advance of cytokines in PMN, and clarifies whether inflammation involves in the pathological process of PMN, based on which certain cytokines are proposed as potential biomarkers or therapeutic targets, and the importance of updating existing therapy regimens is highlighted.

MicroRNAs: Potential mediators between particulate matter 2.5 and Th17/Treg immune disorder in primary membranous nephropathy.

Primary membranous nephropathy (PMN), is an autoimmune glomerular disease and the main reason of nephrotic syndrome in adults. Studies have confirmed that the incidence of PMN increases yearly and is related to fine air pollutants particulate matter 2.5 (PM2.5) exposure. These imply that PM2.5 may be associated with exposure to PMN-specific autoantigens, such as the M-type receptor for secretory phospholipase A2 (PLA2R1). Emerging evidence indicates that Th17/Treg turns to imbalance under PM2.5 exposure, but the molecular mechanism of this process in PMN has not been elucidated. As an important indicator of immune activity in multiple diseases, Th17/Treg immune balance is sensitive to antigens and cellular microenvironment changes. These immune pathways play an essential role in the disease progression of PMN. Also, microRNAs (miRNAs) are susceptible to external environmental stimulation and play link role between the environment and immunity. The contribution of PM2.5 to PMN may induce Th17/Treg imbalance through miRNAs and then produce epigenetic affection. We summarize the pathways by which PM2.5 interferes with Th17/Treg immune balance and attempt to explore the intermediary roles of miRNAs, with a particular focus on the changes in PMN. Meanwhile, the mechanism of PM2.5 promoting PLA2R1 exposure is discussed. This review aims to clarify the potential mechanism of PM2.5 on the pathogenesis and progression of PMN and provide new insights for the prevention and treatment of the disease.

Level of interleukin-35 in patients with idiopathic membranous nephropathy and its predictive value for remission time.

Objective: As a member of interleukin-12 family, interleukin-35 (IL-35) plays an important regulatory role in immune response. The relationship between IL-35 and idiopathic membranous nephropathy (IMN) is still unclear, and the purpose of this study is to clarify the relationship between IL-35 and disease activity and remission of IMN. Methods: This study was a single-center, retrospective study in which all patients were diagnosed with IMN by renal biopsy or aPLA2R titer and treated with Mahuang Fuzi and Shenzhuo Decoction (MFSD). A follow-up was conducted with the endpoint of clinical complete or partial remission (CR+PR). Levels of serum IL-35 were measured and its relationship with IMN remission were analyzed. The regulatory T cell (Treg) and inducible IL-35 producing Tregs (iTR35) in peripheral blood of IMN patients were detected by flow cytometry. Results: A total of 76 IMN patients (age 51.95 ± 13.29) were followed-up for 18 (12, 24) months. The level of serum IL-35 in all patients increased after treatment, but the degree of increase in remission group was significantly higher than that in no remission (NR) group (117.6% vs 83.7%, P<0.01). The baseline IL-35 level in remission group was higher than that in NR group (174.87 vs.151.87 pg/ml, P=0.016). Cox regression analysis showed that baseline IL-35 level was a independent risk factor for IMN remission (HR 1.081, 95%CI 1.048-1.116, P<0.001). Patients with baseline IL-35 lower than the lower quartile (≤145.49 pg/ml) had an average remission time twice as long as those with baseline IL-35 higher than the upper quartile (> 203.05 pg/ml) (12mon vs. 24mon, P<0.01). The baseline IL-35 can predict the remission time of IMN patients with either aPLA2R positive (AUC=0.673) or negative (AUC=0.745). Analysis of 18 patients with IMN showed that IL-35 level had a higher correlation with iTR35, but not Treg (r=0.613, P<0.05). Conclusions: The level of IL-35 in patients with IMN showed an increasing trend with the progress of treatment, and the baseline IL-35 could predict the remission time of IMN patients, including those patients with negative aPLA2R. The level of IL-35 is related to the number of iTR35 cells.

Association Between Diet-Related Inflammation and COPD: Findings From NHANES III.

Background and Aims: Little is known about diet-related inflammation in chronic obstructive pulmonary disease (COPD). In this study, we aimed to explore the association between COPD and dietary inflammatory index (DII) scores in adults over 40 years old. Methods: Data were obtained from the 2013 to 2018 National Health and Nutrition Examination Survey (NHANES). In the present study, 9,929 participants were included and analyzed. The DII score was calculated and divided into tertiles. Logistic regression analysis was performed to determine the odds ratios of DII tertiles. Results: Participants were categorized into COPD (565, 5.69%) and non-COPD groups (9,364, 94.31%) according to interview information. COPD individuals had higher DII scores than non-COPD individuals (0.429 ± 1.809 vs. -0.191 ± 1.791, p < 0.001). The highest DII score tertile included 46.55% of COPD individuals was associated with lower family incomes and education and a higher smoking rate (p < 0.01). The odds ratios (95% CIs) of COPD according to logistic regression were 0.709 (0.512-0.982) for T1 and 0.645 (0.475-0.877) for T2 of the DII score (p = 0.011). Conclusion: Higher DII scores were positively correlated with COPD in participants over 40 years old. These results further support that diet can be used as an intervention strategy for COPD management.

Comparison of Different Clinical Prognostic Scores in Patients with Pulmonary Embolism and Active Cancer.

OBJECTIVE: This article aimed to validate and compare the prognostic performance of generic scores (Pulmonary Embolism Severity Index [PESI] and Hestia) and cancer-specific pulmonary embolism (PE)/venous thromboembolism (VTE) scales (Registro Informatizado de la Enfermedad TromboEmbólica [RIETE], POMPE-C, and modified Ottawa) in PE patients with active cancer. METHODS: A retrospective study was conducted among 460 patients with PE and active cancer. The primary outcome was 30-day overall mortality. Secondary outcomes were 30-day PE-related death and overall adverse outcomes. The prognostic accuracy of clinical scores was determined using receiver operating characteristic (ROC) curve analysis. RESULTS: Within 30 days, 18.0% of patients died, 2.0% suffered major bleeding, and 0.2% presented recurrence of VTE. All scales showed a high area under the ROC curve (AUC) for predicting 30-day overall mortality except modified Ottawa (0.74 [0.70-0.78] for PESI, Hestia, and RIETE; 0.78 (0.74-0.81) for POMPE-C; 0.64 (0.59-0.68) for modified Ottawa]. PESI divided the least patients (9.1%) into low risk, followed by modified Ottawa (17.0%). Hestia stratified the most patients (65.4%) as low risk. But overall mortality of low-risk patients based on these three scales is high (>5%). RIETE and POMPE-C both classified 30.9% of patients as low risk, and low-risk patients stratified by these two scales presented a low overall mortality (1.4 and 3.5%). Similar predictive performance was found for 30-day PE-related death and overall adverse outcomes in these scores. CONCLUSION: Cancer-specific PE prognostic scores (RIETE and POMPE-C) performed better than generic scales (PESI and Hestia) and a cancer-specific VTE prognostic scale (modified Ottawa) in identifying low-risk PE patients with active cancer who may be suitable for outpatient treatment.

A mobile terminal application program was used for endotracheal tube cuff pressure measurement.

We studied the application of a mobile terminal application program in endotracheal tube (ETT) cuff pressure measurement to improve the implementation rate of scientific ETT cuff pressure measurement and to ensure that the pressure falls within the recommended range. A pre-post controlled study lasting for 18 months was undertaken in a 40-bed general intensive care unit (GICU). This included a 6-month baseline period (baseline group) and a 6-month intervention period (intervention group). The mobile terminal application program was applied to monitor the cuff pressure of endotracheal intubation as an intervention measure during the intervention period. ETT pressure was the main outcome measure, while gender, age, causes for ICU admission, sedation score, duration of prior intubation, size of ETT, and number of VAP patients were secondary outcomes. ETT cuff pressure was monitored 742 times in both the baseline group and the intervention group. A total of 56.9% of the cuff pressure measurements in the baseline group were within the recommended range, while 78.4% of measurements in the intervention group were within the recommended range, reflecting a statistically significant difference (P < 0.05). The application of the mobile terminal application program used for ETT cuff pressure measurement could improve the percentage of ETT cuff pressure measurements falling within the recommended range.

Inhaled corticosteroids and risk of lung cancer: A systematic review and meta-analysis.

INTRODUCTION: Current studies investigating the association between inhaled corticosteroid (ICS) use and risk of lung cancer have yielded inconsistent findings. The aim of this systematic review and meta-analysis was to pool all currently available data to estimate this association. METHODS: We systematically searched MEDLINE (1946 to July 2020), EMBASE (1974 to July 2020) and the Cochrane Library (June 2020) via Ovid to identify relevant articles investigating the association between the ICS use and the risk of lung cancer. Random-effects analysis was used to calculate pooled relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: Ten articles including 234 920 patients were analysed. ICS use was identified to have a decreased risk of lung cancer in chronic obstructive pulmonary disease (8 studies, 1806 patients; RR = 0.73, 95% CI: 0.61-0.87, P < .01; I2  = 60.0 %), asthma (1 study, 41 438 patients; RR = 0.44, 95% CI: 0.34-0.57, P < .01) and mixed (1 study, 46 225 patients; RR = 0.79, 95% CI: 0.69-0.90, P < .01) patients. The findings of reduced risk of lung cancer were consistent in all subgroup analyses except for the short-term follow-up (≤5 years) (RR = 0.94, 95% CI: 0.81-1.07, P = .34) and free of immortal time bias (RR = 0.94, 95% CI: 0.82-1.08, P = .38) subgroups. CONCLUSIONS: The present study suggested that ICS use was associated with decreased risk of lung cancer. However, our findings should be interpreted with caution because most original studies were judged to be at high risk of immortal time bias.

Comparison between the Khorana prediction score and Caprini risk assessment models for assessing the risk of venous thromboembolism in hospitalized patients with cancer: a retrospective case control study.

OBJECTIVES: This study aimed to evaluate the optimal risk assessment model (RAM) to stratify the risk of venous thromboembolism (VTE) in hospitalized patients with cancer. We examined and compared the VTE predictive ability of the Khorana score (KS) and the Caprini RAM in hospitalized cancer patients. METHODS: We performed a retrospective case-control study among hospitalized cancer patients admitted to a comprehensive hospital in China from January 2015 to December 2016. A total of 221 cases were confirmed to have VTE during hospitalization and 221 controls were selected randomly. The Caprini RAM and KS were implemented and the individual scores of each risk factor were summed to generate a cumulative risk score. Meanwhile, the sensitivity, specificity, areas under curve of the receiver operating characteristic curve and calibration of these 2 models were analysed. RESULTS: Significant differences were observed in risk factors between VTE and non-VTE hospitalized cancer patients and the VTE risk increased significantly with an increase in the cumulative KS or Caprini RAM score. A classification of 'high risk' according to KS and Caprini RAM was associated with 2.272-fold and 3.825-fold increases in VTE risk, respectively. However, the Caprini RAM could identify 82.4% of the VTE cases that required preventive anticoagulant therapy according to American College of Chest Physicians guidelines, whereas the KS could only identify 35.3% of the VTE cases. In addition, the areas under curve of Caprini RAM were significantly higher than those of the KS (0.705 ± 0.024 vs 0.581 ± 0.025, P < 0.001), with a best cut-off value of 5 score, which happened to be the cut-off value for high risk of VTE in Caprini RAM. Both Caprini RAM and KS showed an excellent calibration curve (0.612 vs 0.141, P > 0.05), but the risk of VTE events predicted by Caprini seemed closer to the observed risk of VTE events. CONCLUSIONS: The Caprini RAM was found to be more effective than the KS in identifying hospitalized patients with cancer at risk of VTE.

Early prediction of extubation failure in patients with severe pneumonia: a retrospective cohort study.

Backgroud: Severe pneumonia is one of the most common causes for mechanical ventilation. We aimed to early identify severe pneumonia patients with high risk of extubation failure in order to improve prognosis. METHODS: From April 2014 to December 2015, medical records of intubated patients with severe pneumonia in intensive care unit were retrieved from database. Patients were divided into extubation success and failure groups, and multivariate logistic regressions were performed to identify independent predictors for extubation failure. RESULTS: A total of 125 eligible patients were included, of which 82 and 43 patients had extubation success and failure, respectively. APACHE II score (odds ratio (OR) 1.141, 95% confident interval (CI) 1.022-1.273, P = 0.019, cutoff at 17.5), blood glucose (OR 1.122, 95%CI 1.008-1.249, P = 0.035, cutoff at 9.87 mmol/l), dose of fentanyl (OR 3.010, 95%CI 1.100-8.237, P = 0.032, cutoff at 1.135 mg/d), and the need for red blood cell (RBC) transfusion (OR 2.774, 95%CI 1.062-7.252, P = 0.037) were independent risk factors for extubation failure. CONCLUSION: In patients with severe pneumonia, APACHE II score > 17.5, blood glucose > 9.87 mmol/l, fentanyl usage > 1.135 mg/d, and the need for RBC transfusion might be associated with higher risk of extubation failure.

The impact of Candida spp airway colonization on clinical outcomes in patients with ventilator-associated pneumonia: A systematic review and meta-analysis.

BACKGROUND: Previous studies have drawn different conclusions about the impact of Candida airway colonization on clinical outcomes in patients with ventilator-associated pneumonia (VAP). METHODS: We searched PubMed, the Cochrane Library, Embase (via OVID), and Web of Science database. We included both retrospective and prospective observational studies. The mean difference (MD) or risk ratio (RR) with 95% confidence intervals (CI) were applied to assess the association between Candida colonization and clinical outcomes. RESULTS: A total of 8 studies with 1,661 patients were pooled in our final studies. Compared with patients with VAP without Candida colonization, patients with Candida colonization had significantly longer durations of mechanical ventilation (MD, 1.93; 95% CI, 0.53-3.33). The intensive care unit (ICU) length of stay seems to be longer among Candida colonized patients than noncolonized patients, although the results were not so significant (MD, 1.15; 95% CI, -1.04 to 3.34). Patients with colonization had higher 28-day mortality and ICU mortality than those without colonization (28-day mortality: RR, 1.64; 95% CI, 1.27-2.12; ICU mortality: RR, 1.57; 95% CI, 1.26-1.94). CONCLUSIONS: The presence of Candida spp airway colonization is associated with longer durations of mechanical ventilation, higher 28-day mortality, higher ICU mortality, and probably longer ICU length of stay compared with the absence of colonization in patients with VAP.

Deciphering the regulatory and catalytic mechanisms of an unusual SAM-dependent enzyme.

S-adenosyl-1-methionine (SAM)-dependent enzymes regulate various disease-related behaviors in all organisms. Recently, the leporin biosynthesis enzyme LepI, a SAM-dependent enzyme, was reported to catalyze pericyclic reactions in leporin biosynthesis; however, the mechanisms underlying LepI activation and catalysis remain unclear. This study aimed to investigate the molecular mechanisms of LepI. Here, we reported crystal structures of LepI bound to SAM/5'-deoxy-5'-(methylthio) adenosine (MTA), S-adenosyl-homocysteine (SAH), and SAM/substrate states. Structural and biochemical analysis revealed that MTA or SAH inhibited the enzyme activities, whereas SAM activated the enzyme. The analysis of the substrate-bound structure of LepI demonstrated that this enzymatic retro-Claisen rearrangement was primarily driven by three critical polar residues His133, Arg197, Arg295 around the active site and assisted by SAM with unclear mechanism. The present studies indicate that the unique mechanisms underlying regulatory and catalysis of the unusual SAM-dependent enzyme LepI, not only strengthening current understanding of the fundamentally biochemical catalysis, but also providing novel insights into the design of SAM-dependent enzyme-specific small molecules.

Structural and functional insights into the regulation of the lysis-lysogeny decision in viral communities.

Communication is vital for all organisms including microorganisms, which is clearly demonstrated by the bacterial quorum-sensing system. However, the molecular mechanisms underlying communication among viruses (phages) via the quorum-sensing-like 'arbitrium' system remain unclear. Viral or host densities are known to be related to an increased prevalence of lysogeny; however, how the switch from the lytic to the lysogenic pathway occurs is unknown. Thus, we sought to reveal mechanisms of communication among viruses and determine the lysogenic dynamics involved. Structural and functional analyses of the phage-derived SAIRGA and GMPRGA peptides and their corresponding receptors, phAimR and spAimR, indicated that SAIRGA directs the lysis-lysogeny decision of phi3T by modulating conformational changes in phAimR, whereas GMPRGA regulates the lysis-lysogeny pathway by stabilizing spAimR in the dimeric state. Although temperate viruses are thought to share a similar lytic-lysogenic cycle switch model, our study suggests the existence of alternative strain-specific mechanisms that regulate the lysis-lysogeny decision. Collectively, these findings provide insights into the molecular mechanisms underlying communication among viruses, offering theoretical applications for the treatment of infectious viral diseases.

Assessment of the Risk of Venous Thromboembolism in Medical Inpatients using the Padua Prediction Score and Caprini Risk Assessment Model.

AIM: The optimal risk assessment model (RAM) to stratify the risk of venous thromboembolism (VTE) in medical inpatients is not known. We examined and compared how well the Padua Prediction Score (PPS) and the Caprini RAM stratify VTE risk in medical inpatients. METHODS: We undertook a retrospective case-control study among medical inpatients admitted to a large general hospital in China during a 4-year period. In total, 902 cases were confirmed to have VTE during hospitalization and 902 controls were selected randomly to match cases by medical service. RESULTS: The VTE risk increased significantly with an increase of the cumulative PPS or Caprini RAM score. A PPS and Caprini RAM "high risk" classification was, respectively, associated with a 5.01-fold and 4.10-fold increased VTE risk. However, the Caprini RAM could identify 84.3% of the VTE cases to receive prophylaxis according to American College of Chest Physicians guidelines, whereas the PPS could only identify 49.1% of the VTE cases. In the medical inpatients studied, five risk factors seen more frequently in VTE cases than in controls in the Caprini RAM were not included in the PPS. The Caprini RAM risk levels were linked almost perfectly to in-hospital and 6-month mortality. CONCLUSIONS: Both the PPS and Caprini RAM can be used to stratify the VTE risk in medical inpatients effectively, but the Caprini RAM may be considered as the first choice in a general hospital because of its incorporation of comprehensive risk factors, higher sensitivity to identify patients who may benefit from prophylaxis, and potential for prediction of mortality.