This study aimed to explore the therapeutic mechanisms of Colquhounia Root Tablets(CRT) in treating diabetic kidney disease(DKD) by integrating biomolecular network mining with animal model verification. By analyzing clinical transcriptomics data, an interaction network was constructed between candidate targets of CRT and DKD-related genes. Based on the topological eigenvalues of network nodes, 101 core network targets of CRT against DKD were identified. These targets were found to be closely related to multiple pathways associated with type 2 diabetes, immune response, and metabolic reprogramming. Given that immune-inflammatory imbalance driven by metabolic reprogramming is one of the key pathogenic mechanisms of DKD, and that many core network targets of CRT are involved in this pathological process, receptor for advanced glycation end products(RAGE)-reactive oxygen species(ROS)-phosphatidylinositol 3-kinase(PI3K)-protein kinase B(AKT)-nuclear factor-κB(NF-κB)-NOD-like receptor family pyrin domain containing 3(NLRP3) signaling axis was selected as a candidate target for in-depth research. Further, a rat model of DKD induced by a high-sugar, high-fat diet and streptozotocin was established to evaluate the pharmacological effects of CRT and verify the expression of related targets. The experimental results showed that CRT could effectively correct metabolic disturbances in DKD, restore immune-inflammatory balance, and improve renal function and its pathological changes by inhibiting the activation of the RAGE-ROS-PI3K-AKT-NF-κB-NLRP3 signaling axis. In conclusion, this study reveals that CRT alleviates the progression of DKD through dual regulation of metabolic reprogramming and immune-inflammatory responses, providing strong experimental evidence for its clinical application in DKD.
Animals ; Diabetic Nephropathies/metabolism* ; Receptor for Advanced Glycation End Products/genetics* ; NF-kappa B/genetics* ; Signal Transduction/drug effects* ; Rats ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Proto-Oncogene Proteins c-akt/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Phosphatidylinositol 3-Kinases/genetics* ; Reactive Oxygen Species/metabolism* ; Humans ; Plant Roots/chemistry* ; Rats, Sprague-Dawley ; Tablets/administration & dosage*

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a major health concern in northwest China; however, the impact of particulate matter (PM) exposure during sand-dust storms (SDS) remains poorly understood. Therefore, this study aimed to investigate the association between PM exposure on SDS days and COPD hospitalization risk in arid regions. METHODS: Data on daily COPD hospitalizations were collected from 323 hospitals from 2018 to 2022, along with the corresponding air pollutant and meteorological data for each city in Gansu Province. Employing a space-time-stratified case-crossover design and conditional Poisson regression, we analyzed 265,379 COPD hospitalizations. RESULTS: PM exposure during SDS days significantly increased COPD hospitalization risk [relative risk ( RR) for PM _2.5, lag 3:1.028, 95% confidence interval ( CI): 1.021-1.034], particularly among men and the elderly, and during the cold season. The burden of PM exposure on COPD hospitalization was substantially high in Northwest China, especially in the arid and semi-arid regions. CONCLUSION Our findings revealed a positive correlation between PM exposure during SDS episodes and elevated hospitalization rates for COPD in arid and semi-arid zones in China. This highlights the urgency of developing region-specific public health strategies to address adverse respiratory outcomes associated with SDS-related air quality deterioration.
Humans ; China/epidemiology* ; Pulmonary Disease, Chronic Obstructive/chemically induced* ; Particulate Matter/analysis* ; Hospitalization/statistics & numerical data* ; Male ; Female ; Middle Aged ; Aged ; Air Pollutants/analysis* ; Environmental Exposure/adverse effects* ; Spatio-Temporal Analysis ; Adult ; Sand ; Air Pollution

Enzymatic cascade catalysis has emerged as an effective means to enhance the sensitivity of biosensors due to its remarkable amplification effect on electrochemical signals.However,the most used natural enzymes have high specificity and high catalytic activity,but are susceptible to environmental factors,easy denaturation and inactivation,and high cost,which limit their practical applications.Additionally,the majority of nanozymes with excellent catalytic activity cannot be directly used as redox probes.The redox signal can only be required under high potentials in strong acid/alkali solutions,or functionalized with electroactive substances.To tackle this problem,herein,AuNPs(glucose oxidase-like activity)and Mn,Zr dual-doped CeO2 nanozymes(Mn,Zr-CeO2,peroxidase-like activity)were used as model enzymes to construct a high-performance nanozymes cascade catalytic system.Owing to high Ce4+/Ce3+ratio and a considerable number of oxygen vacancies,Mn,Zr-CeO2 nanozymes exhibited excellent peroxidase-like activity and could generate amplified electrochemical signals in neutral medium at low potentials.Furthermore,the porous structure of Mn,Zr-CeO2 nanozymes could accelerate the mass transfer of intermediate H2O2,thereby enhancing the efficiency of enzymatic cascade catalysis.As a result,a label-free electrochemical biosensor was constructed for sensitive detection of the cancer marker miRNA-21 at physiological pH,with a detection limit as low as 32.5 fmol/L.This strategy offered a novel approach for the development of a new generation of high-performance nanozymes cascade platforms,which could be widely applied in the fields such as biotechnology,bioanalysis,and disease diagnosis.

Objective:To investigate the predictive value of serum neutrophil gelatinase-associated lipocalin(NGAL),calcitonin gene-related peptide(CGRP),and neutrophil-to-lymphocyte ratio(NLR)for the prognostic regression of elderly patients with stroke complicated with pulmonary infection(SCPI).Methods:This study was a retrospective single-center study,149 elderly patients with SCPI who were admitted to Inner Mongolia Baogang Hospital from June 2020 to June 2024 were selected,they were divided into poor prognosis group(n=56)and good prognosis group(n=93)according to the prognosis.Baseline data and laboratory test indicators were collected,and NLR was calculated.Serum NGAL and CGRP levels were measured by ELISA.Influencing factors of poor prognosis of elderly patients with SCPI were analyzed by Multivariate logistic regression.Predicts value was analyzed by Receiver operating characteristic(ROC)curve.Results:Compared with good prognosis group,the poor prognosis group had higher of aged ≥ 70 years,incidence of hemorrhagic stroke,serum creatinine,white blood cell count,national institute of health stroke scale(NIHSS),platelet count,C-reactive protein,NGAL,and NLR levels,longer nerosurgery intensive care unit(NICU)stay,and lower CGRP levels(P＜0.05).Higher CGRP level was an independent protective factor of poor prognosis of elderly patients with SCPI(OR＜1,P＜0.05).Age ≥ 70 years,hemorrhagic stroke,longer NICU stay,higher NIHSS score,higher NGAL level and higher NLR were independent risk factors of poor prognosis of elderly patients with SCPI(OR＞1,P＜0.05).The area under the curve(AUC)for predicting the prognostic regression of elderly patients with SCPI used NGAL,CGRP,and NLR alone or in combination was 0.777,0.771,0.786,and 0.927,respectively,with the combination of three factors showed the highest predictive power(P＜0.05).Conclusion:Age ≥70 years,hemorrhagic stroke,longer NICU stay,higher NIHSS score,higher NGAL level and higher NLR are independent risk factors of poor prognosis of elderly patients with SCPI,while higher CGRP level is an independent protective factor.The combination detection of NGAL,CGRP and NLR can improve the predictive value of prognostic regression in elderly patients with SCPI.

AIM:Fine particulate matter(PM2.5)is closely associated with airway hyper-responsiveness(AHR).However,the underlying mechanism by which PM2.5 leads to AHR is still unclear.This study aimed to investi-gate the respiratory effects of ambient PM2.5 exposure.METHODS:Forty mice were randomly divided into five groups:control group(intranasal saline),lipopolysaccharide(LPS)group(100 mg/L),PM2.5 low-dose group(0.003 5 mg/d),PM2.5 medium-dose group(0.007 mg/d),and PM2.5 high-dose group(0.014 mg/d).They were treated with intranasal in-stillation for 30 d.Lung function and tracheal contractile responses were evaluated using whole-body plethysmography and sensitive wire myograph.Inflammatory mediators in serum and oxidative stress parameters were detected using enzyme-linked immunosorbent assay(ELISA).Lung tissues were subjected to HE and Masson staining.RT-qPCR and Western blot were used to determine the expression of contractile receptors and the phosphorylation of the mitogen-activated protein kinase(MAPK)signal pathway.RESULTS:Intranasal instillation of PM2.5 significantly increased airway resistance in mice and enhanced tracheal contractility in response to carbachol.PM2.5 elevated levels of tumor necrosis factor-α(TNF-α),interleukin(IL)-1β,and IL-6 in serum.PM2.5 instillation also led to a decrease in glutathione peroxidase(GSH-Px)levels and an increase in malondialdehyde(MDA)levels.Lung tissue exhibited notable pathological changes,including inflammatory cell infiltration,hyperplasia of alveolar epithelial cells,and collagen deposition.Mechanistically,exposure to PM2.5 increased the expression of muscarinic M3 receptor mRNA and protein,as well as the phosphorylation of p-ERK1/2 and p-p38 proteins following PM2.5 instillation.CONCLUSION:Intranasal instillation of PM2.5 induced inflammation and oxidative stress,along with the activation of the extracellular signal-regulated kinase 1/2(ERK1/2)and p38 MAPK pathways,resulting in the upregulation of M3 receptor-induced AHR.

Objective:To investigate the predictive value of serum neutrophil gelatinase-associated lipocalin(NGAL),calcitonin gene-related peptide(CGRP),and neutrophil-to-lymphocyte ratio(NLR)for the prognostic regression of elderly patients with stroke complicated with pulmonary infection(SCPI).Methods:This study was a retrospective single-center study,149 elderly patients with SCPI who were admitted to Inner Mongolia Baogang Hospital from June 2020 to June 2024 were selected,they were divided into poor prognosis group(n=56)and good prognosis group(n=93)according to the prognosis.Baseline data and laboratory test indicators were collected,and NLR was calculated.Serum NGAL and CGRP levels were measured by ELISA.Influencing factors of poor prognosis of elderly patients with SCPI were analyzed by Multivariate logistic regression.Predicts value was analyzed by Receiver operating characteristic(ROC)curve.Results:Compared with good prognosis group,the poor prognosis group had higher of aged ≥ 70 years,incidence of hemorrhagic stroke,serum creatinine,white blood cell count,national institute of health stroke scale(NIHSS),platelet count,C-reactive protein,NGAL,and NLR levels,longer nerosurgery intensive care unit(NICU)stay,and lower CGRP levels(P＜0.05).Higher CGRP level was an independent protective factor of poor prognosis of elderly patients with SCPI(OR＜1,P＜0.05).Age ≥ 70 years,hemorrhagic stroke,longer NICU stay,higher NIHSS score,higher NGAL level and higher NLR were independent risk factors of poor prognosis of elderly patients with SCPI(OR＞1,P＜0.05).The area under the curve(AUC)for predicting the prognostic regression of elderly patients with SCPI used NGAL,CGRP,and NLR alone or in combination was 0.777,0.771,0.786,and 0.927,respectively,with the combination of three factors showed the highest predictive power(P＜0.05).Conclusion:Age ≥70 years,hemorrhagic stroke,longer NICU stay,higher NIHSS score,higher NGAL level and higher NLR are independent risk factors of poor prognosis of elderly patients with SCPI,while higher CGRP level is an independent protective factor.The combination detection of NGAL,CGRP and NLR can improve the predictive value of prognostic regression in elderly patients with SCPI.

Objective:To explore the efficacy and its related factors of rituximab (RTX) in the treatment of children with frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome (FRNS/SDNS).Methods:It was a single-center retrospective study. The clinical data of FRNS/SDNS children first treated with RTX in the First Affiliated Hospital of Sun Yat-sen University from November 1, 2016 to September 1, 2023 were collected. The number of relapse within 1 year before and after RTX treatment, the time to first relapse after RTX treatment, and the time to B-cell reconstitution were analyzed. At the first treatment, a single dose of RTX was given at 375 mg/m 2, with a maximum dose of 500 mg, once a week, for 1 to 4 doses. The count of CD19 + lymphocytes in the peripheral blood of the children was continuously monitored. If B-cell reconstruction was performed, the decision on whether to proceed to the next course of RTX treatment was made based on clinical manifestations. Kaplan-Meier method was used to analyze relapse-free survival rate after receiving RTX. Cox proportional hazards regression model was used to analyze the related factors of relapse after RTX treatment. Results:A total of 98 FRNS/SDNS children receiving RTX treatment were enrolled, including 75 males (76.5%). The age at onset was 4.0 (1.9, 7.1) years and age of receiving RTX was 11.3 (8.5, 13.5) years. There were 90 children (91.8%) achieving complete remission, while 8 patients (8.2%) did not respond to RTX treatment, and 3 patients (3.1%) progressed to end-stage kidney disease after receiving RTX. The relapse-free survival rates at 6 months and 1 year after RTX treatment were 83.3% (75/90) and 57.9% (22/38), respectively. The frequency of relapse 1 year after RTX treatment decreased compared to 1 year before RTX treatment ( Z=-7.398, P<0.001). Compared with children without relapse during the period of B-cell depletion, relapsed children had a higher number of relapse within one year after RTX treatment ( Z=5.246, P<0.001). The time to first relapse after RTX treatment was 8.3 (4.6, 13.9) months in 51 relapse patients. Compared with children receiving 1 dose of RTX in the first course, those receiving 2 or more doses had a longer time to the first relapse ( Z=2.983, P=0.003). There was no statistically significant difference in time to the first relapse between children who received mycophenolate mofetil therapy after RTX treatment and those who didn't ( P>0.05). The reconstruction time of B cells after the first course of RTX was 6.9 (5.3, 9.0) months. Compared to children receiving one dose of RTX in the first course, those receiving two or more doses had a longer B-cell reconstitution time ( Z=2.739, P=0.006). There was no statistically significant difference in B-cell reconstitution time between children who received mycophenolate mofetil therapy after RTX treatment and those who didn't ( P>0.05). Univariate Cox regression analysis showed that recurrence after calcineurin inhibitor (CNI) treatment before RTX treatment and the number of recurrence in one year before RTX treatment were correlated factors of recurrence after RTX treatment (both P<0.05). Multivariate Cox regression analysis showed that recurrence after CNI treatment before RTX treatment was an independent correlated factor of relapse after RTX therapy ( HR=3.496, 95% CI 1.245-9.818, P=0.018). Infusion reactions occurred in 10 patients (10.2%) and infections were observed in 24 patients (24.5%) during B cell depletion. No serious adverse events occurred. Conclusions:RTX is well tolerated and effective in treating FRNS/SDNS. Recurrence after CNI treatment before RTX treatment may be an independent related factor of relapse after RTX treatment.

AIM:Fine particulate matter(PM2.5)is closely associated with airway hyper-responsiveness(AHR).However,the underlying mechanism by which PM2.5 leads to AHR is still unclear.This study aimed to investi-gate the respiratory effects of ambient PM2.5 exposure.METHODS:Forty mice were randomly divided into five groups:control group(intranasal saline),lipopolysaccharide(LPS)group(100 mg/L),PM2.5 low-dose group(0.003 5 mg/d),PM2.5 medium-dose group(0.007 mg/d),and PM2.5 high-dose group(0.014 mg/d).They were treated with intranasal in-stillation for 30 d.Lung function and tracheal contractile responses were evaluated using whole-body plethysmography and sensitive wire myograph.Inflammatory mediators in serum and oxidative stress parameters were detected using enzyme-linked immunosorbent assay(ELISA).Lung tissues were subjected to HE and Masson staining.RT-qPCR and Western blot were used to determine the expression of contractile receptors and the phosphorylation of the mitogen-activated protein kinase(MAPK)signal pathway.RESULTS:Intranasal instillation of PM2.5 significantly increased airway resistance in mice and enhanced tracheal contractility in response to carbachol.PM2.5 elevated levels of tumor necrosis factor-α(TNF-α),interleukin(IL)-1β,and IL-6 in serum.PM2.5 instillation also led to a decrease in glutathione peroxidase(GSH-Px)levels and an increase in malondialdehyde(MDA)levels.Lung tissue exhibited notable pathological changes,including inflammatory cell infiltration,hyperplasia of alveolar epithelial cells,and collagen deposition.Mechanistically,exposure to PM2.5 increased the expression of muscarinic M3 receptor mRNA and protein,as well as the phosphorylation of p-ERK1/2 and p-p38 proteins following PM2.5 instillation.CONCLUSION:Intranasal instillation of PM2.5 induced inflammation and oxidative stress,along with the activation of the extracellular signal-regulated kinase 1/2(ERK1/2)and p38 MAPK pathways,resulting in the upregulation of M3 receptor-induced AHR.

Objective:To explore the efficacy and its related factors of rituximab (RTX) in the treatment of children with frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome (FRNS/SDNS).Methods:It was a single-center retrospective study. The clinical data of FRNS/SDNS children first treated with RTX in the First Affiliated Hospital of Sun Yat-sen University from November 1, 2016 to September 1, 2023 were collected. The number of relapse within 1 year before and after RTX treatment, the time to first relapse after RTX treatment, and the time to B-cell reconstitution were analyzed. At the first treatment, a single dose of RTX was given at 375 mg/m 2, with a maximum dose of 500 mg, once a week, for 1 to 4 doses. The count of CD19 + lymphocytes in the peripheral blood of the children was continuously monitored. If B-cell reconstruction was performed, the decision on whether to proceed to the next course of RTX treatment was made based on clinical manifestations. Kaplan-Meier method was used to analyze relapse-free survival rate after receiving RTX. Cox proportional hazards regression model was used to analyze the related factors of relapse after RTX treatment. Results:A total of 98 FRNS/SDNS children receiving RTX treatment were enrolled, including 75 males (76.5%). The age at onset was 4.0 (1.9, 7.1) years and age of receiving RTX was 11.3 (8.5, 13.5) years. There were 90 children (91.8%) achieving complete remission, while 8 patients (8.2%) did not respond to RTX treatment, and 3 patients (3.1%) progressed to end-stage kidney disease after receiving RTX. The relapse-free survival rates at 6 months and 1 year after RTX treatment were 83.3% (75/90) and 57.9% (22/38), respectively. The frequency of relapse 1 year after RTX treatment decreased compared to 1 year before RTX treatment ( Z=-7.398, P<0.001). Compared with children without relapse during the period of B-cell depletion, relapsed children had a higher number of relapse within one year after RTX treatment ( Z=5.246, P<0.001). The time to first relapse after RTX treatment was 8.3 (4.6, 13.9) months in 51 relapse patients. Compared with children receiving 1 dose of RTX in the first course, those receiving 2 or more doses had a longer time to the first relapse ( Z=2.983, P=0.003). There was no statistically significant difference in time to the first relapse between children who received mycophenolate mofetil therapy after RTX treatment and those who didn't ( P>0.05). The reconstruction time of B cells after the first course of RTX was 6.9 (5.3, 9.0) months. Compared to children receiving one dose of RTX in the first course, those receiving two or more doses had a longer B-cell reconstitution time ( Z=2.739, P=0.006). There was no statistically significant difference in B-cell reconstitution time between children who received mycophenolate mofetil therapy after RTX treatment and those who didn't ( P>0.05). Univariate Cox regression analysis showed that recurrence after calcineurin inhibitor (CNI) treatment before RTX treatment and the number of recurrence in one year before RTX treatment were correlated factors of recurrence after RTX treatment (both P<0.05). Multivariate Cox regression analysis showed that recurrence after CNI treatment before RTX treatment was an independent correlated factor of relapse after RTX therapy ( HR=3.496, 95% CI 1.245-9.818, P=0.018). Infusion reactions occurred in 10 patients (10.2%) and infections were observed in 24 patients (24.5%) during B cell depletion. No serious adverse events occurred. Conclusions:RTX is well tolerated and effective in treating FRNS/SDNS. Recurrence after CNI treatment before RTX treatment may be an independent related factor of relapse after RTX treatment.

Purpose To establish glucose metabolism patterns of Parkinson's disease(PD)at different periods,and to study the changing pattern of target region of interest(ROI)with the period of time,and then explore the relationship between ROIs and cognitive or motor in different periods.Materials and Methods A total of 42 patients with early-stage PD collected from June 2010 to September 2022 in online data from the markers of Parkinson's progression study which included clinical data,and FDG PET imaging was performed at baseline,12,24,36 and 48 months.The data of 8 healthy volunteers were also obtained from the database,and the time range was the same as that of the above-mentioned PD patients.The longitudinal changes of cerebral glucose metabolism in PD patients and the relationship between PD-associated ROI and movement disorder society-sponsored revision of the unified Parkinson's disease rating scale(MDS-UPDRS)score were evaluated.Results PD was relatively reduced activity located in frontal and parietal association areas and relatively increased activity in the cerebellum,the putamen and the cingulate gyrus.In our study of target ROIs over time,FDG uptake in the caudate nucleus,putamen,pallidum,and cerebellum of patients with PD was initially higher than in the normal group,and subsequently decreased.In contrast,the ROI of PD in the anterior cingulate gyrus,posterior cingulate gyrus,the substantia nigra pars compacta and substantia nigra pars reticulata was initially lower than that in healthy controls and subsequently increased.The putamen,pallidum and caudate nucleus metabolic activity showed a positive correlation in 36 month and MDS-UPDRS scores(r=0.659 5,0.678 7,0.716 7,all P<0.05).The caudate nucleus,putamen and pallidum metabolic activity showed a negative correlation in 24 month and baseline(r=-0.541 8,-0.878 9,-0.887 6,all P<0.05).Conclusion We provide 5-year longitudinal data on changes in 18F-FDG imaging outcomes in early PD.In addition,the glucose metabolic activity of caudate nucleus,putamen and globus pallidus are correlated with MDS-UPDRS scores.