The predictive value of crescents in adult Henoch-Sch?lein purpura nephritis

Objective To study the renal prognosis with the type and proportion of crescentic in adult Henoch Schonlein purpura nephritis (HSPN). Methods A total of 275 HSPN cases diagnosed in the First Affiliated Hospital of Zhejiang University were retrospectively analyzed. According to the pathological results, they were divided into four groups: 99 patients in none crescent group (NC), 35 patients in segmental crescents group (SC), 122 patients with circumferential crescent ＜25% (C1), and 19 patients with circumferential crescent≥25% (C2). Renal prognostic events were defined as estimated glomerular filtration rate (eGFR) decreased by 30% over baseline within 2 years, doubling of serum creatinine or end-stage renal disease during follow-up. Kaplan-Meier survival analysis was used to compare the renal survival rate of each group. Univariate and multivariate Cox regression model was used to recognize the risk factor of poor renal outcome. Results There was no significant difference in age, extra renal organ performance and mean arterial pressure among groups. Among NC group, SC group, C1 group and C2 group, difference in serum creatinine (P=0.001), eGFR (P=0.003) and proteinuria levels (P＜0.001) were statistically significant. There was no significant difference in the ratio of global sclerosis, mesangial hypercellularity and interstitial inflammation/fibrosis among the groups. The patients were followed up for 86(58, 116) months. The renal survival rates of NC group, SC group, C1 group and C2 group were 96%, 100%, 83.6% and 68.4% respectively. Kaplan-meier survival analysis showed significant differences (Log Rank=23.24, P＜0.001). Cox multivariate regression analysis indicated that presence of circumferential crescent (HR=3.59, 95%CI 1.34-9.62, P=0.008) and low eGFR (HR=0.979, 95%CI 0.968-0.989, P＜0.001) were independent prognostic factors. Conclusion The presence of circumferential crescent and low eGFR level are independent risk factors for poor renal prognosis in HSPN patients.     

Melatonin safeguards against fatty liver by antagonizing TRAFs‐mediated ASK1 deubiquitination and stabilization in a β‐arrestin‐1 dependent manner

Melatonin has been previously shown to prevent nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms are poorly understood. Here, we identified a previously unknown regulatory action of melatonin on apoptosis signal‐regulating kinase 1 (ASK1) signaling pathway in the pathogenesis and development of NAFLD. Although melatonin administration did not alter food intake, it significantly alleviated fatty liver phenotypes, including the body weight gain, insulin resistance, hepatic lipid accumulation, steatohepatitis, and fibrosis in a high‐fat diet (HFD)‐induced NAFLD mouse model (in vivo). The protection of melatonin against NAFLD was not affected by inactivation of Kupffer cell in this model. In NAFLD mice liver, ASK1 signal cascade was substantially activated, evidence by the enhancement of total ASK1, phospho‐ASK1, phospho‐MKK3/6, phospho‐p38, phospho‐MKK4/7, and phospho‐JNK. Melatonin treatment significantly suppressed the ASK1 upregulation and the phosphorylation of ASK1, MKK3/6, MKK4/7, p38, and JNK. Mechanistically, we found that lipid stress triggered the interaction between ASK1 and TNF receptor‐associated factors (TRAFs), including TRAF1, TRAF2, and TRAF6, which resulted in ASK1 deubiquitination and thereby increased ASK1 protein stability. Melatonin did not alter ASK1 mRNA level; however, it activated a scaffold protein β‐arrestin‐1 and enabled it to bind to ASK1, which antagonized the TRAFs‐mediated ASK1 deubiquitination, and thus reduced ASK1 protein stability. Consistent with these findings, knockout of β‐arrestin‐1 in mice partly abolished the protection of melatonin against NAFLD. Taken together, our results for the first time demonstrate that melatonin safeguards against NAFLD by eliminating ASK1 activation via inhibiting TRAFs‐mediated ASK1 deubiquitination and stabilization in a β‐arrestin‐1 dependent manner.     

Morphine reverses the effects of 1-methyl-4-phenylpyridinium in PC12 cells through activating PI3K/Akt

Aim of the study: Parkinson’s disease (PD) is a neurodegenerative disorder. It is caused by the degeneration of dopaminergic neurons and the dopamine (DA) deletion in the substantia nigra pars compacta (SNpc). Morphine elevates the level of dopamine in the mesolimbic dopamine system and plays a role in alleviating PD symptoms. However, the molecular mechanism is still unclear. The aim of the study is to investigate the mechanism on morphine alleviating PD symptoms.

Materials and methods: The viability of PC12 cells was measured by using MTT assay. The expressions of tyrosine hydroxylase (TH), thioredoxin-1 (Trx-1), CyclinD1 and Cyclin-dependent kinase5 (Cdk5) were detected by Western Blot.

Results: In present study, we found that morphine increased the cell viability in PC12 cells. 1-methyl-4-phenylpyridi-nium (MPP+) reduced the cell viability and TH expression, which were reversed by morphine. MPP+ decreased the expressions of Trx-1, CyclinD1, Cdk5, which were restored by morphine. Moreover, the role of morphine in restoring the expressions of Trx-1, CyclinD1 and Cdk5 decreased by MPP+ was abolished by LY294002, phosphatidylinositol-3-kinase (PI3K)/Akt inhibitor.

Conclusions: These results suggest that morphine reverses effects induced by MPP þ through activating PI3K/Akt pathway.     

Predictive factors analysis of the efficacy of cyclophosphamide combined with glucocorticoids in the treatment of idiopathic membranous nephropathy

Objective To investigate the predictive factors affecting the efficacy of cyclophosphamide (CTX) combined with glucocorticoids in the treatment of idiopathic membranous nephropathy (IMN), and to evaluate the efficacy of calcineurin inhibitor (CNI) adjustment due to poor treatment. Methods A retrospective cohort study was conducted. Two hundreds and twenty-eight patients with IMN diagnosed by renal biopsy in the People's Hospital of Guangxi Zhuang Autonomous Region from January 1, 2007 to December 1, 2016 were enrolled. All subjects were treated with CTX in combination with glucocorticoids. The patients were divided into two groups: remission group and no remission group. Multivariable logistic regression analysis was used to determine the baseline clinical-pathological influencing factors for the remission of IMN in the enrolled patients. Results The number of total remission (including complete and partial remission) of the first CTX combined with glucocorticoid treatment in 228 patients with IMN was 188(82.5%). Among them, 141 patients (61.8%) had complete remission (CR), the median time for CR was 8(6, 12) months, and the median time for partial remission (PR) was 3(1, 4) months. The median follow-up time for this study was 25(13, 43) months. Compared with the remission group, the serum albumin level was lower in the non-remission group, the 24-hour urine protein content, the blood complement C3 and C4 levels were higher, and the pathological stage was milder (all P﹤0.05). Multivariate logistic regression analysis suggested that the levels of baseline serum albumin, complement C4, and pathological stage were independent predictors of clinical remission in IMN patients. Twenty-four non-remission patients were treated with CNI. The overall response rate was 66.7%(16/24) at 6 months and 77.3%(17/22) at 12 months. Conclusions The levels of baseline albumin, blood complement C4, and pathological stage were independent predictors of clinical remission in IMN patients treated with CTX plus glucocorticoids. The non-remission patients with CTX combined with glucocorticoid therapy can still achieve a higher response rate after adjusting for CNI.     

Preservation of Denonvilliers' fascia for nerve‐sparing laparoscopic total mesorectal excision: A neuro‐histological study

Urogenital complications due to pelvic autonomic nerve damage frequently occur following rectal surgery. We investigated whether total mesorectal excision (TME) with preservation of the Denonvilliers' fascia (DVF) can effectively prevent the removal of pelvic autonomic nerves through microscopy. Twenty consecutive male patients with mid‐low rectal cancer who received TME with preservation or resection of the Denonvilliers' fascia (P and R groups, respectively) were included. Serial transverse sections from surgical specimens were studied histologically. Nerve fibers at the surfaces of the mesorectum were counted. Clinical correlation between the amount of nerve fibers removed and post‐operative sexual function was analyzed. Nerve fibers closely localized to the DVF in the R group displaying rich erectile activity (positive anti‐nNOS immunostaining). At the anterior surface of the mesorectum, the mean numbers of nNOS‐positive nerve fibers per specimen in the P group were significantly lower than the R group (3.0 ± 1.8 vs. 5.0 ± 2.3, P < 0.05). Compared to the R group, patients in the P group had higher IIEF scores and better erectile function at 3 and 6 months post‐operatively. The DVF is a key risk zone for pelvic denervation during laparoscopic TME. Preservation of the DVF can prevent the removal of autonomic nerves and protect post‐operative erectile function. Clin. Anat. 32:439–445, 2019. © 2019 Wiley Periodicals, Inc.     

MicroRNA-214 promotes chronic kidney disease by disrupting mitochondrial oxidative phosphorylation

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