Fraxetin pretreatment alleviates cisplatin-induced kidney injury by antagonizing autophagy and apoptosis via mTORC1 activation.

Cisplatin-induced kidney injury (CKI) is a common complication of chemotherapy. Fraxetin, derived from Fraxinus bungeana A. DC. bark, has antioxidant, anti-inflammatory, and anti-fibrotic effects. This study aims to investigate fraxetin's effects on CKI and its underlying mechanism in vivo and in vitro. Tubular epithelial cells (TECs) and mice were exposed to cisplatin with and without fraxetin preconditioning assess fraxetin's role in CKI. TECs autophagy was observed using transmission electron microscopy. Apoptosis levels in animal tissues were measured using TUNEL staining. The protective mechanism of fraxetin was explored through pharmacological and genetic regulation of mTORC1. Molecular docking was used to identify potential binding sites between fraxetin and mTORC1. The results indicated that fraxetin pretreatment reduced cisplatin-induced kidney injury in a time- and concentration-dependent way. Fraxetin also decreased autophagy in TECs, as observed through electron microscopy. Tissue staining confirmed that fraxetin pretreatment significantly reduced cisplatin-induced apoptosis. Inhibition of mTORC1 using rapamycin or siRNA reversed the protective effects of fraxetin on apoptosis and autophagy in cisplatin-treated TECs, while activation of mTORC1 enhanced fraxetin's protective effect. Molecular docking analysis revealed that fraxetin can bind to HEAT-repeats binding site on mTORC1 protein. In  summary, fraxetin pretreatment alleviates CKI by antagonizing autophagy and apoptosis via mTORC1 activation. This provides evidence for the potential therapeutic application of fraxetin in CKI.

Efficacy and safety of belimumab in patients with lupus nephritis: a real-world retrospective observational study.

OBJECTIVES: To evaluate the differences in efficacy and safety between Lupus Nephritis (LN) patients who received belimumab plus standard therapy and those who received only standard therapy in real world practice. METHODS: Patients diagnosed with LN at the First Affiliated Hospital of Wenzhou Medical University from November 2012 to July 2023 were identified, and eligible cases were divided into two groups according to whether they received additional treatment with belimumab during the course of the disease. RESULTS: A total of 1,169 LN patients were identified from our follow-up database. 112 patients receiving add-on treatment with belimumab (BLM group) and 112 control patients matched for relevant baseline characteristics were enrolled in this study. The median duration of treatment with belimumab was 13.82 [7.24, 20.29] months. Compared with the control group, the BLM group had more significant improvement in disease activity indicators such as serum albumin and complement levels, significantly lower B cell count, immunoglobulin, and earlier first attainment of renal remission, but there was no significant improvement in renal function and kidney-related events or death during the 2-year follow-up period. In the BLM group, the treatment effect of belimumab was more prominent in patients with lower levels of proteinuria. The safety profile of belimumab treatment was favorable, with a lower incidence of respiratory tract infection in the BLM group than in the control group during the follow-up period (p= 0.015). CONCLUSIONS: This real-world study revealed that add-on treatment with belimumab provided better disease remission, and the therapeutic effect was more significant in patients with lower proteinuria levels. In addition, it had a favorable safety profile and reduced the risk of respiratory tract infection.

Clinical Significance of Persistent Hematuria Degrees in Primary IgA Nephropathy: A Propensity Score-Matched Analysis of a 10-Year Follow-Up Cohort.

INTRODUCTION: The clinical significance of persistent hematuria degrees has not been expounded in primary IgA nephropathy (IgAN) and requires further research. METHODS: From January 2003 to May 2022, a total of 684 IgAN patients with persistent hematuria were enrolled to conduct a retrospective single-center study. Patients whose hematuria degree at baseline was higher than the second tertiles of the whole were included in the high-degree hematuria cohort (Hh), and the low-degree hematuria cohort (Lh) was constructed with 1:1 matched cases from the rest according to age, gender, and estimated glomerular filtration rate (eGFR) at baseline and follow-up time. Survival was determined using the Kaplan-Meier method (K-M) and generalized linear mixed-effects model (GLMM). Risk factors for survival were determined according to the Cox proportional hazards model. RESULTS: Both the Hh and Lh consisted of 228 cases. While the demographic data and the renal function at baseline were matched, both the K-M (p = 0.02) and GLMM (p = 0.04) proved that the prognosis of the Hh was significantly worse than that of the Lh within 10 years of follow-up. The higher persistent hematuria degree was an independent risk factor (3.93; 95% confidence interval, 1.33-11.6) associated with reaching the endpoint (eGFR decreased from the baseline ≥30% continuously or reached end-stage renal disease [ESRD]). The Hh had a significantly higher proportion of crescent (p = 0.003). The prognosis of the Hh was significantly worse than that of the Lh when accompanied by the crescent and presented an indistinct difference if the crescent was absent. CONCLUSIONS: The clinicopathologic manifestation of IgAN patients with persistent high-degree hematuria was severer, and the prognosis was worse than those with persistent low-degree hematuria.

Clinical significance of massive proteinuria in primary IgA nephropathy with and without nephrotic syndrome: a single center cohort study.

BACKGROUND: Both primary IgA nephropathy (IgAN) with and without nephrotic syndrome (NS) can present massive proteinuria (24-h urinary protein ≥3.5 g/d). The clinical significance of massive proteinuria may be different in the two entities and needs further research. METHODS: Data of 1870 patients with biopsy-proven IgAN in our hospital from January 2011 to December 2022 was retrospectively reviewed. A total of 242 IgAN patients with massive proteinuria were enrolled. Patients who presented with nephrotic syndrome at renal biopsy were included in the IgAN with NS cohort (IgAN-NS). The IgAN with nephrotic-range proteinuria cohort (IgAN-NR) consisted of 1:1 matched cases from the remaining according to age, gender, estimated glomerular filtration rate (eGFR) at baseline, and follow-up time. The clinical and pathological characteristics between the two cohorts were analyzed. RESULTS: The IgAN-NS had a significantly higher proteinuria level than the IgAN-NR (p < .001). Cluster analysis revealed that proteinuria was associated with lipids in IgAN-NS, while it was associated with inflammatory indicators in IgAN-NR. When the complete remission of proteinuria (CR) was not achieved, the Kaplan-Meier analysis showed the prognosis of IgAN-NS was significantly worse than that of IgAN-NR (p = .04). Then, our GLMM model and line chart showed that the serum albumin level of the IgAN-NR was always evidently higher than that of the IgAN-NS while the significant difference in urinary albumin/creatinine ratio between the two cohorts gradually disappeared during the short-term follow-up (1 year). Moreover, the Cox regression analysis showed that the increased serum albumin was an independent protective factor for the poor outcomes (eGFR decreased from the baseline ≥ 30% continuously or reached end-stage renal disease [ESRD]). CONCLUSION: The IgAN-NS had poorer clinicopathologic manifestation than IgAN-NR, including severer massive proteinuria. When the CR was not achieved, the prognosis of IgAN-NS was inferior to that of the IgAN-NR.

Polyphyllin I attenuates cognitive impairments and reduces AD-like pathology through CIP2A-PP2A signaling pathway in 3XTg-AD mice.

Polyphyllin I (PPI) is a natural phytochemical drug isolated from plants which can inhibit the proliferation of cancer cells. One of the PPI tumor-inhibitory effects is through downregulating the expression of Cancerous Inhibitor of PP2A (CIP2A), the latter, is found upregulated in Alzheimer's disease (AD) brains and participates in the development of AD. In this study, we explored the application of PPI in experimental AD treatment in CIP2A-overexpressed cells and 3XTg-AD mice. In CIP2A-overexpressed HEK293 cells or primary neurons, PPI effectively reduced CIP2A level, activated PP2A, and decreased the phosphorylation of tau/APP and the level of Aß. Furthermore, synaptic protein levels were restored by PPI in primary neurons overexpressing CIP2A. Animal experiments in 3XTg-AD mice revealed that PPI treatment resulted in decreased CIP2A expression and PP2A re-activation. With the modification of CIP2A-PP2A signaling, the hyperphosphorylation of tau/APP and Aß overproduction were prevented, and the cognitive impairments of 3XTg-AD mice were rescued. In summary, PPI ameliorated AD-like pathology and cognitive impairment through modulating CIP2A-PP2A signaling pathway. It may be a potential drug candidate for the treatment of AD.

Dysregulation of tRNA-derived small RNAs and their potential roles in lupus nephritis.

OBJECTIVE: Lupus nephritis (LN) is a major end-organ complication of systemic lupus erythematosus (SLE), and the molecular mechanism of LN is not completely clear. Accumulating pieces of evidence indicate the potential vital role of tRNA-derived small RNAs (tsRNAs) in human diseases. Current study aimed to investigate the potential roles of tsRNAs in LN. METHODS: We herein employed high-throughput sequencing to screen the expression profiles of tsRNAs in renal tissues of the LN and control groups. To validate the sequencing data, we performed quantitative real-time PCR (qRT-PCR) analysis. Correlational analysis of verified tsRNAs expression and clinical indicators was conducted using linear regression. The potential target genes were also predicted. The biological functions of tsRNAs were annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. RESULTS: Our findings revealed that the expression profiles of tsRNAs were significantly altered in the kidney tissues from LN patients compared with control. Overall, 160 tsRNAs were significantly dysregulated in the LN group, of which 79 were upregulated, whereas 81 were downregulated. Subsequent qRT-PCR results confirmed the different expression of candidate tsRNAs. Correlation analysis results found that expression of verified tsRNAs were correlated to clinical indicators. The target prediction results revealed that verified tsRNAs might act on 712 target genes. Further bioinformatics analysis uncovered tsRNAs might participate in the pathogenesis of LN through several associated pathways, including cell adhesion molecules, MAPK signaling pathway, PI3K-Akt signaling pathway and B cell receptor signaling pathway. CONCLUSION: This study provides a novel insight for studying the mechanism of LN.

Clinicopathological and prognostic study of IgA-dominant postinfectious glomerulonephritis.

BACKGROUND: The clinicopathological and prognostic features of IgA-dominant postinfectious glomerulonephritis and its difference from the primary IgA nephropathy remains to be investigated. METHODS: The clinical and pathological data of 6542 patients who underwent renal biopsy from 2009 to 2020 in our hospital were reviewed and 50 patients who met the selection criteria of IgA-dominant postinfectious glomerulonephritis were enrolled to conduct a retrospective and observational single-center study. The selection criteria were: meet the characteristics of IgA dominance or codominance in immunofluorescence, and conform to 3 of the following 5 criteria: 1.Clinical or laboratory evidence show that there is infection before or at the onset of glomerulonephritis; 2.The level of serum complement decreased; 3.Renal pathology is consistent with endocapillary proliferative glomerulonephritis; 4. Glomerular immunofluorescence staining showed complement C3 dominance or codominance; 5. Hump-like subepithelial immune complex deposition was observed under electron microscopy. According to age, sex, renal function (estimated glomerular filtration rate, eGFR) and follow-up time, the control group was constructed with 1:3 matched cases of primary IgA nephropathy. The clinicopathological and prognostic differences between the two groups were analyzed. RESULTS: The most common histological pattern of IgA-dominant postinfectious glomerulonephritis was acute endocapillary proliferative glomerulonephritis and exudative glomerulonephritis. Immunofluorescence showed mainly IgA deposition or IgA deposition only, mainly deposited in the mesangial area (deposition rate 100 %), with typical C3 high-intensity staining (intensity++~+++), mainly deposited in the mesangial area (deposition rate 92.0 %). The fluorescence intensity of kappa is usually not weaker than lambda. The probability of the appearance of typical hump-like electron deposition under electron microscopy is low. Compared to primary IgA nephropathy, patients with IgA-dominant postinfectious glomerulonephritis had higher proportion of crescents (p = 0. 005) and endocapillary hypercellularity (p < 0.001) in pathological manifestations. Using serum creatinine level doubled of the baseline or reached end-stage renal disease as the endpoint, the prognosis of IgA-dominant postinfectious glomerulonephritis patients was worse than that of primary IgA nephropathy patients (p = 0.013). CONCLUSIONS: The clinicopathological features of patients with IgA-dominant postinfectious glomerulonephritis was different from that of primary IgA nephropathy, and the prognosis was worse.

Long-term predictive value of acute kidney injury classification in diffuse proliferative lupus nephritis with acute kidney injury.

BACKGROUND: The long-term predictive ability of acute kidney injury (AKI) classification based on "Kidney Disease: Improving Global Outcomes"(KDIGO) AKI diagnosis criteria has not been clinically validated in diffuse proliferative lupus nephritis (DPLN) patients with AKI. Our objective was to assess the long-term predictive value of KDIGO AKI classification in DPLN patients with AKI. METHODS: Retrospective cohort study was conducted by reviewing medical records of biopsy-proven DPLN patients with AKI from the First Affiliated Hospital of Wenzhou Medical University between Jan 1, 2000 and Dec 31, 2014. Multivariate Cox regression and survival analysis were performed. RESULTS: One hundred sixty-seven DPLN patients were enrolled,82(49%) patients were normal renal function (No AKI), 40(24%) patients entered AKI-1 stage (AKI-1), 26(16%) patients entered AKI-2 stage (AKI-2) and 19(16%) patients entered AKI-3 stage (AKI-3). The mean follow-up of all patients was 5.1 ± 3.8 years. The patient survival without ESRD of all patients was 86% at 5 years and 79% at 10 years. The patient survival rate without ESRD at 10 yr was 94.5% for No AKI patients, 81.8% for AKI-1 patients, 44.9% for AKI-2 patients and 14.6% for AKI-3 patients. The area under the ROC curve for KDIGO AKI classification to predict the primary end point was 0.83 (95% CI: 0.73-0.93) (P < 0.001). In Cox regression analysis, AKI stage was independently associated with primary endpoint, with an adjusted hazard ratio (HR) of 3.8(95% CI 2.1-6.7, P < 0.001). CONCLUSION: Severity of AKI based on KDIGO AKI category was associated with progression to ESRD in DPLN patients. Analytical data also confirmed the good discriminative power of the KDIGO AKI classification system for predicting long-term prognosis of DPLN patients with AKI.

Assaying kinase activity of the TPL-2/NF-κB1 p105/ABIN-2 complex using an optimal peptide substrate.

The MKK1/2 kinase tumour progression locus 2 (TPL-2) is critical for the production of tumour necrosis factor alpha (TNFα) in innate immune responses and a potential anti-inflammatory drug target. Several earlier pharmaceutical company screens with the isolated TPL-2 kinase domain have identified small-molecule inhibitors that specifically block TPL-2 signalling in cells, but none of these have progressed to clinical development. We have previously shown that TPL-2 catalytic activity regulates TNF production by macrophages while associated with NF-κB1 p105 and ABIN-2, independently of MKK1/2 phosphorylation via an unknown downstream substrate. In the present study, we used a positional scanning peptide library to determine the optimal substrate specificity of a complex of TPL-2, NF-κB1 p105 and ABIN-2. Using an optimal peptide substrate based on this screen and a high-throughput mass spectrometry assay to monitor kinase activity, we found that the TPL-2 complex has significantly altered sensitivities versus existing ATP-competitive TPL-2 inhibitors than the isolated TPL-2 kinase domain. These results imply that screens with the more physiologically relevant TPL-2/NF-κB1 p105/ABIN-2 complex have the potential to deliver novel TPL-2 chemical series; both ATP-competitive and allosteric inhibitors could emerge with significantly improved prospects for development as anti-inflammatory drugs.

Baseline proteinuria level is associated with prognosis in idiopathic membranous nephropathy.

OBJECTIVES: This study aimed to investigate the unique prognostic, clinical, and renal histopathological characteristics of patients with idiopathic membranous nephropathy (IMN) with different levels of proteinuria. METHODS: This retrospective observational study included 190 IMN patients with low levels of proteinuria (low group), 193 IMN patients with medium levels of proteinuria (medium group), and 123 IMN patients with high levels of proteinuria (high group) treated between September 2006 and November 2015. Prognostic and baseline clinical and histopathological data were compared among the three groups. Poor prognostic events included the occurrence of a persistent 50% reduction in estimated glomerular filtration rate (eGFR), end-stage renal disease, or all-cause mortality. RESULTS: The severity of clinical symptoms and laboratory indices, such as blood pressure; extent of edema and hematuria; levels of fibrinogen, immunoglobulin (Ig)-G, complement (C)-4, total protein, albumin (ALB), and serum creatinine (SCr); and eGFR increased with increasing proteinuria (all p< .001). Based on renal histopathology, the extent of segmental sclerosis and balloon adhesion and renal interstitial lesion stage also increased in severity with increasing proteinuria (all p< .001). The Kaplan-Meier analysis showed that compared with patients with low and medium levels of proteinuria, patients with high levels of proteinuria had significantly lower cumulative poor event-free renal survival rates (p= .0039). CONCLUSIONS: Baseline proteinuria level is indicative of prognosis in IMN patients; the greater the extent of proteinuria is, the worse the prognosis.

NovelmiRNA-25 inhibits AMPD2 in peripheral blood mononuclear cells of patients with systemic lupus erythematosus and represents a promising novel biomarker.

BACKGROUND: Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease with various clinical manifestations. MicroRNAs (miRNAs) and immunometabolism are recognized as key elements in SLE pathogenesis; however, the relationship between miRNAs in peripheral blood mononuclear cells (PBMCs) and metabolism in SLE remains unclear. METHODS: We detected PBMC miRNA and mRNA profiles from 3 pooled SLE patients and 3 healthy controls (HCs) using next-generation sequencing, predicted miRNA targets in dysregulated mRNAs, predicted functions and interactions of differentially expressed genes using bioinformatics analysis, validated candidate miRNAs using qRT-PCR, and investigated the association between the expression of candidate miRNAs and SLE clinical characteristics. Moreover, we validated the direct and transcriptional regulatory effect of NovelmiRNA-25 on adenosine monophosphate deaminase 2 (AMPD2) using a dual-luciferase reporter assay and western blot and confirmed AMPD2 mRNA and protein expression in PBMCs using qRT-PCR and western blot, respectively. RESULTS: Multilayer integrative analysis of microRNA and mRNA regulation showed that 10 miRNAs were down-regulated and 19 miRNAs were up-regulated in SLE patient PBMCs compared with HCs. Bioinformatics analysis of regulatory networks between miRNAs and mRNAs showed that 19 miRNAs were related to metabolic processes. Two candidate miRNAs, NovelmiRNA-25 and miR-1273h-5p, which were significantly increased in the PBMCs of SLE patients (P < 0.05), represented diagnostic biomarkers with sensitivities of 94.74% and 89.47%, respectively (area under the curve = 0.574 and 0.788, respectively). NovelmiRNA-25 expression in PBMCs was associated with disease activity in SLE patients, in both active and stable groups (P < 0.05). NovelmiRNA-25 overexpression downregulated AMPD2 expression in HEK293T cells through direct targeting of the AMPD2 3'UTR (P < 0.01), while inhibition of NovelmiRNA-25 activity led to increased AMPD2 expression (P < 0.01). NovelmiRNA-25 overexpression also downregulated AMPD2 protein expression in HEK293T cells; AMPD2 protein expression in SLE patient PBMCs was decreased. Our results show that differentially expressed miRNAs play an important role in SLE. CONCLUSIONS: Our data demonstrate a novel mechanism in SLE development that involves the targeting of AMPD2 expression by NovelmiRNA-25. miRNAs may serve as novel biomarkers for the diagnosis and evaluation of disease activity of SLE and represent potential therapeutic targets for this disease.

TLR and TNF-R1 activation of the MKK3/MKK6-p38α axis in macrophages is mediated by TPL-2 kinase.

Previous studies suggested that Toll-like receptor (TLR) stimulation of the p38α MAP kinase (MAPK) is mediated by transforming growth factor-ß-activated kinase 1 (TAK1) activation of MAPK kinases, MKK3, MKK4 and MKK6. We used quantitative mass spectrometry to monitor tumour progression locus 2 (TPL-2)-dependent protein phosphorylation following TLR4 stimulation with lipopolysaccharide, comparing macrophages from wild-type mice and Map3k8(D270A/D270A) mice expressing catalytically inactive TPL-2 (MAP3K8). In addition to the established TPL-2 substrates MKK1/2, TPL-2 kinase activity was required to phosphorylate the activation loops of MKK3/6, but not of MKK4. MKK3/6 activation required IκB kinase (IKK) phosphorylation of the TPL-2 binding partner nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB1) p105, similar to MKK1/2 activation. Tumour necrosis factor (TNF) stimulation of MKK3/6 phosphorylation was similarly dependent on TPL-2 catalytic activity and IKK phosphorylation of NF-κB1 p105. Owing to redundancy of MKK3/6 with MKK4, Map3k8(D270A) mutation only fractionally decreased lipopolysaccharide activation of p38α. TNF activation of p38α, which is mediated predominantly via MKK3/6, was substantially reduced. TPL-2 catalytic activity was also required for MKK3/6 and p38α activation following macrophage stimulation with Mycobacterium tuberculosis and Listeria monocytogenes Our experiments demonstrate that the IKK/NF-κB1 p105/TPL-2 signalling pathway, downstream of TAK1, regulates MKK3/6 and p38α activation in macrophages in inflammation.

Risk factors of progressive IgA nephropathy which progress to end stage renal disease within ten years: a case-control study.

BACKGROUND: There were few related studies aiming to severe IgA nephropathy (IgAN) which could progress rapidly to end stage renal disease (ESRD) within ten years. To find valuable clinical or pathological factors and promising precautions is essential. METHODS: A single center case-control study was performed. Fifty ESRD patients with the primary cause of IgAN and a short renal survival time of less than ten years after diagnose were enrolled in the case group. One hundred IgAN patients with a renal survival time of more than ten years were enrolled in the control group. IgA Oxford classification scores, clinical data at baseline and during the follow-up were collected. Multivariate logistic regression was used to investigate factors associated with the development of ESRD. RESULTS: There were significant differences in baseline clinical data between these two groups, as well as the constituent ratio of Oxford MEST-score. Distinct differences were observed in time-average uric acid(TA-UA), time-average hemoglobin(TA-Hb), time-average albumin(TA-Alb), time-average total cholesterol(TA-TC) and time-average urinary protein(TA-P) during the follow-up. In multivariate logistic models, IgA Oxford score M1(OR = 5.10, P = 0.018) and eGFR(OR = 0.97, P = 0.039) at biopsy, TA-UA (OR = 2.06, P = 0.026) and TA-Hb (OR = 0.53, P = 0.022) during the follow-up were identified independent factors for developing ESRD. CONCLUSION: IgAN patients with pathological assessment of M1, low baseline eGFR, TA-Hb and high TA-UA were more likely to progress to ESRD, and should be paid more attention. Appropriate regulations of UA, Hb and urine protein after diagnose may be a promising treatment.

Analysis of potential risk factors for cancer incidence in patients with aristolochic acid nephropathy from Wenzhou, China.

BACKGROUND: The purpose of this study was to investigate the cancer incidence in patients with end-stage aristolochic acid nephropathy (AAN). METHODS: A total of 102 patients with end-stage AAN treated in our hospital between 2004 and 2013 were included in this study. The correlation of cancer incidence with age, gender, dosage of aristolochic acid (AA), the type of renal replacement therapies, and the polymorphisms of quinone oxidoreductase 1 (NQO1) C609T and cytochrome P450 1A1 (CYP1A1) A4889G was examined. RESULTS: The cancer incidence rate in our patients was 41.2% (42 in 102) including 39 cases of urinary cancer. The mortality rate in the patients with cancer was significantly higher than that in the patients without cancer (31%, 13/42 vs. 11.7%, 7/60, p<0.05). Thirteen patients developed cancer before entering end-stage renal disease (ESRD). Cancer incidence was significantly associated with the dosage of AA consumption (p=0.091). Hemodialysis, peritoneal dialysis and renal transplant did not affect the cancer incidence in our patients differently, but appeared to be associated with cancer at particular locations of urinary system. The patients undergoing hemodialysis seemed to more likely have bladder cancer (72.72%), while the patients receiving peritoneal dialysis appeared to develop cancer predominantly in the upper urinary tract (66.67%). CONCLUSIONS: The cancer initiation in our patients seems significantly correlate with the dosage of AA consumption. Different renal replacement therapies appear to be associated with cancer at particular locations of urinary system in our patients.

Puerarin suppresses macrophage M1 polarization to alleviate renal inflammatory injury through antagonizing TLR4/MyD88-mediated NF-κB p65 and JNK/FoxO1 activation.

BACKGROUND: Acute kidney injury (AKI) is a clinically common and serious renal dysfunction, characterized by inflammation and damage to tubular epithelial cells. Puerarin, an isoflavone derivative isolated from Pueraria lobata, has been proven to possess exceptional effectiveness in reducing inflammation. However, the effects and underlying mechanisms of puerarin on AKI remain uncertain. PURPOSE: This study investigated the possible therapeutic effects of puerarin on AKI and explored its underlying mechanism. STUDY DESIGN AND METHODS: The effects of puerarin on AKI and macrophage polarization were investigated in lipopolysaccharide (LPS)-induced or unilateral ureteral obstruction (UUO)-induced mouse models in vivo and LPS-treated macrophages (Raw264.7) in vitro. Additionally, the effects of puerarin on inflammation-related signaling pathways were analyzed. RESULTS: Administration of puerarin effectively alleviated kidney dysfunction and reduced inflammatory response in LPS-induced and UUO-induced AKI. In vitro, puerarin treatment inhibited the polarization of M1 macrophages and the release of inflammatory factors in Raw264.7 cells stimulated by LPS. Mechanistically, puerarin downregulated the activities of NF-κB p65 and JNK/FoxO1 signaling pathways. The application of SRT1460 to activate FoxO1 or anisomycin to activate JNK eliminated puerarin-mediated inhibition of JNK/FoxO1 signaling, leading to suppression of macrophage M1 polarization and reduction of inflammatory factors. Further studies showed that puerarin bound to Toll/interleukin-1 receptor (TIR) domain of MyD88 protein, hindering its binding with TLR4, ultimately resulting in downstream NF-κB p65 and JNK/FoxO1 signaling inactivation. CONCLUSIONS: Puerarin antagonizes NF-κB p65 and JNK/FoxO1 activation via TLR4/MyD88 pathway, thereby suppressing macrophage polarization towards M1 phenotype and alleviating renal inflammatory damage.

An enhanced machine learning approach for effective prediction of IgA nephropathy patients with severe proteinuria based on clinical data.

IgA Nephropathy (IgAN) is a disease of the glomeruli that may eventually lead to chronic kidney disease or kidney failure. The signs and symptoms of IgAN nephropathy are usually not specific enough and are similar to those of other glomerular or inflammatory diseases. This makes a correct diagnosis more difficult. This study collected data from a sample of adult patients diagnosed with primary IgAN at the First Affiliated Hospital of Wenzhou Medical University, with proteinuria ≥1 g/d at the time of diagnosis. Based on these samples, we propose a machine learning framework based on weIghted meaN oF vectOrs (INFO). An enhanced COINFO algorithm is proposed by merging INFO, Cauchy Mutation (CM) and Oppositional-based Learning (OBL) strategies. At the same time, COINFO and Support Vector Machine (SVM) were integrated to construct the BCOINFO-SVM framework for IgAN diagnosis and prediction. Initially, the proposed enhanced COINFO is evaluated using the IEEE CEC2017 benchmark problems, with the outcomes demonstrating its efficient optimization capability and accuracy in convergence. Furthermore, the feature selection capability of the proposed method is verified on the public medical datasets. Finally, the auxiliary diagnostic experiment was carried out through IgAN real sample data. The results demonstrate that the proposed BCOINFO-SVM can screen out essential features such as High-Density Lipoprotein (HDL), Uric Acid (UA), Cardiovascular Disease (CVD), Hypertension and Diabetes. Simultaneously, the BCOINFO-SVM model achieves an accuracy of 98.56%, with sensitivity at 96.08% and specificity at 97.73%, making it a potential auxiliary diagnostic model for IgAN.

Alternative ATPase domain interactions in eukaryotic Hsp70 chaperones.

Hsp70 molecular chaperones are essential components for maintaining protein homeostasis within cells. They interact with substrate or client proteins in a well characterised fashion that is regulated by ATP and supported by co-chaperones. In eukaryotes there is a vast array of Hsp70 isoforms that may facilitate adaption to a particular cellular compartment and distinct biological role. Emerging data indicate a novel type of interaction between Hsp70 and client protein that does not fit with the classical Hsp70 ATP regulated substrate mechanism. In this review, we highlight Hsp70 ATPase domain interactions with binding partners from various biological systems that we refer to as Hsp70 ATPase alternative binding proteins or HAAB proteins. We identify common mechanistic features that may define how Hsp70 operates when associating with proteins in this alternative HAAB mode of action.

Clinical significance of intrarenal vascular lesions in non-hypertensive patients with IgA nephropathy.

BACKGROUND: The clinical significance of intrarenal vascular lesions has not been elucidated in primary IgA nephropathy (IgAN), especially in non-hypertensive subjects. METHODS: From January 2003 to December 2020, data of 3435 patients with biopsy-proven IgAN were reviewed. Two hundred-forty non-hypertensive patients who met the criteria for IgAN and had intrarenal vascular lesions (IgAN-vas) were selected. The control cohort was constructed with 1:1 matched cases of non-hypertensive IgAN patients without vascular lesions according to age, gender, estimated glomerular filtration rate (eGFR) and follow-up time. RESULTS: The IgAN-vas cohort had significantly higher serum uric acid levels than the control IgAN cohort (P < 0.05); glomerulosclerosis was more common in IgAN-vas patients. Moreover, cluster analysis indicated that the serum uric acid level was associated with serum creatinine (s-Cr) levels in IgAN-vas while it was associated with serum lactate dehydrogenase (LDH) levels in control cases with IgAN. Both Kaplan-Meier analysis and generalized linear mixed-effects models revealed that the prognosis of the IgAN-vas cohort was significantly worse than that of the IgAN cohort after > 5 years of follow-up. Intimal thickening was an independent risk factor associated with reaching the endpoint (eGFR decrease ≥ 30% from the baseline or reaching end-stage renal disease [ESRD] or death). CONCLUSIONS: The prognosis of non-hypertensive patients with IgAN-vas was worse than that of matched individuals with IgAN. The clinicopathologic manifestation of IgAN-vas was more severe, and included a higher proportion of glomerulosclerosis, and a higher serum uric acid level correlated with renal function impairment.

Role of crescents for lupus nephritis in clinical, pathological and prognosis: a single-center retrospective cohort study.

BACKGROUND: Referring to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2018 pathological classification, we aim to reveal the significance of cellular/fibrocellular crescents in lupus nephritis (LN) patients. METHODS: Patients with LN proven by renal biopsy at the First Affiliated Hospital of Wenzhou Medical University from December 2001 to November 2017 were identified, and eligible cases were divided into two groups according to the presence or absence of cellular/fibrocellular crescents in renal biopsy tissues. RESULTS: A total of 401 LN patients were identified from our follow-up database, and 296 eligible LN patients were enrolled in the study. Of these patients, 146 patients in the group without cellular/fibrocellular crescents (non-crescent group) and 150 patients in the group with cellular/fibrocellular crescents (Crescent group). The median follow-up time of patients was 47 months, and a total of 54 patients progressed to the composite endpoint. Crescent group had higher serum creatinine, lower serum albumin, higher systemic lupus erythematosus (SLE) disease activity index, and higher activity index of renal tissue. The interaction between cellular/fibrocellular crescents and proteinuria at baseline was associated with the prognostic risk of LN (P = 0.006). In the group with proteinuria < 3.5 g/24 h, the prognosis of crescent group was significantly worse than of non-crescent group (P < 0.001), while in the group with proteinuria ≥ 3.5 g/24 h, there was no significant relationship between crescents and prognosis (p = 0.452). By multivariable Cox hazard analysis, positive anti-dsDNA, chronic index of renal biopsy tissue, cellular/fibrocellular crescents and its interaction with 24 h proteinuria were independent risk factors for poor prognosis of LN. CONCLUSIONS: LN patients with cellular/fibrocellular crescents had more severe and active disease features, and cellular/fibrocellular crescents is a risk factor for poor prognosis of LN. There was an interaction between cellular/fibrocellular crescents and proteinuria in predicting poor prognosis, and among patients with low levels of proteinuria at the time of renal biopsy, those with crescents had a worse long-term prognosis than those without crescents.

A novel method for synthesis of carbon dots and their applications in reactive oxygen species (ROS) and glucose detections.

A simple and novel method is proposed for preparation of water-soluble fluorescent carbon dots (C-dots), which have potential to be applied in detecting reactive oxygen species (ROS). The C-dots with high fluorescence quantum yield were created by hydrothermal methods with lactose as the carbon source and tris(hydroxylmethyl)aminomethane (Tris) as the surface passivation reagent. The C-dots have some unique characteristics such as excellent biocompatibility with a broad pH working range of 5-11 and high fluorescence, which makes them especially useful in the bio-detection field. The optical properties, surface groups, and element components of the prepared C-dots have been systematically studied by fluorescence spectroscopy. This facile approach is efficient and environmentally friendly and allows large-scale production of the C-dots without any further post-treatment. The C-dots have been adopted as probes for fluorescence turn-off detection owing to their high sensitivity to the hydroxyl radical. The detection limit can reach ∼0.1 µM under optimized conditions when using hydrogen peroxide as the source for generating ROS. Moreover, when paired with glucose oxidase, these C-dots can track glucose concentrations in samples. This adaptability suggests their potential in detecting various metabolites, paving the way for practical uses in disease detection.