Dataset Information

Si-Miao-Yong-An (SMYA) Decoction May Protect the Renal Function Through Regulating the Autophagy-Mediated Degradation of Ubiquitinated Protein in an Atherosclerosis Model.

ABSTRACT: Hyperlipidemia is common, and its renal toxicity has attracted a great deal of attention. Si-miao-yong-an (SMYA) is a famous ancient decoction of traditional Chinese medicine (TCM), which is still widely used in clinical treatment. In this study, we observed and explored its efficacy and mechanism in protecting renal function in an atherosclerosis model. The results showed that the serum, Cr urinal KIM-1, and NGAL were significantly decreased in SMYA group. Although SMYA failed to alleviate the lipid accumulation, decrease p-NF?B, or increase SOD in kidney tissue, the levels of ubiquitinated protein and P62 were decreased in SMYA group. What is more, a higher LC3 II level was observed in the SMYA group. In conclusion, these data indicated that SMYA decoction may protect renal function in hyperlipidemia via regulating the autophagy-mediated degradation of ubiquitinated protein.

SUBMITTER: Zhu ZB

PROVIDER: S-EPMC7343850 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Si-Miao-Yong-An (SMYA) Decoction May Protect the Renal Function Through Regulating the Autophagy-Mediated Degradation of Ubiquitinated Protein in an Atherosclerosis Model.

Zhu Ze-Bing ZB Song Ke K Huang Wei-Jun WJ Li Hui H Yang Hui H Bai Yun-Qi YQ Guo Ke-Ting KT Yang Rui-Bing RB Lou Wen-Jiao WJ Xia Chen-Hui CH Nie Bo B Liu Wei-Jing WJ

Frontiers in pharmacology 20200702

Hyperlipidemia is common, and its renal toxicity has attracted a great deal of attention. Si-miao-yong-an (SMYA) is a famous ancient decoction of traditional Chinese medicine (TCM), which is still widely used in clinical treatment. In this study, we observed and explored its efficacy and mechanism in protecting renal function in an atherosclerosis model. The results showed that the serum, Cr urinal KIM-1, and NGAL were significantly decreased in SMYA group. Although SMYA failed to alleviate the ...[more]

PMID: 32714182

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Project description:Objective: The aim of this study was to determine whether Si-Miao-Yong-An decoction (SMYAD) could ameliorate pressure overload-induced heart hypertrophy and its mechanisms. Methods: C57BL/6 mice were subjected to either sham or transverse aortic constriction (TAC) surgery to induce heart hypertrophy. SMYAD (14.85 g/kg/day, ig) or captopril (16.5 mg/kg/day, ig) was administered to the mice for 4 weeks. Cardiac function was evaluated based on echocardiography. Heart hypertrophy was detected using hematoxylin and eosin or wheat germ agglutinin staining. Protein expression of CD41, CD61, and P-selectin were measured with Western blot and immunohistochemistry. The expression levels of atrial natriuretic peptide, brain natriuretic peptide, β-myosin heavy chain, β-thromboglobulin, and von Willebrand factor were evaluated by quantitative polymerase chain reaction. Results: Four weeks after TAC, mice developed exaggerated cardiac hypertrophy and demonstrated a strong decrease in left ventricular ejection fraction compared with sham (29.9 ± 9.3% versus 66.0 ± 9.9%; P < 0.001). Conversely, SMYAD improved cardiac dysfunction with preserved left ventricular ejection fraction (66.5 ± 17.2%; P < 0.001). Shortening fraction was increased by SMYAD, while the left ventricular internal diameter and left ventricular volume were decreased in SMYAD group. SMYAD treatment significantly attenuated cardiac hypertrophy as reflected by the inhibition of atrial natriuretic peptide, brain natriuretic peptide, β-myosin heavy chain mRNA expression, and by the decreasing of cardiac myocyte cross-sectional area. Furthermore, Western blot and immunohistochemistry indicated that the protein expression of platelet aggregation markers (CD41 and CD61) and platelet activation marker (P-selectin) were significantly higher in model mice compared with control. These pathological alterations in TAC-induced mice were significantly ameliorated or blocked by SMYAD administration. Conclusions: Our results suggested that SMYAD exerted its effect by inhibiting platelet aggregation and activation as revealed by CD41/CD61/P-selectin downregulation. Inhibition the activation of the platelets might contribute to the therapeutic effect of SMYAD in failing heart.

Project description:BackgroundAbdominal aortic aneurysm (AAA) is a fatal disease characterized by high morbidity and mortality in old population. Globally, effective drugs for AAA are still limited. Si-Miao-Yong-An decoction (SMYAD), a traditional Chinese medicine (TCM) formula with a high medical value, was reported to be successfully used in an old AAA patient. Thus, we reason that SMYAD may serve as a potential anti-AAA regime.ObjectiveThe exact effects and detailed mechanisms of SMYAD on AAA were explored by using the experimental study and bioinformatics analysis.MethodsFirstly, C57BL/6N mice induced by Bap and Ang II were utilized to reproduce the AAA model, and the effects of SMYAD were systematically assessed according to histology, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA). Then, network pharmacology was applied to identify the biological processes, pathways, and hub targets of SMYAD against AAA; moreover, molecular docking was utilized to identify the binding ability and action targets.ResultsIn an animal experiment, SMYAD was found to effectively alleviate the degree of pathological expansion of abdominal aorta and reduce the incidence of Bap/Ang II-induced AAA, along with reducing the damage to elastic lamella, attenuating infiltration of macrophage, and lowering the circulating IL-6 level corresponding to the animal study, and network pharmacology revealed the detailed mechanisms of SMYAD on AAA that were related to pathways of inflammatory response, defense response, apoptotic, cell migration and adhesion, and reactive oxygen species metabolic process. Then, seven targets, IL-6, TNF, HSP90AA1, RELA, PTGS2, ESR1, and MMP9, were identified as hub targets of SMYAD against AAA. Furthermore, molecular docking verification revealed that the active compounds of SMYAD had good binding ability and clear binding site with core targets related to AAA formation.ConclusionSMYAD can suppress AAA development through multicompound, multitarget, and multipathway, which provides a research direction for further study.

Project description:Proteotoxicity resulting from accumulation of damaged/unwanted proteins contributes prominently to cellular aging and neurodegeneration. Proteasomal removal of these proteins upon covalent polyubiquitination is highly regulated. Recent reports proposed a role for autophagy in clearance of diffuse ubiquitinated proteins delivered by p62/SQSTM1. Here, we compared the turnover dynamics of endogenous ubiquitinated proteins by proteasomes and autophagy by assessing the effect of their inhibitors. Autophagy inhibitors bafilomycin A1, ammonium chloride, and 3-methyladenine failed to increase ubiquitinated protein levels. The proteasome inhibitor epoxomicin raised ubiquitinated protein levels at least 3-fold higher than the lysosomotropic agent chloroquine. These trends were observed in SK-N-SH cells under serum or serum-free conditions and in WT or Atg5(-/-) mouse embryonic fibroblasts (MEFs). Notably, chloroquine considerably inhibited proteasomes in SK-N-SH cells and MEFs. In these cells, elevation of p62/SQSTM1 was greater upon proteasome inhibition than with all autophagy inhibitors tested and was reduced in Atg5(-/-) MEFs. With epoxomicin, soluble p62/SQSTM1 associated with proteasomes and p62/SQSTM1 aggregates contained inactive proteasomes, ubiquitinated proteins, and autophagosomes. Prolonged autophagy inhibition (96 h) failed to elevate ubiquitinated proteins in rat cortical neurons, although epoxomicin did. Moreover, prolonged autophagy inhibition in cortical neurons markedly increased p62/SQSTM1, supporting its degradation mainly by autophagy and not by proteasomes. In conclusion, we clearly demonstrate that pharmacologic or genetic inhibition of autophagy fails to elevate ubiquitinated proteins unless the proteasome is affected. We also provide strong evidence that p62/SQSTM1 associates with proteasomes and that autophagy degrades p62/SQSTM1. Overall, the function of p62/SQSTM1 in the proteasomal pathway and autophagy requires further elucidation.

Dataset Information

Si-Miao-Yong-An (SMYA) Decoction May Protect the Renal Function Through Regulating the Autophagy-Mediated Degradation of Ubiquitinated Protein in an Atherosclerosis Model.

Publications

Si-Miao-Yong-An (SMYA) Decoction May Protect the Renal Function Through Regulating the Autophagy-Mediated Degradation of Ubiquitinated Protein in an Atherosclerosis Model.

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