Ursolic acid molecules dock MAPK1 to modulate gut microbiota diversity to reduce neuropathic pain.

To investigate the efficacy of Ursolic acid in alleviating neuropathic pain in rats with spinal nerve ligation (SNL), the SNL rat model was surgically induced. Different concentrations of Ursolic acid and manipulated target mitogen-activated protein kinase 1 (MAPK1) were administered to the SNL rats. Fecal samples were collected from each group of rats for 16S rDNA analysis to examine the impact of gut microbiota. Molecular docking experiments were conducted to assess the binding energy between Ursolic acid and MAPK1. In vivo studies were carried out to evaluate the expression of inflammatory factors and signaling pathways in spinal cord and colon tissues. Ursolic acid was found to have a beneficial effect on pain reduction in rats by increasing plantar withdrawal latency (PWL) and paw withdrawal threshold (PWT). Comparing the Ursolic acid group with the control group revealed notable differences in the distribution of Staphylococcus, Allobaculum, Clostridium, Blautia, Bifidobacterium, and Prevotella species. Network pharmacology analysis identified MAPK1 and intercellular adhesion molecule-1 (ICAM1) as common targets for Ursolic acid, SNL, and neuropathic pain. Binding sites between Ursolic acid and these targets were identified. Additionally, immunofluorescent staining showed a decrease in GFAP and IBA1 intensity in the spinal cord along with an increase in NeuN following Ursolic acid treatment. Overexpression of MAPK1 in SNL rats led to an increase in inflammatory factors and a decrease in PWL and PWT. Furthermore, MAPK1 counteracted the pain-relieving effects of Ursolic acid in SNL rats. Ursolic acid was found to alleviate neuropathic pain in SNL rats by targeting MAPK1 and influencing gut microbiota homeostasis.

Sex disparities in clinicopathological features and outcomes of patients with myeloperoxidase-ANCA-associated vasculitis: a retrospective study of 366 cases in a single Chinese center.

There are a few studies that reported sex disparities in clinical features, pathological features and outcomes among ANCA-associated vasculitis (AAV) patients, but studies focusing on sex-specific differences of myeloperoxidase (MPO)-AAV patients are scarce. Therefore, the purpose of this study was to analyze sex differences in clinicopathological features and outcomes of MPO-AAV. Patients diagnosed with MPO-AAV in Xiangya Hospital from January 2010 to June 2021 were included in the study and separated into female and male groups. The differences in clinical manifestations, laboratory parameters, pathological features and prognosis between the two groups were retrospectively analyzed. Three hundred and sixty-six patients were included and divided into female group (n = 176) and male group (n = 190). The age of the male group was 62.41 ± 10.49 years, significantly higher than that of the female group (58.69 ± 16.39, p = 0.011). Compared with the female group, the male group had a shorter duration of disease, higher levels of hemoglobin, eosinophil count, proteinuria, serum C4, and lower levels of serum globulin, serum IgG and serum IgM (p < 0.05). No significant differences in kidney pathological features were observed between the two groups. During a median follow-up of 37.6 months, there was no significant difference in renal survival and patient survival between the two groups, but male patients had a worse composite outcome of renal and patient survival compared with the female patients (p = 0.044). This study found that male patients with MPO-AAV had a higher age of onset, shorter duration of disease, higher levels of hemoglobin, eosinophil count, proteinuria, serum C4, and lower levels of serum globulin, serum IgG and serum IgM. Male patients fared worse than female patients in terms of the composite outcome of renal and patient survival.

The effect of discontinuation of maintenance therapy in Chinese patients with MPO-ANCA associated vasculitis who were in long-term stable remission.

There is a consensus that maintenance therapy should be used to prevent relapse of myeloperoxidase-anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-AAV), but there is a debate about the optimal duration of maintenance therapy. Therefore, the purpose of this study was to determine whether discontinuation of maintenance therapy in MPO-AAV patients who were in long-term stable remission affects relapse, renal survival and patient survival. Seventy-nine patients with MPO-AAV diagnosed at Xiangya hospital from June 2010 to June 2019 who were in stable remission for at least 18 months following maintenance therapy were included. Patient records were retrospectively reviewed, and based on whether patients discontinued maintenance therapy 18 months after commencing maintenance therapy, patients were assigned into either the withdrawal group (n = 26) or maintenance group (n = 53). The endpoint was the percentage of relapse, relapse-free survival, renal survival and patient survival during follow-up. Ten relapses (38.5%) occurred in the withdrawal group (n = 26) and 8 relapses (15.1%) occurred in the maintenance group (n = 53) (p = 0.020). Compared to the withdrawal group, the maintenance group had similar relapse-free survival (log-rank test p = 0.099). But maintenance group had a better renal survival (p = 0.035), with no difference in patient survival or adverse events. This study suggests that discontinuing maintenance therapy at 18 months following induction of sustained remission leads to a significant increase in the percentage of relapse, and decreases renal survival in patients with MPO-AAV, but does not decrease relapse-free survival or patient survival.

Clinical features and prognosis of MPO-ANCA and anti-GBM double-seropositive patients.

Background: Several lines of evidence implicate that there are distinct differences between patients with myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane (GBM) antibody double-seropositive patients (DPPs) and single-positive patients. Hence, we conducted a retrospective study from a single center in China to analyze the clinical and pathological features, and prognosis of DPPs. Methods: 109 patients with MPO-ANCA-associated vasculitis (MPO-AAV), 20 DPPs and 23 patients diagnosed with anti-GBM disease from a large center in China were included in this study. The ratio of patients with renal biopsy in three groups were 100%, 50% and 100%, respectively. Their clinical and pathological characteristics, and outcomes were analyzed. The intensity of immune deposits in the kidney at diagnosis was detected by immunofluorescence (IF). Furthermore, multivariate Cox hazard model analysis was used to assess the clinical and histological predictors of end-stage renal disease (ESRD) and death for DPPs. Results: In our study, we found that patients in the DPPs group were older than the other two groups (p = 0.007, MPO-AAV vs. DPPs; p < 0.001, DPPs vs. anti-GBM). The DPPs group had a higher value of serum creatinine (p = 0.041) and lower estimated glomerular filtration rate (eGFR) (p = 0.032) compared with MPO-AAV patients. On the contrary, the DPPs group had a lower serum creatinine (p = 0.003) compared with patients with anti-GBM group. The proportion of patients with cardiac system involvement in the DPPs group was higher than anti-GBM patients (p = 0.014). Cellular crescents could be generally observed in renal biopsy of DPPs and patients with anti-GBM glomerulonephritis. In addition, Bowman's capsule rupture was more common in DPPs than MPO-AAV patients (p = 0.001). MPO-AAV had a better renal and overall survival outcome than DPPs (p < 0.001). There was no significant difference of renal and overall survival outcome between DPPs and patients with anti-GBM disease. The incidence of ESRD in DPPs was negatively associated with lymphocyte count (HR 0.153, 95% CI 0.027 to 0.872, p = 0.034) and eGFR (HR 0.847, 95% CI 0.726 to 0.989, p = 0.036). Elevated serum creatinine was confirmed as a risk factor of both renal (HR 1.003, 95% CI 1.000 to 1.005, p = 0.019) and patient survival in DPPs (HR1.461, 95% CI 1.050 to 2.033, p = 0.024). Conclusion: In summary, compared with anti-GBM disease, DPPs tended to involve multi-organ damage rather than limited to the kidney. It is highlighted that serologic DPPs have a worse renal and patient prognosis than MPO-AAV. Moreover, we found that the risk factors of renal survival of DPPs include low lymphocyte count, elevated serum creatinine and reduced eGFR, and serum creatinine can predict patient survival.

Systemic immune-inflammation index predicts a reduced risk of end-stage renal disease in Chinese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibody-associated vasculitis: A retrospective observational study.

Chronic inflammation has been indicated to be important in the pathogenesis of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). The systemic immune-inflammation index (SII) is a novel marker of inflammation. The present study was thus performed to explore the association between the SII at diagnosis and inflammatory response and disease activity in Chinese patients with myeloperoxidase (MPO)-AAV. Furthermore, it was evaluated whether the SII is able to predict the progression to end-stage renal disease (ESRD) and patient survival. A total of 190 patients with MPO-AAV were included in the present study. The baseline SII was positively correlated with C-reactive protein (CRP; r=0.274, P<0.0001) and the erythrocyte sedimentation rate (ESR; r=0.481, P<0.0001). However, the SII had no obvious correlation with the Birmingham vasculitis activity score. Patients with SII≥2,136.45 exhibited better cumulative renal survival rates than those with SII<2,136.45 (P=0.001). However, no significant difference in patient survival was indicated between patients with SII≥2,136.45 and those with SII<2,136.45 at diagnosis. In conclusion, the SII was positively correlated with CRP and ESR in Chinese patients with MPO-AAV. Furthermore, the SII may be an independent factor associated with a reduced risk of ESRD.

Glomerular Immune Deposition in MPO-ANCA Associated Glomerulonephritis Is Associated With Poor Renal Survival.

Background: Rapidly progressive glomerulonephritis caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is typically characterized as pauci-immune glomerulonephritis. However, immune complex (IC) deposition in the glomerulus has been reported in a growing number of studies. Here, we assess the presence of glomerular immune deposits alongside renal outcome in myeloperoxidase (MPO)-ANCA associated glomerulonephritis (MPO-ANCA GN). Methods: Clinical and histopathologic characteristics of 97 patients with MPO-ANCA GN classified by renal biopsy from January 2008 to December 2019 were extracted retrospectively from electronic medical records. The extent of immune deposits in the kidney (C3, C4, C1q, IgA, IgG, IgM) at diagnosis were analyzed by immunofluorescence (IF). Patients were followed up for a median period of 15 months. The response to treatment and outcomes of renal and histological lesion changes were also assessed. Results: In our study, 41% (40/97) of patients showed positive IF (≥2+) for at least one of the six immunoglobulin or complement components tested. Patients with IC deposits showed higher levels of serum creatinine (p=0.025), lower platelet counts (p=0.009), lower serum complement C3 (sC3) (≤790 ml/L) (p=0.013) and serum IgG (p=0.018) than patients with pauci-immune (PI) deposition at diagnosis. End-stage renal disease was negatively associated with eGFR (HR 0.885, 95% CI 0.837 to 0.935, p<0.0001), platelet count (HR 0.996, 95% CI 0.992 to 1.000, p=0.046) and serum globulin (HR 0.905, 95% CI 0.854 to 0.959, p=0.001). Patients with lower sC3 levels showed a worse renal outcome than the patients with normal sC3 at diagnosis (p=0.003). Analysis of the components of the renal deposits found that patients with IgG deposits exhibited a poorer renal outcome compared to patients that were IgG negative (p=0.028). Moreover, Bowman's capsule rupture occurred less frequently in patients with IgM deposition compared with IgM negative counterparts (p=0.028). Vascular lesions and granuloma-like lesions had been seen more frequently in cases with IgA deposition than those without IgA deposition (p=0.03 and 0.015, respectively). Conclusion: In conclusion, patients with immune complex deposits in the kidney showed less platelet count, lower sC3 and sIgG levels, and higher serum creatinine levels. Patients with low sC3 at initial and with continued low sC3 during the treatment displayed a trend toward poorer kidney survival. Moreover, the IC group showed a worse renal outcome than the PI group, further enforcing the present strategy of introducing complement targeted therapies in AAV.

Differences between myeloperoxidase-antineutrophil cytoplasmic autoantibody (ANCA) and proteinase 3-ANCA associated vasculitis: A retrospective study from a single center in China.

In antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV), the two major target antigens of ANCA are proteinase 3 (PR3) and myeloperoxidase (MPO). Evidence is accumulating that there are distinct differences between patients with PR3-AAV and those with MPO-AAV. In the present study, the clinicopathological features and prognosis of patients with PR3-AAV and MPO-AAV from a single center in China were retrospectively analyzed. A total of 212 Chinese patients with AAV were recruited in the present study; 189/212 (89.15%) patients were classified as having MPO-AAV and 23/212 (10.85%) patients as having PR3-AAV. Compared with those in the PR3-AAV group, patients in the MPO-AAV group were older and less frequently had ear, nose and throat or ophthalmic involvement. MPO-AAV patients had higher levels of serum creatinine and proteinuria at baseline. No significant difference was observed with regard to the pathological changes of the glomeruli and tubulointerstitium between the two groups. The probability of developing end-stage renal disease was significantly higher in patients with MPO-AAV compared with that in patients with PR3-AAV. There was no significant difference in the one-year patient survival rate between the two groups. However, differences in certain clinical characteristics and outcomes were observed between MPO-AAV and PR3-AAV patients. A large national investigation of AAV is required to confirm the concept that PR3-AAV and MPO-AAV are distinct disease entities.

The association of neutrophil-to-lymphocyte ratio with all-cause mortality in Chinese patients with MPO-ANCA associated vasculitis.

Neutrophil-to-lymphocyte ratio (NLR) has been recently reported to be a promising inflammatory marker to assess systemic inflammation in many disorders. However, there are only a few studies looking at NLR in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study was thus undertaken to explore the relationship between NLR at diagnosis with inflammatory response and disease activity among MPO-AAV patients in a single Chinese center. Furthermore, we evaluated whether NLR could predict the renal prognosis and patient outcome. 188 patients with MPO-AAV were included in this study. Baseline NLR was positively correlated with CRP (r = 0.404, P < 0.001) and negatively with serum levels of C3 (r = - 0.163, P = 0.035), but it had no obvious correlation with Birmingham Vasculitis Activity Score (BVAS). Patients with MPO-AAV having NLR ≥ 9.53 exhibited higher risk for all-cause mortality than those having NLR < 9.53 (P < 0.0001). However, no significant difference was found in the kidney survival between patients having NLR ≥ 9.53 and those NLR < 9.53 at diagnosis. In multivariate analysis, NLR was positively associated with all-cause mortality (P = 0.037, HR = 1.98, 95% CI 1.04-3.78). There was no association between NLR with ESRD observed using univariate analysis or multivariate analysis. This large retrospective study of MPO-AAV patients in a single Chinese center demonstrates that NLR positively correlates with CRP and negatively correlates with serum levels of C3 in Chinese patients with MPO-AAV. Importantly, higher NLR predicts increased mortality and is, therefore, a useful independent prognostic in MPO-AAV.

Risk factors for treatment resistance and relapse of Chinese patients with MPO-ANCA-associated vasculitis.

Identification of risk factors for treatment resistance and relapse would be crucial to personalization therapy in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-AAV). Current evidence with regard to the risk factors for treatment resistance and relapse remains limited and inconclusive. We aimed to assess the predictors for treatment resistance and relapse in a single-center cohort of Chinese patients with MPO-AAV in this study. In total, 184 patients with MPO-AAV were included. Treatment resistance occurred in 64 (34.9%) of 184 patients and was positively associated with lung involvement (odds ratio [OR] 3.581, 95% CI 1.137-11.278, p = 0.029) and the initial serum creatinine level (OR 1.004, 95% CI 1.001-1.007, p = 0.010) and was negatively associated with platelet (OR 0.992, 95% CI 0.987-0.998, p = 0.007) and serum C3 levels (OR 0.998, 95% CI 0.996-0.999, p = 0.004). Relapse occurred in 29 (24.17%) of 120 patients in whom remission was achieved and was independently associated with lung involvement (hazard ratio [HR] 4.595, 95% CI 1.272-16.599, p = 0.020) and cardiovascular involvement (HR 3.689, 95% CI 1.237-11, p = 0.019,). The serum globulin was demonstrated to be negatively associated with relapse independently (HR 0.876; 95% CI 0.806-0.953; p = 0.002). This retrospective study of MPO-AAV patients in a single Chinese center suggests that treatment resistance was positively associated with lung involvement and the initial serum creatinine level and was negatively associated with platelet and serum C3 levels. Lung involvement and cardiovascular involvement were associated with an increased risk of relapse, while the higher serum globulin was demonstrated to be in association with a decreased risk of relapse.

The effect of pulse methylprednisolone induction therapy in Chinese patients with dialysis-dependent MPO-ANCA associated vasculitis.

BACKGROUND: Pulse methylprednisolone (MP) was routinely used before commencing standard immunosuppressive therapy for induction of remission in patients with dialysis-dependent anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in spite of the paucity of evidence of benefit. The aim of this study was thus to determine whether the addition of pulse MP to standard induction immunosuppressive therapy in severe myeloperoxidase (MPO) -AAV patients who were on dialysis at onset is associated with an improvement in kidney recovery and patient survival. Furthermore, we analyzed the factors associated with restoration of kidney function and mortality in a single Chinese cohort. METHODS: 69 MPO-AAV patients who were on dialysis at the time of diagnosis were included in this study. The MP group (n = 30) received pulse MP (5-10 mg/kg/day) for 3 days before the standard immunosuppressive therapy. The Non-MP group (n = 39) had no MP pulses. The outcomes and adverse events between the two groups were compared. In addition, the predictive value of the clinical and histological parameters for kidney and patient survival was assessed using univariate and multivariate logistic regression analysis. RESULT: There was no difference in patient survival, kidney recovery and the rates of adverse events between the two groups. A higher Birmingham Vasculitis Activity Score (BVAS) was shown to be a negative prognostic factor for kidney function restoration (p = 0.046, OR 0.811, 95% CI 0.660-0.997). BVAS was also demonstrated to be an independent predictor for both all-cause death (p = 0.007, OR 1.324, 95% CI 1.079-1.624) and therapy-related death (p = 0.003, OR 1.574, 95% CI 1.171-2.115). Patients' eGFR at the presentation of the disease was shown to be an independent predictor for therapy-related death (p = 0.027, OR 2.535, 95% CI 1.112-5.779). CONCLUSIONS: This retrospective study of MPO-AAV patients who required dialysis at presentation in a single Chinese center suggests that the addition of pulse MP to standard immunosuppressive induction therapy for remission appears to confer no benefit in terms of improving patient outcomes. Further research is required to determine the role of pulse MP in severe MPO-AAV.

[Disease spectrum and causes of death in hospitalized children in an upper first-class hospital in Hunan Province, China, from 2010 to 2014].

OBJECTIVE: To study the disease spectrum and causes of death in hospitalized children in an upper first-class hospital in Hunan Province, China. METHODS: The medical records of hospitalized children between 2010 and 2014 in this hospital were collected and analyzed retrospectively. RESULTS: From 2010 to 2014, the number of hospitalized children increased from 7 303 in 2010 to 10 902 in 2014, and the case fatality rate declined from 0.33% to 0.20% (P<0.05). The case fatality rate was highest (0.41%) in infants and lowest (0.11%) in newborns. As for the disease spectrum for these hospitalized children, in 2010, the top three diseases were leukemia, congenital heart disease, and pneumonia; in 2011, the top three diseases were tumor chemotherapy, congenital heart disease, and pneumonia; since 2012, tumor chemotherapy, epilepsy, and pneumonia had remained the top three diseases. The top three causes of death in hospitalized children were congenital malformation (39%, 39/99), tumor (13%, 13/99), and infectious diseases/parasitic diseases (8%, 8/99). CONCLUSIONS: The number of hospitalized children is increasing, while the case fatality rate tends to decrease in this hospital. Tumor, epilepsy, pneumonia, and congenital heart disease are major diseases in hospitalized children, and congenital malformation is the primary cause of death.

[Study the effects of flavonoids of Rhizoma Drynariae on gene level of rats without ovaries by technology of cDNA array].

OBJECTIVE: To study the effects of flavonoids of Rhizoma Drynariae on gene level of rats without ovaries (OP) by technology of cDNA array. METHOD: The models of rats without ovaries were made After. 24 weeks of treatment, put them to death and sampled 6 ml blood from the abdominal aorta and 4cm spinal cord. Take out the total RNA, then separate the mRNA to check. RESULT: There is 70 genes difference between the blank control group and model group, 9 genes difference between the blank control group and flavonoids of Rhizoma Drynariae group. The genes over expression of OP rats models regain normal after the models were fed on flavonoids of Rhizoma Drynariae. There are no differences in the spinal cords genes in the cDNA array analysis of this trail. CONCLUSION: The genes over expression of OP rats models regain normal after the models were fed on flavonoids of Rhizoma Drynariae for 6 months. The result shows that the flavonoids of Rhizoma Drynariae does have certain effects on the gene expression of rats without ovaries.