|
1
|
Michalak KP, Michalak AZ, Brenk-Krakowska A. Acute COVID-19 and LongCOVID syndrome - molecular implications for therapeutic strategies - review. Front Immunol 2025; 16:1582783. [PMID: 40313948 PMCID: PMC12043656 DOI: 10.3389/fimmu.2025.1582783] [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: 02/25/2025] [Accepted: 03/28/2025] [Indexed: 05/03/2025] Open
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been recognized not only for its acute effects but also for its ability to cause LongCOVID Syndrome (LCS), a condition characterized by persistent symptoms affecting multiple organ systems. This review examines the molecular and immunological mechanisms underlying LCS, with a particular focus on autophagy inhibition, chronic inflammation, oxidative, nitrosative and calcium stress, viral persistence and autoimmunology. Potential pathophysiological mechanisms involved in LCS include (1) autoimmune activation, (2) latent viral persistence, where SARS-CoV-2 continues to influence host metabolism, (3) reactivation of latent pathogens such as Epstein-Barr virus (EBV) or cytomegalovirus (CMV), exacerbating immune and metabolic dysregulation, and (4) possible persistent metabolic and inflammatory dysregulation, where the body fails to restore post-infection homeostasis. The manipulation of cellular pathways by SARS-CoV-2 proteins is a critical aspect of the virus' ability to evade immune clearance and establish long-term dysfunction. Viral proteins such as NSP13, ORF3a and ORF8 have been shown to disrupt autophagy, thereby impairing viral clearance and promoting immune evasion. In addition, mitochondrial dysfunction, dysregulated calcium signaling, oxidative stress, chronic HIF-1α activation and Nrf2 inhibition create a self-sustaining inflammatory feedback loop that contributes to tissue damage and persistent symptoms. Therefore understanding the molecular basis of LCS is critical for the development of effective therapeutic strategies. Targeting autophagy and Nrf2 activation, glycolysis inhibition, and restoration calcium homeostasis may provide novel strategies to mitigate the long-term consequences of SARS-CoV-2 infection. Future research should focus on personalized therapeutic interventions based on the dominant molecular perturbations in individual patients.
Collapse
Affiliation(s)
- Krzysztof Piotr Michalak
- Laboratory of Vision Science and Optometry, Physics and Astronomy Faculty, Adam Mickiewicz University in Poznań, Poznań, Poland
| | | | - Alicja Brenk-Krakowska
- Laboratory of Vision Science and Optometry, Physics and Astronomy Faculty, Adam Mickiewicz University in Poznań, Poznań, Poland
| |
Collapse
|
|
2
|
Tripathi S, Sharma Y, Kumar D. Unveiling the link between chronic inflammation and cancer. Metabol Open 2025; 25:100347. [PMID: 39876904 PMCID: PMC11772974 DOI: 10.1016/j.metop.2025.100347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 01/05/2025] [Accepted: 01/06/2025] [Indexed: 01/31/2025] Open
Abstract
The highly nuanced transition from an inflammatory process to tumorigenesis is of great scientific interest. While it is well known that environmental stimuli can cause inflammation, less is known about the oncogenic modifications that chronic inflammation in the tissue microenvironment can bring about, as well as how these modifications can set off pro-tumorigenic processes. It is clear that no matter where the environmental factors come from, maintaining an inflammatory microenvironment encourages carcinogenesis. In addition to encouraging angiogenesis and metastatic processes, sustaining the survival and proliferation of malignant transformed cells, and possibly altering the efficacy of therapeutic agents, inflammation can negatively regulate the antitumoral adaptive and innate immune responses. Because chronic inflammation has multiple pathways involved in tumorigenesis and metastasis, it has gained recognition as a marker of cancer and a desirable target for cancer therapy. Recent advances in our knowledge of the molecular mechanisms that drive cancer's progression demonstrate that inflammation promotes tumorigenesis and metastasis while suppressing anti-tumor immunity. In many solid tumor types, including breast, lung, and liver cancer, inflammation stimulates the activation of oncogenes and impairs the body's defenses against the tumor. Additionally, it alters the microenvironment of the tumor. As a tactical approach to cancer treatment, these findings have underscored the importance of targeting inflammatory pathways. This review highlights the role of inflammation in cancer development and metastasis, focusing on its impact on tumor progression, immune suppression, and therapy resistance. It examines current anti-inflammatory strategies, including NSAIDs, cytokine modulators, and STAT3 inhibitors, while addressing their potential and limitations. The review emphasizes the need for further research to unravel the complex mechanisms linking inflammation to cancer progression and identify molecular targets for specific cancer subtypes.
Collapse
Affiliation(s)
- Siddhant Tripathi
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
| | - Yashika Sharma
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
| | - Dileep Kumar
- Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| |
Collapse
|
|
3
|
Mohamed AA, Nagah Amer N, Osama N, Hafez W, Abdelrahman Ali AE, Shaheen MM, Alhady Alkhalegy AA, Abouahmed EA, Soaida SM, Samy LA, El-Kassas A, Cherrez-Ojeda I, R El-Awady R. Expression of miR-15b-5p and toll-like receptor4 as potential novel diagnostic biomarkers for hepatitis C virus-induced hepatocellular carcinoma. Noncoding RNA Res 2025; 10:262-268. [PMID: 39844891 PMCID: PMC11751402 DOI: 10.1016/j.ncrna.2024.12.003] [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: 07/20/2024] [Revised: 10/08/2024] [Accepted: 12/04/2024] [Indexed: 01/24/2025] Open
Abstract
Objectives Globally, hepatocellular Carcinoma (HCC) ranks seventh in women's cancer and fifth in men's cancer. Early identification can minimize mortality and morbidity. MicroRNAs and Toll-like receptors have been suggested as potential new biomarkers for HCC; Therefore, we explored Toll-like receptor 4 (TLR-4) and miRNA 15b-5p as new non-invasive HCC biomarkers and early detection approaches. Methodology In this case-control study, four primary groups were formed from 400 patients who participated in this study: 100 hepatitis C (HCV) patients without cirrhosis or HCC, 100 HCV with cirrhosis patients, 100 HCC and HCV patients, and 100 healthy controls. The HCC diagnosis was confirmed according to the American Association for the Study of Liver Disease (AASLD) Practice Guidelines. Triphasic computed tomography was used to assess the HCC tumor size. Real-time PCR was used to analyze miRNA 15b-5p and Toll-like receptor 4 (TLR-4) expression profiles. Results Significant diagnostic performance was achieved by miRNA 15b-5p in differentiating the HCC group from the control group, with 90 % sensitivity and 88 % specificity (AUC] 0.935, p < 0.001), while TLR-4 had moderate diagnostic performance with 85 % sensitivity and 86 % specificity (AUC:0.885, p < 0.001). Conclusions The ability of miR-15b-5p to recognize HCC was positive and it outperformed Toll-like receptor4. MiR-15b-5p has the potential to be a more precise and predictive biological marker for HCC than Toll-like receptor4. Future studies exploring different miRNAs and HCC cases from various etiologies are required to better understand the role of miRNAs in this disease and allow for more effective strategies.
Collapse
Affiliation(s)
- Amal Ahmed Mohamed
- Department of Biochemistry and Molecular Biology, National Hepatology and Tropical Medicine Research Institute, GOTHI, Cairo, Egypt
| | - Noha Nagah Amer
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Noha Osama
- Pediatritic Nutrition, Fitoverfat Nutrition Clinic, Cairo, Egypt
| | - Wael Hafez
- Internal Medicine Department, Medical Research and Clinical Studies Institute, The National Research Centre, Cairo, Egypt
| | - Ali Elsaid Abdelrahman Ali
- Department of Diagnostic and Interventional Radiology, National Hepatology and Tropical Medicine Research Institute, GOTHI, Cairo, Egypt
| | | | | | | | | | - Lamees A. Samy
- Department of Clinical Pathology, Cairo University, Cairo, Egypt
| | - Ahmed El-Kassas
- Department of Radiology, Elsahel Teaching Hospital, GOTHI, Cairo, Egypt
| | - Ivan Cherrez-Ojeda
- Department of Allergy and Immunology, Universidad Espiritu Santo, Samborondon, Ecuador
- Respiralab Research Group, Guayaquil, Ecuador
| | - Rehab R El-Awady
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| |
Collapse
|
|
4
|
Perera H, Imsirovic H, Macphail G, Webster D, Fraser C, Borgia S, Liu H, Lee S, Feld JJ, Cooper C. Resistance-Associated Substitution Testing Trends and Impact on HCV Treatment Outcomes in Canada: A CanHepC-CANUHC Analysis. J Viral Hepat 2025; 32:e14058. [PMID: 39785104 DOI: 10.1111/jvh.14058] [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: 10/10/2024] [Revised: 12/17/2024] [Accepted: 12/22/2024] [Indexed: 01/30/2025]
Abstract
Resistance-associated substitutions (RASs) are mutations within the hepatitis C (HCV) genome that may influence the likelihood of achieving a sustained virological response (SVR) with direct acting antiviral (DAA) treatment. Clinicians conduct RAS testing to adapt treatment regimens with the intent of improving the likelihood of cure. The Canadian Network Undertaking against Hepatitis C (CANUHC) prospective cohort consists of chronic HCV patients enrolled between 2015 and 2023 across 17 Canadian sites. Utilisation of RAS testing was assessed across demographics, clinical characteristics and years. SVR was described for the overall cohort and compared across populations of patients with historically negative predictors of SVR. The detection of key RASs and how this information influenced DAA selection were assessed. 2434 patients were identified with information on RAS testing. 98.3% achieved SVR. Out of the 227 patients tested for RAS, 147 (64.8%) had any detected RAS, and 84 (37.0%) had an NS5A RAS. The proportion of patients with SVR did not differ between RAS-tested (98.3%) and non-tested patients (98.3%; p = 0.99). SVR in those with an NS5a RAS was similar (98.6%) to the overall SVR proportion. Proportions with SVR did not differ between those with and without RAS testing in key subgroups (genotype 1a, genotype 3, prior treatment, cirrhosis). The specific DAA regimen and the addition of ribavirin were not associated with SVR outcome. RAS testing has a minimal influence on antiviral treatment selection. Going forward, there is a reduced role for RAS testing in most clinical scenarios.
Collapse
Affiliation(s)
| | | | | | | | | | - Sergio Borgia
- Division of Infectious Diseases, William Osler Health System, Brampton, Canada
- Division of Infectious Diseases, McMaster University, Hamilton, Canada
| | | | - Sam Lee
- University of Calgary, Calgary, Canada
| | - Jordan J Feld
- Toronto Centre for Liver Disease, University Health Network, Tornoto, Canada
| | - Curtis Cooper
- Ottawa Hospital Research Institute, Ottawa, Canada
- University of Ottawa, Ottawa, Canada
| |
Collapse
|
|
5
|
Padilha MDM, Melo FTDV, Laurentino RV, da Silva ANMR, Feitosa RNM. Dysregulation in the microbiota by HBV and HCV infection induces an altered cytokine profile in the pathobiome of infection. Braz J Infect Dis 2025; 29:104468. [PMID: 39608222 PMCID: PMC11636304 DOI: 10.1016/j.bjid.2024.104468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 10/07/2024] [Accepted: 11/03/2024] [Indexed: 11/30/2024] Open
Abstract
Viral hepatitis is a public health problem, about 1 million people die due to complications of this viral disease, the etiological agents responsible for inducing cirrhosis and cellular hepatocarcinoma are HBV and HCV, both hepatotropic viruses that cause asymptomatic infection in most cases. The regulation of the microbiota performs many physiological functions, which can induce normal intestinal function and produce essential nutrients for the human body. Metabolites derived from gut microbiota or direct regulation of host immunity and metabolism have been reported to profoundly affect tumorigenesis in liver disease. If the microbiota is unbalanced, both exogenous and symbiotic microorganisms can affect a pathological process. It is well understood that the microbiota plays a role in viral diseases and infections, specifically the hepatic portal pathway has been linked to the gut-liver axis. In HBV and HCV infections, the altered bacterial representatives undergo a state of dysbiosis, with subsequent establishment of the pathobiome with overexpression of taxons such as Bacteroides, Clostridium, Lactobacillus, Enterobacter, and Enterococcus. This dysregulated microbiome induces a microenvironment conducive to the development of hepatic complications in patients with acute and chronic HBV and HCV infection, with subsequent dysregulation of cytokines IFN-α/β, TNF-α, IL-1β, TGF-β, IL-6 and IL-10, which alter the dysfunction and damage of the hepatic portal system. In view of the above, this review aimed to correlate the pathophysiological mechanisms in HBV and HCV infection, the dysregulation of the microbiome in patients infected with HBV and HCV, the most altered cytokines in the microbiome, and the most altered bacterial representatives in the pathobiome of infection.
Collapse
Affiliation(s)
- Marcos Daniel Mendes Padilha
- Universidade Federal do Pará (UFPA), Instituto de Ciências Biológicas, Laboratório de Virologia, Belém, PA, Brazil.
| | | | - Rogério Valois Laurentino
- Universidade Federal do Pará (UFPA), Instituto de Ciências da Saúde, Health Sciences, Belém, PA, Brazil
| | | | | |
Collapse
|
|
6
|
Ma X, Huang L, Yu M, Dong R, Wang Y, Chen H, Yu R, Huang P, Wang J. Dynamic Prediction of the Risk of Hepatocellular Carcinoma After DAA Treatment for Hepatitis C Patients. Cancer Control 2025; 32:10732748251316609. [PMID: 39957415 PMCID: PMC11831632 DOI: 10.1177/10732748251316609] [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: 09/18/2024] [Revised: 11/23/2024] [Accepted: 01/06/2025] [Indexed: 02/18/2025] Open
Abstract
OBJECTIVES The aim of this study was to develop and internally validate a hepatocellular carcinoma (HCC) risk prediction model incorporating repeated-measures data (longitudinal model), and compare with baseline predictions. METHODS A total of 1097 participants with chronic hepatitis C after direct-acting antivirals (DAA) treatment were included in this prospective cohort study. The framework of joint models for longitudinal and survival data was used to construct the longitudinal prediction model. For comparison, a baseline model incorporating the same predictors was constructed through the multivariate Cox regression models. Model performance was evaluated using dynamic discrimination index (DDI), areas under the receiver-operating characteristics curves (AUROC), and Brier scores. RESULTS Over a median follow-up of 7.25 years, 60 patients (5.5%) developed HCC. Key risk factors identified were aspartate aminotransferase (AST), cholinesterase, gamma-glutamyl transferase (GGT), albumin, hemoglobin (Hb), platelet count, alpha-fetoprotein (AFP), antigen-125 (CA-125), and carcinoembryonic antigen (CEA). The final joint model, with GGT and CEA removed, showed superior average predictive performance (DDI = .871) compared to models with all predictors included. Validation showed high predictive accuracy for HCC, with AUROCs above .9 for 1-, 3-, 4-, and 5-year predictions. In comparison, the baseline Cox model only achieved mediocre AUROCs of .7 (.75, .67, .69, and .67, respectively). CONCLUSION Compared to static models, our dynamic prediction model can predict the risk of HCC in patients after DAA treatment more accurately, providing better information to distinguish high-risk populations.
Collapse
Affiliation(s)
- Xinyan Ma
- Department of Epidemiology, Center for Global Health, National Vaccine Innovation Platform, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Lili Huang
- NHC Key Laboratory of Contraceptives Vigilance and Fertility Surveillance/Jiangsu Health Development Research Center, Nanjing, China
| | - Meijie Yu
- Department of Epidemiology, Center for Global Health, National Vaccine Innovation Platform, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Rui Dong
- Department of Fundamental and Community Nursing, School of Nursing, Nanjing Medical University, Nanjing, China
| | - Yifan Wang
- Department of Infectious Disease, Jurong Hospital Affiliated to Jiangsu University, Jurong, China
| | - Hongbo Chen
- Department of Infectious Disease, Jurong Hospital Affiliated to Jiangsu University, Jurong, China
| | - Rongbin Yu
- Department of Epidemiology, Center for Global Health, National Vaccine Innovation Platform, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Peng Huang
- Department of Epidemiology, Center for Global Health, National Vaccine Innovation Platform, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jie Wang
- Department of Fundamental and Community Nursing, School of Nursing, Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
7
|
Smirne C, Crobu MG, Landi I, Vercellino N, Apostolo D, Pinato DJ, Vincenzi F, Minisini R, Tonello S, D’Onghia D, Ottobrelli A, Martini S, Bracco C, Fenoglio LM, Campanini M, Berton AM, Ciancio A, Pirisi M. Chronic Hepatitis C Infection Treated with Direct-Acting Antiviral Agents and Occurrence/Recurrence of Hepatocellular Carcinoma: Does It Still Matter? Viruses 2024; 16:1899. [PMID: 39772206 PMCID: PMC11680226 DOI: 10.3390/v16121899] [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: 10/09/2024] [Revised: 12/05/2024] [Accepted: 12/06/2024] [Indexed: 01/03/2025] Open
Abstract
Hepatitis C virus (HCV) infection is a significant risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). Traditionally, the primary prevention strategy for HCV-associated HCC has focused on removing infection through antiviral regimes. Currently, highly effective direct-acting antivirals (DAAs) offer extraordinary success across all patient categories, including cirrhotics. Despite these advancements, recent studies have reported that even after sustained virologic response (SVR), individuals with advanced liver disease/cirrhosis at the time of DAA treatment may still face risks of HCC occurrence or recurrence. Based on this premise, this review tries to shed light on the multiple mechanisms that establish a tumorigenic environment, first, during chronic HCV infection and then, after eventual viral eradication by DAAs. Furthermore, it reviews evidence reported by recent observational studies stating that the use of DAAs is not associated with an increased risk of HCC development but rather, with a significantly lower chance of liver cancer compared with DAA-untreated patients. In addition, it seeks to provide some practical guidance for clinicians, helping them to manage HCC surveillance of patients who have achieved SVR with DAAs.
Collapse
Affiliation(s)
- Carlo Smirne
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
- Internal Medicine Unit, Maggiore della Carità Hospital, 28100 Novara, Italy
| | - Maria Grazia Crobu
- Laboratory of Molecular Virology, Maggiore della Carità Hospital, 28100 Novara, Italy;
- Clinical Biochemistry Laboratory, City of Health and Science University Hospital, 10126 Turin, Italy
| | - Irene Landi
- Emergency Medicine Department, Michele e Pietro Ferrero Hospital, 12060 Verduno, Italy;
| | - Nicole Vercellino
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - Daria Apostolo
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - David James Pinato
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London SW7 2AZ, UK
| | - Federica Vincenzi
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - Stelvio Tonello
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - Davide D’Onghia
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - Antonio Ottobrelli
- Gastroenterology Unit, City of Health and Science University Hospital, 10126 Turin, Italy; (A.O.); (S.M.); (A.C.)
| | - Silvia Martini
- Gastroenterology Unit, City of Health and Science University Hospital, 10126 Turin, Italy; (A.O.); (S.M.); (A.C.)
| | - Christian Bracco
- Department of Internal Medicine, Santa Croce e Carle Hospital, 12100 Cuneo, Italy; (C.B.); (L.M.F.)
| | - Luigi Maria Fenoglio
- Department of Internal Medicine, Santa Croce e Carle Hospital, 12100 Cuneo, Italy; (C.B.); (L.M.F.)
| | - Mauro Campanini
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
- Internal Medicine Unit, Maggiore della Carità Hospital, 28100 Novara, Italy
| | - Alessandro Maria Berton
- Division of Endocrinology, Diabetes and Metabolism, City of Health and Science University Hospital, 10126 Turin, Italy;
| | - Alessia Ciancio
- Gastroenterology Unit, City of Health and Science University Hospital, 10126 Turin, Italy; (A.O.); (S.M.); (A.C.)
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
- Internal Medicine Unit, Maggiore della Carità Hospital, 28100 Novara, Italy
| |
Collapse
|
|
8
|
Yıldırım Ç, Yay F, İmre A, Soysal O, Yıldırım HÇ. CXCL10, SCGN, and H2BC5 as Potential Key Genes Regulated by HCV Infection. Genes (Basel) 2024; 15:1502. [PMID: 39766770 PMCID: PMC11675613 DOI: 10.3390/genes15121502] [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: 10/11/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 01/03/2025] Open
Abstract
Introduction: Hepatitis C infections are the main causes of fatal clinical conditions such as cirrhosis and HCC development, and biomarkers are needed to predict the development of these complications. Therefore, it is important to first determine which genes are deregulated in HCV-cells compared to healthy individuals. In our study, we aimed to identify the genes that are commonly upregulated or downregulated in HCV-infected cells using two different databases. Material and Method: In this study, differentially expressed genes (DEGs) that were commonly upregulated or downregulated were identified using publicly available databases GSE66842 and GSE84587. Afterwards, the interactions of DEG products with each other and other proteins were examined using the STRING database. Enrichment analyses of DEGs were performed using the Enrichr-KG web tool including the Gene Ontology Biological Process, KEGG, Jensen_DISEASES and DisGeNET libraries. miRNAs targeting DEGs were detected using miRDB and TargetScanHuman8.0. Results: In HCV-infected cells, the CXCL10 expression is increased in both databases, while the SCGN and H2BC5 (HIST1H2BD) expression is decreased. No direct interaction was found among CXCL10, SCGN, H2BC5 in the top ten proteins. CXCL10 is a member of Hepatitis C and viral protein interactions with cytokine and cytokine receptor KEGG pathways. H2BC5 is a member of viral carcinogenesis KEGG pathways. Predicted overlapping miRNAs targeted by common DEGs were as follows: 59 were where CXCL10 was the estimated target, 22 where SCGN was the estimated target and 29 where H2BC5 (HIST1H2BD) was the estimated target. Conclusions: Our study identified genes that were upregulated or downregulated in HCV-infected cells in both databases and miRNAs associated with these genes, using two different databases. This study creates groundwork for future studies to investigate whether these genes can predict HCV prognosis and HCV-associated HCC development.
Collapse
Affiliation(s)
- Çiğdem Yıldırım
- Department of Infectious Diseases and Clinical Microbiology, Nigde Training and Research Hospital, 51100 Nigde, Turkey; (A.İ.); (O.S.)
| | - Fatih Yay
- Clinical Biochemistry Laboratory, Nigde Training and Research Hospital, 51100 Nigde, Turkey;
| | - Ayfer İmre
- Department of Infectious Diseases and Clinical Microbiology, Nigde Training and Research Hospital, 51100 Nigde, Turkey; (A.İ.); (O.S.)
| | - Orçun Soysal
- Department of Infectious Diseases and Clinical Microbiology, Nigde Training and Research Hospital, 51100 Nigde, Turkey; (A.İ.); (O.S.)
| | - Hasan Çağrı Yıldırım
- Department of Medical Oncology, Nigde Training and Research Hospital, 51100 Nigde, Turkey;
| |
Collapse
|
|
9
|
Yang C, Lv F, Yang J, Ding D, Cui L, Han Y. Surveillance and management of hepatocellular carcinoma after treatment of hepatitis C with direct-acting antiviral drugs. Ann Hepatol 2024; 30:101582. [PMID: 39276980 DOI: 10.1016/j.aohep.2024.101582] [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: 06/20/2024] [Revised: 08/11/2024] [Accepted: 08/15/2024] [Indexed: 09/17/2024]
Abstract
Hepatitis C virus (HCV) belongs to the Flaviviridae family, and is a single-stranded RNA virus with positive polarity. It is the primary cause of hepatocellular carcinoma (HCC) worldwide. The treatment of HCV has entered a new era with the advent of direct-acting antiviral drugs (DAAs) and is associated with cure rates of more than 95 %, making HCV the only curable viral disease. The successful treatment of chronic hepatitis C has greatly reduced, but not eliminated, the risk of HCC. Certain individuals, especially those with cirrhosis already present, remain vulnerable to HCC after achieving a sustained virological response (SVR). This article systematically reviews the recent studies on the risk and mechanisms of HCC development after HCV viral cure, the screening and predictive value of biological markers, and patient surveillance. Factors such as older age, diabetes, hepatic fat accumulation, alcohol use, and lack of fibrosis reversal are linked to increased HCC risk after HCV cure. The mechanism of HCC development after DAAs treatment remains unclear, but the possible mechanisms include immune cell dysfunction during HCV infection, cytokine network imbalance, epigenetic alterations, and host factors. Several biological markers and risk prediction models have been used to monitor the risk of HCC in CHC patients who have achieved SVR, but most still require validation and standardization. The implementation of risk-stratified surveillance programs is becoming urgent from a cost-effective point of view, but the availability of validated biomarkers to predict HCC in cured patients remains an unmet clinical need. Additionally, managing CHC patients who achieve SVR is becoming a growing challenge as an increasing number of HCV patients are cured.
Collapse
Affiliation(s)
- Caiyun Yang
- Xi'an Medical University, Xi'an 710021, Shannxi, PR China; National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, PR China
| | - Fengxiang Lv
- Xi'an Medical University, Xi'an 710021, Shannxi, PR China; National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, PR China
| | - Jiaqi Yang
- National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, PR China
| | - Dawei Ding
- National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, PR China
| | - Lina Cui
- National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, PR China.
| | - Ying Han
- National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, PR China.
| |
Collapse
|
|
10
|
Matičič M, Buti M. Towards eliminating hepatitis C as a public health threat: different speeds, different needs. Euro Surveill 2024; 29:2400462. [PMID: 39056197 PMCID: PMC11274847 DOI: 10.2807/1560-7917.es.2024.29.30.2400462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 07/25/2024] [Indexed: 07/28/2024] Open
Affiliation(s)
- Mojca Matičič
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Clinic for Infectious Diseases and Febrile Illnesses, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Maria Buti
- CIBERehd del Instituto de Salud Carlos III, Madrid, Spain
- Liver Unit, Department of Medicine, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| |
Collapse
|
|
11
|
Bauso LV, La Fauci V, Munaò S, Bonfiglio D, Armeli A, Maimone N, Longo C, Calabrese G. Biological Activity of Natural and Synthetic Peptides as Anticancer Agents. Int J Mol Sci 2024; 25:7264. [PMID: 39000371 PMCID: PMC11242495 DOI: 10.3390/ijms25137264] [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: 06/04/2024] [Revised: 06/25/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
Cancer is one of the leading causes of morbidity and death worldwide, making it a serious global health concern. Chemotherapy, radiotherapy, and surgical treatment are the most used conventional therapeutic approaches, although they show several side effects that limit their effectiveness. For these reasons, the discovery of new effective alternative therapies still represents an enormous challenge for the treatment of tumour diseases. Recently, anticancer peptides (ACPs) have gained attention for cancer diagnosis and treatment. ACPs are small bioactive molecules which selectively induce cancer cell death through a variety of mechanisms such as apoptosis, membrane disruption, DNA damage, immunomodulation, as well as inhibition of angiogenesis, cell survival, and proliferation pathways. ACPs can also be employed for the targeted delivery of drugs into cancer cells. With over 1000 clinical trials using ACPs, their potential for application in cancer therapy seems promising. Peptides can also be utilized in conjunction with imaging agents and molecular imaging methods, such as MRI, PET, CT, and NIR, improving the detection and the classification of cancer, and monitoring the treatment response. In this review we will provide an overview of the biological activity of some natural and synthetic peptides for the treatment of the most common and malignant tumours affecting people around the world.
Collapse
Affiliation(s)
- Luana Vittoria Bauso
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98168 Messina, Italy
| | - Valeria La Fauci
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98168 Messina, Italy
| | - Serena Munaò
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98168 Messina, Italy
| | - Desirèe Bonfiglio
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98168 Messina, Italy
| | - Alessandra Armeli
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98168 Messina, Italy
| | - Noemi Maimone
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98168 Messina, Italy
| | - Clelia Longo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98168 Messina, Italy
| | - Giovanna Calabrese
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98168 Messina, Italy
| |
Collapse
|
|
12
|
Chida T, Ohta K, Noritake H, Matsushita M, Murohisa G, Kageyama F, Sasada Y, Oyaizu T, Tsugiki M, Tamakoshi K, Nakajima T, Suda T, Kawata K. Lysyl oxidase-like 2 as a predictor of hepatocellular carcinoma in patients with hepatitis C virus after sustained virological response. Sci Rep 2024; 14:10864. [PMID: 38740815 PMCID: PMC11091085 DOI: 10.1038/s41598-024-61366-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Accepted: 05/06/2024] [Indexed: 05/16/2024] Open
Abstract
Lysyl oxidase-like 2 (LOXL2) mediates the crosslinking of extracellular collagen, reflecting qualitative changes in liver fibrosis. This study aimed to validate the utility of serum LOXL2 levels as a predictive biomarker for the development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection who achieved a sustained virological response (SVR). This retrospective study included 137 patients with chronic HCV infection without history of HCC development and who achieved SVR via direct-acting antiviral therapy. Median LOXL2 levels decreased significantly after SVR achievement (pre-Tx, 2.33 ng/mL; post-Tx, 1.31 ng/mL, p < 0.001). Post-Tx LOXL2 levels, fibrosis-4 index, platelet counts, Wisteria floribunda agglutinin-positive human Mac-2 binding protein levels, and alpha-fetoprotein (AFP) levels were identified as independent predictive factors for post-SVR HCC development in the univariate analysis. The incidence of post-SVR HCC development was significantly higher in patients with post-Tx LOXL2 levels ≥ 2.08 ng/mL and AFP levels ≥ 5.0 ng/mL than in patients with elevated levels of either marker or with lower marker levels. Serum LOXL2 levels can serve as a predictive biomarker for HCC development after achieving SVR. The combination of serum LOXL2 and AFP levels provides robust risk stratification for HCC development after SVR, suggesting an enhanced surveillance strategy.
Collapse
Affiliation(s)
- Takeshi Chida
- Second Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan.
- Department of Regional Medical Care Support, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan.
| | - Kazuyoshi Ohta
- Second Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Hidenao Noritake
- Second Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Masahiro Matsushita
- Department of Gastroenterology, Shimada General Medical Center, 1200-5 Noda, Shimada, Shizuoka, 427-8502, Japan
| | - Gou Murohisa
- Department of Hepatology, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Hamamatsu, Shizuoka, 430-8558, Japan
| | - Fujito Kageyama
- Department of Hepatology, Hamamatsu Medical Center, 328 Tomitsuka-Cho, Hamamatsu, Shizuoka, 432-8580, Japan
| | - Yuzo Sasada
- Department of Hepatology, Iwata City Hospital, 512-3 Ookubo, Iwata, Shizuoka, 438-8550, Japan
| | - Tatsuki Oyaizu
- Department of Gastroenterology, Shizuoka City Shizuoka Hospital, 10-93 Otemachi, Shizuoka, Shizuoka, 420-8630, Japan
| | - Minoru Tsugiki
- Minoru Medical Clinic, 1784-1 Mishima-Cho, Hamamatsu, Shizuoka, 430-0853, Japan
| | | | - Takeyuki Nakajima
- Elm Medical Clinic, 5-17-22 Handayama, Hamamatsu, Shizuoka, 431-3125, Japan
| | - Takafumi Suda
- Second Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Kazuhito Kawata
- Second Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan
| |
Collapse
|
|
13
|
Meewan I, Panmanee J, Petchyam N, Lertvilai P. HBCVTr: an end-to-end transformer with a deep neural network hybrid model for anti-HBV and HCV activity predictor from SMILES. Sci Rep 2024; 14:9262. [PMID: 38649402 PMCID: PMC11035669 DOI: 10.1038/s41598-024-59933-4] [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: 01/09/2024] [Accepted: 04/16/2024] [Indexed: 04/25/2024] Open
Abstract
Hepatitis B and C viruses (HBV and HCV) are significant causes of chronic liver diseases, with approximately 350 million infections globally. To accelerate the finding of effective treatment options, we introduce HBCVTr, a novel ligand-based drug design (LBDD) method for predicting the inhibitory activity of small molecules against HBV and HCV. HBCVTr employs a hybrid model consisting of double encoders of transformers and a deep neural network to learn the relationship between small molecules' simplified molecular-input line-entry system (SMILES) and their antiviral activity against HBV or HCV. The prediction accuracy of HBCVTr has surpassed baseline machine learning models and existing methods, with R-squared values of 0.641 and 0.721 for the HBV and HCV test sets, respectively. The trained models were successfully applied to virtual screening against 10 million compounds within 240 h, leading to the discovery of the top novel inhibitor candidates, including IJN04 for HBV and IJN12 and IJN19 for HCV. Molecular docking and dynamics simulations identified IJN04, IJN12, and IJN19 target proteins as the HBV core antigen, HCV NS5B RNA-dependent RNA polymerase, and HCV NS3/4A serine protease, respectively. Overall, HBCVTr offers a new and rapid drug discovery and development screening method targeting HBV and HCV.
Collapse
Affiliation(s)
- Ittipat Meewan
- Center for Advanced Therapeutics, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, 73170, Thailand.
| | - Jiraporn Panmanee
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, 73170, Thailand
| | - Nopphon Petchyam
- Center for Advanced Therapeutics, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, 73170, Thailand
| | - Pichaya Lertvilai
- Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, 92037, USA
| |
Collapse
|
|
14
|
Sayaf K, Battistella S, Russo FP. NLRP3 Inflammasome in Acute and Chronic Liver Diseases. Int J Mol Sci 2024; 25:4537. [PMID: 38674122 PMCID: PMC11049922 DOI: 10.3390/ijms25084537] [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: 01/29/2024] [Revised: 04/17/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024] Open
Abstract
NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) is an intracellular complex that upon external stimuli or contact with specific ligands, recruits other components, forming the NLRP3 inflammasome. The NLRP3 inflammasome mainly mediates pyroptosis, a highly inflammatory mode of regulated cell death, as well as IL-18 and IL-1β production. Acute and chronic liver diseases are characterized by a massive influx of pro-inflammatory stimuli enriched in reactive oxygen species (ROS) and damage-associated molecular patterns (DAMPs) that promote the assemblage and activation of the NLRP3 inflammasome. As the major cause of inflammatory cytokine storm, the NLRP3 inflammasome exacerbates liver diseases, even though it might exert protective effects in regards to hepatitis C and B virus infection (HCV and HBV). Here, we summarize the current knowledge concerning NLRP3 inflammasome function in both acute and chronic liver disease and in the post liver transplant setting, focusing on the molecular mechanisms involved in NLRP3 activity.
Collapse
Affiliation(s)
- Katia Sayaf
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padua, Italy; (K.S.); (S.B.)
| | - Sara Battistella
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padua, Italy; (K.S.); (S.B.)
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, 35128 Padua, Italy
| | - Francesco Paolo Russo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padua, Italy; (K.S.); (S.B.)
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, 35128 Padua, Italy
| |
Collapse
|
|
15
|
Farooq HZ, James M, Abbott J, Oyibo P, Divall P, Choudhry N, Foster GR. Risk factors for hepatocellular carcinoma associated with hepatitis C genotype 3 infection: A systematic review. World J Gastrointest Oncol 2024; 16:1596-1612. [PMID: 38660636 PMCID: PMC11037048 DOI: 10.4251/wjgo.v16.i4.1596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 12/21/2023] [Accepted: 01/23/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) is a blood-borne virus which globally affects around 79 million people and is associated with high morbidity and mortality. Chronic infection leads to cirrhosis in a large proportion of patients and often causes hepatocellular carcinoma (HCC) in people with cirrhosis. Of the 6 HCV genotypes (G1-G6), genotype-3 accounts for 17.9% of infections. HCV genotype-3 responds least well to directly-acting antivirals and patients with genotype-3 infection are at increased risk of HCC even if they do not have cirrhosis. AIM To systematically review and critically appraise all risk factors for HCC secondary to HCV-G3 in all settings. Consequently, we studied possible risk factors for HCC due to HCV-G3 in the literature from 1946 to 2023. METHODS This systematic review aimed to synthesise existing and published studies of risk factors for HCC secondary to HCV genotype-3 and evaluate their strengths and limitations. We searched Web of Science, Medline, EMBASE, and CENTRAL for publications reporting risk factors for HCC due to HCV genotype-3 in all settings, 1946-2023. RESULTS Four thousand one hundred and forty-four records were identified from the four databases with 260 records removed as duplicates. Three thousand eight hundred and eighty-four records were screened with 3514 excluded. Three hundred and seventy-one full-texts were assessed for eligibility with seven studies included for analysis. Of the seven studies, three studies were retrospective case-control trials, two retrospective cohort studies, one a prospective cohort study and one a cross-sectional study design. All were based in hospital settings with four in Pakistan, two in South Korea and one in the United States. The total number of participants were 9621 of which 167 developed HCC (1.7%). All seven studies found cirrhosis to be a risk factor for HCC secondary to HCV genotype-3 followed by higher age (five-studies), with two studies each showing male sex, high alpha feto-protein, directly-acting antivirals treatment and achievement of sustained virologic response as risk factors for developing HCC. CONCLUSION Although, studies have shown that HCV genotype-3 infection is an independent risk factor for end-stage liver disease, HCC, and liver-related death, there is a lack of evidence for specific risk factors for HCC secondary to HCV genotype-3. Only cirrhosis and age have demonstrated an association; however, the number of studies is very small, and more research is required to investigate risk factors for HCC secondary to HCV genotype-3.
Collapse
Affiliation(s)
- Hamzah Z Farooq
- Blizard Institute, Queen Mary University of London, London E1 2AT, United Kingdom
| | - Michael James
- Blizard Institute, Queen Mary University of London, London E1 2AT, United Kingdom
| | - Jane Abbott
- Blizard Institute, Queen Mary University of London, London E1 2AT, United Kingdom
| | - Patrick Oyibo
- School of Health and Psychological Sciences, University of London, London EC1V 0HB, United Kingdom
| | - Pip Divall
- University Hospitals of Leicester Library, University Hospitals of Leicester NHS Trust, Leicester LE3 9QP, United Kingdom
| | - Naheed Choudhry
- Blizard Institute, Queen Mary University of London, London E1 2AT, United Kingdom
| | - Graham R Foster
- Blizard Institute, Queen Mary University of London, London E1 2AT, United Kingdom
| |
Collapse
|
|
16
|
Ali H, Vikash F, Moond V, Khalid F, Jamil AR, Dahiya DS, Sohail AH, Gangwani MK, Patel P, Satapathy SK. Global trends in hepatitis C-related hepatocellular carcinoma mortality: A public database analysis (1999-2019). World J Virol 2024; 13:89469. [PMID: 38616850 PMCID: PMC11008397 DOI: 10.5501/wjv.v13.i1.89469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 12/19/2023] [Accepted: 01/18/2024] [Indexed: 03/11/2024] Open
Abstract
BACKGROUND Hepatitis C is the leading cause of chronic liver disease worldwide and it significantly contributes to the burden of hepatocellular carcinoma (HCC). However, there are marked variations in the incidence and mortality rates of HCC across different geographical regions. With the advent of new widely available treatment modalities, such as direct-acting antivirals, it is becoming increasingly imperative to understand the temporal and geographical trends in HCC mortality associated with Hepatitis C. Furthermore, gender disparities in HCC mortality related to Hepatitis C are a crucial, yet underexplored aspect that adds to the disease's global impact. While some studies shed light on gender-specific trends, there is a lack of comprehensive data on global and regional mortality rates, particularly those highlighting gender disparities. This gap in knowledge hinders the development of targeted interventions and resource allocation strategies. AIM To understand the global and regional trends in Hepatitis C-related HCC mortality rates from 1990 to 2019, along with gender disparities. METHODS We utilized the Global Burden of Disease database, a comprehensive repository for global health metrics to age-standardized mortality rates due to Hepatitis C-related HCC from 1999 to 2019. Rates were evaluated per 100000 population and assessed by World Bank-defined regions. Temporal trends were determined using Joinpoint software and the Average Annual Percent Change (AAPC) method, and results were reported with 95% confidence intervals (CI). RESULTS From 1990 to 2019, overall, there was a significant decline in HCC-related mortality rates with an AAPC of -0.80% (95%CI: -0.83 to -0.77). Females demonstrated a marked decrease in mortality with an AAPC of -1.06% (95%CI: -1.09 to -1.03), whereas the male cohort had a lower AAPC of -0.52% (95%CI: -0.55 to -0.48). Regionally, East Asia and the Pacific demonstrated a significant decline with an AAPC of -2.05% (95%CI: -2.10 to -2.00), whereas Europe and Central Asia observed an uptrend with an AAPC of 0.72% (95%CI: 0.69 to 0.74). Latin America and the Caribbean also showed an uptrend with an AAPC of 0.06% (95%CI: 0.02 to 0.11). In the Middle East and North Africa, the AAPC was non-significant at 0.02% (95%CI: -0.09 to 0.12). North America, in contrast, displayed a significant upward trend with an AAPC of 2.63% (95%CI: 2.57 to 2.67). South Asia (AAPC -0.22%, 95%CI: -0.26 to -0.16) and Sub-Saharan Africa (AAPC -0.14%, 95%CI: -0.15 to -0.12) trends significantly declined over the study period. CONCLUSION Our study reports disparities in Hepatitis C-related HCC mortality between 1999 to 2019, both regionally and between genders. While East Asia and the Pacific regions showed a promising decline in mortality, North America has experienced a concerning rise in mortality. These regional variations highlight the need for healthcare policymakers and practitioners to tailor public health strategies and interventions. The data serves as a call to action, particularly for regions where mortality rates are not improving, emphasizing the necessity for a nuanced, region-specific approach to combat the global challenge of HCC secondary to Hepatitis C.
Collapse
Affiliation(s)
- Hassam Ali
- Department of Internal Medicine/Gastroenterology, East Carolina University Brody School of Medicine, Greenville, NC 27834, United States
| | - Fnu Vikash
- Department of Internal Medicine, Jacobi Medical Center/Albert Einstein College of Medicine, Bronx, NY 10461, United States
| | - Vishali Moond
- Department of Internal Medicine, Saint Peter's University Hospital/Robert Wood Johnson Medical School, New Brunswick, NJ 08901, United States
| | - Fatima Khalid
- Department of Internal Medicine, Quaid-e-Azam Medical College, Bahawalpur 63100, Punjab, Pakistan
| | - Abdur Rehman Jamil
- Department of Internal Medicine, Samaritan Medical Centre, Watertown, MA 13601, United States
| | - Dushyant Singh Dahiya
- Division of Gastroenterology, Hepatology & Motility, The University of Kansas School of Medicine, Kansas City, KS 66160, United States
| | - Amir Humza Sohail
- Department of Surgery, New York University Winthrop Hospital, New York, Mineloa, NY 11501, United States
| | - Manesh Kumar Gangwani
- Department of Internal Medicine, The University of Toledo, Toledo, OH 43606, United States
| | - Pratik Patel
- Department of Gastroenterology, Mather Hospital/Hofstra University Zucker School of Medicine, NY 11777, United States
| | - Sanjaya K Satapathy
- Division of Hepatology, Department of Medicine, North Shore University Hospital, Manhasset, NY 11030, United States
| |
Collapse
|
|
17
|
Farouk F, Ibrahim IM, Sherif S, Abdelhamed HG, Sharaky M, Al-Karmalawy AA. Investigating the effect of polymerase inhibitors on cellular proliferation: Computational studies, cytotoxicity, CDK1 inhibitory potential, and LC-MS/MS cancer cell entrapment assays. Chem Biol Drug Des 2024; 103:e14500. [PMID: 38467555 DOI: 10.1111/cbdd.14500] [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: 10/07/2023] [Revised: 02/04/2024] [Accepted: 02/26/2024] [Indexed: 03/13/2024]
Abstract
Directly acting antivirals (DAAs) are a breakthrough in the treatment of HCV. There are controversial reports on their tendency to induce hepatocellular carcinoma (HCC) in HCV patients. Numerous reports have concluded that the HCC is attributed to patient-related factors while others are inclined to attribute this as a DAA side-effect. This study aims to investigate the effect of polymerase inhibitor DAAs, especially daclatasivir (DLT) on cellular proliferation as compared to ribavirin (RBV). The interaction of DAAs with variable cell-cycle proteins was studied in silico. The binding affinities to multiple cellular targets were investigated and the molecular dynamics were assessed. The in vitro effect of the selected candidate DLT on cancer cell proliferation was determined and the CDK1 inhibitory potential in was evaluated. Finally, the cellular entrapment of the selected candidates was assessed by an in-house developed and validated LC-MS/MS method. The results indicated that polymerase inhibitor antiviral agents, especially DLT, may exert an anti-proliferative potential against variable cancer cell lines. The results showed that the effect may be achieved via potential interaction with the multiple cellular targets, including the CDK1, resulting in halting of the cellular proliferation. DLT exhibited a remarkable cell permeability in the liver cancer cell line which permits adequate interaction with the cellular targets. In conclusion, the results reveal that the polymerase inhibitor (DLT) may have an anti-proliferative potential against liver cancer cells. These results may pose DLT as a therapeutic choice for patients suffering from HCV and are liable to HCC development.
Collapse
Affiliation(s)
- Faten Farouk
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt
| | - Ibrahim M Ibrahim
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Salma Sherif
- Faculty of Women for Arts, Science and Education, Ain Shams University, Cairo, Egypt
| | | | - Marwa Sharaky
- Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
- Biochemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt
| | - Ahmed A Al-Karmalawy
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt
| |
Collapse
|
|
18
|
Sun Z, Li X, Liang H, Shi Z, Ren H. A Deep Learning Model Combining Multimodal Factors to Predict the Overall Survival of Transarterial Chemoembolization. J Hepatocell Carcinoma 2024; 11:385-397. [PMID: 38435683 PMCID: PMC10906280 DOI: 10.2147/jhc.s443660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 01/30/2024] [Indexed: 03/05/2024] Open
Abstract
Background To develop and validate an overall survival (OS) prediction model for transarterial chemoembolization (TACE). Methods In this retrospective study, 301 patients with hepatocellular carcinoma (HCC) who received TACE from 2012 to 2015 were collected. The residual network was used to extract prognostic information from CT images, which was then combined with the clinical factors adjusted by COX regression to predict survival using a modified deep learning model (DLOPCombin). The DLOPCombin model was compared with the residual network model (DLOPCTR), multiple COX regression model (DLOPCox), Radiomic model (Radiomic), and clinical model. Results In the validation cohort, DLOPCombin shows the highest TD AUC of all cohorts, which compared with Radiomic (TD AUC: 0.96vs 0.63) and clinical model (TD AUC: 0.96 vs 0.62) model. DLOPCombin showed significant difference in C index compared with DLOPCTR and DLOPCox models (P < 0.05). Moreover, the DLOPCombin showed good calibration and overall net benefit. Patients with DLOPCombin model score ≤ 0.902 had better OS (33 months vs 15.5 months, P < 0.0001). Conclusion The deep learning model can effectively predict the patients' overall survival of TACE.
Collapse
Affiliation(s)
- Zhongqi Sun
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, People’s Republic of China
| | - Xin Li
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, People’s Republic of China
| | - Hongwei Liang
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, People’s Republic of China
| | - Zhongxing Shi
- Department of Interventional Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, People’s Republic of China
| | - Hongjia Ren
- School of Information Science and Engineering, Yanshan University, Qinhuangdao, 066004, People’s Republic of China
| |
Collapse
|
|
19
|
Colak C, Kucukakcali Z, Akbulut S. Artificial intelligence-based prediction of molecular and genetic markers for hepatitis C-related hepatocellular carcinoma. Ann Med Surg (Lond) 2023; 85:4674-4682. [PMID: 37811067 PMCID: PMC10553079 DOI: 10.1097/ms9.0000000000001210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 08/12/2023] [Indexed: 10/10/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the main cause of mortality from cancer globally. This paper intends to classify public gene expression data of patients with Hepatitis C virus-related HCC (HCV+HCC) and chronic HCV without HCC (HCV alone) through the XGboost approach and to identify key genes that may be responsible for HCC. Methods The current research is a retrospective case-control study. Public data from 17 patients with HCV+HCC and 35 patients with HCV-alone samples were used in this study. An XGboost model was established for the classification by 10-fold cross-validation. Accuracy (AC), balanced accuracy (BAC), sensitivity, specificity, positive predictive value, negative predictive value, and F1 score were utilized for performance assessment. Results AC, BAC, sensitivity, specificity, positive predictive value, negative predictive value, and F1 scores from the XGboost model were 98.1, 97.1, 100, 94.1, 97.2, 100, and 98.6%, respectively. According to the variable importance values from the XGboost, the HAO2, TOMM20, GPC3, and PSMB4 genes can be considered potential biomarkers for HCV-related HCC. Conclusion A machine learning-based prediction method discovered genes that potentially serve as biomarkers for HCV-related HCC. After clinical confirmation of the acquired genes in the following medical study, their therapeutic use can be established. Additionally, more detailed clinical works are needed to substantiate the significant conclusions in the current study.
Collapse
Affiliation(s)
- Cemil Colak
- Department of Biostatistics and Medical Informatics
| | | | - Sami Akbulut
- Department of Biostatistics and Medical Informatics
- Department of Surgery, Inonu University Faculty of Medicine, Malatya, Turkey
| |
Collapse
|
|
20
|
Alshimerry AF, Farhood RG. Concept of HBV and HCV as a risk factor and prevention of viral hepatitis-related hepatocellular carcinoma. MEDICAL JOURNAL OF BABYLON 2023; 20:657-660. [DOI: 10.4103/mjbl.mjbl_269_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 03/31/2023] [Indexed: 01/03/2025] Open
Abstract
Abstract
Hepatocellular carcinoma (HCC) represents one of the most common cancers worldwide, and it is a very important reason for cancer-related death. Infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) is considered the major leading cause of HCC. The pathophysiology of HB and HC viral-related HCC includes chronic inflammation, deorganization of cell signaling pathways, and oxidative stress. Contrary to HCV, HBV is oncogenic by itself, due to its integration into the DNA of cell. Six months of ultrasound monitoring is recommended for high-risk patients. Using antiviral drugs to manage viral hepatitis decreases the risk of evolution and reoccurrence of HCC. Also, effective preventive measures are very important in decreasing the risk of HCC. The prevention involves primary prevention which is based on HBV vaccination, treatment of acute infection, and eliminating the route of transmission, while secondary prevention is based on using antiviral drugs against HBV and HCV infection to prevent the progress of disease into carcinoma. However, tertiary prevention involves treating the carcinoma to prevent the reoccurrence of the cancer.
Collapse
Affiliation(s)
| | - Rawaa Ghalib Farhood
- Department of Pathology, College of Medicine, University of Babylon, Babylon, Iraq
| |
Collapse
|
|
21
|
Zhang S, Jiang C, Jiang L, Chen H, Huang J, Zhang J, Wang R, Chi H, Yang G, Tian G. Uncovering the immune microenvironment and molecular subtypes of hepatitis B-related liver cirrhosis and developing stable a diagnostic differential model by machine learning and artificial neural networks. Front Mol Biosci 2023; 10:1275897. [PMID: 37808522 PMCID: PMC10556489 DOI: 10.3389/fmolb.2023.1275897] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 09/14/2023] [Indexed: 10/10/2023] Open
Abstract
Background: Hepatitis B-related liver cirrhosis (HBV-LC) is a common clinical disease that evolves from chronic hepatitis B (CHB). The development of cirrhosis can be suppressed by pharmacological treatment. When CHB progresses to HBV-LC, the patient's quality of life decreases dramatically and drug therapy is ineffective. Liver transplantation is the most effective treatment, but the lack of donor required for transplantation, the high cost of the procedure and post-transplant rejection make this method unsuitable for most patients. Methods: The aim of this study was to find potential diagnostic biomarkers associated with HBV-LC by bioinformatics analysis and to classify HBV-LC into specific subtypes by consensus clustering. This will provide a new perspective for early diagnosis, clinical treatment and prevention of HCC in HBV-LC patients. Two study-relevant datasets, GSE114783 and GSE84044, were retrieved from the GEO database. We screened HBV-LC for feature genes using differential analysis, weighted gene co-expression network analysis (WGCNA), and three machine learning algorithms including least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE), and random forest (RF) for a total of five methods. After that, we constructed an artificial neural network (ANN) model. A cohort consisting of GSE123932, GSE121248 and GSE119322 was used for external validation. To better predict the risk of HBV-LC development, we also built a nomogram model. And multiple enrichment analyses of genes and samples were performed to understand the biological processes in which they were significantly enriched. And the different subtypes of HBV-LC were analyzed using the Immune infiltration approach. Results: Using the data downloaded from GEO, we developed an ANN model and nomogram based on six feature genes. And consensus clustering of HBV-LC classified them into two subtypes, C1 and C2, and it was hypothesized that patients with subtype C2 might have milder clinical symptoms by immune infiltration analysis. Conclusion: The ANN model and column line graphs constructed with six feature genes showed excellent predictive power, providing a new perspective for early diagnosis and possible treatment of HBV-LC. The delineation of HBV-LC subtypes will facilitate the development of future clinical treatment of HBV-LC.
Collapse
Affiliation(s)
- Shengke Zhang
- Department of Clinical Medicine, School of Clinical Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Chenglu Jiang
- Department of Clinical Medicine, School of Clinical Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Lai Jiang
- Department of Clinical Medicine, School of Clinical Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Haiqing Chen
- Department of Clinical Medicine, School of Clinical Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jinbang Huang
- Department of Clinical Medicine, School of Clinical Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jieying Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Rui Wang
- Department of General Surgery (Hepatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
- Academician (Expert) Workstation of Sichuan Province, Luzhou, China
| | - Hao Chi
- Department of Clinical Medicine, School of Clinical Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Guanhu Yang
- Department of Specialty Medicine, Ohio University, Athens, United States
| | - Gang Tian
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Luzhou, China
- Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Luzhou, China
| |
Collapse
|
|
22
|
Asari Y, Yamazaki J, Thandar O, Suzuki T, Aoshima K, Takeuchi K, Kinoshita R, Kim S, Hosoya K, Ishizaki T, Kagawa Y, Jelinek J, Yokoyama S, Sasaki N, Ohta H, Nakamura K, Takiguchi M. Diverse genome-wide DNA methylation alterations in canine hepatocellular tumours. Vet Med Sci 2023; 9:2006-2014. [PMID: 37483163 PMCID: PMC10508506 DOI: 10.1002/vms3.1204] [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: 07/24/2022] [Revised: 06/02/2023] [Accepted: 07/06/2023] [Indexed: 07/25/2023] Open
Abstract
BACKGROUND Canine hepatocellular tumours (HCTs) are common primary liver tumours. However, the exact mechanisms of tumourigenesis remain unclear. Although some genetic mutations have been reported, DNA methylation alterations in canine HCT have not been well studied. OBJECTIVES In this study, we aimed to analyse the DNA methylation status of canine HCT. METHODS Tissues from 33 hepatocellular carcinomas, 3 hepatocellular adenomas, 1 nodular hyperplasia, 21 non-tumour livers from the patients and normal livers from 5 healthy dogs were used. We analysed the DNA methylation levels of 72,367 cytosine-guanine dinucleotides (CpG sites) in all 63 samples. RESULTS AND CONCLUSIONS Although a large fraction of CpG sites that were highly methylated in the normal liver became hypomethylated in tumours from most patients, we also found some patients with less remarkable change or no change in DNA methylation. Hierarchical clustering analysis revealed that 32 of 37 tumour samples differed from normal livers, although the remaining 5 tumour livers fell into the same cluster as normal livers. In addition, the number of hypermethylated genes in tumour livers varied among tumour cases, suggesting various DNA methylation patterns in different tumour groups. However, patient and clinical parameters, such as age, were not associated with DNA methylation status. In conclusion, we found that HCTs undergo aberrant and diverse patterns of genome-wide DNA methylation compared with normal liver tissue, suggesting a complex epigenetic mechanism in canine HCT.
Collapse
Affiliation(s)
- Yu Asari
- Laboratory of Veterinary Internal Medicine, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Jumpei Yamazaki
- Veterinary Teaching HospitalGraduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
- Translational Research Unit, Veterinary Teaching Hospital, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
- One Health Research Center, Cancer Research UnitHokkaido UniversitySapporoJapan
| | - Oo Thandar
- Laboratory of Veterinary Internal Medicine, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Tamami Suzuki
- Laboratory of Comparative Pathology, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Keisuke Aoshima
- One Health Research Center, Cancer Research UnitHokkaido UniversitySapporoJapan
- Laboratory of Comparative Pathology, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Kyosuke Takeuchi
- Veterinary Teaching HospitalGraduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Ryohei Kinoshita
- Veterinary Teaching HospitalGraduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
- One Health Research Center, Cancer Research UnitHokkaido UniversitySapporoJapan
| | - Sangho Kim
- One Health Research Center, Cancer Research UnitHokkaido UniversitySapporoJapan
- Laboratory of Veterinary Surgery, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Kenji Hosoya
- One Health Research Center, Cancer Research UnitHokkaido UniversitySapporoJapan
- Laboratory of Veterinary Surgery, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Teita Ishizaki
- Veterinary Teaching HospitalGraduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
- Laboratory of Comparative Pathology, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
- North LabSapporoJapan
| | | | | | - Shoko Yokoyama
- Veterinary Teaching HospitalGraduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
- Translational Research Unit, Veterinary Teaching Hospital, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
- One Health Research Center, Cancer Research UnitHokkaido UniversitySapporoJapan
| | - Noboru Sasaki
- Laboratory of Veterinary Internal Medicine, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Hiroshi Ohta
- Laboratory of Veterinary Internal Medicine, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Kensuke Nakamura
- Laboratory of Veterinary Internal Medicine, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| | - Mitsuyoshi Takiguchi
- Laboratory of Veterinary Internal Medicine, Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan
| |
Collapse
|
|
23
|
Ali S, Naveed A, Hussain I, Qazi J. Diagnosis and monitoring of hepatocellular carcinoma in Hepatitis C virus patients using attenuated total reflection Fourier transform infrared spectroscopy. Photodiagnosis Photodyn Ther 2023; 43:103677. [PMID: 37390855 DOI: 10.1016/j.pdpdt.2023.103677] [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: 04/27/2023] [Revised: 06/22/2023] [Accepted: 06/23/2023] [Indexed: 07/02/2023]
Abstract
BACKGROUND Current diagnostic methods for assessment of hepatitis C virus related hepatocellular carcinoma and subsequent categorization of hepatocellular carcinoma into non-angio-invasive hepatocellular carcinoma and angio-invasive hepatocellular carcinoma, to establish appropriate treatment strategies, are costly, invasive and requires multiple screening steps. This demands alternative diagnostic approaches that are cost-effective, time-efficient, and minimally invasive, while maintaining their efficacy for screening of hepatitis c virus related hepatocellular carcinoma. In this study, we propose that attenuated total reflection Fourier transform infrared in conjunction with principal component analysis - linear discriminant analysis and support vector machine multivariate algorithms holds a potential as a sensitive tool for the detection of hepatitis C virus-related hepatocellular carcinoma and the subsequent categorization of hepatocellular carcinoma into non-angio-invasive hepatocellular carcinoma and angio-invasive hepatocellular carcinoma. METHODS Freeze-dried sera samples collected from 31 hepatitis c virus related hepatocellular carcinoma patients and 30 healthy individuals, were used to acquire mid-infrared absorbance spectra (3500-900 cm-1) using attenuated total reflection Fourier transform infrared. Chemometric machine learning techniques were utilized to build principal component analysis - linear discriminant analysis and support vector machine discriminant models for the spectral data of hepatocellular carcinoma patients and healthy individuals. Sensitivity, specificity, and external validation on blind samples were calculated. RESULTS Major variations were observed in the two spectral regions i.e., 3500-2800 and 1800-900 cm-1. IR spectral signatures of hepatocellular carcinoma were reliably different from healthy individuals. Principal component analysis - linear discriminant analysis and support vector machine models computed 100% accuracy for diagnosing hepatocellular carcinoma. To classify the non-angio-invasive hepatocellular carcinoma/ angio-invasive hepatocellular carcinoma status, diagnostic accuracy of 86.21% was achieved for principal component analysis - linear discriminant analysis. While the support vector machine showed a training accuracy of 98.28% and a cross-validation accuracy of 82.75%. External validation for support vector machine based classification observed 100% sensitivity and specificity for accurately classifying the freeze-dried sera samples for all categories. CONCLUSIONS We present the specific spectral signatures for non-angio-invasive hepatocellular carcinoma and angio-invasive hepatocellular carcinoma, which were prominently differentiated from healthy individuals. This study provides an initial insight into the potential of attenuated total reflection Fourier transform infrared to diagnose hepatitis C virus related hepatocellular carcinoma but also to further categorize into non-angio-invasive and angio-invasive hepatocellular carcinoma.
Collapse
Affiliation(s)
- Salmann Ali
- Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Ammara Naveed
- Department of gastroenterology and hepatology, Pakistan Kidney and Liver Institute, Lahore, Pakistan
| | - Irshad Hussain
- Department of Chemistry &Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences (LUMS), DHA, Lahore Cantt 54792, Pakistan
| | - Javaria Qazi
- Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
| |
Collapse
|
|
24
|
Singh SP, Arora V, Madke T, Sarin SK. Hepatocellular Carcinoma-Southeast Asia Updates. Cancer J 2023; 29:259-265. [PMID: 37796643 DOI: 10.1097/ppo.0000000000000684] [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: 10/07/2023]
Abstract
ABSTRACT Hepatocellular carcinoma (HCC) is one of the leading cancers worldwide. Classically, HCC develops in genetically susceptible individuals who are exposed to risk factors, especially in the presence of liver cirrhosis. Significant temporal and geographic variations exist for HCC and its etiologies. Over time, the burden of HCC has shifted from the low-moderate to the high sociodemographic index regions, reflecting the transition from viral to nonviral causes. Geographically, the hepatitis viruses predominate as the causes of HCC in Asia and Africa. Although there are genetic conditions that confer increased risk for HCC, these diagnoses are rarely recognized outside North America and Europe. In this review, we evaluate the epidemiologic trends and risk factors of HCC and discuss the prevention with surveillance and short management.
Collapse
Affiliation(s)
- Satender Pal Singh
- From the Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | | | | |
Collapse
|
|
25
|
Elabd WK, Elbakry MMM, Hassany M, Baki AA, Seoudi DM, El Azeem EMA. Evaluation of miRNA-7, miRNA-10 and miRNA-21 as diagnostic non-invasive biomarkers of hepatocellular carcinoma. Clin Exp Hepatol 2023; 9:221-227. [PMID: 37790691 PMCID: PMC10544064 DOI: 10.5114/ceh.2023.130547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 07/02/2023] [Indexed: 10/05/2023] Open
Abstract
Aim of the study Liver cancer (hepatocellular carcinoma - HCC) remains a serious health challenge; it is the fourth leading cause of death worldwide. Egypt ranks fifteenth worldwide and the third in Africa in terms of HCC burden. The present study aimed to assess some microRNAs (miRNAs) including miRNA-7, miRNA-10, and miRNA-21, serum markers such as cluster of differentiation-14 (CD-14) and transforming growth factor b1 (TGF-b1), and other biochemical parameters as non-invasive tools for HCC diagnosis. Material and methods The study included 100 participants divided into five groups: group I (20 normal subjects as a healthy group), group II (20 participants with chronic HCV infection but non-cirrhotic), group III (20 volunteers with chronic HCV infection and compensated cirrhosis), group IV (20 patients with chronic HCV infection and decompensated cirrhosis), and group V (20 participants with HCC). Levels of miR-7, miR-10, and miR-21 were evaluated using qRT-PCR. Serum ALT, AST, total bilirubin, total protein, albumin, PT, INR, and platelet count were determined. FIB-4 and APRI test levels were also calculated. CD-14 and TGF-β1 serum levels were estimated using enzyme-linked immunosorbent assay (ELISA) kits. Results The expression levels of miR-21 followed by miR-10 showed high sensitivity and specificity in predicting HCC. Serum CD-14 and TGF-b1 levels were significantly increased in all patient groups. Conclusions From the study, it is concluded that the expression level of miR-21 has the highest sensitivity and specificity, followed by miR-10, which has high sensitivity and low specificity as non-invasive markers for HCC detection, while miR-7 exhibits high sensitivity and reasonable specificity in fibrosis detection.
Collapse
Affiliation(s)
| | | | - Mohamed Hassany
- National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Amin Abdel Baki
- National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | | | | |
Collapse
|
|
26
|
Han S, Ye T, Mao Y, Hu B, Wang C. Cuproptosis-Related Genes CDK1 and COA6 Involved in the Prognosis Prediction of Liver Hepatocellular Carcinoma. DISEASE MARKERS 2023; 2023:5552798. [PMID: 37215201 PMCID: PMC10195163 DOI: 10.1155/2023/5552798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/07/2023] [Accepted: 03/29/2023] [Indexed: 05/24/2023]
Abstract
Background Liver hepatocellular carcinoma (LIHC) is the most frequently seen type of primary liver cancer. Cuproptosis is a novel form of cell death highly associated with mitochondrial metabolism. However, the clinical impact and pertinent mechanism of cuproptosis genes in LIHC remain largely unknown. Methods From public databases, we systematically assessed common genes from LIHC differentially expressed genes (DEGs) and cuproptosis-related genes using bioinformatics analysis. These common genes were then analyzed by enrichment analysis, mutation analysis, risk score model, and others to find candidate hub genes related to LIHC and cuproptosis. Next, hub genes were determined by expression, clinical factors, immunoassay, and prognostic nomogram. Results Based on 129 cuproptosis-related genes and 3492 LIHC DEGs, we totally identified 21 downregulated and 18 upregulated common genes, and they were enriched in pathways, such as zinc ion homeostasis and oxidative phosphorylation. In the mutation analysis, missense mutation was the most common type in LIHC patients, and the common gene F5 had the highest mutation frequency. After LASSO-Cox regression analysis and prognostic analysis, CDK1, ABCB6, LCAT, and COA6 were identified as prognostic signature genes. Among them, ABCB6 and LCAT were lowly expressed in tumors, and CDK1 and COA6 were highly expressed in tumors. In addition, ABCB6 and LCAT were negatively correlated with 6 kinds of immune cells, while CDK1 and COA6 were positively correlated with them. CDK1 and COA6 were identified as hub genes related to LIHC by Cox regression analysis and prognostic nomogram. Conclusion CDK1 and COA6 are two oncogenes in LIHC, which are involved in the molecular mechanism of cuproptosis and LIHC. Besides, CDK1 and COA6 can positively regulate the expressions of immune cells in LIHC. In clinical practice, they can be used as immunotherapeutic targets and prognostic predictors in LIHC, which sheds new light on the scientific fields of cuproptosis and LIHC.
Collapse
Affiliation(s)
- Sanfeng Han
- Central Laboratory, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, China
| | - Tao Ye
- Department of Oncology, Minhang Hospital, Fudan University, China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, China
| | - Yuqin Mao
- Center for Traditional Chinese Medicine and Gut Microbiota, Minhang Hospital, Fudan University, 201199 Shanghai, China
| | - Bo Hu
- Department of Oncology, Minhang Hospital, Fudan University, China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, China
| | - Chen Wang
- Department of Oncology, Minhang Hospital, Fudan University, China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, China
| |
Collapse
|
|
27
|
Gao YX, Ning QQ, Yang PX, Guan YY, Liu PX, Liu ML, Qiao LX, Guo XH, Yang TW, Chen DX. Recent advances in recurrent hepatocellular carcinoma therapy. World J Hepatol 2023; 15:460-476. [PMID: 37206651 PMCID: PMC10190692 DOI: 10.4254/wjh.v15.i4.460] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/20/2022] [Accepted: 03/24/2023] [Indexed: 04/20/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer, accounting for 75%-85% of cases. Although treatments are given to cure early-stage HCC, up to 50%-70% of individuals may experience a relapse of the illness in the liver after 5 years. Research on the fundamental treatment modalities for recurrent HCC is moving significantly further. The precise selection of individuals for therapy strategies with established survival advantages is crucial to ensuring better outcomes. These strategies aim to minimize substantial morbidity, support good life quality, and enhance survival for patients with recurrent HCC. For individuals with recurring HCC after curative treatment, no approved therapeutic regimen is currently available. A recent study presented novel approaches, like immunotherapy and antiviral medication, to improve the prognosis of patients with recurring HCC with the apparent lack of data to guide the clinical treatment. The data supporting several neoadjuvant and adjuvant therapies for patients with recurring HCC are outlined in this review. We also discuss the potential for future clinical and translational investigations.
Collapse
Affiliation(s)
- Yu-Xue Gao
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Qi-Qi Ning
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Peng-Xiang Yang
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Yuan-Yue Guan
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Peng-Xiang Liu
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Meng-Lu Liu
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Lu-Xin Qiao
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Xiang-Hua Guo
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Tong-Wang Yang
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Academician Workstation, Changsha Medical University, Changsha 410219, Hunan Province, China
- Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha 410219, Hunan Province, China
| | - De-Xi Chen
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| |
Collapse
|
|
28
|
Kouroumalis E, Tsomidis I, Voumvouraki A. Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy. Biomedicines 2023; 11:1166. [PMID: 37189787 PMCID: PMC10135776 DOI: 10.3390/biomedicines11041166] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/09/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. In this review, a concise overview of the pathogenesis of HCC is presented, with emphasis on new developments, including the role of endoplasmic reticulum stress, the implication of microRNAs and the role of gut microbiota. The characteristics of HCC associated with a specific liver disease are also described and a brief description of autophagy and apoptosis is provided. The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. The role of ferroptosis, a recently described specific pathway of regulated cell death, is presented. Finally, the potential therapeutic implications of autophagy and apoptosis in drug resistance are examined.
Collapse
Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, PAGNI University Hospital, University of Crete School of Medicine, 71500 Heraklion, Crete, Greece
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
| |
Collapse
|
|
29
|
McDuffie D, Barr D, Helm M, Baumert T, Agarwal A, Thomas E. Physiomimetic In Vitro Human Models for Viral Infection in the Liver. Semin Liver Dis 2023; 43:31-49. [PMID: 36402129 PMCID: PMC10005888 DOI: 10.1055/a-1981-5944] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Viral hepatitis is a leading cause of liver morbidity and mortality globally. The mechanisms underlying acute infection and clearance, versus the development of chronic infection, are poorly understood. In vitro models of viral hepatitis circumvent the high costs and ethical considerations of animal models, which also translate poorly to studying the human-specific hepatitis viruses. However, significant challenges are associated with modeling long-term infection in vitro. Differentiated hepatocytes are best able to sustain chronic viral hepatitis infection, but standard two-dimensional models are limited because they fail to mimic the architecture and cellular microenvironment of the liver, and cannot maintain a differentiated hepatocyte phenotype over extended periods. Alternatively, physiomimetic models facilitate important interactions between hepatocytes and their microenvironment by incorporating liver-specific environmental factors such as three-dimensional ECM interactions and co-culture with non-parenchymal cells. These physiologically relevant interactions help maintain a functional hepatocyte phenotype that is critical for sustaining viral hepatitis infection. In this review, we provide an overview of distinct, novel, and innovative in vitro liver models and discuss their functionality and relevance in modeling viral hepatitis. These platforms may provide novel insight into mechanisms that regulate viral clearance versus progression to chronic infections that can drive subsequent liver disease.
Collapse
Affiliation(s)
- Dennis McDuffie
- Department of Biomedical Engineering, University of Miami, Coral Gables, Florida
| | - David Barr
- Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida
| | - Madeline Helm
- Department of Biomedical Engineering, University of Miami, Coral Gables, Florida
| | - Thomas Baumert
- Inserm Research Institute for Viral and Liver Diseases, University of Strasbourg, Strasbourg, France
| | - Ashutosh Agarwal
- Department of Biomedical Engineering, University of Miami, Coral Gables, Florida
- Desai Sethi Urology Institute, Miller School of Medicine, University of Miami, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
| | - Emmanuel Thomas
- Department of Biomedical Engineering, University of Miami, Coral Gables, Florida
- Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida
- Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
| |
Collapse
|
|
30
|
Rodia R, Meloni PE, Mascia C, Balestrieri C, Ruggiero V, Serra G, Conti M, Loi M, Pes F, Onali S, Perra A, Littera R, Velluzzi F, Mariotti S, Chessa L, Boi F. Direct-acting antivirals used in HCV-related liver disease do not affect thyroid function and autoimmunity. J Endocrinol Invest 2023; 46:359-366. [PMID: 36048357 PMCID: PMC9859881 DOI: 10.1007/s40618-022-01909-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 08/19/2022] [Indexed: 01/25/2023]
Abstract
PURPOSE It is well known that interferon-α (IFN-α), used for long time as the main therapy for HCV-related disease, induces thyroid alterations, but the impact of the new direct-acting antivirals (DAAs) on thyroid is not established. Aim of this prospective study was to evaluate if DAAs therapy may induce thyroid alterations. METHODS A total of 113 HCV patients, subdivided at the time of the enrollment in naïve group (n = 64) and in IFN-α group (n = 49) previously treated with pegylated interferon-α and ribavirin, were evaluated for thyroid function and autoimmunity before and after 20-32 weeks of DAAs. RESULTS Before starting DAAs, a total of 8/113 (7.1%) patients showed Hashimoto's thyroiditis (HT) all belonging to IFN-α group (8/49, 16.3%), while no HT cases were found in the naïve group. Overall, 7/113 (6.2%) patients were hypothyroid: 3/64 (4.7%) belonging to naïve group and 4/49 (8.2%) to IFN-α group. Furthermore, a total of 8/113 patients (7.1%) showed subclinical hyperthyroidism: 2/64 (3.1%) were from naïve group and 6/49 (12.2%) from IFN-α group. Interestingly, after DAAs therapy, no new cases of HT, hypothyroidism and hyperthyroidism was found in all series, while 6/11 (54.5%) patients with non-autoimmune subclinical thyroid dysfunction became euthyroid. Finally, the only association between viral genotypes and thyroid alterations was genotype 1 and hypothyroidism. CONCLUSIONS This study supports evidence that DAAs have a limited or missing influence on thyroid in patients with HCV-related diseases. Moreover, it provides preliminary evidence that subclinical non-autoimmune thyroid dysfunction may improve after HCV infection resolution obtained by DAAs.
Collapse
Affiliation(s)
- R Rodia
- Endocrinology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Azienda Ospedaliero-Universitaria di Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - P E Meloni
- Endocrinology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Azienda Ospedaliero-Universitaria di Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - C Mascia
- Endocrinology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Azienda Ospedaliero-Universitaria di Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - C Balestrieri
- Centre of Liver Diseases, Department of Medical Sciences and Public Health, University of Cagliari, Azienda Ospedaliero-Universitaria di Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - V Ruggiero
- Endocrinology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Azienda Ospedaliero-Universitaria di Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - G Serra
- Centre of Liver Diseases, Department of Medical Sciences and Public Health, University of Cagliari, Azienda Ospedaliero-Universitaria di Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - M Conti
- Centre of Liver Diseases, Department of Medical Sciences and Public Health, University of Cagliari, Azienda Ospedaliero-Universitaria di Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - M Loi
- Centre of Liver Diseases, Department of Medical Sciences and Public Health, University of Cagliari, Azienda Ospedaliero-Universitaria di Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - F Pes
- Centre of Liver Diseases, Department of Medical Sciences and Public Health, University of Cagliari, Azienda Ospedaliero-Universitaria di Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - S Onali
- Centre of Liver Diseases, Department of Medical Sciences and Public Health, University of Cagliari, Azienda Ospedaliero-Universitaria di Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - A Perra
- Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - R Littera
- Complex Structure of Medical Genetics, R. Binaghi Hospital, ASSL Cagliari, ATS Sardegna, Cagliari, Italy
| | - F Velluzzi
- Endocrinology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Azienda Ospedaliero-Universitaria di Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - S Mariotti
- Endocrinology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Azienda Ospedaliero-Universitaria di Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - L Chessa
- Centre of Liver Diseases, Department of Medical Sciences and Public Health, University of Cagliari, Azienda Ospedaliero-Universitaria di Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - F Boi
- Endocrinology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Azienda Ospedaliero-Universitaria di Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy.
| |
Collapse
|
|
31
|
Floreani A, Bizzaro D, Shalaby S, Taliani G, Burra P. Sex disparity and drug-induced liver injury. Dig Liver Dis 2023; 55:21-28. [PMID: 35843842 DOI: 10.1016/j.dld.2022.06.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/03/2022] [Accepted: 06/21/2022] [Indexed: 12/31/2022]
Abstract
Drug-induced liver injury (DILI) is a potentially serious clinical condition that remains a major problem for patients, physicians and those involved in the development of new drugs. Population and hospital-based studies have reported incidences of DILI varying from 1.4 to 19.1/100.000. Overall, females have a 1.5- to 1.7-fold greater risk of developing adverse drug reactions and the female/male ratio increases after the age of 49 years, suggesting a clear susceptibility of DILI after menopause. Sex differences in pharmacokinetics and pharmacodynamic, sex-specific hormonal effects or interaction with signalling molecules that can influence drug efficacy and safety and differences in abnormal immune response following drug exposure are the main probable causes of the higher vulnerability observed among female patients. A novel phenotype of autoimmune-mediated DILI following the use of check-point inhibitors in oncology and haematology has been recently described. Finally, there have been increasing reports of DILI associated with use of herbal and dietary supplements that is more frequently reported in women.
Collapse
Affiliation(s)
- A Floreani
- Scientific Consultant Scientific Institute for Research, Hospitalization and Healthcare, Negrar, Verona, Italy; Senior Scholar, University of Padova, Padova, Italy.
| | - D Bizzaro
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - S Shalaby
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - G Taliani
- Department of Infectious and Tropical Diseases, La Sapienza University of Rome, Rome, Italy
| | - P Burra
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | | |
Collapse
|
|
32
|
Heredia-Torres TG, Rincón-Sánchez AR, Lozano-Sepúlveda SA, Galan-Huerta K, Arellanos-Soto D, García-Hernández M, Garza-Juarez ADJ, Rivas-Estilla AM. Unraveling the Molecular Mechanisms Involved in HCV-Induced Carcinogenesis. Viruses 2022; 14:2762. [PMID: 36560766 PMCID: PMC9786602 DOI: 10.3390/v14122762] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/01/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022] Open
Abstract
Cancer induced by a viral infection is among the leading causes of cancer. Hepatitis C Virus (HCV) is a hepatotropic oncogenic positive-sense RNA virus that leads to chronic infection, exposing the liver to a continuous process of damage and regeneration and promoting hepatocarcinogenesis. The virus promotes the development of carcinogenesis through indirect and direct molecular mechanisms such as chronic inflammation, oxidative stress, steatosis, genetic alterations, epithelial-mesenchymal transition, proliferation, and apoptosis, among others. Recently, direct-acting antivirals (DAAs) showed sustained virologic response in 95% of cases. Nevertheless, patients treated with DAAs have reported an unexpected increase in the early incidence of Hepatocellular carcinoma (HCC). Studies suggest that HCV induces epigenetic regulation through non-coding RNAs, DNA methylation, and chromatin remodeling, which modify gene expressions and induce genomic instability related to HCC development that persists with the infection's clearance. The need for a better understanding of the molecular mechanisms associated with the development of carcinogenesis is evident. The aim of this review was to unravel the molecular pathways involved in the development of carcinogenesis before, during, and after the viral infection's resolution, and how these pathways were regulated by the virus, to find control points that can be used as potential therapeutic targets.
Collapse
Affiliation(s)
- Tania Guadalupe Heredia-Torres
- Department of Biochemistry and Molecular Medicine, CIIViM, School of Medicine, Universidad Autónoma de Nuevo León (UANL), Monterrey 64460, Mexico
| | - Ana Rosa Rincón-Sánchez
- IBMMTG, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44100, Mexico
| | - Sonia Amelia Lozano-Sepúlveda
- Department of Biochemistry and Molecular Medicine, CIIViM, School of Medicine, Universidad Autónoma de Nuevo León (UANL), Monterrey 64460, Mexico
| | - Kame Galan-Huerta
- Department of Biochemistry and Molecular Medicine, CIIViM, School of Medicine, Universidad Autónoma de Nuevo León (UANL), Monterrey 64460, Mexico
| | - Daniel Arellanos-Soto
- Department of Biochemistry and Molecular Medicine, CIIViM, School of Medicine, Universidad Autónoma de Nuevo León (UANL), Monterrey 64460, Mexico
| | - Marisela García-Hernández
- Department of Biochemistry and Molecular Medicine, CIIViM, School of Medicine, Universidad Autónoma de Nuevo León (UANL), Monterrey 64460, Mexico
| | - Aurora de Jesús Garza-Juarez
- Department of Biochemistry and Molecular Medicine, CIIViM, School of Medicine, Universidad Autónoma de Nuevo León (UANL), Monterrey 64460, Mexico
| | - Ana María Rivas-Estilla
- Department of Biochemistry and Molecular Medicine, CIIViM, School of Medicine, Universidad Autónoma de Nuevo León (UANL), Monterrey 64460, Mexico
| |
Collapse
|
|
33
|
Tripathi SK, Pal A, Ghosh S, Goel A, Aggarwal R, Banerjee S, Das S. LncRNA NEAT1 regulates HCV-induced Hepatocellular carcinoma by modulating the miR-9-BGH3 axis. J Gen Virol 2022; 103. [PMID: 36748628 DOI: 10.1099/jgv.0.001809] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a leading cause of end-stage liver diseases, such as fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Several cellular entities, including paraspeckles and their related components, are involved in viral pathogenesis and cancer progression. NEAT1 lncRNA is a major component of paraspeckles that has been linked to several malignancies. In this study, analysis of the Cancer Genome Atlas (TCGA) database and validation in HCV-induced HCC tissue and serum samples showed significantly high expression of NEAT1 in patients with liver cancer. Moreover, we found that NEAT1 levels increased upon HCV infection. To further understand the mechanism of NEAT1-induced HCC progression, we selected one of its targets, miR-9-5 p, which regulates BGH3 mRNA levels. Interestingly, miR-9-5 p levels were downregulated upon HCV infection, whereas BGH3 levels were upregulated. Additionally, partial NEAT1 knockdown increased miR-9-5 p levels and decreased BGH3 levels, corroborating our initial results. BGH3 levels were also upregulated in HCV-induced HCC and TCGA tissue samples, which could be directly correlated with NEAT1 levels. As a known oncogene, BGH3 is directly linked to HCC progression mediated by NEAT1. We also found that NEAT1 levels remained upregulated in serum samples from patients treated with direct-acting antivirals (DAA), indicating that NEAT1 might be a molecular trigger that promotes HCC development. Collectively, these findings provide molecular insights into HCV-induced HCC progression via the NEAT1-miR-9-BGH3 axis.
Collapse
Affiliation(s)
| | - Apala Pal
- Indian Institute of Science, Bangalore, India
| | - Suchandrima Ghosh
- Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Amit Goel
- Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Rakesh Aggarwal
- Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Soma Banerjee
- Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Saumitra Das
- Indian Institute of Science, Bangalore, India
- National Institute of Biomedical Genomics, Kalyani, India
| |
Collapse
|
|
34
|
Sarantis P, Trifylli EM, Koustas E, Papavassiliou KA, Karamouzis MV, Papavassiliou AG. Immune Microenvironment and Immunotherapeutic Management in Virus-Associated Digestive System Tumors. Int J Mol Sci 2022; 23:13612. [PMID: 36362398 PMCID: PMC9655697 DOI: 10.3390/ijms232113612] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/31/2022] [Accepted: 11/04/2022] [Indexed: 08/29/2023] Open
Abstract
The development of cancer is a multifactorial phenomenon, while it constitutes a major global health problem. Viruses are an important factor that is involved in tumorigenesis and is associated with 12.1% of all cancer cases. Major examples of oncogenic viruses which are closely associated with the digestive system are HBV, HCV, EBV, HPV, JCV, and CMV. EBV, HPV, JCV, and CMV directly cause oncogenesis by expressing oncogenic proteins that are encoded in their genome. In contrast, HBV and HCV are correlated indirectly with carcinogenesis by causing chronic inflammation in the infected organs. In addition, the tumor microenvironment contains various immune cells, endothelial cells, and fibroblasts, as well as several growth factors, cytokines, and other tumor-secreted molecules that play a key role in tumor growth, progression, and migration, while they are closely interrelated with the virus. The presence of T-regulatory and B-regulatory cells in the tumor microenvironment plays an important role in the anti-tumor immune reaction. The tumor immune microenvironments differ in each type of cancer and depend on viral infection. The alterations in the immune microenvironment caused by viruses are also reflected in the effectiveness of immunotherapy. The present review aims at shedding light on the association between viruses and digestive system malignancies, the characteristics of the tumor immune microenvironment that develop, and the possible treatments that can be administered.
Collapse
Affiliation(s)
- Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Eleni-Myrto Trifylli
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece
| | - Evangelos Koustas
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece
| | - Kostas A. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michalis V. Karamouzis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| |
Collapse
|
|
35
|
Devi P, Engdahl K, Punga T, Bergqvist A. Next-Generation Sequencing Analysis of CpG Methylation of a Tumor Suppressor Gene SHP-1 Promoter in Stable Cell Lines and HCV-Positive Patients. Viruses 2022; 14:v14112352. [PMID: 36366451 PMCID: PMC9695419 DOI: 10.3390/v14112352] [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: 10/11/2022] [Revised: 10/19/2022] [Accepted: 10/22/2022] [Indexed: 02/01/2023] Open
Abstract
Hepatitis C virus (HCV) is the major causative pathogen associated with hepatocellular carcinoma and liver cirrhosis. The main virion component, the Core (C) protein, is involved in multiple aspects of HCV pathology including oncogenesis and immune evasion. In this study, we established a next-generation bisulfite sequencing (NGS-BS) protocol to analyze the CpG methylation profile at the tumor suppressor gene SHP-1 P2 promoter as a model system. Our data show that HCV C protein expression in the immortalized T cells correlated with a specific CpG methylation profile at the SHP-1 P2. The NGS-BS on HCV-positive (HCV+) patient-derived PBMCs revealed a considerably different CpG methylation profile compared to the HCV C protein immortalized T cells. Notably, the CpG methylation profile was very similar in healthy and HCV+ PBMCs, suggesting that the SHP-1 P2 CpG methylation profile is not altered in the HCV+ individuals. Collectively, the NGS-BS is a highly sensitive method that can be used to quantitatively characterize the CpG methylation status at the level of individual CpG position and also allows the characterization of cis-acting effects on epigenetic regulation.
Collapse
Affiliation(s)
- Priya Devi
- Department of Medical Sciences, Uppsala University, SE 75185 Uppsala, Sweden
| | - Katarina Engdahl
- Department of Medical Sciences, Uppsala University, SE 75185 Uppsala, Sweden
| | - Tanel Punga
- Department of Medical Biochemistry and Microbiology, Uppsala University, SE 75123 Uppsala, Sweden
| | - Anders Bergqvist
- Department of Medical Sciences, Uppsala University, SE 75185 Uppsala, Sweden
- Clinical Microbiology and Hospital Infection Control, Uppsala University Hospital, SE 75185 Uppsala, Sweden
- Correspondence: ; Tel.: +46-186113937
| |
Collapse
|
|
36
|
Badshah Y, Shabbir M, Khan K, Fatima M, Majoka I, Aslam L, Munawar H. Manipulation of Interleukin-6 (IL-6) and Transforming Growth Factor Beta-1(TGFβ-1) towards viral induced liver cancer pathogenesis. PLoS One 2022; 17:e0275834. [PMID: 36215278 PMCID: PMC9550071 DOI: 10.1371/journal.pone.0275834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 09/22/2022] [Indexed: 11/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver malignancy. Early diagnosis of HCC has always been challenging. This study aims to assess the pathogenicity and the prevalence of IL-6 -174G/C (rs1800795) and TGFβ-1 +29C/T (rs1800470) polymorphisms in HCV-infected HCC patients. Experimental strategies are integrated with computational approaches to analyse the pathogenicity of the TGFβ-1 +29C/T and IL-6-174 G/C polymorphisms in HCV-induced HCC. AliBaba2 was used to predict the effect of IL-6-174 G/C on transcription factor binding site in IL-6 gene. Structural changes in the mutant TGFβ-1 structure were determined through project HOPE. To assess the polymorphic prevalence of IL-6 -174G/C and TGFβ-1 +29C/T genotypes in HCC and control subjects, amplification refractory mutation system PCR (ARMS-PCR) was performed on 213 HCC and 216 control samples. GraphPad Prism version 8.0 was used for the statistical analysis of the results. In-silico analysis revealed the regulatory nature of both IL-6 -174G/C and TGFβ-1 +29C/T polymorphisms. ARMS-PCR results revealed that the individuals carrying TT genotype for TGFβ-1 gene have an increased risk of developing HCC (p<0.0001, OR = 5.403, RR = 2.062) as compared to individuals with CT and CC genotype. Similarly, GC genotype carriers for IL-6 gene exhibit an increased risk of HCC susceptibility (p<0.0001, OR = 2.276, RR = 1.512) as compared to the people carrying the GG genotype. Genotype TT of TGFβ-1 gene and genotype GC of IL-6 gene are found to be associated with HCV-induced HCC. IL-6 polymorphism may alter its transcription that leads to its pathogenicity. TGFβ-1 polymorphism may alter protein structure stability.
Collapse
Affiliation(s)
- Yasmin Badshah
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Maria Shabbir
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Khushbukhat Khan
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Maha Fatima
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Iqra Majoka
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Laiba Aslam
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Huda Munawar
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| |
Collapse
|
|
37
|
Han L, Jia X, Abuduwaili W, Li D, Chen H, Jiang Q, Chen S, Zhang S, Xia R, Xue R. Identification of prognostic miRNA-mRNA regulatory network in the progression of HCV-associated cirrhosis to hepatocellular carcinoma. Transl Cancer Res 2022; 11:3657-3673. [PMID: 36388056 PMCID: PMC9641102 DOI: 10.21037/tcr-22-989] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 08/09/2022] [Indexed: 02/16/2025]
Abstract
BACKGROUND Long-term hepatitis C virus (HCV) infection is strongly associated with hepatocellular carcinoma (HCC), yet the mechanisms of the progression process remain unclear. The research is aiming to establish a crucial prognostic model that indicates the risk of HCV-associated cirrhosis evolving into HCC. METHODS Differentially expressed microRNAs (DE-miRNAs) and differentially expressed genes (DEGs) between HCV-associated cirrhosis and HCC were screened from the GSE40744 and GSE6764 datasets, respectively. Downstream target genes of DE-miRNAs were predicted by the miRNet tool and then overlapped with the DEGs to select intersection genes. The GSE15654 was downloaded to establish a prognostic model. Expression levels of risk genes and their corresponding miRNAs were measured in liver tissues of clinical patients. HCC cell lines with UHRF1 knockdown or overexpression were assayed for cell proliferation and migration. RESULTS Thirty-nine DE-miRNAs and 796 DEGs are identified between HCV-associated cirrhosis and HCC. Main intersection genes and their corresponding miRNAs constitute a miRNA-mRNA regulatory network. PABPC1 (Polyadenylate-binding protein 1), SLC2A9 (solute carrier gene family 2, member 9), and UHRF1 (ubiquitin-like with PHD and ring finger domains 1) form a prognostic model indicating the risk of HCC development among HCV-associated cirrhosis. The genetic mutations of PABPC1, SLC2A9, and UHRF1 in HCC patients are 9%, 0.8%, and 0.6%, respectively. Compared to that in HCV-associated cirrhosis, the expression levels of PABPC1 and UHRF1 are higher while the expression level of SLC2A9 is lower in clinical HCV-associated HCC samples. UHRF1 enhances the proliferation and migration ability of HCC cells. CONCLUSIONS PABPC1, SLC2A9, and UHRF1 and their corresponding miRNAs are involved in the evolution process of HCV-associated cirrhosis into malignant HCC. UHRF1 serves as an oncogene that promotes the proliferation and migration of HCC cells.
Collapse
Affiliation(s)
- Liping Han
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xuemei Jia
- Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China
- Department of Transfusion Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Weinire Abuduwaili
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dongping Li
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - He Chen
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qiuyu Jiang
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - She Chen
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Si Zhang
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Rong Xia
- Department of Transfusion Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Ruyi Xue
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
38
|
Talaat RM, Elsayed SS, Abdel-Hakem NE, El-Shenawy SZ. Genetic Polymorphism in Toll-Like Receptor 3 and Interferon Regulatory Factor 3 in Hepatitis C Virus-Infected Patients: Correlation with Liver Cirrhosis. Viral Immunol 2022; 35:609-615. [PMID: 36048530 DOI: 10.1089/vim.2022.0058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Host genetic factors could play a primary role in determining the risk for cirrhosis development in chronic hepatitis C virus (HCV)-infected patients. We designed this work to study the effect of single-nucleotide polymorphism (SNP) in Toll-like receptor 3 (TLR3) and interferon regulatory factor (IRF) on the risk of HCV-related cirrhosis. This study enrolled 139 Egyptian HCV-infected patients. They were divided into patients with cirrhotic (56) and noncirrhotic (83) liver. Genotyping of rs3775291 F459F (+1234C/T) and rs3775290 L412F (+1377C/T) in TLR3 and IRF3 rs2304204 (-925A/G) was performed by restriction fragment length polymorphism-polymerase chain reaction. Although there is no significant difference in genotype and allele distribution of +1377C/T of TLR3 gene between cirrhotic and noncirrhotic subjects, CC (odds ratio [OR] = 1.572, 95% confidence interval [CI]: 0.781-3.164); TT (OR = 1.463, 95% CI: 0.351-6.104) genotypes might be considered as risk factors for liver cirrhosis. On the contrary, the analysis revealed that only one genotype (CC) and one allele (C) were detected in +1234C/T SNP, with the total disappearance of CT/TT genotypes and T allele in all subjects. On the contrary, lower frequency has been found for the AG genotype of the IRF3 (-925A/G) gene in cirrhotic patients compared with noncirrhotic ones, indicating that AG is a protective genotype (OR = 0.509, 95% CI: 0.256-1.012). Our data stressed the association of AG genotype SNP in IRF3 (-925A/G) in protection against the worth outcome of HCV infection.
Collapse
Affiliation(s)
- Roba M Talaat
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City (USC), Sadat City Egypt
| | - Shimaa S Elsayed
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City (USC), Sadat City Egypt
| | - Nehal E Abdel-Hakem
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City (USC), Sadat City Egypt
| | - Soha Z El-Shenawy
- Hepatology Department, National Liver Institute (NLI), Menoufia University, Shebeen El-Kom, Egypt
| |
Collapse
|
|
39
|
Etiopathogenetic Factors of Hepatocellular Carcinoma, Overall Survival, and Their Evolution over Time-Czech Tertiary Center Overview. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58081099. [PMID: 36013566 PMCID: PMC9414813 DOI: 10.3390/medicina58081099] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 08/01/2022] [Accepted: 08/08/2022] [Indexed: 11/18/2022]
Abstract
Background and Objectives: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer with a highly unfavorable prognosis. Aims: Retrospective statistical analysis of patients with HCC in the field of liver cirrhosis treated at our center from the perspective of demography, and the effects of key changes in diagnostic and therapeutic procedures in the last 10 years on overall survival (OS) and earlier diagnosis. Materials and Methods: This study included 170 cirrhotic patients with HCC (136 men, 80%). Demographic and etiological factors and OS were analyzed based on distribution into three groups according to the period and key changes in diagnostic and therapeutic approaches (BCLC classification staging; standardization of protocol for transarterial chemoembolization (TACE) and the introduction of direct-acting antivirals (DAA) for the treatment of chronic viral hepatitis C (HCV); expansion of systemic oncological therapy). Results: The mean age at the time of diagnosis was 69.3 years (SD = 8.1), and etiology was as follows: non-alcoholic steatohepatitis (NASH) 39%, alcoholic liver disease (ALD) 36%, HCV 18%, cryptogenic liver cirrhosis 3%, chronic hepatitis B infection (HBV) 2%, and other etiology 2%. Distribution of stages according to the BCLC: 0 + A 36%, B 31%, C 22%, and D 11%. However, the distribution in the first studied period was as follows: 0 + A 15%, B 34%, C 36%, and D 15%; and in the last period: 0 + A 45%, B 27%, C 17%, and D 11%, and difference was statistically significant (p < 0.05). The median OS for stages 0 + A, B, C, and D was 58, 19, 6, and 2 months, respectively. During the monitored period, there was a visible increase in the etiology of ALD from 30% to 47% and a decrease in HCV from 22% to 11%. In patients treated with TACE (stage B), the median OS grew from 10 to 24 months (p < 0.0001) between the marginal monitored periods. Conclusions: We described a decreasing number of patients with HCV-related HCC during follow-up possibly linked with the introduction of DAA. In our cohort, an improvement in early-stage diagnosis was found, which we mainly concluded as a result of proper ultrasound surveillance, the institution of a HCV treatment center, and increased experience of our sonographers with an examination of cirrhotic patients. Lastly, we described significantly improved overall survival in patients with intermediate HCC treated by TACE, due to the increased experience of interventional radiologists with the method at our facility and an earlier switch to systemic therapy in case of non-response to TACE.
Collapse
|
|
40
|
Zhang CH, Cheng Y, Zhang S, Fan J, Gao Q. Changing epidemiology of hepatocellular carcinoma in Asia. Liver Int 2022; 42:2029-2041. [PMID: 35319165 DOI: 10.1111/liv.15251] [Citation(s) in RCA: 173] [Impact Index Per Article: 57.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/06/2021] [Accepted: 03/19/2022] [Indexed: 12/24/2022]
Abstract
Liver cancer is the fifth most common cancer and the second leading cause of malignant death in Asia, and Asia reports 72.5% of the world's cases in 2020. As the most common histological type, hepatocellular carcinoma (HCC) accounts for the majority of incidence and mortality of liver cancer cases. This review presents the changing epidemiology of HCC in Asian countries in recent years. Globally, aged, male and Asian populations remain the group with the highest risk of HCC. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are still the leading risk factors of HCC with a slight decline in most Asian countries, which is mainly attributed to HBV vaccination of newborns, prevention of HCV horizontal transmission and treatment of chronic hepatitis. However, the prevalence of HCC caused by metabolic factors, including metabolic syndrome, obesity and non-alcoholic fatty liver diseases, is increasing rapidly in Asian countries, which may eventually become the major cause of HCC. Excessive alcohol consumption continues to be an important risk factor as the average consumption of alcohol is still growing. Hopefully, great effort has been made to better prevention and treatment of HCC in most Asian regions, which significantly prolongs the survival of HCC patients. Asian countries tend to use more aggressive intervention than European and American countries, but it remains unclear whether this preference is related to a better prognosis. In conclusion, HCC remains a major disease burden in Asia, and the management of HCC should be adjusted dynamically based on the changing epidemiology.
Collapse
Affiliation(s)
- Chen-Hao Zhang
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Yifei Cheng
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Shu Zhang
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Qiang Gao
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.,Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| |
Collapse
|
|
41
|
Suhail M, Sohrab SS, Kamal M, Azhar EI. Role of hepatitis c virus in hepatocellular carcinoma and neurological disorders: an overview. Front Oncol 2022; 12:913231. [PMID: 35965577 PMCID: PMC9372299 DOI: 10.3389/fonc.2022.913231] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 06/28/2022] [Indexed: 11/13/2022] Open
Abstract
The hepatitis C virus (HCV) causes serious issues, affecting 71 million people globally. The most common manifestations range from chronic hepatitis to liver cirrhosis, leading to hepatocellular carcinoma. Many mechanisms are known to play an important role in HCV-induced HCC. The interaction of viral proteins with host cells results in oxidative stress damage, liver inflammation, and irregularities in signaling pathways. These results in the activation of oncogenes and metabolic disturbances, liver fibrosis, and angiogenesis. Additionally, some non-coding RNAs (ncRNAs) and toll-like receptors have been identified and play a significant role in HCC development. This virus is also associated with impairment of the central nervous system, resulting in acute or sub-acute encephalopathy and inflammatory disorders. Neurological disorders are associated with the inflammatory responses of many cells, including microglia and astrocytes. Additionally, there are many other extrahepatic manifestations, including neurological disorders such as depression and fatigue, in 50% of infected patients. These manifestations include neuro-invasion, immune-mediated damage, neurotransmitter alterations, sensory-motor polyneuropathy, sensitivity loss, weakness of the leg, and cryoglobulinemia, which significantly results in a reduced quality of life. HCV infection may be improved using an appropriate diagnosis and direct antiviral therapy for sustained virological response. However, the success of therapy depends on the symptoms and organ damage, diagnosis, and therapeutic strategies applied. Some published reports have discussed that HCV is associated with both HCC and neurological disorders. Additionally, it has also been observed that individuals with HCC also develop neurological disorders compared with individuals with HCV alone. This review aims to provide an overview of the latest information about the relationship between HCV-induced HCC and their role in neurological disorders. Additionally, we have also discussed the progress made in the diagnosis, physio-pathological mechanisms, and strong antiviral therapies developed for HCV infection and HCC, as well as the latest advancements made in the study of the neurological disorders associated with HCV infection.
Collapse
Affiliation(s)
- Mohd Suhail
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sayed Sartaj Sohrab
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- *Correspondence: Sayed Sartaj Sohrab,
| | - Mohammad Amjad Kamal
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- West China School of Nursing/Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- Enzymoics Novel Global Community Educational Foundation, Hebersham, NSW, Australia
| | - Esam Ibraheem Azhar
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| |
Collapse
|
|
42
|
Merola E, Menotti E, Branz G, Michielan A, Seligmann S, Ratti A, Agugiaro F, Moser L, Vettori G, Franceschini A, Mantovani W, Pertile R, de Pretis G, Pravadelli C. Hepatitis C virus burden: Treating and educating people without prejudice. World J Hepatol 2022; 14:1495-1503. [PMID: 36158919 PMCID: PMC9376782 DOI: 10.4254/wjh.v14.i7.1495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 05/26/2022] [Accepted: 06/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) infection has a worldwide incidence of 1.1%. In Italy, 60% of people who inject drugs (PWIDs) and are receiving assistance for substance use disorder are infected with HCV. However, this subset of patients has extremely limited access to care due to multiple factors, including alcohol abuse, psychological comorbidities, and homeless status. AIM To describe the impact of our HCV-dedicated service for substance use disorder (SSUD) service on PWIDs receiving anti-HCV therapy. METHODS A dedicated, multidisciplinary team was set up at the SSUD of Trento in October 2020 to provide antiviral treatment to HCV RiboNucleic Acid-positive patients with an active or previous history of substance abuse. The treatment was followed by a health education program. Patients were treated with Direct-Acting Antivirals (DAAs). Data were retrospectively analyzed to assess the efficacy of our dedicated program in terms of therapy completion, HCV eradication, and compliance (primary endpoint). The rate of HCV reinfection and DAA-related toxicity were also assessed (secondary endpoints). RESULTS A total of 40 patients were enrolled in the study: 28 (70.0%) were treated with Sofosbuvir/Velpatasvir, while 12 (30.0%) received Glecaprevir/Pibrentasvir. At the time of inclusion in the study, 36 patients were receiving opioid agonist maintenance therapy, whilst another 4 had just finished the treatment. 37.5% had a history of alcoholism and 42.5% received concomitant psychiatric treatment. All 40 patients (100.0%) completed the therapy cycle and 92.5% of patients adhered to the program. All patients tested negative for viral load at the end of the treatment. There were no significant drug interactions with common psychiatric treatments and no side effects were observed. The sustained virological response was achieved in 92.5% of cases with good tolerability, although two patients discontinued treatment temporarily. After HCV eradication, one patient died from an overdose, another from complications of cirrhosis, and one reinfection occurred. CONCLUSION Very high adherence to therapy and good tolerability was observed in our series of HCV patients treated at the SSUD, regardless of the substance abuse condition. Further validation in a larger population is required.
Collapse
Affiliation(s)
- Elettra Merola
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale Per I Servizi Sanitari (APSS), Trento 38122, Italy
| | - Elisa Menotti
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale Per I Servizi Sanitari (APSS), Trento 38122, Italy
| | - Giovanna Branz
- Department of SerD, Service for Drug Addiction, Azienda Provinciale Per I Servizi Sanitari (APSS), Trento 38122, Italy
| | - Andrea Michielan
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale Per I Servizi Sanitari (APSS), Trento 38122, Italy.
| | - Sonia Seligmann
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale Per I Servizi Sanitari (APSS), Trento 38122, Italy
| | - Annora Ratti
- Department of SerD, Service for Drug Addiction, Azienda Provinciale Per I Servizi Sanitari (APSS), Trento 38122, Italy
| | - Flora Agugiaro
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale Per I Servizi Sanitari (APSS), Trento 38122, Italy
| | - Luisa Moser
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale Per I Servizi Sanitari (APSS), Trento 38122, Italy
| | - Giovanni Vettori
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale Per I Servizi Sanitari (APSS), Trento 38122, Italy
| | - Anna Franceschini
- Department of SerD, Service for Drug Addiction, Azienda Provinciale Per I Servizi Sanitari (APSS), Trento 38122, Italy
| | - William Mantovani
- Department of Prevention, Azienda Provinciale Per I Servizi Sanitari (APSS), Trento 38122, Italy
| | - Riccardo Pertile
- Department of Clinical and Evaluative Epidemiology, Azienda Provinciale Per I Servizi Sanitari (APSS), Trento 38122, Italy
| | - Giovanni de Pretis
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale Per I Servizi Sanitari (APSS), Trento 38122, Italy
| | - Cecilia Pravadelli
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale Per I Servizi Sanitari (APSS), Trento 38122, Italy
| |
Collapse
|
|
43
|
Merola E, Menotti E, Branz G, Michielan A, Seligmann S, Ratti A, Agugiaro F, Moser L, Vettori G, Franceschini A, Mantovani W, Pertile R, de Pretis G, Pravadelli C. Hepatitis C virus burden: Treating and educating people without prejudice. World J Hepatol 2022; 14:1495-1503. [DOI: - merola e, menotti e, branz g, et al.hepatitis c virus burden: treating and educating people without prejudice.world j hepatol.2022 jul 27;14(7):1495-1503.doi: 10.4254/wjh.v14.i7.1495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/16/2025] Open
|
|
44
|
hsa-miR-9-5p-Mediated TSPAN9 Downregulation Is Positively Related to Both Poor Hepatocellular Carcinoma Prognosis and the Tumor Immune Infiltration. J Immunol Res 2022; 2022:9051229. [PMID: 35600044 PMCID: PMC9119760 DOI: 10.1155/2022/9051229] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/16/2022] [Indexed: 12/24/2022] Open
Abstract
Tetraspanins (TSPANs) play crucial roles in cell adhesion, migration, and metastasis of human cancer. However, there is no study in revealing the aspects of TSPAN9 traits and its functions in hepatocellular carcinoma (HCC) prognosis. Our study is the first to portray the TSPAN9 expression in HCC tissues with immunohistochemistry (IHC) analysis. Subsequently, a series of bioinformatics analyses such as expression estimation, survival assessment, and correlation analysis were implemented to dig out the possible upstream noncoding RNAs (ncRNAs) for TSPAN9 in HCC. In this way, the relevance within TSPAN9 and tumor immunity was then explored. We found that the TSPAN9 was downregulated in HCC tissues and had a correlation with HCC prognosis. Furthermore, we identified that the AL139383.1-hsa-miR-9-5p axis was the upstream ncRNA-related pathway most associated with TSPAN9 in HCC. Besides that, expression of TSPAN9 held a significantly negative correlation with tumor immunocyte infiltration as well as immune checkpoint CTLA4. TSPAN9-related immunomodulators were mainly enriched in T cell activation, leukocyte cell-cell adhesion, regulation of T cell activation, and regulation of leukocyte cell-cell adhesion signaling pathway. In conclusion, our results indicated that hsa-miR-9-5p-mediated downregulation of TSPAN9 was associated with poor HCC prognosis, immune-related signaling pathway, and tumor immune infiltration.
Collapse
|
|
45
|
Dalbeni A, Villani R, Bevilacqua M, Sacco F, Faccincani D, Cattazzo F, Cavallone F, Mantovani A, Ceruti V, Ieluzzi D, Paon V, Mantovani A, Serviddio G, Sacerdoti D. Effects of direct-acting antiviral agents on lipid and glucose profile in HCV patients with type 2 diabetes: A real-life Italian experience. J Dig Dis 2022; 23:324-330. [PMID: 35700113 DOI: 10.1111/1751-2980.13103] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 06/09/2022] [Accepted: 06/10/2022] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Hepatitis C virus (HCV) infection is associated with an increased risk of type 2 diabetes mellitus (T2DM) and cardiovascular diseases. The impact of HCV eradication on the metabolic profile in diabetic patients treated with direct-acting antiviral agents (DAAs) is not well defined. The aim of our study was to evaluate the effects of DAAs on a lipid and glucose profile in a cohort of diabetic patients with different liver fibrotic stages. METHODS T2DM patients with active HCV infection were consecutively enrolled in this prospective trial. Glycolipidic status was assessed, before starting DAA treatment (T0) and at 12 months after the beginning of treatment (T1). Liver fibrotic stage was assessed by FibroScan. RESULTS In all, 131 patients were enrolled and all of them achieved a sustained virologic response. At baseline, no significant differences were found in lipid and glucose profiles in subgroup analysis by liver fibrosis, HCV genotype, and cardiovascular risk factors. At T1, total cholesterol and low-density lipoprotein cholesterol, but not triglycerides, significantly increased irrespective of liver fibrotic stage and baseline anthropometric and clinical profiles, while glycated hemoglobin significantly decreased only in F4 patients. CONCLUSIONS HCV eradication in diabetic patients is associated with a worsening lipid profile that could impact future cardiovascular risk. A careful global monitoring of cardiovascular risk factors in all diabetic patients after HCV eradication is needed.
Collapse
Affiliation(s)
- Andrea Dalbeni
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.,Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Rosanna Villani
- Liver Unit, Department of Surgical and Medical Sciences, University of Foggia, Foggia, Italy
| | - Michele Bevilacqua
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Federica Sacco
- Liver Unit, Department of Surgical and Medical Sciences, University of Foggia, Foggia, Italy
| | - Diego Faccincani
- Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Filippo Cattazzo
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Francesco Cavallone
- Liver Unit, Department of Surgical and Medical Sciences, University of Foggia, Foggia, Italy
| | - Anna Mantovani
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Vittoria Ceruti
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Donatella Ieluzzi
- Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Veronica Paon
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.,Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Alessandro Mantovani
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Gaetano Serviddio
- Liver Unit, Department of Surgical and Medical Sciences, University of Foggia, Foggia, Italy
| | - David Sacerdoti
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.,Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| |
Collapse
|
|
46
|
Wang H, Zhang Y, Zhou J, Li M, Chen Y, Liu Y, Liu H, Ding P, Liang C, Zhu X, Zhang Y, Xin C, Zhang G, Wang A. Rapid Visual Detection of Hepatitis C Virus Using Reverse Transcription Recombinase-Aided Amplification–Lateral Flow Dipstick. Front Cell Infect Microbiol 2022; 12:816238. [PMID: 35252031 PMCID: PMC8892114 DOI: 10.3389/fcimb.2022.816238] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/17/2022] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a global public health threat. Reaching the World Health Organization’s objective for eliminating viral hepatitis by 2030 will require a precise disease diagnosis. While immunoassays and qPCR play a significant role in detecting HCV, rapid and accurate point-of-care testing is important for pathogen identification. This study establishes a reverse transcription recombinase-aided amplification–lateral flow dipstick (RT-RAA-LFD) assay to detect HCV. The intact workflow was completed within 30 min, and the detection limit for synthesized C/E1 plasmid gene-containing plasmid was 10 copies/μl. In addition, the test showed good specificity, with no cross-reactivity observed for hepatitis A virus, hepatitis B virus, HIV, syphilis, and human papillomavirus virus. Using extracted RNAs from 46 anti-HCV antibody-positive samples, RT-RAA-LFD showed 100% positive and negative concordance rates with qPCR. In summary, the RT-RAA-LFD assay established in this study is suitable for the rapid clinical detection of HCV at the community level and in remote areas.
Collapse
Affiliation(s)
- Haili Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Yuhang Zhang
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, China
| | - Jingming Zhou
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Ming Li
- Henan Key Laboratory of Population Defects Prevention, National Health Commission Key Laboratory of Birth Defects Prevention, Henan Institute of Reproduction Health Science and Technology, Zhengzhou, China
| | - Yumei Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Yankai Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Hongliang Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Peiyang Ding
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Chao Liang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Xifang Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Ying Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Cheng Xin
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Gaiping Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, China
- *Correspondence: Gaiping Zhang, ; Aiping Wang,
| | - Aiping Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
- *Correspondence: Gaiping Zhang, ; Aiping Wang,
| |
Collapse
|
|
47
|
Tahmaz I, Shahmoradi Ghahe S, Topf U. Prefoldin Function in Cellular Protein Homeostasis and Human Diseases. Front Cell Dev Biol 2022; 9:816214. [PMID: 35111762 PMCID: PMC8801880 DOI: 10.3389/fcell.2021.816214] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 12/29/2021] [Indexed: 01/05/2023] Open
Abstract
Cellular functions are largely performed by proteins. Defects in the production, folding, or removal of proteins from the cell lead to perturbations in cellular functions that can result in pathological conditions for the organism. In cells, molecular chaperones are part of a network of surveillance mechanisms that maintains a functional proteome. Chaperones are involved in the folding of newly synthesized polypeptides and assist in refolding misfolded proteins and guiding proteins for degradation. The present review focuses on the molecular co-chaperone prefoldin. Its canonical function in eukaryotes involves the transfer of newly synthesized polypeptides of cytoskeletal proteins to the tailless complex polypeptide 1 ring complex (TRiC/CCT) chaperonin which assists folding of the polypeptide chain in an energy-dependent manner. The canonical function of prefoldin is well established, but recent research suggests its broader function in the maintenance of protein homeostasis under physiological and pathological conditions. Interestingly, non-canonical functions were identified for the prefoldin complex and also for its individual subunits. We discuss the latest findings on the prefoldin complex and its subunits in the regulation of transcription and proteasome-dependent protein degradation and its role in neurological diseases, cancer, viral infections and rare anomalies.
Collapse
Affiliation(s)
- Ismail Tahmaz
- Laboratory of Molecular Basis of Aging and Rejuvenation, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Somayeh Shahmoradi Ghahe
- Laboratory of Molecular Basis of Aging and Rejuvenation, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Ulrike Topf
- Laboratory of Molecular Basis of Aging and Rejuvenation, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| |
Collapse
|
|
48
|
Badami E, Carcione C, Chinnici CM, Tinnirello R, Conaldi PG, Iannolo G. HCV Interplay With Mir34a: Implications in Hepatocellular Carcinoma. Front Oncol 2022; 11:803278. [PMID: 35127513 PMCID: PMC8812294 DOI: 10.3389/fonc.2021.803278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/27/2021] [Indexed: 12/24/2022] Open
Abstract
Since its identification, HCV has been considered one of the main causes of hepatitis and liver cancer. Currently, the molecular mechanisms of HCC development induced by HCV infection have not been sufficiently clarified. The recent discovery of novel treatments that inhibit HCV replication gave rise to new questions concerning HCC mechanisms. In particular, the HCV eradication mediated by new direct-acting antiviral (DAAs) drugs does not exclude the possibility of de novo HCC development; this finding opened more questions on the interplay between liver cells and the virus. Different groups have investigated the pathways leading to cancer recurrence in patients treated with DAAs. For this reason, we tried to gain molecular insights into the changes induced by HCV infection in the target liver cells. In particular, we observed an increase in microRNA34a (miR34a) expression following HCV infection of HCC cell line Huh7.5. In addition, Huh7.5 treated with extracellular vesicles (EVs) from the previously HCV-infected Huh7.5 underwent apoptosis. Since miR34 expression was increased in Huh7.5 EVs, we hypothesized a paracrine mechanism of viral infection mediated by miR34a cargo of EVs. The balance between viral infection and cell transformation may raise some questions on the possible use of antiviral drugs in association with antineoplastic treatment.
Collapse
Affiliation(s)
- Ester Badami
- Department of Research, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS ISMETT), Palermo, Italy
- Regenerative Medicine and Immunotherapy Area, Fondazione Ri.MED, Palermo, Italy
| | - Claudia Carcione
- Regenerative Medicine and Immunotherapy Area, Fondazione Ri.MED, Palermo, Italy
| | - Cinzia Maria Chinnici
- Department of Research, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS ISMETT), Palermo, Italy
- Regenerative Medicine and Immunotherapy Area, Fondazione Ri.MED, Palermo, Italy
| | - Rosaria Tinnirello
- Neuroscience Unit, Consiglio Nazionale delle Ricerche (CNR), Institute of Biomedicine and Molecular Immunology, Palermo, Italy
| | - Pier Giulio Conaldi
- Department of Research, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS ISMETT), Palermo, Italy
| | - Gioacchin Iannolo
- Department of Research, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS ISMETT), Palermo, Italy
- *Correspondence: Gioacchin Iannolo, ; ; orcid.org/0000-0002-7710-4735
| |
Collapse
|
|
49
|
Identification of Immune-Related Prognostic mRNA and lncRNA in Patients with Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2022; 2022:5313149. [PMID: 35027925 PMCID: PMC8752260 DOI: 10.1155/2022/5313149] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 11/19/2021] [Accepted: 11/30/2021] [Indexed: 12/18/2022]
Abstract
Background As the most common hepatic malignancy, hepatocellular carcinoma (HCC) has a high incidence; therefore, in this paper, the immune-related genes were sought as biomarkers in liver cancer. Methods In this study, a differential expression analysis of lncRNA and mRNA in The Cancer Genome Atlas (TCGA) dataset between the HCC group and the normal control group was performed. Enrichment analysis was used to screen immune-related differentially expressed genes. Cox regression analysis and survival analysis were used to determine prognostic genes of HCC, whose expression was detected by molecular experiments. Finally, important immune cells were identified by immune cell infiltration and detected by flow cytometry. Results Compared with the normal group, 1613 differentially expressed mRNAs (DEmRs) and 1237 differentially expressed lncRNAs (DElncRs) were found in HCC. Among them, 143 immune-related DEmRs and 39 immune-related DElncRs were screened out. These genes were mainly related to MAPK cascade, PI3K-AKT signaling pathway, and TGF-beta. Through Cox regression analysis and survival analysis, MMP9, SPP1, HAGLR, LINC02202, and RP11-598F7.3 were finally determined as the potential diagnostic biomarkers for HCC. The gene expression was verified by RT-qPCR and western blot. In addition, CD4 + memory resting T cells and CD8 + T cells were identified as protective factors for overall survival of HCC, and they were found highly expressed in HCC through flow cytometry. Conclusion The study explored the dysregulation mechanism and potential biomarkers of immune-related genes and further identified the influence of immune cells on the prognosis of HCC, providing a theoretical basis for the prognosis prediction and immunotherapy in HCC patients.
Collapse
|
|
50
|
Servin-Rojas M, Tapia-Sosa R, Páez-Zayas VM, Dithurbide-Hernández M, García-Juárez I. Reply to Alexander Ng. Response to Letter to the Editor. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2022; 87:126-127. [PMID: 34996737 DOI: 10.1016/j.rgmxen.2021.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 07/22/2021] [Indexed: 10/19/2022]
Affiliation(s)
- M Servin-Rojas
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - R Tapia-Sosa
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - V M Páez-Zayas
- Departamento de Donación y Trasplantes, Hospital General de México Dr. Eduardo Liceaga, Mexico City, Mexico
| | - M Dithurbide-Hernández
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - I García-Juárez
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
| |
Collapse
|