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Ruan L, Jiang L, Zhao W, Meng H, Zheng Q, Wang J. Hepatotoxicity or hepatoprotection of emodin? Two sides of the same coin by 1H-NMR metabolomics profiling. Toxicol Appl Pharmacol 2021; 431:115734. [PMID: 34606778 DOI: 10.1016/j.taap.2021.115734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 09/17/2021] [Accepted: 09/27/2021] [Indexed: 10/20/2022]
Abstract
Emodin is the major anthraquinone component of many important traditional Chinese herbs, such as Rheum palmatum L. and Polygonum multiflorum Thunb. They have been popular health products but recently aroused concerns about their hepatotoxicity, which are believed to be arising from the contained anthraquinones, such as emodin. However, emodin exerts potent hepatoprotective ability, such as anti-fibrotic, anti-oxidative, and anti-inflammatory effects. In this study, 1H NMR based metabolomics approach, complemented with histopathological observation, biochemical measurements, western blotting analysis and real-time quantitative PCR (RT-qPCR), was applied to interpret the paradox of emodin (30 mg/kg, 10 mg/kg BW) using both healthy mice (male, ICR) and chronic CCl4-injured mice (0.1 mL/kg, 0.35% CCl4, 3 times a week for a month). Emodin exerted a weight loss property associated with its lipid-lowing effects, which helped alleviate CCl4-induced steatosis. Emodin effectively ameliorated CCl4-induced oxidative stress and energy metabolism dysfunction in mice liver via regulating glucose, lipid and amino acid metabolism, and inhibited excessive inflammatory response. In healthy mice, emodin only exhibited hepatoxicity on high-dosage by disturbing hepatic anti-oxidant homeostasis, especially GSH and xanthine metabolism. This integrated metabolomics approach identified the bidirectional potential of emodin, which are important for its rational use.
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Affiliation(s)
- Lingyu Ruan
- Center for Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing 210094, PR China.
| | - Lei Jiang
- Center for Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing 210094, PR China.
| | - Wenlong Zhao
- Center for Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing 210094, PR China.
| | - Huihui Meng
- Center for Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing 210094, PR China.
| | - Qi Zheng
- Center for Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing 210094, PR China.
| | - Junsong Wang
- Center for Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing 210094, PR China.
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Yin L, Wang Y, Guo X, Xu C, Yu G. Comparison of gene expression in liver regeneration and hepatocellular carcinoma formation. Cancer Manag Res 2018; 10:5691-5708. [PMID: 30532592 PMCID: PMC6245377 DOI: 10.2147/cmar.s172945] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background Liver -cell proliferation occurs in hepatocellular carcinoma (HCC) and liver regeneration (LR). The development and progression of HCC and LR have many similar molecular pathways with very different results. In simple terms, LR is a controllable process of organ recovery and function reconstruction, whereas liver cancer is uncontrollable. Do they share common key pathways and genes? Methods In this study, the dynamic transcriptome profile at ten time points (0, 2, 6, 12, 24, 30, 36, 72, 120, and 168 hours) during LR in rats after two-thirds hepatectomy and eight stages (normal, cirrhosis without HCC, cirrhosis, low-grade dysplastic, high-grade dysplastic, and very early, early advanced, and very advanced HCC) representing a stepwise carcinogenic process from preneoplastic lesions to end-stage HCC were analyzed in detail. A variety of bioinformatic methods, including MaSigPro, weighted gene-coexpression network analysis, and spatial analysis of functional enrichment, were used to analyze, elucidate, and compare similarities and differences between LR and HCC formation. Results Key biological processes and genes were identified. From the comparison, we found that cell proliferation and angiogenesis were the most significantly dysregulated processes shared by LR and HCC. The pattern of cell-proliferation-related gene expression in progression stage during LR is similar to the transition process from dysplasia to early-stage HCC. LR and HCC showed different expression patterns as a whole. Some key genes, including FYN, XPO1, FOXM1, EZH2, and NRF1, were identified as playing critical roles in both LR and HCC. Conclusion These findings could contribute to revealing the molecular mechanism of development and regulation mechanism of normal and abnormal proliferation, which could provide new ideas and treatment methods for regenerative medicine, oncological drug development, and oncological treatment.
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Affiliation(s)
- Li Yin
- College of Life Science, Henan Normal University, Xinxiang, Henan 453007, China, ; .,State Key Laboratory Cultivation Base for Cell Differentiation Regulation and Henan Engineering Laboratory for Bioengineering and Drug Development, Henan Normal University, Xinxiang, Henan 453007, China, ; .,Laboratory of Tropical Biomedicine and Biotechnology, School of Tropical Medicine and Laboratory Medicine, Hainan Medical University, Haikou 571199, China
| | - Yahao Wang
- College of Life Science, Henan Normal University, Xinxiang, Henan 453007, China, ; .,State Key Laboratory Cultivation Base for Cell Differentiation Regulation and Henan Engineering Laboratory for Bioengineering and Drug Development, Henan Normal University, Xinxiang, Henan 453007, China, ;
| | - Xueqiang Guo
- College of Life Science, Henan Normal University, Xinxiang, Henan 453007, China, ; .,State Key Laboratory Cultivation Base for Cell Differentiation Regulation and Henan Engineering Laboratory for Bioengineering and Drug Development, Henan Normal University, Xinxiang, Henan 453007, China, ;
| | - Cunshuan Xu
- College of Life Science, Henan Normal University, Xinxiang, Henan 453007, China, ; .,State Key Laboratory Cultivation Base for Cell Differentiation Regulation and Henan Engineering Laboratory for Bioengineering and Drug Development, Henan Normal University, Xinxiang, Henan 453007, China, ;
| | - Guoying Yu
- College of Life Science, Henan Normal University, Xinxiang, Henan 453007, China, ; .,State Key Laboratory Cultivation Base for Cell Differentiation Regulation and Henan Engineering Laboratory for Bioengineering and Drug Development, Henan Normal University, Xinxiang, Henan 453007, China, ;
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Maggs JRL, Suddle AR, Aluvihare V, Heneghan MA. Systematic review: the role of liver transplantation in the management of hepatocellular carcinoma. Aliment Pharmacol Ther 2012; 35:1113-34. [PMID: 22432733 DOI: 10.1111/j.1365-2036.2012.05072.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 09/18/2011] [Accepted: 03/02/2012] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality worldwide. Liver transplantation offers a potential cure for this otherwise devastating disease. The selection of the most appropriate candidates is paramount in an era of graft shortage. AIM To review systematically the role of liver transplantation in the management of HCC in current clinical practice. METHODS An electronic literature search using PUBMED (1980-2010) was performed. Search terms included HCC, hepatoma, liver cancer, and liver transplantation. RESULTS Liver transplantation is a highly successful treatment for HCC, in patients within Milan criteria (MC), defined as a solitary tumour ≤50 mm in diameter or ≤3 tumours ≤30 mm in diameter in the absence of extra-hepatic or vascular spread. Other eligibility criteria for liver transplantation are also used in clinical practice, such as the University of California, San Francisco criteria, with outcomes comparable to MC. Loco-regional therapies have a role in the bridging treatment of HCC by minimising wait-list drop-out secondary to tumour progression. Beyond MC, encouraging results have been demonstrated for patients with down-staged tumours. Post-liver transplantation, there is no evidence to support a specific immunosuppressive regimen. In the context of an insufficient cadaveric donor pool to meet demand, the role of adult living donation may be increasingly important. CONCLUSIONS Liver transplantation offers a curative therapy for selected patients with HCC. The optimisation of eligibility criteria is paramount to ensure that maximum benefit is accrued. Although wait-list therapies have been incorporated into clinical practice, additional high quality data are required to support this strategy.
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Affiliation(s)
- J R L Maggs
- Institute of Liver Studies, King's College Hospital, London, UK
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Unek T, Karademir S, Arslan NC, Egeli T, Atasoy G, Sagol O, Obuz F, Akarsu M, Astarcioglu I. Comparison of Milan and UCSF criteria for liver transplantation to treat hepatocellular carcinoma. World J Gastroenterol 2011; 17:4206-4212. [PMID: 22072852 PMCID: PMC3208365 DOI: 10.3748/wjg.v17.i37.4206] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2011] [Revised: 08/01/2011] [Accepted: 08/08/2011] [Indexed: 02/06/2023] Open
Abstract
AIM To assess the validity of the Milan and University of California San Francisco (UCSF) criteria and examine the long-term outcome of orthotopic liver transplantation (OLT) in patients with hepatocellular carcinoma (HCC) in a single-center study. METHODS This study is a retrospective review of prospectively collected data. Between 1998 and 2009, 56 of 356 OLTs were performed in patients with HCC. Based on pathological examination of liver explants, patients were retrospectively categorized into 3 grou-ps: Milan + (n = 34), Milan -/UCSF + (n = 7) and UCSF - (n = 14). RESULTS Median follow-up period was 39.5 (1-124) mo. The 5-year overall survival rates in the Milan +, Milan -/UCSF + and UCSF-groups were 87.7%, 53.6% and 33.3%, respectively (P < 0.000). Within these groups, tumor recurrence was determined in 5.8%, 14.3% and 40% of patients, respectively (P < 0.011). Additionally, the presence of microvascular invasion within the explanted liver had a negative effect on the 5-year disease free survival (74.7% vs. 46.7%, P < 0.044). CONCLUSION The Milan criteria are reliable in the selection of suitable candidates for OLT for the treatment of HCC. For cases of OLT involving living donors, the UCSF criteria may be applied.
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Mazzaferro V, Bhoori S, Sposito C, Bongini M, Langer M, Miceli R, Mariani L. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transpl 2011; 17 Suppl 2:S44-57. [PMID: 21695773 DOI: 10.1002/lt.22365] [Citation(s) in RCA: 435] [Impact Index Per Article: 31.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Vincenzo Mazzaferro
- Units of Gastrointestinal Surgery and Liver Transplantation, National Cancer Institute of Milan, Milan, Italy.
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Kishi Y, Sugawara Y, Tamura S, Kaneko J, Kokudo N, Makuuchi M. Impact of incidentally found hepatocellular carcinoma on the outcome of living donor liver transplantation. Transpl Int 2006; 19:720-5. [PMID: 16918532 DOI: 10.1111/j.1432-2277.2006.00338.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Hepatocellular carcinoma (HCC) nodules newly found in the explant liver have been observed, but the impact on patient prognosis is not known. Sixty HCC patients who underwent living donor liver transplantation were the subjects of the study. Radiologic findings prior to transplantation and pathologic findings of the explant liver were compared. Histologic characteristics of preoperatively overlooked tumors were examined. The influence of the discrepancy between these findings on tumor recurrence was evaluated. A total of 227 HCC nodules were found in the explant livers. Of these, 91 nodules (40%) were newly found by pathologic examination. They were smaller and more likely to be well differentiated than the others. The number and size of the tumors were underestimated in 50% (30/60) and 32% (19/60), respectively. There was no significant difference in the recurrence-free survival rate between patients who met the Milan criteria both in the pre- and post-transplant evaluation (n = 29) and those who met the Milan criteria preoperatively, but exceeded the criteria in the explant (n = 19). Nodules newly found in the explant liver had little impact on recurrence-free survival. A decision for liver transplantation according to the Milan criteria based on preoperative evaluation is valuable for securing an excellent outcome.
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Affiliation(s)
- Yoji Kishi
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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Abstract
Long-term graft survival and mortality after liver transplantation continue to improve. However, disease recurrence remains a major stumbling block, especially among patients with hepatitis C. Chronic hepatitis C recurs to varying degrees in nearly all patients who undergo transplantation. Transplantation for hepatitis C is associated with higher rates of graft failure and death compared with transplantation for other indications, and retransplantation for hepatitis C related liver failure remains controversial. Recurrence of hepatitis B has been markedly reduced with improved prophylactic regimens. Further, rates of hepatocellular carcinoma recurrence have also decreased, as improved patient selection criteria have prioritized transplantation for those with a low risk of recurrence. Primary biliary cirrhosis recurs in some patients, but it is often relatively mild. Autoimmune liver disease has also been shown to have a relatively benign post-transplantation course, but some studies have indicated that it slowly progresses in most recipients. It has been recently reported that alcoholic liver disease liver transplant recipients who return to drinking have worsened mortality. In such patients worse outcomes are not due to graft failure, but instead to other comorbidities. Recurrences of other diseases, including nonalcoholic steatohepatitis and primary sclerosing cholangitis, are now being recognized as having potentially detrimental effects on graft survival and mortality. Expert clinical management may help prevent and treat complications associated with disease recurrence.
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Affiliation(s)
- David S Kotlyar
- University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
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Chui AKK, Rao ARN, Island ER, Chan HLY, Leung TWT, Lau WY. Multimodality tumor control and living donor transplantation for unresectable hepatocellular carcinoma. Transplant Proc 2004; 36:2287-8. [PMID: 15561221 DOI: 10.1016/j.transproceed.2004.08.035] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Liver transplantation (LT) is an acceptable mode of treatment for selected patients with unresectable hepatocellular carcinoma (HCC). However, due to the scarcity of cadaveric donor organs, it is considered desirable for patients to opt for living donor liver transplantation (LDLT) or, for those not being transplanted soon, to have some form of tumor control therapy. Such an approach in our program is analyzed and reported. At our institution, 42 LTs were performed between October 1999 and April 2003. Of these, 18 recipients (15 men, 3 women) had 27 HCC. The average number and size of HCC was 1.59 (1 to 4) and 2.31 (0.2 to 6.5) cm, respectively. Thirteen (72%) patients were transplanted primarily for the HCC, whereas five (28%) others were incidental HCC cases. Seven patients (5 LRLT, 2 cadaveric LT) were transplanted soon after listing, and thus did not require tumor control therapy. Six patients waited for 11 (6 to 19) months before LT. Three patients underwent microwave coagulation therapy, and one had additional alcohol injections. One patient received the novel PIAF (cisplatin, interferon, adriamycin, and 5-FU) chemotherapy regimen followed by selective internal irradiation (SIR) treatment. One patient received conformal radiation therapy and another received SIR treatment before LT. Besides 2 postoperative deaths, the remaining 16 patients have been well, with a mean follow-up of 20.4 (3.6 to 41.2) months. In conclusion, for patients with unresectable HCC, in areas with poor cadaveric donor rate, living donation should be the first option. If a suitable live donor is not available, aggressive multimodality therapy is recommended while waiting for cadaveric LT.
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Affiliation(s)
- A K K Chui
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.
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Chui AKK, Wong J, Rao ARN, Ng SSM, Chan FKL, Chan HLY, Chan CJ, Mi R, Lau WY. High incidence of incidental hepatocellular carcinoma exists among hepatitic explanted livers. Transplant Proc 2003; 35:350-1. [PMID: 12591435 DOI: 10.1016/s0041-1345(02)04010-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Affiliation(s)
- A K K Chui
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
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Rao ARN, Chui AKK, Shi LW, Waugh R, Pillay P, Sheil AGR. Sensitivity of radiological investigations in diagnosing hepatocellular carcinoma in cirrhotic livers. Transplant Proc 2003; 35:348-9. [PMID: 12591434 DOI: 10.1016/s0041-1345(02)04006-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- A R N Rao
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
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Chui AKK, Rao ARN, Wong J, Ng SSM, Chan HLY, Chan FKL, Mi R, Lau WY. Liver transplantation for hepatocellular carcinoma in cirrhotic patients-a single-center experience. Transplant Proc 2003; 35:379-80. [PMID: 12591449 DOI: 10.1016/s0041-1345(02)03821-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
- A K K Chui
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
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Cheng SJ, Pratt DS, Freeman RB, Kaplan MM, Wong JB. Living-donor versus cadaveric liver transplantation for non-resectable small hepatocellular carcinoma and compensated cirrhosis: a decision analysis. Transplantation 2001; 72:861-8. [PMID: 11571451 DOI: 10.1097/00007890-200109150-00021] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Cadaveric liver transplantation is effective for nonresectable early hepatocellular carcinoma. However, the scarcity of cadaveric organs has prompted some centers to use living donors, which guarantees transplantation, but entails a risk to the donor. In the absence of controlled trials, decision analysis can be used to help explicate the tradeoffs involved when considering living donor versus cadaveric liver transplantation for nonresectable early hepatocellular carcinoma. METHODS Using a Markov model, a hypothetical cohort of patients with Child's A cirrhosis and a single 3.5-cm tumor received one of three strategies: 1) no transplant; 2) intent to perform cadaveric liver transplantation; or 3) living donor liver transplantation. Data were obtained from natural history and retrospective studies. All probabilities in the model were varied simultaneously using a Monte Carlo simulation. RESULTS Living-donor liver transplantation was the best strategy, improving life expectancy by 4.5 years compared with cadaveric liver transplantation. This strategy remained dominant even when varying severity of cirrhosis, age, tumor doubling time, tumor growth pattern, blood type, regional transplant volume, initial tumor size, and rate of progression of cirrhosis. CONCLUSIONS Living-donor liver transplantation should confer a substantial survival advantage for patients with compensated cirrhosis and non-resectable early stage hepatocellular carcinoma.
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Affiliation(s)
- S J Cheng
- New England Medical Center, Tufts University School of Medicine, 750 Washington St, PO Box 302, Boston, MA 02111, USA
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