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      Preclinical safety assessment of Angelica acutiloba using a 13-week repeated dose oral toxicity study in rats

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          Abstract

          Angelica acutiloba (AA), a Japanese species of Danggui, has been used worldwide as a traditional herbal medicine with several bioactivities including anti-diabetic, anti-allergic, anti-inflammatory, anti-tumor, and anti-obesity. However, there is lack of toxicological data available to evaluate potential long-term toxicity and the no-observed-adverse-effect level (NOAEL) of AA extract in accordance with the test guidelines published by the Organization for Economic Cooperation and Development. In the 14-day repeat-dose toxicity study, no adverse effects on mortality, body weight change, clinical signs, and organ weights was found following repeat oral administration to rats for 14 days (125, 250, 500, 1000, and 2000 mg/kg body weight), leading that 2000 mg/kg is the highest recommended dose of AA extract for the 13-week repeat-dose oral toxicity study. In the 13-week repeat-dose oral toxicity study, the AA extract was orally administered to groups of rats for 13 weeks (125, 250, 500, 1000, and 2000 mg/kg body weight) to compare between control and AA extract groups. The administration of AA extract did not produce mortality or remarkable clinical signs during this 13-week study. And, the data revealed that there were no significant differences in food/water consumption, body weight, hematological parameters, clinical chemistry parameters, gross macroscopic findings, organ weight and histopathology in comparison to the control group. On the basis of these results, the subchronic NOAEL of the AA extract was more than 2000 mg/kg/day when tested in rats. And, the AA extract is considered safe to use orally as a traditional herbal medicine.

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          Most cited references31

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          Kidney Injury Molecule-1 Outperforms Traditional Biomarkers of Kidney Injury in Multi-site Preclinical Biomarker Qualification Studies

          Kidney toxicity accounts for a significant percentage of morbidity and drug candidate failure. Serum creatinine (SCr) and blood urea nitrogen (BUN) have been used to monitor kidney dysfunction for over a century but these markers are insensitive and non-specific. In multi-site preclinical rat toxicology studies the diagnostic performance of urinary kidney injury molecule-1 (Kim-1) was compared to traditional biomarkers as predictors of kidney tubular histopathologic changes, currently considered the “gold standard” of nephrotoxicity. In multiple models of kidney injury, urinary Kim-1 significantly outperformed SCr and BUN. The area under the receiver operating characteristic curve for Kim-1 was between 0.91 and 0.99 as compared to 0.79 to 0.9 for BUN and 0.73 to 0.85 for SCr. Thus urinary Kim-1 is the first injury biomarker of kidney toxicity qualified by the FDA and EMEA and is expected to significantly improve kidney safety monitoring.
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            Molecular genetic and chemical assessment of radix Angelica (Danggui) in China.

            The roots of Angelica sinensis (Danggui), a traditional Chinese medicine, have been used for invigorating blood circulation for over 2000 years in China. Three common species of Angelica roots are found in Asia: A. sinensis from China, A. acutiloba from Japan, and A. gigas from Korea. By using a molecular genetic approach, the 5S-rRNA spacer domains of the three species of Angelica were amplified, and their nucleotide sequences were determined. Diversity in DNA sequences among various species was found in their 5S-rRNA spacer domains, which could serve as markers for authentic identification of Angelica roots. In chemical analyses, the main constituents of Angelica roots including ferulic acid and Z-ligustilide were determined by HPLC; roots of A. sinensis were clearly distinct in that they contained approximately 10-fold higher levels of ferulic acid and Z-ligustilide as compared to roots of A. acutiloba and A. gigas. In addition, the amounts of main constituents in roots of A. sinensis varied according to different regions of cultivation and different methods of preservation. The chemical profile determined by HPLC therefore could serve as a fingerprint for quality control of Angelica roots.
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              Natural medicine: the genus Angelica.

              More than 60 species of medicinal plants belong to the genus Angelica (Family: Apiaceae). Many of these species have long been used in ancient traditional medicine systems, especially in the far-east. Various herbal preparations containing Angelica species are available over-the-counter, not only in the far-eastern countries, but also in the western countries like USA, UK, Germany, etc. For centuries, many species of this genus, e.g. A. acutiloba, A. archangelica, A. atropupurea, A. dahurica, A. japonica, A. glauca, A. gigas, A. koreana, A. sinensis, A. sylvestris, etc., have been used traditionally as anti-inflammatory, diuretic, expectorant and diaphoretic, and remedy for colds, flu, influenza, hepatitis, arthritis, indigestion, coughs, chronic bronchitis, pleurisy, typhoid, headaches, wind, fever, colic, travel sickness, rheumatism, bacterial and fungal infections and diseases of the urinary organs. Active principles isolated from these plants mainly include various types of coumarins, acetylenic compounds, chalcones, sesquiterpenes and polysaccharides. This review evaluates the importance of the genus Angelica in relation to its traditional medicinal uses, alternative medicinal uses in the modern society and potential for drug development, and summarises results of various scientific studies on Angelica species or Angelica-containing preparations for their bioactivities including, antimicrobial, anticancer, antitumour, analgesic, anti-inflammatory, hepatoprotective, nephroprotective, etc.
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                Author and article information

                Journal
                Lab Anim Res
                Lab Anim Res
                LAR
                Laboratory Animal Research
                Korean Association for Laboratory Animal Science
                1738-6055
                2233-7660
                September 2017
                27 September 2017
                : 33
                : 3
                : 223-230
                Affiliations
                [1 ]Department of Biotechnology, The Catholic University of Korea, Bucheon, Gyeonggi-do, Korea.
                [2 ]Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
                [3 ]Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
                [4 ]Department of Urology, Seoul National University College of Medicine, Seoul, Korea.
                [5 ]Biomedical Center for Animal Resource and Development, Seoul National University College of Medicine, Seoul, Korea.
                [6 ]Graduate School of Translational Medicine, Seoul National University College of Medicine, Seoul, Korea.
                [7 ]Designed Animal and Transplantation Research Institute, Institute of GreenBio Science Technology, Seoul National University, Pyeongchang-gun, Gangwon-do, Korea.
                Author notes
                Corresponding authors: Jeong-Hwan Che, Biomedical Center for Animal Resource and Development, Seoul National University College of Medicine, 103 Daehakro, Jongno-gu, Seoul 03080, Korea. Tel: +82-2-740-8526; Fax: +82-2-743-1839; casache@ 123456snu.ac.kr
                Corresponding authors: Byeong-Cheol Kang, Graduate School of Translational Medicine, Seoul National University College of Medicine, 101 Daehakro, Jongno-gu, Seoul 110-744, Korea. Tel: +82-2-2072-0841; Fax: +82-2-741-7620; bckang@ 123456snu.ac.kr
                Article
                10.5625/lar.2017.33.3.223
                5645600
                04983ece-2da3-47eb-96fd-11b5ee269561
                Copyright © 2017 Korean Association for Laboratory Animal Science

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 June 2017
                : 02 September 2017
                : 03 September 2017
                Funding
                Funded by: Ministry of Food and Drug Safety, CrossRef http://dx.doi.org/10.13039/501100003569;
                Award ID: 05122MFDS472
                Categories
                Original Article

                Life sciences
                angelica acutiloba,traditional medicine,toxicity,subchronic
                Life sciences
                angelica acutiloba, traditional medicine, toxicity, subchronic

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