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Knorst JK, de Mello TF, Oltramari AR, da Silva AS, Leite GAA. Hepatic histopathological and morphometric changes in male mice exposed to rosuvastatin from pre-puberty to adulthood: a possible adaptive hepatic response. Drug Chem Toxicol 2025; 48:557-570. [PMID: 39113634 DOI: 10.1080/01480545.2024.2385609] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 06/19/2024] [Accepted: 07/23/2024] [Indexed: 05/27/2025]
Abstract
Lifestyle changes, such as poor eating habits and a reduction in physical exercise, have impaired human lipid profiles. Statins are widely used to treat dyslipidemias, of which rosuvastatin shows greater improvement in the lipid profile and may be used since childhood. This study aimed to assess the hepatic effects when male mice were given 0.9% saline solution or doses of rosuvastatin of 1.5 or 5.5 mg/kg/day from postnatal day (PND) 23 until PND 80. Body mass gain and water and food consumption were monitored during the treatment. Mice were euthanized on PND 80 when blood was collected for serum obtainment, and several organs were collected and weighed. Serum was used for evaluating lipid profiles and markers of hepatic injuries. The liver was assessed for histopathological, morphometric, and stereological changes. There was a temporary reduction in body mass gain and water and food consumption in the rosuvastatin-exposed groups. Both rosuvastatin-treated groups exhibited reduced total cholesterol levels and showed signs of hepatic tissue adaptation in response to prolonged exposure, such as sinusoidal dilation, inflammatory infiltrates, and cell death of hepatocytes. These results are considered side effects of the treatment and may indicate a hepatic adaptation to the chronic exposure.
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Affiliation(s)
- Jennyfer Karen Knorst
- Laboratório de Reprodução e Toxicologia (Laretox), Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
| | - Tainara Fernandes de Mello
- Laboratório de Reprodução e Toxicologia (Laretox), Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
- Programa de Pós-graduação em Biologia Celular e do Desenvolvimento, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
| | - Amanda Rebonatto Oltramari
- Laboratório de Reprodução e Toxicologia (Laretox), Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
- Programa de Pós-graduação em Biologia Celular e do Desenvolvimento, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
| | - Alice Santos da Silva
- Laboratório de Reprodução e Toxicologia (Laretox), Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
- Programa de Pós-graduação em Biologia Celular e do Desenvolvimento, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
| | - Gabriel Adan Araújo Leite
- Laboratório de Reprodução e Toxicologia (Laretox), Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
- Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
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He Z, Tan X, Yuan M, Chen L, Meng Y, Wang Q, Hu J, Qiu Z, Yang Y. Anethole trithione mitigates LPS/D-Gal-induced acute liver injury by suppressing ROS production and NF-κB activity. Int Immunopharmacol 2025; 152:114371. [PMID: 40054324 DOI: 10.1016/j.intimp.2025.114371] [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: 09/04/2024] [Revised: 01/14/2025] [Accepted: 02/24/2025] [Indexed: 03/24/2025]
Abstract
Acute liver injury (ALI) is a prevalent form of hepatic disease associated with significant morbidity and mortality due to medical treatments, exposure to toxins or viral infections. Anethole trithione (ATT) is a heterocyclic sulfur compound recognized for its chemoprotective properties against cancer and drug-induced toxicity. This study aimed to evaluate the effectiveness of ATT in the treatment of ALI. The therapeutic effects of ATT on hepatic injury were evaluated in vivo by inducing ALI in mice through the administration of lipopolysaccharide (LPS) and D-galactosamine (D-Gal). Additionally, HepG2 and Huh7 cells exposed to LPS were utilized to investigate the underlying mechanisms in vitro. The results indicated that ATT significantly reduced the production of reactive oxygen species (ROS), mitigated oxidative stress-related biochemical markers, and inhibited hepatocyte apoptosis in vivo, resulting in marked improvement in ALI in the murine model. Mechanistic studies conducted both in vivo and in vitro demonstrated that ATT alleviates LPS/D-Gal-induced ALI by inhibiting ROS production and the activity of nuclear factor-kappa B (NF-κB). Collectively, these findings underscore the potential therapeutic benefits of ATT in the management of ALI.
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Affiliation(s)
- Zhen He
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Xiangyun Tan
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Ming Yuan
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Liang Chen
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Yan Meng
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Qi Wang
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Junjie Hu
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China.
| | - Zhenpeng Qiu
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China; Center of Traditional Chinese Medicine Modernization for Liver Diseases, Hubei University of Chinese Medicine, Wuhan 430065, China; Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, Hubei University of Chinese Medicine, Wuhan 430065, China; Hubei Shizhen Laboratory, Wuhan 430061, China.
| | - Yuan Yang
- Institute of Maternal and Child Health, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430016, China.
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Fu H, Wang X, Yuan M, Wang N, Zhang X. Callistephus A from Callistephus chinensis Nees alleviates concanavalin A-induced immunological liver injury in mice by inhibiting the activation of JAK/STAT1 and MAPK signaling pathways. Int Immunopharmacol 2025; 148:114153. [PMID: 39864226 DOI: 10.1016/j.intimp.2025.114153] [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: 06/24/2024] [Revised: 11/07/2024] [Accepted: 01/21/2025] [Indexed: 01/28/2025]
Abstract
Callistephus chinensis Nees is an herbaceous plant in the Asteraceae family that has various traditional effects, especially in preventing liver disease. Callistephus A (CA) is a sesquiterpene compound with a rare 6/7 ring skeleton, which has been isolated only from the Callistephus chinensis Nees, but whether CA protects the liver is unknown. Immunological liver injury (ILI) is a common liver disease mediated by the immune system. Therefore, this study investigated whether CA had a protective effect on ILI and uncovered its molecular mechanisms. To study the impact, target, and signal pathway of CA in preventing ILI, we hope to find active components from plants to avoid ILI. In this study, CA regulated the differentiation balance of CD4 + T cells (Th1/Th2 and Th17/Treg balance) and the secretion of inflammatory factors (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interferon-gamma (IFN-γ), interleukin-4 (IL-4), interleukin-17A (IL-17A) and transforming growth factor-β (TGF-β). CA improves liver inflammation by regulating IFN-γ-induced JAK/STAT1 signaling pathways. CA reduced hepatocyte apoptosis by decreasing protein expression of BCL2-associated X (Bax), cleaved caspase-3, and cleaved Poly (ADP-ribose) polymerase 1 (PARP-1), but increased Bcl-2 protein expression, which was achieved by regulating the MAPK pathway. To investigate the role of CA in immune liver injury, we performed in vitro cell experiments using alpha mouse liver 12 (AML12) cells. The cell experiments showed that CA potently inhibited LPS-mediated AML12 cell damage. After adding CA, damaged mitochondria are cleared through mitochondrial autophagy and reduced production of intracellular reactive oxygen species (ROS). Finally, molecular docking results showed that CA had a strong affinity for five essential target proteins (JAK1, JAK2, STAT1, JNK, and p38). CA regulates the differentiation, anti-inflammatory, and anti-apoptosis of CD4 + T cells. The mechanism of CA against ILI is related to inhibiting the activation of JAK/STAT1 and MAPK signaling pathways.
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Affiliation(s)
- Haonan Fu
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Xiaojun Wang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Mingyuan Yuan
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Ning Wang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Xiaoshu Zhang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
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Bhattacharjee P, Sarkar P, Bhadra K. Evaluation of therapeutic role of harmaline: in vitro cytotoxicity targeting nucleic acids. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2024; 26:519-533. [PMID: 37656039 DOI: 10.1080/10286020.2023.2251116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 08/17/2023] [Accepted: 08/17/2023] [Indexed: 09/02/2023]
Abstract
Use of small molecules as valuable drugs against diseases is still an indefinable purpose due to the lack of in-detail knowledge regarding proper bio-target identification, specificity aspects, mode-mechanism of binding and proper in vitro study. Harmaline, an important beta-carboline alkaloid, shows effective anti-proliferative action against different types of human cancers and is also found to be a nucleic acid targeting natural molecule. This review sought to address the different signal pathways of apoptosis by harmaline in different cancer cell lines and simultaneously to characterize the structure activity aspects of the alkaloid with different motifs of nucleic acid to show its preference, biological efficacy and genotoxicity. The results open up new insights for the design and development of small molecule-based nucleic acid therapeutic agents.
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Affiliation(s)
| | - Paromita Sarkar
- Department of Zoology, University of Kalyani, Nadia, W. Bengal 741235, India
| | - Kakali Bhadra
- Department of Zoology, University of Kalyani, Nadia, W. Bengal 741235, India
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Lei Z, Yu J, Wu Y, Shen J, Lin S, Xue W, Mao C, Tang R, Sun H, Qi X, Wang X, Xu L, Wei C, Wang X, Chen H, Hao P, Yin W, Zhu J, Li Y, Wu Y, Liu S, Liang H, Chen X, Su C, Zhou S. CD1d protects against hepatocyte apoptosis in non-alcoholic steatohepatitis. J Hepatol 2024; 80:194-208. [PMID: 38438948 DOI: 10.1016/j.jhep.2023.10.025] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 10/02/2023] [Accepted: 10/17/2023] [Indexed: 03/06/2024]
Abstract
BACKGROUND & AIMS Hepatocyte apoptosis, a well-defined form of cell death in non-alcoholic steatohepatitis (NASH), is considered the primary cause of liver inflammation and fibrosis. However, the mechanisms underlying the regulation of hepatocyte apoptosis in NASH remain largely unclear. We explored the anti-apoptotic effect of hepatocyte CD1d in NASH. METHODS Hepatocyte CD1d expression was analyzed in patients with NASH and mouse models. Hepatocyte-specific gene overexpression or knockdown and anti-CD1d crosslinking were used to investigate the anti-apoptotic effect of hepatocyte CD1d on lipotoxicity-, Fas-, and concanavalin (ConA)-mediated liver injuries. A high-fat diet, a methionine-choline-deficient diet, a Fas agonist, and ConA were used to induce lipotoxic and/or apoptotic liver injuries. Palmitic acid was used to mimic lipotoxicity-induced apoptosis in vitro. RESULTS We identified a dramatic decrease in CD1d expression in hepatocytes of patients with NASH and mouse models. Hepatocyte-specific CD1d overexpression and knockdown experiments collectively demonstrated that hepatocyte CD1d protected against hepatocyte apoptosis and alleviated hepatic inflammation and injuries in NASH mice. Furthermore, decreased JAK2-STAT3 signaling was observed in NASH patient livers. Mechanistically, anti-CD1d crosslinking on hepatocytes induced tyrosine phosphorylation of the CD1d cytoplasmic tail, leading to the recruitment and phosphorylation of JAK2. Phosphorylated JAK2 activated STAT3 and subsequently reduced apoptosis in hepatocytes, which was associated with an increase in anti-apoptotic effectors (Bcl-xL and Mcl-1) and a decrease in pro-apoptotic effectors (cleaved-caspase 3/7). Moreover, anti-CD1d crosslinking effectively protected against Fas- or ConA-mediated hepatocyte apoptosis and liver injury in mice. CONCLUSIONS Our study uncovered a previously unrecognized anti-apoptotic CD1d-JAK2-STAT3 axis in hepatocytes that conferred hepatoprotection and highlighted the potential of hepatocyte CD1d-directed therapy for liver injury and fibrosis in NASH, as well as in other liver diseases associated with hepatocyte apoptosis. IMPACT AND IMPLICATIONS Excessive and/or sustained hepatocyte apoptosis is critical in driving liver inflammation and injury. The mechanisms underlying the regulation of hepatocyte apoptosis in non-alcoholic steatohepatitis (NASH) remain largely unclear. Here, we found that CD1d expression in hepatocytes substantially decreases and negatively correlates with the severity of liver injury in patients with NASH. We further revealed a previously unrecognized anti-apoptotic CD1d-JAK2-STAT3 signaling axis in hepatocytes, which confers significant protection against liver injury in NASH and acute liver diseases. Thus, hepatocyte CD1d-targeted therapy could be a promising strategy to manipulate liver injury in both NASH and other hepatocyte apoptosis-related liver diseases.
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Affiliation(s)
- Zhigang Lei
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jiaojiao Yu
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yu Wu
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Junyao Shen
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shibo Lin
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Weijie Xue
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chenxu Mao
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rui Tang
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haoran Sun
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xin Qi
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaohong Wang
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lei Xu
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chuan Wei
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaowei Wang
- Department of Blood Transfusion, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hongbing Chen
- Department of Clinical Laboratory, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ping Hao
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Wen Yin
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Jifeng Zhu
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yalin Li
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yi Wu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Shouguo Liu
- Center for Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hui Liang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaojun Chen
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Chuan Su
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Sha Zhou
- Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
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Yuan D, Ma R, Sun T, Zhu K, Dang C, Ye H, Li K. Knockdown of RSPH14 inhibits proliferation, migration, and invasion and promotes apoptosis of hepatocellular carcinoma via RelA. Cancer Cell Int 2022; 22:129. [PMID: 35305640 PMCID: PMC8933878 DOI: 10.1186/s12935-022-02515-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 02/05/2022] [Indexed: 11/10/2022] Open
Abstract
Background High RSPH14 expression appears to be related to poor prognosis of hepatocellular carcinoma (HCC). This study aimed to investigate the possible roles of RSPH14 in the proliferation, apoptosis, and invasion of HCC cells. Methods The UALCAN database and Kaplan–Meier Plotter were used to evaluate the expression level and prognostic role of RSPH14 in HCC. Lentiviral vectors containing shRNA against RSPH14 were constructed to transfect the BEL-7404 and SMMC-7721 HCC cell lines. Cell proliferation was investigated by BrdU, MTT, and colony-formation assays. Apoptosis was detected using flow cytometry. Cell migration and invasion were evaluated using the scratch wound-healing and Transwell assays. Immunohistochemistry and western blot were used to determine the expression levels of the proteins. The function of RSPH14 in vivo was evaluated using a xenograft mouse model. Results The expression of RSPH14 was higher in HCC tumor tissues than in adjacent normal tissues and was closely related to unfavorable prognostic factors and poorer survival (all P < 0.05). Knockdown of RSPH14 inhibited the cell proliferation, migration, and invasion of HCC cells and promoted apoptosis (all P < 0.05). Knockdown of RSPH14 inhibited tumor growth in vivo (P < 0.05). RSPH14 knockdown led to decreased expression of RelA (NF-κBp65), CDH2, and AKT1, thereby affecting the functions of the HCC cells (all P < 0.05). RelA overexpression could abate the inhibitory effect of BEL-7404 cell proliferation caused by RSPH14 depletion. Conclusion Knockdown of RSPH14 could decrease cell proliferation, migration, and invasion and increase apoptosis of HCC cells by inhibiting RelA expression. RSPH14 could be a new treatment target for HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02515-z.
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Tu Y, Chen D, Pan T, Chen Z, Xu J, Jin L, Sheng L, Jin X, Wang X, Lan X, Ge Y, Sun H, Chen Y. Inhibition of miR-431-5p attenuated liver apoptosis through KLF15/p53 signal pathway in S100 induced autoimmune hepatitis mice. Life Sci 2021; 280:119698. [PMID: 34111466 DOI: 10.1016/j.lfs.2021.119698] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 05/25/2021] [Accepted: 05/31/2021] [Indexed: 12/18/2022]
Abstract
AIMS The purpose of this study was to investigate the effects of miR-431-5p on hepatocyte apoptosis in AIH. MATERIALS AND METHODS We used intraperitoneal injection of S100 to establish AIH mouse model and injected AAV into tail vein on day 14 of modeling to regulate miR-431-5p expression. The expression of ALT, AST, IgG and apoptosis-related proteins Bax, Bcl-2 and cleaved caspase 3 were measured in each group. Cellular experiments were performed using miR-431-5p mimics or inhibitors to transfect LPS-stimulated AML12 cells, and apoptosis was verified using Western blot and Hoechst 33342/PI Double Staining. The target of miR-431-5p, KLF15, was screened using databases and verified by the luciferase reporter assay. The relationship between KLF15 and p53 was verified by si-KLF15 and PFTβ (a p53-specific inhibitor). KEY FINDINGS Here, we observed that the increase in the level of miR-431-5p was accompanied by a decrease in the expression of Krüppel-like zinc finger transcription factor 15 (KLF15). In addition, the deletion of miR-431-5p significantly reduced hepatocyte apoptosis in AIH mice induced by liver S100 and apoptosis of AML12 cells induced by LPS stimulation, accompanied by decreased expression of Bax and cleaved caspase-3 as well as increased expression of Bcl-2. Moreover, KLF15 was the direct and functional target of miR-431-5p. Furthermore, miR-431-5p negatively regulated the expression of KLF15, and KLF15 deletion partially abolished the inhibitory effect of miR-431-5p deletion on apoptosis by activating p53 signaling. SIGNIFICANCE In summary, miR-431-5p may be a potential therapeutic target for AIH.
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Affiliation(s)
- Yulu Tu
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, Wenzhou 325006, China
| | - Dazhi Chen
- Department of Gastroenterology, The First Hospital of Peking University, Beijing 100032, China
| | - Tongtong Pan
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, Wenzhou 325006, China
| | - Zhengkang Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, Wenzhou 325006, China
| | - Jie Xu
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, Wenzhou 325006, China
| | - Lanling Jin
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, Wenzhou 325006, China
| | - Lina Sheng
- Department of Infectious Diseases, The Affiliated Yiwu Central Hospital of Wenzhou Medical University, Yiwu 322000, China
| | - Xiaozhi Jin
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, Wenzhou 325006, China
| | - Xiaodong Wang
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, Wenzhou 325006, China
| | - Xiaolin Lan
- Department of Infectious Diseases, Lishui People's Hospital, Lishui 323000, China
| | - Yuli Ge
- Department of Infectious Diseases, Lishui People's Hospital, Lishui 323000, China.
| | - Huiling Sun
- Department of Infectious Diseases, Lishui People's Hospital, Lishui 323000, China.
| | - Yongping Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, Wenzhou 325006, China.
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Time-Course Changes of Serum Keratin Concentrations after Liver Transplantation: Contrasting Results of Keratin-18 and Keratin-19 Fragments. Case Reports Hepatol 2020; 2020:8895435. [PMID: 33335785 PMCID: PMC7723486 DOI: 10.1155/2020/8895435] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 11/08/2020] [Accepted: 11/16/2020] [Indexed: 11/18/2022] Open
Abstract
Objective Under normal conditions, adult hepatocytes express only keratin-8 (K8) and keratin-18 (K18), whereas cholangiocytes also express K19. In this study, we delineate the pattern of normal time-course changes in serum K19 and K18 levels after liver transplantation. Patients and Methods. Serum levels of the K19 fragment CYFRA 21-1 and the K18 fragments tissue polypeptide specific antigen (TPS) and M30 (a neoepitope that is generated after caspase cleavage during apoptosis) were measured at baseline and at regular intervals (up to 6 months) after liver transplantation in 11 adult patients. Results There was a gradual decrease in serum K19 concentrations from baseline values after transplantation, following a time-course pattern similar to that of serum bilirubin. In contrast, serum concentrations of K18 fragments increased markedly shortly after transplantation and gradually decreased thereafter, following a time-course pattern similar to that of serum transaminases. The increase in TPS tended to occur earlier than that in M30, suggesting an initial predominance of hepatocyte necrosis followed by a predominance of apoptosis in the first days after transplantation. Five patients presented posttransplant complications (acute rejection in three cases and HCV recurrence in two cases). An early increase in serum K19 concentrations was observed in all cases. An increase in serum concentrations of K18 fragments (M30 and TPS) was observed in the two cases with HCV recurrence and was more variable in the three cases with acute rejection. Conclusions Serum concentrations of K19 and K18 fragments follow a dissimilar pattern of time-course changes after liver transplantation. The diagnostic value of variations in these normal patterns should be addressed in future studies.
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Sarkar S, Bhattacharjee P, Ghosh T, Bhadra K. Pharmaceutical efficacy of harmalol in inhibiting hepatocellular carcinoma. FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2020. [DOI: 10.1186/s43094-020-00045-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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Shi M, Jiang S, Li Y, Yang Q, Jiang S, Yang L, Huang J, Zhou F. Comprehensive expression analysis of the beta integrin from Penaeus monodon indicating its participation in innate immunity and ammonia nitrogen stress response. FISH & SHELLFISH IMMUNOLOGY 2020; 98:887-898. [PMID: 31770641 DOI: 10.1016/j.fsi.2019.11.049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 11/16/2019] [Accepted: 11/18/2019] [Indexed: 06/10/2023]
Abstract
The aim of the present study was to investigate the function of the beta integrin (PmItgb) in Penaeus monodon. The 3011 bp cDNA sequence of PmItgb was cloned from P. monodon using rapid amplification of cDNA ends (RACE) PCR. Phylogenetic tree analyses indicated that the amino acid sequence of PmItgb should be merged into Fenneropenaeus chinensis (93%). Quantitative real-time PCR (q RT-PCR) revealed that PmItgb mRNA was highly expressed in the hemocytes. In addition, with regard to developmental stages, PmItgb showed significantly higher expression in oosperm, nauplius IV, zoea I and III, and post larval stages than that in other development stages. PmItgb expression in the shrimp epidermis was higher in the postmolt (B) stage, and lower in other molting stages. We also found that Vibrio harveyi and V. anguillarum challenge enhanced PmItgb expression in the hepatopancreas and gills. When PmItgb was inhibited, innate immunity-related genes such as ALF, crustin 1, crustin 7, penaeidin 3, and penaeidin 5 were significantly down-regulated. Furthermore, we demonstrated that PmItgb knock-down by specific dsRNA reduced bacterial clearance. In high ammonia nitrogen concentrations, PmItgb was significantly up-regulated in the hepatopancreas and gills. After PmItgb was silenced, the rate of mortality owing to high ammonia nitrogen concentrations decreased; the expression of related anti-apoptotic genes was up-regulated, and that of the apoptotic genes was slightly down-regulated. These results suggested that PmItgb may be involved in shrimp innate immunity and mediate apoptosis of hepatopancreatic cells induced by high ammonia nitrogen environments.
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Affiliation(s)
- Mengke Shi
- South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture, Guangzhou, 510300, PR China; College of Aqua-life Science and Technology, Shanghai Ocean University, Shanghai, PR China
| | - Shigui Jiang
- South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture, Guangzhou, 510300, PR China; Shenzhen Base of South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shenzhen, 518108, PR China
| | - Yundong Li
- South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture, Guangzhou, 510300, PR China; Shenzhen Base of South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shenzhen, 518108, PR China
| | - Qibin Yang
- South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture, Guangzhou, 510300, PR China; Shenzhen Base of South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shenzhen, 518108, PR China
| | - Song Jiang
- South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture, Guangzhou, 510300, PR China; Shenzhen Base of South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shenzhen, 518108, PR China
| | - Lishi Yang
- South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture, Guangzhou, 510300, PR China; Shenzhen Base of South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shenzhen, 518108, PR China
| | - Jianhua Huang
- South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture, Guangzhou, 510300, PR China; Shenzhen Base of South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shenzhen, 518108, PR China
| | - Falin Zhou
- South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture, Guangzhou, 510300, PR China; Shenzhen Base of South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shenzhen, 518108, PR China.
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11
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Chung‐Davidson Y, Ren J, Yeh C, Bussy U, Huerta B, Davidson PJ, Whyard S, Li W. TGF-β Signaling Plays a Pivotal Role During Developmental Biliary Atresia in Sea Lamprey ( Petromyzon marinus). Hepatol Commun 2020; 4:219-234. [PMID: 32025607 PMCID: PMC6996360 DOI: 10.1002/hep4.1461] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 10/25/2019] [Indexed: 12/22/2022] Open
Abstract
Biliary atresia (BA) is a rare neonatal disease with unknown causes. Approximately 10% of BA cases develop in utero with other congenital defects that span a large spectrum of disease variations, including degeneration of the gall bladder and bile duct as well as malformation of the liver, intestines, and kidneys. Similar developmental alterations are manifested in a unique animal model, the sea lamprey (Petromyzon marinus), in which BA occurs naturally during metamorphosis. With the likelihood of conserved developmental mechanisms underlying organogenesis and degeneration, lamprey developmental BA may be a useful model to infer mechanisms underlying human embryonic BA. We reasoned that hepatobiliary transcriptomes regulate the transition between landmark stages of BA. Therefore, we examined sea lamprey hepatobiliary transcriptomes at four stages (M0, metamorphic stage 0 or larval stage, no BA; M2, metamorphic stage 2, onset of BA; M5, metamorphic stage 5, BA, and heightened hepatocyte proliferation and reorganization; and JV, juvenile, completion of BA) using messenger RNA sequencing and Kyoto Encyclopedia of Genes and Genomes pathway analyses. We found gene-expression patterns associated with the transition between these stages. In particular, transforming growth factor β (TGF-β), hedgehog, phosphatidylinositol-4,5-bisphosphate 3-kinase-Akt, Wnt, and mitogen-activated protein kinase pathways were involved during biliary degeneration. Furthermore, disrupting the TGF-β signaling pathway with antagonist or small interfering RNA treatments at the onset of BA delayed gall bladder and bile duct degeneration. Conclusion: Distinctive gene-expression patterns are associated with the degeneration of the biliary system during developmental BA. In addition, disrupting TGF-β signaling pathway at the onset of BA delayed biliary degeneration.
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Affiliation(s)
| | - Jianfeng Ren
- Key Laboratory of Exploration and Utilization of Aquatic Genetic ResourcesCollege of Fisheries and Life SciencesShanghai Ocean UniversityShanghaiChina
| | - Chu‐Yin Yeh
- College of Osteopathic MedicineMichigan State UniversityEast LansingMI
| | - Ugo Bussy
- Department of Fisheries and WildlifeMichigan State UniversityEast LansingMI
| | - Belinda Huerta
- Department of Fisheries and WildlifeMichigan State UniversityEast LansingMI
| | | | - Steven Whyard
- Department of Biological SciencesUniversity of ManitobaWinnipegMBCanada
| | - Weiming Li
- Department of Fisheries and WildlifeMichigan State UniversityEast LansingMI
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12
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Haga S, Kanno A, Ozawa T, Morita N, Asano M, Ozaki M. Detection of Necroptosis in Ligand-Mediated and Hypoxia-Induced Injury of Hepatocytes Using a Novel Optic Probe-Detecting Receptor-Interacting Protein (RIP)1/RIP3 Binding. Oncol Res 2017; 26:503-513. [PMID: 28770700 PMCID: PMC7844641 DOI: 10.3727/096504017x15005102445191] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Liver injury is often observed in various pathological conditions including posthepatectomy state and cancer chemotherapy. It occurs mainly as a consequence of the combined necrotic and apoptotic types of cell death. In order to study liver/hepatocyte injury by the necrotic type of cell death, we studied signal-regulated necrosis (necroptosis) by developing a new optic probe for detecting receptor-interacting protein kinase 1 (RIP)/RIP3 binding, an essential process for necroptosis induction. In the mouse hepatocyte cell line, TIB-73 cells, TNF-α/cycloheximide (T/C) induced RIP1/3 binding only when caspase activity was suppressed by the caspase-specific inhibitor z-VAD-fmk (zVAD). T/C/zVAD-induced RIP1/3 binding was inhibited by necrostatin-1 (Nec-1), an allosteric inhibitor of RIP1. The reduced cell survival by T/C/zVAD was improved by Nec-1. These facts indicate that T/C induces necroptosis of hepatocytes when the apoptotic pathway is inhibited/unavailable. FasL also induced cell death, which was only partially inhibited by zVAD, indicating the possible involvement of necroptosis rather than apoptosis. FasL activated caspase 3 and, similarly, induced RIP1/3 binding when the caspases were inactivated. Interestingly, FasL-induced RIP1/3 binding was significantly suppressed by the antioxidants Trolox and N-acetyl cysteine (NAC), suggesting the involvement of reactive oxygen species (ROS) in FasL-induced necroptotic cellular processes. H₂O₂, by itself, induced RIP1/3 binding that was suppressed by Nec-1, but not by zVAD. Hypoxia induced RIP1/3 binding after reoxygenation, which was suppressed by Nec-1 or by the antioxidants. Cell death induced by hypoxia/reoxygenation (H/R) was also improved by Nec-1. Similar to H₂O₂, H/R did not require caspase inhibition for RIP1/3 binding, suggesting the involvement of a caspase-independent mechanism for non-ligand-induced and/or redox-mediated necroptosis. These data indicate that ROS can induce necroptosis and mediate the FasL- and hypoxia-induced necroptosis via a molecular mechanism that differs from a conventional caspase-dependent pathway. In conclusion, necroptosis is potentially involved in liver/hepatocyte injury induced by oxidative stress and FasL in the absence of apoptosis.
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Affiliation(s)
- Sanae Haga
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido UniversitySapporoJapan
| | - Akira Kanno
- Department of Environmental Applied Chemistry, Faculty of Engineering, University of ToyamaToyamaJapan
| | - Takeaki Ozawa
- Department of Chemistry, School of Science, The University of TokyoTokyoJapan
| | - Naoki Morita
- Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)Sapporo, HokkaidoJapan
| | - Mami Asano
- Laboratory of Molecular and Functional Bio-Imaging, Faculty of Health Sciences, Hokkaido UniversitySapporoJapan
| | - Michitaka Ozaki
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido UniversitySapporoJapan
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Ghare SS, Donde H, Chen WY, Barker DF, Gobejishvilli L, McClain CJ, Barve SS, Joshi-Barve S. Acrolein enhances epigenetic modifications, FasL expression and hepatocyte toxicity induced by anti-HIV drug Zidovudine. Toxicol In Vitro 2016; 35:66-76. [PMID: 27238871 PMCID: PMC4938746 DOI: 10.1016/j.tiv.2016.05.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 05/16/2016] [Accepted: 05/25/2016] [Indexed: 10/21/2022]
Abstract
Zidovudine (AZT) remains the mainstay of antiretroviral therapy against HIV in resource-poor countries; however, its use is frequently associated with hepatotoxicity. Not all HIV patients on AZT develop hepatotoxicity, and the determining factors are unclear. Alcohol consumption and cigarette smoking are known risk factors for HIV hepatotoxicity, and both are significant sources of acrolein, a highly reactive and toxic aldehyde. This study examines the potential hepatotoxic interactions between acrolein and AZT. Our data demonstrate that acrolein markedly enhanced AZT-induced transcriptionally permissive histone modifications (H3K9Ac and H3K9Me3) allowing the recruitment of transcription factor NF-kB and RNA polymerase II at the FasL gene promoter, resulting in FasL upregulation and apoptosis in hepatocytes. Notably, the acrolein scavenger, hydralazine prevented these promoter-associated epigenetic changes and inhibited FasL upregulation and apoptosis induced by the combination of AZT and acrolein, as well as AZT alone. Our data strongly suggest that acrolein enhancement of promoter histone modifications and FasL upregulation are major pathogenic mechanisms driving AZT-induced hepatotoxicity. Moreover, these data also indicate the therapeutic potential of hydralazine in mitigating AZT hepatotoxicity.
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Affiliation(s)
- Smita S Ghare
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - Hridgandh Donde
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - Wei-Yang Chen
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - David F Barker
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - Leila Gobejishvilli
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - Craig J McClain
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - Shirish S Barve
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - Swati Joshi-Barve
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA.
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14
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Tanami S, Ben-Moshe S, Elkayam A, Mayo A, Bahar Halpern K, Itzkovitz S. Dynamic zonation of liver polyploidy. Cell Tissue Res 2016; 368:405-410. [PMID: 27301446 DOI: 10.1007/s00441-016-2427-5] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 05/04/2016] [Indexed: 01/01/2023]
Abstract
The liver is a polyploid organ, consisting of hepatocytes with one or two nuclei each containing 2, 4, 8 or more haploid chromosome sets. The dynamic changes in the spatial distributions of polyploid classes across the liver lobule, its repeating anatomical unit, have not been characterized. Identifying these spatial patterns is important for understanding liver homeostatic and regenerative turnover, as well as potential division of labor among ploidy classes. Here, we use single molecule-based tissue imaging to reconstruct the spatial zonation profiles of liver polyploid classes in mice of different ages. We find that liver polyploidy proceeds in spatial waves, advancing more rapidly in the mid-lobule zone compared to the periportal and perivenous zones. We also measure the spatial zonation profiles of S-phase entry at different ages and identify more rapid S-phase entry in the mid-lobule zone at older ages. Our findings reveal fundamental features of liver spatial heterogeneity and highlight their dynamic changes during development and aging.
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Affiliation(s)
- Sivan Tanami
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Shani Ben-Moshe
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Anat Elkayam
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Avi Mayo
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Keren Bahar Halpern
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Shalev Itzkovitz
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
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15
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Tanoi T, Tamura T, Sano N, Nakayama K, Fukunaga K, Zheng YW, Akhter A, Sakurai Y, Hayashi Y, Harashima H, Ohkohchi N. Protecting liver sinusoidal endothelial cells suppresses apoptosis in acute liver damage. Hepatol Res 2016; 46:697-706. [PMID: 26490536 DOI: 10.1111/hepr.12607] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 09/30/2015] [Accepted: 10/14/2015] [Indexed: 01/01/2023]
Abstract
AIM Apoptosis is associated with various types of hepatic disorders. We have developed a novel cell-transfer drug delivery system (DDS) using a multifunctional envelope-type nano device that targets liver sinusoidal endothelial cells (LSECs). The purpose of this study was to determine the efficacy of the novel DDS containing siRNA at suppressing apoptosis in LSECs. METHODS Bax siRNA was transfected into a sinusoidal endothelial cell line (M1) to suppress apoptosis induced by an anti-Fas antibody and staurosporine. C57BL/6J mice were divided into three groups: (i) a control group, only intravenous saline; (ii) a nonselective group, injections of siRNA sealed in the nonselective DDS; and (iii) an LSEC-transfer efficient group, injections of siRNA sealed in an LSEC-transfer efficient DDS. Hepatic cell apoptosis was induced by an anti-Fas antibody. RESULTS Bax siRNA had an anti-apoptotic effect on M1 cells. Serum alanine aminotransferase was reduced in the LSEC-transfer efficient group, as were cleaved caspase-3 and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling positive hepatocytes. Silver impregnation staining indicated that the sinusoidal space was maintained in the LSEC-transfer efficient group but not in the other groups. Electron microscopy showed that the LSECs were slightly impaired, although the sinusoidal structure was maintained in the LSEC-transfer efficient group. CONCLUSION Hepatocyte apoptosis was reduced by the efficient suppression of LSEC apoptosis with a novel DDS. Protecting the sinusoidal structure by suppressing LSEC damage will be an effective treatment for acute liver failure.
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Affiliation(s)
- Tomohito Tanoi
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Takafumi Tamura
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Naoki Sano
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Ken Nakayama
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Kiyoshi Fukunaga
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Yun-Wen Zheng
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Afsana Akhter
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Yu Sakurai
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Yasuhiro Hayashi
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Hideyoshi Harashima
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Nobuhiro Ohkohchi
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
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16
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Xu SQ, Qin Y, Pan DB, Ye GX, Wu CJ, Wang S, Jiang JY, Fu J, Wang CJ. Inhibition of WWP2 suppresses proliferation, and induces G1 cell cycle arrest and apoptosis in liver cancer cells. Mol Med Rep 2016; 13:2261-6. [PMID: 26783238 DOI: 10.3892/mmr.2016.4771] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 11/24/2015] [Indexed: 11/06/2022] Open
Abstract
Primary liver cancer is one of the most common and aggressive human malignancies worldwide. As numerous studies have revealed that WW domain containing E3 Ub‑protein ligase 2 (WWP2) exerts cancer‑specific functions, the present study assessed the role of WWP2 in liver cancer. WWP2 was revealed to be significantly overexpressed in liver cancer tissues compared with paired normal tissues at the mRNA as well as at the protein level. Furthermore, small interfering RNA-mediated WWP2 knockdown in liver cancer cell lines was demonstrated to inhibit cell proliferation, cause cell cycle arrested in G1 phase and to induce apoptosis as revealed by a Cell Counting Kit-8 assay and flow cytometric analysis. In addition, western blot analysis revealed that WWP2 knockdown significantly increased the expression of apoptosis-associated markers caspase‑7, caspase‑8 and B-cell lymphoma 2 (Bcl-2)-associated X in liver cancer cell lines, while Bcl‑2 was significantly decreased. In conclusion, the present study suggested that WWP2 may exert important functions in the over‑proliferation and evasion of apoptosis of liver cancer, likely through regulating the expression of apoptosis-associated markers. Furthermore, WWP2 may represent a novel diagnostic marker and molecular therapeutic target for liver cancer.
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Affiliation(s)
- Sheng-Qian Xu
- Department of Hepatobiliary Surgery, People's Hospital of Lishui, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China
| | - Yong Qin
- Department of Hepatobiliary Surgery, People's Hospital of Lishui, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China
| | - De-Biao Pan
- Department of Hepatobiliary Surgery, People's Hospital of Lishui, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China
| | - Guan-Xiong Ye
- Department of Hepatobiliary Surgery, People's Hospital of Lishui, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China
| | - Cheng-Jun Wu
- Department of Hepatobiliary Surgery, People's Hospital of Lishui, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China
| | - Shi Wang
- Department of Hepatobiliary Surgery, People's Hospital of Lishui, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China
| | - Jin-Yan Jiang
- Department of Hepatobiliary Surgery, People's Hospital of Lishui, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China
| | - Jing Fu
- Department of Hepatobiliary Surgery, People's Hospital of Lishui, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China
| | - Chao-Jun Wang
- Department of Hepatobiliary Surgery, People's Hospital of Lishui, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China
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Villalba JM, López-Domínguez JA, Chen Y, Khraiwesh H, González-Reyes JA, Del Río LF, Gutiérrez-Casado E, Del Río M, Calvo-Rubio M, Ariza J, de Cabo R, López-Lluch G, Navas P, Hagopian K, Burón MI, Ramsey JJ. The influence of dietary fat source on liver and skeletal muscle mitochondrial modifications and lifespan changes in calorie-restricted mice. Biogerontology 2015; 16:655-70. [PMID: 25860863 DOI: 10.1007/s10522-015-9572-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 04/03/2015] [Indexed: 12/26/2022]
Abstract
The Membrane Theory of Aging proposes that lifespan is inversely related to the level of unsaturation in membrane phospholipids. Calorie restriction (CR) without malnutrition extends lifespan in many model organisms, which may be related to alterations in membrane phospholipids fatty acids. During the last few years our research focused on studying how altering the predominant fat source affects the outcome of CR in mice. We have established four dietary groups: one control group fed 95 % of a pre-determined ad libitum intake (in order to prevent obesity), and three CR groups fed 40 % less than ad libitum intake. Lipid source for the control and one of the CR groups was soybean oil (high in n-6 PUFA) whereas the two remaining CR groups were fed diets containing fish oil (high in n-3 PUFA), or lard (high in saturated and monounsaturated fatty acids). Dietary intervention periods ranged from 1 to 18 months. We performed a longitudinal lifespan study and a cross-sectional study set up to evaluate several mitochondrial parameters which included fatty acid composition, H(+) leak, activities of electron transport chain enzymes, ROS generation, lipid peroxidation, mitochondrial ultrastructure, and mitochondrial apoptotic signaling in liver and skeletal muscle. These approaches applied to different cohorts of mice have independently indicated that lard as a fat source often maximizes the effects of 40 % CR on mice. These effects could be due to significant increases of monounsaturated fatty acids levels, in accordance with the Membrane Theory of Aging.
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Affiliation(s)
- José Manuel Villalba
- Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Campus Rabanales, Edificio Severo Ochoa, 3ª planta, Campus de Excelencia Internacional Agroalimentario, ceiA3, 14014, Córdoba, Spain,
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Abstract
Apoptosis is the predominant mechanism of liver cell death in autoimmune hepatitis, and interventions that can modulate this activity are emerging. The aim of this review was to describe the apoptotic mechanisms, possible aberrations, and opportunities for intervention in autoimmune hepatitis. Studies cited in PubMed from 1972 to 2014 for autoimmune hepatitis, apoptosis in liver disease, apoptosis mechanisms, and apoptosis treatment were examined. Apoptosis is overactive in autoimmune hepatitis, and the principal pathway of cell death is receptor mediated. Surface death receptors are activated by extrinsic factors including liver-infiltrating cytotoxic T cells and the cytokine milieu. The executioner caspases 3 and 7 cleave nuclear deoxyribonucleic acid, and the release of apoptotic bodies can stimulate inflammatory, immune, and fibrotic responses. Changes in mitochondrial membrane permeability can be initiated by caspase 8, and an intrinsic pathway of apoptosis can complement the extrinsic pathway. Defects in the apoptosis of activated effector cells can prolong their survival and sustain the immune response. Caspase inhibitors have been used in diverse experimental and human diseases to retard apoptosis. Oligonucleotides that inhibit the signaling of toll-like receptors can limit the presentation of auto-antigens, and inhibitors of apoptosis that extend the survival of effector cells can be blocked by antisense oligonucleotides. Mechanisms that enhance the clearance of apoptotic bodies and affect key signaling pathways are also feasible. Interventions that influence the survival of liver and effector cells by altering their apoptosis are candidates for study in autoimmune hepatitis.
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19
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Vandewynckel YP, Laukens D, Bogaerts E, Paridaens A, Van den Bussche A, Verhelst X, Van Steenkiste C, Descamps B, Vanhove C, Libbrecht L, De Rycke R, Lambrecht BN, Geerts A, Janssens S, Van Vlierberghe H. Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress: a PERK for hepatocellular carcinoma therapy. Hepatol Int 2014; 9:93-104. [PMID: 25598862 PMCID: PMC4289530 DOI: 10.1007/s12072-014-9582-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2014] [Accepted: 09/09/2014] [Indexed: 12/22/2022]
Abstract
Background Functional disturbances of the endoplasmic reticulum (ER) lead to activation of the unfolded protein response (UPR), which is involved in the consecutive steps of carcinogenesis. In human hepatocellular carcinoma (HCC), the UPR is shown to be activated; however, little is known about the UPR kinetics and effects of UPR modulation in HCC. Methods We sequentially monitored the UPR over time in an orthotopic mouse model for HCC and explored the effects of UPR modulation on cell viability and proliferation in vitro and in the mouse model. Results The expression of ER-resident chaperones peaked during tumor initiation and increased further during tumor progression, predominantly within the nodules. A peak in Ire1 signaling was observed during tumor initiation. The Perk pathway was activated during tumor progression, and the proapoptotic target Chop was upregulated from week 5 and continued to rise, especially in the tumors. The Atf6 pathway was modestly activated only after tumor initiation. Consistent with the UPR activation, electron microscopy demonstrated ER expansion and reorganization in HCC cells in vivo. Strikingly, under ER stress or hypoxia, the Perk inhibitor and not the Ire1 inhibitor reduced cell viability and proliferation via escalating proteotoxic stress in vitro. Notably, the Perk inhibitor significantly decreased tumor burden in the mouse model. Conclusion We provide the first evaluation of the UPR dynamics in a long-term cancer model and identified a small molecule inhibitor of Perk as a promising strategy for HCC therapy. Electronic supplementary material The online version of this article (doi:10.1007/s12072-014-9582-0) contains supplementary material, which is available to authorized users.
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MESH Headings
- Activating Transcription Factor 6/genetics
- Adaptation, Physiological/drug effects
- Animals
- Carcinoma, Hepatocellular/chemistry
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/ultrastructure
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Cell Transformation, Neoplastic/metabolism
- Endoplasmic Reticulum
- Endoplasmic Reticulum Chaperone BiP
- HSP40 Heat-Shock Proteins/genetics
- Heat-Shock Proteins/genetics
- Hep G2 Cells
- Humans
- Liver Neoplasms, Experimental/chemistry
- Liver Neoplasms, Experimental/drug therapy
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/ultrastructure
- Male
- Membrane Glycoproteins/genetics
- Membrane Proteins/antagonists & inhibitors
- Membrane Proteins/genetics
- Mice
- Oxidative Stress
- Phosphorylation/drug effects
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use
- Protein Serine-Threonine Kinases/antagonists & inhibitors
- Protein Serine-Threonine Kinases/genetics
- RNA, Messenger/analysis
- Signal Transduction
- Transcription Factor CHOP/analysis
- Transcription Factor CHOP/genetics
- Tunicamycin/pharmacology
- Unfolded Protein Response/drug effects
- eIF-2 Kinase/antagonists & inhibitors
- eIF-2 Kinase/metabolism
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Affiliation(s)
- Yves-Paul Vandewynckel
- />Department of Hepatology and Gastroenterology, Ghent University, De Pintelaan 185, 1K12 IE, 9000 Ghent, Belgium
| | - Debby Laukens
- />Department of Hepatology and Gastroenterology, Ghent University, De Pintelaan 185, 1K12 IE, 9000 Ghent, Belgium
| | - Eliene Bogaerts
- />Department of Hepatology and Gastroenterology, Ghent University, De Pintelaan 185, 1K12 IE, 9000 Ghent, Belgium
| | - Annelies Paridaens
- />Department of Hepatology and Gastroenterology, Ghent University, De Pintelaan 185, 1K12 IE, 9000 Ghent, Belgium
| | - Anja Van den Bussche
- />Department of Hepatology and Gastroenterology, Ghent University, De Pintelaan 185, 1K12 IE, 9000 Ghent, Belgium
| | - Xavier Verhelst
- />Department of Hepatology and Gastroenterology, Ghent University, De Pintelaan 185, 1K12 IE, 9000 Ghent, Belgium
| | - Christophe Van Steenkiste
- />Department of Hepatology and Gastroenterology, Ghent University, De Pintelaan 185, 1K12 IE, 9000 Ghent, Belgium
| | - Benedicte Descamps
- />Infinity Imaging Lab, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Chris Vanhove
- />Infinity Imaging Lab, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
- />GROUP-ID Consortium, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Louis Libbrecht
- />Department of Pathology, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Riet De Rycke
- />GROUP-ID Consortium, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
- />Unit Immunoregulation and Mucosal Immunology, VIB Inflammation Research Center, Technologiepark 927, 9052 Ghent, Belgium
| | - Bart N. Lambrecht
- />GROUP-ID Consortium, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
- />Unit Immunoregulation and Mucosal Immunology, VIB Inflammation Research Center, Technologiepark 927, 9052 Ghent, Belgium
- />Department of Respiratory Medicine, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Anja Geerts
- />Department of Hepatology and Gastroenterology, Ghent University, De Pintelaan 185, 1K12 IE, 9000 Ghent, Belgium
| | - Sophie Janssens
- />GROUP-ID Consortium, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
- />Unit Immunoregulation and Mucosal Immunology, VIB Inflammation Research Center, Technologiepark 927, 9052 Ghent, Belgium
- />Department of Respiratory Medicine, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Hans Van Vlierberghe
- />Department of Hepatology and Gastroenterology, Ghent University, De Pintelaan 185, 1K12 IE, 9000 Ghent, Belgium
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Beyoğlu D, Krausz KW, Martin J, Maurhofer O, Dorow J, Ceglarek U, Gonzalez FJ, Dufour JF, Idle JR. Disruption of tumor suppressor gene Hint1 leads to remodeling of the lipid metabolic phenotype of mouse liver. J Lipid Res 2014; 55:2309-19. [PMID: 25193995 DOI: 10.1194/jlr.m050682] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
A lipidomic and metabolomic investigation of serum and liver from mice was performed to gain insight into the tumor suppressor gene Hint1. A major reprogramming of lipid homeostasis was found in both serum and liver of Hint1-null (Hint(-/-)) mice, with significant changes in the levels of many lipid molecules, as compared with gender-, age-, and strain-matched WT mice. In the Hint1(-/-) mice, serum total and esterified cholesterol were reduced 2.5-fold, and lysophosphatidylcholines (LPCs) and lysophosphatidic acids were 10-fold elevated in serum, with a corresponding fall in phosphatidylcholines (PCs). In the liver, MUFAs and PUFAs, including arachidonic acid (AA) and its metabolic precursors, were also raised, as was mRNA encoding enzymes involved in AA de novo synthesis. There was also a significant 50% increase in hepatic macrophages in the Hint1(-/-) mice. Several hepatic ceramides and acylcarnitines were decreased in the livers of Hint1(-/-) mice. The changes in serum LPCs and PCs were neither related to hepatic phospholipase A2 activity nor to mRNAs encoding lysophosphatidylcholine acetyltransferases 1-4. The lipidomic phenotype of the Hint1(-/-) mouse revealed decreased inflammatory eicosanoids with elevated proliferative mediators that, combined with decreased ceramide apoptosis signaling molecules, may contribute to the tumor suppressor activity of Hint1.
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Affiliation(s)
- Diren Beyoğlu
- Hepatology Research Group, Department of Clinical Research, University of Bern, Switzerland
| | - Kristopher W Krausz
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Juliette Martin
- Hepatology Research Group, Department of Clinical Research, University of Bern, Switzerland
| | - Olivier Maurhofer
- Hepatology Research Group, Department of Clinical Research, University of Bern, Switzerland
| | - Juliane Dorow
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Uta Ceglarek
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Jean-François Dufour
- Hepatology Research Group, Department of Clinical Research, University of Bern, Switzerland
| | - Jeffrey R Idle
- Hepatology Research Group, Department of Clinical Research, University of Bern, Switzerland Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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21
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Nagasawa T, Matsushima-Nishiwaki R, Toyoda H, Matsuura J, Kumada T, Kozawa O. Heat shock protein 20 (HSPB6) regulates apoptosis in human hepatocellular carcinoma cells: Direct association with Bax. Oncol Rep 2014; 32:1291-5. [PMID: 24969689 DOI: 10.3892/or.2014.3278] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 03/28/2014] [Indexed: 11/05/2022] Open
Abstract
A small heat shock protein (HSP), HSP20 (HSPB6) is ubiquitously expressed in various tissues and has several functions. We previously reported that the expression of HSP20 protein in human hepatocellular carcinoma (HCC) cells is inversely proportional to the progression of HCC. In addition, we showed that HSP20 is associated with phosphoinositide 3-kinase (PI3K) and inhibits the proliferation of HCC cells via suppression of the AKT signaling pathway. However, the relationship between HSP20 and apoptosis in HCC has not yet been elucidated. To clarify whether HSP20 is implicated in the apoptosis of HCC cells, in the present study, we examined the effect of HSP20 on caspases, the central regulators of apoptosis, using human HCC-derived HuH7 cells that are transfected with wild-type human HSP20 (HSP20-overexpressing cells). The cleavage of caspase-3 and caspase-7 in HSP20-overexpressing cells was enhanced compared with the empty vector-transfected cells (control cells). In addition, the cleavage of nuclear poly (ADP-ribose) polymerase (PARP) in HSP20-overexpressing cells was also strengthened. We further investigated the direct targets of HSP20 focusing on Bcl-2 family proteins in the HSP20-overexpressing cells. HSP20 proteins in the cells were coimmunoprecipitated with Bax. On the contrary, Bad, Bcl-2 and Bcl-xL were not coimmunoprecipitated with HSP20. These findings strongly suggest that HSP20 directly associates with Bax and stimulates caspase cascade in human HCC cells.
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Affiliation(s)
- Tomoaki Nagasawa
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | | | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu 503-8502, Japan
| | - Junya Matsuura
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Takashi Kumada
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu 503-8502, Japan
| | - Osamu Kozawa
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
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22
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TRAIL enhances apoptosis of human hepatocellular carcinoma cells sensitized by hepatitis C virus infection: therapeutic implications. PLoS One 2014; 9:e98171. [PMID: 24927176 PMCID: PMC4057066 DOI: 10.1371/journal.pone.0098171] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 04/29/2014] [Indexed: 12/20/2022] Open
Abstract
Hepatitis C virus (HCV) infection causes chronic liver diseases leading to hepatocellular carcinoma (HCC) and liver failure. We have previously shown that HCV sensitizes hepatocytes to mitochondrial apoptosis via the TRAIL death receptors DR4 and DR5. Although TRAIL and its receptors are selective targets for cancer therapy, their potential against HCC with chronic HCV infection has not been explored yet. Here we show that HCV induces DR4/DR5-dependent activation of caspase-8 leading to elevation of apoptotic signaling in infected cells and also present TRAIL effect in HCV-induced apoptotic signaling. HCV induced proteolytic cleavage of caspase-9 by stimulating DR4 and DR5, resulting in subsequent cleavage of caspase-3. Further, HCV-induced proteolytic cleavage in caspase-8, caspase-9, and caspase-3 was enhanced in the presence of recombinant TRAIL. HCV-induced cleavage in caspase-9 and increase in caspase-3/7 activity was completely suppressed by silencing of either DR4 or DR5. Perturbing DR4/DR5-caspase-8 signaling complex by silencing DR4 and DR5 or by chemical inhibitor specific to caspase-8 led to decrease of HCV-induced cleavage of poly(ADP-ribose) polymerase (PARP), a substrate for caspase-3 during apoptosis, indicating the functional role of caspase-8 in HCV-induced apoptotic signaling network. Furthermore, TRAIL enhanced PARP cleavage in apoptotic response induced by HCV infection, indicating the effect of TRAIL for the induction of selective apoptosis of HCC cells infected with HCV. Given the importance of apoptosis in HCC development, our data suggest that HCV-induced DR4 and DR5 may be considered as an attractive target for TRAIL therapy against HCC with chronic HCV infection.
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23
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López-Domínguez JA, Khraiwesh H, González-Reyes JA, López-Lluch G, Navas P, Ramsey JJ, de Cabo R, Burón MI, Villalba JM. Dietary fat and aging modulate apoptotic signaling in liver of calorie-restricted mice. J Gerontol A Biol Sci Med Sci 2014; 70:399-409. [PMID: 24691092 DOI: 10.1093/gerona/glu045] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Imbalance between proliferation and cell death accounts for several age-linked diseases. Aging, calorie restriction (CR), and fat source are all factors that may influence apoptotic signaling in liver, an organ that plays a central metabolic role in the organism. Here, we have studied the combined effect of these factors on a number of apoptosis regulators and effectors. For this purpose, animals were fed diets containing different fat sources (lard, soybean oil, or fish oil) under CR for 6 or 18 months. An age-linked increase in the mitochondrial apoptotic pathway was detected with CR, including a decrease in Bcl-2/Bax ratio, an enhanced release of cytochrome c to the cytosol and higher caspase-9 activity. However, these changes were not fully transmitted to the effectors apoptosis-inducing factor and caspase-3. CR (which abated aging-related inflammatory responses) and dietary fat altered the activities of caspases-8, -9, and -3. Apoptotic index (DNA fragmentation) and mean nuclear area were increased in aged animals with the exception of calorie-restricted mice fed a lard-based fat source. These results suggest possible protective changes in hepatic homeostasis with aging in the calorie-restricted lard group.
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Affiliation(s)
- José Alberto López-Domínguez
- Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Campus de Excelencia Internacional Agroalimentario, ceiA3, Córdoba, Spain
| | - Husam Khraiwesh
- Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Campus de Excelencia Internacional Agroalimentario, ceiA3, Córdoba, Spain
| | - José Antonio González-Reyes
- Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Campus de Excelencia Internacional Agroalimentario, ceiA3, Córdoba, Spain
| | - Guillermo López-Lluch
- Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide-CSIC, and CIBERER, Instituto de Salud Carlos III, Sevilla, Spain
| | - Plácido Navas
- Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide-CSIC, and CIBERER, Instituto de Salud Carlos III, Sevilla, Spain
| | - Jon Jay Ramsey
- VM Molecular Biosciences, University of California, Davis
| | - Rafael de Cabo
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
| | - María Isabel Burón
- Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Campus de Excelencia Internacional Agroalimentario, ceiA3, Córdoba, Spain
| | - José Manuel Villalba
- Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Campus de Excelencia Internacional Agroalimentario, ceiA3, Córdoba, Spain.
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24
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Yokoyama Y, Nagino M. Current scenario for the hepatoprotective effects of Inchinkoto, a traditional herbal medicine, and its clinical application in liver surgery: A review. Hepatol Res 2014; 44:384-94. [PMID: 24450947 DOI: 10.1111/hepr.12299] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2013] [Revised: 01/09/2014] [Accepted: 01/14/2014] [Indexed: 02/08/2023]
Abstract
Inchinkoto (ICKT) is one of the most commonly used herbal medicines as a hepatoprotective agent. Among the numerous chemical compounds included in ICKT, geniposide is the most abundant component. Geniposide, after p.o. intake, is converted to the active metabolite genipin by intestinal bacteria and is absorbed in the portal circulation. The biological properties of ICKT and genipin have been studied in numerous experiments. Administration of ICKT or genipin exerts choleretic effects through upregulation of multidrug resistance-associated protein 2 in hepatocytes. ICKT also exerts an anti-apoptotic action through inhibition of transforming growth factor-β1- or tumor necrosis factor-α-dependent signaling pathways. The excessive inflammatory response induced by various hepatic stresses is also attenuated by ICKT pre-administration. Moreover, ICKT upregulates antioxidant enzymes in the liver under conditions of oxidative stress. These experimental results suggest potential benefit of ICKT in liver disease and particularly in hepatic surgery, which justify further well-designed controlled clinical study. To date, however, clinical data regarding the benefit of ICKT for liver surgery are rare. This review article summarized and discussed recent evidence relating to the hepatoprotective effects of ICKT in the field of basic and clinical science.
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Affiliation(s)
- Yukihiro Yokoyama
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masato Nagino
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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25
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Nowatari T, Murata S, Fukunaga K, Ohkohchi N. Role of platelets in chronic liver disease and acute liver injury. Hepatol Res 2014; 44:165-72. [PMID: 23841688 DOI: 10.1111/hepr.12205] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Revised: 07/03/2013] [Accepted: 07/07/2013] [Indexed: 12/13/2022]
Abstract
Platelets contain not only hemostatic factors but also many growth factors that play important roles in wound healing and tissue repair. Platelets have already been used for the promotion of tissue regeneration in the clinical setting, such as dental implantation and plastic surgery. Thrombocytopenia, which is frequently found in patients with chronic liver disease and cirrhosis, is due to various causes such as decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism. However, the relationship between thrombocytopenia and hepatic pathogenesis and the role of platelets in chronic liver disease are poorly understood. In acute liver injury, it is reported that platelets are recruited to the liver and contribute to liver damage by promoting the induction of chemotactic factors and the accumulation of leukocytes in the liver, whereas platelets or mediators released by platelets can have a protective effect against liver injury. In this review, we highlight the recent accumulated knowledge concerning the role of platelets in chronic liver disease and acute liver injury.
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Affiliation(s)
- Takeshi Nowatari
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery, and Organ Transplantation, University of Tsukuba, Tsukuba, Japan
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26
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Sengupta D, Chowdhury KD, Sarkar A, Paul S, Sadhukhan GC. Berberine and S allyl cysteine mediated amelioration of DEN+CCl4 induced hepatocarcinoma. Biochim Biophys Acta Gen Subj 2014; 1840:219-44. [DOI: 10.1016/j.bbagen.2013.08.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Revised: 08/14/2013] [Accepted: 08/26/2013] [Indexed: 02/07/2023]
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27
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Kaneko M, Nagamine T, Nakazato K, Mori M. The anti-apoptotic effect of fucoxanthin on carbon tetrachloride-induced hepatotoxicity. J Toxicol Sci 2013; 38:115-26. [PMID: 23358145 DOI: 10.2131/jts.38.115] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
This study evaluated the anti-apoptotic activity of fucoxanthin in carbon tetrachloride (CCl(4))-induced hepatotoxicity. An in vitro study using the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay clearly demonstrated an attenuation of CCl(4)-induced hepatotoxicity with fucoxanthin. This effect was dose-dependent; 25 µM was more effective than 10 µM of fucoxanthin for attenuating the hepatotoxicity induced by 5 mM of CCl(4). Acute CCl(4)-hepatotoxicity in rats, with numerous cells positive for the terminal deoxynucleotidyl - transferase (TdT) -mediated deoxyuridine triphosphate-digoxigenin (dUTP) nick-end labeling (TUNEL) stain were seen in the pericentral area of the hepatic lobule. Oral pretreatment of CCl(4)- injected rats with fucoxanthin significantly reduced hepatocyte apoptosis. Fucoxanthin was immunohistochemically shown to increase heme oxygenase-1 expression in the cultured liver cells of Hc cells and TRL1215 cells. By oral pretreatment of CCl(4)-injected rats with fucoxanthin, the hepatic heme oxygenase-1 protein levels were significantly increased compared to those not pretreated with fucoxanthin. Heme oxygenase-1 mRNA expression after CCl(4 )injection was higher in the CCl(4)+fucoxanthin group than in the CCl(4 )group, although the difference was not significant. The findings suggest that fucoxanthin attenuates hepatocyte apoptosis through heme oxygenase-1 induction in CCl(4)-induced acute liver injury.
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Affiliation(s)
- Mieko Kaneko
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma, Japan
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28
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Hepatoprotective effects of reynosin against thioacetamide-induced apoptosis in primary hepatocytes and mouse liver. Arch Pharm Res 2013; 36:485-94. [PMID: 23435943 DOI: 10.1007/s12272-013-0039-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2012] [Accepted: 01/28/2013] [Indexed: 01/06/2023]
Abstract
The aim of this study was to identify the hepatoprotective effects of reynosin, sesquiterpenes from the leaves of Laurus nobilis, against thioacetamide (TAA)-induced apoptosis in primary hepatocyte cultures and an in vivo mouse model. Rat hepatocytes were isolated and pretreated with 0.13, 0.64, or 3.22 μM reynosin and then exposed to 100 mM TAA. Reynosin treatment significantly inhibited TAA-induced apoptosis and hepatocellular DNA damage in primary rat hepatocytes. We observed an increase in levels of antiapoptotic Bcl-2, Bcl-XL mRNA and a decrease in levels of proapoptotic Bax mRNA following reynosin treatment of hepatocytes. Apoptosis in BALB/c mice was induced with intra-peritoneal injection of 200 mg/kg TAA for 2 weeks every other day. Then reynosin (5 mg/kg) and TAA were intragastrically given for 3 weeks every other day. Aspartate aminotransferase and alanine aminotransferase levels in the blood of mice were decreased in the reynosin administration group. Bcl-2 and Bcl-XL mRNA levels were increased, and the Bax mRNA level was decreased in reynosin-treated mice. Thus, reynosin inhibited TAA-induced apoptosis in primary hepatocytes and an in vivo mouse model.
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29
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Ferreira KS, Kreutz C, Macnelly S, Neubert K, Haber A, Bogyo M, Timmer J, Borner C. Caspase-3 feeds back on caspase-8, Bid and XIAP in type I Fas signaling in primary mouse hepatocytes. Apoptosis 2012; 17:503-15. [PMID: 22246639 DOI: 10.1007/s10495-011-0691-0] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The TNF-R1 like receptor Fas is highly expressed on the plasma membrane of hepatocytes and plays an essential role in liver homeostasis. We recently showed that in collagen-cultured primary mouse hepatocytes, Fas stimulation triggers apoptosis via the so-called type I extrinsic signaling pathway. Central to this pathway is the direct caspase-8-mediated cleavage and activation of caspase-3 as compared to the type II pathway which first requires caspase-8-mediated Bid cleavage to trigger mitochondrial cytochrome c release for caspase-3 activation. Mathematical modeling can be used to understand complex signaling systems such as crosstalks and feedback or feedforward loops. A previously published model predicted a positive feedback loop between active caspases-3 and -8 in both type I and type II FasL signaling in lymphocytes and Hela cells, respectively. Here we experimentally tested this hypothesis in our hepatocytic type I Fas signaling pathway by using wild-type and XIAP-deficient primary hepatocytes and two recently characterized, selective caspase-3/-7 inhibitors (AB06 and AB13). Caspase-3/-7 activity assays and quantitative western blotting confirmed that fully processed, active p17 caspase-3 feeds back on caspase-8 by cleaving its partially processed p43 form into the fully processed p18 species. Our data do not discriminate if p18 positively or negatively influences FasL-induced apoptosis or is responsible for non-apoptotic aspects of FasL signaling. However, we found that caspase-3 also feeds back on Bid and degrades its own inhibitor XIAP, both events that may enhance caspase-3 activity and apoptosis. Thus, potent, selective caspase-3 inhibitors are useful tools to understand complex signaling circuitries in apoptosis.
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Affiliation(s)
- Karine Sá Ferreira
- Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany
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30
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Porreca I, De Felice E, Fagman H, Di Lauro R, Sordino P. Zebrafish bcl2l is a survival factor in thyroid development. Dev Biol 2012; 366:142-52. [DOI: 10.1016/j.ydbio.2012.04.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2011] [Revised: 03/17/2012] [Accepted: 04/04/2012] [Indexed: 10/28/2022]
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miR-15b and miR-16 regulate TNF mediated hepatocyte apoptosis via BCL2 in acute liver failure. Apoptosis 2012; 17:702-16. [DOI: 10.1007/s10495-012-0704-7] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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32
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Ozaki M, Haga S, Ozawa T. In vivo monitoring of liver damage using caspase-3 probe. Theranostics 2012; 2:207-14. [PMID: 22375159 PMCID: PMC3287426 DOI: 10.7150/thno.3806] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Accepted: 12/24/2011] [Indexed: 11/30/2022] Open
Abstract
Real-time monitoring of cellular and organ conditions improves our understanding of various physiopathological phenomena. Such monitoring is expected to provide important alternatives for clinical diagnosis and therapy. We have sought to show physiopathological changes of organs as well as cells. Here, we present an example of in vivo imaging of liver states using the luciferase-based caspase-3 optical probe. We examined dynamic changes of apoptosis (caspase-3 activity) of a mouse liver as well as those of liver cells, proving that the emitted signals reflected the biochemically evaluated apoptotic cell death. In live liver cell (AML 12) experiments, the optical probe for caspase-3 activity emitted signals in response to Fas-ligand, staurosporine and hypoxia/reoxygenation, demonstrating that the probe can measure cellular apoptosis quantitatively. We therefore applied this probe for mouse liver ischemia/reperfusion (I/R) and drug-toxicity to liver. By expressing the probe in a mouse liver adenovirally, we imaged liver caspase-3 activity (i.e. apoptotic damage) non-invasively and chronologically in the hepatic I/R model of mice. The duration of liver ischemia affected the post-ischemic caspase-dependent damage. Ischemia (up to 60 min) enhanced liver damage after reperfusion, but prolonged ischemia (90 min of ischemia) induced not apoptotic cell death but necrotic cell death. Direct observations of the changes of organ conditions elucidated the dynamism of organ function and damage. These technologies clearly possess clinical relevance. They are expected to provide a new diagnostic tool for various clinical settings in the future.
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Bishayee A, Mbimba T, Thoppil RJ, Háznagy-Radnai E, Sipos P, Darvesh AS, Folkesson HG, Hohmann J. Anthocyanin-rich black currant (Ribes nigrum L.) extract affords chemoprevention against diethylnitrosamine-induced hepatocellular carcinogenesis in rats. J Nutr Biochem 2011; 22:1035-46. [DOI: 10.1016/j.jnutbio.2010.09.001] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2010] [Revised: 09/15/2010] [Accepted: 09/22/2010] [Indexed: 10/18/2022]
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Wang Y, Zheng C, Liang B, Zhao H, Qian J, Liang H, Feng G. Hepatocellular necrosis, apoptosis, and proliferation after transcatheter arterial embolization or chemoembolization in a standardized rabbit model. J Vasc Interv Radiol 2011; 22:1606-12. [PMID: 21959058 DOI: 10.1016/j.jvir.2011.08.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Revised: 07/23/2011] [Accepted: 08/04/2011] [Indexed: 02/08/2023] Open
Abstract
PURPOSE To evaluate the effect of transcatheter arterial chemoembolization versus transcatheter arterial embolization on hepatocellular damage, apoptosis, proliferation, and proinflammatory response in a rabbit VX2 tumor model. MATERIALS AND METHODS Rabbits implanted with VX2 tumors in left liver lobes were randomly divided into three groups: a control group (n = 9) that underwent infusion of distilled water into the left hepatic artery, an embolization group (n = 15) that underwent left hepatic artery embolization with polyvinyl alcohol (PVA) particles, and a chemoembolization group (n = 15) that underwent left hepatic artery infusion of a mixture of 10-hydroxycamptothecin and iodized oil followed by PVA embolization. Serum and liver samples were collected at 6 hours, 3 days, and 7 days postoperatively. Liver damage was measured by liver function tests and histologic analysis. Ki-67 immunohistochemistry and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling were performed to quantify proliferating and apoptotic cells. Serum tumor necrosis factor (TNF)-α levels were measured to assess proinflammatory response. RESULTS Compared with embolization, chemoembolization caused liver injury with a greater increase in serum alanine aminotransferase and aspartate aminotransferase levels on days 3 and 7; histologic analysis showed increased hepatic necrosis in adjacent liver tissue beginning at day 3 and increased serum levels of TNF-α at 6 hours. By contrast, chemoembolization resulted in a slower increase in hepatocyte proliferation. Additionally, increased apoptotic hepatocytes were observed after embolization and chemoembolization. CONCLUSIONS In contrast to embolization, nonsuperselective transcatheter arterial chemoembolization increased hepatocellular damage and stimulated systemic proinflammatory cytokine release, but inhibited hepatocyte proliferation.
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Affiliation(s)
- Yong Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie-fang Rd., Wuhan 430022, China
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Krupp M, Maass T, Marquardt JU, Staib F, Bauer T, König R, Biesterfeld S, Galle PR, Tresch A, Teufel A. The functional cancer map: a systems-level synopsis of genetic deregulation in cancer. BMC Med Genomics 2011; 4:53. [PMID: 21718500 PMCID: PMC3148554 DOI: 10.1186/1755-8794-4-53] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2010] [Accepted: 06/30/2011] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Cancer cells are characterized by massive dysegulation of physiological cell functions with considerable disruption of transcriptional regulation. Genome-wide transcriptome profiling can be utilized for early detection and molecular classification of cancers. Accurate discrimination of functionally different tumor types may help to guide selection of targeted therapy in translational research. Concise grouping of tumor types in cancer maps according to their molecular profile may further be helpful for the development of new therapeutic modalities or open new avenues for already established therapies. METHODS Complete available human tumor data of the Stanford Microarray Database was downloaded and filtered for relevance, adequacy and reliability. A total of 649 tumor samples from more than 1400 experiments and 58 different tissues were analyzed. Next, a method to score deregulation of KEGG pathway maps in different tumor entities was established, which was then used to convert hundreds of gene expression profiles into corresponding tumor-specific pathway activity profiles. Based on the latter, we defined a measure for functional similarity between tumor entities, which yielded to phylogeny of tumors. RESULTS We provide a comprehensive, easy-to-interpret functional cancer map that characterizes tumor types with respect to their biological and functional behavior. Consistently, multiple pathways commonly associated with tumor progression were revealed as common features in the majority of the tumors. However, several pathways previously not linked to carcinogenesis were identified in multiple cancers suggesting an essential role of these pathways in cancer biology. Among these pathways were 'ECM-receptor interaction', 'Complement and Coagulation cascades', and 'PPAR signaling pathway'. CONCLUSION The functional cancer map provides a systematic view on molecular similarities across different cancers by comparing tumors on the level of pathway activity. This work resulted in identification of novel superimposed functional pathways potentially linked to cancer biology. Therefore, our work may serve as a starting point for rationalizing combination of tumor therapeutics as well as for expanding the application of well-established targeted tumor therapies.
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Affiliation(s)
- Markus Krupp
- Department of Medicine I, Johannes Gutenberg University, Mainz, Germany.
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Qi H, Xue B. Role of early growth response 1 in liver injury. Shijie Huaren Xiaohua Zazhi 2011; 19:1914-1921. [DOI: 10.11569/wcjd.v19.i18.1914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Liver injury is a sophisticated pathophysiological process caused by many factors. Currently, the role of early growth response 1 (EGR1) in liver injury is still controversial. Some studies show that EGR1 can amplify the systemic inflammatory response and promote apoptosis in galactosamine/lipopolysaccharide-induced acute liver injury and alpha-naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis as well as other non-liver injuries, while some other studies indicate that EGR1 protects the liver from CCl4 exposure by regulating the expression of inducible nitric oxide synthase, cyclooxygenase-2, and tumor necrosis factor-α-regulated genes that have hepatoprotective function.
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Serbetçi K, Uysal O, Erkasap N, Köken T, Baydemir C, Erkasap S. Anti-apoptotic and antioxidant effect of leptin on CCl₄-induced acute liver injury in rats. Mol Biol Rep 2011; 39:1173-80. [PMID: 21607623 DOI: 10.1007/s11033-011-0847-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2011] [Accepted: 05/12/2011] [Indexed: 01/30/2023]
Abstract
The aim of this study is to investigate the effect of leptin in rats on carbon tetrachloride (CCl(4)) induced acute liver damage using immunohistochemical methods for apoptosis and biochemical parameters. In this experimental study, 18 Spraque-Dawley rats were divided into three groups viz; control, CCl(4) and CCl(4)+leptin treatment. 0.8 ml/kg olive oil was administered intraperitoneally (i.p.) to the control group and 0.8 ml/kg CCl(4) (1:1 dissolved in olive oil) was administered i.p. to the CCl(4) and CCl(4)+leptin treatment groups, respectively. After 6 h of administrating CCl(4), CCl(4)+leptin treatment group was given i.p. leptin (10 μg/kg). Twenty-four hours after administrating CCl(4) all of the groups were euthanized. Biochemical assessments were performed using serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), plasma tumor necrosis factor alpha (TNF-α) levels and tissue malondialdehyde (MDA), and TNF-α levels. Histological assessments were then performed using Hematoxylin&Eosin (H&E) staining in light microscope and apoptosis assessment using Terminal Transferase dUTP Nick End Labeling (TUNEL)-staining. Serum AST, ALT, ALP and plasma TNF-α levels, tissue MDA and TNF-α levels had all increased in CCl(4) group, but were found to be significantly decreased in CCl(4)+leptin treatment group. Moreover, TUNEL-positive cell counts in liver had significantly increased in CCl(4) group, but decreased in CCl(4)+leptin treatment group (P < 0.05). The results of our study the biochemical, histological and TUNEL-staining showed that leptin has treatment effects on liver CCl(4) induced injury. It plays a role as a potent free radical scavenger, a powerful antioxidant and it also has anti-apoptotic effects.
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Affiliation(s)
- Kerim Serbetçi
- Department of General Surgery, Eskişehir Osmangazi University, Medical Faculty, Eskisehir, Turkey
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Hisakura K, Murata S, Takahashi K, Matsuo R, Pak S, Ikeda N, Kawasaki T, Kohno K, Myronovych A, Nakano Y, Ikeda O, Watanabe M, Ohkohchi N. Platelets prevent acute hepatitis induced by anti-fas antibody. J Gastroenterol Hepatol 2011; 26:348-355. [PMID: 21261726 DOI: 10.1111/j.1440-1746.2010.06334.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Platelets provide many functions in the body, especially to the liver. The purpose of this study is to investigate the effect of thrombocytosis with acute hepatitis induced by anti-Fas antibody and its mechanism. METHODS Acute hepatitis was induced by administration of anti-Fas antibody in normal and thrombocytotic C57BL6J mice. For thrombocytosis, thrombopoietin; PEG-rHuMGDF was injected 5 days before and just prior to administration of anti-Fas antibody. To investigate the mechanisms, hepatocyte cell line (AML12) and sinusoidal endothelial cell line (M1) were induced apoptosis by staurosporine. They were cultured with platelets or thrombopoietin. Examination items were as follows: platelet number, alanine aminotransferase (ALT), histological findings, TUNEL (TdT-mediated dUTP-biotin Nick End Labeling) staining, and the expression of proteins associated with apoptosis in vivo and in vitro. RESULTS Platelets were significantly increased in the thrombocytotic group (P < 0.01). Serum ALT levels were significantly reduced by thrombocytosis at 6, 24 and 72 h after the administration (P < 0.05). In histological findings, hemorrhagic necrosis was observed in the normal group, but not observed in the thrombocytotic group. TUNEL-positive hepatocytes were reduced and the expression of cleaved caspase-3 was significantly decreased in the thrombocytotic group. The phosphorylation of Akt, the increment of Bcl-xL and the decrease of cleaved caspase-3 were observed in AML12 cells cultured with platelets, but were not observed cultured with thrombopoietin. Platelets and thrombopoietin had no anti-apoptotic effect on M1 cells. CONCLUSION Increase of platelets has a preventative effect against acute hepatitis induced by the anti-Fas antibody. It is suggested that platelets have a direct protective effect against apoptosis of hepatocytes.
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Affiliation(s)
- Katsuji Hisakura
- Department of Surgery, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan
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Teufel A, Maass T, Strand S, Kanzler S, Galante T, Becker K, Strand D, Biesterfeld S, Westphal H, Galle PR. Liver-specific Ldb1 deletion results in enhanced liver cancer development. J Hepatol 2010; 53:1078-84. [PMID: 20828852 PMCID: PMC5903435 DOI: 10.1016/j.jhep.2010.05.027] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2009] [Revised: 05/23/2010] [Accepted: 05/26/2010] [Indexed: 01/15/2023]
Abstract
BACKGROUND & AIMS LIM-domain-binding (Ldb) proteins have been demonstrated to be essential not only to key embryonic developmental processes but also to carcinogenesis. We have previously demonstrated Ldb1 to be of high biological and developmental relevance, as a targeted deletion of the Ldb1 gene in mice results in an embryonic lethal and pleiotropic phenotype. METHODS We have now established a liver-specific Ldb1 knock out to investigate the role of Ldb1 in carcinogenesis, in particular in hepatocellular carcinoma (HCC) development, in vivo. RESULTS These mice demonstrated a significantly enhanced growth of liver cancer by means of tumor size and number, advocating for an essential role of Ldb1 in HCC development. In addition, proliferation and resistance against apoptosis were increased. In order to identify the functional disturbances due to a lack of Ldb1, we performed a 15k mouse gene microarray expression analysis. We found the Myc oncogene to be regulated in the microarray analysis and were able to further confirm this regulation by demonstrating an over-expression of its downstream target Cyclin D1. Furthermore, we were able to demonstrate a down-regulation of the tumor suppressor p21. Finally, the liver stem cell marker EpCAM was also identified to be over expressed in Ldb1(-/-) knock out mice. CONCLUSIONS We have established a significant role of Ldb1 in cancer development. Furthermore, we provided evidence for a myc/cyclin D1, p21, and EpCAM-dependent signalling to be key downstream regulators of this novel concept in HCC development.
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Affiliation(s)
- Andreas Teufel
- Department of Medicine I, Johannes Gutenberg University, Mainz, Germany.
| | - Thorsten Maass
- Department of Medicine I, Johannes Gutenberg University, Mainz, Germany
| | - Susanne Strand
- Department of Medicine I, Johannes Gutenberg University, Mainz, Germany
| | - Stephan Kanzler
- Department of Medicine I, Johannes Gutenberg University, Mainz, Germany
| | - Tiziana Galante
- Department of Medicine I, Johannes Gutenberg University, Mainz, Germany
| | - Kevin Becker
- Gene Expression Unit, National Institute On Aging, National Institutes of Health, Bethesda, MD, USA
| | - Dennis Strand
- Department of Medicine I, Johannes Gutenberg University, Mainz, Germany
| | | | - Heiner Westphal
- Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Peter R. Galle
- Department of Medicine I, Johannes Gutenberg University, Mainz, Germany
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An R, Meng J, Shi Q, Dai XX, Chen JH, Lei YJ, Shan B, Gao C, Chu YL, Dong XP. Expressions of nucleoside diphosphate kinase (nm23) in tumor tissues are related with metastasis and length of survival of patients with hepatocellular carcinoma. BIOMEDICAL AND ENVIRONMENTAL SCIENCES : BES 2010; 23:267-272. [PMID: 20934113 DOI: 10.1016/s0895-3988(10)60062-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2009] [Accepted: 06/09/2010] [Indexed: 05/30/2023]
Abstract
OBJECTIVE To evaluate the relationship of expressions of nucleoside diphosphate kinase (nm23) and proliferating cell nuclear antigen (PCNA), as well as apoptosis, with the prognosis of HCC patients by analyzing their pathological and clinical data. METHODS The expressions of nm23 and PCNA were analyzed by immunohistochemistry and the apoptotic phenomena were detected by TUNEL technique in the liver samples from 43 HCC tissues, 39 para-neoplastic tissues, and 10 normal tissues. The mean apoptosis index (AI) and proliferative index (PI) in individual sample were calculated. RESULTS As shown by the detection, 32.6% of carcinomas had negative nm23 signal in tumor tissues, whereas all para-neoplastic and normal tissues had positive nm23. The AI in nm23 positive HCC was significantly higher than that in nm23 negative one, with statistical difference (P<0.05). Furthermore, the expressions of nm23, and the values of AI and PI were contrastively analyzed with some main pathological and clinical data of HCC. It revealed that HCC with extrahepatic metastasis showed remarkable correlation with the negative nm23 (P=0.013) and higher PI values of HCC (P=0.015). The disease-free survival in HCC patients with negative nm23 expression was significantly poorer than that in patients with positive nm23 expression. CONCLUSIONS These data suggest that expressions of nm23 protein in tumor tissues are correlated with occurrences of metastasis and length of survival of the HCC patients, which may be an indicator for their prognosis.
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Affiliation(s)
- Run An
- School of Medicine, Xi'an Jiao-Tong University, Xi'an 710061, Shanxi, China
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Shieh YS, Chang YS, Hong JR, Chen LJ, Jou LK, Hsu CC, Her GM. Increase of hepatic fat accumulation by liver specific expression of Hepatitis B virus X protein in zebrafish. Biochim Biophys Acta Mol Cell Biol Lipids 2010; 1801:721-30. [PMID: 20416398 DOI: 10.1016/j.bbalip.2010.04.008] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2009] [Revised: 03/25/2010] [Accepted: 04/12/2010] [Indexed: 02/06/2023]
Abstract
The pathogenesis of fatty liver disease remains largely unknown. Here, we assessed the importance of hepatic fat accumulation on the progression of hepatitis in zebrafish by liver specific expression of Hepatitis B virus X protein (HBx). Transgenic zebrafish lines, GBXs, which selectively express the GBx transgene (GFP-fused HBx gene) in liver, were established. GBX Liver phenotypes were evaluated by histopathology and molecular analysis of fatty acid (FA) metabolism-related genes expression. Most GBXs (66-81%) displayed obvious emaciation starting at 4 months old. Over 99% of the emaciated GBXs developed hepatic steatosis or steatohepatitis, which in turn led to liver hypoplasia. The liver histology of GBXs displayed steatosis, lobular inflammation, and balloon degeneration, similar to non-alcoholic steatohepatitis (NASH). Oil red O stain detected the accumulation of fatty droplets in GBXs. RT-PCR and Q-rt-PCR analysis revealed that GBx induced hepatic steatosis had significant increases in the expression of lipogenic genes, C/EBP-alpha, SREBP1, ChREBP and PPAR-gamma, which then activate key enzymes of the de novo FA synthesis, ACC1, FAS, SCD1, AGAPT, PAP and DGAT2. In addition, the steatohepatitic GBX liver progressed to liver degeneration and exhibited significant differential gene expression in apoptosis and stress. The GBX models exhibited both the genetic and functional factors involved in lipid accumulation and steatosis-associated liver injury. In addition, GBXs with transmissible NASH-like phenotypes provide a promising model for studying liver disease.
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Affiliation(s)
- Yun-Sheng Shieh
- Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan
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Hussein AM, Ahmed OM. Regioselective one-pot synthesis and anti-proliferative and apoptotic effects of some novel tetrazolo[1,5-a]pyrimidine derivatives. Bioorg Med Chem 2010; 18:2639-2644. [PMID: 20227281 DOI: 10.1016/j.bmc.2010.02.028] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2009] [Revised: 02/15/2010] [Accepted: 02/17/2010] [Indexed: 11/27/2022]
Abstract
An easy and efficient route for the synthesis of some tetrazolo[1,5-a]-pyrimidine derivatives was described through the reaction of sodium salts of formyl cycloalkanones with 5-aminotetrazole monohydrate. The derivative 6,7,8,9-tetrahydrotetrazolo[1,5-a]quinazoline (6b) has profound anti-tumor cytotoxic effects against Ehrlich ascites carcinoma (EAC) both in vivo and in vitro and against hepatocellular carcinoma (HepG2) cell line in vitro. These anti-tumor effects may be mediated via stimulation of cell cycle arrest and apoptosis through down-regulation of Bcl-2 and up-regulation of p53 transcription factors.
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Affiliation(s)
- Ahmed M Hussein
- Chemistry Department (Organic Chemistry Division), Faculty of Science, Beni-Suef University, Egypt
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Bai J, Meng Z. Expression of caspase and apoptotic signal pathway induced by sulfur dioxide. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2010; 51:112-122. [PMID: 19621461 DOI: 10.1002/em.20517] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Sulfur dioxide (SO(2)) is a common air pollutant that is released in low concentrations into the atmosphere and in higher concentrations in some work places. In the present study, male Wistar rats were housed in exposure chambers and treated with 14.00 +/- 1.01, 28.00 +/- 1.77, and 56.00 +/- 3.44 mg/m(3) SO(2) for 7 days (6 hr/day), while control rats were exposed to filtered air under the same conditions. The mRNA and protein levels of caspase-3, caspase-8, and caspase-9 were analyzed using a real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) assay and an immunohistochemistry method. Activities of caspases were detected using colorimetric and fluorescent assays. Chromatin degradation and cell morphological changes were investigated by TUNEL assay and H&E staining in livers and lungs, respectively. The results showed that mRNA levels, protein levels and activities of caspase-3, caspase-8, and caspase-9 were increased in a dose-dependent manner in livers and lungs of rats after SO(2) inhalation. In addition, livers were infiltrated with lymphocytes, congestion and inflammation occurred in lungs, and eosinophil cells and apoptotic cells increased in both livers and lungs after SO(2) inhalation. These results suggest that SO(2) exposure increases the expression and activity of both initiator and and effector caspases, and may induce apoptosis in liver and lung of rats through both death receptor and mitochondrial pathways.
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Affiliation(s)
- Juli Bai
- Institute of Environmental Medicine and Toxicology, Research Center of Environmental Science and Engineering, Shanxi University, Taiyuan 030006, China
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Park JH, Kim KH, Kim SJ, Lee WR, Lee KG, Park JH, Park KK. Effect of bee venom on transforming growth factor-beta1-treated hepatocytes. Int J Toxicol 2010; 29:49-56. [PMID: 20075187 DOI: 10.1177/1091581809353948] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/14/2023]
Abstract
Bee venom (BV) has been used as treatment against a wide variety of ailments, including inflammatory diseases. Various studies have demonstrated anti-inflammatory and anticancer effects of BV. Transforming growth factor (TGF)-beta1 induces hepatocyte apoptosis via the mitochondrial permeability transition. However, there is no evidence or information regarding the antiapoptotic effect of BV on hepatocytes. The authors investigated the antiapoptotic effect of BV on TGF-beta1-treated hepatocytes. The results showed significant protection from DNA damage by BV treatment compared to corresponding TGF-beta1-treated hepatocytes without BV. BV suppressed TGF-beta1-induced activation of the bcl-2 family and caspase family of proteins, which resulted in inhibition of poly ADP-ribose polymerase (PARP) cleavage. Furthermore, BV is not cytotoxic in the low concentrations used in this study. Low concentrations of BV potently suppress the apoptotic response in TGF-beta1-treated hepatocytes; therefore, BV may have therapeutic potential for the treatment of liver diseases.
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Affiliation(s)
- Jung-Hyun Park
- Department of Rehabilitation Medicine, Eulji University Hospital, Daejeon, South Korea
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Gazzana G, Borlak J. An update on the mouse liver proteome. Proteome Sci 2009; 7:35. [PMID: 19737410 PMCID: PMC2752743 DOI: 10.1186/1477-5956-7-35] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2009] [Accepted: 09/08/2009] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Decoding of the liver proteome is subject of intense research, but hampered by methodological constraints. We recently developed an improved protocol for studying rat liver proteins based on 2-DE-MALDI-TOF-MS peptide mass finger printing.This methodology was now applied to develop a mouse liver protein database. RESULTS Liver proteins were extracted by two different lysis buffers in sequence followed by a liquid-phase IEF pre-fractionation and separation of proteins by 2 DE at two different pH ranges, notably 5-8 and 7-10. Based on 9600 in gel digests a total of 643 mouse liver proteins with high sequence coverage (> 20 peptides per protein) could be identified by MALDI-TOF-MS peptide mass finger printing. Notably, 255 proteins are novel and have not been reported so far by conventional two-dimensional electrophoresis proteome mapping. Additionally, the results of the present findings for mouse liver were compared to published data of the rat proteome to compile as many proteins as possible in a rodent liver database. CONCLUSION Based on 2-DE MALDI-TOF-MS a significantly improved proteome map of mouse liver was obtained. We discuss some prominent members of newly identified proteins for a better understanding of liver biology.
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Affiliation(s)
- Giuseppe Gazzana
- Department of Molecular Medicine and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany.
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Schneider-Merck T, Borbath I, Charette N, De Saeger C, Abarca J, Leclercq I, Horsmans Y, Stärkel P. The Ras inhibitor farnesylthiosalicyclic acid (FTS) prevents nodule formation and development of preneoplastic foci of altered hepatocytes in rats. Eur J Cancer 2009; 45:2050-60. [DOI: 10.1016/j.ejca.2009.04.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2008] [Accepted: 04/06/2009] [Indexed: 10/20/2022]
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Resveratrol-mediated chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis: Inhibition of cell proliferation and induction of apoptosis. Chem Biol Interact 2009; 179:131-44. [DOI: 10.1016/j.cbi.2008.11.015] [Citation(s) in RCA: 130] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2008] [Revised: 11/17/2008] [Accepted: 11/19/2008] [Indexed: 12/11/2022]
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Continentalic acid from Aralia continentalis induces growth inhibition and apoptosis in HepG2 cells. Arch Pharm Res 2009; 31:1172-8. [DOI: 10.1007/s12272-001-1285-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2008] [Revised: 07/31/2008] [Accepted: 07/31/2008] [Indexed: 12/19/2022]
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Baust JM, Snyder KK, VanBuskirk RG, Baust JG. Changing Paradigms in Biopreservation. Biopreserv Biobank 2009; 7:3-12. [DOI: 10.1089/bio.2009.0701.jmb] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Affiliation(s)
- John M. Baust
- Institute of Biomedical Technology, State University of New York at Binghamton, Binghamton, New York
- Department of Biological Sciences, Binghamton University, Binghamton, New York
- Cell Preservation Services, Inc., Owego, New York
| | - Kristi K. Snyder
- Institute of Biomedical Technology, State University of New York at Binghamton, Binghamton, New York
- Department of Biological Sciences, Binghamton University, Binghamton, New York
- Cell Preservation Services, Inc., Owego, New York
| | - Robert G. VanBuskirk
- Institute of Biomedical Technology, State University of New York at Binghamton, Binghamton, New York
- Department of Biological Sciences, Binghamton University, Binghamton, New York
- Cell Preservation Services, Inc., Owego, New York
| | - John G. Baust
- Institute of Biomedical Technology, State University of New York at Binghamton, Binghamton, New York
- Department of Biological Sciences, Binghamton University, Binghamton, New York
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Walter D, Schmich K, Vogel S, Pick R, Kaufmann T, Hochmuth FC, Haber A, Neubert K, McNelly S, von Weizsäcker F, Merfort I, Maurer U, Strasser A, Borner C. Switch from type II to I Fas/CD95 death signaling on in vitro culturing of primary hepatocytes. Hepatology 2008; 48:1942-53. [PMID: 19003879 PMCID: PMC2993691 DOI: 10.1002/hep.22541] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
UNLABELLED Fas/CD95-induced apoptosis of hepatocytes in vivo proceeds through the so-called type II pathway, requiring the proapoptotic BH3-only Bcl-2 family member Bid for mitochondrial death signaling. Consequently, Bid-deficient mice are protected from anti-Fas antibody injection induced fatal hepatitis. We report the unexpected finding that freshly isolated mouse hepatocytes, cultured on collagen or Matrigel, become independent of Bid for Fas-induced apoptosis, thereby switching death signaling from type II to type I. In such in vitro cultures, Fas ligand (FasL) activates caspase-3 without Bid cleavage, Bax/Bak activation or cytochrome c release, and neither Bid ablation nor Bcl-2 overexpression is protective. The type II to type I switch depends on extracellular matrix adhesion, as primary hepatocytes in suspension die in a Bid-dependent manner. Moreover, the switch is specific for FasL-induced apoptosis as collagen-plated Bid-deficient hepatocytes are protected from tumor necrosis factor alpha/actinomycin D (TNFalpha/ActD)-induced apoptosis. CONCLUSION Our data suggest a selective crosstalk between extracellular matrix and Fas-mediated signaling that favors mitochondria-independent type I apoptosis induction.
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Affiliation(s)
- Dorothée Walter
- Institute of Molecular Medicine and Cell Research, Centre of Biochemistry and Molecular Research (ZBMZ), Albert Ludwigs University Freiburg, Stefan Meier Strasse 17, D-79104 Freiburg, Germany,Faculty of Biology, Albert Ludwigs University Freiburg
| | - Kathrin Schmich
- Department of Pharmaceutical Biology and Biotechnology, Stefan Meier Str. 19, Albert Ludwigs University Freiburg, D-79104 Freiburg
| | - Sandra Vogel
- Institute of Molecular Medicine and Cell Research, Centre of Biochemistry and Molecular Research (ZBMZ), Albert Ludwigs University Freiburg, Stefan Meier Strasse 17, D-79104 Freiburg, Germany,Faculty of Biology, Albert Ludwigs University Freiburg,Spemann Graduate School of Biology and Medicine (SGBM), Albertstrasse 19a, Albert Ludwigs University Freiburg, D-79104 Freiburg
| | - Robert Pick
- Institute of Molecular Medicine and Cell Research, Centre of Biochemistry and Molecular Research (ZBMZ), Albert Ludwigs University Freiburg, Stefan Meier Strasse 17, D-79104 Freiburg, Germany
| | - Thomas Kaufmann
- The Walter and Eliza Hall Institute Medical Research, Parkville, VIC 3050, Australia
| | - Florian Christoph Hochmuth
- Institute of Molecular Medicine and Cell Research, Centre of Biochemistry and Molecular Research (ZBMZ), Albert Ludwigs University Freiburg, Stefan Meier Strasse 17, D-79104 Freiburg, Germany
| | - Angelika Haber
- Institute of Molecular Medicine and Cell Research, Centre of Biochemistry and Molecular Research (ZBMZ), Albert Ludwigs University Freiburg, Stefan Meier Strasse 17, D-79104 Freiburg, Germany
| | - Karin Neubert
- Institute of Molecular Medicine and Cell Research, Centre of Biochemistry and Molecular Research (ZBMZ), Albert Ludwigs University Freiburg, Stefan Meier Strasse 17, D-79104 Freiburg, Germany
| | - Sabine McNelly
- Internal Medicine, University Clinic Freiburg, Hugstetterstrasse 55, D-79106 Freiburg
| | - Fritz von Weizsäcker
- Internal Medicine, University Clinic Freiburg, Hugstetterstrasse 55, D-79106 Freiburg
| | - Irmgard Merfort
- Department of Pharmaceutical Biology and Biotechnology, Stefan Meier Str. 19, Albert Ludwigs University Freiburg, D-79104 Freiburg
| | - Ulrich Maurer
- Institute of Molecular Medicine and Cell Research, Centre of Biochemistry and Molecular Research (ZBMZ), Albert Ludwigs University Freiburg, Stefan Meier Strasse 17, D-79104 Freiburg, Germany
| | - Andreas Strasser
- The Walter and Eliza Hall Institute Medical Research, Parkville, VIC 3050, Australia
| | - Christoph Borner
- Institute of Molecular Medicine and Cell Research, Centre of Biochemistry and Molecular Research (ZBMZ), Albert Ludwigs University Freiburg, Stefan Meier Strasse 17, D-79104 Freiburg, Germany,Department of Pharmaceutical Biology and Biotechnology, Stefan Meier Str. 19, Albert Ludwigs University Freiburg, D-79104 Freiburg,To whom correspondence should be addressed:
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