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TLR and hepatitis C

Xiaojing Dai, Jintian He, Ruxia Zhang, Guanghao Wu, Fangfang Xiong, Baohua Zhao
The aim of the present work was to investigate the synergistic effect between toll-like receptor (TLR) 3 ligand polyinosinic:polycytidylic acid (pI:C) and TLR5 ligand flagellin (FLN) on immune responses induced by nasally delivered hepatitis B virus surface antigen (HBsAg). Mannan and chitosan oligosaccharide-modified, pH-responsive poly(lactic-co-glycolic acid) (MC-PLGA) microparticles (MPs) containing HBsAg, FLN, pI:C or both ligands were prepared with a double-emulsion method. In vitro uptake experiments show that cellular uptake of MC-PLGA MPs by macrophages was through energy-dependent, receptor-mediated endocytosis mechanism...
2017: International Journal of Nanomedicine
Jing Chen, Jin Li, Jensen H C Yiu, Jenny K W Lam, Chi-Ming Wong, Bernhard Dorweiler, Aimin Xu, Connie W Woo
Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of diseases that ranges in severity from hepatic steatosis to steatohepatitis, the latter of which is a major predisposing factor for liver cirrhosis and cancer. Toll-like receptor (TLR) signaling, which is critical for innate immunity, is generally believed to aggravate disease progression by inducing inflammation. Unexpectedly, we found that deficiency in TIR domain-containing adaptor-inducing interferon-β (TRIF), a cytosolic adaptor that transduces some TLR signals, worsened hepatic steatosis induced by a high-fat diet (HFD) and that such exacerbation was independent of myeloid cells...
August 8, 2017: Science Signaling
Auvro R Mridha, Fahrettin Haczeyni, Matthew M Yeh, W Geoffrey Haigh, George N Ioannou, Vanessa Barn, Hussam Ajamieh, Leon Adams, Jeffrey M Hamdorf, Narci C Teoh, Geoffrey C Farrell
Background and aims: TLR9 deletion protects against steatohepatitis due to choline-amino acid depletion and high-fat diet. We measured TLR9 in human non-alcoholic steatohepatitis (NASH) livers, and tested whether TLR9 mediates inflammatory recruitment in three murine models of non-alcoholic fatty liver disease (NAFLD). Methods: We assayed TLR mRNA in liver biopsies from bariatric surgery patients. Wild-type (Wt), appetite-dysregulated Alms1 mutant (foz/foz), Tlr9(-/-), and Tlr9(-/-)foz/foz C57BL6/J mice and bone marrow (BM) chimeras were fed 0...
August 15, 2017: Clinical Science (1979-)
Liyan Wu, Maoxiang Yan, Jianping Jiang, Beihui He, Wei Hong, Zhiyun Chen
OBJECTIVE: This study investigated the possible molecular mechanisms of pure total flavonoids from citrus (PTFC) for the treatment of non-alcoholic fatty liver disease (NAFLD) via toll-like receptor/C-C chemokine ligand (TLR/CCL) signaling pathways by monitoring the changes in gene expression profile in liver tissues induced by high-fat diet. METHODS: We performed systematical analyses on hepatic expression profiles of mRNAs in a high-fat diet (HFD)-induced steatotic animal model with or without PTFC treatment...
September 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Mohammad Enamul Hoque Kayesh, Sayeh Ezzikouri, Haiying Chi, Takahiro Sanada, Naoki Yamamoto, Bouchra Kitab, Takumi Haraguchi, Rika Matsuyama, Chimène Nze Nkogue, Hitoshi Hatai, Noriaki Miyoshi, Shuko Murakami, Yasuhito Tanaka, Jun-Ichiro Takano, Yumiko Shiogama, Yasuhiro Yasutomi, Michinori Kohara, Kyoko Tsukiyama-Kohara
To date, the chimpanzee has been used as the natural infection model for hepatitis B virus (HBV). However, as this model is very costly and difficult to use because of ethical and animal welfare issues, we aimed to establish the tupaia (Tupaia belangeri) as a new model for HBV infection and characterized its intrahepatic innate immune response upon HBV infection. First, we compared the propagation of HBV genotypes A2 and C in vivo in tupaia hepatocytes. At 8-10days post infection (dpi), the level of HBV-A2 propagation in the tupaia liver was found to be higher than that of HBV-C...
May 25, 2017: Virus Research
Vincent Soriano, Pablo Barreiro, Laura Benitez, Jose M Peña, Carmen de Mendoza
Current treatment with oral nucleos(t)ides entecavir or tenofovir provide sustained suppression of HBV replication and clinical benefit in most chronic hepatitis B virus (HBV) infected persons. However, HBV rebound generally occurs upon drug discontinuation due to persistence of genomic HBV reservoirs as episomic cccDNA and chromosomic integrated HBV-DNA. There is renewed enthusiasm on HBV drug discovery following recent successes with antivirals for hepatitis C and immunotherapies for some cancers. Areas covered: New drugs that target distinct steps of the HBV life cycle are been developed, including inhibitors of viral entry, new polymerase inhibitors, capsid and assembly inhibitors, virus release blockers, and disruptors of cccDNA formation and transcription...
July 2017: Expert Opinion on Investigational Drugs
Rania A Zayed, Dalia Omran, Doha A Mokhtar, Zinab Zakaria, Sameera Ezzat, Mohamed A Soliman, Lamiaa Mobarak, Hossam El-Sweesy, Ghada Emam
AbstractToll-like receptors (TLRs) are recognized as fundamental contributors to the immune system function against infections. Hepatitis C virus (HCV) infection represents a global health problem especially in Egypt having the highest HCV prevalence worldwide where HCV infection is a continuing epidemic. The aim of the present study was to investigate the possible association between genetic variation in TLR-3 and TLR-9 and HCV infection and hepatic fibrosis in chronic HCV-positive Egyptian patients. The present study included 100 naïve chronic HCV-positive patients and 100 age- and sex-matched healthy controls...
March 2017: American Journal of Tropical Medicine and Hygiene
Usman Ali Ashfaq, Muhammad Sarfaraz Iqbal, Saba Khaliq
Viral infections are rising every day, and viruses appear to be the most dangerous pathogens in the world. Hepatitis C virus (HCV) is accepted as one of the major destructive factors of promoting severe hepatic disorders by infecting more than 180 million individuals throughout the world. Chronic infection caused by HCV poses a serious global health emergency and appears to be a powerful threat to humanity. Almost 20 years have passed since the disclosure of HCV, but even now, treatment preferences remain limited...
2016: Critical Reviews in Eukaryotic Gene Expression
Erina Joo, Toru Fukushima, Norio Harada, John C Reed, Shu-Ichi Matsuzawa, Nobuya Inagaki
Obesity is associated with low-grade inflammation that leads to insulin resistance and type 2 diabetes via Toll-like Receptor (TLR) and TNF-family cytokine receptor (TNFR) signaling pathways. Ubc13 is an ubiquitin-conjugating enzyme responsible for non-canonical K63-linked polyubiquitination of TNF receptor-associated factor (TRAF)-family adapter proteins involved in TLR and TNFR pathways. However, the relationship between Ubc13 and metabolic disease remains unclear. In this study, we investigated the role of Ubc13 in insulin resistance and high-fat diet (HFD)-induced obesity...
October 31, 2016: Scientific Reports
Stephanie T Chan, Jiyoung Lee, Mansi Narula, J-H James Ou
Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an important adaptor molecule that mediates the TNFR family and interleukin-1 (IL-1)/Toll-like receptor (TLR) signaling cascades. These pathways are important for the host to control viral infections. In this report, we demonstrated that hepatitis C virus (HCV) depleted TRAF6 from its host cells through a posttranslational mechanism. This depletion was independent of proteasomes, as it was not affected by the proteasome inhibitor MG132, but it was suppressed by bafilomycin A1, which led to the association of TRAF6 with autophagosomes...
December 1, 2016: Journal of Virology
Yuehua Wang, Bin Li, Jinyan Zhu, Qi Zhang, Xiuyan Zhang, Li Li, Yan Ma, Xianjun Meng
The protective effects of Lonicera caerulea berry extract (LCBE) against hepatic inflammation and the underlying mechanisms were investigated in a rat model of lipopolysaccharide (LPS)-induced chronic liver inflammation. Male Sprague-Dawley rats were injected with LPS (200 μg per kg bw) with or without LCBE co-administration (50, 100 and 200 mg per kg bw intragastrically once daily) for 4 weeks. We found that LCBE supplementation inhibited the increase in Toll-like receptor (TLR)2 and TLR4 expression induced by LPS, while preventing glutathione depletion and reactive oxidative species generation and abrogating increases in C-reactive protein and interleukin-6 levels, restoring alanine and aspartate aminotransferase activities, and blocking the phosphorylation of p38 and c-Jun N-terminal kinase mitogen-activated protein kinases (MAPKs)...
October 12, 2016: Food & Function
Benjamin Krämer, Claudia Finnemann, Beatriz Sastre, Philipp Lutz, Andreas Glässner, Franziska Wolter, Felix Goeser, Pavlos Kokordelis, Dominik Kaczmarek, Hans-Dieter Nischalke, Christian P Strassburg, Ulrich Spengler, Jacob Nattermann
BACKGROUND: Immuno-genetic studies suggest a functional link between NK cells and λ-IFNs. We recently showed that NK cells are negative for the IFN-λ receptor IFN-λR1 and do not respond to IFN-λ, suggesting a rather indirect association between IL-28B genotype and NK cell activity. METHODS: A total of 75 HCV(+) patients and 67 healthy controls were enrolled into this study. IL-28B (rs12979860) and IFNL-4 (rs368234815) genotypes were determined by rtPCR. Total PBMC, monocytes, and NK cells were stimulated with IL-29, the TLR-7/8 agonist R848, or a combination of both...
2016: PloS One
Chuan-Mo Lee, Tsung-Hui Hu, Sheng-Nan Lu, Jing-Houng Wang, Chao-Hung Hung, Chien-Hung Chen, Yi-Hao Yen
BACKGROUND: Toll-like receptors (TLRs) are effectors of the innate immune system that are able to recognize hepatitis C virus (HCV) and give rise to an immune response. Failure of interferon (IFN)-α-based treatment is related to host immunity. Therefore, we sought to study the clinical importance of TLRs in HCV genotype 1 patients who received pegylated IFN (PEG-IFN) plus ribavirin (RBV) therapy. METHODS: We enrolled 79 treatment-naïve patients with HCV genotype 1...
July 25, 2016: BMC Gastroenterology
Yuhan Chen, Zhaochong Zeng, Xiaoyun Shen, Zhifeng Wu, Yinying Dong, Jason Chia-Hsien Cheng
Lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway is demonstrated to be involved in the hepatic fibrosis. MicroRNA (miR)-146a-5p is a key regulator of the innate immune response. The functional significance of miR-146a-5p during the LPS/TLR4 mediated hepatic fibrosis process remains unclear. In this study, we found that TLR4 and α-smooth muscle actin (α-SMA) were up-regulated and miR-146a-5p was down-regulated in human hepatic stellate cell (HSC) line LX2 after LPS stimulation. Overexpression of miR-146a-5p inhibited LPS induced pro-inflammatory cytokines secretion through down-regulating the expression levels of TLR-4, IL-1 receptor-associated kinase 1 (IRAK1), TNF receptor associated factor-6 (TRAF6) and phosphorylation of nuclear factor-kappa B (NF-κB)...
July 7, 2016: International Journal of Molecular Sciences
Yue-Min Nan, Shan-Shan Su, Xue-Min Niu, Su-Xian Zhao, Yu-Guo Zhang, Rong-Qi Wang, Ling-Bo Kong, Huan He, Huan-Wei Zheng, Dian-Xing Sun
OBJECTIVE: To investigate the regulation mechanism of T cell immunoglobulin and mucin domain-3 (Tim-3) combined with toll-like receptor 3 (TLR3) or TLR4 on antiviral immune and inflammatory response in patients with chronic hepatitis C virus (HCV) infection. METHODS: Patients with chronic HCV infection and healthy control subjects were recruited. Patients received interferon (IFN)-α based therapy. Plasma galectin-9 (Gal-9) was quantitated. Peripheral blood mononuclear cells (PBMCs) were cultured with TLR3 or TLR4 agonists, alone or in combination with Tim-3 antagonist...
August 2016: Journal of International Medical Research
Swee Lin G Chen Yi Mei, Jodie Burchell, Narelle Skinner, Rosie Millen, Gail Matthews, Margaret Hellard, Gregory J Dore, Paul V Desmond, Vijaya Sundararajan, Alexander J Thompson, Kumar Visvanathan, Joe Sasadeusz
BACKGROUND: Mechanisms by which spontaneous clearance of acute hepatitis C occurs are unclear. A critical role for the innate immune system and IFNL4 polymorphisms has been proposed. This study investigates whether Toll-like receptor (TLR) expression and signaling during acute hepatitis C correlates with clinical outcomes. METHODS: Participants identified from the Australian Trial in Acute Hepatitis C and the Networks study were followed longitudinally from the time of diagnosis of acute hepatitis C...
September 1, 2016: Journal of Infectious Diseases
Man He, Min Wang, Ying Huang, Wenju Peng, Zizheng Zheng, Ningshao Xia, Jian Xu, Deying Tian
Hepatitis E virus (HEV) genotype 1 infection is common and can emerge as outbreaks in developing areas, thus posing a threat to public health. However, due to the absence of feasible animal models, the mechanism of HE pathogenesis remains obscure. The HEV pathogenic mechanism has been suggested to be mediated by the immune system and not by direct viral duplication. We firstly discovered that the open reading frame 3 (ORF3) protein of genotype 1 HEV downregulates TLR3-mediated NF-κB signaling in Human A549 Lung Epithelial Cells (A549 cells) which were exposed to different TLR agonists associated with viral nucleic acids...
2016: Scientific Reports
Besma Aouar, Denisa Kovarova, Sebastien Letard, Albert Font-Haro, Jonathan Florentin, Jan Weber, David Durantel, Laurence Chaperot, Joel Plumas, Katerina Trejbalova, Jiri Hejnar, Jacques A Nunès, Daniel Olive, Patrice Dubreuil, Ivan Hirsch, Ruzena Stranska
Crosslinking of regulatory immunoreceptors (RR), such as BDCA-2 (CD303) or ILT7 (CD85g), of plasmacytoid dendritic cells (pDCs) efficiently suppresses production of type-I interferon (IFN)-α/β and other cytokines in response to Toll-like receptor (TLR) 7/9 ligands. This cytokine-inhibitory pathway is mediated by spleen tyrosine kinase (Syk) associated with the ITAM-containing adapter of RR. Here we demonstrate by pharmacological targeting of Syk that in addition to the negative regulation of TLR7/9 signaling via RR, Syk also positively regulates the TLR7/9 pathway in human pDCs...
2016: PloS One
Maria J Citores, Sofia Pérez-Pulgar, Ana Duca, Gonzalo Crespo, Sara de la Fuente, Carlos Vilches, Miquel Navasa, Valentin Cuervas-Mons
Liver transplantation activates the innate immune system through toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. We evaluated the association of single-nucleotide polymorphisms in TLR genes with the severity of hepatitis C virus recurrence after liver transplantation (LT). This is a two-center study of 176 adult patients who received a first LT from deceased donors for hepatitis C virus (HCV) cirrhosis. Eleven polymorphisms were evaluated by real-time polymerase chain reaction and melting curves analyses: TLR1 (Asp248Ser and Ser602Ile), TLR2 (Arg753Gln), TLR3 (Leu412Phe), TLR4 (Asp299Gly), TLR5 (Arg392Stop), TLR6 (Ser249Pro), TLR7 (Gln11Leu), TLR8 (Met1Val), and TLR9 (-1237T/C and -1486C/T)...
July 2016: Clinical Transplantation
Zia-Ur-Rehman Farooqi, Samar H K Tareen, Jamil Ahmed, Najam-Us-Sahar S Zaidi
Hepatitis C virus (HCV) triggers coordinated innate and adaptive response in host cell. HCV genome and proteins of the replicating virus are recognized as non-self-antigens by host cell to activate Toll Like Receptors (TLRs). Activated TLRs ultimately express cytokines, which can clear virus either by activating interferon (IFN), protein kinase C (PKC) and RNA Lase system or through activation of cytotoxic T-lymphocytes. Interleukin-12 (IL-12) is a potent antiviral cytokine, capable of clearing HCV by bridging both innate and adaptive antiviral immune response...
2016: Protein and Peptide Letters
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