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Elabd NS, Helal ML, Elkhayat M, Abd-ElKhalek HK, Ahmed DM, El-Shemy AM, Elsaadawy YS, Abdelmoneum RA, AboShabaan HS, Seddik RM. Insights into the Correlation between Toll-Like Receptor 2 Polymorphism and HBV-Related Disease Progression and Occurrence of Hepatocellular Carcinoma: A Case-Control Study in Egyptian Patients. THE CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY = JOURNAL CANADIEN DES MALADIES INFECTIEUSES ET DE LA MICROBIOLOGIE MEDICALE 2024; 2024:5797895. [PMID: 39071840 PMCID: PMC11281855 DOI: 10.1155/2024/5797895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 02/18/2024] [Accepted: 06/27/2024] [Indexed: 07/30/2024]
Abstract
Methods In total, 170 chronic HBV patients and 50 healthy controls of comparable age and gender were included in this case-control study. Clinical, laboratory, and imaging evaluations were conducted. ELISA was used to determine serum IL-6 levels, and TLR2 (rs3804099) genotyping allelic discrimination assay was performed using real-time PCR. Results IL-6 values were significantly higher in the HCC group, followed by the cirrhotic group, than those in chronic hepatitis and control groups (p < 0.001), with a significant correlation with disease activity and progression parameters. TRL2 homozygous TT was the most frequent in the control group, but the CC genotype was significantly more prevalent in the HCC group than that in the other groups. Furthermore, the CC genetic variant was associated with higher levels of IL-6 and viral load in all HBV patients, whereas the TT genotype was associated with larger tumor size. Multivariate regression analysis demonstrated that in chronic HBV patients, viral load and TRL2 polymorphism are independent risk factors associated with the progression from chronic hepatitis to liver cirrhosis and to HCC. Similarly, the HBV viral load (p=0.03, OR = 2.45, and 95% CI: 1.69-3.65), IL-6 levels (p=0.04, OR = 3.45, and 95% CI: 2.01-6.9), and TRL2 variants (p=0.01, OR = 4.25, and 95% CI: 2.14-13.5) are independent risk factors associated with disease progression from cirrhosis to HCC. Conclusion In chronic HBV patients, TRL2 polymorphism and higher IL-6 levels were positively correlated with a higher likelihood of HCC and chronic hepatitis B disease activity and progression.
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Affiliation(s)
- Naglaa S. Elabd
- Department of Tropical MedicineFaculty of MedicineMenoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Marwa L. Helal
- Department of Clinical Biochemistry and Molecular DiagnosticsNational Liver InstituteMenoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Mohsen Elkhayat
- Department of Tropical MedicineFaculty of MedicineMenoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Heba Kamal Abd-ElKhalek
- Department of Internal MedicineFaculty of MedicineMenoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Doaa M. Ahmed
- Department of RadiologyFaculty of MedicineMenoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Asmaa M. El-Shemy
- Department of Clinical PathologyFaculty of MedicineMenoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Yara S. Elsaadawy
- Department of Medical Microbiology and ImmunologyFaculty of MedicineAin Shams University, Cairo, Egypt
| | - Rasha A. Abdelmoneum
- Department of Clinical Oncology and Nuclear MedicineFaculty of MedicineMenoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Hind S. AboShabaan
- BiochemistryNational Liver Institute HospitalMenoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Randa M. Seddik
- Department of Tropical MedicineFaculty of MedicineMenoufia University, Shebin El-Kom, Menoufia, Egypt
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Rytkönen A, Eray M, Suominen A, Mäkitie A, Haglund C, Hagström J, Laine HK. Immunoexpression pattern of TLR3 and TLR7 in minor salivary gland adenoid cystic carcinoma and its role in prognosis. Cancer Treat Res Commun 2024; 40:100822. [PMID: 38810370 DOI: 10.1016/j.ctarc.2024.100822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/17/2024] [Accepted: 05/21/2024] [Indexed: 05/31/2024]
Abstract
OBJECTIVES Adenoid cystic carcinoma (ACC) of the salivary glands has poor long-term prognosis and a high metastatic rate. Toll-like receptors (TLRs), first-line immune activators, have been associated with both tumor progression and suppression. We aimed to study TLR3 and TLR7 behavior in ACC. MATERIALS AND METHODS We studied TLR3 and TLR7 immunoexpression of 46 minor salivary gland ACCs diagnosed at the Department of Otorhinolaryngology - Head and Neck Surgery, Helsinki University Hospital, Helsinki, Finland over the period 1974-2012. The associations of TLR3 and TLR7 immunoexpression with clinicopathological factors were evaluated by χ2-test and Fisher's exact test. RESULTS In the majority of samples, both TLR3 and TLR7 were immunoexpressed in cytoplasm. The immunoexpression was heterogeneous between individual tumors. Stronger TLR7 immunoexpression associated with recurrence rate and poorer disease-specific survival (DSS). TLR3 did not associate significantly with survival although we found an inverse correlation between TLR3 and TLR7 immunopositivity. Hence, when TLR3 immunoexpression was negative or mild, TLR7 immunoexpression was moderate to strong, and vice versa. CONCLUSIONS TLR3 and TLR7 are immunoexpressed in minor salivary gland ACC. TLR7 is potentially an independent prognostic marker for recurrence rate and DSS.
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MESH Headings
- Humans
- Toll-Like Receptor 7/metabolism
- Toll-Like Receptor 3/metabolism
- Carcinoma, Adenoid Cystic/pathology
- Carcinoma, Adenoid Cystic/mortality
- Carcinoma, Adenoid Cystic/metabolism
- Carcinoma, Adenoid Cystic/immunology
- Salivary Gland Neoplasms/mortality
- Salivary Gland Neoplasms/pathology
- Salivary Gland Neoplasms/metabolism
- Salivary Gland Neoplasms/immunology
- Female
- Prognosis
- Male
- Middle Aged
- Salivary Glands, Minor/pathology
- Salivary Glands, Minor/metabolism
- Adult
- Aged
- Biomarkers, Tumor/metabolism
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/metabolism
- Aged, 80 and over
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Affiliation(s)
- Aleksi Rytkönen
- Department of Pathology, Oulu University Hospital, Oulu, Finland; Department of Oral Pathology and Radiology, University of Turku and Turku University Hospital, Turku, Finland
| | - Mine Eray
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Auli Suominen
- Department of Community Dentistry, University of Turku, Turku, Finland
| | - Antti Mäkitie
- Department of Otorhinolaryngology - Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Division of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Caj Haglund
- Research Programs Unit, Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland; Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jaana Hagström
- Department of Oral Pathology and Radiology, University of Turku and Turku University Hospital, Turku, Finland; Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Programs Unit, Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland
| | - Hanna K Laine
- Department of Oral Pathology and Radiology, University of Turku and Turku University Hospital, Turku, Finland; Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.
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3
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Kalita S, Kalita MJ, Talukdar AJ, Das PP, Dutta K, Hazarika G, Dutta S, Das P, Idris G, Kaur H, Medhi S. Altered TLR7 Expression-Mediated Immune Modulation Is Supportive of Persistent Replication and Intrauterine Transmission of HBV. Viral Immunol 2024; 37:149-158. [PMID: 38573237 DOI: 10.1089/vim.2023.0117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2024] Open
Abstract
Hepatitis B Virus (HBV) is posing as a serious public health threat mainly due to its asymptomatic nature of infection in pregnancy and vertical transmission. Viral sensing toll-like receptors (TLR) and Interleukins (IL) are important molecules in providing an antiviral state. The study aimed to assess the role of TLR7-mediated immune modulation, which might have an impact in the intrauterine transmission of HBV leading to mother to child transmission of the virus. We investigated the expression pattern of TLR7, IL-3, and IL-6 by RT-PCR in the placentas of HBV-infected pregnant women to see their role in the intrauterine transmission of HBV. We further validated the expression of TLR7 in placentas using Immunohistochemistry. Expression analysis by RT-PCR of TLR7 revealed significant downregulation among the Cord blood (CB) HBV DNA positive and negative cases with mean ± standard deviation (SD) of 0.43 ± 0.22 (28) and 1.14 ± 0.57 (44) with p = 0.001. IL-3 and IL-6 expression revealed significant upregulation in the CB HBV DNA-positive cases with p = 0.001. Multinomial logistic regression analysis revealed that TLR7 and IL-3 fold change and mother HBeAg status are important predictors for HBV mother to child transmission. Immunohistochemistry revealed the decreased expression of TLR7 in CB HBV DNA-positive cases. This study reveals that the downregulation of TLR7 in the placenta along with CB HBV DNA-positive status may lead to intrauterine transmission of HBV, which may lead to vertical transmission of HBV.
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Affiliation(s)
- Simanta Kalita
- Department of Bioengineering & Technology, Gauhati University, Guwahati India
| | - Manash Jyoti Kalita
- Department of Bioengineering & Technology, Gauhati University, Guwahati India
| | | | - Partha Pratim Das
- Department of Bioengineering & Technology, Gauhati University, Guwahati India
- Multidisciplinary Research Unit, Fakhruddin Ali Ahmed Medical College and Hospital, Barpeta, India
| | - Kalpajit Dutta
- Department of Bioengineering & Technology, Gauhati University, Guwahati India
| | - Gautam Hazarika
- Department of Bioengineering & Technology, Gauhati University, Guwahati India
| | - Sangit Dutta
- Department of Medicine, Gauhati Medical College and Hospital, Guwahati, India
| | - Panchanan Das
- Department of Obstetrics and Gynaecology, Gauhati Medical College and Hospital, Guwahati, India
| | - Ghaznavi Idris
- Department of Bioengineering & Technology, Gauhati University, Guwahati India
| | - Harpreet Kaur
- Epidemiology and Communicable Diseases Division, Indian Council of Medical Research, New Delhi, India
| | - Subhash Medhi
- Department of Bioengineering & Technology, Gauhati University, Guwahati India
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Soleiman-Meigooni S, Yarahmadi A, Kheirkhah AH, Afkhami H. Recent advances in different interactions between toll-like receptors and hepatitis B infection: a review. Front Immunol 2024; 15:1363996. [PMID: 38545106 PMCID: PMC10965641 DOI: 10.3389/fimmu.2024.1363996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 02/26/2024] [Indexed: 04/17/2024] Open
Abstract
Hepatitis B virus (HBV) B infections remain a primary global health concern. The immunopathology of the infection, specifically the interactions between HBV and the host immune system, remains somewhat unknown. It has been discovered that innate immune reactions are vital in eliminating HBV. Toll-like receptors (TLRs) are an essential category of proteins that detect pathogen-associated molecular patterns (PAMPs). They begin pathways of intracellular signals to stimulate pro-inflammatory and anti-inflammatory cytokines, thus forming adaptive immune reactions. HBV TLRs include TLR2, TLR3, TLR4, TLR7 and TLR9. Each TLR has its particular molecule to recognize; various TLRs impact HBV and play distinct roles in the pathogenesis of the disease. TLR gene polymorphisms may have an advantageous or disadvantageous efficacy on HBV infection, and some single nucleotide polymorphisms (SNPs) can influence the progression or prognosis of infection. Additionally, it has been discovered that similar SNPs in TLR genes might have varied effects on distinct populations due to stress, diet, and external physical variables. In addition, activation of TLR-interceded signaling pathways could suppress HBV replication and increase HBV-particular T-cell and B-cell reactions. By identifying these associated polymorphisms, we can efficiently advance the immune efficacy of vaccines. Additionally, this will enhance our capability to forecast the danger of HBV infection or the threat of dependent liver disease development via several TLR SNPs, thus playing a role in the inhibition, monitoring, and even treatment guidance for HBV infection. This review will show TLR polymorphisms, their influence on TLR signaling, and their associations with HBV diseases.
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Affiliation(s)
| | - Aref Yarahmadi
- Department of Biology, Khorramabad Branch, Islamic Azad University, Khorramabad, Iran
| | - Amir-Hossein Kheirkhah
- Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Hamed Afkhami
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
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5
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Al-Alawi FZM, Kariminik A, Tajbakhsh E. Toll-like receptors and Streptococcus mutans: An updated review article. Allergol Immunopathol (Madr) 2024; 52:79-84. [PMID: 38186197 DOI: 10.15586/aei.v52i1.935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 10/10/2023] [Indexed: 01/09/2024]
Abstract
It has been reported that toll-like receptors (TLRs) are the main innate immune receptors that recognize gram-positive pathogen-associated molecular patterns (PAMPs). The molecules can induce expression of the innate immune-related molecules that are essential against the bacteria. Streptococcus mutans (S. mutans) is a potential caries-associated pathogen, and innate immunity plays a key role in inhibiting its development and the progression of inflammatory responses. Recently, the roles played by TLRs against S. mutans and the induction of inflammatory responses were evaluated by several investigations. This review article discusses updated information regarding the roles played by TLRs and their potential therapeutic effects against S. mutans.
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Affiliation(s)
| | - Ashraf Kariminik
- Department of Microbiology, Kerman Branch, Islamic Azad University, Kerman, Iran;
| | - Elaheh Tajbakhsh
- Department of Microbiology, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
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6
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Zhang MH, Yuan YF, Liu LJ, Wei YX, Yin WY, Zheng LZY, Tang YY, Lv Z, Zhu F. Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:4706-4735. [PMID: 37664153 PMCID: PMC10473924 DOI: 10.3748/wjg.v29.i31.4706] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/29/2023] [Accepted: 08/01/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a high incidence and fatality rate worldwide. Hepatitis B virus (HBV) infection is one of the most important risk factors for its occurrence and development. Early detection of HBV-associated HCC (HBV-HCC) can improve clinical decision-making and patient outcomes. Biomarkers are extremely helpful, not only for early diagnosis, but also for the development of therapeutics. MicroRNAs (miRNAs), a subset of non-coding RNAs approximately 22 nucleotides in length, have increasingly attracted scientists' attention due to their potential utility as biomarkers for cancer detection and therapy. HBV profoundly impacts the expression of miRNAs potentially involved in the development of hepatocarcinogenesis. In this review, we summarize the current progress on the role of miRNAs in the diagnosis and treatment of HBV-HCC. From a molecular standpoint, we discuss the mechanism by which HBV regulates miRNAs and investigate the exact effect of miRNAs on the promotion of HCC. In the near future, miRNA-based diagnostic, prognostic, and therapeutic applications will make their way into the clinical routine.
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Affiliation(s)
- Ming-He Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Feng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li-Juan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Xin Wei
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wan-Yue Yin
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Lan-Zhuo-Yin Zheng
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ying-Ying Tang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhao Lv
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, Hubei Province, China
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7
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Patil VS, Harish DR, Sampat GH, Roy S, Jalalpure SS, Khanal P, Gujarathi SS, Hegde HV. System Biology Investigation Revealed Lipopolysaccharide and Alcohol-Induced Hepatocellular Carcinoma Resembled Hepatitis B Virus Immunobiology and Pathogenesis. Int J Mol Sci 2023; 24:11146. [PMID: 37446321 DOI: 10.3390/ijms241311146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 07/15/2023] Open
Abstract
Hepatitis B infection caused by the hepatitis B virus is a life-threatening cause of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Researchers have produced multiple in vivo models for hepatitis B virus (HBV) and, currently, there are no specific laboratory animal models available to study HBV pathogenesis or immune response; nonetheless, their limitations prevent them from being used to study HBV pathogenesis, immune response, or therapeutic methods because HBV can only infect humans and chimpanzees. The current study is the first of its kind to identify a suitable chemically induced liver cirrhosis/HCC model that parallels HBV pathophysiology. Initially, data from the peer-reviewed literature and the GeneCards database were compiled to identify the genes that HBV and seven drugs (acetaminophen, isoniazid, alcohol, D-galactosamine, lipopolysaccharide, thioacetamide, and rifampicin) regulate. Functional enrichment analysis was performed in the STRING server. The network HBV/Chemical, genes, and pathways were constructed by Cytoscape 3.6.1. About 1546 genes were modulated by HBV, of which 25.2% and 17.6% of the genes were common for alcohol and lipopolysaccharide-induced hepatitis. In accordance with the enrichment analysis, HBV activates the signaling pathways for apoptosis, cell cycle, PI3K-Akt, TNF, JAK-STAT, MAPK, chemokines, NF-kappa B, and TGF-beta. In addition, alcohol and lipopolysaccharide significantly activated these pathways more than other chemicals, with higher gene counts and lower FDR scores. In conclusion, alcohol-induced hepatitis could be a suitable model to study chronic HBV infection and lipopolysaccharide-induced hepatitis for an acute inflammatory response to HBV.
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Affiliation(s)
- Vishal S Patil
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Darasaguppe R Harish
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
| | - Ganesh H Sampat
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Subarna Roy
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
| | - Sunil S Jalalpure
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Pukar Khanal
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Swarup S Gujarathi
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Harsha V Hegde
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
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8
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Zhao J, Jeong H, Yang D, Tian W, Kim JW, Woong Lim C, Kim B. Toll-like receptor-7 signaling in Kupffer cells exacerbates concanavalin A-induced liver injury in mice. Int Immunopharmacol 2023; 119:110238. [PMID: 37126986 DOI: 10.1016/j.intimp.2023.110238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 04/19/2023] [Accepted: 04/21/2023] [Indexed: 05/03/2023]
Abstract
Concanavalin A (ConA) is a plant lectin that can induce immune-mediated liver damage. ConA induced liver damage animal model is a widely accepted model that can mimic clinical acute hepatitis and immune-mediated liver injury in humans. Toll-like receptor-7 (TLR7), a member of the TLR family, plays a key role in pathogen recognition and innate immune activation. The aim of this study was to examine the role of TLR7 in the pathogenesis of ConA-induced liver injury. Acute liver injury was induced by intravenous injection with ConA in WT (wild-type) and TLR7 knockout (KO) mice. Results showed that attenuated liver injury in TLR7-deficient mice, as indicated by increased survival rate, decreased aminotransferase levels, and reduced pathological lesions, was associated with decreased release of pro-inflammatory cytokines in livers. Consistently, significantly decreased proliferation of CD4+ T cell was detected in ConA-stimulated TLR7-deficient splenocytes, but not in CD3/CD28 stimulated TLR7-deficient CD4+ T cells. Moreover, TLR7 deficiency in KCs specifically suppressed the expression of TNF-α (tumor necrosis factor-α). Depletion of KCs abolished the detrimental role of TLR7 in ConA-induced liver injury. Taken together, these results demonstrate that TLR7 can regulate the expression of TNF-α in KCs, which is necessary for the full progression of ConA-induced liver injury.
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Affiliation(s)
- Jing Zhao
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China; Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea.
| | - Hyuneui Jeong
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea.
| | - Daram Yang
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea.
| | - Weishun Tian
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China.
| | - Jong-Won Kim
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea.
| | - Chae Woong Lim
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea.
| | - Bumseok Kim
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea.
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9
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Osawa Y, Ohtake T, Suto D, Akita T, Yamada H, Kohgo Y, Murata K. Cases of Rapid Hepatitis B Surface Antigen Reduction after COVID-19 Vaccination. Intern Med 2023; 62:51-57. [PMID: 36261382 PMCID: PMC9876716 DOI: 10.2169/internalmedicine.0842-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Objective One of the therapeutic goals for chronic infection with hepatitis B virus is the clearance of hepatitis B surface antigen (HBsAg) from the blood, as a high load of HBsAg has been proposed to induce antigen-specific immunotolerance. To achieve HBsAg reduction, Pegylated interferon and nucleos (t) ide analogs are used to treat chronic hepatitis B. Following the coronavirus disease 2019 (COVID-19) outbreak, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has rapidly spread worldwide, and vaccination with mRNA COVID-19 vaccines has been conducted since 2021 in Japan. We experienced three clinical cases in which HBsAg levels rapidly decreased after injection of the COVID-19 vaccine without any incentive. Method To examine whether the vaccine administration was involved in the HBsAg reduction, the number of patients with chronic hepatitis B showing a change in the HBsAg levels during the period before the commencement of the COVID-19 vaccination program in Japan (i.e. until the end of 2020; pre-vaccination-program period) was compared to the number of those who showed a change in HBsAg levels after the initiation of the program (i.e. 2021 onwards; post-vaccination-program period). Results The number of patients whose HBsAg levels was reduced by >50% per year was prominent after the initiation of the vaccination program. Although the involvement of vaccination in HBsAg reduction was not statistically proven (p=0.0532), the result suggests that the administration of COVID-19 vaccines may have been involved in HBsAg reduction in patients with chronic hepatitis B. Conclusion COVID-19 vaccines may be involved in HBsAg reduction.
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Affiliation(s)
- Yosuke Osawa
- Department of Gastroenterology, International University of Health and Welfare Hospital, Japan
| | - Takaaki Ohtake
- Department of Gastroenterology, International University of Health and Welfare Hospital, Japan
| | - Daisuke Suto
- Department of Gastroenterology, International University of Health and Welfare Hospital, Japan
| | - Takayuki Akita
- Department of Gastroenterology, International University of Health and Welfare Hospital, Japan
| | - Hidehiko Yamada
- Department of Gastroenterology, International University of Health and Welfare Hospital, Japan
| | - Yutaka Kohgo
- Department of Gastroenterology, International University of Health and Welfare Hospital, Japan
| | - Kazumoto Murata
- Department of Gastroenterology, International University of Health and Welfare Hospital, Japan
- Division of Virology, Department of Infection and Immunity, Jichi Medical University, Japan
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10
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Suresh M, Menne S. Recent Drug Development in the Woodchuck Model of Chronic Hepatitis B. Viruses 2022; 14:v14081711. [PMID: 36016334 PMCID: PMC9416195 DOI: 10.3390/v14081711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/22/2022] [Accepted: 07/31/2022] [Indexed: 11/24/2022] Open
Abstract
Infection with hepatitis B virus (HBV) is responsible for the increasing global hepatitis burden, with an estimated 296 million people being carriers and living with the risk of developing chronic liver disease and cancer. While the current treatment options for chronic hepatitis B (CHB), including oral nucleos(t)ide analogs and systemic interferon-alpha, are deemed suboptimal, the path to finding an ultimate cure for this viral disease is rather challenging. The lack of suitable laboratory animal models that support HBV infection and associated liver disease progression is one of the major hurdles in antiviral drug development. For more than four decades, experimental infection of the Eastern woodchuck with woodchuck hepatitis virus has been applied for studying the immunopathogenesis of HBV and developing new antiviral therapeutics against CHB. There are several advantages to this animal model that are beneficial for performing both basic and translational HBV research. Previous review articles have focused on the value of this animal model in regard to HBV replication, pathogenesis, and immune response. In this article, we review studies of drug development and preclinical evaluation of direct-acting antivirals, immunomodulators, therapeutic vaccines, and inhibitors of viral entry, gene expression, and antigen release in the woodchuck model of CHB since 2014 until today and discuss their significance for clinical trials in patients.
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11
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Wildum S, Korolowicz KE, Suresh M, Steiner G, Dai L, Li B, Yon C, De Vera Mudry MC, Regenass-Lechner F, Huang X, Hong X, Murreddu MG, Kallakury BV, Young JAT, Menne S. Toll-Like Receptor 7 Agonist RG7854 Mediates Therapeutic Efficacy and Seroconversion in Woodchucks With Chronic Hepatitis B. Front Immunol 2022; 13:884113. [PMID: 35677037 PMCID: PMC9169629 DOI: 10.3389/fimmu.2022.884113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 04/22/2022] [Indexed: 01/04/2023] Open
Abstract
Conventional treatment of chronic hepatitis B (CHB) is rarely curative due to the immunotolerant status of patients. RG7854 is an oral double prodrug of a toll-like receptor 7 (TLR7) agonist that is developed for the treatment of CHB. The therapeutic efficacy, host immune response, and safety of RG7854 were evaluated in the woodchuck model of CHB. Monotreatment with the two highest RG7854 doses and combination treatment with the highest RG7854 dose and entecavir (ETV) suppressed viral replication, led to loss of viral antigens, and induced seroconversion in responder woodchucks. Since viral suppression and high-titer antibodies persisted after treatment ended, this suggested that a sustained antiviral response (SVR) was induced by RG7854 in a subset of animals. The SVR rate, however, was comparable between both treatment regimens, suggesting that the addition of ETV did not enhance the therapeutic efficacy of RG7854 although it augmented the proliferation of blood cells in response to viral antigens and magnitude of antibody titers. The induction of interferon-stimulated genes in blood by RG7854/ETV combination treatment demonstrated on-target activation of TLR7. Together with the virus-specific blood cell proliferation and the transient elevations in liver enzymes and inflammation, this suggested that cytokine-mediated non-cytolytic and T-cell mediated cytolytic mechanisms contributed to the SVR, in addition to the virus-neutralizing effects by antibody-producing plasma cells. Both RG7854 regimens were not associated with treatment-limiting adverse effects but accompanied by dose-dependent, transient neutropenia and thrombocytopenia. The study concluded that finite, oral RG7854 treatment can induce a SVR in woodchucks that is based on the retrieval of antiviral innate and adaptive immune responses. This supports future investigation of the TLR7 agonist as an immunotherapeutic approach for achieving functional cure in patients with CHB.
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Affiliation(s)
- Steffen Wildum
- Roche Pharma, Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Kyle E Korolowicz
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Manasa Suresh
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Guido Steiner
- Roche Pharma, Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Lue Dai
- Roche Pharma, Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China
| | - Bin Li
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Changsuek Yon
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | | | | | - Xu Huang
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Xupeng Hong
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Marta G Murreddu
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Bhaskar V Kallakury
- Department of Pathology, Georgetown University Medical Center, Washington, DC, United States
| | - John A T Young
- Roche Pharma, Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Stephan Menne
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
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12
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Douzandeh-Mobarrez B, Kariminik A, Kazemi Arababadi M, Kheirkhah B. TLR9 in the Human Papilloma Virus Infections: Friend or Foe? Viral Immunol 2022; 35:457-464. [PMID: 35588473 DOI: 10.1089/vim.2021.0223] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Immune system plays dual roles during human papilloma virus (HPV) infections, from defense against the virus to induction or stimulation of the HPV-related cancers. It appears that various differences within the immune-related genes and the functions of the immunological parameters of the patients are the main factors responsible for the roles played by immune system during HPV infections. Toll-like receptors (TLRs) play key roles in the recognition of viruses and activation of immune responses. The molecules also can alter the target cell intracellular signaling and may participate in the transformation of the infected cells. TLR9 is the unique intracellular member of TLRs that recognize foreign DNA, including viral DNA. Thus, TLR9 may play significant roles in the defense against HPV and its related cancers. This review article discusses TLR9 antiviral and pathological roles during HPV infection.
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Affiliation(s)
| | - Ashraf Kariminik
- Department of Microbiology, Kerman Branch, Islamic Azad University, Kerman, Iran
| | - Mohammad Kazemi Arababadi
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Babak Kheirkhah
- Department of Veterinary Medicine, Baft Branch, Islamic Azad University, Baft, Iran
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13
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Naghib M, Kariminik A, Kazemi Arababadi M. TLR2, as a Pathogen Recognition Receptor, Plays Critical Roles in Hepatitis B Outcome. Viral Immunol 2022; 35:15-23. [PMID: 35020525 DOI: 10.1089/vim.2021.0141] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The immune system of active and inactive chronic hepatitis B, as prolonged forms of hepatitis B, is unable to eradicate hepatitis B virus (HBV) from the infected hepatocytes completely. Toll-like receptors (TLRs) play key roles in the viral recognition and promotion of appropriate immune responses. The molecules also participate in the alteration of the target cell functions and transformation. TLR2 is the unique molecule that makes either homodimer or heterodimer with TLR1 and 6 and shows variable roles against viral infections. Therefore, it has been hypothesized that TLR2 may participate in both immune response against HBV and induction of the virus-related hepatic complications. The studies confirm the hypothesis and revealed that TLR2 is not only one of the main molecules altering the course of HBV infection, but also plays key roles in induction of hepatocellular carcinoma (HCC) and liver cirrhosis. However, recent studies demonstrated that the molecule can fight against HCC and liver cirrhosis. Collectively, it appears that nutrition habits, TLR2 gene polymorphisms, gut microbiome, HBV antigens, and activation of other receptors may play key roles in the determination of TLR2 functions.
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Affiliation(s)
- Maryam Naghib
- Department of Microbiology, Kerman Branch, Islamic Azad University, Kerman, Iran
| | - Ashraf Kariminik
- Department of Microbiology, Kerman Branch, Islamic Azad University, Kerman, Iran
| | - Mohammad Kazemi Arababadi
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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14
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Xu C, Chen J, Chen X. Host Innate Immunity Against Hepatitis Viruses and Viral Immune Evasion. Front Microbiol 2021; 12:740464. [PMID: 34803956 PMCID: PMC8598044 DOI: 10.3389/fmicb.2021.740464] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/29/2021] [Indexed: 11/13/2022] Open
Abstract
Hepatitis viruses are primary causative agents of hepatitis and represent a major source of public health problems in the world. The host innate immune system forms the first line of defense against hepatitis viruses. Hepatitis viruses are sensed by specific pathogen recognition receptors (PRRs) that subsequently trigger the innate immune response and interferon (IFN) production. However, hepatitis viruses evade host immune surveillance via multiple strategies, which help compromise the innate immune response and create a favorable environment for viral replication. Therefore, this article reviews published findings regarding host innate immune sensing and response against hepatitis viruses. Furthermore, we also focus on how hepatitis viruses abrogate the antiviral effects of the host innate immune system.
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Affiliation(s)
- Chonghui Xu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jizheng Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.,Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Xinwen Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.,Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
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15
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Ionizing radiation and toll like receptors: A systematic review article. Hum Immunol 2021; 82:446-454. [PMID: 33812705 DOI: 10.1016/j.humimm.2021.03.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 03/07/2021] [Accepted: 03/19/2021] [Indexed: 11/24/2022]
Abstract
Ionizing radiation, including X and gamma rays, are used for various purposes such as; medicine, nuclear power, research, manufacturing, food preservation and construction. Furthermore, people are also exposed to ionizing radiation from their workplace or the environment. Apart from DNA fragmentation resulting in apoptosis, several additional mechanisms have been proposed to describe how radiation can alter human cell functions. Ionizing radiation may alter immune responses, which are the main cause of human disorders. Toll like receptors (TLRs) are important human innate immunity receptors which participate in several immune and non-immune cell functions including, induction of appropriate immune responses and immune related disorders. Based on the role played by ionizing radiation on human cell systems, it has been hypothesized that radiation may affect immune responses. Therefore, the main aim of this review article is to discuss recent information regarding the effects of ionizing radiation on TLRs and their related disorders.
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16
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Safaei S, Karimi-Googheri M. Letter to the Editor: Toll-Like Receptor Antagonists as a Potential Therapeutic Strategy Against Cytokine Storm in COVID-19-Infected Patients. Viral Immunol 2020; 34:361-362. [PMID: 33012270 DOI: 10.1089/vim.2020.0074] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Affiliation(s)
- Sadegh Safaei
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Student Research Committee, Iran University of Medical Sciences, Tehran, Iran.,Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Masoud Karimi-Googheri
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Student Research Committee, Iran University of Medical Sciences, Tehran, Iran.,Department of Clinical Laboratory, Shafa Hospital, Kerman University of Medical Sciences, Kerman, Iran
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17
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Moghbeli M. Genetic and Molecular Biology of Multiple Sclerosis Among Iranian Patients: An Overview. Cell Mol Neurobiol 2020; 40:65-85. [PMID: 31482432 PMCID: PMC11448812 DOI: 10.1007/s10571-019-00731-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 08/24/2019] [Indexed: 12/16/2022]
Abstract
Multiple sclerosis (MS) is one if the common types of autoimmune disorders in developed countries. Various environmental and genetic factors are associated with initiation and progression of MS. It is believed that the life style changes can be one of the main environmental risk factors. The environmental factors are widely studied and reported, whereas minority of reports have considered the role of genetic factors in biology of MS. Although Iran is a low-risk country in the case of MS prevalence, it has been shown that there was a dramatically rising trend of MS prevalence among Iranian population during recent decades. Therefore, it is required to assess the probable MS risk factors in Iran. In the present study, we summarized all of the reported genes until now which have been associated with MS susceptibility among Iranian patients. To clarify the probable molecular biology of MS progression, we categorized these reported genes based on their cellular functions. This review paves the way of introducing a specific population-based diagnostic panel of genetic markers among the Iranian population for the first time in the world.
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Affiliation(s)
- Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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18
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A comprehensive mechanistic review insight into the effects of micronutrients on toll-like receptors functions. Pharmacol Res 2019; 152:104619. [PMID: 31887355 DOI: 10.1016/j.phrs.2019.104619] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/23/2019] [Accepted: 12/26/2019] [Indexed: 12/29/2022]
Abstract
Toll-like receptors (TLRs) are the special proteins receptors for recognition of molecules related to the pathogens. In this way, TLRs and secreted cytokines as a result of TLRs activation are involved in the inflammation pathways. So far, in vivo and in vitro studies have demonstrated that micronutrients (vitamins & minerals) with a broad range of effects on body health, can regulate TLRs signaling pathways. Current review aimed at determining the possible mechanisms of micronutrient effects on TLRs functions. In the aspect of gene expression, micronutrients have inconsistent effects on mRNA level of TLRs which are dependent on time, dose and type of studied TLR. Also, some micronutrients affect gene expression of TLRs signaling mediators namely TLRs adaptors like Myeloid differentiation primary response 88 (MyD88). In the aspect of TLRs signaling pathways, nuclear factor-κB (NF-κB) is an important mediator which is regulated by micronutrients. Also, the regulatory effects of micronutrients on phosphorylation reactions may be effective in the activation/inactivation of TLRs signaling mediators. In addition, zinc can regulate TLRs signaling indirectly via the zinc finger proteins which have contradictory effects on TLRs cascade. In conclusion, the relationship between micronutrients and TLRs signaling is complicated and depends on some known internal, external and genetic factors like form of studied micronutrient, cell type, TLR agonist, dose and time of exposure, inflammation, apoptosis, cell cycle, and environmental factors. Some unknown factors may be effective in TLRs response and as a result additional mechanistic studies are needed to elucidate exact effect of micronutrients on TLRs signaling.
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19
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Korolowizc KE, Li B, Huang X, Yon C, Rodrigo E, Corpuz M, Plouffe DM, Kallakury BV, Suresh M, Wu TY, Miller AT, Menne S. Liver-Targeted Toll-Like Receptor 7 Agonist Combined With Entecavir Promotes a Functional Cure in the Woodchuck Model of Hepatitis B Virus. Hepatol Commun 2019; 3:1296-1310. [PMID: 31592075 PMCID: PMC6771164 DOI: 10.1002/hep4.1397] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 06/19/2019] [Indexed: 01/02/2023] Open
Abstract
Current therapeutics for chronic infection with hepatitis B virus (HBV) rarely induce functional cure due to the immunotolerant status of patients. Small molecule agonists targeting toll-like receptor 7 (TLR7) have been shown to elicit a functional cure in animal models of HBV but sometimes with poor tolerability due to immune-related toxicities. In an effort to increase the therapeutic window of TLR7 agonists to treat chronic hepatitis B (CHB), we developed an oral TLR7 agonist, APR002, designed to act locally in the gastrointestinal tract and liver, thus minimizing systemic exposure and improving tolerability. Here, we describe the pharmacokinetic/pharmacodynamic (PK/PD) profile of APR002 in mice and uninfected woodchucks as well as the safety and antiviral efficacy in combination with entecavir (ETV) in woodchucks with CHB. Treatment of woodchucks chronically infected with woodchuck hepatitis virus (WHV) with weekly oral doses of APR002 was well-tolerated. While APR002 and ETV single agents did not elicit sustained viral control, combination therapy resulted in durable immune-mediated suppression of the chronic infection. These woodchucks also had detectable antibodies to viral antigens, enhanced interferon-stimulated gene expression, and loss of WHV covalently closed circular DNA. Conclusion: APR002 is a novel TLR7 agonist exhibiting a distinct PK/PD profile that in combination with ETV can safely attain a functional cure in woodchucks with chronic WHV infection. Our results support further investigation of liver-targeted TLR7 agonists in human CHB.
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Affiliation(s)
- Kyle E. Korolowizc
- Department of Microbiology and ImmunologyGeorgetown University Medical CenterWashingtonDC
| | - Bin Li
- Department of Microbiology and ImmunologyGeorgetown University Medical CenterWashingtonDC
| | - Xu Huang
- Department of Microbiology and ImmunologyGeorgetown University Medical CenterWashingtonDC
| | - Changsuek Yon
- Department of Microbiology and ImmunologyGeorgetown University Medical CenterWashingtonDC
| | | | | | | | | | - Manasa Suresh
- Department of Microbiology and ImmunologyGeorgetown University Medical CenterWashingtonDC
| | | | | | - Stephan Menne
- Department of Microbiology and ImmunologyGeorgetown University Medical CenterWashingtonDC
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20
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The Interplay between Host Innate Immunity and Hepatitis E Virus. Viruses 2019; 11:v11060541. [PMID: 31212582 PMCID: PMC6630959 DOI: 10.3390/v11060541] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 05/24/2019] [Accepted: 06/06/2019] [Indexed: 12/15/2022] Open
Abstract
Hepatitis E virus (HEV) infection represents an emerging global health issue, whereas the clinical outcomes vary dramatically among different populations. The host innate immune system provides a first-line defense against the infection, but dysregulation may partially contribute to severe pathogenesis. A growing body of evidence has indicated the active response of the host innate immunity to HEV infection both in experimental models and in patients. In turn, HEV has developed sophisticated strategies to counteract the host immune system. In this review, we aim to comprehensively decipher the processes of pathogen recognition, interferon, and inflammatory responses, and the involvement of innate immune cells in HEV infection. We further discuss their implications in understanding the pathogenic mechanisms and developing antiviral therapies.
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21
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Sepehri Z, Kiani Z, Kohan F, Ghavami S. Toll-Like Receptor 4 as an Immune Receptor Against Mycobacterium tuberculosis: A Systematic Review. Lab Med 2019; 50:117-129. [PMID: 30124945 DOI: 10.1093/labmed/lmy047] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVE To review the main Mycobacterium tuberculosis (Mtb) pathogen-associated molecular patterns (PAMPs) and the roles played by toll-like receptor (TLR)4 in determination of Mtb infection outcome. METHODS Several scientific databases, including Scopus, PubMed, and Google Scholar, were used for searching appropriate research articles from the literature for information on our topic. RESULTS TLR4 plays positive roles in induction of immune responses against Mtb and participates in eradication of the infection. Some limited investigations approved the roles of TLR4 in induction of apoptosis in macrophages during tuberculosis (TB) and attenuation of immune responses in some situations. CONCLUSIONS TB outcome appears to be dependent on TLR4/Mtb interaction and several factors, including bacterial load and immune or nonimmune cells, as hosts. Also, other TLR/Mtb interactions can affect TLR4 responses.
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Affiliation(s)
- Zahra Sepehri
- Department of Internal Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Zohre Kiani
- Zabol Medicinal Plant Research Center, Zabol University of Medical Sciences, Zabol, Iran and Kerman University of Medical Sciences, Kerman, Iran
| | - Farhad Kohan
- Zabol University of Medical Sciences, Zabol, Iran
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
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22
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Safari-Arababadi M, Modarressi MH, Arababadi MK. Up-regulation of RIP1 and IPS-1 in chronic HBV infected patients. Genet Mol Biol 2019; 42:337-343. [PMID: 31429854 PMCID: PMC6726166 DOI: 10.1590/1678-4685-gmb-2018-0071] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 08/02/2018] [Indexed: 12/28/2022] Open
Abstract
IPS-1 and RIP1 are the main downstream molecules of RIG1 and MDA5, as intracytoplasmic receptors, which are the main receptors involved in recognition of internal and external viral double-stranded RNA. In this project, mRNA levels of IPS-1 and RIP1 were investigated in the peripheral blood immune cells of chronic hepatitis B (CHB) patients. IPS-1 and RIP1 mRNA levels were measured in 60 CHB patients and 120 healthy subjects, using RT-qPCR technique. A significant increase in expression levels of IPS-1 and RIP1 was found in patients when compared to healthy individuals. There was no correlation between IPS-1 and RIP1expression levels with the serum levels of hepatitis B e-Antigen (HBeAg) and liver enzymes in patients. Based on the results, it seems that IPS-1 and RIP1 can participate in the induction of low chronic inflammation, which is a main cause of liver cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Minoo Safari-Arababadi
- Department of Genetics, Faculty of Basic Sciences, Science and
Research Branch, Islamic Azad University, Tehran, Iran
| | - Mohammad Hossein Modarressi
- Department of Genetics, Faculty of Basic Sciences, Science and
Research Branch, Islamic Azad University, Tehran, Iran
- Department of Medical Genetics, School of Medicine, Tehran
University of Medical Sciences, Tehran, Iran
| | - Mohammad Kazemi Arababadi
- Immunology of Infectious Diseases Research Center, Research
Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences,
Rafsanjan, Iran
- Department of Laboratory Sciences, Faculty of Paramedicine,
Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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23
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Dadmanesh M, Ranjbar MM, Ghorban K. Inflammasomes and their roles in the pathogenesis of viral hepatitis and their related complications: An updated systematic review. Immunol Lett 2019; 208:11-18. [PMID: 30831142 PMCID: PMC7112799 DOI: 10.1016/j.imlet.2019.03.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 02/26/2019] [Accepted: 03/01/2019] [Indexed: 02/06/2023]
Abstract
Inflammasomes are a set of innate receptors which are the responsible molecules for activation of pro-interleukin (IL)-1β and IL-18 and induction of inflammation. Due to the key roles of the inflammasomes in the induction of inflammation, it has been hypothesized that the molecules may be the main parts of immune responses against viral infections and the tissue damage. Because some cases of viral hepatitis infections, including hepatitis B and C, are diagnosed as chronic and may be associated with various complications such as liver cirrhosis and hepatocellular carcinoma (HCC), several studies focused on the roles played by the inflammation on the pathogenesis of viral hepatitis. Based on the roles played by inflammasomes in induction of inflammation, it has been hypothesized that inflammasomes may be the main parts of the puzzle of the viral hepatitis complications. This article reviews the roles of the inflammasomes in the pathogenesis of hepatitis B and C viral infections and their complications, liver cirrhosis, and HCC.
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Affiliation(s)
- Maryam Dadmanesh
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Infectious Diseases, Medical School, Aja University of Medical Sciences, Tehran, Iran
| | - Mohammad Mehdi Ranjbar
- Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran.
| | - Khodayar Ghorban
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Immunology, Medical School, Aja University of Medical Sciences, Tehran, Iran.
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24
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Mycoplasma pneumoniae and toll-like receptors: A mutual avenue. Allergol Immunopathol (Madr) 2018; 46:508-513. [PMID: 29331619 DOI: 10.1016/j.aller.2017.09.021] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 09/13/2017] [Indexed: 02/07/2023]
Abstract
Mycoplasma pneumoniae is an intracellular bacterium leading to several complications in humans. M. pneumoniae is cleared in some cases and induces complications in others. The main responsible mechanisms regarding the controversy are yet to be cleared. Toll-like receptors (TLRs) are the important cell membrane and intracellular receptors which recognize a wide range of microbial macromolecules. The roles of TLRs in the eradication of several pathogens and also induction of their related complications have been demonstrated. This review article presents recent data about the roles of TLRs in the induction of immune responses which lead to M. pneumoniae eradication and related complications.
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25
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Golshiri-Isfahani A, Amizadeh M, Arababadi M. The roles of toll like receptor 3, 7 and 8 in allergic rhinitis pathogenesis. Allergol Immunopathol (Madr) 2018; 46:503-507. [PMID: 29398117 DOI: 10.1016/j.aller.2017.09.026] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 09/13/2017] [Indexed: 01/29/2023]
Abstract
Allergic rhinitis, as an allergic and nasal hypersensitivity disease, is associated with the inflammation of nasal mucosa. It appears that innate immune receptors are the important risk factors in the pathogenesis of the inflammatory disease. Toll-like receptors (TLRs) are the most important receptors of innate immunity; their crucial roles in the recognition of allergens and subsequently pathogenesis of allergic diseases have been evaluated recently. TLR3, 7 and 8 are the intracellular members of the innate immune receptors and recognize intracellular single and double strand RNAs. This review article collected the investigations regarding the roles of TLR3, 7 and 8 in the allergic rhinitis pathogenesis.
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26
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Mohammadi Shahrokhi V, Ravari A, Mirzaei T, Zare-Bidaki M, Asadikaram G, Arababadi MK. IL-17A and IL-23: plausible risk factors to induce age-associated inflammation in Alzheimer's disease. Immunol Invest 2018; 47:812-822. [PMID: 30081688 DOI: 10.1080/08820139.2018.1504300] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Background: Aging and its complications such as Alzheimer's disease (AD) are associated with chronic low-grade inflammation entitled age-associated inflammation. However, the main mechanisms whichinduce age-associated inflammation in aging and AD are yet to beclarified. L-23/IL-17A axis plays important roles in the induction of inflammation and consequently autoimmune disease. This review evaluates the main roles played by IL-17A, IL-23, and IL-17A/IL-23 axis in the pathogenesis of age-associated inflammation in AD patients. Result: IL-23/IL-17A axis, is an important factor participate in the pathogenesis of age-associated inflammation. The genetic variations and microbial infection can be considered as the most important candidates to induce AD via upregulation of IL-17A. IL-17A also deteriorates AD via induction by amyloid-β. IL-17A participates in the induction of AD by increasing neutrophils infiltration to brain, induction of neuroinflammation, increase in FASL, and amyloid-βdeposition as well as activation of microglia. Conclusions: Due to the important roles played by IL-23/IL-17A axis in AD pathogenesis, it can be considered as a target for immunotherapy against AD. Abbreviations: Aβ: β-Amyloid; AD: Alzheimer's disease; CD: cluster of differentiation; DAMPs: Damage-associated molecular patterns; DCs: dendritic cells; HLA: human leukocyte antigen; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; RAR: retinoic-acid receptor; RORγt: RAR-related orphan receptor gamma t; SAMP8: senescence-accelerated mouse prone 8 strain; TGF-β: tumor growth factor-β; TLRs: toll-like receptors.
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Affiliation(s)
- Vahid Mohammadi Shahrokhi
- a Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences , Rafsanjan University of Medical Sciences , Rafsanjan , Iran.,b Dept. of Immunology, Faculty of Medicine , Rafsanjan University of Medical Sciences , Rafsanjan , Iran
| | - Ali Ravari
- c Geriatric Care Research Center, Research Institute of Basic Medical Sciences , Rafsanjan , Iran.,d Dept. of Medical Surgical Nursing, Faculty of Nursing and Midwifery , Rafsanjan University of Medical Sciences , Rafsanjan , Iran
| | - Tayebeh Mirzaei
- c Geriatric Care Research Center, Research Institute of Basic Medical Sciences , Rafsanjan , Iran.,d Dept. of Medical Surgical Nursing, Faculty of Nursing and Midwifery , Rafsanjan University of Medical Sciences , Rafsanjan , Iran
| | - Mohammad Zare-Bidaki
- a Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences , Rafsanjan University of Medical Sciences , Rafsanjan , Iran.,e Dept. of Microbiology, Faculty of Medicine , Rafsanjan University of Medical Sciences , Rafsanjan , Iran
| | - Gholamreza Asadikaram
- f Neuroscience Research Center, Institute of Neuropharmacology , Kerman University of Medical Sciences , Kerman , Iran.,g Department of Biochemistry, School of Medicine , Kerman University of Medical Sciences , Kerman , Iran
| | - Mohammad Kazemi Arababadi
- a Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences , Rafsanjan University of Medical Sciences , Rafsanjan , Iran.,b Dept. of Immunology, Faculty of Medicine , Rafsanjan University of Medical Sciences , Rafsanjan , Iran
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27
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Arababadi MK, Nosratabadi R, Asadikaram G. Vitamin D and toll like receptors. Life Sci 2018; 203:105-111. [PMID: 29596922 DOI: 10.1016/j.lfs.2018.03.040] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Revised: 03/10/2018] [Accepted: 03/20/2018] [Indexed: 12/17/2022]
Abstract
It has been demonstrated that vitamin D (VD) significantly modulates immune responses. Toll like receptors (TLRs) are the main innate immunity receptors which are expressed on the cell membrane and intracellular vesicles and recognize several pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) to induce immune responses. Based on the important roles played by TLRs in physiologic and pathologic functions of immune responses and due to the immunomodulatory functions of VD, it has been hypothesized that VD may present its immunomodulatory functions via modulation of TLRs. This review article collates recent studies regarding the interactions between VD and TLRs and discussed the controversial investigations.
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Affiliation(s)
- Mohammad Kazemi Arababadi
- Department of Immunology, Faculty of Medicine, Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Reza Nosratabadi
- Department of Immunology, Faculty of Medicine, Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Gholamreza Asadikaram
- Neuroscience Research Center, Institute of Neuropharmacology and Department of Biochemistry, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
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28
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Smirnov VS, Petlenko SV. INFLUENCE OF THE IMIQUIMOD ON THE INTERFERON PRODUCTION AND TREATMENT OF THE EXPERIMENTAL HERPES SIMPLEX VIRUS INFECTION. Vopr Virusol 2017; 62:128-134. [PMID: 36494980 DOI: 10.18821/0507-4088-2017-62-3-128-134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Imiquimod is an imidazole derivative acting as an immunomodulator on the level of innate and adaptive immune system. Our objective was to evaluate the antiviral activity of generically reproduced imiquimod administered subcutaneously in mice and intravaginally in guinea pigs against herpes simplex virus (HSV), as well as to study the dynamics of serum interferon (IFN) synthesis under different dosing regimens. RESULTS When administered subcutaneously at doses of 0.5, 1.0 and 10 mg/kg imiquimod increased IFN production in mice in a dose-dependent manner with maximum serum IFN concentrations occurring 4 hours after dosing. Imiquimod protected mice from intraperitoneal HSV infection at doses of 3.2 and 32 LD50.The utmost protection (100% survival) was observed when imiquimod was administered at a dose of 100 mg/kg daily for 5 days before infection. Topical application of imiquimod 5% cream exhibited significantly more rapid and complete virus elimination in guinea pigs intravaginally infected with HSV type 2 compared to control group. CONCLUSION Imiquimod produced as a generic possesses the same immunomodulatory and antiviral properties as the originally synthesized substance.
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Affiliation(s)
- V S Smirnov
- Biomedical Research and Production Complex «Cytomed»
| | - S V Petlenko
- Biomedical Research and Production Complex «Cytomed»
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29
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Nosratababadi R, Bagheri V, Zare-Bidaki M, Hakimi H, Zainodini N, Kazemi Arababadi M. Toll like receptor 4: an important molecule in recognition and induction of appropriate immune responses against Chlamydia infection. Comp Immunol Microbiol Infect Dis 2017; 51:27-33. [PMID: 28504091 DOI: 10.1016/j.cimid.2017.03.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 02/06/2017] [Accepted: 03/12/2017] [Indexed: 01/09/2023]
Abstract
Chlamydia species are obligate intracellular pathogens causing different infectious diseases particularly asymptomatic genital infections and are also responsible for a wide range of complications. Previous studies showed that there are different immune responses to Chlamydia species and their infections are limited to some cases. Moreover, Chlamydia species are able to alter immune responses through modulating the expression of some immune system related molecules including cytokines. Toll like receptors (TLRs) belonge to pathogen recognition receptors (PRRs) and play vital roles in recognition of microbes and stimulation of appropriate immune responses. Therefore, it appears that TLRs may be considered as important sensors for recognition of Chlamydia and promotion of immune responses against these bacterial infections. Accordingly, TLR4 detects several microbial PAMPs such as bacterial lipopolysacharide (LPS) and subsequently activates transcription from pro-inflammatory cytokines in both MYD88 and TRIF pathways dependent manner. The purpose of this review is to provide the recent data about the status and major roles played by TLR4 in Chlamydia species recognition and promotion of immune responses against these infections and also the relationship between TLR4 activities and pathogenesis of Chlamydia infections.
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Affiliation(s)
- Reza Nosratababadi
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Immunology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Vahid Bagheri
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mohammad Zare-Bidaki
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Microbiology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Hamid Hakimi
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Microbiology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Nahid Zainodini
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Microbiology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mohammad Kazemi Arababadi
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Immunology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
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