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1
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Agrawal HG, Giri PS, Sahoo T, Rath SN, Mishra AK. Flavin-based probe for real-time monitoring of hypochlorous acid dynamics in live cells. J Mater Chem B 2025. [PMID: 40183154 DOI: 10.1039/d4tb02727b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
The present study introduces TPA-vinylene-flavin (TVF) as a flavin-based turn-on fluorescent probe. TVF effectively detects HOCl, as evaluated by the solution phase studies with a detection limit of 0.36 μM. This probe shows excellent biocompatibility and rapid cellular internalization, making it suitable for real-time monitoring of HOCl fluctuations in both physiological and pathological conditions. Furthermore, the TVF probe exhibits specific mitochondrial localization and selectively detects HOCl in both endogenous and exogenous contexts within live cells. It demonstrates excellent sensitivity to HOCl concentrations over time, enabling precise tracking of dynamic fluctuations, which is critical for understanding its role in cellular processes and oxidative stress-related pathologies.
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Affiliation(s)
- Harsha Gopal Agrawal
- Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi, 502284, Telangana, India.
| | - Pravin Shankar Giri
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, 502284, Telangana, India
| | - Tanima Sahoo
- Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi, 502284, Telangana, India.
| | - Subha Narayan Rath
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, 502284, Telangana, India
| | - Ashutosh Kumar Mishra
- Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi, 502284, Telangana, India.
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2
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Paranthaman S, Hani U, Osmani RAM, Bhosale RR, Haider N. Current advances in nanoparticle-based approaches for the hepatocellular carcinoma treatment. Clin Res Hepatol Gastroenterol 2025; 49:102508. [PMID: 39613027 DOI: 10.1016/j.clinre.2024.102508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 11/18/2024] [Accepted: 11/26/2024] [Indexed: 12/01/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most common form of liver (LC) with a high mortality rate, driven by risk factors including viral hepatitis, alcoholic liver disease, and nonalcoholic steatohepatitis. The incident of HCC increases 2-4% of the worldwide population each year which would most certainly exceed one million per year by 2025. Despite advances in our knowledge, 25% of HCC tumors have actionable mutations which demands for innovative treatments strategies. In this perspective, we are providing a comprehensive summary of nanoparticles (NPs) based therapeutic approaches for HCC. We begin with an overview of HCC, concentrating on its pathogenesis, current conventional therapies, and their limitations. Then we delve into the therapeutic application of various nanoparticles (NPs) platforms for HCC, including polymeric micelles, dendrimers, liposomes, solid-lipid nanoparticles, nanostructured lipid carriers, exosomes, niosomes, mesoporous silica nanoparticles, carbon nanotubes. Special attention is given to the application of NPs in photothermal and photodynamic treatment was also investigated, with a focus on their effectiveness in targeted cancer ablation. Additionally, the review discusses recent patents and clinical studies that demonstrate the promise of NPs-based therapies in improving HCC treatment outcomes. This article underscores the potential of NPs based technologies to address the challenges faced by traditional therapies and offers insights into future directions for HCC management.
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Affiliation(s)
- Sathishbabu Paranthaman
- Department of Cell Biology and Molecular Genetics, Sri Devaraj Urs Medical College, Sri Devaraj Urs Academy of Higher Education and Research, Kolar, Tamaka, Karnataka, 563103, India.
| | - Umme Hani
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, 62529, Saudi Arabia
| | - Riyaz Ali M Osmani
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Shivarathreeshwara Nagara, Mysuru, 570015, India
| | - Rohit R Bhosale
- Department of Pharmaceutics, Krishna Foundation's Jaywant Institute of Pharmacy, Wathar, Tal. Karad, Maharashtra, 415539, India
| | - Nazima Haider
- Department of Pathology, College of Medicine, King Khalid University, Abha, 62529, Saudi Arabia
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3
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Fu Y, Maccioni L, Wang XW, Greten TF, Gao B. Alcohol-associated liver cancer. Hepatology 2024; 80:1462-1479. [PMID: 38607725 DOI: 10.1097/hep.0000000000000890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024]
Abstract
Heavy alcohol intake induces a wide spectrum of liver diseases ranging from steatosis, steatohepatitis, cirrhosis, and HCC. Although alcohol consumption is a well-known risk factor for the development, morbidity, and mortality of HCC globally, alcohol-associated hepatocellular carcinoma (A-HCC) is poorly characterized compared to viral hepatitis-associated HCC. Most A-HCCs develop after alcohol-associated cirrhosis (AC), but the direct carcinogenesis from ethanol and its metabolites to A-HCC remains obscure. The differences between A-HCC and HCCs caused by other etiologies have not been well investigated in terms of clinical prognosis, genetic or epigenetic landscape, molecular mechanisms, and heterogeneity. Moreover, there is a huge gap between basic research and clinical practice due to the lack of preclinical models of A-HCC. In the current review, we discuss the pathogenesis, heterogeneity, preclinical approaches, epigenetic, and genetic profiles of A-HCC, and discuss the current insights into and the prospects for future research on A-HCC. The potential effect of alcohol on cholangiocarcinoma and liver metastasis is also discussed.
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Affiliation(s)
- Yaojie Fu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Luca Maccioni
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Xin Wei Wang
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Tim F Greten
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
- Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
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4
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Chen Y, Xue X, Bao L, Bi J, Wu Q, Li S, Kong F, Liu K. A chitosan-based near-infrared ratiometric fluorescent nanoprobe created by molecular assembly with applications in hypochlorous acid detection in live mouse. Int J Biol Macromol 2024; 280:136165. [PMID: 39357697 DOI: 10.1016/j.ijbiomac.2024.136165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 09/16/2024] [Accepted: 09/29/2024] [Indexed: 10/04/2024]
Abstract
Hypochlorous acid (HClO/ClO-) is a key reactive oxidative species (ROS) in the body. The HClO/ClO- concentrations are imbalanced during cancer formation due to the ROS stress response. This paper introduces a novel chitosan-based self-calibration fluorescent nanoprobe (ChCyNil) constructed by molecular assembly for the ratiometric detection of HClO/ClO-. Two chromophores with different fluorescence characteristics and HClO/ClO- sensitivity were labeled on chitosan, and nanoparticles were prepared by a self-assembly strategy for HClO/ClO- detection. ChCyNil exhibits several advantages, such as dual near-infrared emissions at 670 nm and 845 nm, tunable fluorescence intensity, self-calibration fluorescence, and good biocompatibility, improving its accuracy in HClO/ClO- detection. Our study confirmed that ChCyNil exhibits a well-assembled spheroidal nanostructure and good photophysical properties in solution. The fluorescence imaging properties were further proved by detecting endogenous HClO/ClO- produced by LPS/PMA stimuli in cells and zebrafish. In addition, ChCyNil was used to detect the fluorescence behavior of HClO/ClO- in tumors of live mice. The successful design and fabrication of ChCyNil have presented a new strategy for constructing detection tools with improved fluorescence properties for HClO/ClO- in live animals.
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Affiliation(s)
- Yunling Chen
- State Key Laboratory of Biobased Material and Green Papermaking, Key Laboratory of Pulp & Paper Science and Technology of Shandong Province, Ministry of Education, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250353, China
| | - Xia Xue
- Department of General Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan 250022, China
| | - Luo Bao
- State Key Laboratory of Biobased Material and Green Papermaking, Key Laboratory of Pulp & Paper Science and Technology of Shandong Province, Ministry of Education, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250353, China; Key Laboratory of Marine Drug, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China
| | - Jianling Bi
- Shandong Institute of Geophysical and Geochemical Exploration, Jinan 250109, China
| | - Qin Wu
- State Key Laboratory of Biobased Material and Green Papermaking, Key Laboratory of Pulp & Paper Science and Technology of Shandong Province, Ministry of Education, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250353, China
| | - Shen Li
- State Key Laboratory of Biobased Material and Green Papermaking, Key Laboratory of Pulp & Paper Science and Technology of Shandong Province, Ministry of Education, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250353, China
| | - Fangong Kong
- State Key Laboratory of Biobased Material and Green Papermaking, Key Laboratory of Pulp & Paper Science and Technology of Shandong Province, Ministry of Education, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250353, China
| | - Keyin Liu
- State Key Laboratory of Biobased Material and Green Papermaking, Key Laboratory of Pulp & Paper Science and Technology of Shandong Province, Ministry of Education, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250353, China.
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5
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Sinha S, Hassan N, Schwartz RE. Organelle stress and alterations in interorganelle crosstalk during liver fibrosis. Hepatology 2024; 79:482-501. [PMID: 36626634 DOI: 10.1097/hep.0000000000000012] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 10/03/2022] [Indexed: 01/12/2023]
Abstract
The synchronous functioning and quality control of organelles ensure cell survival and function and are essential for maintaining homeostasis. Prolonged exposure to stressors (viruses, bacteria, parasitic infections, alcohol, drugs) or genetic mutations often disrupt the functional integrity of organelles which plays a critical role in the initiation and progression of several diseases including chronic liver diseases. One of the most important pathologic consequences of chronic liver diseases is liver fibrosis, characterized by tissue scarring due to the progressive accumulation of extracellular matrix components. Left untreated, fibrosis may advance to life-threatening complications such as cirrhosis, hepatic decompensation, and HCC, which collectively accounts for ∼1 million deaths per year worldwide. Owing to the lack of treatment options that can regress or reverse cirrhosis, liver transplantation is currently the only available treatment for end-stage liver disease. However, the limited supply of usable donor organs, adverse effects of lifelong immunosuppressive regimes, and financial considerations pose major challenges and limit its application. Hence, effective therapeutic strategies are urgently needed. An improved understanding of the organelle-level regulation of fibrosis can help devise effective antifibrotic therapies focused on reducing organelle stress, limiting organelle damage, improving interorganelle crosstalk, and restoring organelle homeostasis; and could be a potential clinical option to avoid transplantation. This review provides a timely update on the recent findings and mechanisms covering organelle-specific dysfunctions in liver fibrosis, highlights how correction of organelle functions opens new treatment avenues and discusses the potential challenges to clinical application.
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Affiliation(s)
- Saloni Sinha
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, New York, USA
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Panneerselvam S, Wilson C, Kumar P, Abirami D, Pamarthi J, Reddy MS, Varghese J. Overview of hepatocellular carcinoma: from molecular aspects to future therapeutic options. Cell Adh Migr 2023; 17:1-21. [PMID: 37726886 PMCID: PMC10512929 DOI: 10.1080/19336918.2023.2258539] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 09/08/2023] [Indexed: 09/21/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the seventh most highly prevalent malignant tumor globally and the second most common cause of mortality. HCC develops with complex pathways that occur through multistage biological processes. Non-alcoholic fatty liver disease, metabolic-associated fatty liver disease, alcoholic liver disease, autoimmune hepatitis, hepatitis B, and hepatitis C are the causative etiologies of HCC. HCC develops as a result of epigenetic changes, protein-coding gene mutations, and altered signaling pathways. Biomarkers and potential therapeutic targets for HCC open up new possibilities for treating the disease. Immune checkpoint inhibitors are included in the treatment options in combination with molecular targeted therapy.
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Affiliation(s)
- Sugan Panneerselvam
- Department of Hepatology and Transplant Hepatology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Cornelia Wilson
- Natural and Applied Sciences, School of Psychology and Life Sciences, Canterbury Christ Church University, Discovery Park, Sandwich, UK
| | - Prem Kumar
- Department of Hepatology and Transplant Hepatology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Dinu Abirami
- Department of Gastroenterology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Jayakrishna Pamarthi
- Multi-Disciplinary Research Unit, Madras Medical College, Chennai, Tamil Nadu, India
| | - Mettu Srinivas Reddy
- The Director and Head, Liver Transplant and HPB surgery, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Joy Varghese
- Department of Gastroenterology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
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Chen L, Zhou M, Li H, Liu D, Liao P, Zong Y, Zhang C, Zou W, Gao J. Mitochondrial heterogeneity in diseases. Signal Transduct Target Ther 2023; 8:311. [PMID: 37607925 PMCID: PMC10444818 DOI: 10.1038/s41392-023-01546-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 02/21/2023] [Accepted: 06/13/2023] [Indexed: 08/24/2023] Open
Abstract
As key organelles involved in cellular metabolism, mitochondria frequently undergo adaptive changes in morphology, components and functions in response to various environmental stresses and cellular demands. Previous studies of mitochondria research have gradually evolved, from focusing on morphological change analysis to systematic multiomics, thereby revealing the mitochondrial variation between cells or within the mitochondrial population within a single cell. The phenomenon of mitochondrial variation features is defined as mitochondrial heterogeneity. Moreover, mitochondrial heterogeneity has been reported to influence a variety of physiological processes, including tissue homeostasis, tissue repair, immunoregulation, and tumor progression. Here, we comprehensively review the mitochondrial heterogeneity in different tissues under pathological states, involving variant features of mitochondrial DNA, RNA, protein and lipid components. Then, the mechanisms that contribute to mitochondrial heterogeneity are also summarized, such as the mutation of the mitochondrial genome and the import of mitochondrial proteins that result in the heterogeneity of mitochondrial DNA and protein components. Additionally, multiple perspectives are investigated to better comprehend the mysteries of mitochondrial heterogeneity between cells. Finally, we summarize the prospective mitochondrial heterogeneity-targeting therapies in terms of alleviating mitochondrial oxidative damage, reducing mitochondrial carbon stress and enhancing mitochondrial biogenesis to relieve various pathological conditions. The possibility of recent technological advances in targeted mitochondrial gene editing is also discussed.
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Affiliation(s)
- Long Chen
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Mengnan Zhou
- Department of Pathogenic Biology, School of Basic Medical Science, China Medical University, Shenyang, 110001, China
| | - Hao Li
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Delin Liu
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Peng Liao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yao Zong
- Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia
| | - Changqing Zhang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Weiguo Zou
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
- Shanghai Sixth People's Hospital Fujian, No. 16, Luoshan Section, Jinguang Road, Luoshan Street, Jinjiang City, Quanzhou, Fujian, China.
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8
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Jia X, Li R, Zhang X, Zhou T, Sun D, Yang N, Luo Z. Increased age, bilirubin, international normalized ratio, and creatinine score to triglyceride ratio are associated with alcohol-associated primary liver carcinoma: a single-centered retrospective study. Lipids Health Dis 2023; 22:117. [PMID: 37537579 PMCID: PMC10401853 DOI: 10.1186/s12944-023-01888-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 07/28/2023] [Indexed: 08/05/2023] Open
Abstract
BACKGROUND This study analyzed the clinical features and biomarkers of alcohol-associated liver disease (ALD) to investigate the diagnostic value of age, bilirubin, international normalized ratio (INR), and creatinine (ABIC) score to triglyceride (TG) ratio (ABIC/TG) in ALD-associated primary liver carcinoma (PLC). MATERIALS AND METHODS Data were collected from 410 participants with ALD, and the epidemiological and clinical records of 266 participants were analyzed. Participants were divided into ALD-without-PLC and ALD-associated-PLC groups. Relationships between clinical characteristics, biomarkers and ALD-associated PLC were estimated. Serum lipid levels and liver function were compared between ALD patients without PLC and patients with ALD-associated PLC. Scoring systems were calculated to investigate ALD severity. The robustness of the relationship was analyzed by the receiver operating characteristic (ROC) curve. RESULTS Age and dyslipidemia were more strongly associated with ALD-associated PLC than with ALD-without PLC, with AORs of 2.39 and 0.25, respectively, with P less than 0.05. Drinking time and average daily intake, ABIC score, and ABIC/TG ratio were significantly higher in the ALD-associated-PLC group than in the ALD-without-PLC group. The AUC for the ABIC/TG ratio predicting the incidence of PLC was 0.80 (P < 0.01), which was higher than that of the ABIC and TG scores alone; additionally, the specificity and Youden index for the ABIC/TG ratio were also higher, and the cutoff value was 6.99. CONCLUSIONS In ALD patients, age, drinking time, and average daily intake were risk factors for PLC. Drinking time, average daily intake, TG and ABIC score have diagnostic value for ALD-associated PLC. The ABIC/TG ratio had a higher AUC value and Youden index than the ABIC score and TG level.
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Affiliation(s)
- Xiaoqing Jia
- Department of Gastroenterology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, 250010, P.R. China
| | - Rong Li
- Department of Geriatric Medicine, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, 250010, P.R. China
| | - Xiaoting Zhang
- Department of Geriatric Medicine, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, 250010, P.R. China
| | - Tao Zhou
- Department of Geriatric Medicine, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, 250010, P.R. China
| | - Dalong Sun
- Department of Geriatric Medicine, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, 250010, P.R. China
| | - Na Yang
- Department of Geriatric Medicine, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, 250010, P.R. China
| | - Zheng Luo
- Department of Geriatric Medicine, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, 250010, P.R. China.
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Di Ciaula A, Bonfrate L, Krawczyk M, Frühbeck G, Portincasa P. Synergistic and Detrimental Effects of Alcohol Intake on Progression of Liver Steatosis. Int J Mol Sci 2022; 23:2636. [PMID: 35269779 PMCID: PMC8910376 DOI: 10.3390/ijms23052636] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/24/2022] [Accepted: 02/25/2022] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the most common liver disorders worldwide and the major causes of non-viral liver cirrhosis in the general population. In NAFLD, metabolic abnormalities, obesity, and metabolic syndrome are the driving factors for liver damage with no or minimal alcohol consumption. ALD refers to liver damage caused by excess alcohol intake in individuals drinking more than 5 to 10 daily units for years. Although NAFLD and ALD are nosologically considered two distinct entities, they show a continuum and exert synergistic effects on the progression toward liver cirrhosis. The current view is that low alcohol use might also increase the risk of advanced clinical liver disease in NAFLD, whereas metabolic factors increase the risk of cirrhosis among alcohol risk drinkers. Therefore, special interest is now addressed to individuals with metabolic abnormalities who consume small amounts of alcohol or who binge drink, for the role of light-to-moderate alcohol use in fibrosis progression and clinical severity of the liver disease. Evidence shows that in the presence of NAFLD, there is no liver-safe limit of alcohol intake. We discuss the epidemiological and clinical features of NAFLD/ALD, aspects of alcohol metabolism, and mechanisms of damage concerning steatosis, fibrosis, cumulative effects, and deleterious consequences which include hepatocellular carcinoma.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School—Piazza Giulio Cesare 11, 70124 Bari, Italy; (A.D.C.); (L.B.)
| | - Leonilde Bonfrate
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School—Piazza Giulio Cesare 11, 70124 Bari, Italy; (A.D.C.); (L.B.)
| | - Marcin Krawczyk
- Department of Medicine II Saarland University Medical Center, Saarland University, 66424 Homburg, Germany;
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Gema Frühbeck
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, 31008 Pamplona, Spain;
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), ISCIII, 31009 Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31009 Pamplona, Spain
| | - Piero Portincasa
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School—Piazza Giulio Cesare 11, 70124 Bari, Italy; (A.D.C.); (L.B.)
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Liu M, Huang Q, Zhu Y, Chen L, Li Y, Gong Z, Ai K. Harnessing reactive oxygen/nitrogen species and inflammation: Nanodrugs for liver injury. Mater Today Bio 2022; 13:100215. [PMID: 35198963 PMCID: PMC8850330 DOI: 10.1016/j.mtbio.2022.100215] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 02/04/2022] [Accepted: 02/06/2022] [Indexed: 12/11/2022] Open
Abstract
Overall, 12% of the global population (800 million) suffers from liver disease, which causes 2 million deaths every year. Liver injury involving characteristic reactive oxygen/nitrogen species (RONS) and inflammation plays a key role in progression of liver disease. As a key metabolic organ of the human body, the liver is susceptible to injury from various sources, including COVID-19 infection. Owing to unique structural features and functions of the liver, most current antioxidants and anti-inflammatory drugs are limited against liver injury. However, the characteristics of the liver could be utilized in the development of nanodrugs to achieve specific enrichment in the liver and consequently targeted treatment. Nanodrugs have shown significant potential in eliminating RONS and regulating inflammation, presenting an attractive therapeutic tool for liver disease through controlling liver injury. Therefore, the main aim of the current review is to provide a comprehensive summary of the latest developments contributing to our understanding of the mechanisms underlying nanodrugs in the treatment of liver injury via harnessing RONS and inflammation. Meanwhile, the prospects of nanodrugs for liver injury therapy are systematically discussed, which provides a sound platform for novel therapeutic insights and inspiration for design of nanodrugs to treat liver disease.
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Affiliation(s)
- Min Liu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Qiong Huang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yan Zhu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Li Chen
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
- Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Yumei Li
- Department of Assisted Reproduction, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhicheng Gong
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Kelong Ai
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
- Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
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Curti RRDJ, Castilha EP, Bonaldo ALL, Okuyama NCM, Trugilo KP, Guembarovski RL, Couto-Filho JD, Watanabe MAE, de Oliveira KB. Development of cervical intraepithelial lesions and cervical cancer is not influenced by SOD2 RS4880 polymorhism. Pathol Res Pract 2021; 230:153742. [PMID: 34959097 DOI: 10.1016/j.prp.2021.153742] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 12/14/2021] [Accepted: 12/16/2021] [Indexed: 01/17/2023]
Abstract
Some of the more than 200 known HPV types are essential for cervical cancer development, the third type of cancer most incident in the female population. However, for the malignant transformation occur, some cofactors are needed, as the reactive oxygen species (ROS), which can be neutralized by the antioxidant system. The SOD2 enzyme, encoded by the same name gene, is found in mitochondria and is part of the first line of defense against oxidative stress damage. Genetic polymorphisms can act by altering the efficiency of the enzyme, among which the most studied is the rs4880. Thus, the purpose of the present study was to evaluate the association of this polymorphism with HPV infection and the development of low and high grade squamous intraepithelial lesions (LSIL and HSIL) and cervical cancer, in 407 women attended by the public health system in Brazil. HPV detection in cervical secretion samples was carried out by polymerase chain reaction (PCR) and blood samples were used for polymorphism genotyping through PCR followed by restriction fragment length polymorphism (RFLP). PCR and restriction products were subjected to 10% polyacrylamide gel electrophoresis. HPV negative group (control) included 158 women and the HPV positive group (case) 249 women. The infected group was divided into No Lesion (n = 90), LSIL (n = 20), HSIL (n = 67) and cervical cancer (n = 72). The data found on socio-epidemiological characteristics and habits corroborated with data found in the literature. The distribution of genotypes in the control group was 51.9% women TC, 29.8% TT and 18.3% CC. In the case group, the distribution was 55.0% women TC, 26.1% TT and 18.9% CC. This is the first study evaluating the influence of SOD2 rs4880 polymorphism on HPV infection, the development of cervical intraepithelial lesions and cervical cancer in a Brazilian population, although additional studies are needed to corroborate the results.
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Affiliation(s)
- Rafaela Roberta de Jaime Curti
- Laboratory of Molecular Genetics and Immunology, Department of Pathological Sciences, State University of Londrina, 86.057-970 Paraná, Brazil
| | - Eliza Pizarro Castilha
- Laboratory of Molecular Genetics and Immunology, Department of Pathological Sciences, State University of Londrina, 86.057-970 Paraná, Brazil
| | - Ana Luiza Labbate Bonaldo
- Laboratory of Molecular Genetics and Immunology, Department of Pathological Sciences, State University of Londrina, 86.057-970 Paraná, Brazil
| | - Nádia Calvo Martins Okuyama
- Laboratory of Molecular Genetics and Immunology, Department of Pathological Sciences, State University of Londrina, 86.057-970 Paraná, Brazil
| | - Kleber Paiva Trugilo
- Laboratory of Molecular Genetics and Immunology, Department of Pathological Sciences, State University of Londrina, 86.057-970 Paraná, Brazil
| | - Roberta Losi Guembarovski
- Laboratory of Mutagenesis and Oncogenetics, Molecular Genetics and Immunology, Department of Biological Sciences, Londrina State University, Londrina, Paraná, Brazil
| | | | - Maria Angelica Ehara Watanabe
- Laboratory of Study and Application of DNA Polymorphism, Department of Pathological Science, Londrina State University, Londrina, Paraná, Brazil
| | - Karen Brajão de Oliveira
- Laboratory of Molecular Genetics and Immunology, Department of Pathological Sciences, State University of Londrina, 86.057-970 Paraná, Brazil.
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12
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Angelis D, León RL, Chalak L. Part III. Neuronal biochemical effects of acetaminophen and neurodevelopmental outcomes: Friend or foe? Early Hum Dev 2021; 159:105408. [PMID: 34158208 DOI: 10.1016/j.earlhumdev.2021.105408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Dimitrios Angelis
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Rachel L León
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Lina Chalak
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX, USA
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13
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Brahma MK, Gilglioni EH, Zhou L, Trépo E, Chen P, Gurzov EN. Oxidative stress in obesity-associated hepatocellular carcinoma: sources, signaling and therapeutic challenges. Oncogene 2021; 40:5155-5167. [PMID: 34290399 PMCID: PMC9277657 DOI: 10.1038/s41388-021-01950-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 07/01/2021] [Accepted: 07/08/2021] [Indexed: 02/06/2023]
Abstract
Obesity affects more than 650 million individuals worldwide and is a well-established risk factor for the development of hepatocellular carcinoma (HCC). Oxidative stress can be considered as a bona fide tumor promoter, contributing to the initiation and progression of liver cancer. Indeed, one of the key events involved in HCC progression is excessive levels of reactive oxygen species (ROS) resulting from the fatty acid influx and chronic inflammation. This review provides insights into the different intracellular sources of obesity-induced ROS and molecular mechanisms responsible for hepatic tumorigenesis. In addition, we highlight recent findings pointing to the role of the dysregulated activity of BCL-2 proteins and protein tyrosine phosphatases (PTPs) in the generation of hepatic oxidative stress and ROS-mediated dysfunctional signaling, respectively. Finally, we discuss the potential and challenges of novel nanotechnology strategies to prevent ROS formation in obesity-associated HCC.
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Affiliation(s)
- Manoja K Brahma
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université libre de Bruxelles, Brussels, Belgium
| | - Eduardo H Gilglioni
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université libre de Bruxelles, Brussels, Belgium
| | - Lang Zhou
- Materials Research and Education Center, Auburn University, Auburn, AL, 36849, United States
| | - Eric Trépo
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, C.U.B. Hôpital Erasme, Université libre de Bruxelles, Brussels, Belgium
- Laboratory of Experimental Gastroenterology, Université libre de Bruxelles, Brussels, Belgium
| | - Pengyu Chen
- Materials Research and Education Center, Auburn University, Auburn, AL, 36849, United States
| | - Esteban N Gurzov
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université libre de Bruxelles, Brussels, Belgium.
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14
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Reig M, Forner A, Ávila MA, Ayuso C, Mínguez B, Varela M, Bilbao I, Bilbao JI, Burrel M, Bustamante J, Ferrer J, Gómez MÁ, Llovet JM, De la Mata M, Matilla A, Pardo F, Pastrana MA, Rodríguez-Perálvarez M, Tabernero J, Urbano J, Vera R, Sangro B, Bruix J. Diagnosis and treatment of hepatocellular carcinoma. Update of the consensus document of the AEEH, AEC, SEOM, SERAM, SERVEI, and SETH. Med Clin (Barc) 2021; 156:463.e1-463.e30. [PMID: 33461840 DOI: 10.1016/j.medcli.2020.09.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/12/2020] [Accepted: 09/15/2020] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver neoplasm and one of the most common causes of death in patients with cirrhosis of the liver. In parallel, with recognition of the clinical relevance of this cancer, major new developments have recently appeared in its diagnosis, prognostic assessment and in particular, in its treatment. Therefore, the Spanish Association for the Study of the Liver (AEEH) has driven the need to update the clinical practice guidelines, once again inviting all the societies involved in the diagnosis and treatment of this disease to participate in the drafting and approval of the document: Spanish Society for Liver Transplantation (SETH), Spanish Society of Diagnostic Radiology (SERAM), Spanish Society of Vascular and Interventional Radiology (SERVEI), Spanish Association of Surgeons (AEC) and Spanish Society of Medical Oncology (SEOM). The clinical practice guidelines published in 2016 and accepted as National Health System Clinical Practice Guidelines were taken as the reference documents, incorporating the most important recent advances. The scientific evidence and the strength of the recommendation is based on the GRADE system.
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Affiliation(s)
- María Reig
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España
| | - Alejandro Forner
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España
| | - Matías A Ávila
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Programa de Hepatología, Centro de Investigación Médica Aplicada, Universidad de Navarra-IDISNA, Pamplona, España
| | - Carmen Ayuso
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Radiodiagnóstico, Hospital Clínic Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Beatriz Mínguez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Hepatología, Hospital Universitario Vall d́Hebron, Grupo de Investigación en Enfermedades Hepáticas (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universidad Autónoma de Barcelona. Barcelona, España
| | - María Varela
- Sección de Hepatología, Servicio de Aparato Digestivo, Hospital Universitario Central de Asturias. Oviedo, España
| | - Itxarone Bilbao
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Cirugía Hepatobiliopancreática y Trasplantes Digestivos, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona. Barcelona, España
| | - José Ignacio Bilbao
- Unidad de Radiología Vascular e Intervencionista, Departamento de Radiodiagnóstico, Clínica Universidad de Navarra, Pamplona, España
| | - Marta Burrel
- Servicio de Radiodiagnóstico, Hospital Clínic Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Javier Bustamante
- Servicio de Gastroenterología y Hepatología, Sección de Hepatología y Trasplante, Hospital Universitario de Cruces, Baracaldo, España
| | - Joana Ferrer
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Cirugía Hepatobiliopancreática, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Miguel Ángel Gómez
- Unidad de Cirugía Hepatobiliopancreática y Trasplantes, Hospital Universitario Virgen del Rocío, Sevilla, España
| | - Josep María Llovet
- Grupo de Investigación Traslacional en Oncología Hepática, Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Manuel De la Mata
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad Clínica de Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, España
| | - Ana Matilla
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Sección de Hepatología, Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, España
| | - Fernando Pardo
- Servicio de Cirugía Hepatobiliopancreática y Trasplante, Clínica Universidad de Navarra, Pamplona, España
| | - Miguel A Pastrana
- Servicio de Radiodiagnóstico, Hospital Universitario Puerta de Hierro, Universidad Autónoma de Madrid, Madrid, España
| | - Manuel Rodríguez-Perálvarez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad Clínica de Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, España
| | - Josep Tabernero
- Servicio de Oncología Médica, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, España
| | - José Urbano
- Unidad de Radiología Vascular e Intervencionista, Servicio de Radiodiagnóstico, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, España
| | - Ruth Vera
- Servicio de Oncología Médica, Complejo hospitalario de Navarra, Navarrabiomed-IDISNA, Pamplona, España
| | - Bruno Sangro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad de Hepatología y Área de Oncología HBP, Clínica Universidad de Navarra-IDISNA, Pamplona, España.
| | - Jordi Bruix
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España.
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15
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Tang J, Yan Z, Feng Q, Yu L, Wang H. The Roles of Neutrophils in the Pathogenesis of Liver Diseases. Front Immunol 2021; 12:625472. [PMID: 33763069 PMCID: PMC7982672 DOI: 10.3389/fimmu.2021.625472] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/25/2021] [Indexed: 01/30/2023] Open
Abstract
Neutrophils are the largest population of circulating leukocytes and the first responder against invading pathogens or other danger signals. Sophisticated machineries help them play critical roles in immunity and inflammation, including phagocytosis, superoxide production, cytokine and chemokine production, degranulation, and formation of neutrophil extracellular traps (NETs). After maturation and release from the bone marrow, neutrophils migrate to inflamed tissues in response to many stimuli. Increasing evidences indicate that neutrophils are critically involved in the pathogenesis of liver diseases, including liver cancer, thus making them promising target for the treatment of liver diseases. Here, we would like to provide the latest finding about the role of neutrophils in liver diseases and discuss the potentiality of neutrophils as target for liver diseases.
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Affiliation(s)
- Jiaojiao Tang
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Zijun Yan
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- Graduate Management Unit, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Qiyu Feng
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Lexing Yu
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Hongyang Wang
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
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16
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Nutrigenetics of antioxidant enzymes and micronutrient needs in the context of viral infections. Nutr Res Rev 2020; 34:174-184. [PMID: 33081856 DOI: 10.1017/s0954422420000244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Sustaining adequate nutritional needs of a population is a challenging task in normal times and a priority in times of crisis. There is no 'one-size-fits-all' solution that addresses nutrition. In relevance to the COVID-19 (coronavirus disease 2019) pandemic crisis, viral infections in general and RNA viruses in particular are known to induce and promote oxidative stress, consequently increasing the body's demand for micronutrients, especially those related to antioxidant enzymic systems, thus draining the body of micronutrients, and so hindering the human body's ability to cope optimally with oxidative stress. Common polymorphisms in major antioxidant enzymes, with world population minor allele frequencies ranging from 0·5 to 50 %, are related to altered enzymic function, with substantial potential effects on the body's ability to cope with viral infection-induced oxidative stress. In this review we highlight common SNP of the major antioxidant enzymes relevant to nutritional components in the context of viral infections, namely: superoxide dismutases, glutathione peroxidases and catalase. We delineate functional polymorphisms in several human antioxidant enzymes that require, especially during a viral crisis, adequate and potentially additional nutritional support to cope with the pathological consequences of disease. Thus, in face of the COVID-19 pandemic, nutrition should be tightly monitored and possibly supplemented, with special attention to those carrying common polymorphisms in antioxidant enzymes.
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17
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Liu H, Zhang P, Zhang C, Chen J, Jiang JH. Self-Assembly of a Dual-Targeting and Self-Calibrating Ratiometric Polymer Nanoprobe for Accurate Hypochlorous Acid Imaging. ACS APPLIED MATERIALS & INTERFACES 2020; 12:45822-45829. [PMID: 32969225 DOI: 10.1021/acsami.0c13857] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Exploiting an intelligent fluorescent probe, which can precisely target to the lysosome of hepatoma cells and enable accurate molecular imaging, is a key challenge in hepatoma diagnoses. Herein, a single-dye-based polymer nanoprobe (named SPN) with dual-targeting and self-calibrating ratiometric characteristics is rationally fabricated via a simple self-assembly strategy for accurate hypochlorous acid (HClO) imaging in the lysosome of HepG2 cells. Of note, the covalent incorporation of self-calibrating ratiometric fluorophore (pyrene derivatives) into the core of polymer nanoparticles can not only validly avoid the leakage of fluorophores but also greatly enhance their brightness. Besides, this polymer nanoprobe (SPN) displays high water dispersibility, ultrafast response (<1s), favorable selectivity, outstanding long-term stability (>90 days), and good biocompatibility. Furthermore, thanks to the hepatocyte-targeting moiety (galactose) and the interplay of surface charge and size of nanoparticles, the SPN is able to enter into asialoglycoprotein receptor-positive HepG2 cells and further locate at lysosomes, successfully enabling accurate HClO detection in lysosomes of HepG2 cells. This study demonstrates that the versatile SPN can provide more precise dual-targeting and accurate molecular imaging.
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Affiliation(s)
- Hui Liu
- State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, P. R. China
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule of Ministry of Education, Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers, Hunan Province College Key Laboratory of QSAR/QSPR, Hunan Provincial Key Lab of Advanced Materials for New Energy Storage and Conversion, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, China
| | - Peisheng Zhang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, P. R. China
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule of Ministry of Education, Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers, Hunan Province College Key Laboratory of QSAR/QSPR, Hunan Provincial Key Lab of Advanced Materials for New Energy Storage and Conversion, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, China
| | - Chonghua Zhang
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule of Ministry of Education, Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers, Hunan Province College Key Laboratory of QSAR/QSPR, Hunan Provincial Key Lab of Advanced Materials for New Energy Storage and Conversion, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, China
| | - Jian Chen
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule of Ministry of Education, Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers, Hunan Province College Key Laboratory of QSAR/QSPR, Hunan Provincial Key Lab of Advanced Materials for New Energy Storage and Conversion, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, China
- State Key Laboratory of Luminescent Materials and Devices, South China University of Technology, Guangzhou 510640, P. R. China
| | - Jian-Hui Jiang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, P. R. China
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18
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Koop AC, Thiele ND, Steins D, Michaëlsson E, Wehmeyer M, Scheja L, Steglich B, Huber S, Schulze Zur Wiesch J, Lohse AW, Heeren J, Kluwe J. Therapeutic Targeting of Myeloperoxidase Attenuates NASH in Mice. Hepatol Commun 2020; 4:1441-1458. [PMID: 33024915 PMCID: PMC7527691 DOI: 10.1002/hep4.1566] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 06/02/2020] [Accepted: 06/14/2020] [Indexed: 12/12/2022] Open
Abstract
Myeloperoxidase (MPO) activity has been associated with the metabolic syndrome, cardiovascular and liver disease. Here, we evaluate the therapeutic potential of MPO inhibition on nonalcoholic steatohepatitis (NASH) and NASH-induced fibrosis, the main determinant of outcomes. MPO plasma levels were elevated in patients with nonalcoholic fatty liver disease (NAFLD) compared with healthy controls. In a second cohort, hepatic MPO messenger RNA expression correlated with higher body mass index and hemoglobin A1c, both being risk factors for NAFLD. We could establish by immunohistochemistry that MPO-positive cells were recruited to the liver in various mouse models of fibrogenic liver injury, including bile duct ligation, carbon tetrachloride (CCl4) treatment, spontaneous liver fibrogenesis in multidrug resistance 2 knockout (MDR2 KO) mice, and NASH-inducing diet. Comparison of MPO-deficient mice and their wild-type littermates exposed to a high-caloric diet revealed that MPO deficiency protects against NASH-related liver injury and fibrosis. In line with this, hepatic gene expression analysis demonstrated a MPO-dependent activation of pathways relevant for wound healing, inflammation, and cell death in NASH. MPO deficiency did not affect NAFLD-independent liver injury and fibrosis in MDR2 KO or CCl4-treated mice. Finally, we treated wild-type mice exposed to NASH-inducing diet with an oral MPO inhibitor. Pharmacological MPO inhibition not only reduced markers of MPO-mediated liver damage, serum alanine aminotransferase levels, and hepatic steatosis, but also significantly decreased NASH-induced liver fibrosis. MPO inhibitor treatment, but not MPO deficiency, significantly altered gut microbiota including a significant expansion of Akkermansia muciniphila. Conclusions: MPO specifically promotes NASH-induced liver fibrosis. Pharmacological MPO inhibition attenuates NASH progression and NASH-induced liver fibrosis in mice and is associated with beneficial changes of intestinal microbiota.
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Affiliation(s)
- Anja Christina Koop
- 1st Department of Medicine University Medical Center Hamburg-Eppendorf Hamburg Germany
| | - Nina Doreen Thiele
- 1st Department of Medicine University Medical Center Hamburg-Eppendorf Hamburg Germany
| | - David Steins
- 1st Department of Medicine University Medical Center Hamburg-Eppendorf Hamburg Germany
| | - Erik Michaëlsson
- Bioscience Cardiovascular, Research and Early Development Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden
| | - Malte Wehmeyer
- 1st Department of Medicine University Medical Center Hamburg-Eppendorf Hamburg Germany
| | - Ludger Scheja
- Department of Biochemistry and Molecular Cell Biology University Medical Center Hamburg-Eppendorf Hamburg Germany
| | - Babett Steglich
- 1st Department of Medicine University Medical Center Hamburg-Eppendorf Hamburg Germany.,Department of General, Internal and Thoracic Surgery University Medical Center Hamburg-Eppendorf Hamburg Germany
| | - Samuel Huber
- 1st Department of Medicine University Medical Center Hamburg-Eppendorf Hamburg Germany
| | | | - Ansgar W Lohse
- 1st Department of Medicine University Medical Center Hamburg-Eppendorf Hamburg Germany
| | - Jörg Heeren
- Department of Biochemistry and Molecular Cell Biology University Medical Center Hamburg-Eppendorf Hamburg Germany
| | - Johannes Kluwe
- 1st Department of Medicine University Medical Center Hamburg-Eppendorf Hamburg Germany
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19
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Abstract
An excessive alcohol intake may result in fatty liver, acute/chronic hepatitis, cirrhosis, and lead to hepatocellular carcinoma (HCC). The aim of this review is to clarify the present condition and the mechanisms of alcohol-related hepatocarcinogenesis and clinical risk factors for alcohol-related HCC. There are several possible mechanisms through which alcohol may induce hepatocarcinogenesis, including the mutagenic effects of acetaldehyde toxicity through the formation of protein and DNA adducts and the production of reactive oxygen species due to the excessive hepatic deposition of iron, changes to lipid peroxidation and metabolism, inflammation and an impaired immune response and modifications to DNA methylation. Furthermore, it has been reported that alcohol accelerates liver carcinogenesis through several signaling pathways including gut-liver axis. From a clinical perspective, it is well known that alcohol interacts with other factors, such as age, gender, viral hepatitis, obesity, and diabetes leading to an increased risk of HCC.
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Affiliation(s)
- Makiko Taniai
- Department of Internal Medicine, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
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20
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Sepulveda-Villegas M, Rojo R, Garza-Hernandez D, de la Rosa-Garza M, Treviño V. A systematic review of genes affecting mitochondrial processes in cancer. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165846. [PMID: 32473387 DOI: 10.1016/j.bbadis.2020.165846] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 05/01/2020] [Accepted: 05/21/2020] [Indexed: 02/07/2023]
Abstract
Malignant conversion of cancer cells requires efficient mitochondria reprogramming orchestrated by hundreds of genes. The transformation includes increased energy demand, biosynthesis of precursors, and reactive oxygen species needed to accelerate cell growth, proliferation, and survival. Reprogramming involves complex gene alterations that have not been methodically curated. Therefore, we systematically analyzed the literature of cancer-related genes in mitochondria. Through the analysis of >2500 PubMed abstracts and >1600 human genes, we identified 228 genes showing clear roles in cancer. Each gene was classified according to their homeostatic function, together with the pathological transitions that contribute to specific cancer hallmarks. The potential clinical relevance of these hallmarks and genes is discussed by representative examples and validated by detecting differences in gene expression levels across 16 different types of cancer. A compendium, including the gene functions and alterations underpinning cancer progression, can be explored at http://bioinformatica.mty.itesm.mx/MitoCancer.
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Affiliation(s)
- Maricruz Sepulveda-Villegas
- Tecnologico de Monterrey, Escuela de Medicina, Cátedra de Bioinformática, Av. Morones Prieto No. 3000, Colonia Los Doctores, Monterrey, Nuevo León 64710, Mexico
| | - Rocio Rojo
- Tecnologico de Monterrey, Escuela de Medicina, Cátedra de Bioinformática, Av. Morones Prieto No. 3000, Colonia Los Doctores, Monterrey, Nuevo León 64710, Mexico
| | - Debora Garza-Hernandez
- Tecnologico de Monterrey, Escuela de Medicina, Cátedra de Bioinformática, Av. Morones Prieto No. 3000, Colonia Los Doctores, Monterrey, Nuevo León 64710, Mexico
| | - Mauricio de la Rosa-Garza
- Tecnologico de Monterrey, Escuela de Medicina, Cátedra de Bioinformática, Av. Morones Prieto No. 3000, Colonia Los Doctores, Monterrey, Nuevo León 64710, Mexico
| | - Victor Treviño
- Tecnologico de Monterrey, Escuela de Medicina, Cátedra de Bioinformática, Av. Morones Prieto No. 3000, Colonia Los Doctores, Monterrey, Nuevo León 64710, Mexico.
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21
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Hanumanthappa N, Cho BH, McKay A, Peretz D, Y Minuk G, Lambert P, Nashed M. Epidemiology, clinical treatment patterns, and survival of hepatocellular carcinoma in Manitoba. CANADIAN LIVER JOURNAL 2020; 3:194-202. [PMID: 35991857 PMCID: PMC9202782 DOI: 10.3138/canlivj.2019-0015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 09/14/2019] [Indexed: 01/08/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) has a very poor survival rate, especially for those who do not receive a potentially curative therapy. METHODS Treatment details were collected for 320 HCC patients diagnosed in Manitoba between January 2011 and December 2015. Patients had a mean age of 67.3 years, and 71.6% were men. Of these patients, 67 (20.9%) received curative treatment, 36 (11.3%) received non-curative treatment, and 217 (67.8%) received supportive care only; 71.3% of patients had liver cirrhosis. Alcoholic cirrhosis was the most common etiology of chronic liver disease (22.2%). RESULTS Those who received curative treatment had a significantly lower incidence of portal vein thrombosis and multinodular disease than those in other groups. Patients who received supportive care only had a higher incidence of ascites. We found no difference in the distribution of cirrhosis or portal hypertension among the treatment groups. The 2- and 5-year overall survival rates for the whole cohort were 27% and 14%, respectively. No significant change was found in 2-year survival for patients diagnosed in each year from 2011 to 2015 (p = 0.250). Also, we found no significant change in proportion of treatment given to patients over the same period (p = 0.432). CONCLUSION The poor survival rate of HCC patients in Manitoba could potentially be improved by maximizing the use of local therapy and by implementing multidisciplinary-based case discussion. Efforts should also be directed toward early management of infective, alcoholic, and non-alcoholic steatohepatitis, which will, we hope, lead to a reduction in the incidence of HCC.
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Affiliation(s)
- Nikesh Hanumanthappa
- Department of Radiation Oncology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Byung Heon Cho
- Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Andrew McKay
- Section of Hepatology, Department of Surgery, Health Sciences Centre, University of Manitoba, Winnipeg, Manitoba, Canada
| | - David Peretz
- Section of Hepatology, Department of Surgery, Health Sciences Centre, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Gerald Y Minuk
- Section of Hepatology, Department of Internal Medicine, Health Sciences Centre, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Pascal Lambert
- Department of Epidemiology and Statistics, CancerCare Manitoba, Winnipeg, Manitoba, Canada
| | - Maged Nashed
- Department of Radiation Oncology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
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22
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Modification of PARP4, XRCC3, and RAD51 Gene Polymorphisms on the Relation between Bisphenol A Exposure and Liver Abnormality. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17082794. [PMID: 32316696 PMCID: PMC7216258 DOI: 10.3390/ijerph17082794] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 04/13/2020] [Accepted: 04/16/2020] [Indexed: 12/18/2022]
Abstract
Repair genes may play critical roles in the relationships between environmental exposure and health outcomes. However, no evidence is available about the effect of repair gene polymorphisms on the relationship between bisphenol A (BPA) exposure and liver abnormality. Therefore, we evaluated the effect of nine genotyped polymorphisms in three repair genes, poly(ADP-ribose) polymerase family member 4 (PARP4), X-ray repair cross complementing 3 (XRCC3), and RAD51 recombinase (RAD51), on the relationship between BPA exposure and liver abnormality using repeated measures data for an elderly population. A significant association between BPA levels and liver abnormality was found only in elders with the PARP4 G-C-G haplotype, XRCC3 G-A-G haplotype, or RAD51 T-A-A haplotype (odds ratio (OR) = 2.16 and p = 0.0014 for PARP4; OR = 1.57 and p = 0.0249 for XRCC3; OR = 1.43 and p = 0.0422 for RAD51). Particularly, PARP4 and XRCC3 showed significant interactions with BPA exposure in relation to liver abnormality (p < 0.05 for both genes). These results indicate that PARP4, XRCC3, and RAD51 gene polymorphisms have modification effects on the relationship between BPA exposure and liver abnormality.
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Abstract
HCC (hepatocellular carcinoma) is the second leading cause of cancer deaths worldwide, with several etiologic causes, mostly inflammation-associated. Different inflammatory responses in the liver can be triggered by different etiological agents. The inflammatory process can be resolved or be persistent, depending on the etiology and multiple other factors. Chronic inflammation, tissue remodeling, genetic alterations, and modifications in cellular signaling are considered to be key processes promoting immunosuppression. The progressive immunosuppression leads to the inactivation of anti-tumor immunity involved in HCC carcinogenesis and progression. Tumor cellular processes including DNA damage, necrosis, and ER (endoplasmic reticulum) stress can affect both immune-surveillance and cancer-promoting inflammation, supporting a mutual interdependence. Here, we review the current understanding of how chronic liver injury and inflammation is triggered and sustained, and how inflammation is linked to HCC. The identification of many hepatic microenvironmental inflammatory processes and their effector molecules, has resulted in extensive translational work and promising clinical trials of new immunomodulatory agents.
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24
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Fu H, Archer KJ. High-dimensional variable selection for ordinal outcomes with error control. Brief Bioinform 2020; 22:334-345. [PMID: 32031572 DOI: 10.1093/bib/bbaa007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 01/06/2020] [Indexed: 12/24/2022] Open
Abstract
Many high-throughput genomic applications involve a large set of potential covariates and a response which is frequently measured on an ordinal scale, and it is crucial to identify which variables are truly associated with the response. Effectively controlling the false discovery rate (FDR) without sacrificing power has been a major challenge in variable selection research. This study reviews two existing variable selection frameworks, model-X knockoffs and a modified version of reference distribution variable selection (RDVS), both of which utilize artificial variables as benchmarks for decision making. Model-X knockoffs constructs a 'knockoff' variable for each covariate to mimic the covariance structure, while RDVS generates only one null variable and forms a reference distribution by performing multiple runs of model fitting. Herein, we describe how different importance measures for ordinal responses can be constructed that fit into these two selection frameworks, using either penalized regression or machine learning techniques. We compared these measures in terms of the FDR and power using simulated data. Moreover, we applied these two frameworks to high-throughput methylation data for identifying features associated with the progression from normal liver tissue to hepatocellular carcinoma to further compare and contrast their performances.
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25
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Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: New trends. J Hepatol 2020; 72:250-261. [PMID: 31954490 PMCID: PMC6986771 DOI: 10.1016/j.jhep.2019.08.025] [Citation(s) in RCA: 739] [Impact Index Per Article: 147.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 08/28/2019] [Accepted: 08/30/2019] [Indexed: 02/07/2023]
Abstract
The burden of hepatocellular carcinoma (HCC) is highest in East Asia and Africa, although its incidence and mortality are rapidly rising in the United States and Europe. With the implementation of hepatitis B vaccination and hepatitis C treatment programmes worldwide, the epidemiology of HCC is shifting away from a disease predominated by viral hepatitis - an increasing proportion of cases are now attributable to non-alcoholic steatohepatitis. Surveillance using ultrasound, with or without alpha-fetoprotein, every 6 months has been associated with improved early detection and improved overall survival; however, limitations in implementation lead to a high proportion of HCC being detected at late stages in clinical practice. Herein, we review the current state of HCC surveillance and highlight areas for future research, including improved risk stratification of at-risk patients, surveillance tools with higher sensitivity and specificity for early HCC, and interventions to increase surveillance utilisation.
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Affiliation(s)
- Amit G Singal
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Pietro Lampertico
- CRC "A. M. and A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Pierre Nahon
- Centre de Recherche des Cordeliers, Sorbonne Universités, Université Paris Descartes, Université Paris Diderot, Université Paris, Paris, France; Functional Genomics of Solid Tumors, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris, Paris, France; Service d'hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France; Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France
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Rebouissou S, Nault JC. Advances in molecular classification and precision oncology in hepatocellular carcinoma. J Hepatol 2020; 72:215-229. [PMID: 31954487 DOI: 10.1016/j.jhep.2019.08.017] [Citation(s) in RCA: 326] [Impact Index Per Article: 65.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 07/16/2019] [Accepted: 08/06/2019] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) arises from hepatocytes through the sequential accumulation of multiple genomic and epigenomic alterations resulting from Darwinian selection. Genes from various signalling pathways such as telomere maintenance, Wnt/β-catenin, P53/cell cycle regulation, oxidative stress, epigenetic modifiers, AKT/mTOR and MAP kinase are frequently mutated in HCC. Several subclasses of HCC have been identified based on transcriptomic dysregulation and genetic alterations that are closely related to risk factors, pathological features and prognosis. Undoubtedly, integration of data obtained from both preclinical models and human studies can help to accelerate the identification of robust predictive biomarkers of response to targeted biotherapy and immunotherapy. The aim of this review is to describe the main advances in HCC in terms of molecular biology and to discuss how this knowledge could be used in clinical practice in the future.
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Affiliation(s)
- Sandra Rebouissou
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Functional Genomics of Solid Tumors Laboratory, F-75006 Paris, France
| | - Jean-Charles Nault
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Functional Genomics of Solid Tumors Laboratory, F-75006 Paris, France; Liver Unit, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France; Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.
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Ahmed MW, Mahjabeen I, Gul S, Khursheed A, Mehmood A, Kayani MA. Relationship of single nucleotide polymorphisms and haplotype interaction of mitochondrial unfolded protein response pathway genes with head and neck cancer. Future Oncol 2019; 15:3819-3829. [PMID: 31651195 DOI: 10.2217/fon-2019-0365] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Aim: In this study, we evaluated the effect of selected polymorphisms of mitochondrial unfolded protein response (UPRmt) pathway in 500 head and neck cancer (HNC) patients and 500 healthy controls from Pakistan. Materials & methods: The experiments were conducted using tetra-ARMS PCR followed by DNA sequencing. Results: Multivariate analysis showed that AA genotype of rs3782116 showed fivefold, GG genotype of rs6598072 approximately twofold and CC genotype of rs4946936 and TT genotype of rs12212067 showed twofold increased risk of HNC. Furthermore, haplotype analysis showed that certain haplotypes of UPRmt pathway single nucleotide polymorphisms have significant association with increased HNC risk. Conclusion: These results show that genetic aberrations in UPRmt pathway genes have association with increased HNC risk and can be an indicator of advance clinical outcome especially invasion and metastasis.
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Affiliation(s)
- Malik Waqar Ahmed
- Cancer Genetics & Epigenetics Lab, Department of Biosciences, COMSATS University Islamabad, Park Road Tarlai Kalan, Islamabad Pakistan
| | - Ishrat Mahjabeen
- Cancer Genetics & Epigenetics Lab, Department of Biosciences, COMSATS University Islamabad, Park Road Tarlai Kalan, Islamabad Pakistan
| | - Shazma Gul
- Cancer Genetics & Epigenetics Lab, Department of Biosciences, COMSATS University Islamabad, Park Road Tarlai Kalan, Islamabad Pakistan
| | - Anum Khursheed
- Cancer Genetics & Epigenetics Lab, Department of Biosciences, COMSATS University Islamabad, Park Road Tarlai Kalan, Islamabad Pakistan
| | - Azhar Mehmood
- Cancer Genetics & Epigenetics Lab, Department of Biosciences, COMSATS University Islamabad, Park Road Tarlai Kalan, Islamabad Pakistan
| | - Mahmood Akhtar Kayani
- Cancer Genetics & Epigenetics Lab, Department of Biosciences, COMSATS University Islamabad, Park Road Tarlai Kalan, Islamabad Pakistan
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28
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Pocha C, Xie C. Hepatocellular carcinoma in alcoholic and non-alcoholic fatty liver disease-one of a kind or two different enemies? Transl Gastroenterol Hepatol 2019; 4:72. [PMID: 31728429 DOI: 10.21037/tgh.2019.09.01] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 08/22/2019] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular cancer (HCC) is a cancer with an overall poor prognosis and an alarming globally rising incidence. While viral etiology of chronic liver disease and HCC is down-trending, alcohol and excess calorie intake have emerged as major culprits. Alcohol related liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) share similar pathogenetic mechanism of hepatic injury and in promoting development of HCC; yet some genetic and epigenetic features are distinct and may promise clinical utility. Population based intervention are urgently needed to reduce alcohol use and improve metabolic factors such as obesity and diabetes. The goal is to identify at-risk patients, to link these patients to care and to provide effective management of chronic liver disease and HCC. This review focuses on the epidemiology, pathophysiology including genetic and epigenetic altercation as well as clinical aspects of ALD and NAFLD associated HCC.
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Affiliation(s)
- Christine Pocha
- Avera McKennnan Hospital and University Medical Center, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA.,Department of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Chencheng Xie
- Avera McKennnan Hospital and University Medical Center, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA.,Department of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia, PA, USA
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29
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Almomani R, Herkert JC, Posafalvi A, Post JG, Boven LG, van der Zwaag PA, Willems PHGM, van Veen-Hof IH, Verhagen JMA, Wessels MW, Nikkels PGJ, Wintjes LT, van den Berg MP, Sinke RJ, Rodenburg RJ, Niezen-Koning KE, van Tintelen JP, Jongbloed JDH. Homozygous damaging SOD2 variant causes lethal neonatal dilated cardiomyopathy. J Med Genet 2019; 57:23-30. [PMID: 31494578 DOI: 10.1136/jmedgenet-2019-106330] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/22/2019] [Accepted: 07/29/2019] [Indexed: 01/05/2023]
Abstract
BACKGROUND Idiopathic dilated cardiomyopathy (DCM) is recognised to be a heritable disorder, yet clinical genetic testing does not produce a diagnosis in >50% of paediatric patients. Identifying a genetic cause is crucial because this knowledge can affect management options, cardiac surveillance in relatives and reproductive decision-making. In this study, we sought to identify the underlying genetic defect in a patient born to consanguineous parents with rapidly progressive DCM that led to death in early infancy. METHODS AND RESULTS Exome sequencing revealed a potentially pathogenic, homozygous missense variant, c.542G>T, p.(Gly181Val), in SOD2. This gene encodes superoxide dismutase 2 (SOD2) or manganese-superoxide dismutase, a mitochondrial matrix protein that scavenges oxygen radicals produced by oxidation-reduction and electron transport reactions occurring in mitochondria via conversion of superoxide anion (O2 -·) into H2O2. Measurement of hydroethidine oxidation showed a significant increase in O2 -· levels in the patient's skin fibroblasts, as compared with controls, and this was paralleled by reduced catalytic activity of SOD2 in patient fibroblasts and muscle. Lentiviral complementation experiments demonstrated that mitochondrial SOD2 activity could be completely restored on transduction with wild type SOD2. CONCLUSION Our results provide evidence that defective SOD2 may lead to toxic increases in the levels of damaging oxygen radicals in the neonatal heart, which can result in rapidly developing heart failure and death. We propose SOD2 as a novel nuclear-encoded mitochondrial protein involved in severe human neonatal cardiomyopathy, thus expanding the wide range of genetic factors involved in paediatric cardiomyopathies.
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Affiliation(s)
- Rowida Almomani
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid, Jordan
| | - Johanna C Herkert
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Anna Posafalvi
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jan G Post
- Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Ludolf G Boven
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Paul A van der Zwaag
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Peter H G M Willems
- Department of Biochemistry, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ingrid H van Veen-Hof
- Laboratory of Metabolic Diseases, Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Judith M A Verhagen
- Department of Clinical Genetics, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Marja W Wessels
- Department of Clinical Genetics, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Peter G J Nikkels
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Liesbeth T Wintjes
- Department of Paediatrics, Radboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Maarten P van den Berg
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Richard J Sinke
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Richard J Rodenburg
- Department of Paediatrics, Radboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Klary E Niezen-Koning
- Laboratory of Metabolic Diseases, Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - J Peter van Tintelen
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jan D H Jongbloed
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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30
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Lleo A, de Boer YS, Liberal R, Colombo M. The risk of liver cancer in autoimmune liver diseases. Ther Adv Med Oncol 2019; 11:1758835919861914. [PMID: 31320937 PMCID: PMC6628541 DOI: 10.1177/1758835919861914] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 06/13/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC), the dominant primary malignancy of the liver, has
almost invariably a fatal outcome that can be averted only by early diagnosis
and treatment. While the close association of HCC with chronic viral hepatitis
and alcohol abuse has impacted favourably on screening and treatment of this
deadly tumour, at the same time it has long obscured the etiologic role of
autoimmune liver diseases. Recently, a systematic analysis of 25 published
cohorts disclosed a 3.1 × 1000 patients/year incidence of HCC in autoimmune
hepatitis patients that tripled in those with cirrhosis. HCC is also a sequela
of primary biliary cholangitis, where the incidence is more relevant in males,
those with advanced liver disease and nonresponders to ursodeoxycholic acid
therapy. Cholangiocarcinoma (CCA), the second ranking primary cancer of the
liver, is also on the rise with its intrahepatic pattern, in part reflecting an
association with chronic liver diseases of diverse aetiology. In the USA and
northern Europe, perihilar CCA is a frequent complication of primary sclerosing
cholangitis, a cholestatic disorder thought to be immune mediated. International
Guidelines clearly recommend HCC screening with abdominal ultrasonography every
6 months in autoimmune cirrhotic patients. While surveillance of patients with
autoimmune liver disorders who are at risk of HCC affects both early diagnosis
and radical therapy of this tumour, this is not the case for CCA, where early
diagnosis is challenged by the lack of sensitive and accurate tests for
screening.
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Affiliation(s)
- Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Via A. Manzoni 56, 20089 Rozzano (MI), Italy
| | - Ynto S de Boer
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers - VU University Medical Center, The Netherlands
| | | | - Massimo Colombo
- Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy
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31
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Ganne-Carrié N, Nahon P. Hepatocellular carcinoma in the setting of alcohol-related liver disease. J Hepatol 2019; 70:284-293. [PMID: 30658729 DOI: 10.1016/j.jhep.2018.10.008] [Citation(s) in RCA: 240] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 10/01/2018] [Accepted: 10/08/2018] [Indexed: 01/27/2023]
Abstract
Alcohol-related liver disease is the most prevalent type of chronic liver disease worldwide, accounting for 30% of hepatocellular carcinoma (HCC) cases and HCC-specific deaths. Alcohol has been associated with an increased risk of several malignancies, this risk starting at doses as low as 10 g/1 unit/day. The carcinogenic process includes direct acetaldehyde toxicity through the formation of protein and DNA adducts, an increased production of reactive oxygen species, changes to lipid peroxidation and metabolism, inflammation and an impaired immune response and modifications to DNA methylation. A high annual incidence of HCC has been observed in large European cohorts of patients with alcoholic cirrhosis, reaching 2.9%, with numerous host factors modulating this risk (age, gender, liver failure, genetic polymorphisms affecting oncogenic pathways). Because of impaired surveillance and poor patient compliance, HCC is often detected late in patients with chronic liver disease of alcoholic aetiology. This delay in detection, which is frequently made in the context of advanced liver cirrhosis rather than in surveillance programmes, results in more advanced HCC that is less amenable to curative treatment. Consequently, patients with alcohol-related HCC generally have a worse prognosis than those with non-alcoholic HCC.
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Affiliation(s)
- Nathalie Ganne-Carrié
- AP-HP, Hôpital Jean Verdier, Liver Unit, Bondy, France; University Paris 13, Sorbonne Paris Cité, "équipe labellisée Ligue Contre le Cancer", F-93000 Bobigny, France; INSERM UMR-1162: Functional Genomics of Solid Tumours, F-75010 Paris, France.
| | - Pierre Nahon
- AP-HP, Hôpital Jean Verdier, Liver Unit, Bondy, France; University Paris 13, Sorbonne Paris Cité, "équipe labellisée Ligue Contre le Cancer", F-93000 Bobigny, France; INSERM UMR-1162: Functional Genomics of Solid Tumours, F-75010 Paris, France
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32
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Abdel-Hamid M, Nada OH, Ellakwa DES, Ahmed LK. Role of Myeloperoxidase in hepatitis C virus related hepatocellular carcinoma. Meta Gene 2018. [DOI: 10.1016/j.mgene.2018.07.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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34
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Xing Y, Liu X, Pu Q, Wu M, Zhao JX. Biocompatible G-Quadruplex/Hemin for Enhancing Antibacterial Activity of H2O2. ACS APPLIED BIO MATERIALS 2018; 1:1019-1027. [DOI: 10.1021/acsabm.8b00211] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Yuqian Xing
- Department of Chemistry, University of North Dakota, Grand Forks, North Dakota 58202, United States
| | - Xiao Liu
- Department of Chemistry, University of North Dakota, Grand Forks, North Dakota 58202, United States
| | - Qinqin Pu
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58202, United States
| | - Min Wu
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58202, United States
| | - Julia Xiaojun Zhao
- Department of Chemistry, University of North Dakota, Grand Forks, North Dakota 58202, United States
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35
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Li T, Wang L, Lin S, Xu X, Liu M, Shen S, Yan Z, Mo R. Rational Design and Bioimaging Applications of Highly Specific “Turn-On” Fluorescent Probe for Hypochlorite. Bioconjug Chem 2018; 29:2838-2845. [DOI: 10.1021/acs.bioconjchem.8b00430] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Teng Li
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China
| | - Leikun Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China
| | - Shiqi Lin
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China
| | - Xiao Xu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China
| | - Meng Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China
| | - Shiyang Shen
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China
| | - Zhengyu Yan
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China
| | - Ran Mo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China
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36
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Galle PR, Forner A, Llovet JM, Mazzaferro V, Piscaglia F, Raoul JL, Schirmacher P, Vilgrain V. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2018; 69:182-236. [PMID: 29628281 DOI: 10.1016/j.jhep.2018.03.019] [Citation(s) in RCA: 5841] [Impact Index Per Article: 834.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 03/20/2018] [Indexed: 02/06/2023]
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Pravalika K, Sarmah D, Kaur H, Wanve M, Saraf J, Kalia K, Borah A, Yavagal DR, Dave KR, Bhattacharya P. Myeloperoxidase and Neurological Disorder: A Crosstalk. ACS Chem Neurosci 2018; 9:421-430. [PMID: 29351721 DOI: 10.1021/acschemneuro.7b00462] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Myeloperoxidase (MPO) is a protein present in azurophilic granules, macrophages, and neutrophils that are released into extracellular fluid (ECF) during inflammation. MPO releases hypochlorous acid (HOCl) and other chlorinated species. It is derived from hydrogen peroxide (H2O2) showing response during inflammatory conditions and plays a role in the immune defense against pathogens. MPO may show unwanted effects by indirectly increasing the formation of reactive nitrogen species (RNS), reactive oxygen species (ROS), and tumor necrosis factor alpha (TNF-α) leading to inflammation and oxidative stress. As neuroinflammation is one of the inevitable biological components among most of neurological disorders, MPO and its receptor may be explored as candidates for future clinical interventions. The purpose of this review is to provide an overview of the pathophysiological characteristics of MPO and further explore the possibilities to target it for clinical use. Targeting MPO is promising and may open an avenue to act as a biomarker for diagnosis with defined risk stratification in patients with various neurological disorders.
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Affiliation(s)
- Kanta Pravalika
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad Gandhinagar, 382 355 Gujarat, India
| | - Deepaneeta Sarmah
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad Gandhinagar, 382 355 Gujarat, India
| | - Harpreet Kaur
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad Gandhinagar, 382 355 Gujarat, India
| | - Madhuri Wanve
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad Gandhinagar, 382 355 Gujarat, India
| | - Jackson Saraf
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad Gandhinagar, 382 355 Gujarat, India
| | - Kiran Kalia
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad Gandhinagar, 382 355 Gujarat, India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, 788 011 Assam, India
| | - Dileep R Yavagal
- Department of Neurology and Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida 33136, United States
| | - Kunjan R Dave
- Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida 33136, United States
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad Gandhinagar, 382 355 Gujarat, India
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38
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Ayuso C, Rimola J, Vilana R, Burrel M, Darnell A, García-Criado Á, Bianchi L, Belmonte E, Caparroz C, Barrufet M, Bruix J, Brú C. Diagnosis and staging of hepatocellular carcinoma (HCC): current guidelines. Eur J Radiol 2018; 101:72-81. [PMID: 29571804 DOI: 10.1016/j.ejrad.2018.01.025] [Citation(s) in RCA: 240] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 01/10/2018] [Accepted: 01/27/2018] [Indexed: 12/20/2022]
Abstract
One of the key strategies to improve the prognosis of HCC, beside prevention, is to diagnose the tumor in early stages, when the patient is asymptomatic and the liver function is preserved, because in this clinical situation effective therapies with survival benefit can be applied. Imaging techniques are a key tool in the surveillance and diagnosis of HCC. Screening should be based in US every 6 months and non-invasive diagnostic criteria of HCC based on imaging findings on dynamic-MR and/or dynamic-CT have been validated and thus, accepted in clinical guidelines. The typical vascular pattern depicted by HCC on CT and or MRI consists on arterial enhancement, stronger than the surrounding liver (wash-in), and hypodensity or hyposignal intensity compared to the surrounding liver (wash-out) in the venous phase. This has a sensitivity of around 60% with a 96-100% specificity. Major improvements on liver imaging have been introduced in the latest years, adding functional information that can be quantified: the use of hepatobiliary contrast media for liver MRI, the inclusion of diffusion-weighted sequences in the standard protocols for liver MRI studies and new radiotracers for positron-emission tomography (PET). However, all them are still a matter of research prior to be incorporated in evidence based clinical decision making. This review summarizes the current knowledge about imaging techniques for the early diagnosis and staging of HCC, and it discusses the most relevant open questions.
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Affiliation(s)
- Carmen Ayuso
- Barcelona Clinic Liver Cancer (BCLC) Group: Radiology Department. Hospital Clínic, University of Barcelona. CIBER ehd. Spain.
| | - Jordi Rimola
- Barcelona Clinic Liver Cancer (BCLC) Group: Radiology Department. Hospital Clínic, University of Barcelona. CIBER ehd. Spain
| | - Ramón Vilana
- Barcelona Clinic Liver Cancer (BCLC) Group: Radiology Department. Hospital Clínic, University of Barcelona. CIBER ehd. Spain
| | - Marta Burrel
- Barcelona Clinic Liver Cancer (BCLC) Group: Radiology Department. Hospital Clínic, University of Barcelona. CIBER ehd. Spain
| | - Anna Darnell
- Barcelona Clinic Liver Cancer (BCLC) Group: Radiology Department. Hospital Clínic, University of Barcelona. CIBER ehd. Spain
| | - Ángeles García-Criado
- Barcelona Clinic Liver Cancer (BCLC) Group: Radiology Department. Hospital Clínic, University of Barcelona. CIBER ehd. Spain
| | - Luis Bianchi
- Barcelona Clinic Liver Cancer (BCLC) Group: Radiology Department. Hospital Clínic, University of Barcelona. CIBER ehd. Spain
| | - Ernest Belmonte
- Barcelona Clinic Liver Cancer (BCLC) Group: Radiology Department. Hospital Clínic, University of Barcelona. CIBER ehd. Spain
| | - Carla Caparroz
- Barcelona Clinic Liver Cancer (BCLC) Group: Radiology Department. Hospital Clínic, University of Barcelona. CIBER ehd. Spain
| | - Marta Barrufet
- Barcelona Clinic Liver Cancer (BCLC) Group: Radiology Department. Hospital Clínic, University of Barcelona. CIBER ehd. Spain
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer (BCLC) Group: Liver Unit. Hospital Clínic, University of Barcelona. CIBER ehd. Spain
| | - Concepción Brú
- Barcelona Clinic Liver Cancer (BCLC) Group: Radiology Department. Hospital Clínic, University of Barcelona. CIBER ehd. Spain
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Fatty Liver Disease and Hepatocellular Carcinoma: The Pathologist's View. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1032:55-69. [PMID: 30362090 DOI: 10.1007/978-3-319-98788-0_4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chronic alcohol misuse and progressed nonalcoholic fatty liver disease (NAFLD) due to the metabolic syndrome and resulting to nonalcoholic steatohepatitis (NASH) are prime causes of hepatocellular carcinoma (HCC) in Western industrialized countries. The incidence of HCC in NASH-cirrhosis is lower than that of HCC occuring in HCV-related or alcoholic cirrhosis. Up to 20% of cases of alcohol-associated HCC may develop in pre-cirrhotic liver while HCC is also increasingly recognised in pre-cirrhotic NASH raising questions on appropriate surveillance measures for these patient populations. The recently described steatohepatitic subtype of HCC presents with higher frequency in NAFLD compared to alcoholic liver disease (ALD) patients. This review will mainly focus on histopathology and summarize current data on the epidemiology, pathogenesis, diagnosis and management of NAFLD- and ALD-related HCC.
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40
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Nahon P, Nault JC. Constitutional and functional genetics of human alcohol-related hepatocellular carcinoma. Liver Int 2017; 37:1591-1601. [PMID: 28296015 DOI: 10.1111/liv.13419] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 03/08/2017] [Indexed: 02/13/2023]
Abstract
Exploration of the constitutional genetics of hepatocellular carcinoma (HCC) has identified numerous variants associated with a higher risk of liver cancer in alcoholic cirrhotic patients. Although Genome-Wide Association studies have not been carried out in the field of alcohol-related HCC, common single nucleotide polymorphisms conferring a small increase in the risk of liver cancer risk have been identified and shown to modulate ethanol metabolism, inflammation, oxidative stress, iron or lipid metabolism. Specific patterns of gene mutations including CTNNB1, TERT, ARID1A and SMARCA2 exist in alcohol-related HCC. Moreover, a specific mutational process observed at the nucleotide level by next generation sequencing has revealed cooperation between alcohol and tobacco in the development of HCC. Combining this genetic information with epidemiological and clinical data that might define specific HCC risk classes and refine surveillance strategies needs to be assessed in large prospective cohorts of patients with alcoholic cirrhosis.
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Affiliation(s)
- Pierre Nahon
- AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy, France.,Université Paris 13, Bobigny, France.,Inserm UMR-1162, "Functional Genetics of Solid Tumours", Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Oncoimmunology, Equipe labellisée Ligue contre le Cancer, Paris, France
| | - Jean-Charles Nault
- AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy, France.,Université Paris 13, Bobigny, France.,Inserm UMR-1162, "Functional Genetics of Solid Tumours", Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Oncoimmunology, Equipe labellisée Ligue contre le Cancer, Paris, France
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41
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Wang C, Gong J, Wu H. Development of gene polymorphisms in meditators of nonalcoholic fatty liver disease. Biomed Rep 2017; 7:95-104. [PMID: 28804621 DOI: 10.3892/br.2017.926] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 05/12/2017] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, the morbidity of which closely correlates with diversity of ethnicity, minority, family and location. Its histology spans from simple steatosis, to nonalcoholic steatohepatitis, which ultimately results in fibrosis, cirrhosis and hepatocellular carcinoma. The accelerating prevalence of NAFLD is due to an incremental incidence of metabolic syndrome that is distinguished by dyslipidemia, glucose impairment, obesity, excessive oxidative stress and adipocytokine impairment. Additionally, the pathogenesis of NAFLD is thought to be a multifactorial and complicated disease associated with lifestyle habits, nutritional factors and genetics. However, the pathogenesis and underlying mechanism in the development of NAFLD caused by genetics remains unclear. People have been increasingly emphasizing on the relationship between NAFLD and gene polymorphisms in recent years, with the aim of having a comprehensive elucidation of associated gene polymorphisms influencing the pathogenesis of the disease. In the current article, the authors attempted to critically summarize the most recently identified gene polymorphisms from the facets of glucose metabolism, fatty acid metabolism, oxidative stress and related cytokines in NAFLD that contribute to promoting the progression of the disease.
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Affiliation(s)
- Chun Wang
- Department of General Surgery, Yongchuan Hospital of Traditional Chinese Medicine, Chongqing 402161, P.R. China
| | - Jianping Gong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, P.R. China
| | - Hao Wu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, P.R. China
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42
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Joshi K, Kohli A, Manch R, Gish R. Alcoholic Liver Disease: High Risk or Low Risk for Developing Hepatocellular Carcinoma? Clin Liver Dis 2016; 20:563-80. [PMID: 27373617 DOI: 10.1016/j.cld.2016.02.012] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
In this review we critically assess the literature to evaluate the level of risk posed by alcohol as both a primary etiology of hepatocellular carcinoma (HCC) and as a cofactor in its development. Although there have been conflicting findings, based on the body of evidence to date, it appears that the linkage between compensated alcoholic liver disease-associated cirrhosis and HCC is best characterized as medium-high risk, with the risk increasing with age and with quantity and duration of alcohol consumption and is more pronounced in females. While abstinence is the most effective way to reduce HCC risk, its effect seems largely dependent on the severity of liver damage at the point of cessation. Alcohol clearly interacts with other etiologies and conditions including viral hepatitis B and C, hereditary hemochromatosis, diabetes, and obesity to increase the risk for developing HCC, either synergistically or additively. Continued progress in genetics, especially through mechanistic-based and genome-wide association studies may ultimately identify which single nucleotide polymorphisms are risk factors for the onset of alcoholic liver disease and its progression to HCC and lead to the development of targeted therapeutics which may help providers better manage at-risk patients.
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Affiliation(s)
- Kartik Joshi
- Division of Hepatology, St. Joseph's Hospital and Medical Center, Creighton University School of Medicine, 500 West Thomas Road, Suite 900, Phoenix, AZ 85013, USA
| | - Anita Kohli
- Division of Hepatology, St. Joseph's Hospital and Medical Center, Creighton University School of Medicine, 500 West Thomas Road, Suite 900, Phoenix, AZ 85013, USA; Division of Infectious Disease, St. Joseph's Hospital and Medical Center, Creighton University School of Medicine, 500 West Thomas Road, Suite 900, Phoenix, AZ 85013, USA
| | - Richard Manch
- Division of Hepatology, St. Joseph's Hospital and Medical Center, Creighton University School of Medicine, 500 West Thomas Road, Suite 900, Phoenix, AZ 85013, USA
| | - Robert Gish
- Division of Hepatology, St. Joseph's Hospital and Medical Center, Creighton University School of Medicine, 500 West Thomas Road, Suite 900, Phoenix, AZ 85013, USA; Division of Hepatology and Gastroenterology, Stanford University Hospitals and Clinics, 300 Pasteur Drive, Palo Alto, CA 94304, USA.
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43
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Abstract
Genome-wide association studies (GWAS) in the field of liver diseases have revealed previously unknown pathogenic loci and generated new biological hypotheses. In 2008, a GWAS performed in a population-based sample study, where hepatic liver fat content was measured by magnetic spectroscopy, showed a strong association between a variant (rs738409 C>G p.I148M) in the patatin-like phospholipase domain containing 3 (PNPLA3) gene and nonalcoholic fatty liver disease. Further replication studies have shown robust associations between PNPLA3 and steatosis, fibrosis/cirrhosis, and hepatocellular carcinoma on a background of metabolic, alcoholic, and viral insults. The PNPLA3 protein has lipase activity towards triglycerides in hepatocytes and retinyl esters in hepatic stellate cells. The I148M substitution leads to a loss of function promoting triglyceride accumulation in hepatocytes. Although PNPLA3 function has been extensively studied, the molecular mechanisms leading to hepatic fibrosis and carcinogenesis remain unclear. This unsuspected association has highlighted the fact that liver fat metabolism may have a major impact on the pathophysiology of liver diseases. Conversely, alone, this locus may have limited predictive value with regard to liver disease outcomes in clinical practice. Additional studies at the genome-wide level will be required to identify new variants associated with liver damage and cancer to explain a greater proportion of the heritability of these phenotypes. Thus, incorporating PNPLA3 and other genetic variants in combination with clinical data will allow for the development of tailored predictive models. This attractive approach should be evaluated in prospective cohorts.
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44
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Ray RS, Katyal A. Myeloperoxidase: Bridging the gap in neurodegeneration. Neurosci Biobehav Rev 2016; 68:611-620. [PMID: 27343997 DOI: 10.1016/j.neubiorev.2016.06.031] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 06/20/2016] [Accepted: 06/21/2016] [Indexed: 10/21/2022]
Abstract
Neurodegenerative conditions present a group of complex disease pathologies mostly due to unknown aetiology resulting in neuronal death and permanent neurological disability. Any undesirable stress to the brain, disrupts homeostatic balance, through a remarkable convergence of pathophysiological changes and immune dysregulation. The crosstalk between inflammatory and oxidative mechanisms results in the release of neurotoxic mediators apparently spearheaded by myeloperoxidase derived from activated microglia, astrocytes, neurons as well as peripheral inflammatory cells. These isolated entities combinedly have the potential to flare up and contribute significantly to neuropathology and disease progression. Recent, clinicopathological evidence support the association of myeloperoxidase and its cytotoxic product, hypochlorous acid in a plethora of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, Stroke, Epilepsy etc. But the biochemical and mechanistic insights into myeloperoxidase mediated neuroinflammation and neuronal death is still an uncharted territory. The current review outlines the emerging recognition of myeloperoxidase in neurodegeneration, which may offer novel therapeutic and diagnostic targets for neurodegenerative disorders.
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Affiliation(s)
- R S Ray
- Dr. B.R. Ambedkar Center for Biomedical Research (ACBR), University of Delhi, North Campus, Delhi 110 007, India.
| | - Anju Katyal
- Dr. B.R. Ambedkar Center for Biomedical Research (ACBR), University of Delhi, North Campus, Delhi 110 007, India.
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45
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Goossens N, Hoshida Y. Is Hepatocellular Cancer the Same Disease in Alcoholic and Nonalcoholic Fatty Liver Diseases? Gastroenterology 2016; 150:1710-7. [PMID: 26784140 PMCID: PMC5120760 DOI: 10.1053/j.gastro.2016.01.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Revised: 01/03/2016] [Accepted: 01/07/2016] [Indexed: 12/14/2022]
Affiliation(s)
- Nicolas Goossens
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA,Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland
| | - Yujin Hoshida
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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46
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The Role of Catalase C262T Gene Polymorphism in the Susceptibility and Survival of Cancers. Sci Rep 2016; 6:26973. [PMID: 27225983 PMCID: PMC4880922 DOI: 10.1038/srep26973] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 05/10/2016] [Indexed: 02/07/2023] Open
Abstract
Catalase (CAT), one antioxidant enzyme, may provide resistance against many diseases. Many previous studies reported predictive and prognostic values of CAT C262T polymorphism in cancers, with divergent results. This study aimed to summarize the overall relationships between CAT C262T polymorphism and cancer risk or survival. A total of 27 eligible publications were included in susceptibility analysis, while 8 publications contained survival outcomes. The results revealed significant relationship between CAT C262T polymorphism and cancer risk(TT + CT vs CC: OR = 1.05, 95%CI = 1.00–1.10, P = 0.036), subgroup analyses indicated the CAT C262T polymorphism was significantly correlated with an increased risk for prostate cancer (TT vs CC + CT: OR = 1.43, 95%CI = 1.20–1.70, P < 0.001) and increased risk among Caucasians (TT vs CC + CT: OR = 1.19, 95%CI = 1.09–1.31, P < 0.001), while no associations between the polymorphism and Asian or mixed population were established. In the survival analysis, no interactions were identified between this polymorphism and cancer survival (TT + CT vs CC: HR = 1.37, 95%CI = 0.70–2.70, P = 0.36). In conclusion, the CAT C262T polymorphismmay be a candidate markerfor cancer risk with type-specific and population-specific effects but not a fine prognostic factor for cancer survival.
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47
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Kim JH, Lee MR, Hong YC. Modification of the association of bisphenol A with abnormal liver function by polymorphisms of oxidative stress-related genes. ENVIRONMENTAL RESEARCH 2016; 147:324-30. [PMID: 26922413 DOI: 10.1016/j.envres.2016.02.026] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 01/26/2016] [Accepted: 02/18/2016] [Indexed: 05/22/2023]
Abstract
Some studies suggested oxidative stress as a possible mechanism for the relation between exposure to bisphenol A (BPA) and liver damage. Therefore, we evaluated modification of genetic polymorphisms of cyclooxygenase 2 (COX2 or PTGS2), epoxide hydrolase 1 (EPHX1), catalase (CAT), and superoxide dismutase 2 (SOD2 or MnSOD), which are oxidative stress-related genes, on the relation between exposure to BPA and liver function in the elderly. We assessed the association of visit-to-visit variations in BPA exposure with abnormal liver function by each genotype or haplotype after controlling for age, sex, BMI, alcohol consumption, exercise, urinary cotinine levels, and low density lipoprotein cholesterol using a GLIMMIX model. A significant association of BPA with abnormal liver function was observed only in participants with COX2 GG genotype at rs5277 (odds ratio (OR)=3.04 and p=0.0231), CAT genotype at rs769218 (OR=4.16 and p=0.0356), CAT CT genotype at rs769217 (OR=4.19 and p=0.0348), SOD2 TT genotype at rs4880 (OR=2.59 and p=0.0438), or SOD2 GG genotype at rs2758331 (OR=2.57 and p=0.0457). Moreover, we also found higher OR values in participants with a pair of G-G haplotypes for COX2 (OR=2.81 and p=0.0384), G-C-A haplotype for EPHX1 (OR=4.63 and p=0.0654), A-T haplotype for CAT (OR=4.48 and p=0.0245), or T-G-A haplotype for SOD2 (OR=2.91 and p=0.0491) compared with those with the other pair of haplotypes for each gene. Furthermore, the risk score composed of 4 risky pair of haplotypes showed interactive effect with BPA on abnormal liver function (p=0.0057). Our study results suggest that genetic polymorphisms of COX2, EPHX1, CAT, and SOD2 modify the association of BPA with liver function.
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Affiliation(s)
- Jin Hee Kim
- Department of Environmental Health, Graduate School of Public Health, Seoul National University, Seoul 151-742, Republic of Korea; Department of Bioscience and Bioengineering, Sejong University, Seoul, 05006, Republic of Korea
| | - Mee-Ri Lee
- (c)Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
| | - Yun-Chul Hong
- (c)Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea; (d)Institute of Environmental Medicine, Seoul National University Medical Research Center, Seoul 110-799, Republic of Korea.
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48
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Sousa VCSD, Carmo RF, Vasconcelos LRS, Aroucha DCBL, Pereira LMMB, Moura P, Cavalcanti MSM. Association of Catalase and Glutathione Peroxidase 1 Polymorphisms with Chronic Hepatitis C Outcome. Ann Hum Genet 2016; 80:145-53. [PMID: 26990426 DOI: 10.1111/ahg.12152] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 02/03/2016] [Indexed: 12/14/2022]
Abstract
The hepatic damage caused by hepatitis C virus (HCV) infection is associated with the host immune response and viral regulatory factors. Catalase (CAT) and glutathione peroxidase 1 (GPX1) are antioxidant enzymes located in the peroxisomes and mitochondria, respectively, and are responsible for the control of intracellular hydrogen peroxide levels. Polymorphisms in CAT (C-262T) and GPX1 (Pro198Leu) are correlated with serum levels and enzyme activity. This study aimed to investigate the association of genetic polymorphisms of CAT C-262T (rs1001179) and GPX1 Pro198Leu (rs1050450) with different stages of liver fibrosis and development of hepatocellular carcinoma (HCC). This study included 445 patients with chronic hepatitis C, of whom 139 patients had mild fibrosis (F0-F1), 200 had moderate/severe fibrosis (F2-F4), and 106 had HCC. Genotyping of SNPs was performed by real-time PCR using TaqMan probes. The Pro/Pro genotype of GPX1 was significantly associated with fibrosis severity, HCC, Child Pugh score, and BCLC staging. Additionally, patients carrying both CT+TT genotypes in the CAT gene and the Pro/Pro genotype in the GPX1 gene had higher risk for developing moderate/severe fibrosis or HCC (p = 0.009, OR 2.40 and p = 0.002, OR 3.56, respectively). CAT and GPX1 polymorphisms may be implicated in the severity of liver fibrosis and HCC caused by HCV.
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Affiliation(s)
- Vanessa C S D Sousa
- Instituto de Ciências Biológicas - ICB, Universidade de Pernambuco - UPE, Brazil
| | - Rodrigo F Carmo
- Colegiado de Farmácia, Universidade Federal do Vale do São Francisco - UNIVASF, Brazil.,Rede Nordeste de Biotecnologia - RENORBIO, Brazil
| | - Luydson R S Vasconcelos
- Instituto do Fígado e Transplantes de Pernambuco - IFP, Brazil.,Centro de Pesquisas Aggeu Magalhães (FIOCRUZ), Brazil
| | - Dayse C B L Aroucha
- Instituto do Fígado e Transplantes de Pernambuco - IFP, Brazil.,Faculdade de Ciências Médicas, UPE, Brazil
| | - Leila M M B Pereira
- Instituto do Fígado e Transplantes de Pernambuco - IFP, Brazil.,Faculdade de Ciências Médicas, UPE, Brazil
| | - Patrícia Moura
- Instituto de Ciências Biológicas - ICB, Universidade de Pernambuco - UPE, Brazil
| | - Maria S M Cavalcanti
- Instituto de Ciências Biológicas - ICB, Universidade de Pernambuco - UPE, Brazil
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49
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Forner A, Reig M, Varela M, Burrel M, Feliu J, Briceño J, Sastre J, Martí-Bonmati L, Llovet JM, Bilbao JI, Sangro B, Pardo F, Ayuso C, Bru C, Tabernero J, Bruix J. [Diagnosis and treatment of hepatocellular carcinoma. Update consensus document from the AEEH, SEOM, SERAM, SERVEI and SETH]. Med Clin (Barc) 2016; 146:511.e1-511.e22. [PMID: 26971984 DOI: 10.1016/j.medcli.2016.01.028] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 01/22/2016] [Accepted: 01/28/2016] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma is the most common primary malignancy of the liver and one of the most frequent causes of death in patients with liver cirrhosis. Simultaneously with the recognition of the clinical relevance of this neoplasm, in recent years there have been important developments in the diagnosis, staging and treatment of HCC. Consequently, the Asociación Española para el Estudio del Hígado has driven the need to update clinical practice guidelines, continuing to invite all the societies involved in the diagnosis and treatment of this disease to participate in the drafting and approval of the document (Sociedad Española de Trasplante Hepático, Sociedad Española de Radiología Médica, Sociedad Española de Radiología Vascular e Intervencionista y Sociedad Española de Oncología Médica). The clinical practice guidelines published in 2009 accepted as Clinical Practice Guidelines of the National Health System has been taken as reference document, incorporating the most important advances that have been made in recent years. The scientific evidence for the treatment of HCC has been evaluated according to the recommendations of the National Cancer Institute (www.cancer.gov) and the strength of recommendation is based on the GRADE system.
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Affiliation(s)
- Alejandro Forner
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España
| | - María Reig
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España
| | - María Varela
- Sección de Hepatología, Servicio de Aparato Digestivo, Hospital Universitario Central de Asturias (HUCA), Universidad de Oviedo, Oviedo, España
| | - Marta Burrel
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Radiodiagnóstico, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Jaime Feliu
- Servicio de Oncología Médica, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Sociedad Española de Oncología Médica, Madrid, España
| | - Javier Briceño
- Unidad de Trasplante Hepático, Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, España
| | - Javier Sastre
- Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, España
| | - Luis Martí-Bonmati
- Departamento de Radiología, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - Josep María Llovet
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, Estados Unidos
| | - José Ignacio Bilbao
- Unidad de Radiología Vascular e Intervencionista, Departamento de Radiodiagnóstico, Clínica Universidad de Navarra, Pamplona, España
| | - Bruno Sangro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Unidad de Hepatología, Departamento de Medicina Interna, Clínica Universidad de Navarra, Pamplona, España
| | - Fernando Pardo
- Servicio de Cirugía Hepatobliopancreática y Trasplante, Clínica Universidad de Navarra, Pamplona, España
| | - Carmen Ayuso
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Radiodiagnóstico, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Concepció Bru
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Radiodiagnóstico, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Josep Tabernero
- Servicio de Oncología Médica, Hospital Universitario Vall d'Hebrón, Barcelona, Universidad Autónoma de Barcelona, Barcelona, España
| | - Jordi Bruix
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España.
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Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. Genetic Landscape and Biomarkers of Hepatocellular Carcinoma. Gastroenterology 2015; 149:1226-1239.e4. [PMID: 26099527 DOI: 10.1053/j.gastro.2015.05.061] [Citation(s) in RCA: 923] [Impact Index Per Article: 92.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Revised: 05/08/2015] [Accepted: 05/20/2015] [Indexed: 12/02/2022]
Abstract
Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death. Its mortality has increased in Western populations, with a minority of patients diagnosed at early stages, when curative treatments are feasible. Only the multikinase inhibitor sorafenib is available for the management of advanced cases. During the last 10 years, there has been a clear delineation of the landscape of genetic alterations in HCC, including high-level DNA amplifications in chromosome 6p21 (VEGFA) and 11q13 (FGF19/CNND1), as well as homozygous deletions in chromosome 9 (CDKN2A). The most frequent mutations affect TERT promoter (60%), associated with an increased telomerase expression. TERT promoter can also be affected by copy number variations and hepatitis B DNA insertions, and it can be found mutated in preneoplastic lesions. TP53 and CTNNB1 are the next most prevalent mutations, affecting 25%-30% of HCC patients, that, in addition to low-frequency mutated genes (eg, AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2), help define some of the core deregulated pathways in HCC. Conceptually, some of these changes behave as prototypic oncogenic addiction loops, being ideal biomarkers for specific therapeutic approaches. Data from genomic profiling enabled a proposal of HCC in 2 major molecular clusters (proliferation and nonproliferation), with differential enrichment in prognostic signatures, pathway activation and tumor phenotype. Translation of these discoveries into specific therapeutic decisions is an unmet medical need in this field.
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Affiliation(s)
- Jessica Zucman-Rossi
- Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hematologie, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, Bobigny, France; Université Paris Diderot, Paris.
| | - Augusto Villanueva
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jean-Charles Nault
- Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hematologie, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Service d'hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France
| | - Josep M Llovet
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Liver Unit, CIBEREHD, Hospital Clínic, Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
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