肝臟是人體最重要的代謝器官，其功能主要包含代謝宿主及外來分子等。由氧化壓力所引起之肝損傷是造成不同肝臟疾病最主要原因之一。四氯化碳(CCl4)是一種肝毒性化合物，常被使用於建立肝損傷之動物模型。牛樟芝(Antrodia cinnamomea, AC)為一種生長於台灣山區之特有種，先前實驗證實其具有解毒、保肝及抗腫瘤等相關活性作用。利用抗氧化物輔助營養或食品補充以減低ROS的產生會是減低長期肝發炎或是慢性肝發炎的策略之ㄧ。故本研究主要是以四氯化碳(CCl4)誘導大白鼠慢性肝損傷，探討不同牛樟芝子實體試驗樣品對於大白鼠慢性肝損傷之影響。研究成果顯示CCl4會造成肝臟組織外觀及病理組織破壞，肝損傷之大鼠其體重上升變化量變大， GOT、GPT、T-cholesterol、ALP、γ-GT表現量會上升，肝臟會產生纖維化，這和4HNE/Caspase-3/PARP介導的細胞凋亡有關，而在Silymarin治療組或牛樟芝子實體試驗樣品組皆可有效緩解CCl4引起的這些效應。這些結果表明，牛樟芝子實體可改善四氯化碳誘導的大鼠肝損傷，未來在輔助食品之應用上具有改善潛力。

The liver is the most important metabolic organ of the human body, and it’s functions mainly include the metabolic host and foreign molecules. Liver injury caused by oxidative stress is one of the most important causes of different liver diseases. Carbon tetrachloride(CCl4) is a hepatotoxic compound that is often used to establish animal models of liver injury. Antrodia cinnamomea is an endemic species that grows in the mountains of Taiwan. Previous experiments have confirmed that it has detoxification, liver protection and anti-tumor activities. Using antioxidants to assist nutrition or food supplements to reduce the production of ROS will be one of the strategies to reduce long-term liver inflammation or chronic liver inflammation. Therefore, this study aim to explored the effects of different Antrodia camphorata fruit bodies test samples on chronic liver injury in rats. Research results show that CCl4 can cause liver tissue appearance and pathological tissue damage. Rats with liver injury have larger changes in weight gain, GOT, GPT, T-cholesterol, ALP, and γ-GT expression levels will increase, and liver fibrosis will occur. This is related to 4HNE/Caspase-3/PARP-mediated apoptosis, which can effectively alleviate these effects caused by CCl4 in the Silymarin treatment group or the Antrodia camphorata fruit body test sample group. These results indicate that Antrodia cinnamomea fruitbodies can improve liver damage induced by carbon tetrachloride in rats, and have potential for improvement in the application of supplementary food in the future.

1. Xiao wei Huo, Xiang bo Meng, Jun Zhang and Yan yan Zhao. Hepatoprotective effect of different combinations of 18α-and 18β-Glycyrrhizic acid against CCl4-induced liver injury in rats. Biomedicine & Pharmacotherapy. Volume 122: 109354 (2020).
2. Veronika Sarnatskaya, Mikhailenko,Igor Prokopenko, Bogdan I. Gerashchenko, Oksana Shevchuk, Larysa Yushko, Alexei Glavin, Lyudmila Makovetska, Larysa Sakhno, Oleksii Sydorenko, Oleksandr Kozynchenko and Vladimir Nikolaev. The effect of two formulations of carbon enterosorbents on oxidative stress indexes and molecular conformation of serum albumin in experimental animals exposed to CCl4. Heliyon. Published online 2020 6(1): e03126 (2020).
3. Qin Lin, Xiaolin Kang, Xuefeng Li, Tao Wang, Fengting Liu, Jinxue Jia, Ziqi Jin, Data curation, and Yongzhi Xue, NF-κB-mediated regulation of rat CYP2E1 by two independent signaling pathways. PLOS ONE. Published online 2019 14(12): e0225531 (2019)
4. Hong-Ye Ju, Kun-Xia Hu, Guo-Wang Zhao, Zhi-Shu Tang and Xiao Song. Design, Preparation, and Characterization of Dioscin Nanosuspensions and Evaluation of Their Protective Effect against Carbon Tetrachloride-Induced Acute Liver Injury in Mice. Evidence-Based Complementary and Alternative Medicine. Published online 2019: 3907915 (2019).
5. Yasmina Abd-Elhakim, Mervat Ghoneim, Mohamed Khairy and Smr Eissa. Single or combined protective and therapeutic impact of taurine and hesperidin on carbon tetrachloride-induced acute hepatic injury in rat. Environmental Science and Pollution Research. Published: 03 February 2020 (2020).
6. Mina Mirnezami, Hadi Jafarimanesh, Masoud Rezagholizamenjany, Abbas Alimoradian and Mehdi Ranjbaran. The effect of silymarin on liver enzymes in patients taking isotretinoin: A randomized clinical trial. Dermatologic Therapy/ Early View. Published online 30 January 2020: e13236 (2020).
7. Camila Ribeiro de Avelar, Emile Miranda Pereira, Priscila Ribas de Farias Costa, Rosângela Passos de Jesus and Lucivalda Pereira Magalhães de Oliveira. Effect of silymarin on biochemical indicators in patients with liver disease: Systematic review with meta-analysis. World Journal of Gastroenterlogy. 23(27): 5004–5017 (2020).
8. Alessandro Federico, Marcello Dallio and Carmelina Loguercio. Silymarin/Silybin and Chronic Liver Disease: A Marriage of Many Years. Molecules. 22(2): 191 (2017).
9. Anton Gillessen, Hartmut H.-J. Schmidt. Silymarin as Supportive Treatment in Liver Diseases: A Narrative Review. Published: 17 February 2020 (2020).
10. Caicheng Wang, Weiwei Zhang, Jack Ho Wong, Tzibun Ng and Xiujuan Ye. Diversity of potentially exploitable pharmacological activities of the highly prized edible medicinal fungus Antrodia camphorate. Applied Microbiology and Biotechnology. 103: 7843–7867 (2019).
11. Namal Perera, Feng-Ling Yang, Yueh-Tung Lu, Lan-Hui Li, Kuo-Feng Hua, and Shih-Hsiung Wu. Antrodia cinnamomea Galactomannan Elicits Immuno-stimulatory Activity Through Toll-like Receptor 4. International Journal of Biological Sciences. 14(10): 1378–1388 (2018).
12. Yung-Luen Shih, Ming-Fang Wu, Ching-Hsiao Lee, Ming-Yang Yeh, Jason Chou, Jia-You Liu, Hsu-Feng Lu, Yi-Ping Huang, Nien-Chieh Liao, and Jing-Gung Chung,. Antrodia Cinnamomea Reduces Carbon Tetrachloride-induced Hepatotoxicity In Male Wister Rats. In vivo. 31(5): 877–884 (2017).
13. Lu Xu, Yifan Yu, Rui Sang, Jinxia Li, Bingjie Ge, and Xuemei Zhang. Protective Effects of Taraxasterol against Ethanol-Induced Liver Injury by Regulating CYP2E1/Nrf2/HO-1 and NF-κB Signaling Pathways in Mice. Oxidative Medicine and Cellular Longevity. Published online 2018 Sep 23 (2018).
14. Akram Eidi, Pejman Mortazavi, Khodabakhsh Behzadi, Ali Haeri Rohani & Shahabeddin Safi. Hepatoprotective Effect of Manganese Chloride Against CCl4-Induced Liver Injury in Rats. Biological Trace Element Research. 155: 267–275 (2013).
15. Mohammad Hosein Farzaei, Mahdi Zobeiri, Fatemeh Parvizi, Fardous F. El-Senduny, Ilias Marmouzi, Ericsson Coy-Barrera, Rozita Naseri, Seyed Mohammad Nabavi, Roja Rahimi, and Mohammad Abdollahi. Curcumin in Liver Diseases: A Systematic Review of the Cellular Mechanisms of Oxidative Stress and Clinical Perspective. Nutrients. 10(7): 855 (2018).
16. Shiyue Li, Jinxin Zhou, Shangfu Xu, Jin Li, Jie Liu, Yuanfu Lu, Jingshan Shi, Shaoyu Zhou, Qin Wu. Induction of Nrf2 pathway by Dendrobium nobile Lindl. alkaloids protects against carbon tetrachloride induced acute liver injury. Biomedicine & Pharmacotherapy. 117: 109073 (2019).
17. Zhipeng Meng, Yandong Wang, Lin Wang, Wen Jin, Nian Liu, Hao Pan, Lucy Liu, Lawrence Wagman, Barry M. Forman, and Wendong Huang. FXR Regulates Liver Repair after CCl4-Induced Toxic Injury. Molecular Endocrinology. 24(5): 886–897 (2010).
18. Mesias Pedroza, Sarah To, Jennifer Smith, Sandeep K. Agarwal. Cadherin-11 contributes to liver fibrosis induced by carbon tetrachloride. PLoS ONE. 14(7): e0218971 (2019).
19. Kenneth D Kochanek, Sherry L Murphy, Jiaquan Xu, Elizabeth Arias. Deaths: Final Data for 2017. National Vital Statistics Reports. 68(9):1-77 (2019).
20. Xiang-lan Wei, Ru-tang Fang, Yong-hua Yang, Xue-yuan Bi, Guo-xia Ren, A-li Luo, Ming Zhao and Wei-jin Zang. Protective effects of extracts from Pomegranate peels and seeds on liver fibrosis induced by carbon tetrachloride in rats. BMC Complementary Medicine and Therapies. 15: 389 (2015).
21. Sakhria Mbarki, Hichem Alimi, Hafsia Bouzenna, Abdelfettah Elfeki, Najla Hfaiedh. Phytochemical study and protective effect of Trigonella foenum graecum (Fenugreek seeds) against carbon tetrachloride-induced toxicity in liver and kidney of male rat. Biomedicine & Pharmacotherapy. 88: 19-26 (2017).
22. Yasser El-Sayed, Mohamed Lebda, Mohammed Hassinin and Saad Neoman. Chicory (Cichorium intybus L.) Root Extract Regulates the Oxidative Status and Antioxidant Gene Transcripts in CCl4-Induced Hepatotoxicity. PLoS ONE. 10(3): e0121549 (2015).
23. Lucija Kuna, Ivana Božić, Tomislav Kizivat, Kristina Bojanić, Margareta Mršo, Edgar Kralj, Robert Smolić, George Y. Wu and Martina Smolić. Models of Drug Induced Liver Injury (DILI) – Current Issues and Future Perspectives. Current Drug Metabolism. 19(10): 830–838 (2018).
24. Dai-Hua Tsai, Cheng-Han Chung, and Kung-Ta Lee. Antrodia cinnamomea induces autophagic cell death via the CHOP/TRB3/Akt/mTOR pathway in colorectal cancer cells. Scientific Reports. 8: 17424 Published online 2018 Nov 27 (2018).
25. Jelena Krstic, Markus Galhuber, Tim J. Schulz, Michael Schupp and Andreas Prokesch. p53 as a Dichotomous Regulator of Liver Disease: The Dose Makes the Medicin. International Journal of Molecular Sciences. 19(3): 921. 2018.
26. Wenting Wang, Mingyue Zhu, Zhixin Xu, Wei Li, Xu Dong, Yi Chen, Bo Lin, and Mengsen Li. Ropivacaine promotes apoptosis of hepatocellular carcinoma cells through damaging mitochondria and activating caspase-3 activity. Biological Research. 52: 36. 2019.
27. Simonetta Pazzaglia and Claudio Pioli. Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases. Cells. 9(1): 41. 2020.
28. Mei-Yeh Lu, Wen-Lang Fan, Woei-Fuh Wang, Ting-chun Chen, Yi-Ching Tang, Fang-Hu Chu, Tun-Tschu Chang, Sheng-Yang Wang, Meng-yun Li, Yi-Hua Chen, Ze-Shiang Lin, Kai-Jung Yang, Shih-May Chen, Yu-Chuan Teng, Yan-Liang Lin, Jei-Fu Shaw, Ting-Fang Wang, and Wen-Hsiung Li. Genomic and transcriptomic analyses of the medicinal fungus Antrodia cinnamomea for its metabolite biosynthesis and sexual development. Proceedings of the National Academy of Sciences of the United States of America. 111(44): E4743–E4752. 2014.
29. Yu Liu, Pei-Hao Wen, Xin-Xue Zhang, Yang Dai, and Qiang He. Breviscapine ameliorates CCl4-induced liver injury in mice through inhibiting inflammatory apoptotic response and ROS generation. International Journal of Molecular Medicine. 42(2): 755–768. 2018.
30. Shaoru Chen, Liyi Zou, Li Li, and Tie Wu. The Protective Effect of Glycyrrhetinic Acid on Carbon Tetrachloride-Induced Chronic Liver Fibrosis in Mice via Upregulation of Nrf2. Plos one. 8(1): e53662. 2013.
31. Huan-Wen Chiu and Kuo-Feng Hua. Hepatoprotective Effect of Wheat-Based Solid-State Fermented Antrodia cinnamomea in Carbon Tetrachloride-Induced Liver Injury in Rat. Plos one. 11(4): e0153087. 2016.
32. Meital Charni-Natan, Hilla Solomon, Alina Molchadsky, Adi Jacob-Berger, Naomi Goldfinger, and Varda Rotter. Various stress stimuli rewire the profile of liver secretome in a p53-dependent manner. Cell death & disease. 9(6): 647. 2018.
33. Xin Ma, Qin Luo, Hong Zhu, Xuejing Liu, Zhen Dong, Kaili Zhang, Yunzeng Zou, Jian Wu, Junbo Ge, and Aijun Sun. Aldehyde dehydrogenase 2 activation ameliorates CCl4‐induced chronic liver fibrosis in mice by up‐regulating Nrf2/HO‐1 antioxidant pathway. Journal of cellular and molecular medicine. 22(8): 3965–3978. 2018.
34. Qi Liu, Tianlei Si, Xiaoyun Xu, Fuqiang Liang, Lufeng Wang, and Siyi Pan. Electromagnetic radiation at 900 MHz induces sperm apoptosis through bcl-2, bax and caspase-3 signaling pathways in rats. Reproductive Health. 12: 65. 2015.
35. Ruolin Chen, Shuang Liu, Fengyuan Piao, Zhemin Wang, Yuan Qi, Shuangyue Li, Dongmei Zhang, and Jingshun Shen. 2,5-hexanedione induced apoptosis in mesenchymal stem cells from rat bone marrow via mitochondria-dependent caspase-3 pathway. Industrial Health. 53(3): 222–235. 2015.
36. Wenting Wang, Mingyue Zhu, Zhixin Xu, Wei Li, Xu Dong, Yi Chen, Bo Lin, and Mengsen Li. Ropivacaine promotes apoptosis of hepatocellular carcinoma cells through damaging mitochondria and activating caspase-3 activity. Biologicl Research. 52:36. 2019.
37. Li Wang, Jinsong Pan, Tingle Wang, Meng Song, and Wantao Chen. Pathological Cyclic Strain-Induced Apoptosis in Human Periodontal Ligament Cells through the RhoGDIα/Caspase-3/PARP Pathway. Plos One. 8(10): e75973. 2013.
38. Sharad S Singhal, Sharda P. Singh, Preeti Singhal, David Horne, Jyotsana Singhal, and Sanjay Awasthi. Toxicol Appl Pharmacol. Antioxidant Role of Glutathione S-Transferases: 4-Hydroxynonenal, a Key Molecule in Stress-Mediated Signaling. 289(3):361-370. 2015.
39. Lauren Tebay, Holly Robertson, Stephen Durant, Steven Vitale, Trevor Penning, Albena Dinkova-Kostova, and John Hayes. Free Radic Biol Med. Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radical Biology and Medicine. 88:108-146. 2015.
40. Marina Galicia-Moreno, Silvia Lucano-Landeros, Hugo Christian Monroy-Ramirez, Jorge Silva-Gomez, Jorge Gutierrez-Cuevas, Arturo Santos, and Juan Armendariz-Borunda. Roles of Nrf2 in Liver Diseases: Molecular, Pharmacological, and Epigenetic Aspects. 9(10):980. 2020.
41. Claudia Orrù, Silvia Giordano, and Amedeo Columbano. Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases. Antioxidants. 12(10):2932. 2020.