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      Effects of Periostracum Cicadae on Cytokines and Apoptosis Regulatory Proteins in an IgA Nephropathy Rat Model


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          Periostracum cicadae, the cast-off shell of the cicada Cryptotympana pustulata Fabricius, is used in traditional Chinese medicine for its diaphoretic, anticonvulsive, sedative, antipyretic, and antiallergic effects. However, the exact pathogenesis of immunoglobulin A nephropathy (IgAN) remains unclear, thereby hindering investigations to identify novel therapeutic agents. A rat IgAN model was established by administration of bovine serum albumin, lipopolysaccharide, and carbon tetrachloride, which simultaneously established blood stasis and a heat syndrome model. The animals were sacrificed to detect changes in protein levels in urine and blood. Immunofluorescence was performed to assess IgA deposition in the glomeruli. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin 6 (IL-6) levels were measured in bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assay. Hematology and eosin, periodic acid-Schiff, TUNEL (TdT-mediated dUTP Nick-End Labeling), and immunohistochemical staining were performed to evaluate histopathological changes in kidney tissues. Additionally, target-related proteins were measured by Western blotting. Periostracum cicadae resulted in a reduction in blood and urine protein levels. Serum TNF-α, IL-1β, and IL-6 levels significantly decreased in the periostracum cicadae-treated groups compared to the IgAN group. Furthermore, a reduction in MCP-1 (Monocyte Chemotactic Protein-1), TLR4 ( (Toll-Like Receptor 4 )), and IgA expression levels and a dose-dependent increase in caspase 3 expression were observed in response to periostracum cicadae treatment. TGF-β1(Transforming Growth Factor-β) levels decreased, whereas that of Fas increased in the kidney tissues of the periostracum cicadae-treated groups. The findings of the present study indicate that periostracum cicadae induces apoptosis and improves kidney inflammation and fibrosis in IgA nephropathy rat models.

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          FLICE is activated by association with the CD95 death-inducing signaling complex (DISC).

          Upon activation, the apoptosis-inducing cell membrane receptor CD95 (APO-1/Fas) recruits a set of intracellular signaling proteins (CAP1-4) into a death-inducing signaling complex (DISC). In the DISC, CAP1 and CAP2 represent FADD/MORT1. CAP4 was identified recently as an ICE-like protease, FLICE, with two death effector domains (DED). Here we show that FLICE binds to FADD through its N-terminal DED. This is an obligatory step in CD95 signaling detected in the DISC of all CD95-sensitive cells tested. Upon prolonged triggering of CD95 with agonistic antibodies all cytosolic FLICE gets proteolytically activated. Physiological FLICE cleavage requires association with the DISC and occurs by a two-step mechanism. Initial cleavage generates a p43 and a p12 fragment further processed to a p10 fragment. Subsequent cleavage of the receptor-bound p43 results in formation of the prodomain p26 and the release of the active site-containing fragment p18. Activation of FLICE is blocked by the peptide inhibitors zVAD-fmk, zDEVD-fmk and zIETD-fmk, but not by crmA or Ac-YVAD-CHO. Taken together, our data indicate that FLICE is the first in a cascade of ICE-like proteases activated by CD95 and that this activation requires a functional CD95 DISC.
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            Validation of the Oxford classification of IgA nephropathy.

            The Oxford classification of IgA nephropathy (IgAN) identified four pathological elements that were of prognostic value and additive to known clinical and laboratory variables in predicting patient outcome. These features are segmental glomerulosclerosis/adhesion, mesangial hypercellularity, endocapillary proliferation, and tubular atrophy/interstitial fibrosis. Here, we tested the Oxford results using an independent cohort of 187 adults and children with IgAN from 4 centers in North America by comparing the performance of the logistic regression model and the predictive value of each of the four lesions in both data sets. The cohorts had similar clinical and histological findings, presentations, and clinicopathological correlations. During follow-up, however, the North American cohort received more immunosuppressive and antihypertensive therapies. Identifying patients with a rapid decline in the rate of renal function using the logistic model from the original study in the validation data set was good (c-statistic 0.75), although less precise than in the original study (0.82). Individually, each pathological variable offered the same predictive value in both cohorts except mesangial hypercellularity, which was a weaker predictor. Thus, this North American cohort validated the Oxford IgAN classification and supports its utilization. Further studies are needed to determine the relationship to the impact of treatment and to define the value of the mesangial hypercellularity score.
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              Pathologic predictors of renal outcome and therapeutic efficacy in IgA nephropathy: validation of the oxford classification.

              The Oxford classification of IgA nephropathy (IgAN) may aid in predicting prognosis and providing therapeutic strategy but must be validated in different ancestry. A total of 410 patients with IgAN, enrolled from one of the largest renal centers in China, were evaluated for the predictive value of the Oxford classification to prognosis defined as end stage renal disease. A total of 294 of these patients were prospectively treated with renin-angiotensin system blockade and immunosuppressants sequentially and were evaluated separately to assess the predictive value to therapeutic efficacy (defined as time-averaged proteinuria 25% of glomeruli with endocapillary hypercellularity showed higher proteinuria, lower estimated GFR, and higher mean BP than patients with less endocapillary hypercellularity. Immunosuppressive therapy showed a protective effect to prognosis of endocapillary hypercellularity in patients with endoncapillary hypercellularity could benefit from immunosuppressive therapy. Mesangial hypercellularity and tubular atrophy and interstitial fibrosis were independent factors of inefficiency of renin-angiotensin system blockade alone. Crescents were not significant in predicting prognosis or in therapeutic efficacy. The Oxford classification may aid in predicting prognosis and providing a therapeutic strategy in Chinese patients with IgAN.

                Author and article information

                Int J Mol Sci
                Int J Mol Sci
                International Journal of Molecular Sciences
                29 May 2018
                June 2018
                : 19
                : 6
                : 1599
                [1 ]Xinjiang Academy of Forestry, Urumqi 830000, China; yanglukitty127@ 123456163.com (L.Y.); 18999537981@ 123456163.com (Y.W.); chengping1985@ 123456163.com (P.C.)
                [2 ]Economic Forest Product Quality Inspection and Testing Center of the State Forestry Administration (Urumqi), Urumqi 830052, China
                [3 ]Xinjiang Medical University, Urumqi 830000, China; renakasimu@ 123456vip.sina.com or xjlky_2@ 123456163.com (A.N.); tcm_shz@ 123456aliyun.com (J.-H.W.); renakasimu@ 123456vip.sina.com (R.K.)
                [4 ]Harbin Medical University, Harbin 150081, China
                Author notes
                [* ]Correspondence: xjlky_sys@ 123456163.com ; Tel.: +188-9916-1201
                Author information
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                : 26 March 2018
                : 22 May 2018

                Molecular biology
                periostracum cicadae,iga nephropathy,inflammation,fibrosis,apoptosis
                Molecular biology
                periostracum cicadae, iga nephropathy, inflammation, fibrosis, apoptosis


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