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1
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Cao P, Jaeschke H, Ni HM, Ding WX. The Ways to Die: Cell Death in Liver Pathophysiology. Semin Liver Dis 2025. [PMID: 40199509 DOI: 10.1055/a-2576-4332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/10/2025]
Abstract
Liver diseases are closely associated with various cell death mechanisms, including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis. Each process contributes uniquely to the pathophysiology of liver injury and repair. Importantly, these mechanisms are not limited to hepatocytes; they also significantly involve nonparenchymal cells. This review examines the molecular pathways and regulatory mechanisms underlying these forms of cell death in hepatocytes, emphasizing their roles in several liver diseases, such as ischemia-reperfusion injury, metabolic dysfunction-associated steatotic liver disease, drug-induced liver injury, and alcohol-associated liver disease. Recent insights into ferroptosis and pyroptosis may reveal novel therapeutic targets for managing liver diseases. This review aims to provide a comprehensive overview of these cell death mechanisms in the context of liver diseases, detailing their molecular signaling pathways and implications for potential treatment strategies.
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Affiliation(s)
- Peng Cao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
- Division of Gastroenterology, Hepatology and Mobility, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas
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2
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Cheng X, Zeng T, Xu Y, Xiong Y. The emerging role of PANoptosis in viral infections disease. Cell Signal 2024; 125:111497. [PMID: 39489200 DOI: 10.1016/j.cellsig.2024.111497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 10/19/2024] [Accepted: 10/28/2024] [Indexed: 11/05/2024]
Abstract
PANoptosis is a distinct inflammatory cell death mechanism that involves interactions between pyroptosis, apoptosis, and necroptosis. It can be regulated by diverse PANoptosome complexes built by integrating components from various cell death modalities. There is a rising interest in PANoptosis' process and functions. Viral infection is an important trigger of PANoptosis. Viruses invade host cells through their unique mechanisms and utilize host cell resources for replication and proliferation. In this process, viruses interfere with the normal physiological functions of host cells, including cell death mechanisms. A variety of viruses, such as influenza A virus (IAV), herpes simplex virus 1 (HSV1) and coronaviruses, have been found to induce PANoptosis in host cells. Given the importance of PANoptosis across the disease spectrum, this review briefly describes the relationships between pyroptosis, apoptosis, and necroptosis, highlights the key molecules in PANoptosome formation and activation, and outlines the multifaceted roles of PANoptosis in viral diseases, including potential therapeutic targets. We also talk about key principles and significant concerns for future PANoptosis research. Improved understanding of PANoptosis and its mechanisms is critical for discovering new treatment targets and methods.
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Affiliation(s)
- Xu Cheng
- Department of Pharmaceutics, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi, China; Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
| | - Taoyuan Zeng
- Department of Pharmaceutics, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi, China; Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
| | - Yingshu Xu
- Department of Pharmaceutics, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi, China; Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China.
| | - Yongai Xiong
- Department of Pharmaceutics, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi, China; Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China.
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3
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Sun D, Xie C, Zhao Y, Liao J, Li S, Zhang Y, Wang D, Hua K, Gu Y, Du J, Huang G, Huang J. The gut microbiota-bile acid axis in cholestatic liver disease. Mol Med 2024; 30:104. [PMID: 39030473 PMCID: PMC11265038 DOI: 10.1186/s10020-024-00830-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 05/07/2024] [Indexed: 07/21/2024] Open
Abstract
Cholestatic liver diseases (CLD) are characterized by impaired normal bile flow, culminating in excessive accumulation of toxic bile acids. The majority of patients with CLD ultimately progress to liver cirrhosis and hepatic failure, necessitating liver transplantation due to the lack of effective treatment. Recent investigations have underscored the pivotal role of the gut microbiota-bile acid axis in the progression of hepatic fibrosis via various pathways. The obstruction of bile drainage can induce gut microbiota dysbiosis and disrupt the intestinal mucosal barrier, leading to bacteria translocation. The microbial translocation activates the immune response and promotes liver fibrosis progression. The identification of therapeutic targets for modulating the gut microbiota-bile acid axis represents a promising strategy to ameliorate or perhaps reverse liver fibrosis in CLD. This review focuses on the mechanisms in the gut microbiota-bile acids axis in CLD and highlights potential therapeutic targets, aiming to lay a foundation for innovative treatment approaches.
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Affiliation(s)
- Dayan Sun
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Chuanping Xie
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Yong Zhao
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Junmin Liao
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Shuangshuang Li
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Yanan Zhang
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Dingding Wang
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Kaiyun Hua
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Yichao Gu
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Jingbin Du
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Guoxian Huang
- Department of Pediatric Surgery, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, 361000, China
| | - Jinshi Huang
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China.
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Feng J, Ye S, Hai B, Lou Y, Duan M, Guo P, Lv P, Lu W, Chen Y. RNF115/BCA2 deficiency alleviated acute liver injury in mice by promoting autophagy and inhibiting inflammatory response. Cell Death Dis 2023; 14:855. [PMID: 38129372 PMCID: PMC10739886 DOI: 10.1038/s41419-023-06379-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 11/30/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023]
Abstract
The E3 ubiquitin ligase RING finger protein 115 (RNF115), also known as breast cancer-associated gene 2 (BCA2), has been linked with the growth of some cancers and immune regulation, which is negatively correlated with prognosis. Here, it is demonstrated that the RNF115 deletion can protect mice from acute liver injury (ALI) induced by the treatment of lipopolysaccharide (LPS)/D-galactosamine (D-GalN), as evidenced by decreased levels of alanine aminotransaminase, aspartate transaminase, inflammatory cytokines (e.g., tumor necrosis factor α and interleukin-6), chemokines (e.g., MCP1/CCL2) and inflammatory cell (e.g., monocytes and neutrophils) infiltration. Moreover, it was found that the autophagy activity in Rnf115-/- livers was increased, which resulted in the removal of damaged mitochondria and hepatocyte apoptosis. However, the administration of adeno-associated virus Rnf115 or autophagy inhibitor 3-MA impaired autophagy and aggravated liver injury in Rnf115-/- mice with ALI. Further experiments proved that RNF115 interacts with LC3B, downregulates LC3B protein levels and cell autophagy. Additionally, Rnf115 deletion inhibited M1 type macrophage activation via NF-κB and Jnk signaling pathways. Elimination of macrophages narrowed the difference in liver damage between Rnf115+/+ and Rnf115-/- mice, indicating that macrophages were linked in the ALI induced by LPS/D-GalN. Collectively, for the first time, we have proved that Rnf115 inactivation ameliorated LPS/D-GalN-induced ALI in mice by promoting autophagy and attenuating inflammatory responses. This study provides new evidence for the involvement of autophagy mechanisms in the protection against acute liver injury.
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Affiliation(s)
- Jinqiu Feng
- Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Shufang Ye
- Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Bao Hai
- Department of Orthopedics, Peking University Third Hospital, 49 North Garden Road, Beijing, 100191, China
| | - Yaxin Lou
- Medical and Healthy Analytical Center, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Mengyuan Duan
- Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Pengli Guo
- Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Ping Lv
- Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Wenping Lu
- Department of Hepatobiliary Surgery, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
| | - Yingyu Chen
- Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
- Center for Human Disease Genomics, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
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Verçosa BLA, Muniz-Junqueira MI, Barradas ALB, Costa FAL, Melo MN, Vasconcelos AC. Enhanced apoptotic index in hepatocytes, Kupffer cells, and inflammatory infiltrate showed positive correlation with hepatic lesion intensity, parasite load, and clinical status in naturally Leishmania-infected dogs. Microb Pathog 2023:106194. [PMID: 37269879 DOI: 10.1016/j.micpath.2023.106194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/09/2023] [Accepted: 05/31/2023] [Indexed: 06/05/2023]
Abstract
It is unknown if Leishmania amastigote infections affect hepatocytes and Kupffer cell apoptosis, and the role played by apoptosis in liver lesions in leishmaniasis is still unclear. Clinically affected and subclinically infected dogs with leishmaniosis and uninfected controls were assessed. Parasite load, biochemical markers for evaluation of liver damage, morphometry (area, perimeter, number of inflammatory focus, major and minor diameters), apoptosis in hepatic tissue (hepatocytes, Kupffer cells, and inflammatory infiltrates) and cellularity in inflammatory foci were quantified. The parasite load in clinically affected dogs proved to be higher than in the other groups. All morphometric parameters (area, perimeter, number of inflammatory focus, major and minor diameters) from clinically affected were higher than the values found in the subclinically infected and uninfected control dogs. Only clinically affected dogs presented high levels of ALT, FA, GGT and cholesterol in serum. Strong positive correlation was observed between biochemical markers for evaluation of liver damage (ALT, FA, GGT and cholesterol) and hepatic apoptosis (hepatocytes, Kupffer cells, and inflammation). Clinically affected dogs showed a more intense hepatic lesion. Hepatocytes showed a higher rate of apoptosis in Leishmania-infected dogs than in uninfected control dogs. The Kupffer cell apoptotic index and apoptosis within the inflammatory infiltrates were higher in clinically affected dogs. The apoptotic index evaluated in hepatocytes, Kupffer cells, and inflammatory infiltrates showed a positive correlation with the intensity of the hepatic lesion, parasite load, and clinical status. Apoptotic cells also showed positive immunostaining for TUNEL, Bcl2, and Bax. Our data showed that hepatic apoptosis was related to the severity of liver damage, the progression of infection, and the parasite load in leishmaniasis. Apoptotic regulated cell recruitment modulated the inflammatory response and favored the survival and dissemination of parasites, depending on the clinical status of the Leishmania-infected dogs.
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Affiliation(s)
- Bárbara Laurice Araujo Verçosa
- Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Laboratório de Imunologia Celular, Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil; Faculdade de Ciências da Saúde Pitágoras de Codó, Maranhão, Brazil.
| | | | - Ana Lys Bezerra Barradas
- Departamento de Clínica e Cirurgia veterinária, Centro de Ciências Agrárias, Universidade Federal do Piauí, Teresina, Piauí, Brazil
| | - Francisco Assis Lima Costa
- Departamento de Clínica e Cirurgia veterinária, Centro de Ciências Agrárias, Universidade Federal do Piauí, Teresina, Piauí, Brazil
| | - Maria Norma Melo
- Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Anilton Cesar Vasconcelos
- Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Rahman MS, Pang WK, Amjad S, Ryu DY, Adegoke EO, Park YJ, Pang MG. Hepatic consequences of a mixture of endocrine-disrupting chemicals in male mice. JOURNAL OF HAZARDOUS MATERIALS 2022; 436:129236. [PMID: 35739755 DOI: 10.1016/j.jhazmat.2022.129236] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/22/2022] [Accepted: 05/23/2022] [Indexed: 06/15/2023]
Abstract
The global epidemic of metabolic syndrome has been partially linked to ubiquitous exposure to endocrine-disrupting chemicals (EDCs). Although the impacts of exposure to single EDCs have been thoroughly studied, the consequences of simultaneous uncontrolled exposure to multiple EDCs require further investigations. Therefore, in this study, we evaluated how exposure to mixtures containing bisphenol A and seven phthalates impacts liver functions and metabolic homeostasis. Male mice were gavaged with either EDCs at four different dose combinations or corn oil (control) for six weeks. The results showed that exposure to EDCs at the human daily exposure limit had a negligible impact on liver function. However, EDC at ≥ 25 orders of magnitude of human-relevant doses had detrimental impacts on overall liver function, leading to metabolic abnormalities, steatohepatitis, and hepatic fibrosis via the activation of both genomic and non-genomic pathways. The metabolic phenotype was linked to alterations in key genes involved in hepatic lipid and glucose metabolism. In contrast, alterations in cytokine expression, oxidative stress, and apoptosis impacted steatohepatitis and fibrosis. Because EDC exposure does not occur independently, the findings of the combined effects of exposure to multiple EDCs have significant relevance for public health.
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Affiliation(s)
- Md Saidur Rahman
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea
| | - Won-Ki Pang
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea
| | - Shehreen Amjad
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea
| | - Do-Yeal Ryu
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea
| | - Elikanah Olusayo Adegoke
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea
| | - Yoo-Jin Park
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea
| | - Myung-Geol Pang
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea.
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Saxena N, Dhaked RK, Nagar DP. Silibinin ameliorates abrin induced hepatotoxicity by attenuating oxidative stress, inflammation and inhibiting Fas pathway. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2022; 93:103868. [PMID: 35504510 DOI: 10.1016/j.etap.2022.103868] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 04/11/2022] [Accepted: 04/25/2022] [Indexed: 06/14/2023]
Abstract
Abrin is a toxin from the seeds of Abrus precatorius. Abrin is considerably more toxic than ricin and a potent bio-warfare agent. The mechanism of abrin induced hepatotoxicity remains unclear. Silibinin has antioxidant, anti-inflammatory and hepatoprotective activities. But, its therapeutic potential in abrin toxicity is unknown. In view of these facts, the purpose of this study was to delineate the mechanisms and ameliorative role of silibinin against abrin induced hepatotoxicity. Parameters related to liver functions, oxidative stress, inflammation, Fas pathway and histopathology were evaluated in the liver of BALB/c mice after abrin exposure. Abrin intoxication resulted in hepatotoxicity, oxidative stress, inflammation, altered histopathology and increased Fas pathway signaling. Silibinin improves survival of abrin-exposed mice by decreasing serum liver enzymes and reinstating the antioxidant capacity. Silibinin also inhibits abrin-induced inflammation and Fas pathway. Present study for the first time demonstrates the hepatoprotective potential of silibinin against abrin toxicity.
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Affiliation(s)
- Nandita Saxena
- Division of Pharmacology & Toxicology, Defence Research Development & Establishment, Defence Research Development Organization, Gwalior 474002, India.
| | - Ram Kumar Dhaked
- Biotechnology Division, Defence Research Development & Establishment, Defence Research Development Organization, Gwalior 474002, India
| | - D P Nagar
- Division of Pharmacology & Toxicology, Defence Research Development & Establishment, Defence Research Development Organization, Gwalior 474002, India
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Yu Z, Wang Y, Liu L, Zhang X, Jiang S, Wang B. Apoptosis Disorder, a Key Pathogenesis of HCMV-Related Diseases. Int J Mol Sci 2021; 22:ijms22084106. [PMID: 33921122 PMCID: PMC8071541 DOI: 10.3390/ijms22084106] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/09/2021] [Accepted: 04/13/2021] [Indexed: 02/07/2023] Open
Abstract
Human cytomegalovirus (HCMV) belongs to the β-herpesvirus family, which is transmitted in almost every part of the world and is carried by more than 90% of the general population. Increasing evidence indicates that HCMV infection triggers numerous diseases by disrupting the normal physiological activity of host cells, particularly apoptosis. Apoptosis disorder plays a key role in the initiation and development of multiple diseases. However, the relationship and molecular mechanism of HCMV-related diseases and apoptosis have not yet been systematically summarized. This review aims to summarize the role of apoptosis in HCMV-related diseases and provide an insight into the molecular mechanism of apoptosis induced by HCMV infection. We summarize the literature on HCMV-related diseases and suggest novel strategies for HCMV treatment by regulating apoptosis.
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Affiliation(s)
- Zhongjie Yu
- Department of Special Medicine, School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao 266000, China;
| | - Yashuo Wang
- College of Life Sciences, Qingdao University, Qingdao 266000, China;
| | - Lili Liu
- Department of Basic Medicine, School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao 266000, China;
| | - Xianjuan Zhang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao 266000, China; (X.Z.); (S.J.)
| | - Shasha Jiang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao 266000, China; (X.Z.); (S.J.)
| | - Bin Wang
- Department of Special Medicine, School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao 266000, China;
- Correspondence: ; Tel.: +86-136-8532-6203
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Cui J, Zhang N, Liu Y, Zhang L, Gao C, Liu S. Microarray gene expression profiling provides insights into functions of TIPE2 in HBV-related apoptosis. Mol Immunol 2021; 131:137-143. [PMID: 33419563 DOI: 10.1016/j.molimm.2020.12.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 11/06/2020] [Accepted: 12/24/2020] [Indexed: 10/22/2022]
Abstract
Tumor necrosis factor-α-induced protein-8 like-2 (TNFAIP8L2, TIPE2), a member of TNFAIP8 family, functions as a regulator in inflammation. Our previous studies showed that TIPE2 can negatively regulate HBV-specific CD8+ T lymphocyte functions. But the effect of TIPE2 on the apoptosis of HBV-infected hepatocytes which is very important for eliminating viruses remains unclear. Using gene expression microarray analysis, we find that TIPE2 deficiency can regulate the expression of apoptotic genes in liver tissues from HBV hydrodynamic injection (HI) mouse model. TIPE2 protein was detected in TUNEL staining positive hepatocytes in HBV-infected C57 mice. Interestingly, the TIPE2 expressed hepatocytes were just the HBV infected cells. Furthermore, TIPE2 upregulates the mRNA levels of FasL, Bim and TNFRsF1b which promote cells death, when TIPE2 was transfected into HepG2 cells in vitro. As a result, TIPE2 overexpression cells showed a higher number of apoptotic cells and increased level of cleavage caspase3 compared to controls. Those results indicate that TIPE2 participates in HBV infection by regulating apoptosis of virus-infected hepatocytes.
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Affiliation(s)
- Jian Cui
- Department of Immunology, Shandong University School of Basic Medical Science, Ji'nan, China; Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Science, Jinan, China
| | - Na Zhang
- Department of Immunology, Shandong University School of Basic Medical Science, Ji'nan, China
| | - Ying Liu
- Department of Immunology, Shandong University School of Basic Medical Science, Ji'nan, China
| | - Lei Zhang
- Department of Immunology, Shandong University School of Basic Medical Science, Ji'nan, China
| | - Chengjiang Gao
- Department of Immunology, Shandong University School of Basic Medical Science, Ji'nan, China; Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Science, Jinan, China
| | - Suxia Liu
- Department of Immunology, Shandong University School of Basic Medical Science, Ji'nan, China; Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Science, Jinan, China.
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Shao R, Yang Y, Fan K, Wu X, Jiang R, Tang L, Li L, Shen Y, Liu G, Zhang L. REV-ERBα Agonist GSK4112 attenuates Fas-induced Acute Hepatic Damage in Mice. Int J Med Sci 2021; 18:3831-3838. [PMID: 34790059 PMCID: PMC8579287 DOI: 10.7150/ijms.52011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 10/07/2021] [Indexed: 12/04/2022] Open
Abstract
Fas-induced apoptosis is a central mechanism of hepatocyte damage during acute and chronic hepatic disorders. Increasing evidence suggests that circadian clock plays critical roles in the regulation of cell fates. In the present study, the potential significance of REV-ERBα, a core ingredient of circadian clock, in Fas-induced acute liver injury has been investigated. The anti-Fas antibody Jo2 was injected intraperitoneally in mice to induce acute liver injury and the REV-ERBα agonist GSK4112 was administered. The results indicated that treatment of GSK4112 decreased the level of plasma ALT and AST, attenuated the liver histological changes, and promoted the survival rate in Jo2-insulted mice. Treatment with GSK4112 also downregulated the activities of caspase-3 and caspase-8, suppressed hepatocyte apoptosis. In addition, treatment with GSK4112 decreased the level of Fas and enhanced the phosphorylation of Akt. In conclusion, treatment with GSK4112 alleviated Fas-induced apoptotic liver damage in mice, suggesting that REV-ERBα agonist might have potential value in pharmacological intervention of Fas-associated liver injury.
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Affiliation(s)
- Ruyue Shao
- Clinical Medical School, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China.,Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing 401331, China
| | - Yongqiang Yang
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing 400016, China
| | - Kerui Fan
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing 400016, China
| | - Xicheng Wu
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing 400016, China
| | - Rong Jiang
- Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Li Tang
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing 400016, China
| | - Longjiang Li
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing 400016, China
| | - Yi Shen
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing 400016, China
| | - Gang Liu
- Department of Emergency, University-Town Hospital of Chongqing Medical University, Chongqing 401331, China
| | - Li Zhang
- Department of Pathophysiology, Basic Medical College, Chongqing Medical University, Chongqing 400016, China
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12
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Wen B, Zhang C, Zhou J, Zhang Z, Che Q, Cao H, Bai Y, Guo J, Su Z. Targeted treatment of alcoholic liver disease based on inflammatory signalling pathways. Pharmacol Ther 2020; 222:107752. [PMID: 33253739 DOI: 10.1016/j.pharmthera.2020.107752] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/15/2020] [Accepted: 11/20/2020] [Indexed: 02/06/2023]
Abstract
Targeted therapy is an emerging treatment strategy for alcoholic liver disease (ALD). Inflammation plays an important role in the occurrence and development of ALD, and is a key choice for its targeted treatment, and anti-inflammatory treatment has been considered beneficial for liver disease. Surprisingly, immune checkpoint inhibitors have become important therapeutic agents for hepatocellular carcinoma (HCC). Moreover, studies have shown that the combination of inflammatory molecule inhibitors and immune checkpoint inhibitors can exert better effects than either alone in mouse models of HCC. This review discusses the mechanism of hepatic ethanol metabolism and the conditions under which inflammation occurs. In addition, we focus on the potential molecular targets in inflammatory signalling pathways and summarize the potential targeted inhibitors and immune checkpoint inhibitors, providing a theoretical basis for the targeted treatment of ALD and the development of new combination therapy strategies for HCC.
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Affiliation(s)
- Bingjian Wen
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Chengcheng Zhang
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jingwen Zhou
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Zhengyan Zhang
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Qishi Che
- Guangzhou Rainhome Pharm & Tech Co., Ltd., Guangzhou 510663, China
| | - Hua Cao
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China
| | - Yan Bai
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Zhengquan Su
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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13
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Octreotide and melatonin alleviate inflammasome-induced pyroptosis through inhibition of TLR4-NF-κB-NLRP3 pathway in hepatic ischemia/reperfusion injury. Toxicol Appl Pharmacol 2020; 410:115340. [PMID: 33264646 DOI: 10.1016/j.taap.2020.115340] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 11/07/2020] [Accepted: 11/13/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIM The Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB)/NLRP3 inflammasome signaling pathway is essential in the pathogenesis of hepatic ischemia/ reperfusion (HIR) injury. Pyroptosis is a proinflammatory programmed cell death that is related to several diseases. Thus, the purpose of this study was to examine whether pretreatment with octreotide (somatostatin analogue, OCT) at different doses or OCT at 75μg/kg combined with melatonin (N-acetyl-5-methoxytryptamine, MLT) can alleviate HIR injury via targeting NLRP3 inflammasome-induced pyroptosis in a TLR4/MyD88/NF-κB dependent manner. METHODS Rats were randomized into sham, HIR, OCT (50, 75, and 100 µg/kg), MLT, and MLT + OCT75 groups. Ischemia was induced via occlusion of the portal triad for 30 min followed by 24 h reperfusion. RESULTS OCT pretreatment at doses (50 or 75 μg/kg), MLT alone, and MLT + OCT75 significantly ameliorated the biochemical with histopathological changes, oxidative stress, inflammation, apoptosis, then augmented anti-oxidant and anti-apoptotic markers through downregulation of HMGB1, TLR4, MyD88, TRAF-6, p-IκBα (S32), p-NF-κBp65 (S536), NLRP3, ASC, caspase-1(p20), and GSDMD-N expressions compared with HIR group. CONCLUSION OCT at doses (50 or 75 µg/kg) showed for the first time a hepatoprotective effect against HIR injury via inhibiting TLR4-NLRP3-mediated pyroptosis in rats. As well, OCT75 was more effective than OCT50 or MLT alone, and its effect was not enhanced after the addition of MLT, through downregulation of TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway.
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14
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Ono A, Aikata H, Yamauchi M, Kodama K, Ohishi W, Kishi T, Ohya K, Teraoka Y, Osawa M, Fujino H, Nakahara T, Murakami E, Miki D, Kawaoka T, Abe-Chayama H, Zhang P, Liu S, Makokha GN, Tsuge M, Imamura M, Hayes CN, Chayama K. Circulating cytokines and angiogenic factors based signature associated with the relative dose intensity during treatment in patients with advanced hepatocellular carcinoma receiving lenvatinib. Ther Adv Med Oncol 2020; 12:1758835920922051. [PMID: 32547646 PMCID: PMC7249573 DOI: 10.1177/1758835920922051] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 03/13/2020] [Indexed: 12/14/2022] Open
Abstract
Background: Although lenvatinib was recently approved for treatment of advanced unresectable hepatocellular carcinoma (HCC) based on the phase III REFLECT trial, no biomarkers for management of lenvatinib treatment have been established. The aim of this study is to identify predictive biomarkers for the management of lenvatinib treatment in advanced HCC patients. Methods: A total of 41 patients with advanced HCC were enrolled in this retrospective study. Serum levels of 22 circulating cytokines and angiogenic factors (CAFs) were measured by multiplex Luminex assay. Profiles of CAFs, clinical chemistry/hematology parameters, and clinical background were evaluated to explore biomarkers associated with clinical outcomes. Results: Relative dose intensity (RDI) decreased significantly between weeks 1–2 and 3–4 (p < 0.001), and RDI during weeks 3–4 was a prominent indicator of progression-free survival (PFS). A signature based on baseline serum levels of nine CAFs associated with low RDI was identified. In a multivariate Cox regression analysis, patients with a favorable 9-CAFs signature [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.18–0.96, p = 0.040] had lower risk, and Child-Pugh grade B (HR 1.6, 95% CI 1.1–8.3, p = 0.026) and presence of macrovascular invasion (MVI; HR 2.9, 95% CI 1.0–8.3, p = 0.045) had higher risk of shorter PFS. Conclusion: This study demonstrates that RDI is an important predictive factor for longer PFS during lenvatinib treatment. In this hypothesis-generating exploratory analysis, we report that a CAF-signature associated with adverse events and RDI could predict PFS, which might contribute to improved management of lenvatinib treatment in HCC patients.
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Affiliation(s)
- Atsushi Ono
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kenichiro Kodama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Waka Ohishi
- Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima, Japan
| | - Takeshi Kishi
- Biosample Research Center, Radiation Effects Research Foundation, Hiroshima, Japan
| | - Kazuki Ohya
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Mitsutaka Osawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiromi Abe-Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Peiyi Zhang
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Songyao Liu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Grace Naswa Makokha
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
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15
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Qu C, Sun J, Xu Q, Lv X, Yang W, Wang F, Wang Y, Yi Q, Jia Z, Wang L, Song L. An inhibitor of apoptosis protein (EsIAP1) from Chinese mitten crab Eriocheir sinensis regulates apoptosis through inhibiting the activity of EsCaspase-3/7-1. Sci Rep 2019; 9:20421. [PMID: 31892728 PMCID: PMC6938513 DOI: 10.1038/s41598-019-56971-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 12/19/2019] [Indexed: 01/13/2023] Open
Abstract
Inhibitor of apoptosis proteins (IAPs) maintain the balance between cell proliferation and cell death by inhibiting caspase activities and mediating immune responses. In the present study, a homolog of IAP (designated as EsIAP1) was identified from Chinese mitten crab Eriocheir sinensis. EsIAP1 consisted of 451 amino acids containing two baculoviral IAP repeat (BIR) domains with the conserved Cx2 Cx6 Wx3 Dx5 Hx6 C motifs. EsIAP1 mRNA was expressed in various tissues and its expression level in hemocytes increased significantly (p < 0.01) at 12–48 h after lipopolysaccharide stimulation. In the hemocytes, EsIAP1 protein was mainly distributed in the cytoplasm. The hydrolytic activity of recombinant EsCaspase-3/7-1 against the substrate Ac-DEVD-pNA decreased after incubation with rEsIAP1. Moreover, rEsIAP1 could directly combine with rEsCaspase-3/7-1 in vitro. After EsIAP1 was interfered by dsRNA, the mRNA expression and the hydrolytic activity of EsCaspase-3/7-1 increased significantly, which was 2.26-fold (p < 0.05) and 1.71-fold (p < 0.05) compared to that in the dsGFP group, respectively. These results collectively demonstrated that EsIAP1 might play an important role in apoptosis pathway by regulating the activity of EsCaspase-3/7-1 in E. sinensis.
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Affiliation(s)
- Chen Qu
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China
| | - Jiejie Sun
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China
| | - Qingsong Xu
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China.,Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Xiaojing Lv
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China.,Laboratory of Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China.,Liaoning Key Laboratory of Marine Animal Immunology & Disease Control, Dalian Ocean University, Dalian, 116023, China.,Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Wen Yang
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China
| | - Feifei Wang
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China
| | - Ying Wang
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China
| | - Qilin Yi
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China.,Liaoning Key Laboratory of Marine Animal Immunology & Disease Control, Dalian Ocean University, Dalian, 116023, China.,Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Zhihao Jia
- Laboratory of Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China
| | - Lingling Wang
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China.,Laboratory of Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China.,Liaoning Key Laboratory of Marine Animal Immunology & Disease Control, Dalian Ocean University, Dalian, 116023, China.,Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Linsheng Song
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China. .,Laboratory of Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China. .,Liaoning Key Laboratory of Marine Animal Immunology & Disease Control, Dalian Ocean University, Dalian, 116023, China. .,Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China.
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16
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Hu SJ, Jiang SS, Zhang J, Luo D, Yu B, Yang LY, Zhong HH, Yang MW, Liu LY, Hong FF, Yang SL. Effects of apoptosis on liver aging. World J Clin Cases 2019; 7:691-704. [PMID: 30968034 PMCID: PMC6448073 DOI: 10.12998/wjcc.v7.i6.691] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 01/10/2019] [Accepted: 01/26/2019] [Indexed: 02/05/2023] Open
Abstract
As an irreversible and perennial process, aging is accompanied by functional and morphological declines in organs. Generally, aging liver exhibits a decline in volume and hepatic blood flow. Even with a preeminent regenerative capacity to restore its functions after liver cell loss, its biosynthesis and metabolism abilities decline, and these are difficult to restore to previous standards. Apoptosis is a programmed death process via intrinsic and extrinsic pathways, in which Bcl-2 family proteins and apoptosis-related genes, such as p21 and p53, are involved. Apoptosis inflicts both favorable and adverse influences on liver aging. Apoptosis eliminates transformed abnormal cells but promotes age-related liver diseases, such as nonalcoholic fatty liver disease, liver fibrosis, cirrhosis, and liver cancer. We summarize the roles of apoptosis in liver aging and age-related liver diseases.
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Affiliation(s)
- Shao-Jie Hu
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Sha-Sha Jiang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jin Zhang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Dan Luo
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Bo Yu
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Liang-Yan Yang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Hua-Hua Zhong
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Mei-Wen Yang
- Department of Nurse, Nanchang University Hospital, Nanchang 330006, Jiangxi Province, China
| | - Li-Yu Liu
- Department of Nurse, Nanchang University Hospital, Nanchang 330006, Jiangxi Province, China
| | - Fen-Fang Hong
- Experimental Teaching Center, Nanchang University, Nanchang 330031, Jiangxi Province, China
| | - Shu-Long Yang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
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17
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Abstract
Cell death represents a basic biological paradigm that governs outcomes and long-term sequelae in almost every hepatic disease condition. Acute liver failure is characterized by massive loss of parenchymal cells but is usually followed by restitution ad integrum. By contrast, cell death in chronic liver diseases often occurs at a lesser extent but leads to long-term alterations in organ architecture and function, contributing to chronic hepatocyte turnover, the recruitment of immune cells and activation of hepatic stellate cells. These chronic cell death responses contribute to the development of liver fibrosis, cirrhosis and cancer. It has become evident that, besides apoptosis, necroptosis is a highly relevant form of programmed cell death in the liver. Differential activation of specific forms of programmed cell death might not only affect outcomes in liver diseases but also offer novel opportunities for therapeutic intervention. Here, we summarize the underlying molecular mechanisms and open questions about disease-specific activation and roles of programmed cell death forms, their contribution to response signatures and their detection. We focus on the role of apoptosis and necroptosis in acute liver injury, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and liver cancer, and possible translations into clinical applications.
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Affiliation(s)
- Robert F Schwabe
- Department of Medicine, Columbia University, New York, NY, USA.
- Institute of Human Nutrition, Columbia University, New York, NY, USA.
| | - Tom Luedde
- Department of Medicine III, Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany.
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18
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Exploring Crimean-Congo Hemorrhagic Fever Virus-Induced Hepatic Injury Using Antibody-Mediated Type I Interferon Blockade in Mice. J Virol 2018; 92:JVI.01083-18. [PMID: 30111561 DOI: 10.1128/jvi.01083-18] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 08/07/2018] [Indexed: 01/22/2023] Open
Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) can cause severe hepatic injury in humans. However, the mechanism(s) causing this damage is poorly characterized. CCHFV produces an acute disease, including liver damage, in mice lacking type I interferon (IFN-I) signaling due to either STAT-1 gene deletion or disruption of the IFN-I receptor 1 gene. Here, we explored CCHFV-induced liver pathogenesis in mice using an antibody to disrupt IFN-I signaling. When IFN-I blockade was induced within 24 h postexposure to CCHFV, mice developed severe disease with greater than 95% mortality by 6 days postexposure. In addition, we observed increased proinflammatory cytokines, chemoattractants, and liver enzymes in these mice. Extensive liver damage was evident by 4 days postexposure and was characterized by hepatocyte necrosis and the loss of CLEC4F-positive Kupffer cells. Similar experiments in CCHFV-exposed NOD-SCID-γ (NSG), Rag2-deficient, and perforin-deficient mice also demonstrated liver injury, suggesting that cytotoxic immune cells are dispensable for hepatic damage. Some apoptotic liver cells contained viral RNA, while other apoptotic liver cells were negative, suggesting that cell death occurred by both intrinsic and extrinsic mechanisms. Protein and transcriptional analysis of livers revealed that activation of tumor necrosis factor superfamily members occurred by day 4 postexposure, implicating these molecules as factors in liver cell death. These data provide insights into CCHFV-induced hepatic injury and demonstrate the utility of antibody-mediated IFN-I blockade in the study of CCHFV pathogenesis in mice.IMPORTANCE CCHFV is an important human pathogen that is both endemic and emerging throughout Asia, Africa, and Europe. A common feature of acute disease is liver injury ranging from mild to fulminant hepatic failure. The processes through which CCHFV induces severe liver injury are unclear, mostly due to the limitations of existing small-animal systems. The only small-animal model in which CCHFV consistently produces severe liver damage is mice lacking IFN-I signaling. In this study, we used antibody-mediated blockade of IFN-I signaling in mice to study CCHFV liver pathogenesis in various transgenic mouse systems. We found that liver injury did not depend on cytotoxic immune cells and observed extensive activation of death receptor signaling pathways in the liver during acute disease. Furthermore, acute CCHFV infection resulted in a nearly complete loss of Kupffer cells. Our model system provides insight into both the molecular and the cellular features of CCHFV hepatic injury.
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19
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Nielsen KO, Jacobsen KS, Mirza AH, Winther TN, Størling J, Glebe D, Pociot F, Hogh B. Hepatitis B virus upregulates host microRNAs that target apoptosis-regulatory genes in an in vitro cell model. Exp Cell Res 2018; 371:92-103. [DOI: 10.1016/j.yexcr.2018.07.044] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 07/08/2018] [Accepted: 07/26/2018] [Indexed: 12/18/2022]
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20
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Sun YY, Zhao YX, Li XF, Huang C, Meng XM, Li J. β-Arrestin 2 Promotes Hepatocyte Apoptosis by Inhibiting Akt Pathway in Alcoholic Liver Disease. Front Pharmacol 2018; 9:1031. [PMID: 30283336 PMCID: PMC6156347 DOI: 10.3389/fphar.2018.01031] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Accepted: 08/24/2018] [Indexed: 12/20/2022] Open
Abstract
Alcoholic liver disease (ALD) is a complex process that includes a wide range of hepatic lesions, from steatosis to cirrhosis, and even hepatocellular carcinoma (HCC). Accumulating evidence shows that the cytotoxic effects of ethanol metabolism lead to cell apoptosis and necrosis in ALD. Recently, several studies revealed that multifunctional protein β-arrestin 2 (Arrb2) modulated cell apoptosis in liver fibrosis and HCC, but its role in ALD has not been fully understood. The aim of this study is to explore the function and underlying mechanism of Arrb2 in hepatocyte survival and apoptosis in ALD. In our study, the primary hepatocytes were isolated from the livers of C57BL/6 mice fed EtOH-containing diet, it showed an increased level of Arrb2. EtOH also significantly up-regulated Arrb2 production in AML-12 cells in vitro. Furthermore, TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) and FCM results demonstrated that knockdown of Arrb2 could inhibit hepatocyte apoptosis induced by EtOH in vivo and vitro while over-expression of Arrb2 induced apoptosis in ALD. In addition, western blot results revealed that Arrb2 remarkably suppressed the Akt signaling. Taken together, our data suggested that Arrb2 may serve as a potential therapeutic target for ALD by promoting hepatocyte apoptosis via Akt suppression.
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Affiliation(s)
- Ying-Yin Sun
- Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yu-Xin Zhao
- Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Xiao-Feng Li
- Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Cheng Huang
- Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Xiao-Ming Meng
- Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jun Li
- Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, China
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21
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Yuan Y, Zhang Y, Zhao S, Chen J, Yang J, Wang T, Zou H, Wang Y, Gu J, Liu X, Bian J, Liu Z. Cadmium-induced apoptosis in neuronal cells is mediated by Fas/FasL-mediated mitochondrial apoptotic signaling pathway. Sci Rep 2018; 8:8837. [PMID: 29891925 PMCID: PMC5995901 DOI: 10.1038/s41598-018-27106-9] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 05/25/2018] [Indexed: 12/27/2022] Open
Abstract
Cadmium (Cd) is a toxic metal capable of damaging brain. Studies have demonstrated that Cd can induce apoptosis in neuronal cells. The CD95/APO-1 (Fas)/Fas Ligand (FasL) signaling pathway is one of the primary apoptosis pathways, but the role and regulatory mechanism of this pathway in neuronal cells remain unclear. Here, we demonstrated the underlying mechanism of the Fas/FasL system involving the mitochondrial apoptotic pathway in neuronal cells. Primary rat cerebral cortical neurons and PC12 cells were exposed to Cd, which significantly activated expression of Fas, FasL, Fas-associated death domain (FADD) and cleaved caspase-8. However, expression of cleaved caspase-8 decreased at 20 µM Cd in primary cerebral cortical neurons. Importantly, Cd-induced apoptotic morphological changes and increase in the apoptosis rate were partially blocked by Z-IETD-FMK, which is a specific inhibitor of caspase-8. Cd-mediated increase of apoptosis rate was inhibited by anti-FasL antibody. Furthermore, our data revealed that Z-IETD-FMK also blocked increase of truncated BH3 interacting domain death agonist (tBID)/BID, decrease of the B-cell lymphoma 2 (Bcl-2)/Bcl-2 associate X protein (Bax) ratio and mitochondrial membrane potential (MMP), release of cytochrome c, as well as cleavage of caspase-9/3 and poly (ADP-ribose) polymerase (PARP) induced by Cd. Taken together, our results demonstrate that the Fas/FasL-mediated mitochondrial apoptotic pathway plays an important role in Cd-induced neuronal apoptosis.
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Affiliation(s)
- Yan Yuan
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, People's Republic of China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, People's Republic of China
| | - Yajing Zhang
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, People's Republic of China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, People's Republic of China
| | - Shiwen Zhao
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, People's Republic of China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, People's Republic of China
| | - Jie Chen
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, People's Republic of China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, People's Republic of China
| | - Jinlong Yang
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, People's Republic of China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, People's Republic of China
| | - Tao Wang
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, People's Republic of China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, People's Republic of China
| | - Hui Zou
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, People's Republic of China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, People's Republic of China
| | - Yi Wang
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, People's Republic of China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, People's Republic of China
| | - Jianhong Gu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, People's Republic of China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, People's Republic of China
| | - Xuezhong Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, People's Republic of China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, People's Republic of China
| | - Jianchun Bian
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, People's Republic of China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, People's Republic of China
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, People's Republic of China. .,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, People's Republic of China.
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22
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function, and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:1-87. [DOI: 10.1016/b978-0-7020-6697-9.00001-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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23
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Bile acids and intestinal microbiota in autoimmune cholestatic liver diseases. Autoimmun Rev 2017; 16:885-896. [PMID: 28698093 DOI: 10.1016/j.autrev.2017.07.002] [Citation(s) in RCA: 168] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 05/11/2017] [Indexed: 12/13/2022]
Abstract
Autoimmune cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are manifested as an impairment of normal bile flow and excessive accumulation of potentially toxic bile acids. Endogenous bile acids are involved in the pathogenesis and progression of cholestasis. Consequently, chronic cholestasis affects the expression of bile acid transporters and nuclear receptors, and results in liver injury. Several lines of evidence suggest that intestinal microbiota plays an important role in the etiopathogenesis of cholestatic liver diseases by regulating metabolism and immune responses. However, progression of the disease may also affect the composition of gut microbiota, which in turn exacerbates the progression of cholestasis. In addition, the interaction between intestinal microbiota and bile acids is not unidirectional. Bile acids can shape the gut microbiota community, and in turn, intestinal microbes are able to alter bile acid pool. In general, gut microbiota actively communicates with bile acids, and together play an important role in the pathogenesis of PBC and PSC. Targeting the link between bile acids and intestinal microbiota offers exciting new perspectives for the treatment of those cholestatic liver diseases. This review highlights current understanding of the interactions between bile acids and intestinal microbiota and their roles in autoimmune cholestatic liver diseases. Further, we postulate a bile acids-intestinal microbiota-cholestasis triangle in the pathogenesis of autoimmune cholestatic liver diseases and potential therapeutic strategies by targeting this triangle.
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24
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Chen XZ, Cao ZY, Zhang YQ, Li JN, Liao LM, Du J. Fuzheng Qingjie granules potentiate the anticancer effect of cyclophosphamide by regulating cellular immune function and inducing apoptosis in Hepatoma 22 tumor-bearing mice. Oncol Lett 2017; 13:3261-3268. [PMID: 28529567 DOI: 10.3892/ol.2017.5849] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 01/06/2017] [Indexed: 01/02/2023] Open
Abstract
Fuzheng Qingjie (FZQJ) is a polyherbal Chinese medicine that has previously been implemented as an adjuvant therapy for gastrointestinal cancer. The present study investigated whether FZQJ is able to potentiate the anticancer effect of cyclophosphamide (CTX). Hepatoma 22 tumor-bearing mice were randomly divided into a vehicle group, CTX group, FZQJ group and combination (CTX+FZQJ) group. In addition, untreated mice without H22 cells served as blank controls. Seven days post-treatment, the mice were sacrificed and the tumors were weighed. Blood cells were evaluated using an automatic hemocytometer analyzer and flow cytometer. The expression levels of interleukin (IL)-2 and tumor necrosis factor (TNF)-α were evaluated using a radioimmunoassay. Apoptotic cells were observed using a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Alanine transaminase, aspartate aminotransferase, blood urea nitrogen and creatinine were examined using an automatic biochemical analyzer. The results demonstrated that the tumor inhibitory rate and apoptosis index were higher in the combination group, compared with those in the CTX group. Notably, FZQJ was able to alleviate CTX-induced decreases in the numbers of white blood cells and platelets, CD3+ and CD4+ T lymphocyte subsets, and the concentration of hemoglobin, body weight and thymus index, and increase serum TNF-α and IL-2 levels without overt hepatorenal toxicity. These results suggest that FZQJ granules may enhance the anticancer effect of CTX, in addition to alleviating the side effects.
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Affiliation(s)
- Xu-Zheng Chen
- Center of Oncology, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Zhi-Yun Cao
- Center of Oncology, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - You-Quan Zhang
- Department of Clinical Laboratory, The Second Affiliated Hospital, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350003, P.R. China
| | - Jin-Nong Li
- Department of Pharmacognosy, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Lian-Ming Liao
- Center of Oncology, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Jian Du
- Center of Oncology, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
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25
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Chao X, Wang S, Ding WX. Cell Death in Alcohol-Induced Liver Injury. CELLULAR INJURY IN LIVER DISEASES 2017:119-142. [DOI: 10.1007/978-3-319-53774-0_6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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26
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Cao L, Quan XB, Zeng WJ, Yang XO, Wang MJ. Mechanism of Hepatocyte Apoptosis. J Cell Death 2016; 9:19-29. [PMID: 28058033 PMCID: PMC5201115 DOI: 10.4137/jcd.s39824] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 08/14/2016] [Accepted: 08/18/2016] [Indexed: 12/12/2022] Open
Abstract
Hepatocyte apoptosis plays important roles in both the removal of external microorganisms and the occurrence and development of liver diseases. Different conditions, such as virus infection, fatty liver disease, hepatic ischemia reperfusion, and drug-induced liver injury, are accompanied by hepatocyte apoptosis. This review summarizes recent research on the mechanism of hepatocyte apoptosis involving the classical extrinsic and intrinsic apoptotic pathways, endoplasmic reticulum stress, and oxidative stress-induced apoptosis. We emphasized the major causes of apoptosis according to the characteristics of different liver diseases. Several concerns regarding future research and clinical application are also raised.
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Affiliation(s)
- Lei Cao
- Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xi-Bing Quan
- Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Wen-Jiao Zeng
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xiao-Ou Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Beijing, China
| | - Ming-Jie Wang
- Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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27
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Erol M, Bostan Gayret O, Tekin Nacaroglu H, Yigit O, Zengi O, Salih Akkurt M, Tasdemir M. Association of Osteoprotegerin with Obesity, Insulin Resistance and Non-Alcoholic Fatty Liver Disease in Children. IRANIAN RED CRESCENT MEDICAL JOURNAL 2016; 18:e41873. [PMID: 28203453 PMCID: PMC5294423 DOI: 10.5812/ircmj.41873] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 09/28/2016] [Accepted: 10/24/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Osteoprotegerin (OPG) is a member of the tumor necrosis factor superfamily. Reduced OPG levels are related to obesity, insulin resistance, and non-alcoholic fatty liver disease (NAFLD). OBJECTIVES The aim of this study was to evaluate the relationship between OPG levels, obesity, insulin resistance, and NAFLD in pediatric patients. METHODS This was a prospective, cross-sectional, controlled study that was conducted in the department of pediatrics at Bagcilar training and research hospital in Istanbul, Turkey, between April and August 2015. The study was performed on 107 children with obesity and 37 controls aged 5 - 17 years. In the obese subset, 62 patients had NAFLD. Homeostatic model assessment-insulin resistance (HOMA-IR) was used to calculate insulin resistance. Insulin resistance was defined as a HOMA-IR value greater than 2.5. Plasma OPG levels were measured using enzyme-linked immunosorbent assays. NAFLD was diagnosed by hepatic ultrasound. RESULTS The mean age was 11.25 ± 3.38 years in the patient group and 10.41 ± 3.15 years in the control group. The OPG level in the obese group with the mean of 55.20 ± 24.55 pg/mL (median = 48.81 pg/mL) was significantly lower than that in the control group with the mean of 70.78 ± 33.41 pg/mL (median = 64.57 pg/mL) (P = 0.0001). The optimal cut-off point (sensitivity, specificity) of the OPG level for the diagnosis of obesity was ≤ 46, 19 pg/mL. According to logistic regression analysis, fasting insulin (P = 0.036) and OPG (P = 0.01) levels were most affected by obesity. In the obese patients, who had HOMA-IR < 2.5, the mean level of OPG was 58.91 ± 6.88729 pg/mL (median = 49.55). In the obese patients, who had HOMA-IR ≥ 2.5, the mean level of OPG was 54.19 ± 22.21 pg/mL (median = 48.47). No significant correlations were found between OPG and HOMA-IR (P = 0.791). No statistically significant difference was observed in the mean OPG between patients with hepatosteatosis (mean = 54.55 ± 25.01 pg/mL) (median = 49.46) and those without the disease (56.30 ± 24.02 pg/mL) (mean = 48.34) (P = 0.089). CONCLUSIONS We confirmed that serum OPG concentrations reduce in obese children. However, no correlation was identified between OPG and insulin resistance. OPG levels are not meaningful in the diagnosis of NAFLD in children with obesity.
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Affiliation(s)
- Meltem Erol
- Bagcilar Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey
- Corresponding Author: Meltem Erol, Bagcilar Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey. Tel: +90-2124404000-1344, Fax: +90-2124404242, E-mail:
| | - Ozlem Bostan Gayret
- Bagcilar Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey
| | - Hikmet Tekin Nacaroglu
- Bagcilar Training and Research Hospital, Department of Pediatric Allergy, Istanbul, Turkey
| | - Ozgul Yigit
- Bagcilar Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey
| | - Oguzhan Zengi
- Bagcilar Training and Research Hospital, Department of Biochemistry, Istanbul, Turkey
| | - Mehmet Salih Akkurt
- Bagcilar Training and Research Hospital, Department of Radiology, Istanbul, Turkey
| | - Mehmet Tasdemir
- Department of Pediatric Nephology, Koc University Hospital, Istanbul, Turkey
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28
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Huang YQ, Li PY, Wang JB, Zhou HQ, Yang ZR, Yang RC, Bai ZF, Wang LF, Li JY, Liu HH, Zhao YL, Xiao XH. Inhibition of Sophocarpine on Poly I: C/D-GalN-Induced Immunological Liver Injury in Mice. Front Pharmacol 2016; 7:256. [PMID: 27570511 PMCID: PMC4981750 DOI: 10.3389/fphar.2016.00256] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 08/02/2016] [Indexed: 11/13/2022] Open
Abstract
Increasing evidence has suggested that natural killer (NK) cells contribute to the pathogenesis of human immunological liver injury (ILI). Previous studies have demonstrated that Sophocarpine exerts activity in immune modulation. It also has a therapeutic effect on liver protection in that it can alleviate liver fibrosis by suppressing both the activation of hepatic stellate cells and the proliferation of the activated hepatic stellate cells. However, whether Sophocarpine protects the liver by regulating NK cell activity remains unclear. In this study, the modulating effect of Sophocarpine on NK cells in the liver was investigated. The results showed that Sophocarpine dramatically decreased the production of pro-inflammatory cytokines and attenuated the liver injury induced by Poly I: C/D-GalN in C57BL/6- mice. More importantly, Sophocarpine pre-treatment significantly suppressed NK cell activation and downregulated the expression of NKG2D, a receptor responsible for NK cell activation. Moreover, the protein levels of DAP12, ZAP76 and Syk decreased, as did their corresponding mRNA levels. Overall, our study demonstrates that Sophocarpine inhibits NK cell activity, thus making it a promising therapy for ILI.
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Affiliation(s)
- Yin-Qiu Huang
- Pharmacy College, Chengdu University of Traditional Chinese MedicineChengdu, China
- Department of Pharmacy, 302 Military Hospital of ChinaBeijing, China
| | - Peng-Yan Li
- China Military Institute of Chinese Medicine, 302 Military Hospital of ChinaBeijing, China
| | - Jia-Bo Wang
- China Military Institute of Chinese Medicine, 302 Military Hospital of ChinaBeijing, China
| | - Hou-Qin Zhou
- Pharmacy College, Chengdu University of Traditional Chinese MedicineChengdu, China
- Department of Pharmacy, 302 Military Hospital of ChinaBeijing, China
| | - Zhi-Rui Yang
- Pharmacy College, Chengdu University of Traditional Chinese MedicineChengdu, China
- Department of Pharmacy, 302 Military Hospital of ChinaBeijing, China
| | - Rui-Chuang Yang
- Research Center for Clinical and Translational Medicine, 302 Hospital of People’s Liberation ArmyBeijing, China
| | - Zhao-Fang Bai
- China Military Institute of Chinese Medicine, 302 Military Hospital of ChinaBeijing, China
| | - Li-Fu Wang
- Department of Integrative Medical Center, 302 Hospital of People’s Liberation ArmyBeijing, China
| | - Jian-Yu Li
- Department of Integrative Medical Center, 302 Hospital of People’s Liberation ArmyBeijing, China
| | - Hong-Hong Liu
- Department of Integrative Medical Center, 302 Hospital of People’s Liberation ArmyBeijing, China
| | - Yan-Ling Zhao
- Department of Pharmacy, 302 Military Hospital of ChinaBeijing, China
| | - Xiao-He Xiao
- China Military Institute of Chinese Medicine, 302 Military Hospital of ChinaBeijing, China
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29
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Aly HAA, Mansour AM, Hassan MH, Abd-Ellah MF. Lipoic acid attenuates Aroclor 1260-induced hepatotoxicity in adult rats. ENVIRONMENTAL TOXICOLOGY 2016; 31:913-922. [PMID: 25533183 DOI: 10.1002/tox.22101] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 12/05/2014] [Accepted: 12/07/2014] [Indexed: 06/04/2023]
Abstract
The present study was aimed to investigate the mechanistic aspect of Aroclor 1260-induced hepatotoxicity and its protection by lipoic acid. The adult male Albino rats were divided into six groups. Group I served as control. Group II received lipoic acid (35 mg/kg/day). Aroclor 1260 was given to rats by oral gavage at doses 20, 40, or 60 mg/kg/day (Groups III, IV, and V, respectively). Group VI was pretreated with lipoic acid (35 mg/kg/day) 24 h before Aroclor 1260 (40 mg/kg/day). Treatment in all groups was continued for further 15 consecutive days. Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities and total bilirubin, total cholesterol, and triglycerides were significantly increased while total protein, total albumin, and high-density lipoprotein were significantly decreased. Hydrogen peroxide production and lipid peroxidation were significantly increased while superoxide dismutase and catalase activities and reduced glutathione (GSH) content was significantly decreased in liver. Caspase-3 & -9 activities were significantly increased in liver. Lipoic acid pretreatment significantly reverted all these abnormalities toward their normal levels. In conclusion, Aroclor 1260 induced liver dysfunction, at least in part, by induction of oxidative stress. Apoptotic effect of hepatic cells is involved in Aroclor 1260-induced liver injury. Lipoic acid could protect rats against Aroclor 1260-induced hepatotoxicity. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 913-922, 2016.
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Affiliation(s)
- Hamdy A A Aly
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
| | - Ahmed M Mansour
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
| | - Memy H Hassan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, El-Madinah El-Munaworah, Saudi Arabia
| | - Mohamed F Abd-Ellah
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
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Wang S, Pacher P, De Lisle RC, Huang H, Ding WX. A Mechanistic Review of Cell Death in Alcohol-Induced Liver Injury. Alcohol Clin Exp Res 2016; 40:1215-1223. [PMID: 27130888 PMCID: PMC5455778 DOI: 10.1111/acer.13078] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Accepted: 03/29/2016] [Indexed: 12/18/2022]
Abstract
Alcoholic liver disease (ALD) is a major health problem in the United States and worldwide without successful treatments. Chronic alcohol consumption can lead to ALD, which is characterized by steatosis, inflammation, fibrosis, cirrhosis, and even liver cancer. Recent studies suggest that alcohol induces both cell death and adaptive cell survival pathways in the liver, and the balance of cell death and cell survival ultimately decides the pathogenesis of ALD. This review summarizes the recent progress on the role and mechanisms of apoptosis, necroptosis, and autophagy in the pathogenesis of ALD. Understanding the complex regulation of apoptosis, necrosis, and autophagy may help to develop novel therapeutic strategies by targeting all 3 pathways simultaneously.
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Affiliation(s)
- Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Robert C. De Lisle
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160
| | - Heqing Huang
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160
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31
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Ding WX, Jaeschke H. Autophagy in macrophages regulates the inflammasome and protects against liver injury. J Hepatol 2016; 64:16-8. [PMID: 26456339 PMCID: PMC4888871 DOI: 10.1016/j.jhep.2015.10.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 10/01/2015] [Accepted: 10/05/2015] [Indexed: 01/08/2023]
Affiliation(s)
- Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
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32
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Zhang F, Chen L, Jin H, Shao J, Wu L, Lu Y, Zheng S. Activation of Fas death receptor pathway and Bid in hepatocytes is involved in saikosaponin D induction of hepatotoxicity. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2016; 41:8-13. [PMID: 26645133 DOI: 10.1016/j.etap.2015.11.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 11/01/2015] [Accepted: 11/02/2015] [Indexed: 06/05/2023]
Abstract
Drug-induced liver injury can lead to acute liver failure. Saikosaponin D (SSD) is a major component isolated from the medicinal herb Bupleurum falcatum, which has been linked to hepatotoxicity. We previously reported that SSD disrupted PDGF-βR pathway leading to mitochondrial apoptosis in human LO2 hepatocytes. The present study was aimed at further exploring the underlying mechanisms in vitro and in vivo. We initially determined the concentration range of SSD at up to 2μM for subsequent apoptosis examinations. SSD significantly upregulated Fas expression, promoted caspase-8 cleavage and activated the pro-apoptotic protein Bid in LO2 cells. Moreover, SSD reduced the abundance of cytochrome c in mitochondria and increased the cleaved-caspase-3 in LO2 cells, but did not apparently affect PI3K/AKT, ERK and STAT3 pathways that are involved in cell fate regulation. Experiments in vivo showed that one-week treatment with SSD at 300 mg/kg significantly elevated the liver/body weight ratio and caused histological injury in mouse liver. Furthermore, SSD treatment induced massive hepatocyte apoptosis, and significantly downregulated Bcl-2 but upregulated Bax in mouse liver. Taken together, these results revealed a specific mechanism of activation of extrinsic apoptosis pathway and Bid by SSD, which was involved in SSD-induced mitochondrial apoptosis in hepatocytes and potential hepatotoxicity.
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Affiliation(s)
- Feng Zhang
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Li Chen
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Huanhuan Jin
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jiangjuan Shao
- Department of Pharmacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Li Wu
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yin Lu
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Shizhong Zheng
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
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33
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Abouzied MM, Eltahir HM, Taye A, Abdelrahman MS. Experimental evidence for the therapeutic potential of tempol in the treatment of acute liver injury. Mol Cell Biochem 2015; 411:107-15. [DOI: 10.1007/s11010-015-2572-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 09/26/2015] [Indexed: 01/04/2023]
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34
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Nelms MD, Mellor CL, Cronin MTD, Madden JC, Enoch SJ. Development of an in Silico Profiler for Mitochondrial Toxicity. Chem Res Toxicol 2015; 28:1891-902. [PMID: 26375963 DOI: 10.1021/acs.chemrestox.5b00275] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
This study outlines the analysis of mitochondrial toxicity for a variety of pharmaceutical drugs extracted from Zhang et al. ((2009) Toxicol. In Vitro, 23, 134-140). These chemicals were grouped into categories based upon structural similarity. Subsequently, mechanistic analysis was undertaken for each category to identify the molecular initiating event driving mitochondrial toxicity. The mechanistic information elucidated during the analysis enabled mechanism-based structural alerts to be developed and combined together to form an in silico profiler. This profiler is envisaged to be used to develop chemical categories based upon similar mechanisms as part of the adverse outcome pathway paradigm. Additionally, the profiler could be utilized in screening large data sets in order to identify chemicals with the potential to induce mitochondrial toxicity.
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Affiliation(s)
- Mark D Nelms
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Byrom Street, Liverpool L3 3AF, United Kingdom
| | - Claire L Mellor
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Byrom Street, Liverpool L3 3AF, United Kingdom
| | - Mark T D Cronin
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Byrom Street, Liverpool L3 3AF, United Kingdom
| | - Judith C Madden
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Byrom Street, Liverpool L3 3AF, United Kingdom
| | - Steven J Enoch
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Byrom Street, Liverpool L3 3AF, United Kingdom
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35
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Wen J, Song C, Liu J, Chen J, Zhai X, Hu Z. Expression quantitative trait loci for TNFRSF10 influence both HBV infection and hepatocellular carcinoma development. J Med Virol 2015; 88:474-80. [PMID: 26297860 DOI: 10.1002/jmv.24363] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/20/2015] [Indexed: 12/26/2022]
Abstract
Tumor necrosis factor receptor superfamily member 10 (TNFRSF10) is a death domain-containing receptor for the apoptotic ligand TNFSF10, which involves multiple processes, including hepatocarcinogenesis and immune response against HBV infection. Several single nucleotide polymorphisms (SNPs) were identified as expression quantitative trait loci (eQTLs) for TNFRSF10. To assess the association of TNFRSF10 eQTL SNPs with the risk of hepatocellular carcinoma (HCC) and chronic HBV infection, we designed a case-control study that included 1,300 HBV-related HCC patients, 1,344 chronic HBV carriers, and 1,344 subjects with HBV natural clearance, and then genotyped two TNFRSF10 eQTL SNPs (rs79037040 and rs2055822). We found that rs79037040 GT/TT genotypes were associated with a decreased HCC risk (adjusted odds ratio [OR] = 0.83, 95% confidence intervals [CIs] = 0.71-0.97, P = 0.021) but an increased chronic HBV infection risk of borderline significance (adjusted OR = 1.14, 95%CIs = 0.98-1.33, P = 0.085). In contrast, the rs2055822 G allele was a risk factor for HCC (adjusted OR = 1.12, 95%CIs = 1.00-1.25, P = 0.041) but a protective factor for chronic HBV infection (adjusted OR = 0.89, 95%CIs = 0.80-0.99, P = 0.038). Furthermore, we observed a dose-dependent relationship between the number of alleles (rs79037040-T and rs2055822-A) and the risk of HCC and chronic HBV infection. In comparison with "0" alleles, having "1-4" alleles was significantly associated with decreased HCC risk and increased HBV infection risk. These findings suggest that eQTL SNPs for TNFRSF10 may be susceptibility markers for HCC and chronic HBV infection.
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Affiliation(s)
- Juan Wen
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ci Song
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jibin Liu
- Department of Hepatobiliary Surgery, Nantong Tumor Hospital, Nantong, China
| | | | - Xiangjun Zhai
- Department of Infection Diseases, Jiangsu Province Center for Disease Prevention and Control, Nanjing, China
| | - Zhibin Hu
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
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Yang G, Zhou Z, Cen Y, Gui X, Zeng Q, Ao Y, Li Q, Wang S, Li J, Zhang A. Death receptor and mitochondria-mediated hepatocyte apoptosis underlies liver dysfunction in rats exposed to organic pollutants from drinking water. Drug Des Devel Ther 2015; 9:4719-33. [PMID: 26316710 PMCID: PMC4547633 DOI: 10.2147/dddt.s86843] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Persistent organic pollutants in drinking water impose a substantial risk to the health of human beings, but the evidence for liver toxic effect and the underlying mechanism is scarce. This study aimed to examine the liver toxicity and elucidate the molecular mechanism of organic pollutants in drinking water in normal human liver cell line L02 cells and rats. The data showed that organic extraction from drinking water remarkably impaired rat liver function, evident from the increase in the serum level of alanine aminotransferase, aspartate aminotransferase, and cholinesterase, and decrease in the serum level of total protein and albumin. Organic extraction dose-dependently induced apoptotic cell death in rat liver and L02 cells. Administration of rats with organic extraction promoted death receptor signaling pathway through the increase in gene and protein expression level of Fas and FasL. Treatment of rats with organic extraction also induced mitochondria-mediated apoptosis via increasing the expression level of proapoptotic protein, Bax, but decreasing the expression level of antiapoptotic protein, Bcl-2, resulting in an upregulation of cytochrome c and activation of caspase cascade at both transcriptional and post-transcriptional levels. Moreover, organic extraction enhanced rat liver glutathione S-transferases activity and reactive oxygen species generation, and upregulated aryl hydrocarbon receptor and glutathione S-transferase A1 at both transcriptional and translational levels. Collectively, the results indicate that organic extraction from drinking water impairs liver function, with the involvement of death receptor and mitochondria-mediated apoptosis in rats. The results provide evidence and molecular mechanisms for organic pollutants in drinking water-induced liver dysfunction, which may help prevent and treat organic extraction-induced liver injury.
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Affiliation(s)
- Guanghong Yang
- Key Laboratory of Environment Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Zhiwei Zhou
- Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Yanli Cen
- Key Laboratory of Environment Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Xiaolin Gui
- Key Laboratory of Environment Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Qibing Zeng
- Key Laboratory of Environment Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Yunxia Ao
- Key Laboratory of Environment Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Qian Li
- Key Laboratory of Environment Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Shiran Wang
- Key Laboratory of Environment Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Jun Li
- Key Laboratory of Environment Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Aihua Zhang
- Key Laboratory of Environment Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China
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Ma X, Han S, Zhang W, Fan YJ, Liu MN, Liu AY, Liu BR. Protection of cultured human hepatocytes from hydrogen peroxide‑induced apoptosis by relaxin‑3. Mol Med Rep 2014; 11:1228-34. [PMID: 25370004 DOI: 10.3892/mmr.2014.2842] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 10/01/2014] [Indexed: 11/06/2022] Open
Abstract
Previous studies have suggested that hepatocyte apoptosis may be a fundamental underlying mechanism of liver injury and diseases, such as liver fibrosis. Relaxin‑3 has been reported to have anti‑fibrotic actions in the heart and to attenuate isoproterenol‑induced myocardial injury; however, the beneficial role of relaxin‑3 on hepatocyte apoptosis remains to be elucidated. The aim of the present study was to explore the role and possible mechanisms of relaxin‑3 through hydrogen peroxide (H2O2)‑induced apoptosis in primary human hepatocytes. Cells were treated with relaxin‑3 and then cell viability, morphological features, the presence of cleaved caspases as well as the levels of endoplasmic reticulum stress (ERS) protein markers and autophagy markers were evaluated. The H2O2 group showed significantly decreased cell viability, increased apoptosis as well as upregulation of caspases (cleaved caspase‑3, ‑8 and ‑9) and ERS protein markers compared with those of the control group. However, cells treated with relaxin‑3 (10 ng/ml) demonstrated improved cell viability, reduced apoptosis and decreased expression of cleaved caspases and ERS markers. However, the expression of autophagy markers remained unchanged following H2O2‑induced apoptosis and relaxin‑3 treatment. In conclusion, relaxin‑3 was shown to protect hepatocytes from H2O2‑induced apoptosis via downregulation of cleaved caspase‑8 and ‑9, as well as inhibition of the ERS pathway.
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Affiliation(s)
- Xiao Ma
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Su Han
- Department of Microbiology and Parasitology, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Wei Zhang
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Yu-Jing Fan
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Ming-Na Liu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Ai-Yun Liu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Bing-Rong Liu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
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Tao X, Wan X, Xu Y, Xu L, Qi Y, Yin L, Han X, Lin Y, Peng J. Dioscin attenuates hepatic ischemia-reperfusion injury in rats through inhibition of oxidative-nitrative stress, inflammation and apoptosis. Transplantation 2014; 98:604-611. [PMID: 25083618 DOI: 10.1097/tp.0000000000000262] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Dioscin shows potent effects against liver damage in our previous studies; however, the action of it on hepatic ischemia-reperfusion (I/R) injury is still unknown. In the present article, the effects and possible mechanisms of dioscin against hepatic I/R injury were investigated. METHODS Seventy percent partial hepatic warm ischemia was induced in Wistar rats for 60 min followed by succedent reperfusion. In the prophylactic test, dioscin was administered intragastrically to the rats at doses of 20, 40, and 60 mg/kg once daily for seven consecutive days before I/R. In the therapeutic test, the rats received dioscin intragastrically at a dose of 60 mg/kg once 2 hr before I/R. RESULTS We found that dioscin significantly decreased serum alanine aminotransferase and aspartate aminotransferase activities, increased survival rate of rats, and improved I/R-induced hepatocyte abnormality. In addition, dioscin obviously increased the levels of SOD, CAT, GSH-Px, GSH, decreased the levels of MDA, TNOS, iNOS, NO, and prevented DNA fragmentation caused by I/R injury. Further research indicated that dioscin markedly decreased the gene expressions of interleukin-1β, interleukin-6, tumor necrosis factor-α, intercellular adhesion molecule-1, MIP-1α, MIP-2, Fas, FasL, decreased the protein expressions of NF-κB, AP-1, COX-2, HMGB-1, CYP2E1, Bak, caspase-3, p53, PARP, Caspase-9, decreased the levels of JNK, ERK and p38 MAPKs phosphorylation, and upregulated the levels of Bcl-2 and Bcl-x. CONCLUSION Our results suggest that dioscin has potent actions against hepatic I/R injury through suppression of inflammation, oxidative-nitrative stress, and apoptosis, which should be developed as a new drug to treat hepatic I/R injury in the future.
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Affiliation(s)
- Xufeng Tao
- 1 College of Pharmacy, Dalian Medical University, Liaoning Province, China. 2 Department of Critical Care Medicine of the First Affiliated Hospital of Dalian Medical University, Dalian, China. 3 Research Institute of Integrated Traditional and Western Medicine of Dalian Medical University, Dalian, China. 4 Address correspondence to: Jinyong Peng, M.D., College of Pharmacy, Dalian Medical University, Dalian, China
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Vitamin D ameliorates hepatic ischemic/reperfusion injury in rats. J Physiol Biochem 2014; 70:659-66. [PMID: 24752458 DOI: 10.1007/s13105-014-0335-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Accepted: 04/02/2014] [Indexed: 02/08/2023]
Abstract
Vitamin D, most commonly associated with the growth and remodeling of bone, has been shown to ameliorate ischemia/reperfusion injury (IRI) in some tissues, yet its underlying mechanism remains elusive. This study was designed to examine the protective effect of vitamin D, if any, against hepatic IRI in rats and the underlying mechanism involved. Adult female Wistar rats were randomly divided into control, sham-operated (sham), ischemia/reperfusion (I/R), and ischemic-reperfused vitamin D-treated (vit D) groups. Rats in the I/R and vit D groups were subjected to partial (70%) hepatic ischemia for 45 min, followed by 1 h of reperfusion. Vitamin D was given to rats orally in a dose of 500 IU/kg daily for 2 weeks before being subjected to I/R. Markers of liver damage, oxidative stress, inflammation and apoptosis were evaluated. Hepatic morphology was also examined. Vit D-treated rats had significantly lower serum levels of alanine aminotransferase, aspartate aminotransferase, and γ glutamyl transferase compared to rats in the I/R group. Also, vit D-treated rats showed a significant decrease in malondialdehyde, interleukin-1 beta, interleukin-6, tumor necrosis factor-α, nuclear factor κB, B cell leukemia/lymphoma 2-associated X protein, cytochrome c, and caspase-3 levels, with higher levels of glutathione peroxidase and B cell lymphoma 2 protein levels in liver tissues compared to I/R rats. Histological examination showed less damaged liver tissues with amelioration of apoptotic signs in the vit D group compared to the I/R group. In conclusion, vitamin D supplementation ameliorates hepatic IRI mostly by alleviating the inflammatory-apoptotic response mediated by the oxidative reperfusion injury insult.
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Yu H, Zheng L, Yin L, Xu L, Qi Y, Han X, Xu Y, Liu K, Peng J. Protective effects of the total saponins from Dioscorea nipponica Makino against carbon tetrachloride-induced liver injury in mice through suppression of apoptosis and inflammation. Int Immunopharmacol 2014; 19:233-244. [PMID: 24491258 DOI: 10.1016/j.intimp.2014.01.019] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Revised: 01/13/2014] [Accepted: 01/17/2014] [Indexed: 01/29/2023]
Abstract
The present study was to investigate the effects and possible mechanisms of the total saponins from Dioscorea nipponica Makino (TSDN) against CCl₄-induced hepato-toxicity in mice. The mice were orally administrated with TSDN for seven days and then given CCl₄ (0.3%, 10 ml/kg i.p.). The results showed that TSDN significantly attenuated the activities of ALT and AST, consistent with hematoxylin-eosin staining. The ALP levels and relative liver weight were significantly decreased by TSDN compared with model group. Moreover, TSDN dramatically decreased MDA, iNOS and NO levels, while the levels of GSH, GSH-Px and SOD were increased. Further investigations showed that TSDN inhibited CCl₄-induced metabolic activation and CYP2E1 expression, down-regulated the levels of MAPKs phosphorylation, NF-κB, HMGB1, COX-2 as well as effectively suppressed the expressions of Caspase-3, Caspase-9, PARP and Bak. Quantitative real-time PCR assay demonstrated that TSDN obviously decreased the gene expressions of TNF-a, IL-1β, IL-6, IL-10, Fas, FasL, Bax as well as modulated Bcl-2 mRNA level. This is the first time to report the protective actions of the TSDN against CCl₄-induced liver damage in mice through suppression of inflammation and apoptosis. This natural product should be developed as a new drug for treatment of liver injury in future.
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Affiliation(s)
- Hao Yu
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Lvshunkou District, Dalian, Liaoning Province 116044, China
| | - Lingli Zheng
- The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Lianhong Yin
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Lvshunkou District, Dalian, Liaoning Province 116044, China; Research Institute of Integrated Traditional and Western Medicine of Dalian Medical University, Dalian 116011, China
| | - Lina Xu
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Lvshunkou District, Dalian, Liaoning Province 116044, China
| | - Yan Qi
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Lvshunkou District, Dalian, Liaoning Province 116044, China; The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Xu Han
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Lvshunkou District, Dalian, Liaoning Province 116044, China
| | - Youwei Xu
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Lvshunkou District, Dalian, Liaoning Province 116044, China
| | - Kexin Liu
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Lvshunkou District, Dalian, Liaoning Province 116044, China
| | - Jinyong Peng
- College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Lvshunkou District, Dalian, Liaoning Province 116044, China; Research Institute of Integrated Traditional and Western Medicine of Dalian Medical University, Dalian 116011, China.
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DING WENXING. Induction of autophagy, a promising approach for treating liver injury. Hepatology 2014; 59:340-3. [PMID: 23775596 PMCID: PMC4096158 DOI: 10.1002/hep.26572] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Revised: 05/25/2013] [Accepted: 05/30/2013] [Indexed: 12/20/2022]
Abstract
Recent investigations have demonstrated a complex interrelationship between autophagy and cell death. A common mechanism of cell death in liver injury is tumor necrosis factor (TNF) cytotoxicity. To better delineate the in vivo function of autophagy in cell death, we examined the role of autophagy in TNF-induced hepatic injury. Atg7Δhep mice with a hepatocyte-specific knockout of the autophagy gene atg7 were generated and cotreated with D-galactosamine (GalN) and lipopolysaccharide (LPS). GalN/LPS-treated Atg7Δhep mice had increased serum alanine aminotransferase levels, histological injury, numbers of TUNEL (terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling)-positive cells and mortality as compared with littermate controls. Loss of hepatocyte autophagy similarly sensitized to GalN/TNF liver injury. GalN/LPS injury in knockout animals did not result from altered production of TNF or other cytokines. Atg7Δhep mice had accelerated activation of the mitochondrial death pathway and caspase-3 and -7 cleavage. Increased cell death did not occur from direct mitochondrial toxicity or a lack of mitophagy, but rather from increased activation of initiator caspase-8 causing Bid cleavage. GalN blocked LPS induction of hepatic autophagy, and increased autophagy from beclin 1 overexpression prevented GalN/LPS injury. Autophagy, therefore, mediates cellular resistance to TNF toxicity in vivo by blocking activation of caspase-8 and the mitochondrial death pathway, suggesting that autophagy is a therapeutic target in TNF-dependent tissue injury.
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Affiliation(s)
- WEN-XING DING
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas
Medical Center, Kansas City, KS 66160
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Dong D, Zhang S, Yin L, Tang X, Xu Y, Han X, Qi Y, Peng J. Protective effects of the total saponins from Rosa laevigata Michx fruit against carbon tetrachloride-induced acute liver injury in mice. Food Chem Toxicol 2013; 62:120-130. [PMID: 23994094 DOI: 10.1016/j.fct.2013.08.050] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Revised: 08/18/2013] [Accepted: 08/20/2013] [Indexed: 02/07/2023]
Abstract
Saponins are the major chemicals from Rosa laevigata Michx fruit. However, there have no papers to report the activities of the natural product against liver damage. In the present work, total saponins from R. laevigata Michx fruit (RLTS) with purity>70% was produced and then the protective effects of it against CCl4-induced acute liver injury in mice was tested. The results showed that RLTS decreased serum ALT and AST activities compared with model group, as well as the relative liver weight and histological findings. In addition, RLTS remarkably increased the levels of SOD, CAT, GSH-Px, GSH and decreased MDA, iNOS and NO levels in liver. Transmission electron microscopy and TUNEL assays showed that RLTS repaired fragmented DNA and mitochondrial change caused by CCl4. Further investigation demonstrated that RLTS pretreatment down-regulated the protein expression of CYP2E1, ATF6, GRP78, EIF2, COX-2, NF-κB, p53, Caspase-3, Caspase-9, Cytokeratin 18 and the levels of MAPKs phosphorylation, up-regulated Bcl-2 expression, and markedly decreased the gene expression of TNF-α, IL-6, Fas/FasL and Bax. This is the first time to reveal the hepatoprotective effect of total saponins from R. laevigata Michx fruit, which should be developed as a new drug for treatment of live injury in future.
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Affiliation(s)
- Deshi Dong
- College of Pharmacy, Dalian Medical University, 9 Western Lvshun South Road, Dalian 116044, China; Research Institute of Integrated Traditional and Western Medicine of Dalian Medical University, Dalian 116011, China; The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
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Sun Y, Yang J, Wang LZ, Sun LR, Dong Q. Crocin attenuates cisplatin-induced liver injury in the mice. Hum Exp Toxicol 2013; 33:855-62. [PMID: 24275644 DOI: 10.1177/0960327113511475] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cisplatin (CDDP) is one of the most frequently used antitumor agents, but its application is significantly limited by its hepatotoxicity. In the present study, we investigated the effects of crocin against CDDP-induced oxidative stress and apoptosis in the liver of Kunming mice. Crocin was administered to the mice once daily for 7 consecutive days at the doses of 6.25 and 12.5 mg/kg body weight orally. On day 1, a single intraperitoneal injection of CDDP was given at the dose of 10 mg/kg body weight. Crocin treatment significantly improved CDDP-induced hepatic damage as indicated by serum aspartate aminotransferase and alanine aminotransferase levels. Crocin relieved CDDP-induced oxidative stress by reducing malondialdehyde level and recovering the levels of glutathione and antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. In addition, liver histopathology indicated that crocin alleviated CDDP-induced focal necrosis. Immunohistochemical staining and Western blot analysis showed that crocin significantly decreased the levels of phospho-p38 mitogen-activated protein kinase (MAPK), tumor protein 53 (p53), and cleaved caspase-3. Taken together, our data suggest that crocin provides protective effects against CDDP-induced hepatoxicity by attenuating oxidative stress and inhibiting the activation of p38 MAPK, p53, and caspase-3.
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Affiliation(s)
- Y Sun
- Department of Pediatric Hematology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, People’s Republic of China
| | - J Yang
- Department of Pediatric Hematology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, People’s Republic of China
| | - L-Z Wang
- Department of Pediatric Hematology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, People’s Republic of China
| | - L-R Sun
- Department of Pediatric Hematology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, People’s Republic of China
| | - Q Dong
- Department of Pediatric Surgery, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, People’s Republic of China
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Abstract
Because of its unique function and anatomical location, the liver is exposed to a multitude of toxins and xenobiotics, including medications and alcohol, as well as to infection by hepatotropic viruses, and therefore, is highly susceptible to tissue injury. Cell death in the liver occurs mainly by apoptosis or necrosis, with apoptosis also being the physiologic route to eliminate damaged or infected cells and to maintain tissue homeostasis. Liver cells, especially hepatocytes and cholangiocytes, are particularly susceptible to death receptor-mediated apoptosis, given the ubiquitous expression of the death receptors in the organ. In a quite unique way, death receptor-induced apoptosis in these cells is mediated by both mitochondrial and lysosomal permeabilization. Signaling between the endoplasmic reticulum and the mitochondria promotes hepatocyte apoptosis in response to excessive free fatty acid generation during the metabolic syndrome. These cell death pathways are partially regulated by microRNAs. Necrosis in the liver is generally associated with acute injury (i.e., ischemia/reperfusion injury) and has been long considered an unregulated process. Recently, a new form of "programmed" necrosis (named necroptosis) has been described: the role of necroptosis in the liver has yet to be explored. However, the minimal expression of a key player in this process in the liver suggests this form of cell death may be uncommon in liver diseases. Because apoptosis is a key feature of so many diseases of the liver, therapeutic modulation of liver cell death holds promise. An updated overview of these concepts is given in this article.
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Affiliation(s)
- Maria Eugenia Guicciardi
- 1Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
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Paul A, Das J, Das S, Samadder A, Khuda-Bukhsh AR. Poly (lactide-co-glycolide) nano-encapsulation of chelidonine, an active bioingredient of greater celandine (Chelidonium majus), enhances its ameliorative potential against cadmium induced oxidative stress and hepatic injury in mice. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2013; 36:937-947. [PMID: 24035924 DOI: 10.1016/j.etap.2013.08.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 07/12/2013] [Accepted: 08/16/2013] [Indexed: 06/02/2023]
Abstract
This study evaluates the possible protective potentials of chelidonine and its poly lactide-co-glycolide (PLGA) encapsulated nano-form against cadmium chloride (CdCl₂) induced oxidative stress and hepatotoxicity in mice, ex vivo and in vivo. Acute exposure to CdCl₂ (1.0 mg/kg b.w; i.p., twice a week for 30 days) generated oxidative stress in mice through accumulation of reactive oxygen species and increased lipid peroxidation, and levels of certain liver marker enzymes (ALT, AST, ALP) with decrease in levels of GSH and certain other antioxidant enzymes (SOD, CAT, GR) in liver. Treatment with nano-chelidonine for 30 days after CdCl₂ intoxication significantly reduced oxidative stress and lipid peroxidation and restored levels of GSH, cholesterol, triglyceride and antioxidant enzymes, showing ameliorative changes in histopathology of liver. Expression pattern of certain inflammatory and apoptotic signal proteins also indicated better hepato-protective abilities of nano-chelidonine, making it a more suitable protective drug than chelidonine against cadmium toxicity in mice.
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Affiliation(s)
- Avijit Paul
- Cytogenetics and Molecular Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani 741235, India
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Burdelya LG, Brackett CM, Kojouharov B, Gitlin II, Leonova KI, Gleiberman AS, Aygun-Sunar S, Veith J, Johnson C, Haderski GJ, Stanhope-Baker P, Allamaneni S, Skitzki J, Zeng M, Martsen E, Medvedev A, Scheblyakov D, Artemicheva NM, Logunov DY, Gintsburg AL, Naroditsky BS, Makarov SS, Gudkov AV. Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist. Proc Natl Acad Sci U S A 2013; 110:E1857-66. [PMID: 23630282 PMCID: PMC3657788 DOI: 10.1073/pnas.1222805110] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Vertebrate Toll-like receptor 5 (TLR5) recognizes bacterial flagellin proteins and activates innate immune responses to motile bacteria. In addition, activation of TLR5 signaling can inhibit growth of TLR5-expressing tumors and protect normal tissues from radiation and ischemia-reperfusion injuries. To understand the mechanisms behind these phenomena at the organismal level, we assessed nuclear factor kappa B (NF-κB) activation (indicative of TLR5 signaling) in tissues and cells of mice treated with CBLB502, a pharmacologically optimized flagellin derivative. This identified the liver and gastrointestinal tract as primary CBLB502 target organs. In particular, liver hepatocytes were the main cell type directly and specifically responding to systemic administration of CBLB502 but not to that of the TLR4 agonist LPS. To assess CBLB502 impact on other pathways, we created multireporter mice with hepatocytes transduced in vivo with reporters for 46 inducible transcription factor families and found that along with NF-κB, CBLB502 strongly activated STAT3-, phenobarbital-responsive enhancer module (PREM), and activator protein 1 (AP-1-) -driven pathways. Livers of CBLB502-treated mice displayed induction of numerous immunomodulatory factors and massive recruitment of various types of immune cells. This led to inhibition of growth of liver metastases of multiple tumors regardless of their TLR5 status. The changed liver microenvironment was not, however, hepatotoxic, because CBLB502 induced resistance to Fas-mediated apoptosis in normal liver cells. Temporary occlusion of liver blood circulation prevented CBLB502 from protecting hematopoietic progenitors in lethally irradiated mice, indicating involvement of a factor secreted by responding liver cells. These results define the liver as the key mediator of TLR5-dependent effects in vivo and suggest clinical applications for TLR5 agonists as hepatoprotective and antimetastatic agents.
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Affiliation(s)
- Lyudmila G. Burdelya
- Roswell Park Cancer Institute, Buffalo, NY 14263
- Cleveland BioLabs, Inc., Buffalo, NY 14203
| | | | | | | | | | | | | | - Jean Veith
- Roswell Park Cancer Institute, Buffalo, NY 14263
| | | | | | | | | | | | - Ming Zeng
- Attagene, Inc., Research Triangle Park, NC 27709; and
| | - Elena Martsen
- Attagene, Inc., Research Triangle Park, NC 27709; and
| | | | - Dmitry Scheblyakov
- Gamaleya Research Institute for Epidemiology and Microbiology, Moscow 123098, Russia
| | | | - Denis Y. Logunov
- Gamaleya Research Institute for Epidemiology and Microbiology, Moscow 123098, Russia
| | | | - Boris S. Naroditsky
- Gamaleya Research Institute for Epidemiology and Microbiology, Moscow 123098, Russia
| | | | - Andrei V. Gudkov
- Roswell Park Cancer Institute, Buffalo, NY 14263
- Cleveland BioLabs, Inc., Buffalo, NY 14203
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Wang K, Lin B. Pathophysiological Significance of Hepatic Apoptosis. ISRN HEPATOLOGY 2012; 2013:740149. [PMID: 27335822 PMCID: PMC4890876 DOI: 10.1155/2013/740149] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2012] [Accepted: 12/13/2012] [Indexed: 12/19/2022]
Abstract
Apoptosis is a classical pathological feature in liver diseases caused by various etiological factors such as drugs, viruses, alcohol, and cholestasis. Hepatic apoptosis and its deleterious effects exacerbate liver function as well as involvement in fibrosis/cirrhosis and carcinogenesis. An imbalance between apoptotic and antiapoptotic capabilities is a prominent characteristic of liver injury. The regulation of apoptosis and antiapoptosis can be a pivotal step in the treatment of liver diseases.
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Affiliation(s)
- Kewei Wang
- Departments of Surgery and Pediatrics, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA
| | - Bingliang Lin
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
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Hepatoprotective Activity of the Total Saponins from Actinidia valvata Dunn Root against Carbon Tetrachloride-Induced Liver Damage in Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:216061. [PMID: 23243434 PMCID: PMC3518303 DOI: 10.1155/2012/216061] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Revised: 09/27/2012] [Accepted: 10/04/2012] [Indexed: 01/12/2023]
Abstract
The protective activity of the total saponins from Actinidia valvata Dunn root (TSAV) was studied against carbon-tetrachloride- (CCl4-) induced acute liver injury in mice. Mice were orally administered TSAV (50, 100, and 200 mg/kg) for five days and then given CCl4. TSAV pretreatment significantly prevented the CCl4-induced hepatic damage as indicated by the serum marker enzymes (AST, ALT, and ALP). Parallel to these changes, TSAV also prevented CCl4-induced oxidative stress by inhibiting lipid peroxidation (MDA) and restoring the levels of antioxidant enzymes (SOD, CAT, GR, and GPX), GSH and GSSG. In addition, TSAV attenuated the serum TNF-α and IL-6 levels and inhibited the serum iNOS and NO levels. Liver histopathology indicated that TSAV alleviated CCl4-induced inflammatory infiltration and focal necrosis. TSAV (200 mg/kg) also significantly decreased Bak, Bax mRNA and Fas, FasL, p53, and NF-κB p65 protein expressions and increased Bcl-2 mRNA and protein expressions. Meanwhile, TSAV significantly downregulated caspase-3 and caspase-8 activities and prevented CCl4-induced hepatic cell apoptosis. In addition, TSAV exhibited antioxidant activity through scavenging hydroxyl and DPPH free radicals in vitro. These results indicated that TSAV could protect mice against CCl4-induced acute liver damage possibly through antioxidant, anti-inflammatory activities and regulating apoptotic-related genes.
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Lu B, Xu Y, Xu L, Cong X, Yin L, Li H, Peng J. Mechanism investigation of dioscin against CCl4-induced acute liver damage in mice. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2012; 34:127-135. [PMID: 22516057 DOI: 10.1016/j.etap.2012.03.010] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Revised: 03/09/2012] [Accepted: 03/22/2012] [Indexed: 05/31/2023]
Abstract
The mechanisms of the ameliorating effects of dioscin against CCl(4) induced acute liver damage are investigated in this study. Dioscin significantly inhibited (p<0.01) the increases of serum ALT and AST activities compared with the CCl(4)-treated animals. The hepatic lipid peroxidation formation and, concentrations of TNF-α and IL-6 were also decreased. Liver histopathologic studies and a DNA laddering assay indicated that dioscin protected hepatocytes against CCl(4)-induced apoptosis and necrosis. Furthermore, dioscin decreased the protein expressions of Fas/FasL, increased Bcl-2/Bax ratio, inhibited the release of cytochrome c from mitochondrion to cytosol and attenuated CCl(4)-induced caspase-3 and -8 activities. The expressions of ICAM-1, vimentin, prohibitin, HGF, c-MET and GSTA1 were also regulated by dioscin and iNOS was also involved in the effects of this agent. These protective effects against CCl(4) induced acute liver damage might be through inhibiting lipid peroxidation, inflammatory cytokines, necrosis and apoptosis, and dioscin shows promise for development toward the treatment of acute chemically mediated liver injury.
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Affiliation(s)
- Binan Lu
- College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Yousong Xu
- Department of Neurosurgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Lina Xu
- College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Xiaonan Cong
- College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Lianhong Yin
- College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Hua Li
- College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Jinyong Peng
- College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
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Qu Y, Chen WH, Zong L, Xu MY, Lu LG. 18α-Glycyrrhizin induces apoptosis and suppresses activation of rat hepatic stellate cells. Med Sci Monit 2012; 18:BR24-32. [PMID: 22207106 PMCID: PMC3560665 DOI: 10.12659/msm.882196] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Background To investigate the potential mechanisms underlying the protective effects of 18α Glycyrrhizin (GL) on rat hepatic stellate cells (HSCs) and hepatocytes in vivo and in vitro. Material/Methods Sprague-Dawley (SD) rats were randomly divided into 5 groups: normal control group, liver fibrosis group, high-dose 18α GL group (25 mg/kg/d), intermediate-dose 18α GL group (12.5 mg/kg/d) and low-dose 18α GL group (6.25 mg/kg/d). The rat liver fibrosis model was induced by carbon tetrachloride (CCl4). The expressions of α-smooth muscle actin (αSMA) and NF-κB were determined by real-time PCR and immunohistochemistry. Results 18αGL dose-dependently inhibited the CCl4-induced liver fibrosis. There were significant differences in the mRNA and protein expressions of αSMA between the fibrosis group and 18α-GL treatment groups, suggesting that 18α GL can suppress the proliferation and activation of HSCs. Few HSCs were apoptotic in the portal area and fibrous septum in the liver fibrosis group. However, the double-color staining of a-SMA and TUNEL showed that 18α-GL treatment groups increased HSC apoptosis. NF-κB was mainly found in the nucleus in the fibrosis group, while cytoplasmic expression of NF-κB was noted in the 18αGL groups. In the in vitro experiments, 18α GL promoted the proliferation of hepatocytes, but inhibited that of HSCs. HSCs were arrested in the G2/M phase following 18α GL treatment and were largely apoptotic. Conclusions 18α-GL can suppress the activation of HSCs and induce the apoptosis of HSCs by blocking the translocation of NF-κB into the nucleus, which plays an important role in the protective effect of 18α-GL on liver fibrosis.
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Affiliation(s)
- Ying Qu
- Department of Gastroenterology, Shanghai 1st People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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