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Baraka K, Abozahra RR, Badr E, Abdelhamid SM. Study of some potential biomarkers in Egyptian hepatitis C virus patients in relation to liver disease progression and HCC. BMC Cancer 2023; 23:938. [PMID: 37798688 PMCID: PMC10552374 DOI: 10.1186/s12885-023-11420-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 09/19/2023] [Indexed: 10/07/2023] Open
Abstract
BACKGROUND Egypt has the greatest prevalence of hepatitis C worldwide according to the WHO reports, accounting for 13% of the global HCV infections. HCV is a substantial precursor for fibrosis, cirrhosis, and hepatocellular carcinoma. This study aimed to investigate the potential relevance of some cytokines, miR-122 and miR-221 for the diagnosis of liver disease progression associated to HCV infection. METHODS One hundred and twenty blood samples were collected from patients with chronic liver disease, HCC, and healthy individuals. Total bilirubin, alanine aminotransferase, aspartate aminotransferase, platelet count, albumin, and creatinine were measured. Serum level of selected cytokines was conducted by ELISA. Serum miRNA expression was detected by RT-PCR. RESULTS IL-2R was higher among HCC patients and the mean concentration of both TNF-αRII and IL-6R was higher among cirrhotic patients. The expression of miRNA-122 showed a little fold decrease in all studied groups; the highest level was observed in HCC patients. The expression of miRNA-221 showed a significant fold increase in HCC and cirrhotic groups. CONCLUSIONS This study revealed that there is no difference in liver disease progression in patients regarding sex and age. Routine liver function tests performed poorly in terms of early diagnosis of liver disease progression; however, serum total bilirubin gave somewhat useful guide for discrimination between fibrotic, cirrhotic and HCC cases. IL-2R showed a significant consistent increase in its level with disease progression. The miR-221 serum level showed significant fold increase with liver disease progression. Therefore, making miR-221 a potential non-invasive biomarker for liver disease progression in the diagnostic setting is recommended.
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Affiliation(s)
- Kholoud Baraka
- Microbiology and Immunology Department, Faculty of Pharmacy, Damanhour University, El Gomhoreya Street, Damanhour, El Behira Egypt
| | - Rania R. Abozahra
- Microbiology and Immunology Department, Faculty of Pharmacy, Damanhour University, El Gomhoreya Street, Damanhour, El Behira Egypt
| | - Eman Badr
- Microbiology and Immunology Department, Faculty of Pharmacy, Damanhour University, El Gomhoreya Street, Damanhour, El Behira Egypt
| | - Sarah M. Abdelhamid
- Microbiology and Immunology Department, Faculty of Pharmacy, Damanhour University, El Gomhoreya Street, Damanhour, El Behira Egypt
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2
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Zarkasi KA, Abdullah N, Abdul Murad NA, Ahmad N, Jamal R. Genetic Factors for Coronary Heart Disease and Their Mechanisms: A Meta-Analysis and Comprehensive Review of Common Variants from Genome-Wide Association Studies. Diagnostics (Basel) 2022; 12:2561. [PMID: 36292250 PMCID: PMC9601486 DOI: 10.3390/diagnostics12102561] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/18/2022] [Accepted: 10/20/2022] [Indexed: 11/17/2022] Open
Abstract
Genome-wide association studies (GWAS) have discovered 163 loci related to coronary heart disease (CHD). Most GWAS have emphasized pathways related to single-nucleotide polymorphisms (SNPs) that reached genome-wide significance in their reports, while identification of CHD pathways based on the combination of all published GWAS involving various ethnicities has yet to be performed. We conducted a systematic search for articles with comprehensive GWAS data in the GWAS Catalog and PubMed, followed by a meta-analysis of the top recurring SNPs from ≥2 different articles using random or fixed-effect models according to Cochran Q and I2 statistics, and pathway enrichment analysis. Meta-analyses showed significance for 265 of 309 recurring SNPs. Enrichment analysis returned 107 significant pathways, including lipoprotein and lipid metabolisms (rs7412, rs6511720, rs11591147, rs1412444, rs11172113, rs11057830, rs4299376), atherogenesis (rs7500448, rs6504218, rs3918226, rs7623687), shared cardiovascular pathways (rs72689147, rs1800449, rs7568458), diabetes-related pathways (rs200787930, rs12146487, rs6129767), hepatitis C virus infection/hepatocellular carcinoma (rs73045269/rs8108632, rs56062135, rs188378669, rs4845625, rs11838776), and miR-29b-3p pathways (rs116843064, rs11617955, rs146092501, rs11838776, rs73045269/rs8108632). In this meta-analysis, the identification of various genetic factors and their associated pathways associated with CHD denotes the complexity of the disease. This provides an opportunity for the future development of novel CHD genetic risk scores relevant to personalized and precision medicine.
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Affiliation(s)
- Khairul Anwar Zarkasi
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia
- Biochemistry Unit, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (UPNM), Kuala Lumpur 57000, Malaysia
| | - Noraidatulakma Abdullah
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia
- Faculty of Health Sciences, Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 50300, Malaysia
| | - Nor Azian Abdul Murad
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia
| | - Norfazilah Ahmad
- Epidemiology and Statistics Unit, Department of Community Health, Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia
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Mabrouk AA, Eltablawy NA, El-Allawy RM, Abdel Maksoud H, Elsenosi YA. The ameliorating effect of Terminalia muelleri extract on oxidative stress–related factors in induced hepatocellular carcinoma rat model. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2021.101482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Naga IS, Kamel AAF, Ooda SA, Elbab HMF, El-Sharkawy RM. Effect of directly acting anti-viral agents on immunological imprints in chronic HCV-4a patients: interleukin-10 and vascular endothelial growth factor genes expression level. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00108-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Hepatitis C virus infection is a global health challenge with Egypt being one of the highly affected countries. IL-10 has been suggested as a suitable marker to assess necroinflammation and to monitor the progression of liver damage. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor playing a central role in many physiological as well as pathological processes. Several factors can be predictive of the response to treatment and achievement of SVR; some of which are host-related, and others are virus-related. The gene expression of IL-10 and VEGF have multiple effects for treatment response. The aim of the present work was to study the effect of treatment with directly acting agents (DAA) on the expression of VEGF and IL-10 genes in chronic hepatitis C virus-infected Egyptian genotype-4a patients. Twenty-five HCV subjects where evaluated for IL-10 and VEGF gene expression before and after treatment with DAA.
Results
IL-10 expression was downregulated in 92% of the cases. VEGF expression was heterogeneous showing spreading of values along a wide range with 64% of the cases being downregulated.
Conclusion
DAAs do not completely reverse the immunological imprints established upon chronic HCV infection.
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Babiker A, Hassan M, Muhammed S, Taylor G, Poonia B, Shah A, Bagchi S. Inflammatory and cardiovascular diseases biomarkers in chronic hepatitis C virus infection: A review. Clin Cardiol 2019; 43:222-234. [PMID: 31785111 PMCID: PMC7068107 DOI: 10.1002/clc.23299] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 11/09/2019] [Accepted: 11/12/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infects 180 million people worldwide and over 4 million people in the United States. HCV infection is a major cause of chronic liver disease and is recognized as a risk factor for clinical cardiovascular disease (CVD). Many studies have shown increased prevalence of cardiac and inflammatory biomarkers in patients with chronic HCV infection (CHC), and though these markers may be used to risk stratify people for cardiac disease in the general population their role in the HCV population is unknown. Patients with CHC have elevated cardiac and inflammatory biomarkers compared to noninfected controls which may play a role in CVD risk stratification. We undertook a systematic review of inflammatory and cardiac biomarkers in people with HCV infection with a focus on the effect of CHC on serum levels of these markers and their utility as predictors of CVD in this population. Medline, EMBASE, and Cochrane databases were searched for relevant articles until June 2019. A total of 2430 results were reviewed with 115 studies included. Our review revealed that HCV infection significantly alters serum levels of markers of inflammation, endothelial function, and cardiac dysfunction prior to HCV treatment, and some of which may change in response to HCV therapy. Current risk stratification tools for development of CVD in the general population may not account for the increased inflammatory markers that appear to be elevated among HCV‐infected patients contributing to increased CVD risk.
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Affiliation(s)
- Ahmed Babiker
- Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Mohamed Hassan
- Division of General Internal Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Safwan Muhammed
- Department of Medicine, University of Maryland Medical Center, Baltimore, Maryland.,Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Gregory Taylor
- Department of Family Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Bhawna Poonia
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Anoop Shah
- Division of Cardiology, University of Edinburgh, Little France, Edinburgh
| | - Shashwatee Bagchi
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland.,Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, Maryland
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Hatab HM, Abdel Hamid FF, Soliman AF, Al-Shafie TA, Ismail YM, El-Houseini ME. A combined treatment of curcumin, piperine, and taurine alters the circulating levels of IL-10 and miR-21 in hepatocellular carcinoma patients: a pilot study. J Gastrointest Oncol 2019; 10:766-776. [PMID: 31392057 PMCID: PMC6657326 DOI: 10.21037/jgo.2019.03.07] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 03/14/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Investigating and evaluating possible alternative therapeutic strategies to control hepatocellular carcinoma (HCC) is a critical need because of its high prevalence and being one of the most lethal cancers. Curcumin and taurine showed potent anti-tumor activities in pre-clinical and clinical studies by targeting multiple pathways. Thus, this study was designed to assess the effect of a combined treatment consisted of curcumin, piperine, and taurine on circulating levels of interleukin-10 (IL-10), and microRNAs miR-141 and miR-21. METHODS Twenty eligible HCC patients administrated an oral dose of 4 g curcumin, 40 mg piperine, and 500 mg taurine daily for three successive treatment cycles, each was a 30-day. The level of IL-10 along with the expression levels of miR-141, and miR-21 were monitored in serum before starting the treatment and after each cycle. Patients were followed-up for a period of 24 months. RESULTS The combined treatment was able to produce a significant decrease in the levels of serum IL-10, and miR-21 while it resulted in a non-significant up-regulation of serum miR-141 expression level. At the end of the follow-up period, the median overall survival (OS) rate was found to be 17.00 months with a worse OS in patients with high baseline levels of circulating IL-10 and miR-21 compared to those with low levels. In contrast, a low baseline level of circulating miR-141 was associated with poor prognosis. CONCLUSIONS The combined treatment may be able to increase the OS rate by altering the circulating level of IL-10 and miR-21.
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Affiliation(s)
- Hala M. Hatab
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | | | - Ahmed F. Soliman
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Tamer A. Al-Shafie
- Pharmacology and Therapeutics Department, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Alexandria, Egypt
| | - Yahia M. Ismail
- Medical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Motawa E. El-Houseini
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
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El-Fakharany EM, El-Baky NA, Linjawi MH, Aljaddawi AA, Saleem TH, Nassar AY, Osman A, Redwan EM. Influence of camel milk on the hepatitis C virus burden of infected patients. Exp Ther Med 2017; 13:1313-1320. [PMID: 28413471 PMCID: PMC5377298 DOI: 10.3892/etm.2017.4159] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 12/12/2016] [Indexed: 12/18/2022] Open
Abstract
Hepatitis C virus (HCV) infection represents a world health problem and no protective vaccine or effective drug currently exists. For economic reasons, many patients use traditional medicines to control the infection. In Egypt, camel milk is one of the traditional medicines widely consumed by patients infected with HCV. The present study aimed to evaluate the efficacy of camel milk in the treatment of patients infected with HCV. Whole camel milk from a local farm was administered to patients for 4 months (250 ml/day/patient). Patient sera were collected prior to and following camel milk drinking, and three markers were set-up for sera-evaluation. The three markers indicating the effect of camel milk on HCV infection were: Liver function assays [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)]; a viral load assay; and anti-HCV antibodies profile and isotyping against synthetic HCV epitopes. Camel milk demonstrated the ability to improve general fatigue, health and liver function (ALT and AST levels); ALT was reduced in ~88% of patients and AST was reduced in all patients subsequent to drinking camel milk for four months. The majority of patients responded positively to camel milk treatment; RNA viral load decreased in 13 out of the 17 patients (76.47%) and one patient exhibited undetected viremia following camel milk treatment. The anti-HCV antibodies profile and isotyping were significantly decreased (P<0.05) in immunoglobulin (Ig)G1 following treatment in 70-76% of patients. However, the treatment was ineffective in 23.53% of patients who experienced no reduction in RNA viral load following treatment with camel milk. In conclusion, whole camel milk treatment demonstrated efficacy in vivo; the viral load in the majority of patient sera was reduced and the IgG isotype profile was converted to Th1 immunity.
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Affiliation(s)
- Esmail Mohamad El-Fakharany
- Protective and Therapeutic Protein Laboratory, Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, New Borg El-Arab, Alexandria 21394, Egypt
| | - Nawal Abd El-Baky
- Protective and Therapeutic Protein Laboratory, Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, New Borg El-Arab, Alexandria 21394, Egypt
| | - Mustafa Hassan Linjawi
- Department of Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Makkah 21589, Saudi Arabia
| | | | - Tahya Hussein Saleem
- Department of Biochemistry, Faculty of Medicine, Assiut University, Assiut 71511, Egypt
| | - Ahmed Yassine Nassar
- Department of Biochemistry, Faculty of Medicine, Assiut University, Assiut 71511, Egypt
| | - Ashraf Osman
- Department of Tropical Medicine, Faculty of Medicine, Assiut University, Assiut 71511, Egypt
| | - Elrashdy Moustafa Redwan
- Protective and Therapeutic Protein Laboratory, Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, New Borg El-Arab, Alexandria 21394, Egypt
- Biological Sciences Department, Faculty of Science, King Abdulaziz University, Jeddah, Makkah 21589, Saudi Arabia
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Motawi T, Shaker OG, Hussein RM, Houssen M. Polymorphisms of α1-antitrypsin and Interleukin-6 genes and the progression of hepatic cirrhosis in patients with a hepatitis C virus infection. Balkan J Med Genet 2017; 19:35-44. [PMID: 28289587 PMCID: PMC5343329 DOI: 10.1515/bjmg-2016-0034] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Hepatitis C virus (HCV) infection represents a serious health problem. The –174 G/C mutation in the pro inflammatory cytokine interleukin-6 (IL-6) is associated with developing liver diseases. Likewise, the S and Z mutations in the serine protease inhibitor α1-antitrypsin (A1AT) are associated with pulmonary emphysema and/or liver cirrhosis. We explored the distribution of the single nucleotide polymorphisms (SNPs) of IL-6 and A1AT genes in chronic HCV-infected patients and evaluated their impact on the progression of liver cirrhosis. One hundred and fifty Egyptian HCV-infected patients together with 100 healthy controls were enrolled in this study. The patient groups were subdivided into chronic hepatitis patients (n = 85) and cirrhotic patients (n = 65). The SNP of IL-6 (–174 G/C, rs1800795), A1AT Z mutation (342 Glu/Lys, rs28929474) and A1AT S mutation (264 Glu/Val, rs17580) were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Cirrhotic patients exhibited significantly increased frequency of the A1AT S allele compared with the controls (34.6 vs. 5.0%), while the chronic hepatitis patients showed a higher frequency of the A1AT Z allele compared with the controls (14.7 vs. 2.5%). Remarkably, IL-6 (CC genotype) was detected only in the chronic hepatitis patients. Multivariate regression analysis showed that aspartate transaminase (AST) and the S alleles of A1AT, represented as SS+MS genotypes, were significantly independent predictors for development of liver cirrhosis. We concluded that inheritance of deficient S and Z alleles of the A1AT gene but not IL-6 (–174 G/C), were associated with progressive liver diseases.
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Affiliation(s)
- T Motawi
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - O G Shaker
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - R M Hussein
- Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - M Houssen
- Department of Biochemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt
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9
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Bader El Din NG, Farouk S, El-Shenawy R, Elhady MM, Ibrahim MK, Dawood RM, Salem AM, El Awady MK. The Synergistic Effect of TNFα -308 G/A and TGFβ1 -509 C/T Polymorphisms on Hepatic Fibrosis Progression in Hepatitis C Virus Genotype 4 Patients. Viral Immunol 2017; 30:127-135. [PMID: 28151059 DOI: 10.1089/vim.2016.0083] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Tumor necrosis factor-alpha (TNFα) and transforming growth factor-beta (TGFβ1) cytokines are highly implicated in liver fibrosis. Polymorphisms in these cytokines affect their expression, secretion, and activity. This study aimed to evaluate the influence of TNFα -308 G/A and TGFβ1 -509 C/T polymorphism on hepatic fibrosis progression in Egyptian patients with hepatitis C virus (HCV) genotype 4. Genotyping of TNFα -308 G/A and TGFβ1 -509 C/T was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 122 subjects (50 healthy controls and 72 HCV patients). Also, serum TNFα and TGFβ1 levels were detected by enzyme-linked immunosorbent assay (ELISA). The genotyping results of early (F0-F1, n = 36) and late (F2-F4, n = 36) HCV fibrosis patients showed that late fibrosis patients had higher TNFα -308 AA genotype and TGFβ1 -509 TT genotype than early fibrosis patients (p = 0.016, 0.028, respectively). Moreover, the TNFα and TGFβ1 serum levels were significantly higher in HCV patients with TNFα A containing genotypes (GA+AA) (p = 0.004) and patients with TGFβ1 T containing genotypes (CT+TT) (p = 0.001), respectively. The combined unfavorable TNFα (GA/AA) and TGFβ1 (CT/TT) genotypes were highly associated with abnormal liver function parameters and were significantly higher in high activity (A2-A3) and late fibrosis (F2-F4) HCV patients (p = 0.023, 0.029). The multivariate analysis results confirmed that the combined TNFα-308 (AA) and TGFβ1 -509 (TT) unfavorable genotypes increased the risk of hepatic fibrosis progression by 6.4-fold than combined favorable genotypes (odds ratio: 6.417, 95% confidence interval [1.490-27.641], p = 0.013). In conclusion, both TNFα -308 G/A and TGFβ1 -509 C/T polymorphisms synergistically influence the hepatic fibrosis progression and can be used as potential biomarkers to predict hepatic disease progression in chronic hepatitis C patients.
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Affiliation(s)
- Noha G Bader El Din
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Sally Farouk
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Reem El-Shenawy
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Mostafa M Elhady
- 2 Department of Biochemistry, Faculty of Science, Ain Shams University , Cairo, Egypt
| | - Marwa K Ibrahim
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Reham M Dawood
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Ahmed M Salem
- 2 Department of Biochemistry, Faculty of Science, Ain Shams University , Cairo, Egypt
| | - Mostafa K El Awady
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
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Tuttolomondo A, Di Raimondo D, Bellia C, Clemente G, Pecoraro R, Maida C, Simonetta I, Vassallo V, Di Bona D, Gulotta E, Ciaccio M, Pinto A. Immune-Inflammatory and Metabolic Effects of High Dose Furosemide plus Hypertonic Saline Solution (HSS) Treatment in Cirrhotic Subjects with Refractory Ascites. PLoS One 2016; 11:e0165443. [PMID: 27941973 PMCID: PMC5152809 DOI: 10.1371/journal.pone.0165443] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 10/07/2016] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Patients with chronic liver diseases are usually thin as a result of hypermetabolism and malnutrition expressed by reduced levels of leptin and impairment of other adyponectins such as visfatin. AIMS We evaluated the metabolic and inflammatory effects of intravenous high-dose furosemide plus hypertonic saline solutions (HSS) compared with repeated paracentesis and a standard oral diuretic schedule, in patients with cirrhosis and refractory ascites. METHODS 59 consecutive cirrhotic patients with refractory ascites unresponsive to outpatient treatment. Enrolled subjects were randomized to treatment with intravenous infusion of furosemide (125-250mg⁄bid) plus small volumes of HSS from the first day after admission until 3 days before discharge (Group A, n:38), or repeated paracentesis from the first day after admission until 3 days before discharge (Group B, n: 21). Plasma levels of ANP, BNP, Leptin, visfatin, IL-1β, TNF-a, IL-6 were measured before and after the two type of treatment. RESULTS Subjects in group A were observed to have a significant reduction of serum levels of TNF-α, IL-1β, IL-6, ANP, BNP, and visfatin, thus regarding primary efficacy endpoints, in Group A vs. Group B we observed higher Δ-TNF-α, Δ-IL-1β, Δ-IL-6, Δ-ANP, Δ-BNP, Δ-visfatin, Δ-Leptin at discharge. DISCUSSION Our findings underline the possible inflammatory and metabolic effect of saline overload correction in treatment of cirrhosis complications such as refractory ascites, suggesting a possible role of inflammatory and metabolic-nutritional variables as severity markers in these patients.
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Affiliation(s)
- Antonino Tuttolomondo
- U.O.C di Medicina Interna e con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università degli Studi di Palermo (Italy)
| | - Domenico Di Raimondo
- U.O.C di Medicina Interna e con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università degli Studi di Palermo (Italy)
| | - Chiara Bellia
- Sezione di Biochimica Clinica e Medicina Molecolare Clinica, Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università degli Studi di Palermo U.O.C. CoreLab, Azienda Ospedaliera Universitaria Policlinico, Palermo, Italy
| | - Giuseppe Clemente
- U.O.C di Medicina Interna e con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università degli Studi di Palermo (Italy)
| | - Rosaria Pecoraro
- U.O.C di Medicina Interna e con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università degli Studi di Palermo (Italy)
| | - Carlo Maida
- U.O.C di Medicina Interna e con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università degli Studi di Palermo (Italy)
| | - Irene Simonetta
- U.O.C di Medicina Interna e con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università degli Studi di Palermo (Italy)
| | - Valerio Vassallo
- U.O.C di Medicina Interna e con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università degli Studi di Palermo (Italy)
| | - Danilo Di Bona
- School and Chair of Allergology, Dipartimento delle Emergenze e Trapianti d'Organo, University of Bari, Italy
| | - Eliana Gulotta
- Dipartimento di Chirurgia Generale e d'Urgenza, Policlinico Universitario "Paolo Giaccone, University of Palermo, Italy
| | - Marcello Ciaccio
- Sezione di Biochimica Clinica e Medicina Molecolare Clinica, Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università degli Studi di Palermo U.O.C. CoreLab, Azienda Ospedaliera Universitaria Policlinico, Palermo, Italy
| | - Antonio Pinto
- U.O.C di Medicina Interna e con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università degli Studi di Palermo (Italy)
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11
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Nasr MY, Ali Deeb AS, Badra G, El Sayed IH. Lack of Any Relationship Between Circulating Autoantibodies and Interleukin–6 Levels in Egyptian Patients Infected with the Hepatitis C Virus. Asian Pac J Cancer Prev 2016; 17:4977-4979. [PMID: 28032726 PMCID: PMC5454706 DOI: 10.22034/apjcp.2016.17.11.4977] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Introduction: Elevated serum interleukin (IL) 6 has been reported in patients infected with the hepatitis C virus (HCV), but it remains debatable whether this influences the production of autoantibodies and the biochemical profile of HCV disease. Therefore, this current study was conducted to evaluate the relationship between IL-6 and circulating autoantibody levels in HCV positive patients. Methods: Levels of IL-6 in serum samples from 102 patients with HCV and 103 normal controls were determined by enzyme linked immunosorbent assay (ELISA). Autoantibodies were detected by immunofluorescence. Results: Levels of IL-6 were significantly higher (p=0.028) in patients infected with (HCV) compared with normal group. Autoantibodies were noted in in 43.1% of the patients; of these, 23.5% featured anti-nuclear antibodies (ANA+), 16.7% anti-smooth muscle antibodies (ASMA+), 7.8% anti-mitochondrial antibodies (AMA+), 17.6% anti-parietal cell antibodies (APCA+), 7.8% anti canalicular antibodies, and 2.9% anti reticulin antibodies (ARA+). No patients were found to be positive for anti-brush border antibodies (ABBA) or anti-ribosomal antibodies. (ARiA). No links with IL-6 levels were apparent. Conclusions: IL-6 levels are increased in patients infected with HCV disease and could influence the production of autoantibodies. However, this study did not provide evidence of a specific relationship between IL6 and circulating autoantibodies in such cases.
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Affiliation(s)
- Mohamed Y Nasr
- Molecular Biology department, Genetic Engineering and Biotechnology Research Institute, Sadat City University,Egypt.
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Liu J, Wang L, Wang W, Li Y, Jia X, Zhai S, Shi J, Dang S. Application of network construction to estimate functional changes to insulin receptor substrates 1 and 2 in Huh7 cells following infection with the hepatitis C virus. Mol Med Rep 2016; 14:2379-2388. [PMID: 27432476 PMCID: PMC4991679 DOI: 10.3892/mmr.2016.5527] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 05/03/2016] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) is closely associated with insulin resistance (IS), acting primarily by interfering with insulin signaling pathways, increasing cytokine-mediated (tumor necrosis factor α, interleukin 6) inflammatory responses and enhancing oxidative stress. In the insulin signaling pathways, the insulin receptor substrate (IRS) is one of the key regulatory factors. The present study constructed gene regulatory sub‑networks specific for IRS1 and IRS2 in Huh7 cells and HCV‑infected Huh7 (HCV‑Huh7) cells using linear programming and a decomposition algorithm, and investigated the possible mechanisms underlying the function of IRS1/2 in HCV‑induced IS in Huh7 cells. All data were obtained from GSE20948 of the Gene Expression Omnibus database from the National Center for Biotechnology Information. Genes which were significantly differentially expressed between Huh7 and HCV‑Huh7 cells were analyzed using the significance analysis of microarray algorithm. The top 50 genes, including IRS1/2, were used as target genes to determine the gene regulatory networks and next the sub‑networks of IRS1 and IRS2 in HCV‑Huh7 and Huh7 cells using Gene Regulatory Network Inference Tool, an algorithm based on linear programming and the decomposition process. The IRS1/2 sub‑networks were divided into upstream/downstream groups and activation/suppression clusters, and were further analyzed using Molecule Annotation System 3.0 and Database for Annotation, Visualization, and Integrated Discovery software, two online platforms for enrichment and clustering analysis and visualization. The results indicated that in Huh7 cells, the downstream network of IRS2 is more complex than that of IRS1, indicating that the insulin metabolism in Huh7 cells may be primarily mediated by IRS2. In HCV‑Huh7 cells, the downstream pathway of IRS2 is blocked, suggesting that this may be the underlying mechanism in HCV infection that leads to insulin resistance. The present findings add a further dimension to the understanding of the pathological mechanisms of HCV infection-associated insulin resistance, and provide novel concepts for insulin resistance and glucose metabolism research.
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Affiliation(s)
- Jingkun Liu
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004
| | - Linbang Wang
- The First Clinical Department, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Wenjun Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004
| | - Yaping Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004
| | - Xiaoli Jia
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004
| | - Song Zhai
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004
| | - Juan Shi
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004
| | - Shuangsuo Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004
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Tomer S, Chawla YK, Duseja A, Arora SK. Dominating expression of negative regulatory factors downmodulates major histocompatibility complex Class-II expression on dendritic cells in chronic hepatitis C infection. World J Gastroenterol 2016; 22:5173-82. [PMID: 27298560 PMCID: PMC4893464 DOI: 10.3748/wjg.v22.i22.5173] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 04/26/2016] [Accepted: 05/04/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To elucidate the molecular mechanisms leading to development of functionally impaired dendritic cells (DCs) in chronic hepatitis C (CHC) patients infected with genotype 3 virus. METHODS This prospective study was conducted on the cohorts of CHC individuals identified as responders or non-responders to antiviral therapy. Myeloid DCs were isolated from the peripheral blood of each subject using CD1c (BDCA1)(+) DC isolation Kit. Monocytes from healthy donor were cultured with DC growth factors such as IL-4 and GM-CSF either in the presence or absence of hepatitis C virus (HCV) viral proteins followed by LPS stimulation. Phenotyping was done by flowcytometry and gene expression profiling was evaluated by real-time PCR. RESULTS Non-responders [sustained virological response (SVR)-ve] to conventional antiviral therapy had significantly higher expression of genes associated with interferon responsive element such as IDO1 and PD-L1 (6-fold) and negative regulators of JAK-STAT pathway such as SOCS (6-fold) as compared to responders (SVR+ve) to antiviral therapy. The down-regulated genes in non-responders included factors involved in antigen processing and presentation mainly belonging to major histocompatibility complex (MHC) Class-II family as HLA-DP, HLA-DQ (2-fold) and superoxide dismutase (2-fold). Cells grown in the presence of HCV viral proteins had genes down-regulated for factors involved in innate response, interferon signaling, DC maturation and co-stimulatory signaling to T-cells, while the genes for cytokine signaling and Toll-like receptors (4-fold) were up-regulated as compared to cells grown in absence of viral proteins. CONCLUSION Underexpressed MHC class-II genes and upregulated negative regulators in non-responders indicate diminished capacity to present antigen and may constitute mechanism of functionally defective state of DCs.
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Zekri ARN, Youssef ASED, Bakr YM, Gabr RM, Ahmed OS, Elberry MH, Mayla AM, Abouelhoda M, Bahnassy AA. Early detection of hepatocellular carcinoma co-occurring with hepatitis C virus infection: A mathematical model. World J Gastroenterol 2016; 22:4168-4182. [PMID: 27122667 PMCID: PMC4837434 DOI: 10.3748/wjg.v22.i16.4168] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 02/16/2016] [Accepted: 03/02/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To develop a mathematical model for the early detection of hepatocellular carcinoma (HCC) with a panel of serum proteins in combination with α-fetoprotein (AFP).
METHODS: Serum levels of interleukin (IL)-8, soluble intercellular adhesion molecule-1 (sICAM-1), soluble tumor necrosis factor receptor II (sTNF-RII), proteasome, and β-catenin were measured in 479 subjects categorized into four groups: (1) HCC concurrent with hepatitis C virus (HCV) infection (n = 192); (2) HCV related liver cirrhosis (LC) (n = 96); (3) Chronic hepatitis C (CHC) (n = 96); and (4) Healthy controls (n = 95). The R package and different modules for binary and multi-class classifiers based on generalized linear models were used to model the data. Predictive power was used to evaluate the performance of the model. Receiver operating characteristic curve analysis over pairs of groups was used to identify the best cutoffs differentiating the different groups.
RESULTS: We revealed mathematical models, based on a binary classifier, made up of a unique panel of serum proteins that improved the individual performance of AFP in discriminating HCC patients from patients with chronic liver disease either with or without cirrhosis. We discriminated the HCC group from the cirrhotic liver group using a mathematical model (-11.3 + 7.38 × Prot + 0.00108 × sICAM + 0.2574 ×β-catenin + 0.01597 × AFP) with a cutoff of 0.6552, which achieved 98.8% specificity and 89.1% sensitivity. For the discrimination of the HCC group from the CHC group, we used a mathematical model [-10.40 + 1.416 × proteasome + 0.002024 × IL + 0.004096 × sICAM-1 + (4.251 × 10-4) × sTNF + 0.02567 ×β-catenin + 0.02442 × AFP] with a cutoff 0.744 and achieved 96.8% specificity and 89.7% sensitivity. Additionally, we derived an algorithm, based on a binary classifier, for resolving the multi-class classification problem by using three successive mathematical model predictions of liver disease status.
CONCLUSION: Our proposed mathematical model may be a useful method for the early detection of different statuses of liver disease co-occurring with HCV infection.
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Tavakolpour S, Sali S. Tumor Necrosis Factor-α-308 G/A Polymorphisms and Risk of Hepatocellular Carcinoma: A Meta-Analysis. HEPATITIS MONTHLY 2016; 16:e33537. [PMID: 27257425 PMCID: PMC4888758 DOI: 10.5812/hepatmon.33537] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 03/14/2016] [Indexed: 12/11/2022]
Abstract
CONTEXT Hepatocellular carcinoma (HCC) is a common disorder throughout the world that can develop due to various factors, including genetics. Tumor necrosis factor-α (TNF-α) is the most frequently studied cytokine related to the risk of developing HCC, and an association between the 308 position of the TNF-α promoter (TNF-α-308) and HCC risk has been confirmed in various reports. EVIDENCE ACQUISITION The PubMed, Scopus, and Google Scholar databases were searched through July 12, 2015, for studies on associations between TNF-α-308 and the risk of HCC. To determine this association, odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS A total of 23 case-control studies were investigated, involving 3,389 cases and 4,235 controls. The overall conclusion was that the A allele was more frequent in case groups compared to control groups (13.4% vs. 8.4%). Thus, the A allele was significantly associated with increased HCC risk (OR = 1.77; 95% CI = [1.26-2.50]; P value < 0.002). In addition to the allelic model, the dominant model (AA + AG vs. GG) was significantly associated with HCC risk (OR = 1.80; CI = [1.29-2.51]; P value < 0.001). In the sensitivity analysis for co-dominant (AA vs. GG) and recessive models (AA vs. AG + GG), no trustworthy associations with the risk of HCC development were observed. CONCLUSIONS This meta-analysis indicated that the TNF-α-308 G/A polymorphism is significantly associated with increased susceptibility to HCC. However, to confirm this finding, more studies are needed on TNF-α-308 G/A polymorphisms associated with HCC.
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Affiliation(s)
- Soheil Tavakolpour
- Iran University of Medical Sciences, Tehran, IR Iran
- Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
| | - Shahnaz Sali
- Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
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Serum level of interleukin-8 and interleukin-10 as predictors for response to interferon–ribavirin combined therapy. EGYPTIAN LIVER JOURNAL 2016. [DOI: 10.1097/01.elx.0000481902.94221.61] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Serum Cytokine of IL-10 and IL-12 in Chronic Liver Disease: The Immune and Inflammatory Response. DISEASE MARKERS 2015; 2015:707254. [PMID: 26783377 PMCID: PMC4689924 DOI: 10.1155/2015/707254] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 11/12/2015] [Accepted: 11/23/2015] [Indexed: 12/23/2022]
Abstract
The current study was designed to investigate the potential association of serum interleukin-10 and interleukin-12 with HCV infection in chronic liver disease and to evaluate their possible role as new biomarkers in HCC development. Material and Methods. Forty-one patients suffering from chronic liver disease (33 patients harbor HCV infection and 8 are HCV-negative patients) were enrolled in the present study and histopathologically diagnosed into 15 patients with HCC, 16 patients with LC, and 10 patients with liver histology compatible with precirrhotic hepatitis (PCH). Ten patients complaining of cholecystitis were included as nondisease control. Serum levels of IL-10 and IL-12 were measured by enzyme linked immunosorbent assay (ELISA). Results. HCV-infected patients showed elevated expression of IL-10 and IL-12 compared to nondisease controls (P < 0.0001) but there is no significant difference with respect to their expression in HCV-negative patients. Serum IL-10 and IL-12 were elevated significantly with disease progression (P < 0.0001) and a positive correlation coefficient was detected between IL-10, IL-12 (r = 0.785, P < 0.0001), and transaminase values suggesting their possible role in chronic inflammation progression leading to HCC. Conclusion. IL-10 and IL-12 might be involved in chronic inflammation progression leading to HCC and their evaluation could be used as new biomarkers to reflect the degree of inflammation in HCC development.
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Lee J. Cyclophilin A as a New Therapeutic Target for Hepatitis C Virus-induced Hepatocellular Carcinoma. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2013; 17:375-83. [PMID: 24227937 PMCID: PMC3823949 DOI: 10.4196/kjpp.2013.17.5.375] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Revised: 09/21/2013] [Accepted: 09/23/2013] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is thought to account for more than 80% of primary liver cancers. Both HBV and HCV can establish chronic liver inflammatory infections, altering hepatocyte and liver physiology with potential liver disease progression and HCC development. Cyclophilin A (CypA) has been identified as an essential host factor for the HCV replication by physically interacting with the HCV non structural protein NS5A that in turn interacts with RNA-dependent RNA polymerase NS5B. CypA, a cytosolic binding protein of the immunosuppressive drug cyclosporine A, is overexpressed in many cancer types and often associated with malignant transformation. Therefore, CypA can be a good target for molecular cancer therapy. Because of antiviral activity, the CypA inhibitors have been tested for the treatment of chronic hepatitis C. Nonimmunosuppressive Cyp inhibitors such as NIM811, SCY-635, and Alisporivir have attracted more interests for appropriating CypA for antiviral chemotherapeutic target on HCV infection. This review describes CypA inhibitors as a potential HCC treatment tool that is contrived by their obstructing chronic HCV infection and summarizes roles of CypA in cancer development.
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Affiliation(s)
- Jinhwa Lee
- Department of Clinical Lab Science, School of Health Science, Dongseo University, Busan 617-716, Korea
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Othman MS, Aref AM, Mohamed AA, Ibrahim WA. Serum Levels of Interleukin-6 and Interleukin-10 as Biomarkers for Hepatocellular Carcinoma in Egyptian Patients. ISRN HEPATOLOGY 2013; 2013:412317. [PMID: 27335826 PMCID: PMC4890868 DOI: 10.1155/2013/412317] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Accepted: 08/12/2013] [Indexed: 02/07/2023]
Abstract
Interleukin-10 (IL-10) and interleukin-6 (IL-6) have been reported to be related to hepatocellular carcinoma (HCC) prognosis. This study aimed to investigate the clinical usefulness of serum levels of IL-6 and IL-10 as biomarkers for HCC among high-risk patients. Materials and Methods. 80 individuals were enrolled in this study; they were categorized into 4 groups: group 1 healthy individuals (NC) (n = 20), group 2 chronic hepatitis C virus (HCV) patients (n = 20), group 3 cirrhotic patients (LC) (n = 20), and HCC group (n = 20). Using ELISA technique serum levels of IL-6, IL-10, and alpha fetoprotein (AFP) were evaluated in all groups. Results. The mean serum levels of IL-6 were significantly higher in HCC than in LC, HCV, and NC groups (13.99 ± 1.80, 7.49 ± 0.43, 5.78 ± 0.74, and 2.57 ± 0.31), respectively (P < 0.05); also the serum levels of IL-10 were significantly higher in HCC compared with LC, HCV, and NC groups (13.69 ± 1.89, 7.37 ± 0.53, 5.18 ± 0.6, and 3.31 ± 0.42) (P < 0.05). We also found that the tumor size is correlated strongly with IL-6 and IL-10 levels (r = 0.925, P < 0.001; r = 0.821, P < 0.001), respectively. Conclusion. The combination of those markers may help to identify a group of HCC patients with low AFP.
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Affiliation(s)
- Mohamed S. Othman
- Biochemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza 11787, Egypt
| | - Ahmed M. Aref
- Biology Department, Faculty of Dentistry, October University for Modern Sciences and Arts (MSA), Giza 11787, Egypt
| | - Amal A. Mohamed
- Biochemsitry Department, National Hepatology and Tropical Medicine Research Institute, Fom El-Khalig, Cairo 11796, Egypt
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Gelu-Simeon M, Samuel D. Role of cytokine levels in assessment of prognosis and post-treatment outcome in hepatocellular carcinoma. Hepatol Int 2013. [PMID: 26201913 DOI: 10.1007/s12072-013-9441-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Moana Gelu-Simeon
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, 94800, Villejuif, France.
| | - Didier Samuel
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, 94800, Villejuif, France. .,INSERM, U785, 94800, Villejuif, France. .,Faculté de Médecine, Université Paris-Sud, 94270, Le Kremlin-Bicêtre, France.
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Fuster D, Tsui JI, Cheng DM, Quinn EK, Armah KA, Nunes D, Freiberg MS, Samet JH. Interleukin-6 is associated with noninvasive markers of liver fibrosis in HIV-infected patients with alcohol problems. AIDS Res Hum Retroviruses 2013; 29:1110-6. [PMID: 23601055 DOI: 10.1089/aid.2012.0348] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Both HIV and hepatitis C virus (HCV) cause chronic inflammation and alterations in serum inflammatory cytokines. The impact of inflammatory cytokines on liver fibrosis is not well understood. We studied the association between interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α and liver fibrosis in HIV-infected patients with current or past alcohol problems (CAGE ≥2 or physician investigator diagnosis). Liver fibrosis was estimated with FIB-4 (FIB-4 <1.45 defined the absence of liver fibrosis and FIB-4 >3.25 defined advanced fibrosis). Logistic regression was used to assess the association between cytokines and fibrosis, adjusting for age, sex, CD4, HIV RNA, current antiretroviral therapy, body mass index, and HCV. Secondary analyses explored whether the association between HCV and liver fibrosis was mediated by these cytokines. Participants (n=308) were all HIV-infected; 73% were male with a mean age of 42 years; half had detectable HCV-RNA, 60.7% had an absence of liver fibrosis, and 10.1% had advanced fibrosis. In models that adjusted for each cytokine separately, higher levels of IL-6 were significantly associated with an absence of fibrosis [adjusted OR (95% CI): 0.43 (0.19, 0.98), p=0.05] and were borderline significant for advanced fibrosis [adjusted OR (95% CI): 8.16 (0.96, 69.54), p=0.055]. In the final model, only higher levels of IL-6 remained significantly associated with advanced liver fibrosis [adjusted OR (95% CI): 11.78 (1.17, 118.19), p=0.036]. Adjustment for inflammatory cytokines attenuated the adjusted OR for the association between HCV and fibrosis in the case of IL-6 [for the absence of fibrosis from 0.32 (0.17, 0.57) p<0.01 to 0.47 (0.23, 0.96) p=0.04; and for advanced fibrosis from 7.22 (2.01, 25.96) p<0.01 to 6.62 (1.20, 36.62) p=0.03], suggesting IL-6 may be a partial mediator of the association between HCV and liver fibrosis. IL-6 was strongly and significantly associated with liver fibrosis in a cohort of HIV-infected patients with alcohol problems. IL-6 may be a useful predictive marker for liver fibrosis for HIV-infected patients.
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Affiliation(s)
- Daniel Fuster
- Clinical Addiction Research and Education (CARE) Unit, Section of General Internal Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
| | - Judith I. Tsui
- Clinical Addiction Research and Education (CARE) Unit, Section of General Internal Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
| | - Debbie M. Cheng
- Clinical Addiction Research and Education (CARE) Unit, Section of General Internal Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
- Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
| | - Emily K. Quinn
- Data Coordinating Center, Boston University School of Public Health, Boston, Massachusetts
| | - Kaku A. Armah
- Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | - David Nunes
- Section of Gastroenterology, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
| | - Matthew S. Freiberg
- Division of General Internal Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jeffrey H. Samet
- Clinical Addiction Research and Education (CARE) Unit, Section of General Internal Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
- Department of Community Health Sciences, Boston University School of Public Health, Boston, Massachusetts
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Zekri ARN, Bahnassy AA, Mohamed WS, Alam EL-Din HM, Shousha HI, Zayed N, Eldahshan DH, Abdel-Aziz AO. Dynamic interplay between CXCL levels in chronic hepatitis C patients treated by interferon. Virol J 2013; 10:218. [PMID: 23816271 PMCID: PMC3707769 DOI: 10.1186/1743-422x-10-218] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Accepted: 05/17/2013] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Combined pegylated interferon-α and ribavirin therapy has sustained virological response (SVR) rates of 54% to 61%. Pretreatment predictors of SVR to interferon therapy have not been fully investigated yet. The current study assesses a group of chemokines that may predict treatment response in Egyptian patients with chronic HCV infection. PATIENTS AND METHODS CXCL5, CXCL9, CXCL11, CXCL12, CXCL 13, CXCL 16 chemokines and E-Cadherin were assayed in 57 chronic HCV patients' sera using quantitative ELISA plate method. All studied patients were scheduled for combined pegylated interferon alpha and ribavirin therapy (32 patients received pegylated interferon α 2b, and 25 patients received pegylated interferon α 2a). Quantitative hepatitis C virus RNA was done by real time RT-PCR and HCV genotyping by INNOLIPAII. RESULTS There was no significant difference (p > 0.05) in baseline HCV RNA levels between responders and non-responders to interferon. A statistically significant difference in CXCL13 (p = 0.017) and E-Cadherin levels (P = 0.041) was reported between responders and nonresponders at week 12. Significant correlations were found between changes in the CXCL13 levels and CXCL9, CXCL16, E-cadherin levels as well as between changes in E-cadherin levels and both CXCL16 and ALT levels that were maintained during follow up. Also, significant changes have been found in the serum levels of CXCL5, CXCL13, and CXCL16 with time (before pegylated interferon α 2 a and α 2 b therapy, and at weeks 12 and 24) with no significant difference in relation to interferon type and response to treatment. CONCLUSION Serum levels of CXCL13 and E-Cadherin could be used as surrogate markers to predict response of combined PEG IFN-α/RBV therapy, especially at week 12. However, an extended study including larger number of patients is needed for validation of these findings. CLINICAL TRIAL NO NCT01758939.
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Affiliation(s)
- Abdel-Rahman N Zekri
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, 1st Kasr El-Aini st, Cairo, Egypt
| | - Abeer A Bahnassy
- Pathology Department, National Cancer Institute, Cairo University, 1st Kasr El-Aini st, Cairo, Egypt
| | - Waleed S Mohamed
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, 1st Kasr El-Aini st, Cairo, Egypt
| | - Hanaa M Alam EL-Din
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, 1st Kasr El-Aini st, Cairo, Egypt
| | - Hend I Shousha
- Tropical Medicine Department, Faculty of Medicine, Cairo University, Kasr El-Aini st, Cairo, Egypt
| | - Naglaa Zayed
- Tropical Medicine Department, Faculty of Medicine, Cairo University, Kasr El-Aini st, Cairo, Egypt
| | - Dina H Eldahshan
- Clinical Pathology Department, Faculty of Medicine, Benisuef University, Cairo, Egypt
| | - Ashraf Omar Abdel-Aziz
- Tropical Medicine Department, Faculty of Medicine, Cairo University, Kasr El-Aini st, Cairo, Egypt
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Hammam O, Mahmoud O, Zahran M, Sayed A, Salama R, Hosny K, Farghly A. A Possible Role for TNF-α in Coordinating Inflammation and Angiogenesis in Chronic Liver Disease and Hepatocellular Carcinoma. GASTROINTESTINAL CANCER RESEARCH : GCR 2013; 6:107-14. [PMID: 24147158 PMCID: PMC3782877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Accepted: 07/19/2013] [Indexed: 06/02/2023]
Abstract
BACKGROUND Increasing evidence supports the hypothesis that chronic and persistent inflammation contributes to cancer development. However, the molecular mechanisms that lead to cancer in chronic inflammation and the role of angiogenesis in inflammation-associated cancer remain poorly understood. METHODS NINETY PATIENTS WERE ENROLLED: 30 cases of CHC without cirrhosis, 28 cases of CHC with liver cirrhosis, and 32 cases of HCC and hepatitis C virus infection. Ten wedge liver biopsies, taken during laparoscopic cholecystectomy, served as normal controls. Serum TNF-α levels were measured using the ELISA technique; in situ hybridization and immunohistochemical studies were used to detect hepatic levels of messenger RNA (mRNA) transcripts and mature protein, respectively, for both TNF-α and VEGF. RESULTS The highest hepatic expression of TNF-α was noticed in liver cirrhosis specimens compared to noncirrhotic CHC and HCC. Hepatic expression of VEGF and serum level of TNF-α revealed significant increases in the progression of the disease. Moreover, cases with higher grades of inflammation or stages of fibrosis showed significant increases in serum TNF-α and expression of TNF-α and VEGF. Expression of mRNA of both TNF-α and VEGF shows increasing expression with positive correlation to progression of viral hepatitis to cirrhosis with more positivity in cases developed HCC. CONCLUSIONS VEGF signaling could be one of the molecular signaling pathways involved in TNF-α induced angiogenesis which might pose an important link between inflammation and fibrosis in CHC and HCC development and progression. Moreover, serum inflammatory biomarkers can be used to monitor the disease progression.
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Affiliation(s)
| | - Ola Mahmoud
- Department of Hematology Theodor Bilharz Research Institute Cairo, Egypt
| | - Manal Zahran
- Department of Hematology Theodor Bilharz Research Institute Cairo, Egypt
| | - Azza Sayed
- Department of Hematology Theodor Bilharz Research Institute Cairo, Egypt
| | | | - Karim Hosny
- Department of Surgery Kasr El Aini Hospital Cairo, Egypt
| | - Ahmed Farghly
- Department of Surgery Kasr El Aini Hospital Cairo, Egypt
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Naing C, Mak JW, Wai N, Maung M. Diabetes and infections-hepatitis C: is there type 2 diabetes excess in hepatitis C infection? Curr Diab Rep 2013; 13:428-34. [PMID: 23463119 DOI: 10.1007/s11892-013-0370-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Individual epidemiologic studies as well as the pooled analysis of observational studies have indicated the association between type 2 diabetes (T2D) and hepatitis C virus infection (HCV). Whether HCV infection is the cause of diabetes or diabetic patients are more prone to get HCV infection is still in question. The objective of the present review was to provide answers to this issue, based on available evidence from epidemiologic, molecular, experimental and therapeutic studies. Our current understanding of how chronic HCV infection could induce T2D is incomplete, but it seems twofold based on both direct and indirect roles of the virus. HCV may directly induce insulin resistance (IR) through its proteins. HCV core protein was shown to stimulate suppressor of cytokine signaling, resulting in ubiquitination and degradation of tyrosine kinase phosphorylated insulin receptor substrates (IRS1/2) in proteasomes. HCV-nonstructural protein could increase protein phosphatase 2A which has been shown to inactivate the key enzyme Akt by dephosphorylating it. Insulin signaling defects in hepatic IRS-1 tyrosine phosphorylation and PI3-kinase association/activation may contribute to IR, which leads to the development of T2D in patients with HCV infection. The peroxisome proliferator-activated receptors (PPARs) are also implicated. PPARα/γ, together with their obligate partner RXR, are the main nuclear receptors expressed in the liver. PPARα upregulates glycerol-3-phosphate dehydrogenase, glycerol kinase, and glycerol transport proteins, which allows for glucose synthesis during fasting states. Decreased activity of PPARs could attribute to HCV-induced IR. Immune-mediated mechanisms may be involved in the indirect role of HCV in inducing IR. It is speculated that TNF-alpha plays a major role in the pathogenesis of IR through lowering IRS1/2. Furthermore, HCV infection- triggered ER stress could lead to the activation of PP2A, which inhibits both Akt and the AMP-activated kinase, the regulators of gluconeogenesis. In summary, we illustrate that HCV infection is accompanied by multiple defects in the upstream insulin signaling pathway in the liver that may contribute to the observed prevalence of IR and diabetes. Future studies are needed to resolve this issue.
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Affiliation(s)
- Cho Naing
- School of Postgraduate Studies and Research, International Medical University, Kuala Lumpur, Malaysia.
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Neuman MG, McKinney KK, Nanau RM, Kong V, Malkiewicz I, Mazulli T, Moussa G, Cohen LB. Drug-induced severe adverse reaction enhanced by human herpes virus-6 reactivation. Transl Res 2013; 161:430-40. [PMID: 23333110 DOI: 10.1016/j.trsl.2012.12.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Revised: 12/17/2012] [Accepted: 12/20/2012] [Indexed: 01/20/2023]
Abstract
Reactivation of certain latent viruses has been linked with a more severe course of drug-induced hypersensitivity reaction (HSR). For example, reactivation of human herpes virus (HHV)-6 is associated with severe organ involvement and a prolonged course of disease. The present study discusses an HSR developed in a previously healthy male exposed to ceftriaxone, doxycycline, vancomycin, and trimethoprim/sulfamethoxazole (co-trimoxazole; TMP/SMX). Initially, the patient presented clinical manifestations of HSR, as well as clinical and laboratory measurements compatible with liver and renal failure. Moreover, the patient presented skin desquamation compatible with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis. During the reaction, it was observed HHV-6 reactivation. The severity of clinical symptoms is correlated with HHV-6 titer, as well as with results of the in vitro lymphocyte toxicity assay (LTA). Serum levels of a large panel of cytokines are compared between the patient, a large population of SJS patients, and a cohort of healthy controls, using data collected by our laboratory over the years. HHV-6 was measured in the cell culture media from lymphocytes incubated with each of the 4 drugs. Moreover, we describe a new assay using cytokines released by patient lymphocytes following in vitro exposure to the incriminated drugs as biomarkers of HSR. Based on LTA results, HHV-6 reactivation and cytokine measurements, we establish that only doxycycline and TMP/SMX were involved in the HSR. As result of this analysis, the patient could continue to use the other 2 antibiotics safely.
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Affiliation(s)
- Manuela G Neuman
- In Vitro Drug Safety and Biotechnology, Toronto, Ontario, Canada.
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Lin CC, Yin MC. Clinical significance of circulating IL-10 and fibronectin levels in hepatocellular carcinoma patients with HBV infection. Biomedicine (Taipei) 2012. [DOI: 10.1016/j.biomed.2012.06.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
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Radwan MI, Pasha HF, Mohamed RH, Hussien HIM, El-Khshab MN. Influence of transforming growth factor-β1 and tumor necrosis factor-α genes polymorphisms on the development of cirrhosis and hepatocellular carcinoma in chronic hepatitis C patients. Cytokine 2012; 60:271-6. [PMID: 22682513 DOI: 10.1016/j.cyto.2012.05.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Revised: 05/13/2012] [Accepted: 05/14/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Host genetic factors may affect clinical outcomes of hepatitis C virus (HCV) infection; however, the possible mechanisms remain largely unknown. This study aimed to evaluate transforming growth factor-β1 (TGF-β1)-509 and tumor necrosis factor-α (TNF-α)-308 genes polymorphisms as a risk factors for cirrhosis and hepatocellular carcinoma (HCC) in chronic hepatitis C patients. MATERIALS AND METHODS Two hundred and eighty HCV patients (152 patients with cirrhosis, 128 patients with HCC) and 160 controls were enrolled in the study. Polymorphisms of TGF-β1-509 and TNF-α-308 gene were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum TGF-β1 and TNF-α were determined using ELISA. RESULTS TGF-β1-509 TT, TNF-α-308 AA and GA genotypes frequencies were significantly increased in cirrhotic and HCC groups. Serum TGF-β1 and TNF-α level were significantly increased in TGF-β1-509 TT and TNF-α-308 AA genotypes respectively. CONCLUSION TGF-β1-509 and TNF-α-308 genes polymorphisms are associated with risk of liver cirrhosis and HCC in patients with chronic HCV infection.
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Affiliation(s)
- Mohamed I Radwan
- Tropical Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Martin M, Herceg Z. From hepatitis to hepatocellular carcinoma: a proposed model for cross-talk between inflammation and epigenetic mechanisms. Genome Med 2012; 4:8. [PMID: 22293089 PMCID: PMC3334556 DOI: 10.1186/gm307] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Inflammation represents the body's natural response to tissue damage; however, chronic inflammation may activate cell proliferation and induce deregulation of cell death in affected tissues. Chronic inflammation is an important factor in the development of hepatocellular carcinoma (HCC), although the precise underlying mechanism remains unknown. Epigenetic events, which are considered key mechanisms in the regulation of gene activity states, are also commonly deregulated in HCC. Here, we review the evidence that chronic inflammation might deregulate epigenetic processes, thus promoting oncogenic transformation, and we propose a working hypothesis that epigenetic deregulation is an underlying mechanism by which inflammation might promote HCC development. In this scenario, different components of the inflammatory response might directly and indirectly induce changes in epigenetic machineries ('epigenetic switch'), including those involved in setting and propagating normal patterns of DNA methylation, histone modifications and non-coding RNAs in hepatocytes. We discuss the possibility that self-reinforcing cross-talk between inflammation and epigenetic mechanisms might amplify inflammatory signals and maintain a chronic state of inflammation culminating in cancer development. The potential role of inflammation-epigenome interactions in the emergence and maintenance of cancer stem cells is also discussed.
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Affiliation(s)
- Marion Martin
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon CEDEX 08, France
| | - Zdenko Herceg
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon CEDEX 08, France
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Markers of inflammation and fibrosis in alcoholic hepatitis and viral hepatitis C. Int J Hepatol 2012; 2012:231210. [PMID: 22530132 PMCID: PMC3296182 DOI: 10.1155/2012/231210] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2011] [Revised: 10/31/2011] [Accepted: 11/23/2011] [Indexed: 12/15/2022] Open
Abstract
High levels of profibrinogenic cytokine transforming factor beta (TGF-β), metalloprotease (MMP2), and tissue inhibitor of matrix metalloprotease 1 (TIMP1) contribute to fibrogenesis in hepatitis C virus (HCV) infection and in alcohol-induced liver disease (ALD). The aim of our study was to correlate noninvasive serum markers in ALD and HCV patients with various degrees of inflammation and fibrosis in their biopsies. Methods. Serum cytokines levels in HCV-infected individuals in the presence or absence of ALD were measured. Student's-t-test with Bonferroni correction determined the significance between the groups. Results. Both tumor-necrosis-factor- (TNF)-α and TGF-β levels increased significantly with the severity of inflammation and fibrosis. TGF-β levels increased significantly in ALD patients versus the HCV patients. Proinflammatory cytokines' responses to viral and/or toxic injury differed with the severity of liver inflammation. A combination of these markers was useful in predicting and diagnosing the stages of inflammation and fibrosis in HCV and ALD. Conclusion. Therapeutic monitoring of TGF-β and metalloproteases provides important insights into fibrosis.
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El-Mesallamy HO, Hamdy NM, Rizk HH, El-Zayadi AR. Apelin serum level in Egyptian patients with chronic hepatitis C. Mediators Inflamm 2011; 2011:703031. [PMID: 22007137 PMCID: PMC3189591 DOI: 10.1155/2011/703031] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2011] [Revised: 07/08/2011] [Accepted: 08/25/2011] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVE Highlighting the apelin system would present a new therapeutic target for liver disease. Apelin; endogenous ligand for the orphan receptor APJ, was recently suggested to be associated with fibrosis progression and cirrhosis in addition to insulin resistance (IR) and inflammation. The present study was conducted to evaluate blood apelin level changes among 73 chronic hepatitis C (CHC) Egyptian patients and if associated with body mass index (BMI), IR, and tumor necrosis factor-alpha (TNF-α). Serum apelin levels were significantly higher in patients with CHC with median value (3.25) when compared with controls (1.11), at P < 0.0001, with significant apelin variations among asymptomatic carriers (ASC), fibrosis, and cirrhosis patients, and also among obese and nonobese patients. Multiple regression analysis depicted that BMI, triglycerides, and total cholesterol were independent correlation factors to apelin levels, whereas TNF-α was found to be significantly negatively correlated to adjusted apelin in CHC patients (r = -0.5944, P < 0.0001). IR was positively correlated to adjusted apelin in CHC patients (r = 0.2663, P < 0.05). CONCLUSION Apelin level varies among stages of CHC, which may contribute to fibrosis progression. In addition, obesity and IR could act as comorbid factors affecting apelin level in patients with CHC.
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Affiliation(s)
- Hala O. El-Mesallamy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt
| | - Nadia M. Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt
| | - Hanan H. Rizk
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt
| | - Abdel-Rahman El-Zayadi
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
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Bruno CM, Valenti M, Bertino G, Ardiri A, Amoroso A, Consolo M, Mazzarino CM, Neri S. Relationship between circulating interleukin-10 and histological features in patients with chronic C hepatitis. Ann Saudi Med 2011; 31:360-4. [PMID: 21808111 PMCID: PMC3156511 DOI: 10.4103/0256-4947.83215] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND AND OBJECTIVES An imbalance in cytokine production may be involved in the pathogenesis of chronic C hepatitis. The aim of the study was to investigate circulating levels of interleukin-10 (IL-10) in a selected cohort of patients affected by chronic C hepatitis. DESIGN AND SETTING Retrospective study based on consecutive hepatitis C virus patients, affected by chronic active hepatitis, attending the general hospital of hepatology unit from June to September 2009 PATIENTS AND METHODS A total of 49 patients with chronic C hepatitis and 20 healthy control subjects similar in gender and age were examined. Circulating IL-10 was assessed by ELISA commercial kit (R and D Systems) in all investigated subjects. RESULTS There was no significant difference in IL-10 values between controls and overall patients (P>.05). Nevertheless, among patients, subjects with more severe necroinflammation had higher values than others (P<.001). Moreover, a close relationship was found between IL-10 values and serum aspartate aminotransferase (r=0.61; P<.001). CONCLUSIONS These findings suggest that IL-10 may be a useful additional marker to assess necroinflammation and to monitor the evolution of liver damage. They also argue for a potential pathophysiological role for IL-10 in the persistence and progression of hepatitis.
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Affiliation(s)
- Cosimo Marcello Bruno
- Department of Internal Medicine and Systemic Diseases, University of Catania, Catania, Italy.
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González-Casas R, Trapero-Marugán M, Moreno-Otero R. Hepatitis crónica por virus de la hepatitis C genotipo 4. Med Clin (Barc) 2011; 137:31-5. [DOI: 10.1016/j.medcli.2010.03.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2010] [Accepted: 03/11/2010] [Indexed: 12/25/2022]
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Mohran ZY, Ali-Eldin FA, Abdel Aal HA. Serum interleukin-18: does it have a role in the diagnosis of hepatitis C virus related hepatocellular carcinoma? Arab J Gastroenterol 2011; 12:29-33. [PMID: 21429452 DOI: 10.1016/j.ajg.2010.11.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2010] [Revised: 09/02/2010] [Accepted: 11/18/2010] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND STUDY AIMS Early diagnosis of hepatocellular carcinoma (HCC) is the only hope for cure. Although the role of alpha foetoprotein (AFP) in the diagnosis of advanced HCC is well recognised, at least one-third of cases will be missed unless another diagnostic tool is used. Increased levels of circulating interleukin-18 (IL-18) have been observed in patients with several cancer types and were described in patients with chronic hepatitis. The aim of this study is to assess the role of serum IL-18 level in the diagnosis of hepatitis C virus (HCV)-related HCC. PATIENTS AND METHODS A total of 75 subjects categorised into four groups, including 25 patients with HCV-related HCC and AFP above 200ng/ml, 25 patients with HCV-related HCC and AFP below 200ng/ml, 15 patients with HCV-related chronic liver disease and 10 healthy controls, were enrolled. HCC was diagnosed according to guidelines of the American Association for the Study of Liver Diseases. AFP and IL-18 were assessed in all subjects. RESULTS AFP and IL-18 levels are significantly higher in patients with HCC than in disease control and healthy control subjects. IL-18 level is not correlating with the size or the number of hepatic focal lesions neither with the presence of lymphovascular invasion or abdominal lymphadenopathy. The best cut-off value of IL-18 for the diagnosis of HCC is 500pg/ml with 84% sensitivity and 86.7% specificity and the area under receiver operating characteristic curve is 0.675. CONCLUSION Serum IL-18 level is a suitable marker for the diagnosis of HCV-related HCC complementary to AFP, especially in cases with AFP level less than the diagnostic value.
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Affiliation(s)
- Zakaria Y Mohran
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Abbasseya Square, Cairo, Egypt
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Elattar G, Saleh Z, EL-Shebini S, Farrag A, Zoheiry M, Hassanein A, EL-Ghannam M, Shendy S, EL-Dabaa E, Zahran N. The use of whey protein concentrate in management of chronic hepatitis C virus - a pilot study. Arch Med Sci 2010; 6:748-55. [PMID: 22419935 PMCID: PMC3298345 DOI: 10.5114/aoms.2010.17091] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2009] [Revised: 03/31/2009] [Accepted: 06/13/2009] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Whey protein contains biologically active ingredients that can prevent and attenuate disease besides being nutritive. The aim of the study was to clarify the effects of oral administration of whey protein on viral load and host defence mechanisms, in particular, phagocytic function of neutrophils, selected immunomodulatory cytokines and serum inflammatory markers, in compensated chronic hepatitis C virus (HCV) patients. MATERIAL AND METHODS Twenty-seven HCV patients (20 males and 7 females) recruited from the hepatology clinic of the Theodor Bilharz Research Institute (TBRI) were given whey protein concentrate (WPC) twice daily for two months. In addition, 15 age and sex matched healthy participants were included in the study, as a control group. Neutrophil phagocytic activity, serum intercellular adhesion molecule (sICAM), interleukin-2 (IL-2), nitric oxide (NO), as well as HCV-RNA levels and routine investigations were determined for patients, before and after WPC supplementation and once for the control group. RESULTS There was a significant decrease in viral load and markers of active inflammation, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), while serum albumin, total leucocyte counts and absolute neutrophil counts showed significant elevation accompanied by improvement of neutrophil phagocytic activity after WPC supplementation compared to pre-treated levels. The oral WPC supplementation was well tolerated without any serious adverse events. CONCLUSIONS Oral supplementation of WPC has promising results as a new therapeutic strategy against HCV and its sequelae by decreasing the viral load and active inflammation as well as improving the synthetic capacity of the liver and the phagocytic function of neutrophils, in these patients.
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Affiliation(s)
- Gamal Elattar
- Theodor Bilharz Research Institute, Imbaba Giza, Egypt
| | | | | | | | - Mona Zoheiry
- Theodor Bilharz Research Institute, Imbaba Giza, Egypt
| | | | | | - Shendy Shendy
- Theodor Bilharz Research Institute, Imbaba Giza, Egypt
| | - Ehab EL-Dabaa
- Theodor Bilharz Research Institute, Imbaba Giza, Egypt
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Banerjee A, Ray RB, Ray R. Oncogenic potential of hepatitis C virus proteins. Viruses 2010; 2:2108-2133. [PMID: 21994721 PMCID: PMC3185750 DOI: 10.3390/v2092108] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Revised: 09/23/2010] [Accepted: 09/24/2010] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a major risk factor for liver disease progression, and may lead to cirrhosis and hepatocellular carcinoma (HCC). The HCV genome contains a single-stranded positive sense RNA with a cytoplasmic lifecycle. HCV proteins interact with many host-cell factors and are involved in a wide range of activities, including cell cycle regulation, transcriptional regulation, cell proliferation, apoptosis, lipid metabolism, and cell growth promotion. Increasing experimental evidences suggest that HCV contributes to HCC by modulating pathways that may promote malignant transformation of hepatocytes. At least four of the 10 HCV gene products, namely core, NS3, NS5A and NS5B play roles in several potentially oncogenic pathways. Induction of both endoplasmic reticulum (ER) stress and oxidative stress by HCV proteins may also contribute to hepatocyte growth promotion. The current review identifies important functions of the viral proteins connecting HCV infections and potential for development of HCC. However, most of the putative transforming potentials of the HCV proteins have been defined in artificial cellular systems, and need to be established relevant to infection and disease models. The new insight into the mechanisms for HCV mediated disease progression may offer novel therapeutic targets for one of the most devastating human malignancies in the world today.
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Affiliation(s)
- Arup Banerjee
- Department of Internal Medicine, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104, USA; E-Mail:
| | - Ratna B. Ray
- Department of Pathology, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 2nd Floor, St. Louis, MO 63104, USA; E-Mail:
| | - Ranjit Ray
- Department of Internal Medicine, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104, USA; E-Mail:
- Molecular Microbiology & Immunology, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104, USA
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: 1-314- 977-9034; Fax: 1-314-771-3816
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Gomez EV, Perez YM, Sanchez HV, Forment GR, Soler EA, Bertot LC, Garcia AY, del Rosario Abreu Vazquez M, Fabian LG. Antioxidant and immunomodulatory effects of Viusid in patients with chronic hepatitis C. World J Gastroenterol 2010; 16:2638-47. [PMID: 20518086 PMCID: PMC2880777 DOI: 10.3748/wjg.v16.i21.2638] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the efficacy of Viusid, a nutritional supplement, as an antioxidant and an immunomodulator in patients with chronic hepatitis C.
METHODS: Sixty patients with chronic hepatitis C who were non-responders to standard antiviral treatment were randomly assigned to receive Viusid (3 sachets daily, n = 30) or placebo (n = 30) for 24 wk. The primary outcome was the change in serum malondialdehyde and 4-hydroxyalkenals (lipid peroxidation products). Secondary outcomes were changes in serum tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and interleukin-10 (IL-10).
RESULTS: Statistically significant reductions in serum 4-hydroxyalkenals and malondialdehyde levels were observed in both groups in comparison with pretreatment values, but the patients who received Viusid showed a more marked reduction as compared with the control group (P = 0.001). TNF-α levels significantly increased from 6.9 to 16.2 pg/mL (P < 0.01) in the patients who received placebo in comparison with almost unchanged levels, from 6.6 to 7.1 pg/mL (P = 0.26), in the patients treated with Viusid (P = 0.001). In addition, IL-10 levels were markedly increased in the patients treated with Viusid (from 2.6 to 8.3 pg/mL, P = 0.04) in contrast to the patients assigned to placebo (from 2.8 to 4.1 pg/mL, P = 0.09) (P = 0.01). Likewise, the administration of Viusid markedly increased mean IFN-γ levels from 1.92 to 2.89 pg/mL (P < 0.001) in comparison with a reduction in mean levels from 1.80 to 1.68 pg/mL (P = 0.70) in the placebo group (P < 0.0001). Viusid administration was well tolerated.
CONCLUSION: Our results indicate that treatment with Viusid leads to a notable improvement of oxidative stress and immunological parameters in patients with chronic hepatitis C.
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Gomez EV, Perez YM, Sanchez HV, Forment GR, Soler EA, Bertot LC, Garcia AY, del Rosario Abreu Vazquez M, Fabian LG. Antioxidant and immunomodulatory effects of Viusid in patients with chronic hepatitis C. World J Gastroenterol 2010. [PMID: 20518086 DOI: pmid/20518086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/10/2023] Open
Abstract
AIM To investigate the efficacy of Viusid, a nutritional supplement, as an antioxidant and an immunomodulator in patients with chronic hepatitis C. METHODS Sixty patients with chronic hepatitis C who were non-responders to standard antiviral treatment were randomly assigned to receive Viusid (3 sachets daily, n = 30) or placebo (n = 30) for 24 wk. The primary outcome was the change in serum malondialdehyde and 4-hydroxyalkenals (lipid peroxidation products). Secondary outcomes were changes in serum tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and interleukin-10 (IL-10). RESULTS Statistically significant reductions in serum 4-hydroxyalkenals and malondialdehyde levels were observed in both groups in comparison with pretreatment values, but the patients who received Viusid showed a more marked reduction as compared with the control group (P = 0.001). TNF-alpha levels significantly increased from 6.9 to 16.2 pg/mL (P < 0.01) in the patients who received placebo in comparison with almost unchanged levels, from 6.6 to 7.1 pg/mL (P = 0.26), in the patients treated with Viusid (P = 0.001). In addition, IL-10 levels were markedly increased in the patients treated with Viusid (from 2.6 to 8.3 pg/mL, P = 0.04) in contrast to the patients assigned to placebo (from 2.8 to 4.1 pg/mL, P = 0.09) (P = 0.01). Likewise, the administration of Viusid markedly increased mean IFN-gamma levels from 1.92 to 2.89 pg/mL (P < 0.001) in comparison with a reduction in mean levels from 1.80 to 1.68 pg/mL (P = 0.70) in the placebo group (P < 0.0001). Viusid administration was well tolerated. CONCLUSION Our results indicate that treatment with Viusid leads to a notable improvement of oxidative stress and immunological parameters in patients with chronic hepatitis C.
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Affiliation(s)
- Eduardo Vilar Gomez
- Department of Hepatology, National Institute of Gastroenterology, 25th Avenue, 503, Vedado, Havana 10400, Cuba.
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Zekri ARN, Alam El-Din HM, Bahnassy AA, Zayed NA, Mohamed WS, El-Masry SH, Gouda SK, Esmat G. Serum levels of soluble Fas, soluble tumor necrosis factor-receptor II, interleukin-2 receptor and interleukin-8 as early predictors of hepatocellular carcinoma in Egyptian patients with hepatitis C virus genotype-4. COMPARATIVE HEPATOLOGY 2010; 9:1. [PMID: 20051112 PMCID: PMC2819041 DOI: 10.1186/1476-5926-9-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2009] [Accepted: 01/05/2010] [Indexed: 02/08/2023]
Abstract
BACKGROUND Liver disease progression from chronic hepatitis C virus (HCV) infection to hepatocellular carcinoma (HCC) is associated with an imbalance between T-helper 1 and T-helper 2 cytokines. Evaluation of cytokines as possible candidate biomarkers for prediction of HCC was performed using soluble Fas(sFas), soluble tumor necrosis factor receptor-II (sTNFR-II), interleukin-2 receptor (IL-2R) and interleukin-8 (IL-8). RESULTS The following patients were recruited: 79 with HCV infection, 30 with HCC, 32 with chronic liver disease associated with elevated liver enzyme levels (with or without cirrhosis) in addition to 17 with chronic HCV with persistent normal alanine aminotransferase levels (PNALT). Nine normal persons negative either for HCV or for hepatitis B virus were included as a control group. All persons were tested for sFas, sTNFR-II, IL-2R and IL-8 in their serum by quantitative ELISA. HCC patients had higher levels of liver enzymes but lower log-HCV titer when compared to the other groups. HCC patients had also significantly higher levels of sFas, sTNFR-II and IL-2R and significantly lower levels of IL-8 when compared to the other groups. Exclusion of HCC among patients having PNALT could be predicted with 90 % sensitivity and 70.6 % specificity when sTNFR-II is [greater than or equal to] 389 pg/ml or IL-8 is < 290 pg/ml. CONCLUSIONS Serum TNFR-II, IL-2Ralpha and IL-8, may be used as combined markers in HCV-infected cases for patients at high risk of developing HCC; further studies, however, are mandatory to check these findings before their application at the population level.
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Atta AM, Oliveira IS, Sousa GM, Paraná R, Atta MLS. Serum cytokine profile in hepatitis C virus carriers presenting cryoglobulinaemia and non-organ-specific autoantibodies. Microb Pathog 2009; 48:53-6. [PMID: 20005287 DOI: 10.1016/j.micpath.2009.12.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2009] [Revised: 11/29/2009] [Accepted: 12/03/2009] [Indexed: 01/26/2023]
Abstract
This work investigated the serum cytokine profile (IL-2, IL-4, IL-5, IL-10, IFN-gamma and BAFF) of hepatitis C virus (HCV) carriers with autoimmunity. Forty-seven HCV carriers and 28 healthy controls were evaluated. Cytokine levels were measured by ELISA. Patients and controls presented similar levels of IL-2, IL-4, IL-5, IL-10, IFN-gamma and BAFF (p>0.05). Cryoglobulinaemic HCV carriers had increased IL-2 (p=0.013), IL-5 (p=0.018) and BAFF (p=0.050). IFN-gamma level was decreased in HCV carriers with rheumatoid factor in comparison with those that were RF-seronegative (p=0.035). Patients with beta2GPI IgA antibodies when were compared with those without this autoantibody, had more serum IL-2 (p=0.009), IL-5 (p=0.018) and BAFF (p=0.039). Interleukin-2 was increased in HCV carriers with positive ANA when they were compared with ANA-seronegative carriers (p=0.044). Interleukins IL-4 and IL-10 were not associated with autoimmunity (P>0.05). In HCV carriers, IL-2 was correlated with IL-5 (p<0.0001) and IFN-gamma (p=0.015), and IL-5 with IFN-gamma (p=0.015). We concluded that the serum profile of cytokines in HCV carriers presenting autoimmune markers may be mainly represented by increased IL-2, IL-5 and BAFF.
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Affiliation(s)
- Ajax M Atta
- Departamento de Análises Clínicas e Toxicologicas, Faculdade de Farmácia, Universidade Federal da Bahia, Rua Barão de Jeremoabo s/n, 40170115 Salvador, Bahia, Brazil.
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Castello G, Scala S, Palmieri G, Curley SA, Izzo F. HCV-related hepatocellular carcinoma: From chronic inflammation to cancer. Clin Immunol 2009; 134:237-50. [PMID: 19910258 DOI: 10.1016/j.clim.2009.10.007] [Citation(s) in RCA: 111] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2009] [Revised: 10/16/2009] [Accepted: 10/16/2009] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) infection is a worldwide health problem because of its incidence and pathogenicity. It might evolve into chronic disease, cirrhosis, and/or hepatocellular carcinoma (HCC) and the outcome is mainly determined by the host immune response. For viral clearance, combined innate and adaptive immune responses are required; resolution requires a vigorous, durable, polyclonal CD4(+) and CD8(+) T-cell response, with an increase in virus-specific CD8(+) T cells or cytotoxic T lymphocytes. Failure of efficient immune response can lead to chronic inflammation, tissue remodeling through cell growth, apoptosis and/or necrosis and induction of oxidative stress. Development of fibrosis and/or cirrhosis plus a microenvironment conducive to genomic instability mutations will promote neoplastic transformation. System governance derives from cellular (regulatory cells) and humoral (cytokines and chemokines) immune networks. Therefore, HCC pathogenesis may be a model to study the disease progression from chronic inflammation to cancer allowing design of new strategies targeting the immune response, thereby modifying disease outcome.
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Abstract
The present study aimed to estimate the cellular immune response to infection by different HCV genotypes in some Egyptian patients with chronic liver disease. HCV-RNA and HCV genotypes were conducted using type-specific primers to amplify the core region of HCV genome. The levels of IFN-gamma and TNF-alpha, PIIINP, SOD enzyme were also determined. The results showed that genotype 4 was the prevalent one (88.57%).Genotype 3 was found mixed with genotype 2 and 4 (11.42% and 34.28% respectively). Genotype 1 was absent from patients under study. No significant differences were observed in the level of IFN-gamma interferon, SOD enzyme and ALT enzyme between those genotypes. On the other hand the level of TNF-alpha was greatly increased in patients infected with mixed HCV genotypes 3, 4 compared with patients with genotype 4 and those infected with mixed genotypes 2, 3. Otherwise PIIINP was decreased significantly of the same group compared with other groups.
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Braicu C, Burz C, Berindan-Neagoe I, Balacescu O, Graur F, Cristea V, Irimie A. Hepatocellular Carcinoma: Tumorigenesis and Prediction Markers. Gastroenterology Res 2009; 2:191-199. [PMID: 27942274 PMCID: PMC5139741 DOI: 10.4021/gr2009.07.1304] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/18/2009] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies. Although many advances have been made in the clinical study of HCC, the prognosis remains poor. Despite the discoveries in cancer biology in respect with physiological and pathological factors in relation to prognosis, HCC remains still a fatal disease due to late diagnosis. For improving the outcomes of patients with HCC, it is important to identify the factors predisposing to patient death. In recent years, based on cellular and molecular biology techniques, many tumor markers related to invasion, metastasis, recurrence and survival have been explored. However, routine biomarkers for the prediction of HCC evolution and prognosis are available in small number and less specific. These reviews focus on the recent advances in HCC tumorigenesis, revealing those biomarkers with prognosis significance or can be used for early detection.
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Affiliation(s)
| | - Claudia Burz
- University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Cancer Institute "I Chiricuta", Cluj-Napoca, Romania; University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania
| | | | - Florin Graur
- University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania
| | - Victor Cristea
- University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania
| | - Alexandru Irimie
- Cancer Institute "I Chiricuta", Cluj-Napoca, Romania; University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania
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Zekri ARN, Bahnassy AA, Abdel-Wahab SA, Khafagy MM, Loutfy SA, Radwan H, Shaarawy SM. Expression of pro- and anti-inflammatory cytokines in relation to apoptotic genes in Egyptian liver disease patients associated with HCV-genotype-4. J Gastroenterol Hepatol 2009; 24:416-28. [PMID: 19054267 DOI: 10.1111/j.1440-1746.2008.05699.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide strongly linked to hepatitis C virus (HCV) infection. However, the exact pathogenetic mechanisms are still unclear. METHODS We assessed the expression of apoptosis genes (GSK3-B, AKT-1, Bcl-2), inflammatory cytokines (TNFalpha, TNF-RI, TNF-RII, IL-6, IL-6R), anti-inflammatory IL-10, CRP and alphaFP by reverse transcription-polymerase chain reaction (RT-PCR) in 33 HCC, 25 chronic hepatitis and 16 asymptomatic HCV carrier positive for HCV subjects. Also, pooled normal liver tissues and HepG2 cells were used as controls. RESULTS Hepatocellular carcinoma and liver disease (LD) showed reduced expression of GSK-3beta, TNFalpha, TNF-R I, TNF-RII, IL-10 and overexpression of IL-6R and CRP with no significant difference between the two groups. AFP was expressed in HCC only (33%). AKT, BCL2 and IL-6 showed normal, reduced and overexpression in studied patients with a significant difference between AFP, AKT overexpression (67% and 30%), BCL2 overexpression (49% and 10%) and reduced IL-6 in between HCC and LD. The morphologically normal tissues adjacent to tumors showed aberrant expression of AKT, IL-6, CRP, TNFalpha and TNFRI. A significant relation was observed between cirrhosis and GSK-3beta, AKT and IL-6 (P = 0.0018, P = 0.018, P = 0.0001; respectively). CONCLUSIONS Aberrant expressions of AKT, GSK3-B, and BCL2 are common events in HCV-associated LD and HCC. AKT, GSK3-B and IL-6 are significantly associated with cirrhosis and could be used as biomarkers for both early detection and molecular target therapy for the prevention of HCC development. TNFRII, GSK3-B and s-AFP could be used as prognostic factors that can predict the clinical outcome of HCC patients.
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Affiliation(s)
- Abdel-Rahman N Zekri
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
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Cellular and molecular interactions in coinfection with hepatitis C virus and human immunodeficiency virus. Expert Rev Mol Med 2008; 10:e30. [PMID: 18928579 DOI: 10.1017/s1462399408000847] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) is associated with increased HCV replication and a more rapid progression to severe liver disease, including the development of cirrhosis and hepatocellular carcinoma. In this review, we discuss the current understanding of the pathogenesis of HCV/HIV coinfection and the cellular and molecular mechanisms associated with the accelerated course of liver disease. The strength and breadth of HCV-specific T-cell responses are reduced in HCV/HIV-coinfected patients compared with those infected with HCV alone, suggesting that the immunosuppression induced by HIV compromises immune responses to HCV. HCV is not directly cytopathic, but many of the pathological changes observed in the liver of infected patients are a direct result of the intrahepatic antiviral immune responses. Apoptosis also has a role in HCV-mediated liver damage through the induction of apoptotic pathways involving the host immune response and HCV viral proteins. This review summarises the evidence correlating the role of cell-mediated immune responses and apoptosis with liver disease progression in HCV/HIV-coinfected patients.
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Cytokine levels of TGF-beta, IL-10, and sTNFalphaRII in type C chronic liver disease. Dig Dis Sci 2008; 53:2233-7. [PMID: 18080762 DOI: 10.1007/s10620-007-0130-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2007] [Accepted: 11/09/2007] [Indexed: 01/14/2023]
Abstract
Cytokines play a key role in regulation of immunity and inflammation. The aim of the study was to detect serum levels of TGF-beta, IL-10, and sTNFalphaRII in patients with type C chronic liver disease (CLD) and to correlate these with biochemical and histopathological parameters used to assess the severity of the disease. Blood samples were aseptically collected from 90 CLD patients. Cytokine levels were also followed up in 39 chronic hepatitis cases. Levels of the cytokines in 90 CLD patients were significantly higher than in controls. In the follow up patients, 12 were non-responders and the serum levels of cytokines were still elevated after therapy whereas in 27 responders cytokine levels were significantly reduced after therapy and correlated well with biochemical and histopathological parameters. It is inferred that cytokine levels reflect the level of inflammation in chronic hepatitis C virus (HCV) infection and can be used as indirect markers to assess the severity of liver disease.
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Neuman MG, Sha K, Esguerra R, Zakhari S, Winkler RE, Hilzenrat N, Wyse J, Cooper CL, Seth D, Gorrell MD, Haber PS, McCaughan GW, Leo MA, Lieber CS, Voiculescu M, Buzatu E, Ionescu C, Dudas J, Saile B, Ramadori G. Inflammation and repair in viral hepatitis C. Dig Dis Sci 2008; 53:1468-87. [PMID: 17994278 DOI: 10.1007/s10620-007-0047-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2007] [Accepted: 09/26/2007] [Indexed: 02/07/2023]
Abstract
Hepatitis C viral infection (HCV) results in liver damage leading to inflammation and fibrosis of the liver and increasing rates of hepatic decompensation and hepatocellular carcinoma (HCC). However, the host's immune response and viral determinants of liver disease progression are poorly understood. This review will address the determinants of liver injury in chronic HCV infection and the risk factors leading to rapid disease progression. We aim to better understand the factors that distinguish a relatively benign course of HCV from one with progression to cirrhosis. We will accomplish this task by discussion of three topics: (1) the role of cytokines in the adaptive immune response against the HCV infection; (2) the progression of fibrosis; and (3) the risk factors of co-morbidity with alcohol and human immunodeficiency virus (HIV) in HCV-infected individuals. Despite recent improvements in treating HCV infection using pegylated interferon alpha (PEGIFN-alpha) and ribavirin, about half of individuals infected with some genotypes, for example genotypes 1 and 4, will not respond to treatment or cannot be treated because of contraindications. This review will also aim to describe the importance of IFN-alpha-based therapies in HCV infection, ways of monitoring them, and associated complications.
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Affiliation(s)
- Manuela G Neuman
- In Vitro Drug Safety and Biotechnology, Department of Pharmacology, Biophysics and Global Health, Institute of Drug Research, University of Toronto, Toronto, ON, Canada.
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Zekri ARN, Haleem HA, Esmat GED, Bahnassy AA, El-Din HMA, Hafez MM, Sharaby AF, Sharaf H, Zakaria MSED. Immunomodulators, sFas and Fas-L as potential noninvasive predictors of IFN treatment in patients with HCV genotype-4. J Viral Hepat 2007; 14:468-77. [PMID: 17576388 DOI: 10.1111/j.1365-2893.2006.00832.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Recent studies have indicated that cytokines can be used as markers for disease progression in hepatitis C virus (HCV)-infected patients, therefore this study was conducted to determine the influence of pegylated IFN vs standard IFN on interleukin-2 receptor (IL-2R), IL-6R, IL-8, TNFR-I, TNFR-II, sFas, and sFas-L in Egyptian patients with chronic hepatitis C genotype 4, as no previous studies have been performed on this genotype. We also aim at establishing a possible relationship between these cytokines and the response to INF to determine whether they can be used as noninvasive markers for the response to INF therapy and as monitors for the outcome of treatment. Thirty-eight patients with chronic HCV hepatitis were investigated for the serum levels of the previously mentioned cytokines in a randomized opened controlled trial (22 patients treated with pegylated IFN and 16 patients treated with standard IFN). Cytokine levels were measured by ELISA at 0, 1 and 12 months of IFN therapy. There was marked increase in the serum levels of IL-2R and IL-6R in nonresponders to pegylated interferon, IL-8, TNFR-I and II were significantly higher in nonresponders to standard interferon but were also high in responders of pegylated interferon. sFas and sFas-L showed high levels among responders to pegylated interferon but the standard interferon was again less effective in this regard. Serum levels of TNFR-II, sFas and sFas-L have the potential to be used as serological markers for response to pegylated IFN therapy, and IL-8 is a predictor for nonresponse. Moreover, TNFR-I and II have the potential to be used as markers of response to standard IFN treatment. The persistent correlation between sFas and TNFR-II may elaborate the possible role of pegylated IFN in the induction of apoptosis as a possible new mechanism of viral clearance during treatment with pegylated interferon treatment.
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Affiliation(s)
- A R N Zekri
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
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Abstract
Hepatocellular carcinoma (HCC) is a frequent malignancy worldwide with a high rate of metastasis. The hepatitis B and C viruses are considered major etiological factors associated with the development of HCC, particularly as a result of their induction of chronic inflammation. There is increasing evidence that the inflammatory process is inherently associated with many different cancer types, including HCC. Specifically, this review aims to cover evidence for the potential roles of cytokines, an important component of the immune system, in promoting HCC carcinogenesis and progression. A global summary of cytokine levels, functions, polymorphisms, and therapies with regard to HCC is presented. In particular, the role of proinflammatory Th1 and anti-inflammatory Th2 cytokine imbalances in the microenvironment of HCC patients with metastasis and the possible clinical significance of these findings are addressed. Overall, multiple studies, spanning many decades, have begun to elucidate the important role of cytokines in HCC.
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Affiliation(s)
- Anuradha Budhu
- National Cancer Institute, 37 Convent Dr., Bldg. 37, Rm. 3044A, Bethesda, MD 20892, USA
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