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      Anisodamine Suppressed the Growth of Hepatocellular Carcinoma Cells, Induced Apoptosis and Regulated the Levels of Inflammatory Factors by Inhibiting NLRP3 Inflammasome Activation

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          Abstract

          Introduction

          Hepatocellular carcinoma (HCC) is a primary liver cancer with a 5-year incidence of over 70%. Anisodamine (ANI), an alkaloid extracted from Anisodus, has a good therapeutic effect in septic shock and morphine addiction. Our study designed to investigate the anticancer effect of anisodamine (ANI) on HCC.

          Materials and Methods

          HepG2 cells were subcutaneously injected into BALB/C nude mice and the tumor tissue was subcutaneously inoculated to construct the transplanted tumor. Mice were randomly divided into 10 groups (n = 5): control group, ANI-10 group, ANI-50 group, ANI-200 group, ANI-200+pcDNA-NLRP3 group, ANI-200+EV group, sh-NLRP3 group, ANI-200 + sh-NLRP3 group, normal group and normal+ANI-200 group.

          Results

          Studies indicated that ANI inhibited the growth of HCC xenografts and reduced liver damage in a dose-dependent manner. Besides, ANI increased the survival rate of tumor-bearing mice and suppressed the expression of NLRP3 in a dose-dependent manner. It is worth noting that NLRP3 overexpression reversed the inhibitory effect of ANI on HCC xenografts. In addition, TUNEL analysis showed that ANI-induced apoptosis of tumor cells, and NLRP3 overexpression reversed the inhibitory effect of ANI on HCC. Moreover, ANI further regulated the levels of IFN-γ, TNF-α, IL-4 and IL-27. Notably, low expression of NLRP3 enhanced the inhibitory effect of ANI on the development of HCC xenografts in mice.

          Discussion

          These findings indicate that ANI suppressed the growth of HCC cells, induced apoptosis and regulated the levels of inflammatory factors by inhibiting NLRP3 inflammasome activation.

          Most cited references30

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          Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine

          Chronic fibrotic liver disease caused by viral or metabolic etiologies is a high-risk condition for developing hepatocellular carcinoma (HCC). Even after complete HCC tumor resection or ablation, the carcinogenic tissue microenvironment in the remnant liver can give rise to recurrent de novo HCC tumors, which progress into incurable, advanced-stage disease in the majority of patients. Thus, early detection and prevention of HCC development is, in principle, the most impactful strategy to improve patient prognosis. However, practice guideline-recommended “one-size-fits-all” HCC screening for early tumor detection is utilized in less than 20% of the target population, and performance of screening modalities, i.e., ultrasound and alpha-fetoprotein is suboptimal. Furthermore, optimal screening strategies for emerging at-risk patient populations such as chronic hepatitis C after viral cure and non-cirrhotic non-alcoholic fatty liver disease remain controversial. New HCC biomarkers and imaging modalities may improve sensitivity and specificity of HCC detection. Clinical and molecular HCC risk scores will enable precise HCC risk prediction followed by tailored HCC screening for individual patients to maximize its cost-effectiveness and optimize allocation of limited medical resources. Several etiology-specific and generic HCC chemoprevention strategies are evolving. Epidemiological and experimental studies have identified candidate chemoprevention targets and therapies, including statins, anti-diabetic drugs, and selective molecular targeted agents, although their clinical testing has been limited by the lengthy process of cancer development that requires long-term, costly studies. Individual HCC risk prediction is expected to overcome the challenge by enabling personalized chemoprevention targeting high-risk patients to achieve precision HCC prevention and substantially improve the dismal prognosis of HCC.
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            NLRP3 inflammasome: Its regulation and involvement in atherosclerosis.

            Inflammasomes are intracellular complexes involved in the innate immunity that convert proIL-1β and proIL-18 to mature forms and initiate pyroptosis via cleaving procaspase-1. The most well-known inflammasome is NLRP3. Several studies have indicated a decisive and important role of NLRP3 inflammasome, IL-1β, IL-18, and pyroptosis in atherosclerosis. Modern hypotheses introduce atherosclerosis as an inflammatory/lipid-based disease and NLRP3 inflammasome has been considered as a link between lipid metabolism and inflammation because crystalline cholesterol and oxidized low-density lipoprotein (oxLDL) (two abundant components in atherosclerotic plaques) activate NLRP3 inflammasome. In addition, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and lysosome rupture, which are implicated in inflammasome activation, have been discussed as important events in atherosclerosis. In spite of these clues, some studies have reported that NLRP3 inflammasome has no significant effect in atherogenesis. Our review reveals that some molecules such as JNK-1 and ASK-1 (upstream regulators of inflammasome activation) can reduce atherosclerosis through inducing apoptosis in macrophages. Notably, NLRP3 inflammasome can also cause apoptosis in macrophages, suggesting that NLRP3 inflammasome may mediate JNK-induced apoptosis, and the apoptotic function of NLRP3 inflammasome may be a reason for the conflicting results reported. The present review shows that the role of NLRP3 in atherogenesis can be significant. Here, the molecular pathways of NLRP3 inflammasome activation and the implications of this activation in atherosclerosis are explained.
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              Mortality assessment of patients with hepatocellular carcinoma according to underlying disease and treatment modalities

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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                29 April 2020
                2020
                : 14
                : 1609-1620
                Affiliations
                [1 ]Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, Capital Medical University , Beijing 100020, People’s Republic of China
                Author notes
                Correspondence: Qiang He Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, Capital Medical University , No. 8, Gongti South Road, Chaoyang District, Beijing100020, People’s Republic of ChinaTel + 86-010-85231504 Email heqiang349@sina.com
                Article
                243383
                10.2147/DDDT.S243383
                7196779
                32425506
                dda2d66e-95d8-49a5-b660-e762b6edd418
                © 2020 Li et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 22 December 2019
                : 17 March 2020
                Page count
                Figures: 6, References: 32, Pages: 12
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                hepatocellular carcinoma,anisodamine,nod-like receptor family pyrin domain containing 3,nlrp3,inflammatory factors,anticancer

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