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      Overview of Pharmacokinetics and Liver Toxicities of Radix Polygoni Multiflori

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          Abstract

          Radix Polygoni Multiflori (RPM), a traditional Chinese medicine, has been used as a tonic and an anti-aging remedy for centuries. However, its safe and effective application in clinical practice could be hindered by its liver injury potential and lack of investigations on its hepatotoxicity mechanism. Our current review aims to provide a comprehensive overview and a critical assessment of the absorption, distribution, metabolism, excretion of RPM, and their relationships with its induced liver injury. Based on the well-reported intrinsic liver toxicity of emodin, one of the major components in RPM, it is concluded that its plasma and liver concentrations could attribute to RPM induced liver injury via metabolic enzymes alteration, hepatocyte apoptosis, bile acids homeostasis disruption, and inflammatory damage. Co-administered 2,3,5,4′-tetrahydroxystilbene-2- O- β-D-glucopyranoside in RPM and other drugs/herbs could further aggravate the hepatotoxicity of emodin via enhancing its absorption and inhibiting its metabolism. To ensure the safe clinical use of RPM, a better understanding of the toxicokinetics and effect of its co-occurring components or other co-administered drugs/herbs on the pharmacokinetics of emodin is warranted.

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          Most cited references86

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          Cellular and molecular mechanisms of liver injury.

          Derangements in apoptosis of liver cells are mechanistically important in the pathogenesis of end-stage liver disease. Vulnerable hepatocytes can undergo apoptosis via an extrinsic, death receptor-mediated pathway, or alternatively intracellular stress can activate the intrinsic pathway of apoptosis. Both pathways converge on mitochondria, and mitochondrial dysfunction is a prerequisite for hepatocyte apoptosis. Persistent apoptosis is a feature of chronic liver diseases, and massive apoptosis is a feature of acute liver diseases. Fibrogenesis is stimulated by ongoing hepatocyte apoptosis, eventually resulting in cirrhosis of the liver in chronic liver diseases. Endothelial cell apoptosis occurs in ischemia-reperfusion injury. Natural killer and natural killer T cells remove virus-infected hepatocytes by death receptor-mediated fibrosis. Lastly, activated stellate cell apoptosis leads to slowing and resolution of apoptosis. This review summarizes recent cellular and molecular advances in the understanding of the injury mechanisms leading to end-stage liver disease.
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            RUCAM in Drug and Herb Induced Liver Injury: The Update

            RUCAM (Roussel Uclaf Causality Assessment Method) or its previous synonym CIOMS (Council for International Organizations of Medical Sciences) is a well established tool in common use to quantitatively assess causality in cases of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI). Historical background and the original work confirm the use of RUCAM as single term for future cases, dismissing now the term CIOMS for reasons of simplicity and clarity. RUCAM represents a structured, standardized, validated, and hepatotoxicity specific diagnostic approach that attributes scores to individual key items, providing final quantitative gradings of causality for each suspect drug/herb in a case report. Experts from Europe and the United States had previously established in consensus meetings the first criteria of RUCAM to meet the requirements of clinicians and practitioners in care for their patients with suspected DILI and HILI. RUCAM was completed by additional criteria and validated, assisting to establish the timely diagnosis with a high degree of certainty. In many countries and for more than two decades, physicians, regulatory agencies, case report authors, and pharmaceutical companies successfully applied RUCAM for suspected DILI and HILI. Their practical experience, emerging new data on DILI and HILI characteristics, and few ambiguous questions in domains such alcohol use and exclusions of non-drug causes led to the present update of RUCAM. The aim was to reduce interobserver and intraobserver variability, to provide accurately defined, objective core elements, and to simplify the handling of the items. We now present the update of the well accepted original RUCAM scale and recommend its use for clinical, regulatory, publication, and expert purposes to validly establish causality in cases of suspected DILI and HILI, facilitating a straightforward application and an internationally harmonized approach of causality assessment as a common basic tool.
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              Molecular mechanisms of hepatic apoptosis

              K. Wang (2014)
              Apoptosis is a prominent feature of liver diseases. Causative factors such as alcohol, viruses, toxic bile acids, fatty acids, drugs, and immune response, can induce apoptotic cell death via membrane receptors and intracellular stress. Apoptotic signaling network, including membrane death receptor-mediated cascade, reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress, lysosomal permeabilization, and mitochondrial dysfunction, is intermixed each other, but one mechanism may dominate at a particular stage. Mechanisms of hepatic apoptosis are complicated by multiple signaling pathways. The progression of liver disease is affected by the balance between apoptotic and antiapoptotic capabilities. Therapeutic options of liver injury are impacted by the clear understanding toward mechanisms of hepatic apoptosis.
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                Author and article information

                Journal
                Toxins (Basel)
                Toxins (Basel)
                toxins
                Toxins
                MDPI
                2072-6651
                21 November 2020
                November 2020
                : 12
                : 11
                : 729
                Affiliations
                School of Pharmacy, The Chinese University of Hong Kong, Hong Kong 999077, China; 1155133238@ 123456link.cuhk.edu.hk (D.L.); yangmb1022@ 123456gmail.com (M.Y.)
                Author notes
                [* ]Correspondence: joanzuo@ 123456cuhk.edu.hk
                Author information
                https://orcid.org/0000-0002-6976-6157
                Article
                toxins-12-00729
                10.3390/toxins12110729
                7700391
                33233441
                3d92bafd-2206-4010-8d16-d33e5c55e78e
                © 2020 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/).

                History
                : 10 October 2020
                : 19 November 2020
                Categories
                Review

                Molecular medicine
                radix polygoni multiflori,herb induced liver injury,pharmacokinetics,mechanism,herb–drug/herb interaction

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