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Zhao X, Zhang Y, Luo B. Ferroptosis, from the virus point of view: opportunities and challenges. Crit Rev Microbiol 2025; 51:246-263. [PMID: 38588443 DOI: 10.1080/1040841x.2024.2340643] [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: 03/24/2023] [Revised: 12/21/2023] [Accepted: 04/01/2024] [Indexed: 04/10/2024]
Abstract
Ferroptosis is a new type of cell death, which is mainly dependent on the formation and accumulation of reactive oxygen species and lipid peroxides mediated by iron. It is distinct from other forms of regulation of cell death in morphology, immunology, biochemistry, and molecular biology. Various cell death mechanisms have been observed in many viral infections, and virus-induced cell death has long been considered as a double-edged sword that can inhibit or aggravate viral infections. However, understanding of the role of ferroptosis in various viral infections is limited. Special attention will be paid to the mechanisms of ferroptosis in mediating viral infection and antiviral treatment associated with ferroptosis. In this paper, we outlined the mechanism of ferroptosis. Additionally, this paper also review research on ferroptosis from the perspective of the virus, discussed the research status of ferroptosis in virus infection and classified and summarized research on the interaction between viral infections and ferroptosis.
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Affiliation(s)
- Xia Zhao
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Yan Zhang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China
- Department of Clinical Laboratory, Zibo Central Hospital, Zibo, China
| | - Bing Luo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China
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2
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Sah J, Singh I. Role of Essential Oils and Antioxidants in the Treatment of Fibrosis. Curr Drug Res Rev 2025; 17:76-89. [PMID: 40183147 DOI: 10.2174/0125899775271616231205111827] [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: 08/14/2023] [Revised: 10/14/2023] [Accepted: 11/06/2023] [Indexed: 04/05/2025]
Abstract
Fibrosis is the leading cause of many lethal diseases. It is characterized by the accumulation of extracellular matrix (ECM) components, which leads to damaged tissue functioning in the influenced organs. Essential oils are concentrated hydrophobic liquid having volatile compounds extracted from plant or plant parts while antioxidants are the compounds that help in scavenging free radicals and prevent reducing the oxidation processes. In this review, challenges that come during the treatment of fibrosis have been covered, mechanism of action of both essential oil and antioxidants is also outlined in this article. This review aimed to provide scientific fundamental and knowledge, ideas for the development and application of essential oils and antioxidants in the treatment of fibrosis.
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Affiliation(s)
- Jaishree Sah
- Amity Institute of Pharmacy, Amity University, Noida, India
| | - Indu Singh
- Amity Institute of Pharmacy, Amity University, Noida, India
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Jassey A, Paudel B, Wagner MA, Pollack N, Cheng IT, Godoy-Ruiz R, Weber DJ, Jackson WT. Mitophagosomes induced during EV-D68 infection promote viral nonlytic release. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.05.627125. [PMID: 39677747 PMCID: PMC11643070 DOI: 10.1101/2024.12.05.627125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Enterovirus-D68 (EV-D68) is a plus-strand RNA virus that primarily causes infant respiratory infections. In rare pediatric cases, infection with EV-D68 has been associated with acute flaccid myelitis, a polio-like paralytic disease. We have previously demonstrated that EV-D68 induces nonselective autophagy for its benefit. Here, we demonstrate that EV-D68 induces mitophagy, the specific autophagic degradation of mitochondria. EV-D68 infection induces mitophagosome formation and several hallmarks of mitophagy, including mitochondrial fragmentation, mitochondrial membrane potential loss, and Parkin translocation to the mitochondria were observed in EV-D68 infected cells. The 3C protease of EV-D68 cleaves the mitochondrial fusion protein, mitofusin-2, near the C-terminal HR2 domain to induce mitochondrial fragmentation, and these fragmented mitochondria colocalized with double-stranded RNA (dsRNA), which labels viral RNA replication sites after peak viral RNA replication. Depleting components of mitophagy signaling specifically reduced EV-D68 release without impacting viral intracellular titers. Our results suggest that whereas the machinery of macroautophagy supports various stages of enterovirus replication, including viral genomic RNA replication and capsid maturation, mitophagy is the specific form of autophagy that regulates the nonlytic release of enteroviruses from cells.
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Affiliation(s)
- Alagie Jassey
- Department of Microbiology and Immunology and Center for Pathogen Research, University of Maryland School of Medicine, 685 W. Baltimore Avenue, Baltimore, MD 21201, USA
| | - Bimal Paudel
- Department of Microbiology and Immunology and Center for Pathogen Research, University of Maryland School of Medicine, 685 W. Baltimore Avenue, Baltimore, MD 21201, USA
| | - Michael A. Wagner
- Department of Microbiology and Immunology and Center for Pathogen Research, University of Maryland School of Medicine, 685 W. Baltimore Avenue, Baltimore, MD 21201, USA
| | - Noah Pollack
- Department of Microbiology and Immunology and Center for Pathogen Research, University of Maryland School of Medicine, 685 W. Baltimore Avenue, Baltimore, MD 21201, USA
| | - I-Ting Cheng
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore
- Institute for Bioscience and Biotechnology Research, Rockville
- The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore
| | - Raquel Godoy-Ruiz
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore
- Institute for Bioscience and Biotechnology Research, Rockville
- The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore
| | - David J. Weber
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore
- Institute for Bioscience and Biotechnology Research, Rockville
- The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore
| | - William T. Jackson
- Department of Microbiology and Immunology and Center for Pathogen Research, University of Maryland School of Medicine, 685 W. Baltimore Avenue, Baltimore, MD 21201, USA
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Ikuta S, Aihara T, Kasai M, Nakajima T, Yamanaka N. Construction and validation of a preoperative prognostic model integrating the novel aspartate aminotransferase-albumin score for hepatocellular carcinoma patients undergoing liver resection. Ann Hepatobiliary Pancreat Surg 2024; 28:440-450. [PMID: 39129152 PMCID: PMC11599819 DOI: 10.14701/ahbps.24-110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/05/2024] [Accepted: 07/12/2024] [Indexed: 08/13/2024] Open
Abstract
Backgrounds/Aims Patients undergoing liver resection for hepatocellular carcinoma (HCC) often possess good liver reserve, which may limit the prognostic effectiveness of existing liver function scores. This study aimed to develop a novel liver function score and a preoperative prognostic model specifically for HCC resection patients. Methods Eight hundred twenty-seven HCC patients undergoing initial liver resection were segregated into training and validation cohorts in a 6:4 ratio. Cox regression analysis was employed to identify significant parameters influencing overall survival. The efficacy of the liver function score and prognostic model was evaluated using metrics such as the area under the receiver operating characteristic curve. Results Aspartate aminotransferase (AST) and albumin emerged as significant prognostic indicators. The AST-albumin (ASAL) score, calculated as exp [AST (IU/L) × 0.005 - albumin (g/dL) × 1.043] × 100, outperformed existing scores such as Child-Turcotte-Pugh, albumin-bilirubin, platelet-albumin, and AST-platelet ratio index in both training and validation cohorts. Additionally, a scoring model that combined the ASAL score with alpha-fetoprotein and the up-to-seven criterion exhibited superior discriminatory capabilities compared to the American Joint Committee on Cancer tumor, node, metastasis stage, and Barcelona Clinic Liver Cancer stage. Conclusions The proposed prognostic model that integrates the novel ASAL score offers promising prognostic potential for HCC patients undergoing liver resection.
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Affiliation(s)
| | | | - Meidai Kasai
- Department of Surgery, Meiwa Hospital, Hyogo, Japan
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You Y, Qian Z, Jiang Y, Chen L, Wu D, Liu L, Zhang F, Ning X, Zhang Y, Xiao J. Insights into the pathogenesis of gestational and hepatic diseases: the impact of ferroptosis. Front Cell Dev Biol 2024; 12:1482838. [PMID: 39600338 PMCID: PMC11588751 DOI: 10.3389/fcell.2024.1482838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 10/30/2024] [Indexed: 11/29/2024] Open
Abstract
Ferroptosis, a distinct form of non-apoptotic cell death characterized by iron dependency and lipid peroxidation, is increasingly linked to various pathological conditions in pregnancy and liver diseases. It plays a critical role throughout pregnancy, influencing processes such as embryogenesis, implantation, and the maintenance of gestation. A growing body of evidence indicates that disruptions in these processes can precipitate pregnancy-related disorders, including pre-eclampsia (PE), gestational diabetes mellitus (GDM), and intrahepatic cholestasis of pregnancy (ICP). Notably, while ICP is primarily associated with elevated maternal serum bile acid levels, its precise etiology remains elusive. Oxidative stress induced by bile acid accumulation is believed to be a significant factor in ICP pathogenesis. Similarly, the liver's susceptibility to oxidative damage underscores the importance of lipid metabolism dysregulation and impaired iron homeostasis in the progression of liver diseases such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), cholestatic liver injury, autoimmune hepatitis (AIH), acute liver injury, viral hepatitis, liver fibrosis, and hepatocellular carcinoma (HCC). This review discusses the shared signaling mechanisms of ferroptosis in gestational and hepatic diseases, and explores recent advances in understanding the mechanisms of ferroptosis and its potential role in the pathogenesis of gestational and hepatic disorders, with the aim of identifying viable therapeutic targets.
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Affiliation(s)
- Yilan You
- Departments of Obstetrics and Gynecology, Wuxi Maternal and Child Healthcare Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Zhiwen Qian
- Departments of Obstetrics and Gynecology, Wuxi Maternal and Child Healthcare Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Ying Jiang
- Departments of Obstetrics and Gynecology, Wuxi Maternity and Child Healthcare Hospital, Women’s Hospital of Jiangnan University, Jiangnan University, Wuxi, China
| | - Lingyan Chen
- Departments of Obstetrics and Gynecology, Wuxi Maternal and Child Healthcare Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Danping Wu
- Departments of Obstetrics and Gynecology, Wuxi Maternity and Child Healthcare Hospital, Women’s Hospital of Jiangnan University, Jiangnan University, Wuxi, China
| | - Lu Liu
- Departments of Obstetrics and Gynecology, Wuxi Maternity and Child Healthcare Hospital, Women’s Hospital of Jiangnan University, Jiangnan University, Wuxi, China
| | - Feng Zhang
- Departments of Obstetrics and Gynecology, Wuxi Maternal and Child Healthcare Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Xin Ning
- Departments of Obstetrics and Gynecology, Wuxi Maternity and Child Healthcare Hospital, Women’s Hospital of Jiangnan University, Jiangnan University, Wuxi, China
| | - Yan Zhang
- Departments of Obstetrics and Gynecology, Wuxi Maternal and Child Healthcare Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
- Departments of Obstetrics and Gynecology, Wuxi Maternity and Child Healthcare Hospital, Women’s Hospital of Jiangnan University, Jiangnan University, Wuxi, China
| | - Jianping Xiao
- Departments of Obstetrics and Gynecology, Wuxi Maternal and Child Healthcare Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
- Departments of Obstetrics and Gynecology, Wuxi Maternity and Child Healthcare Hospital, Women’s Hospital of Jiangnan University, Jiangnan University, Wuxi, China
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Hsieh TJ, Pan HW, Lan YY, Hua GY, Hsu YC, Chiu WC. The Prognostic Significance of Plasma Beta2-Glycoprotein I Levels in Hepatocellular Carcinoma Patients. CANCER DIAGNOSIS & PROGNOSIS 2024; 4:735-742. [PMID: 39502607 PMCID: PMC11534042 DOI: 10.21873/cdp.10389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 07/22/2024] [Accepted: 08/16/2024] [Indexed: 11/08/2024]
Abstract
Background/Aim Beta2-glycoprotein I (β2-GPI) is a plasma glycoprotein with multiple physiological functions, but its relationship with hepatocellular carcinoma (HCC) is still poorly understood. HCC is one of the most common forms of liver cancer and is a leading cause of cancer-related death worldwide. This study aimed to investigate the association between β2-GPI and liver cancer and further validate its potential as a biomarker for HCC. Patients and Methods Thirty-six patients diagnosed with HCC at the Division of Gastroenterology and Hepatology, E-Da Hospital, Taiwan, were included in the study. The expression levels of β2-GPI in plasma specimens from patients with HCC were determined by enzyme immunoassay and analyzed in relation to clinicopathological variables using the Chi-square test or Fisher's exact test. The predictive significance of β2-GPI for both overall survival (OS) and disease-free survival (DFS) was assessed using Kaplan-Meier estimates, and the statistical significance of differences was evaluated through the log-rank test. Cox proportional hazards regression models were used to evaluate the association between OS/DFS time and clinicopathological characteristics. Results Results: Plasma β2-GPI levels were significantly lower in patients with HCC compared to non-cancer controls and significantly correlated with aspartate aminotransferase (AST) levels of HCC. High plasma β2-GPI levels were significantly associated with better OS and DFS in HCC patients. Furthermore, in multiple variates analyses, OS was found to be significantly better in HCC patients with higher plasma β2-GPI expression. Conclusion Elevated levels of β2-GPI protein in the plasma of HCC patients were identified as an independent factor predictive of improved OS and DFS. Activating β2-GPI in individuals at high risk could serve as a promising way for mitigating the progression of HCC.
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Affiliation(s)
- Tsung-Jen Hsieh
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan, R.O.C
| | - Hung-Wei Pan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan, R.O.C
- School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung, Taiwan, R.O.C
| | - Yu-Yan Lan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan, R.O.C
| | - Guan-Ying Hua
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan, R.O.C
| | - Yao-Chun Hsu
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan, R.O.C
- Division of Gastroenterology and Hepatology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan, R.O.C
| | - Wen-Chin Chiu
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan, R.O.C
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Tani J, Masaki T, Oura K, Tadokoro T, Morishita A, Kobara H. Extrahepatic Cancer Risk in Patients with Hepatitis C Virus Infection Treated with Direct-Acting Antivirals. Microorganisms 2024; 12:1926. [PMID: 39338599 PMCID: PMC11434491 DOI: 10.3390/microorganisms12091926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 09/30/2024] Open
Abstract
Chronic hepatitis C virus (HCV) infection is associated with an increased risk of extrahepatic cancers, particularly non-Hodgkin lymphoma. The introduction of direct-acting antivirals (DAAs) has revolutionized HCV therapy, resulting in high cure rates. However, concerns have been raised about potential effects on cancer risk. This review summarizes the current evidence on extrahepatic cancer risk in HCV-infected patients treated with DAAs. We examined epidemiologic data on HCV-associated extrahepatic cancers and explored potential mechanisms linking HCV to carcinogenesis outside the liver. Studies evaluating cancer outcomes after DAA therapy were critically reviewed while considering methodological challenges. While some studies suggested a reduced risk of extrahepatic cancers after DAA therapy, others showed no significant change. Limitations included short follow-up periods and confounding variables. Immunological changes following rapid HCV clearance may have complex effects on cancer risk. Long-term prospective studies and mechanistic investigations are needed to fully elucidate the relationship between DAA therapy and extrahepatic cancer risk in HCV patients. Clinicians should remain vigilant for extrahepatic malignancies in this population.
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Affiliation(s)
- Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Takamatsu 761-0793, Kagawa, Japan
| | - Tsutomu Masaki
- Kagawa Saiseikai Hospital, Takamatsu 761-8076, Kagawa, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Takamatsu 761-0793, Kagawa, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Takamatsu 761-0793, Kagawa, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Takamatsu 761-0793, Kagawa, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Takamatsu 761-0793, Kagawa, Japan
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Egresi A, Blázovics A, Lengyel G, Tóth AG, Csongrády B, Jakab Z, Hagymási K. Redox Homeostasis and Non-Invasive Assessment of Significant Liver Fibrosis by Shear Wave Elastography. Diagnostics (Basel) 2024; 14:1945. [PMID: 39272729 PMCID: PMC11394606 DOI: 10.3390/diagnostics14171945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/15/2024] [Accepted: 08/30/2024] [Indexed: 09/15/2024] Open
Abstract
Hepatic fibrosis with various origins can be estimated non-invasively by using certain biomarkers and imaging-based measurements. The aim of our study was to examine redox homeostasis biomarkers and liver stiffness measurements for the assessment of significant liver fibrosis in different etiologies of chronic liver diseases. A cohort study consisting of 88 chronic liver disease patients of both sexes (age 49.1 ± 14.7 years) was performed. Cytokine profiles as well as redox homeostasis characteristics were determined. Liver fibrosis stages were assessed with shear wave elastography. The plasma levels of four cytokines showed no significant alteration between the four fibrotic stages; however, higher values were measured in the F2-4 stages. Free sulfhydryl group concentration, the marker of redox homeostasis, was lower in significant fibrosis (F0-F1: 0.36 ± 0.06 vs. F2-4: 0.29 ± 0.08 mmol/L, p < 0.05). Higher chemiluminescence values, as free radical-antioxidant parameters, were detected in advanced fibrosis stages in erythrocytes (F0-F1: 36.00 ± 37.13 vs. F2-4: 51.47 ± 44.34 RLU%). These data suggest that oxidative stress markers can predict significant fibrosis, with the aim of reducing the number of protocol liver biopsies in patients unlikely to have significant disease; however, their role in distinguishing between the certain fibrosis groups needs further studies.
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Affiliation(s)
- Anna Egresi
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, 1091 Budapest, Hungary
| | - Anna Blázovics
- Department of Surgical Research and Techniques, The Heart and Vascular Center, Semmelweis University, 1091 Budapest, Hungary
| | - Gabriella Lengyel
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, 1091 Budapest, Hungary
| | - Adrienn Gréta Tóth
- Centre for Bioinformatics, University of Veterinary Medicine, 1078 Budapest, Hungary
| | - Barbara Csongrády
- Department of Radiology, Semmelweis University, 1091 Budapest, Hungary
| | - Zsuzsanna Jakab
- Department of Internal Medicine and Oncology, Semmelweis University, 1091 Budapest, Hungary
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Wang F, Yan CY, Qin Y, Wang ZM, Liu D, He Y, Yang M, Wen L, Zhang D. Multiple Machine-Learning Fusion Model Based on Gd-EOB-DTPA-Enhanced MRI and Aminotransferase-to-Platelet Ratio and Gamma-Glutamyl Transferase-to-Platelet Ratio to Predict Microvascular Invasion in Solitary Hepatocellular Carcinoma: A Multicenter Study. J Hepatocell Carcinoma 2024; 11:427-442. [PMID: 38440051 PMCID: PMC10911084 DOI: 10.2147/jhc.s449737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 02/20/2024] [Indexed: 03/06/2024] Open
Abstract
Background Currently, it is still confused whether preoperative aminotransferase-to-platelet ratio (APRI) and gamma-glutamyl transferase-to-platelet ratio (GPR) can predict microvascular invasion (MVI) in solitary hepatocellular carcinoma (HCC). We aimed to develop and validate a machine-learning integration model for predicting MVI using APRI, GPR and gadoxetic acid disodium (Gd-EOB-DTPA) enhanced MRI. Methods A total of 314 patients from XinQiao Hospital of Army Medical University were divided chronologically into training set (n = 220) and internal validation set (n = 94), and recurrence-free survival was determined to follow up after surgery. Seventy-three patients from Chongqing University Three Gorges Hospital and Luzhou People's Hospital served as external validation set. Overall, 387 patients with solitary HCC were analyzed as whole dataset set. Least absolute shrinkage and selection operator, tenfold cross-validation and multivariate logistic regression were used to gradually filter features. Six machine-learning models and an ensemble of the all models (ENS) were built. The area under the receiver operating characteristic curve (AUC) and decision curve analysis were used to evaluate model's performance. Results APRI, GPR, HBPratio3 ([liver SI‒tumor SI]/liver SI), PLT, peritumoral enhancement, non-smooth margin and peritumoral hypointensity were independent risk factors for MVI. Six machine-learning models showed good performance for predicting MVI in training set (AUCs range, 0.793-0.875), internal validation set (0.715-0.832), external validation set (0.636-0.746) and whole dataset set (0.756-0.850). The ENS achieved the highest AUCs (0.879 vs 0.858 vs 0.839 vs 0.851) in four cohorts with excellent calibration and more net benefit. Subgroup analysis indicated that ENS obtained excellent AUCs (0.900 vs 0.809 vs 0.865 vs 0.908) in HCC >5cm, ≤5cm, ≤3cm and ≤2cm cohorts. Kaplan‒Meier survival curves indicated that ENS achieved excellent stratification for MVI status. Conclusion The APRI and GPR may be new potential biomarkers for predicting MVI of HCC. The ENS achieved optimal performance for predicting MVI in different sizes HCC and may aid in the individualized selection of surgical procedures.
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Affiliation(s)
- Fei Wang
- Department of Radiology, XinQiao Hospital of Army Medical University, Chongqing, 400037, People’s Republic of China
- Department of Medical Imaging, Luzhou People’s Hospital, Luzhou, 646000, People’s Republic of China
| | - Chun Yue Yan
- Department of Emergency Medicine, Luzhou People’s Hospital, Luzhou, 646000, People’s Republic of China
| | - Yuan Qin
- Department of Radiology, Chongqing University Three Gorges Hospital, Chongqing, 404031, People’s Republic of China
| | - Zheng Ming Wang
- Department of Radiology, XinQiao Hospital of Army Medical University, Chongqing, 400037, People’s Republic of China
| | - Dan Liu
- Department of Radiology, XinQiao Hospital of Army Medical University, Chongqing, 400037, People’s Republic of China
| | - Ying He
- Department of Radiology, XinQiao Hospital of Army Medical University, Chongqing, 400037, People’s Republic of China
| | - Ming Yang
- Department of Medical Imaging, Luzhou People’s Hospital, Luzhou, 646000, People’s Republic of China
| | - Li Wen
- Department of Radiology, XinQiao Hospital of Army Medical University, Chongqing, 400037, People’s Republic of China
| | - Dong Zhang
- Department of Radiology, XinQiao Hospital of Army Medical University, Chongqing, 400037, People’s Republic of China
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Fernandez CJ, Alkhalifah M, Afsar H, Pappachan JM. Metabolic Dysfunction-Associated Fatty Liver Disease and Chronic Viral Hepatitis: The Interlink. Pathogens 2024; 13:68. [PMID: 38251375 PMCID: PMC10821334 DOI: 10.3390/pathogens13010068] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 01/05/2024] [Accepted: 01/07/2024] [Indexed: 01/23/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) has now affected nearly one-third of the global population and has become the number one cause of chronic liver disease in the world because of the obesity pandemic. Chronic hepatitis resulting from hepatitis B virus (HBV) and hepatitis C virus (HCV) remain significant challenges to liver health even in the 21st century. The co-existence of MAFLD and chronic viral hepatitis can markedly alter the disease course of individual diseases and can complicate the management of each of these disorders. A thorough understanding of the pathobiological interactions between MAFLD and these two chronic viral infections is crucial for appropriately managing these patients. In this comprehensive clinical review, we discuss the various mechanisms of chronic viral hepatitis-mediated metabolic dysfunction and the impact of MAFLD on the progression of liver disease.
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Affiliation(s)
- Cornelius J. Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, UK;
| | - Mohammed Alkhalifah
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
- Department of Family Medicine and Polyclinics, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia
- University Diabetes Center, King Saud University Medical City, King Saud University, Riyadh 11411, Saudi Arabia
| | - Hafsa Afsar
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
| | - Joseph M. Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, UK
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, UK
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11
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Milosevic I, Todorovic N, Filipovic A, Simic J, Markovic M, Stevanovic O, Malinic J, Katanic N, Mitrovic N, Nikolic N. HCV and HCC Tango-Deciphering the Intricate Dance of Disease: A Review Article. Int J Mol Sci 2023; 24:16048. [PMID: 38003240 PMCID: PMC10671156 DOI: 10.3390/ijms242216048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/12/2023] [Accepted: 10/25/2023] [Indexed: 11/26/2023] Open
Abstract
Hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC) accounting for around one-third of all HCC cases. Prolonged inflammation in chronic hepatitis C (CHC), maintained through a variety of pro- and anti-inflammatory mediators, is one of the aspects of carcinogenesis, followed by mitochondrial dysfunction and oxidative stress. Immune response dysfunction including the innate and adaptive immunity also plays a role in the development, as well as in the recurrence of HCC after treatment. Some of the tumor suppressor genes inhibited by the HCV proteins are p53, p73, and retinoblastoma 1. Mutations in the telomerase reverse transcriptase promoter and the oncogene catenin beta 1 are two more important carcinogenic signaling pathways in HCC associated with HCV. Furthermore, in HCV-related HCC, numerous tumor suppressor and seven oncogenic genes are dysregulated by epigenetic changes. Epigenetic regulation of gene expression is considered as a lasting "epigenetic memory", suggesting that HCV-induced changes persist and are associated with liver carcinogenesis even after cure. Epigenetic changes and immune response dysfunction are recognized targets for potential therapy of HCC.
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Affiliation(s)
- Ivana Milosevic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Nevena Todorovic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Ana Filipovic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Jelena Simic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Marko Markovic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Olja Stevanovic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Jovan Malinic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Natasa Katanic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
- Faculty of Medicine, University of Pristina Situated in Kosovska Mitrovica, 28000 Kosovska Mitrovica, Serbia
| | - Nikola Mitrovic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Natasa Nikolic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
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Zhou Q, Yang Y, Xu Z, Deng K, Zhang Z, Hao J, Li N, Wang Y, Wang Z, Chen H, Yang Y, Xiao F, Zhang X, Gao S, Li Y. ATAD1 inhibits hepatitis C virus infection by removing the viral TA-protein NS5B from mitochondria. EMBO Rep 2023; 24:e56614. [PMID: 37789674 PMCID: PMC10626439 DOI: 10.15252/embr.202256614] [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: 12/06/2022] [Revised: 08/24/2023] [Accepted: 09/01/2023] [Indexed: 10/05/2023] Open
Abstract
ATPase family AAA domain-containing protein 1 (ATAD1) maintains mitochondrial homeostasis by removing mislocalized tail-anchored (TA) proteins from the mitochondrial outer membrane (MOM). Hepatitis C virus (HCV) infection induces mitochondrial fragmentation, and viral NS5B protein is a TA protein. Here, we investigate whether ATAD1 plays a role in regulating HCV infection. We find that HCV infection has no effect on ATAD1 expression, but knockout of ATAD1 significantly enhances HCV infection; this enhancement is suppressed by ATAD1 complementation. NS5B partially localizes to mitochondria, dependent on its transmembrane domain (TMD), and induces mitochondrial fragmentation, which is further enhanced by ATAD1 knockout. ATAD1 interacts with NS5B, dependent on its three internal domains (TMD, pore-loop 1, and pore-loop 2), and induces the proteasomal degradation of NS5B. In addition, we provide evidence that ATAD1 augments the antiviral function of MAVS upon HCV infection. Taken together, we show that the mitochondrial quality control exerted by ATAD1 can be extended to a novel antiviral function through the extraction of the viral TA-protein NS5B from the mitochondrial outer membrane.
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Affiliation(s)
- Qing Zhou
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- Technology Center, China Tobacco Henan Industrial Co., LtdZhengzhouChina
- Department of Infectious DiseasesThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Yuhao Yang
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Zhanxue Xu
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Kai Deng
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- Guangzhou Eighth People's HospitalGuangzhou Medical UniversityGuangzhouChina
| | - Zhenzhen Zhang
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Jiawei Hao
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Ni Li
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- Department of Infectious DiseasesThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Yanling Wang
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Ziwen Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Haihang Chen
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Yang Yang
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Fei Xiao
- Department of Infectious DiseaseThe Fifth Affiliated Hospital of Sun Yat‐sen UniversityZhuhaiChina
| | - Xiaohong Zhang
- Department of Infectious DiseasesThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Song Gao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Yi‐Ping Li
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- Department of Infectious DiseasesThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
- Department of Infectious DiseaseThe Fifth Affiliated Hospital of Sun Yat‐sen UniversityZhuhaiChina
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13
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Lampimukhi M, Qassim T, Venu R, Pakhala N, Mylavarapu S, Perera T, Sathar BS, Nair A. A Review of Incidence and Related Risk Factors in the Development of Hepatocellular Carcinoma. Cureus 2023; 15:e49429. [PMID: 38149129 PMCID: PMC10750138 DOI: 10.7759/cureus.49429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/26/2023] [Indexed: 12/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver malignancy, ranking as the seventh most common cancer globally and the second leading cause of deaths due to cancer. This review examines the incidence of HCC, its associated risk factors, and constantly changing global trends. Incidence has been noted to be varying worldwide, particularly due to environmental and infectious risk factors. Chronic hepatitis B (HBV) and C (HCV) virus infections, alcohol abuse, aflatoxin exposure, diabetes, obesity, and tobacco consumption are some of the leading risk factors noted. Eastern Asia and sub-Saharan Africa were noted to have the highest disease burden for HCC, with China representing a considerably large majority. On the contrary, the United States reports a lower HCC incidence overall due to improved vaccination programs against HBV; however, with a rising incidence of prominent risk factor in non-alcoholic fatty liver disease (NAFLD), the trend may very well change. Gender disparities were noted to be evident with men experiencing higher rates of HCC compared to women, which may be due to various environmental and biological factors, including alcohol intake, smoking, and androgen hormone levels. Currently, efforts to reduce the overall incidence of HCC include universal HBV vaccinations, antiviral therapies, aflatoxin prevention measures, genetic screening for hereditary hemochromatosis, and early ultrasound evaluation in patients with liver cirrhosis. Understanding these evolving trends and risk factors is essential in combating the rising HCC incidence, especially in Western countries, where risk factors, such as obesity, diabetes, and metabolic disorders, are on the rise.
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Affiliation(s)
| | - Tabarak Qassim
- School of Medicine, Royal College of Surgeons in Ireland - Medical University of Bahrain, Busaiteen, BHR
| | - Rakshaya Venu
- College of Medicine, Saveetha Medical College, Chennai, IND
| | - Nivedita Pakhala
- College of Medicine, Sri Padmavathi Medical College for Women, Tirupati, IND
| | - Suchita Mylavarapu
- College of Medicine, Malla Reddy Medical College for Women, Hyderabad, IND
| | - Tharindu Perera
- General Medicine, Grodno State Medical University, Grodno, BLR
| | - Beeran S Sathar
- College of Medicine, Jagadguru Jayadeva Murugarajendra Medical College, Davanagere, IND
| | - Arun Nair
- Pediatrics, Saint Peter's University Hospital, Somerset, USA
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14
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Yang D, Zhang S, Zheng C, Zhou G, Hu Y, Hao Q. Refractive index tomography with a physics-based optical neural network. BIOMEDICAL OPTICS EXPRESS 2023; 14:5886-5903. [PMID: 38021108 PMCID: PMC10659804 DOI: 10.1364/boe.504242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 09/27/2023] [Accepted: 09/27/2023] [Indexed: 12/01/2023]
Abstract
The non-interference three-dimensional refractive index (RI) tomography has attracted extensive attention in the life science field for its simple system implementation and robust imaging performance. However, the complexity inherent in the physical propagation process poses significant challenges when the sample under study deviates from the weak scattering approximation. Such conditions complicate the task of achieving global optimization with conventional algorithms, rendering the reconstruction process both time-consuming and potentially ineffective. To address such limitations, this paper proposes an untrained multi-slice neural network (MSNN) with an optical structure, in which each layer has a clear corresponding physical meaning according to the beam propagation model. The network does not require pre-training and performs good generalization and can be recovered through the optimization of a set of intensity images. Concurrently, MSNN can calibrate the intensity of different illumination by learnable parameters, and the multiple backscattering effects have also been taken into consideration by integrating a "scattering attenuation layer" between adjacent "RI" layers in the MSNN. Both simulations and experiments have been conducted carefully to demonstrate the effectiveness and feasibility of the proposed method. Experimental results reveal that MSNN can enhance clarity with increased efficiency in RI tomography. The implementation of MSNN introduces a novel paradigm for RI tomography.
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Affiliation(s)
- Delong Yang
- School of Optics and Photonics, Beijing Institute of Technology, Beijing 100081, China
| | - Shaohui Zhang
- School of Optics and Photonics, Beijing Institute of Technology, Beijing 100081, China
- Yangtze Delta Region Academy of Beijing Institute of Technology, China
| | - Chuanjian Zheng
- School of Optics and Photonics, Beijing Institute of Technology, Beijing 100081, China
| | - Guocheng Zhou
- School of Optics and Photonics, Beijing Institute of Technology, Beijing 100081, China
| | - Yao Hu
- School of Optics and Photonics, Beijing Institute of Technology, Beijing 100081, China
| | - Qun Hao
- School of Optics and Photonics, Beijing Institute of Technology, Beijing 100081, China
- Yangtze Delta Region Academy of Beijing Institute of Technology, China
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15
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Miyasaka A, Yoshida Y, Suzuki A, Endo K, Kakisaka K, Oikawa T, Abe T, Obara W, Matsumoto T. Current elimination status of hepatitis C virus-infected maintenance hemodialysis patients in Iwate Prefecture, Japan. Ther Apher Dial 2023; 27:848-854. [PMID: 37125473 DOI: 10.1111/1744-9987.13999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 04/13/2023] [Accepted: 04/15/2023] [Indexed: 05/02/2023]
Abstract
INTRODUCTION The aim is to clarify the hepatitis C virus (HCV) status of hemodialysis (HD) patients and patient management after HCV elimination. METHODS Questionnaire survey was conducted in Iwate prefecture, Japan from 2016 to 2021. RESULTS Patients underwent HD was 2944, including 132 anti-HCV antibody-positive patients, with 91 HCV RNA-positive patients. Of the 91 HCV RNA-positive patients, 51 received antiviral treatment. Sustained virological response (SVR) rate was 94%. The patients treated with direct antiviral agents had significantly lower mortality rate than the untreated patients, and no liver-related deaths occurred in patients who achieved SVR or in HCV RNA-negative patients. The HCV RNA-positive prevalence was finally 0.79%. Approximately 40% of the facilities had dedicated beds and dialysis-related items for patients who achieved an SVR. CONCLUSION To eliminate HCV in HD facilities, it is necessary to promote HCV RNA testing for anti-HCV antibody-positive patients and to provide antiviral treatment for HCV RNA-positive patients. Additionally, collaboration among hepatologists and HD specialists are essential.
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Affiliation(s)
- Akio Miyasaka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Shiwa-gun, Japan
| | - Yuichi Yoshida
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Shiwa-gun, Japan
| | - Akiko Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Shiwa-gun, Japan
| | - Kei Endo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Shiwa-gun, Japan
| | - Keisuke Kakisaka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Shiwa-gun, Japan
| | - Takayoshi Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Shiwa-gun, Japan
| | - Takaya Abe
- Department of Urology, Iwate Medical University, School of Medicine, Shiwa-gun, Japan
| | - Wataru Obara
- Department of Urology, Iwate Medical University, School of Medicine, Shiwa-gun, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Shiwa-gun, Japan
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16
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Martin de Fourchambault E, Callens N, Saliou JM, Fourcot M, Delos O, Barois N, Thorel Q, Ramirez S, Bukh J, Cocquerel L, Bertrand-Michel J, Marot G, Sebti Y, Dubuisson J, Rouillé Y. Hepatitis C virus alters the morphology and function of peroxisomes. Front Microbiol 2023; 14:1254728. [PMID: 37808318 PMCID: PMC10551450 DOI: 10.3389/fmicb.2023.1254728] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 09/07/2023] [Indexed: 10/10/2023] Open
Abstract
Despite the introduction of effective treatments for hepatitis C in clinics, issues remain regarding the liver disease induced by chronic hepatitis C virus (HCV) infection. HCV is known to disturb the metabolism of infected cells, especially lipid metabolism and redox balance, but the mechanisms leading to HCV-induced pathogenesis are still poorly understood. In an APEX2-based proximity biotinylation screen, we identified ACBD5, a peroxisome membrane protein, as located in the vicinity of HCV replication complexes. Confocal microscopy confirmed the relocation of peroxisomes near HCV replication complexes and indicated that their morphology and number are altered in approximately 30% of infected Huh-7 cells. Peroxisomes are small versatile organelles involved among other functions in lipid metabolism and ROS regulation. To determine their importance in the HCV life cycle, we generated Huh-7 cells devoid of peroxisomes by inactivating the PEX5 and PEX3 genes using CRISPR/Cas9 and found that the absence of peroxisomes had no impact on replication kinetics or infectious titers of HCV strains JFH1 and DBN3a. The impact of HCV on peroxisomal functions was assessed using sub-genomic replicons. An increase of ROS was measured in peroxisomes of replicon-containing cells, correlated with a significant decrease of catalase activity with the DBN3a strain. In contrast, HCV replication had little to no impact on cytoplasmic and mitochondrial ROS, suggesting that the redox balance of peroxisomes is specifically impaired in cells replicating HCV. Our study provides evidence that peroxisome function and morphology are altered in HCV-infected cells.
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Affiliation(s)
- Esther Martin de Fourchambault
- Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U 1019 – UMR9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
| | - Nathalie Callens
- Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U 1019 – UMR9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
| | - Jean-Michel Saliou
- Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UAR CNRS 2014 - US Inserm 41 - PLBS, Lille, France
| | - Marie Fourcot
- Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UAR CNRS 2014 - US Inserm 41 - PLBS, Lille, France
| | - Oceane Delos
- MetaToul-MetaboHUB, National Infrastructure of Metabolomics and Fluxomics, Toulouse, France
- I2MC, Université de Toulouse, Inserm, Université Toulouse III – Paul Sabatier (UPS), Toulouse, France
| | - Nicolas Barois
- Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U 1019 – UMR9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
- Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UAR CNRS 2014 - US Inserm 41 - PLBS, Lille, France
| | - Quentin Thorel
- Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, Lille, France
| | - Santseharay Ramirez
- Faculty of Health and Medical Sciences, Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital Hvidovre and Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Jens Bukh
- Faculty of Health and Medical Sciences, Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital Hvidovre and Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Laurence Cocquerel
- Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U 1019 – UMR9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
| | - Justine Bertrand-Michel
- MetaToul-MetaboHUB, National Infrastructure of Metabolomics and Fluxomics, Toulouse, France
- I2MC, Université de Toulouse, Inserm, Université Toulouse III – Paul Sabatier (UPS), Toulouse, France
| | - Guillemette Marot
- Université de Lille, Inria, CHU Lille, ULR 2694 - METRICS: Évaluation des technologies de santé et des pratiques médicales, Lille, France
| | - Yasmine Sebti
- Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, Lille, France
| | - Jean Dubuisson
- Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U 1019 – UMR9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
| | - Yves Rouillé
- Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U 1019 – UMR9017 – CIIL – Center for Infection and Immunity of Lille, Lille, France
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Allameh A, Niayesh-Mehr R, Aliarab A, Sebastiani G, Pantopoulos K. Oxidative Stress in Liver Pathophysiology and Disease. Antioxidants (Basel) 2023; 12:1653. [PMID: 37759956 PMCID: PMC10525124 DOI: 10.3390/antiox12091653] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 08/15/2023] [Accepted: 08/20/2023] [Indexed: 09/29/2023] Open
Abstract
The liver is an organ that is particularly exposed to reactive oxygen species (ROS), which not only arise during metabolic functions but also during the biotransformation of xenobiotics. The disruption of redox balance causes oxidative stress, which affects liver function, modulates inflammatory pathways and contributes to disease. Thus, oxidative stress is implicated in acute liver injury and in the pathogenesis of prevalent infectious or metabolic chronic liver diseases such as viral hepatitis B or C, alcoholic fatty liver disease, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Moreover, oxidative stress plays a crucial role in liver disease progression to liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Herein, we provide an overview on the effects of oxidative stress on liver pathophysiology and the mechanisms by which oxidative stress promotes liver disease.
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Affiliation(s)
- Abdolamir Allameh
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 1411713116, Iran; (A.A.); (R.N.-M.); (A.A.)
| | - Reyhaneh Niayesh-Mehr
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 1411713116, Iran; (A.A.); (R.N.-M.); (A.A.)
| | - Azadeh Aliarab
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 1411713116, Iran; (A.A.); (R.N.-M.); (A.A.)
| | - Giada Sebastiani
- Chronic Viral Illness Services, McGill University Health Center, Montreal, QC H4A 3J1, Canada;
- Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
| | - Kostas Pantopoulos
- Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
- Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada
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18
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Aoyagi H, Iijima H, Gaber ES, Zaitsu T, Matsuda M, Wakae K, Watashi K, Suzuki R, Masaki T, Kahn J, Saito T, El-Kassas M, Shimada N, Kato K, Enomoto M, Hayashi K, Tsubota A, Mimata A, Sakamaki Y, Ichinose S, Muramatsu M, Wake K, Wakita T, Aizaki H. Hepatocellular organellar abnormalities following elimination of hepatitis C virus. Liver Int 2023; 43:1677-1690. [PMID: 37312620 DOI: 10.1111/liv.15624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 04/14/2023] [Accepted: 05/14/2023] [Indexed: 06/15/2023]
Abstract
BACKGROUND AND AIMS The future development of hepatocellular carcinoma (HCC) in patients after sustained virologic response (SVR) is an important issue. The purposes of this study were to investigate pathological alterations in organelle of the liver of SVR patients and to characterize organelle abnormalities that may be related to carcinogenesis after SVR. METHODS The ultrastructure of liver biopsy specimens from patients with chronic hepatitis C (CHC) and SVR were compared to cell and mouse models and assessed semi-quantitatively using transmission electron microscopy. RESULTS Hepatocytes in patients with CHC showed abnormalities in the nucleus, mitochondria, endoplasmic reticulum, lipid droplet, and pericellular fibrosis, comparable to those seen in hepatitis C virus (HCV)-infected mice and cells. DAA treatment significantly reduced organelle abnormalities such as the nucleus, mitochondria, and lipid droplet in the hepatocytes of patients and mice after SVR, and cured cells, but it did not change dilated/degranulated endoplasmic reticulum and pericellular fibrosis in patients and mice after SVR. Further, samples from patients with a post-SVR period of >1 year had significantly larger numbers of abnormalities in the mitochondria and endoplasmic reticulum than those of <1 year. A possible cause of organelle abnormalities in patients after SVR could be oxidative stress of the endoplasmic reticulum and mitochondria associated with abnormalities of the vascular system due to fibrosis. Interestingly, abnormal endoplasmic reticulum was associated with patients with HCC for >1 year after SVR. CONCLUSIONS These results indicate that patients with SVR exhibit a persistent disease state and require long-term follow-up to detect early signs of carcinogenesis.
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Affiliation(s)
- Haruyo Aoyagi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hiroko Iijima
- Department of Internal Medicine, Division of Hepatobiliary and Pancreatic Disease, Hyogo College of Medicine, Hyogo, Japan
| | - Eman S Gaber
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takuma Zaitsu
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Mami Matsuda
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kosho Wakae
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Ryosuke Suzuki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takahiro Masaki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
- Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Jeffrey Kahn
- Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Takeshi Saito
- Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Noritomo Shimada
- Division of Gastroenterology and Hepatology, Ootakanomori Hospital, Chiba, Japan
| | - Keizo Kato
- Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Chiba, Japan
| | - Masaru Enomoto
- Department of Hepatology, Osaka Metropolitan University, Osaka, Japan
| | - Kazuhiko Hayashi
- Division of Gastroenterology and Hepatology, Meijo Hospital, Nagoya, Japan
| | - Akihito Tsubota
- Core Research Facilities, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan
| | - Ayako Mimata
- Research Core, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yuriko Sakamaki
- Research Core, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shizuko Ichinose
- Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School, Tokyo, Japan
| | - Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kenjiro Wake
- Liver Research Unit, Minophagen Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hideki Aizaki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
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19
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Wróblewska J, Wróblewski M, Hołyńska-Iwan I, Modrzejewska M, Nuszkiewicz J, Wróblewska W, Woźniak A. The Role of Glutathione in Selected Viral Diseases. Antioxidants (Basel) 2023; 12:1325. [PMID: 37507865 PMCID: PMC10376684 DOI: 10.3390/antiox12071325] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/20/2023] [Accepted: 06/21/2023] [Indexed: 07/30/2023] Open
Abstract
During inflammatory processes, immunocompetent cells are exposed to substantial amounts of free radicals and toxic compounds. Glutathione is a cysteine-containing tripeptide that is an important and ubiquitous antioxidant molecule produced in human organs. The intracellular content of GSH regulates the detoxifying capacity of cells, as well as the inflammatory and immune response. GSH is particularly important in the liver, where it serves as the major non-protein thiol involved in cellular antioxidant defense. There are numerous causes of hepatitis. The inflammation of the liver can be caused by a variety of infectious viruses. The relationship between oxidative stress and the hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis E virus (HEV) infection is not fully known. The aim of this study was to examine the relationship between hepatotropic viruses and glutathione status, including reduced glutathione (GSH) and oxidized glutathione (GSSG), as well as antioxidant enzymes, e.g., glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST) in liver diseases.
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Affiliation(s)
- Joanna Wróblewska
- Department of Medical Biology and Biochemistry, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Marcin Wróblewski
- Department of Medical Biology and Biochemistry, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Iga Hołyńska-Iwan
- Department of Pathobiochemistry and Clinical Chemistry, Faculty of Pharmacy, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Martyna Modrzejewska
- Department of Medical Biology and Biochemistry, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Jarosław Nuszkiewicz
- Department of Medical Biology and Biochemistry, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Weronika Wróblewska
- Students Research Club of Medical Biology, Department of Medical Biology and Biochemistry, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Alina Woźniak
- Department of Medical Biology and Biochemistry, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
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20
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Androutsakos T, Mouziouras D, Katelani S, Psichogiou M, Sfikakis PP, Protogerou AD, Argyris AA. A Comparative Study on the Presence and Reversibility of Subclinical Arterial Damage in HCV-Infected Individuals and Matched Controls. Viruses 2023; 15:1374. [PMID: 37376673 PMCID: PMC10305524 DOI: 10.3390/v15061374] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/12/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Background: The arterial pathology and mechanisms of increased cardiovascular disease (CVD) risk in HCV-infected individuals are not yet clear. The aim of this study was to identify types of arterial pathology in treatment-naive chronic HCV patients and to test their reversibility after successful treatment. Methods: Consecutive, never-treated, HCV-infected patients were compared with age and CVD-related risk factors, matched controls, healthy individuals (HI), patients with rheumatoid arthritis (RA) and people living with HIV (PLWH), in terms of arterial stiffening by pulse wave velocity, arterial atheromatosis/hypertrophy by carotid plaques/intima-media thickness and impaired pressure wave reflections by augmentation index. After three months of sustained virological response (SVR) administered using direct-acting antivirals, vascular examination was repeated in HCV-infected patients to test drug and viral-elimination effect in subclinical CVD. Results: Thirty HCV patients were examined at baseline; fourteen of them were re-examined post-SVR. Compared with HI, HCV patients had significantly more plaques, which is similar to that of RA patients and the PLWH group. No other differences were found in all other vascular biomarkers, and regression among HCV patients also revealed no differences 3 months post-SVR. Conclusions: Accelerated atheromatosis, rather than arterial stiffening, arterial remodeling and peripheral impaired hemodynamics is the underlying pathology leading to increased CVD risk in HCV patients.
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Affiliation(s)
- Theodoros Androutsakos
- Clinic/Laboratory of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.K.); (A.D.P.)
| | - Dimitrios Mouziouras
- Department of Gastroenterology, Laiko General Hospital, School of Medicine, National and Kapodistrian University Athens, 11527 Athens, Greece;
- Cardiovascular Prevention and Research Unit, Clinic/Laboratory of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Stamatia Katelani
- Clinic/Laboratory of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.K.); (A.D.P.)
| | - Mina Psichogiou
- First Department of Internal Medicine, Laiko General Hospital, School of Medicine, National and Kapodistrian University Athens, 11527 Athens, Greece;
| | - Petros P. Sfikakis
- First Department of Propaedeutic Medicine, Laiko General Hospital, School of Medicine, National and Kapodistrian University Athens, 11527 Athens, Greece;
| | - Athanase D. Protogerou
- Clinic/Laboratory of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.K.); (A.D.P.)
- Cardiovascular Prevention and Research Unit, Clinic/Laboratory of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Antonios A. Argyris
- Cardiovascular Prevention and Research Unit, Clinic/Laboratory of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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21
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Zheng H, Yang F, Deng K, Wei J, Liu Z, Zheng YC, Xu H. Relationship between iron overload caused by abnormal hepcidin expression and liver disease: A review. Medicine (Baltimore) 2023; 102:e33225. [PMID: 36930080 PMCID: PMC10019217 DOI: 10.1097/md.0000000000033225] [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: 12/04/2022] [Accepted: 02/16/2023] [Indexed: 03/18/2023] Open
Abstract
Iron is essential to organisms, the liver plays a vital role in its storage. Under pathological conditions, iron uptake by the intestine or hepatocytes increases, allowing excess iron to accumulate in liver cells. When the expression of hepcidin is abnormal, iron homeostasis in humans cannot be regulated, and resulting in iron overload. Hepcidin also regulates the release of iron from siderophores, thereby regulating the concentration of iron in plasma. Important factors related to hepcidin and systemic iron homeostasis include plasma iron concentration, body iron storage, infection, inflammation, and erythropoietin. This review summarizes the mechanism and regulation of iron overload caused by hepcidin, as well as related liver diseases caused by iron overload and treatment.
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Affiliation(s)
- Haoran Zheng
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China
| | - Fan Yang
- Division of Liver Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Kaige Deng
- Division of Liver Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Jiaxin Wei
- Department of Emergency, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhenting Liu
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China
| | - Yong-Chang Zheng
- Division of Liver Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Haifeng Xu
- Division of Liver Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
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22
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Kasztelan-Szczerbinska B, Rycyk-Bojarzynska A, Szczerbinska A, Cichoz-Lach H. Selected Aspects of the Intricate Background of Immune-Related Cholangiopathies-A Critical Overview. Nutrients 2023; 15:760. [PMID: 36771465 PMCID: PMC9921714 DOI: 10.3390/nu15030760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/28/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are rare immune-related cholangiopathies with still poorly explained pathogenesis. Although triggers of chronic inflammation with subsequent fibrosis that affect cholangiocytes leading to obliteration of bile ducts and conversion to liver cirrhosis are unclear, both disorders are regarded to be multifactorial. Different factors can contribute to the development of hepatocellular injury in the course of progressive cholestasis, including (1) body accumulation of bile acids and their toxicity, (2) decreased food intake and nutrient absorption, (3) gut microbiota transformation, and (4) reorganized host metabolism. Growing evidence suggests that intestinal microbiome composition not only can be altered by liver dysfunction, but in turn, it actively impacts hepatic conditions. In this review, we highlight the role of key factors such as the gut-liver axis, intestinal barrier integrity, bile acid synthesis and circulation, and microbiome composition, which seem to be strongly related to PBC and PSC outcome. Emerging treatments and future therapeutic strategies are also presented.
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Affiliation(s)
- Beata Kasztelan-Szczerbinska
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
| | - Anna Rycyk-Bojarzynska
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
| | | | - Halina Cichoz-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
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23
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Vignoli A, Meoni G, Ghini V, Di Cesare F, Tenori L, Luchinat C, Turano P. NMR-Based Metabolomics to Evaluate Individual Response to Treatments. Handb Exp Pharmacol 2023; 277:209-245. [PMID: 36318327 DOI: 10.1007/164_2022_618] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The aim of this chapter is to highlight the various aspects of metabolomics in relation to health and diseases, starting from the definition of metabolic space and of how individuals tend to maintain their own position in this space. Physio-pathological stimuli may cause individuals to lose their position and then regain it, or move irreversibly to other positions. By way of examples, mostly selected from our own work using 1H NMR on biological fluids, we describe the effects on the individual metabolomic fingerprint of mild external interventions, such as diet or probiotic administration. Then we move to pathologies (such as celiac disease, various types of cancer, viral infections, and other diseases), each characterized by a well-defined metabolomic fingerprint. We describe the effects of drugs on the disease fingerprint and on its reversal to a healthy metabolomic status. Drug toxicity can be also monitored by metabolomics. We also show how the individual metabolomic fingerprint at the onset of a disease may discriminate responders from non-responders to a given drug, or how it may be prognostic of e.g., cancer recurrence after many years. In parallel with fingerprinting, profiling (i.e., the identification and quantification of many metabolites and, in the case of selected biofluids, of the lipoprotein components that contribute to the 1H NMR spectral features) can provide hints on the metabolic pathways that are altered by a disease and assess their restoration after treatment.
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Affiliation(s)
- Alessia Vignoli
- Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino, Italy.,Department of Chemistry "Ugo Schiff", University of Florence, Sesto Fiorentino, Italy
| | - Gaia Meoni
- Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino, Italy.,Department of Chemistry "Ugo Schiff", University of Florence, Sesto Fiorentino, Italy
| | - Veronica Ghini
- Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino, Italy.,Department of Chemistry "Ugo Schiff", University of Florence, Sesto Fiorentino, Italy
| | - Francesca Di Cesare
- Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino, Italy.,Department of Chemistry "Ugo Schiff", University of Florence, Sesto Fiorentino, Italy
| | - Leonardo Tenori
- Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino, Italy.,Department of Chemistry "Ugo Schiff", University of Florence, Sesto Fiorentino, Italy.,Consorzio Interuniversitario Risonanze Magnetiche MetalloProteine (CIRMMP), Sesto Fiorentino, Italy
| | - Claudio Luchinat
- Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino, Italy.,Department of Chemistry "Ugo Schiff", University of Florence, Sesto Fiorentino, Italy.,Consorzio Interuniversitario Risonanze Magnetiche MetalloProteine (CIRMMP), Sesto Fiorentino, Italy
| | - Paola Turano
- Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino, Italy. .,Department of Chemistry "Ugo Schiff", University of Florence, Sesto Fiorentino, Italy. .,Consorzio Interuniversitario Risonanze Magnetiche MetalloProteine (CIRMMP), Sesto Fiorentino, Italy.
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24
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Potential Therapeutic Implication of Herbal Medicine in Mitochondria-Mediated Oxidative Stress-Related Liver Diseases. Antioxidants (Basel) 2022; 11:antiox11102041. [PMID: 36290765 PMCID: PMC9598588 DOI: 10.3390/antiox11102041] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/10/2022] [Accepted: 10/10/2022] [Indexed: 11/22/2022] Open
Abstract
Mitochondria are double-membrane organelles that play a role in ATP synthesis, calcium homeostasis, oxidation-reduction status, apoptosis, and inflammation. Several human disorders have been linked to mitochondrial dysfunction. It has been found that traditional therapeutic herbs are effective on alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) which are leading causes of liver cirrhosis and hepatocellular carcinoma. The generation of reactive oxygen species (ROS) in response to oxidative stress is caused by mitochondrial dysfunction and is considered critical for treatment. The role of oxidative stress, lipid toxicity, and inflammation in NAFLD are well known. NAFLD is a chronic liver disease that commonly progresses to cirrhosis and chronic liver disease, and people with obesity, insulin resistance, diabetes, hyperlipidemia, and hypertension are at a higher risk of developing NAFLD. NAFLD is associated with a number of pathological factors, including insulin resistance, lipid metabolic dysfunction, oxidative stress, inflammation, apoptosis, and fibrosis. As a result, the improvement in steatosis and inflammation is enough to entice researchers to look into liver disease treatment. However, antioxidant treatment has not been very effective for liver disease. Additionally, it has been suggested that the beneficial effects of herbal medicines on immunity and inflammation are governed by various mechanisms for lipid metabolism and inflammation control. This review provided a summary of research on herbal medicines for the therapeutic implementation of mitochondria-mediated ROS production in liver disease as well as clinical applications through herbal medicine. In addition, the pathophysiology of common liver disorders such as ALD and NAFLD would be investigated in the role that mitochondria play in the process to open new therapeutic avenues in the management of patients with liver disease.
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25
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Yao Y, Satapathy SK, Fernandes EDSM, Ramírez-Fernández O, Vitale A, Chen Z. Hepatic venous pressure gradient (HVPG) predicts liver failure after transjugular intrahepatic portal shunt: a retrospective cohort study. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1122. [PMID: 36388791 PMCID: PMC9652563 DOI: 10.21037/atm-22-4737] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 10/14/2022] [Indexed: 08/10/2023]
Abstract
BACKGROUND Esophagogastric variceal bleeding is a serious complication of decompensated cirrhosis. Transjugular intrahepatic portal shunt (TIPS) is a salvage treatment with clear hemostatic results. However, various complications may occur after TIPS, including postoperative liver failure, and the prognosis is very poor once occurs. Liver failure is a common symptom of severe liver disease with a high mortality rate. This study investigated the incidence of liver failure after TIPS treatment for varicose bleeding. METHODS We analyzed the data of patients admitted to the First Affiliated Hospital of Soochow University between January 2013 and December 2018 with portal hypertension with an episode of acute gastroesophageal variceal bleeding. A total of 121 patients were referred to the regional liver unit for TIPS. Hepatic venous pressure gradient (HVPG) and clinical data were collected. Patients with incomplete data were excluded, and 93 patients were ultimately enrolled in the study. Primary outcomes were morbidity and hospital mortality within 4 weeks of surgery. The data were retrospectively and consecutively collected and evaluated by univariate and multivariate analyses to identify risk factors of liver failure. RESULTS The patients included 58 males (62.37%) and 35 females (37.63%), and the mean age was 58.43±11.85 years. The main cause was hepatitis B virus (HBV), which was found in 50.54% of patient. The overall surgical success rate was 83.87% (78/93). Of 15 treatment-failure patients, 9 (9.68%) died in hospital. Four patients died of liver failure, accounting for 44.44% of postoperative all-cause deaths. Univariate logistic regression analysis showed that only hepatic venous pressure gradient (HVPG) was an independent risk factor for post-TIPS morbidity [relative risk (RR) 1.156; 95% confidence interval (CI): 1.041 to 1.283; P=0.006]. In addition, HVPG was an independent risk factor for hospital mortality within 4 weeks (RR 1.133; 95% CI: 1.021 to 0.539; P=0.016). CONCLUSIONS Post-TIPS liver failure is a serious complication in patients with cirrhosis. Pre-TIPS HVPG level may be used as a predictor of potential short-term postoperative adverse events.
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Affiliation(s)
- Yunhai Yao
- Department of Infectious Disease, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Sanjaya K. Satapathy
- Division of Hepatology, Department of Medicine and Northwell Center for Liver Diseases & Transplantation, Northwell Health, Manhasset, NY, USA
| | | | - Odin Ramírez-Fernández
- Faculty of Mechanical and Electrical Engineering North Unit, Autonomous University of Coahuila, Monclova, Mexico
- Mexico University of Technology-Online Campus of Unitec Mexico-Anahuac College, Mexico City, Mexico
| | - Alessandro Vitale
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation Unit, Padova University Hospital, Padova, Italy
| | - Zutao Chen
- Department of Infectious Disease, the First Affiliated Hospital of Soochow University, Suzhou, China
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26
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Pinus roxburghii and Nauplius graveolens Extracts Elevate Apoptotic Gene Markers in C26 Colon Carcinoma Cells Induced in a BALB/c Mouse Model. SEPARATIONS 2022. [DOI: 10.3390/separations9100277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
The present study aimed to evaluate the chemopreventive potential of Pinus roxburghii branch (P. roxburghii) and Nauplius graveolens (N. graveolens) extracts against human colorectal cancer (CRC) induced by C26 murine cells in a BALB/c mouse model. Real-time qRT-PCR was used to evaluate the apoptotic pathway by measuring the relative mRNA expression levels of the Bcl-2, Bax, Cas3, NF-κB, and PI3k genes. At the termination of the 30-day period, blood samples were collected to assay the biomarkers. The results showed a significant increase (p < 0.05) in the levels of TGF-β, CEA, CA19-9, malondialdehyde, ALT, AST, ALP, urea, and creatinine in the positive control compared to the negative control group. In addition, the glutathione reductase activity and total antioxidant activity were reduced in the positive control compared to the negative control. The biomarkers mentioned above were restored to almost normal levels after administering a safe dose (1/10) of a lethal dose of P. roxburghii and N. graveolens extracts. Administration of one-tenth of the LD50 of P. roxburghii and N. graveolens extracts caused a significant upregulation of the expression of Bax and Cas-3 and downregulation of the Bcl-2, NF-ĸB, and PI3k genes vs. the GAPDH gene as a housekeeping gene compared to the control group. Furthermore, the Bax/Bcl-2 ratio increased upon treatment. After administration of P. roxburghii and N. graveolens at a safe dose (1/10) of a lethal dose, the results showed improvement in both body weight gain and a significant decrease (p < 0.05) in tumor volume. Histopathological changes supported these improvements. Conclusively, the research outputs show that P. roxburghii and N. graveolens extracts can be utilized as potential chemopreventive agents for CRC treatment by stimulating cancer cell apoptosis and suppressing CRC survival and proliferation.
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27
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Machida K. HCV and tumor-initiating stem-like cells. Front Physiol 2022; 13:903302. [PMID: 36187761 PMCID: PMC9520593 DOI: 10.3389/fphys.2022.903302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
Neoplasms contain tumor-initiating stem-like cells (TICs) that are characterized by increased drug resistance. The incidence of many cancer types have trended downward except for few cancer types, including hepatocellular carcinoma (HCC). Therefore mechanism of HCC development and therapy resistance needs to be understood. These multiple hits by hepatitis C virus (HCV) eventually promotes transformation and TIC genesis, leading to HCC development. This review article describes links between HCV-associated HCC and TICs. This review discusses 1) how HCV promotes genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hall marks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities.
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28
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TAK-242 Ameliorates Hepatic Fibrosis by Regulating the Liver-Gut Axis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:4949148. [PMID: 36017390 PMCID: PMC9398794 DOI: 10.1155/2022/4949148] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/15/2022] [Accepted: 07/25/2022] [Indexed: 11/17/2022]
Abstract
Objective. The aims of this study were to investigate the impact of TAK-242 on the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear transcription factor-κB (NF-κB) signal transduction pathway in rats with hepatic fibrosis (HF) using the liver gut axis and to investigate the molecular mechanism of its intervention on HF. Methods. SPF grade SD male rats were randomly allocated to the control, model, and TAK-242 groups. For 8 weeks, the model and TAK-242 groups received 3 mL·kg-1 (the initial dose 5 mL·kg-1) intraperitoneal injections of 40% CCL4 olive oil solution. TAK-242 (5 mg·kg-1) was administered once a day for 5 days after modeling. The pathological alterations of liver and small intestine tissues in each group were observed using H&E and Masson staining. ELISA was used to measure serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin (DBIL), total bilirubin (TBIL), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). RT-qPCR was utilized to identify the mRNA expression level of IL-1β, IL-6, TNF-α, TLR4, MyD88, and NF-κB in rat liver and small intestine tissues. The protein level of IL-1β, IL-6, TNF-α, TLR4, MyD88, and NF-κB protein in rat liver and small intestine tissues was determined utilizing Western blot and IHC. Results. TAK-242 significantly reduced AST, ALT, TBIL, and DBIL expression in HF rats’ serum (
) and alleviated liver tissue injury. Hematoxylin-eosin (H&E) and Masson staining revealed inflammatory cell infiltration and fibrous proliferation in the liver and small intestine tissue in the model group and partial cell swelling in the TAK-242 group, which indicated a considerable improvement compared to the model group. RT-qPCR, Western blot, and IHC data indicated that TAK-242 reduced the IL-1β, IL-6, TNF-α, TLR4, MyD88, and NF-κB expression in the liver and small intestine tissues of HF rats. Conclusion. TAK-242 might downregulate the TLR4/MyD88/NF-κB signal pathway through the liver-gut axis, suppress the inflammatory response, and eventually alleviate HF in rats.
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29
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Mofed D, Sabet S, Baiomy AA, Salem TZ. The Transgene Expression of the Immature Form of the HCV Core Protein (C191) and the LncRNA MEG3 Increases Apoptosis in HepG2 Cells. Curr Issues Mol Biol 2022; 44:3632-3647. [PMID: 36005145 PMCID: PMC9406719 DOI: 10.3390/cimb44080249] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 11/16/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) are regulated in cancer cells, including lncRNA MEG3, which is downregulated in Hepatocellular Carcinoma (HCC). In addition, hepatitis C virus (HCV) core proteins are known to dysregulate important cellular pathways that are linked to HCC development. In this study, we were interested in evaluating the overexpression of lncRNA MEG3, either alone or in combination with two forms of HCV core protein (C173 and C191) in HepG2 cells. Cell viability was assessed by MTT assay. Transcripts' levels of key genes known to be regulated in HCC, such as p53, DNMT1, miRNA152, TGF-b, and BCL-2, were measured by qRT-PCR. Protein expression levels of caspase-3 and MKI67 were determined by immunocytochemistry and apoptosis assays. The co-expression of lncRNA MEG3 and C191 resulted in a marked increase and accumulation of dead cells and a reduction in cell viability. In addition, a marked increase in the expression of tumor suppressor genes (p53 and miRNA152), as well as a marked decrease in the expression of oncogenes (DNMT1, BCL2, and TGF-b), were detected. Moreover, apoptosis assay results revealed a significant increase in total apoptosis (early and late). Finally, immunocytochemistry results detected a significant increase in apoptotic marker caspase-3 and a decrease in tumor marker MKI67. In this study, transgene expression of C191 and lncRNA MEG3 showed induction in apoptosis in HepG2 cells greater than the expression of each one alone. These results suggest potential anticancer characteristics.
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Affiliation(s)
- Dina Mofed
- Molecular Biology and Virology Lab, Biomedical Sciences Program, Zewail City of Science and Technology, October Gardens, 6th of October City, Giza 12578, Egypt
- Zoology Graduate Program, Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Salwa Sabet
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Ahmed A. Baiomy
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Tamer Z. Salem
- Molecular Biology and Virology Lab, Biomedical Sciences Program, Zewail City of Science and Technology, October Gardens, 6th of October City, Giza 12578, Egypt
- Department of Microbial Genetics, Agricultural Genetic Engineering Research Institute (AGERl), Agricultural Research Center (ARC), Giza 12619, Egypt
- National Biotechnology Network of Expertise (NBNE), Academy of Science Research and Technology (ASRT), Cairo 11334, Egypt
- Correspondence: ; Tel.: +20-1014114122
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Leslie J, Geh D, Elsharkawy AM, Mann DA, Vacca M. Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions. J Hepatol 2022; 77:219-236. [PMID: 35157957 DOI: 10.1016/j.jhep.2022.01.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/12/2022] [Accepted: 01/31/2022] [Indexed: 12/16/2022]
Abstract
HCV hijacks many host metabolic processes in an effort to aid viral replication. The resulting hepatic metabolic dysfunction underpins many of the hepatic and extrahepatic manifestations of chronic hepatitis C (CHC). However, the natural history of CHC is also substantially influenced by the host metabolic status: obesity, insulin resistance and hepatic steatosis are major determinants of CHC progression toward hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed the treatment and natural history of CHC. While DAA therapy effectively eradicates the virus, the long-lasting overlapping metabolic disease can persist, especially in the presence of obesity, increasing the risk of liver disease progression. This review covers the mechanisms by which HCV tunes hepatic and systemic metabolism, highlighting how systemic metabolic disturbance, lipotoxicity and chronic inflammation favour disease progression and a precancerous niche. We also highlight the therapeutic implications of sustained metabolic dysfunction following sustained virologic response as well as considerations for patients who develop HCC on the background of metabolic dysfunction.
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Affiliation(s)
- Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Daniel Geh
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Ahmed M Elsharkawy
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, B15 2TH UK; National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey.
| | - Michele Vacca
- Interdisciplinary Department of Medicine, Università degli Studi di Bari "Aldo Moro", Bari, Italy.
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Abdelkawy KS, Belal F, Abdelaziz A, Elmekawy HA, Abdelgaied MY, El-Khodary NM. Statins Increase the Bioavailability of Fixed-Dose Combination of Sofosbuvir/Ledipasvir by Inhibition of P-glycoprotein. Drug Res (Stuttg) 2022; 72:319-326. [PMID: 35724670 DOI: 10.1055/a-1835-1690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
BACKGROUND Coadministration of statins and direct acting antiviral agents is frequently used. This study explored the effects of both atorvastatin and lovastatin on pharmacokinetics of a fixed-dose combination of sofosbuvir/ledipasvir "FDCSL". METHODS 12 healthy volunteers participated in a randomized, three-phase crossover trial and were administered a single atorvastatin dose 80 mg plus tablet containing 400/90 mg FDCSL, a single lovastatin dose 40 mg plus tablet containing 400/90 mg FDCSL, or tablets containing 400/90 mg FDCSL alone. Liquid chromatography-tandem mass spectrometry was used to analyze plasma samples of sofosbuvir, ledipasvir and sofosbuvir metabolite "GS-331007" and their pharmacokinetic parameters were determined. RESULTS Atorvastatin caused a significant rise in sofosbuvir bioavailability as explained by increasing in AUC0-∞ and Cmax by 34.36% and 11.97%, respectively. In addition, AUC0-∞ and Cmax of GS-331007 were increased by 73.73% and 67.86%, respectively after atorvastatin intake. Similarly, co-administration of lovastatin with FDCSL increased the bioavailability of sofosbuvir, its metabolite (AUC0-∞ increase by 17.2%, 17.38%, respectively, and Cmax increase by 12.03%, 22.24%, respectively). However, neither atorvastatin nor lovastatin showed a change in ledipasvir bioavailability. Hepatic elimination was not affected after statin intake with FDCSL. Compared to lovastatin, atorvastatin showed significant increase in AUC0-∞ and Cmax of both sofosbuvir and its metabolite. CONCLUSIONS Both atorvastatin and lovastatin increased AUC of sofosbuvir and its metabolite after concurrent administration with FDCSL. Statins' P-glycoprotein inhibition is the attributed mechanism of interaction. The increase in sofosbuvir bioavailability was more pronounced after atorvastatin intake. Close monitoring is needed after co-administration of atorvastatin and FDCSL.
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Affiliation(s)
- K S Abdelkawy
- Department of Clinical Pharmacy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - Fathalla Belal
- Department of Analytical Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt
| | - AbdelazizE Abdelaziz
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - H A Elmekawy
- Department of Clinical Pharmacy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - M Y Abdelgaied
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt
| | - N M El-Khodary
- Department of Clinical Pharmacy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
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Badami E, Busà R, Douradinha B, Russelli G, Miceli V, Gallo A, Zito G, Conaldi PG, Iannolo G. Hepatocellular carcinoma, hepatitis C virus infection and miRNA involvement: Perspectives for new therapeutic approaches. World J Gastroenterol 2022; 28:2417-2428. [PMID: 35979260 PMCID: PMC9258280 DOI: 10.3748/wjg.v28.i22.2417] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/22/2022] [Accepted: 04/15/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is the principal etiology of cirrhosis and, ultimately, hepatocellular carcinoma (HCC). At present, approximately 71 million people are chronically infected with HCV, and 10%-20% of these are expected to develop severe liver complications throughout their lifetime. Scientific evidence has clearly shown the causal association between miRNAs, HCV infection and HCC. Although it is not completely clear whether miRNA dysregulation in HCC is the cause or the consequence of its development, variations in miRNA patterns have been described in different liver diseases, including HCC. Many studies have analyzed the importance of circulating miRNAs and their effect on cell proliferation and apoptosis. In this Review, we aim to summarize current knowledge on the association between miRNA, HCV and HCC from a diagnostic point of view, and also the potential implications for therapeutic approaches.
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Affiliation(s)
- Ester Badami
- Regenerative Medicine and Immunotherapy Area, Fondazione Ri.MED, Palermo 90127, Italy
| | - Rosalia Busà
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Bruno Douradinha
- Regenerative Medicine and Immunotherapy Area, Fondazione Ri.MED, Palermo 90127, Italy
| | - Giovanna Russelli
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Vitale Miceli
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Alessia Gallo
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Giovanni Zito
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Pier Giulio Conaldi
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Gioacchin Iannolo
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
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Mathew R, Churchill G, Cheema B, Desai K, Alkhasawneh A, Liu S, Siddiqi A. Concomitant Gastric Malignancy and Hepatocellular Carcinoma. Cureus 2022; 14:e25607. [PMID: 35686196 PMCID: PMC9170374 DOI: 10.7759/cureus.25607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/02/2022] [Indexed: 11/19/2022] Open
Abstract
Multiple primary malignant tumors (MPMTs) are two or more separate malignancies found at different sites concurrently. Prior studies have shown that the most common tumor associations in MPMTs are typically between two tumors in the digestive system. We present a case of a male patient in his 60s who initially presented with melena and was found to have a clean-based gastric ulcer on initial endoscopic evaluation. Repeat endoscopy on later admission revealed persistent ulceration. Biopsy showed Epstein-Barr virus (EBV) positive lymphoepithelioma-like gastric carcinoma (LELGC), a rare gastric malignancy. The patient underwent endoscopic ultrasound (EUS) for assessment of tumor depth and involvement of perigastric lymph nodes, but was incidentally found to have a liver lesion. Biopsy of the liver lesion was positive for hepatocellular carcinoma (HCC) with no morphologic similarity to the gastric malignancy. This case highlights a rare finding of MPMTs. In addition to the diagnosis of a rare gastric malignancy, the patient developed a well-known but uncommon phenomenon of non-cirrhotic HCC associated with hepatitis C virus (HCV). Due to an increasing number of advances in cancer therapy that are leading to increased survival times, clinicians can expect for a patient to develop MPMTs in their lifetime. A high index of suspicion must exist for the possibility of MPMTs because treatment options and outcomes can be vastly affected by their findings.
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Li W, Yue L, Sun L, Xiao S. An Increased Aspartate to Alanine Aminotransferase Ratio Is Associated With a Higher Risk of Cognitive Impairment. Front Med (Lausanne) 2022; 9:780174. [PMID: 35463002 PMCID: PMC9021637 DOI: 10.3389/fmed.2022.780174] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 03/03/2022] [Indexed: 11/13/2022] Open
Abstract
Background Recent Alzheimer's disease (AD) hypotheses implicate that hepatic metabolic disorders might contribute to the disease pathogenesis of AD, but the mechanism remains unclear. Aims To investigate whether the elevated aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ratio is associated with future cognitive decline, and to explore the possible mechanisms of liver enzymes affecting cognitive function. Methods Three different clinical cohorts were included in the current study, including one cross-sectional study (Cohort 1) and two longitudinal follow-up studies (Cohort 2 and 3). All participants completed a detailed clinical evaluation, neuropsychological tests, and liver enzyme tests. In addition, some of them also underwent structural magnetic resonance imaging (MRI) scans. Results Cohort 1 was derived from the CRC2017ZD02 program, including 135 amnestic mild cognitive impairment (aMCI) patients, 22 AD patients, and 319 normal controls. In this cross-sectional study, we found that the AST/ALT ratio was associated with AD (p = 0.014, OR = 1.848, 95%CI: 1.133∼3.012), but not aMCI; Cohort 2 was derived from the Shanghai Brain Health Program. A total of 260 community elderly people with normal cognitive function were included in the study and followed up for 2 years. In this 2-year longitudinal follow-up study, we found that a higher AST/ALT ratio was a risk factor for future development of aMCI (p = 0.014, HR = 1.848, 95%CI: 1.133∼3.021); Cohort 3 was derived from the China longitudinal aging study (CLAS) Program. A total of 94 community elderly people with normal cognitive function were followed up for 7 years, and all of them completed MRI scans. In this 7-year longitudinal follow-up study, we found that a higher AST/ALT ratio was a risk factor for future development of aMCI (p = 0.006, HR = 2.247, 95%CI: 1.248∼4.049), and the AST/ALT ratio was negatively correlated with right hippocampal volume (r = -0.148, p = 0.043). Conclusion An increased ratio of AST to ALT is associated with a higher risk of cognitive impairment and may impair cognitive function by affecting hippocampal volume.
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Affiliation(s)
- Wei Li
- Department of Geriatric Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Alzheimer's Disease and Related Disorders Center, Shanghai Jiao Tong University, Shanghai, China
| | - Ling Yue
- Department of Geriatric Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Alzheimer's Disease and Related Disorders Center, Shanghai Jiao Tong University, Shanghai, China
| | - Lin Sun
- Department of Geriatric Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Alzheimer's Disease and Related Disorders Center, Shanghai Jiao Tong University, Shanghai, China
| | - Shifu Xiao
- Department of Geriatric Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Alzheimer's Disease and Related Disorders Center, Shanghai Jiao Tong University, Shanghai, China
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35
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Meuren LM, Prestes EB, Papa MP, de Carvalho LRP, Mustafá YM, da Costa LS, Da Poian AT, Bozza MT, Arruda LB. Infection of Endothelial Cells by Dengue Virus Induces ROS Production by Different Sources Affecting Virus Replication, Cellular Activation, Death and Vascular Permeability. Front Immunol 2022; 13:810376. [PMID: 35185902 PMCID: PMC8847576 DOI: 10.3389/fimmu.2022.810376] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 01/11/2022] [Indexed: 01/20/2023] Open
Abstract
Exacerbated inflammatory response and altered vascular function are hallmarks of dengue disease. Reactive oxygen species (ROS) production has been associated to endothelial barrier disturbance and microvascular alteration in distinct pathological conditions. Increased ROS has been reported in in vitro models of dengue virus (DENV) infection, but its impact for endothelial cell physiology had not been fully investigated. Our group had previously demonstrated that infection of human brain microvascular endothelial cells (HBMEC) with DENV results in the activation of RNA sensors and production of proinflammatory cytokines, which culminate in cell death and endothelial permeability. Here, we evaluated the role of mitochondrial function and NADPH oxidase (NOX) activation for ROS generation in HBMEC infected by DENV and investigated whether altered cellular physiology could be a consequence of virus-induced oxidative stress. DENV-infected HBMECs showed a decrease in the maximal respiratory capacity and altered membrane potential, indicating functional mitochondrial alteration, what might be related to mtROS production. Indeed, mtROS was detected at later time points after infection. Specific inhibition of mtROS diminished virus replication, cell death, and endothelial permeability, but did not affect cytokine production. On the other hand, inhibition of NOX-associated ROS production decreased virus replication and cell death, as well as the secretion of inflammatory cytokines, including IL-6, IL-8, and CCL5. These results demonstrated that DENV replication in endothelial cells induces ROS production by different pathways, which impacts biological functions that might be relevant for dengue pathogenesis. Those data also indicate oxidative stress events as relevant therapeutical targets to avoid vascular permeability, inflammation, and neuroinvasion during DENV infection.
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Affiliation(s)
- Lana Monteiro Meuren
- Departamento de Virologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Elisa Beatriz Prestes
- Laboratório de Inflamação e Imunidade, Departamento de Imunologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Michelle Premazzi Papa
- Departamento de Virologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.,Department of Microbiology, Immunology and Tropical Medicine, The George Washington University, Washington, DC, United States
| | | | - Yasmin Mucunã Mustafá
- Departamento de Virologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Leandro Silva da Costa
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Andrea T Da Poian
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcelo Torres Bozza
- Laboratório de Inflamação e Imunidade, Departamento de Imunologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luciana Barros Arruda
- Departamento de Virologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Lin C, Hu Q, Dong J, Wei Z, Li J, Chen Z. Serum metabolic signatures of schizophrenia patients complicated with hepatitis B virus infection: A 1H NMR-based metabolomics study. Front Psychiatry 2022; 13:998709. [PMID: 36620683 PMCID: PMC9810819 DOI: 10.3389/fpsyt.2022.998709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 11/30/2022] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Schizophrenia (SZ) is a severe chronic mental disorder with increased risk of hepatitis B virus (HBV) infection, which is incurable currently and induces various negative emotions and psychological pressures in patients to exacerbate mental disorders. To facilitate the therapeutic design for SZ patients complicated with HBV infection (SZ + HBV), it is helpful to first elucidate the metabolic perturbations in SZ + HBV patients. METHODS In this study, metabolic profiles of the serum samples from four groups of participants comprising healthy controls (HC, n = 72), HBV infection (n = 52), SZ patients (n = 37), and SZ + HBV (n = 41) patients were investigated using a high-resolution 1H NMR-based metabolomics approach. RESULTS AND DISCUSSION Distinguishable metabolic profiles were found in the four groups. In comparison with HC, HBV infection induced increased levels of citrate and succinate to perturbate the tricarboxylic acid cycle and succinate-related pathways. Similar to SZ cases, SZ + HBV patients exhibited decreased glucose but increased citrate, pyruvate, and lactate, suggesting the occurrence of disturbance in glucose metabolism. Moreover, in comparison with HC, several serum amino acid levels in SZ + HBV patients were significantly altered. Our findings suggest that Warburg effect, energy metabolism disorders, neurotransmitter metabolism abnormalities, mitochondrial dysfunction and several disturbed pathways in relation to tyrosine and choline appear to play specific and central roles in the pathophysiology of SZ + HBV. Apart from replicating metabolic alterations induced by SZ and HBV separately (e.g., in energy metabolism and Warburg effect), the specific metabolic abnormalities in the SZ + HBV group (e.g., several tyrosine- and choline-related pathways) highlighted the existence of a synergistic action between SZ and HBV pathologies. Current study revealed the metabolic alterations specific to the interaction between SZ and HBV pathologies, and may open important perspectives for designing precise therapies for SZ + HBV patients beyond the simple combination of two individual treatments.
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Affiliation(s)
- Caigui Lin
- Fujian Provincial Key Laboratory for Plasma and Magnetic Resonance, Department of Electronic Science, Xiamen University, Xiamen, Fujian, China.,National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian, China
| | - Qing Hu
- Xiamen Xianyue Hospital, Xiamen, Fujian, China
| | - Jiyang Dong
- Fujian Provincial Key Laboratory for Plasma and Magnetic Resonance, Department of Electronic Science, Xiamen University, Xiamen, Fujian, China
| | - Zhiliang Wei
- Department of Radiology, Johns Hopkins University, Baltimore, MD, United States
| | - Jie Li
- Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China
| | - Zhong Chen
- Fujian Provincial Key Laboratory for Plasma and Magnetic Resonance, Department of Electronic Science, Xiamen University, Xiamen, Fujian, China
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Han HS, Koo SY, Choi KY. Emerging nanoformulation strategies for phytocompounds and applications from drug delivery to phototherapy to imaging. Bioact Mater 2021; 14:182-205. [PMID: 35310344 PMCID: PMC8892098 DOI: 10.1016/j.bioactmat.2021.11.027] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 11/20/2021] [Accepted: 11/30/2021] [Indexed: 12/18/2022] Open
Abstract
Over thousands of years, natural bioactive compounds derived from plants (bioactive phytocompounds, BPCs) have been used worldwide to address human health issues. Today, they are a significant resource for drug discovery in the development of modern medicines. Although many BPCs have promising biological activities, most of them cannot be effectively utilized in drugs for therapeutic applications because of their inherent limitations of low solubility, structural instability, short half-life, poor bioavailability, and non-specific distribution to organs. Researchers have utilized emerging nanoformulation (NF) technologies to overcome these limitations as they have demonstrated great potential to improve the solubility, stability, and pharmacokinetic and pharmacodynamic characteristics of BPCs. This review exemplifies NF strategies for resolving the issues associated with BPCs and summarizes recent advances in their preclinical and clinical applications for imaging and therapy. This review also highlights how innovative NF technologies play a leading role in next-generation BPC-based drug development for extended therapeutic applications. Finally, this review discusses the opportunities to take BPCs with meaningful clinical impact from bench to bedside and extend the patent life of BPC-based medicines with new formulations or application to new adjacent diseases beyond the primary drug indications.
Natural bioactive phytocompounds derived from plants have been used worldwide to address human health issues. However, most of them cannot be effectively utilized in drugs for therapeutic applications because of their inherent limitations. Nanoformulation approach has recently been underlined as an emerging pharmaceutical strategy to overcome the intrinsic drawbacks of bioactive phytocompounds. Various types of nanoformulation and their up-to-date applications for targeted delivery, phototherapy, and imaging are reviewed. Finally, their clinical implications for the repurposing of bioactive phytocompounds are deliberated.
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Affiliation(s)
- Hwa Seung Han
- Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung, 25451, Republic of Korea
| | - Song Yi Koo
- Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung, 25451, Republic of Korea
| | - Ki Young Choi
- Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung, 25451, Republic of Korea
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul, 02792, Republic of Korea
- Corresponding author. Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung, 25451, Republic of Korea.
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Cerrito L, Ainora ME, Nicoletti A, Garcovich M, Riccardi L, Pompili M, Gasbarrini A, Zocco MA. Elastography as a predictor of liver cirrhosis complications after hepatitis C virus eradication in the era of direct-acting antivirals. World J Hepatol 2021; 13:1663-1676. [PMID: 34904036 PMCID: PMC8637667 DOI: 10.4254/wjh.v13.i11.1663] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 07/08/2021] [Accepted: 08/17/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic inflammation due to hepatitis C virus (HCV) infection leads to liver fibrosis and rearrangement of liver tissue, which is responsible for the development of portal hypertension (PH) and hepatocellular carcinoma (HCC). The advent of direct-acting antiviral drugs has revolutionized the natural history of HCV infection, providing an overall eradication rate of over 90%. Despite a significant decrease after sustained virological response (SVR), the rate of HCC and liver-related complications is not completely eliminated in patients with advanced liver disease. Although the reasons are still unclear, cirrhosis itself has a residual risk for the development of HCC and other PH-related complications. Ultrasound elastography is a recently developed non-invasive technique for the assessment of liver fibrosis. Following the achievement of SVR, liver stiffness (LS) usually decreases, as a consequence of reduced inflammation and, possibly, fibrosis. Recent studies emphasized the application of LS assessment in the management of patients with SVR in order to define the risk for developing the complications of chronic liver disease (functional decompensation, gastrointestinal bleeding, HCC) and to optimize long-term prognostic outcomes in clinical practice.
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Affiliation(s)
- Lucia Cerrito
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Catholic University of Rome (Italy), Rome 00168, Italy
| | - Maria Elena Ainora
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Catholic University of Rome (Italy), Rome 00168, Italy
| | - Alberto Nicoletti
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Catholic University of Rome (Italy), Rome 00168, Italy
| | - Matteo Garcovich
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Catholic University of Rome (Italy), Rome 00168, Italy
| | - Laura Riccardi
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Catholic University of Rome (Italy), Rome 00168, Italy
| | - Maurizio Pompili
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Catholic University of Rome (Italy), Rome 00168, Italy
| | - Antonio Gasbarrini
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Catholic University of Rome (Italy), Rome 00168, Italy
| | - Maria Assunta Zocco
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Catholic University of Rome (Italy), Rome 00168,
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Xiao X, Hu Q, Deng X, Shi K, Zhang W, Jiang Y, Ma X, Zeng J, Wang X. Old wine in new bottles: Kaempferol is a promising agent for treating the trilogy of liver diseases. Pharmacol Res 2021; 175:106005. [PMID: 34843960 DOI: 10.1016/j.phrs.2021.106005] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 02/07/2023]
Abstract
As a source of various compounds, natural products have long been important and valuable for drug development. Kaempferol (KP) is the most common flavonol with bioactive activity and has been extracted from many edible plants and traditional Chinese medicines. It has a wide range of pharmacological effects on inflammation, oxidation, and tumour and virus regulation. The liver is an important organ and is involved in metabolism and activity. Because the pathological process of liver diseases is extremely complicated, liver diseases involving ALD, NASH, liver fibrosis, and HCC are often complicated and difficult to treat. Fortunately, there have been many reports that KP has a good pharmacological effect on a series of complex liver diseases. To fully understand the mechanism of KP and provide new ideas for its clinical application in the treatment of liver diseases, this article reviews the pharmacological mechanism and potential value of KP in different studies involving various liver diseases. In the trilogy of liver disease, high concentrations of ROS stimulate peroxidation and activate the inflammatory signal cascade, which involves signalling pathways such as MAPK/JAK-STAT/PERK/Wnt/Hipp, leading to varying degrees of cell degradation and liver damage. The development of liver disease is promoted in an inflammatory environment, which is conducive to the activation of TGF-β1, leading to increased expression of pro-fibrosis and pro-inflammatory genes. Inflammation and oxidative stress promote the formation of tumour microenvironments, and uncontrolled autophagy of cancer cells further leads to the development of liver cancer. The main pathway in this process is AMPK/PTEN/PI3K-Akt/TOR. KP can not only protect liver parenchymal cells through a variety of antioxidant and anti-apoptotic mechanisms but also reduces the immune inflammatory response in the liver microenvironment, thereby preventing cell apoptosis; it can also inhibit the ER stress response, prevent inflammation and inhibit tumour growth. KP exerts multiple therapeutic effects on liver disease by regulating precise signalling targets and is expected to become an emerging therapeutic opportunity to treat liver disease in the future.
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Affiliation(s)
- Xiaolin Xiao
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Qichao Hu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xinyu Deng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Kaiyun Shi
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Wenwen Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yinxiao Jiang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Jinhao Zeng
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Xiaoyin Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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Moretti R, Giuffrè M, Merli N, Caruso P, Di Bella S, Tiribelli C, Crocè LS. Hepatitis C Virus-Related Central and Peripheral Nervous System Disorders. Brain Sci 2021; 11:1569. [PMID: 34942871 PMCID: PMC8699483 DOI: 10.3390/brainsci11121569] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatitis C Virus (HCV), despite being a hepatotropic virus, is the causative agent of many systemic disorders, such as vasculitis, autoimmune diseases, lymphoproliferative disorders, and a broad spectrum of neurological and psychiatric manifestations. Although symptoms have been misdiagnosed or underdiagnosed, only recently, evidence of direct (inflammatory) or indirect (immune-mediated) HCV-dependent cerebral effects has been established. HCV infection can promote acute inflammatory response, pro-coagulative status and ischemic disorders, and neurodegeneration. These effects rely on cerebral HCV replication, possibly mediated by blood-brain barrier alterations. Further study is needed to better understand the HCV-related mechanisms of brain damage.
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Affiliation(s)
- Rita Moretti
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Mauro Giuffrè
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Nicola Merli
- Department Neurological Sciences, University of Ferrara, 44121 Ferrara, Italy;
| | - Paola Caruso
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Stefano Di Bella
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | | | - Lory Saveria Crocè
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
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Mitochondrial Mechanisms of Apoptosis and Necroptosis in Liver Diseases. Anal Cell Pathol (Amst) 2021; 2021:8900122. [PMID: 34804779 PMCID: PMC8601834 DOI: 10.1155/2021/8900122] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/20/2021] [Accepted: 10/26/2021] [Indexed: 12/23/2022] Open
Abstract
In addition to playing a pivotal role in cellular energetics and biosynthesis, mitochondrial components are key operators in the regulation of cell death. In addition to apoptosis, necrosis is a highly relevant form of programmed liver cell death. Differential activation of specific forms of programmed cell death may not only affect the outcome of liver disease but may also provide new opportunities for therapeutic intervention. This review describes the role of mitochondria in cell death and the mechanism that leads to chronic liver hepatitis and liver cirrhosis. We focus on mitochondrial-driven apoptosis and current knowledge of necroptosis and discuss therapeutic strategies for targeting mitochondrial-mediated cell death in liver diseases.
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Hsu SJ, Xu X, Chen MP, Zhao ZY, Wang Y, Yin X, Zhang L, Ge NL, Chen Y, Wang YH, Luo JF, Ren ZG, Chen RX. Hepatic Arterial Infusion Chemotherapy with Modified FOLFOX as an Alternative Treatment Option in Advanced Hepatocellular Carcinoma Patients with Failed or Unsuitability for Transarterial Chemoembolization. Acad Radiol 2021; 28 Suppl 1:S157-S166. [PMID: 33653656 DOI: 10.1016/j.acra.2021.01.024] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/09/2021] [Accepted: 01/15/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVE This study aimed to assess the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with modified FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) as an alternative treatment option in advanced hepatocellular carcinoma (HCC) patients with failed or unsuitability for transarterial chemoembolization (TACE). MATERIALS AND METHODS: From September 2018 to January 2020, 87 advanced HCC patients who progressed on TACE or were not eligible for TACE received HAIC treatment with modified FOLFOX. The primary endpoint was overall survival (OS) and secondary endpoints included progression-free survival (PFS), tumor response assessed by Response Evaluation Criteria in Solid Tumors 1.1, and adverse events graded according to CTCAE 5.0. Based on prognostic factors determined by multivariate analysis, a nomogram was developed to predict patient survival. RESULTS The median OS and PFS were 9.0 months (95%CI 7.6-10.4) and 3.7 months (95%CI 3.1-4.3), respectively. The objective response rate was 13.8%, with a disease control rate of 48.3%. Grade 3 adverse events were observed, such as infection (9.2%), thrombocytopenia (5.7%), hyperbilirubinemia (3.4%), abdominal pain (2.3%) and alanine aminotransferase increase (2.3%). Albumin, AST, and extrahepatic metastasis were incorporated to construct a new nomogram that could stratify patients into three prognostic subgroups, including low-, intermediate-, and high-risk groups, with significant differences in 9-month OS rates (71%, 42% and 6%, respectively; p< 0.001). The nomogram was better than the Okuda, AJCC, and CLIP staging systems for OS prediction. CONCLUSION These findings support the feasibility of HAIC with modified FOLFOX as an alternative treatment strategy for advanced HCC when TACE is ineffective or unsuitable.
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Romero‐Cordero S, Noguera‐Julian A, Cardellach F, Fortuny C, Morén C. Mitochondrial changes associated with viral infectious diseases in the paediatric population. Rev Med Virol 2021; 31:e2232. [PMID: 33792105 PMCID: PMC9286481 DOI: 10.1002/rmv.2232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/15/2021] [Accepted: 02/17/2021] [Indexed: 12/24/2022]
Abstract
Infectious diseases occur worldwide with great frequency in both adults and children, causing 350,000 deaths in 2017, according to the latest World Health Organization reports. Both infections and their treatments trigger mitochondrial interactions at multiple levels: (i) incorporation of damaged or mutated proteins into the complexes of the electron transport chain; (ii) impact on mitochondrial genome (depletion, deletions and point mutations) and mitochondrial dynamics (fusion and fission); (iii) membrane potential impairment; (iv) apoptotic regulation; and (v) generation of reactive oxygen species, among others. Such alterations may result in serious adverse clinical events with considerable impact on the quality of life of the children and could even cause death. Herein, we use a systematic review to explore the association between mitochondrial alterations in paediatric infections including human immunodeficiency virus, cytomegalovirus, herpes viruses, various forms of hepatitis, adenovirus, T-cell lymphotropic virus and influenza. We analyse how these paediatric viral infectious processes may cause mitochondrial deterioration in this especially vulnerable population, with consideration for the principal aspects of research and diagnosis leading to improved disease understanding, management and surveillance.
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Affiliation(s)
- Sonia Romero‐Cordero
- Faculty of MedicinePompeu Fabra UniversityBarcelonaSpain
- Faculty of MedicineUniversitat Autònoma de BarcelonaBellaterraSpain
| | - Antoni Noguera‐Julian
- Malalties Infeccioses i Resposta Inflamatòria Sistèmica en PediatriaUnitat d´InfeccionsServei de PediatriaInstitut de Recerca Pediàtrica Hospital Sant Joan de DéuBarcelonaSpain
- Departament de PediatriaUniversitat de BarcelonaBarcelonaSpain
- CIBER de Epidemiología y Salud Pública, CIBERESP (ISCIII)MadridSpain
- Red de Investigación Translacional en Infectología PediátricaRITIPMadridSpain
| | - Francesc Cardellach
- Faculty of Medicine and Health SciencesMuscle Research and Mitochondrial Function LaboratoryCellex‐IDIBAPSUniversity of BarcelonaBarcelonaSpain
- CIBER de Enfermedades RarasCIBERER (ISCIII)MadridSpain
- Internal Medicine DepartmentHospital Clínic of Barcelona (HCB)BarcelonaSpain
| | - Clàudia Fortuny
- Malalties Infeccioses i Resposta Inflamatòria Sistèmica en PediatriaUnitat d´InfeccionsServei de PediatriaInstitut de Recerca Pediàtrica Hospital Sant Joan de DéuBarcelonaSpain
- Departament de PediatriaUniversitat de BarcelonaBarcelonaSpain
- CIBER de Epidemiología y Salud Pública, CIBERESP (ISCIII)MadridSpain
- Red de Investigación Translacional en Infectología PediátricaRITIPMadridSpain
| | - Constanza Morén
- Faculty of Medicine and Health SciencesMuscle Research and Mitochondrial Function LaboratoryCellex‐IDIBAPSUniversity of BarcelonaBarcelonaSpain
- CIBER de Enfermedades RarasCIBERER (ISCIII)MadridSpain
- Internal Medicine DepartmentHospital Clínic of Barcelona (HCB)BarcelonaSpain
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Ho GT, Theiss AL. Mitochondria and Inflammatory Bowel Diseases: Toward a Stratified Therapeutic Intervention. Annu Rev Physiol 2021; 84:435-459. [PMID: 34614372 DOI: 10.1146/annurev-physiol-060821-083306] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Mitochondria serve numerous critical cellular functions, rapidly responding to extracellular stimuli and cellular demands while dynamically communicating with other organelles. Mitochondrial function in the gastrointestinal epithelium plays a critical role in maintaining intestinal health. Emerging studies implicate the involvement of mitochondrial dysfunction in inflammatory bowel disease (IBD). This review presents mitochondrial metabolism, function, and quality control that converge in intestinal epithelial stemness, differentiation programs, barrier integrity, and innate immunity to influence intestinal inflammation. Intestinal and disease characteristics that set the stage for mitochondrial dysfunction being a key factor in IBD, and in turn, pathogenic mitochondrial mechanisms influencing and potentiating the development of IBD, are discussed. These findings establish the basis for potential mitochondrial-targeted interventions for IBD therapy. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Gwo-Tzer Ho
- Edinburgh IBD Science Unit, Centre for Inflammation Research, Queens Medical Research Unit, University of Edinburgh, Edinburgh, United Kingdom
| | - Arianne L Theiss
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA;
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Chi X, Liu Z, Wei W, Hu X, Wang Y, Wang H, Xu B. Selenium-rich royal jelly inhibits hepatocellular carcinoma through PI3K/AKT and VEGF pathways in H22 tumor-bearing mice. Food Funct 2021; 12:9111-9127. [PMID: 34397053 DOI: 10.1039/d1fo01070k] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Royal jelly (RJ) and selenium (Se)-rich foods have well-known health benefits that are attributable to a broad range of pharmacological effects including antioxidant, anti-tumor, and immunoregulatory activities. However, the physiological effects of Se-rich RJ, which is produced by feeding Apis mellifera (Hymenoptera: Apidae) sodium selenite sucrose solution, are not well understood. The anti-hepatoma activity and mechanism of Se-rich RJ in H22 tumor-bearing mice were investigated in the current study. The findings showed that the content of organic and inorganic Se in Se-rich RJ was significantly higher than that in RJ. Furthermore, interleukin-2 (IL-2) levels and tumor necrosis factor-α (TNF-α) production in serum were increased and the malondialdehyde (MDA) content in liver was decreased in mice fed RJ and Se-rich RJ. 16SrRNA sequencing and serum untargeted metabolomics showed that RJ and Se-rich RJ could modulate the gut microbiota, and fisetin and l-glutathione oxidized were the main anti-tumor components in RJ and Se-rich RJ. Further analysis showed 11-deoxy prostaglandin F1β was the specific anti-tumor metabolite in mice treated with Se-rich RJ compared with RJ. The results indicated that RJ and Se-rich RJ could inhibit the expression of PI3K and phosphorylation of AKT, induce cell apoptosis through the activation of caspase-9 and caspase-3, and regulate Bcl-2/Bax expression. RJ and Se-rich RJ also inhibited the expression of COX-2 and VEGF. To summarize, the findings clearly demonstrate that Se-rich RJ could inhibit tumor growth by inducing apoptosis and inhibiting angiogenesis as well as exhibit anti-tumor effects by improving immune function and antioxidant activities. The results indicated that Se-rich RJ could be a potential functional food for the management and prevention of cancer.
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Affiliation(s)
- Xuepeng Chi
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai' an, Shandong 271018, China.
| | - Zhenguo Liu
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai' an, Shandong 271018, China.
| | - Wei Wei
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai' an, Shandong 271018, China.
| | - Xiyi Hu
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai' an, Shandong 271018, China.
| | - Ying Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai' an, Shandong 271018, China.
| | - Hongfang Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai' an, Shandong 271018, China.
| | - Baohua Xu
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai' an, Shandong 271018, China.
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Qiu H, Liu C, Huang M, Shen S, Wang W. Prognostic Value of Combined CA19-9 with Aspartate Aminotransferase to Lymphocyte Ratio in Patients with Intrahepatic Cholangiocarcinoma After Hepatectomy. Cancer Manag Res 2021; 13:5969-5980. [PMID: 34377017 PMCID: PMC8349206 DOI: 10.2147/cmar.s320380] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 07/16/2021] [Indexed: 02/05/2023] Open
Abstract
Purpose The prognosis of intrahepatic cholangiocarcinoma (ICC) patients after surgical resection remains poor. Effective prognostic biomarkers are expected to stratify ICC patients and optimize their treatment strategies. To investigate the prognostic value of carbohydrate antigen 19-9 (CA19-9), aspartate aminotransferase to lymphocyte ratio index (ALRI), and their combination (CAC) in predicting long-term outcomes in ICC patients after hepatectomy. Patients and Methods ICC patients underwent initial hepatectomy for curative purpose from January 2009 to September 2017 were reviewed retrospectively. Area under the receiver operating characteristics curve (AUC) was used to distinguish the identification effectiveness of three different measures. Kaplan–Meier curves and Cox proportional hazards regression were used to assess the value of preoperative CAC grade in predicting overall survival (OS) and disease-free survival (DFS). Results A total of 530 patients were included and randomly divided into two groups (derivation cohort and validation cohort). During a median follow-up of 18 months (1–115.4 months), 317 patients (59.8%) died and 381 patients (71.9%) developed tumor recurrence. Lower ALRI, decreased serum CA19-9 level and CAC grade were found to be associated with better OS and DFS (both P<0.001). Importantly, the AUC for CAC grade was significantly greater than ALRI and CA19-9. In addition, results from Cox proportional hazards regression from both cohorts suggest that tumor number, node invasion, and CAC grade as independent prognostic factors for both OS and DFS. Conclusion This study demonstrated that CAC grade is a valuable biomarker for the prognosis of ICC patients. Specifically, patients with elevated CAC grades were correlated to worse long-term outcome after the hepatectomy. Our data suggest that increased CAC grades can be used to stratify patients and help to decide their treatment strategies.
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Affiliation(s)
- Haizhou Qiu
- Department of Liver Surgery and Liver Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Chang Liu
- Department of Liver Surgery and Liver Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Min Huang
- Department of Liver Surgery and Liver Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Shu Shen
- Department of Liver Surgery and Liver Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Wentao Wang
- Department of Liver Surgery and Liver Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
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Hatta MNA, Mohamad Hanif EA, Chin SF, Neoh HM. Pathogens and Carcinogenesis: A Review. BIOLOGY 2021; 10:533. [PMID: 34203649 PMCID: PMC8232153 DOI: 10.3390/biology10060533] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 05/30/2021] [Accepted: 06/02/2021] [Indexed: 12/24/2022]
Abstract
Cancer is a global health problem associated with genetics and unhealthy lifestyles. Increasingly, pathogenic infections have also been identified as contributors to human cancer initiation and progression. Most pathogens (bacteria, viruses, fungi, and parasites) associated with human cancers are categorized as Group I human carcinogens by the International Agency for Research on Cancer, IARC. These pathogens cause carcinogenesis via three known mechanisms: persistent infection that cause inflammation and DNA damage, initiation of oncogene expression, and immunosuppression activity of the host. In this review, we discuss the carcinogenesis mechanism of ten pathogens, their implications, and some future considerations for better management of the disease. The pathogens and cancers described are Helicobacter pylori (gastric cancer), Epstein-Barr virus (gastric cancer and lymphoma), Hepatitis B and C viruses (liver cancer), Aspergillus spp. (liver cancer), Opisthorchis viverrine (bile duct cancer), Clonorchis sinensis (bile duct cancer), Fusobacterium nucleatum (colorectal cancer), Schistosoma haematobium (bladder cancer); Human Papillomavirus (cervical cancer), and Kaposi's Sarcoma Herpes Virus (Kaposi's sarcoma).
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Affiliation(s)
| | | | | | - Hui-min Neoh
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Jalan Ya’acob Latiff, Cheras, Kuala Lumpur 56000, Malaysia; (M.N.A.H.); (E.A.M.H.); (S.-F.C.)
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Hatano Y, Ideta T, Hirata A, Hatano K, Tomita H, Okada H, Shimizu M, Tanaka T, Hara A. Virus-Driven Carcinogenesis. Cancers (Basel) 2021; 13:2625. [PMID: 34071792 PMCID: PMC8198641 DOI: 10.3390/cancers13112625] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/22/2021] [Accepted: 05/25/2021] [Indexed: 12/13/2022] Open
Abstract
Cancer arises from the accumulation of genetic and epigenetic alterations. Even in the era of precision oncology, carcinogens contributing to neoplastic process are still an important focus of research. Comprehensive genomic analyses have revealed various combinations of base substitutions, referred to as the mutational signatures, in cancer. Each mutational signature is believed to arise from specific DNA damage and repair processes, including carcinogens. However, as a type of carcinogen, tumor viruses increase the cancer risk by alternative mechanisms, including insertional mutagenesis, viral oncogenes, and immunosuppression. In this review, we summarize virus-driven carcinogenesis to provide a framework for the control of malignant cell proliferation. We first provide a brief overview of oncogenic viruses and describe their implication in virus-related tumors. Next, we describe tumor viruses (HPV, Human papilloma virus; HBV, Hepatitis B virus; HCV, Hepatitis C virus; EBV, Epstein-Barr virus; Kaposi sarcoma herpesvirus; MCV, Merkel cell polyoma virus; HTLV-1, Human T-cell lymphotropic virus, type-1) and tumor virus-related cancers. Lastly, we introduce emerging tumor virus candidates, human cytomegalovirus (CMV), human herpesvirus-6 (HHV-6) and adeno-associated virus-2 (AAV-2). We expect this review to be a hub in a complex network of data for virus-associated carcinogenesis.
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Affiliation(s)
- Yuichiro Hatano
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; (H.T.); (A.H.)
| | - Takayasu Ideta
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; (T.I.); (M.S.)
- Department of Laboratory Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Akihiro Hirata
- Laboratory of Veterinary Pathology, Joint Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu 501-1194, Japan;
| | - Kayoko Hatano
- Department of Obstetrics and Gynecology, Gifu University Hospital, Gifu 501-1194, Japan;
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; (H.T.); (A.H.)
| | - Hideshi Okada
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan;
| | - Masahito Shimizu
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; (T.I.); (M.S.)
| | - Takuji Tanaka
- Department of Diagnostic Pathology (DDP) and Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, Gifu 500-8513, Japan;
| | - Akira Hara
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; (H.T.); (A.H.)
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Liu M, Rao H, Liu J, Li X, Feng W, Gui L, Tang H, Xu J, Gao WQ, Li L. The histone methyltransferase SETD2 modulates oxidative stress to attenuate experimental colitis. Redox Biol 2021; 43:102004. [PMID: 34020310 PMCID: PMC8141928 DOI: 10.1016/j.redox.2021.102004] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 04/19/2021] [Accepted: 05/07/2021] [Indexed: 12/12/2022] Open
Abstract
Epigenetic regulation disorder is important in the onset and pathogenesis of inflammatory bowel disease (IBD). SETD2, a trimethyltransferase of histone H3K36, is frequently mutated in IBD samples with a high risk of developing colorectal cancer (CRC). However, functions of SETD2 in IBD and colitis-associated CRC remain largely undefined. Here, we found that SETD2 modulates oxidative stress to attenuate colonic inflammation and tumorigenesis in mice. SETD2 expression became decreased in IBD patients and dextran sodium sulfate (DSS)-induced colitic mice. Setd2Vil-KO mice showed increased susceptibility to DSS-induced colitis, accompanied by more severe epithelial barrier disruption and markedly increased intestinal permeability that subsequently facilitated inflammation-associated CRC. Mechanistically, we found that Setd2 depletion resulted in excess reactive oxygen species (ROS) by directly down-regulating antioxidant genes, which led to defects in barrier integrity and subsequently inflammatory damage. Moreover, overexpression of antioxidant PRDX6 in Setd2Vil-KO intestinal epithelial cells (IECs) largely alleviated the overproductions of ROS and improved the cellular survival. Together, our findings highlight an epigenetic mechanism by which SETD2 modulates oxidative stress to regulate intestinal epithelial homeostasis and attenuate colonic inflammation and tumorigenesis. SETD2 might therefore be a pivotal regulator that maintains the homeostasis of the intestinal mucosal barrier.
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Affiliation(s)
- Min Liu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Hanyu Rao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Liu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoxue Li
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Wenxin Feng
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Liming Gui
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Huayuan Tang
- State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Jin Xu
- School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Wei-Qiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
| | - Li Li
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
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Hejrati A, Nurzadeh M, Roham M. Association of coronavirus pathogencity with the level of antioxidants and immune system. J Family Med Prim Care 2021; 10:609-614. [PMID: 34041049 PMCID: PMC8138403 DOI: 10.4103/jfmpc.jfmpc_1007_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/31/2020] [Accepted: 10/25/2020] [Indexed: 12/27/2022] Open
Abstract
Viruses are non-living organisms that annually cause many problems for human societies. The spread of some of the most dangerous viruses causing acute pneumonia, including novel Corona virus has led to the largest death toll in the world. With a long incubation period, Corona virus causes many problems for the immune system. Studies have shown that antioxidant enzymes play an important role in reducing infection and boosting the immune system. The immune system of people with chronic infections is often weak. Specific immunity is one of the most important responses to the virus. The present study therefore investigates association of Coronavirus pathogenicity with the level of antioxidants and immune system.
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Affiliation(s)
- Alireza Hejrati
- Department of Internal Medicine, School of Medicine, Hazrat-e Rasool Hospital, Iran University of Medical Sciences. Tehran, Iran
| | - Maryam Nurzadeh
- Department of Fetomaternal, Faculty of Medicine, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Roham
- Infectious Disease Specialist, Antimicrobial-Resistant Research Center, Iran University of Medical Sciences, Tehran, Iran
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