Sinomenine Hydrochloride Attenuates Renal Fibrosis by Inhibiting Excessive Autophagy Induced by Adriamycin: An Experimental Study.
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ABSTRACT:
SUBMITTER: Zhao MM
PROVIDER: S-EPMC5535740 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:Astragaloside IV (ASIV) is the main active component of Astragalus, and can ameliorate cardiomyocyte hypertrophy, apoptosis and fibrosis. In this experiment, we studied how ASIV reduces the cardiotoxicity caused by adriamycin and protects the heart. To this end, rats were randomly divided into the control, ADR, ADR + ASIV and ASIV groups (n = 6). Echocardiography was used to observe cardiac function, HE staining was used to observe myocardial injury, TUNEL staining was used to observe myocardial cell apoptosis, and immunofluorescence and Western blotting was used to observe relevant proteins expression. Experiments have shown that adriamycin can damage heart function in rats, and increase the cell apoptosis index, autophagy level and oxidative stress level. Further results showed that ADR can inhibit the PI3K/Akt pathway. ASIV treatment can significantly improve the cardiac function of rats treated with ADR and regulate autophagy, oxidative stress and apoptosis. Our findings indicate that ASIV may reduce the heart damage caused by adriamycin by activating the PI3K/Akt pathway.
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Project description:It is well known that rennin-angiotensin-aldosterone system (RAAS) plays a critical role in the development of diabetic cardiomyopathy. The present study was aimed to clarify the role of a novel member of RAAS, angiotensin IV (Ang IV) and its downstream mediator forkhead box protein O1 (FoxO1), in the pathogenesis of diabetic cardiomyopathy. In vivo, diabetic mice were treated with low-, medium- and high-dose Ang IV, AT4R antagonist divalinal, FoxO1 inhibitor AS1842856 (AS), or their combinations. In vitro, cardiomyocytes and cardiofibroblasts were treated with different concentrations of glucose, low-, medium- and high-dose Ang IV, divalinal, FoxO1-overexpression plasmid (FoxO1-OE), AS or their combinations. The results showed that Ang IV treatment dose-dependently attenuated left ventricular dysfunction, fibrosis, and myocyte apoptosis in diabetic mice. Besides, enhanced autophagy and FoxO1 protein expression by diabetes were dose-dependently suppressed by Ang IV treatment. However, these cardioprotective effects of Ang IV were completely abolished by divalinal administration. Bioinformatics analysis revealed that the differentially expressed genes were enriched in autophagy, apoptosis, and FoxO signaling pathways among control, diabetes, and diabetes+high-dose Ang IV groups. Similar to Ang IV, AS treatment ameliorated diabetic cardiomyopathy in mice. In vitro, high glucose stimulation increased collagen expression, apoptosis, overactive autophagy flux and FoxO1 nuclear translocation in cardiomyocytes, and upregulated collagen and FoxO1 expression in cardiofibroblasts, which were substantially attenuated by Ang IV treatment. However, these protective effects of Ang IV were completely blocked by the use of divalinal or FoxO1-OE, and these detrimental effects were reversed by the additional administration of AS. In summary, Ang IV treatment dose-dependently attenuated left ventricular dysfunction and remodeling in a mouse model of diabetic cardiomyopathy, and the mechanisms involved stimulation of AT4R and suppression of FoxO1-mediated fibrosis, apoptosis, and overactive autophagy.
2020-09-03 | GSE157331 | GEO
Project description:Studies have found that neutrophil extracellular traps (NETs) which are the specific dying form of neutrophil upon activation have fundamental role in the rheumatoid arthritis onset and progression. The purpose of this study was to explore the therapeutic effect of Sinomenine on adjuvant-induced arthritis in mice, and the neutrophil activities regulated by Sinomenine. The rheumatoid arthritis model was established by local injection of adjuvant and the Sinomenine treatment was administered orally for 30 days, during which, arthritic scores were evaluated and the joint diameter was measured to determine disease progression. The joint tissues and serum were acquired for further tests after sacrifice. Cytometric beads assay was performed to measure the concentration of cytokines. For paraffin-embedded ankle tissues, hematoxylin and erosin staining and Safranin O-fast staining were adopted to monitor the tissue changes of joint. In order to analyze the inflammation, NETs and autophagy of neutrophils in vivo, immunohistochemistry assays were applied to detect the protein expression levels in the local joints. To describe the effect brought by Sinomenine on inflammation, autophagy and NETs in vitro, the western blotting and the immunofluorescence assays were performed. The joint symptoms of the adjuvant induced arthritis were alleviated by the Sinomenine treatment significantly in terms of the ankle diameter and scores. The improvement of local histopathology changes and decrease of inflammatory cytokines in the serum also confirmed the efficacy. The expression levels of interleukin-6, P65 and p-P65 in the ankle areas of mice were remarkably reduced by Sinomenine. Compared with the model group, the decreased expression levels of lymphocyte antigen 6 complex and myeloperoxidase in the Sinomenine treating group showed the inhibitory effect of Sinomenine on the neutrophil migration. The expression of protein arginine deiminase type 4 (PAD4), ctrullinated histone H3 (CitH3) and microtubule-associated protein 1 light chain 3B (LC3B) had the similar tendency. Upon activation of lipopolysaccharide (LPS) in vitro, Sinomenine suppressed the phosphorylation of P65, extracellular signal-regulated kinase (ERK) and P38 of neutrophil. Meanwhile, Sinomenine inhibited NETs formation induced by phorbol 12-myristate 13-acetate (PMA), which were demonstrated by the decreased expression of neutrophil elastase (NE), PAD4 and CitH3. Sinomenine also inhibited PMA-induced autophagy in vitro based on the changes of Beclin-1 and LC3B. Sinomenine has good efficacy in treating adjuvant induced arthritis via regulating neutrophil activities. Apart from inhibiting activation of nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, the mechanism includes suppression of NETs formation via autophagy inhibition.
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Project description:Hypoxia and its induced autophagy are involved in the initiation and progression of liver fibrosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recognized as a potential regulator of autophagy. Our previously reported study found that PCSK9 expression increased in liver fibrosis and that anti-PCSK9 treatment alleviated liver injury. This study aimed to investigate the mechanism of anti-PCSK9 treatment on liver fibrosis by inhibiting hypoxia-induced autophagy. Carbon tetrachloride-induced mouse liver fibrosis and mouse hepatocyte line AML12, cultured under the hypoxic condition, were established to undergo PCSK9 inhibition. The degree of liver fibrosis was shown with histological staining. The reactive oxygen species (ROS) generation was detected by flow cytometry. The expression of PCSK9, hypoxia-inducible factor-1α (HIF-1α), and autophagy-related proteins was examined using Western blot. The autophagic flux was assessed under immunofluorescence and transmission electron microscope. The mouse liver samples were investigated via RNA-sequencing to explore the underlying signaling pathway. The results showed that PCSK9 expression was upregulated with the development of liver fibrosis, which was accompanied by enhanced autophagy. In vitro data verified that PCSK9 increased via hypoxia and inflammation, accompanied by the hypoxia-induced autophagy increased. Then, the validation was acquired of the bidirectional interaction of hypoxia-ROS and PCSK9. The hypoxia reversal attenuated PCSK9 expression and autophagy. Additionally, anti-PCSK9 treatment alleviated liver inflammation and fibrosis, reducing hypoxia and autophagy in vivo. In mechanism, the AMPK/mTOR/ULK1 signaling pathway was identified as a target for anti-PCSK9 therapy. In conclusion, anti-PCSK9 treatment could alleviate liver inflammation and fibrosis by regulating AMPK/mTOR/ULK1 signaling pathway to reduce hypoxia-induced autophagy in hepatocytes.
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Project description:Rationale: The rennin-angiotensin-aldosterone system (RAAS) plays a critical role in the pathogenesis of diabetic cardiomyopathy, but the role of a member of RAAS, angiotensin IV (Ang IV), in this disease and its underlying mechanism are unclear. This study was aimed to clarify the effects of Ang IV and its downstream mediator forkhead box protein O1 (FoxO1) on diabetic cardiomyopathy. Methods: In vivo, diabetic mice were treated with low-, medium- and high-dose Ang IV, AT4R antagonist divalinal, FoxO1 inhibitor AS1842856 (AS), or their combinations. In vitro, H9C2 cardiomyocytes and cardiac fibroblasts were treated with different concentrations of glucose, low-, medium- and high-dose Ang IV, divalinal, FoxO1-overexpression plasmid (FoxO1-OE), AS, or their combinations. Results: Ang IV treatment dose-dependently attenuated left ventricular dysfunction, fibrosis, and myocyte apoptosis in diabetic mice. Besides, enhanced autophagy and FoxO1 protein expression by diabetes were dose-dependently suppressed by Ang IV treatment. However, these cardioprotective effects of Ang IV were completely abolished by divalinal administration. Bioinformatics analysis revealed that the differentially expressed genes were enriched in autophagy, apoptosis, and FoxO signaling pathways among control, diabetes, and diabetes+high-dose Ang IV groups. Similar to Ang IV, AS treatment ameliorated diabetic cardiomyopathy in mice. In vitro, high glucose stimulation increased collagen expression, apoptosis, overactive autophagy flux and FoxO1 nuclear translocation in cardiomyocytes, and upregulated collagen and FoxO1 expression in cardiac fibroblasts, which were substantially attenuated by Ang IV treatment. However, these protective effects of Ang IV were completely blocked by the use of divalinal or FoxO1-OE, and these detrimental effects were reversed by the additional administration of AS. Conclusions: Ang IV treatment dose-dependently attenuated left ventricular dysfunction and remodeling in a mouse model of diabetic cardiomyopathy, and the mechanisms involved stimulation of AT4R and suppression of FoxO1-mediated fibrosis, apoptosis, and overactive autophagy.
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