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Hui Xu, Shi-Jun Xu, Shu-Juan Xie, Yin Zhang, Jian-Hua Yang, Wei-Qi Zhang, Man-Ni Zheng, Hui Zhou, Liang-Hu Qu
MicroRNA-122 (miR-122) is the most abundant microRNA in hepatocytes and a central player in liver biology and disease. Herein, we report a previously unknown role for miR-122 in hepatocyte intrinsic innate immunity. Restoring miR-122 levels in hepatoma cells markedly enhanced the activation of interferons (IFNs) in response to a variety of viral nucleic acids or simulations, especially of hepatitis C virus RNA and poly (I:C). Mechanistically, miR-122 down-regulated the phosphorylation (Tyr705) of STAT3 and thereby removed the negative regulation of STAT3 on IFN-signaling...
February 8, 2019: ELife
Sweta Ghosh, Junaid Jibran Jawed, Kuntal Halder, Sayantan Banerjee, Bidisha Paul Chowdhury, Akata Saha, Subir Kumar Juin, Suchandra Bhattacharyya Majumdar, Anamika Bose, Rathindranath Baral, Subrata Majumdar
Ceramide is one of the important cellular components involved in cancer regulation and exerts its pleiotropic role in the protective immune response without exhibiting any adverse effects during malignant neoplasm. Although, the PKCδ-ceramide axis in cancer cells has been an effective target in reduction of cancer, involvement of PKCδ in inducing nephrotoxicity have become a major questionnaire. In the present study, we have elucidated the mechanism by which cisplatin exploits the ceramide to render cancer cell apoptosis leading to the abrogation of malignancy in a PKCδ independent pathway with lesser toxicity...
December 28, 2018: Oncotarget
Dalila L Zanette, Rayra P Santiago, Ivana Paula Ribeiro Leite, Sanzio S Santana, Caroline da Guarda, Vitor V Maffili, Junia Raquel Dutra Ferreira, Corynne Stephanie Ahouefa Adanho, Setondji Cocou Modeste Alexandre Yahouedehou, Isa Lyra Menezes, Marilda Souza Goncalves
Sickle cell anemia is one of the most prevalent genetic diseases worldwide, showing great clinical heterogeneity. This study compared the gene expression patterns between sickle cell anemia pediatric patients in steady state and in crisis state, as compared to age-paired, healthy individuals. RNA sequencing was performed from these groups of patients/controls using Illumina HiSeq 2500 equipment. The resulting differentially expressed genes were loaded into QIAGEN's ingenuity pathway analysis. The results showed that EIF2 pathway and NRF2-mediated oxidative stress-response pathways were more highly activated both in steady state and in crisis patients, as compared to healthy individuals...
January 30, 2019: Annals of Human Genetics
Kayla A Chase, Jennifer K Melbourne, Cherise Rosen, Simon McCarthy-Jones, Nev Jones, Benjamin M Feiner, Rajiv P Sharma
Early childhood trauma, including physical, sexual or emotional abuse, neglect, harm or threat of harm, is associated with adulthood dysregulation of the immune system. Trauma can induce chronic immune system activation. Associations between a chronic pro-inflammatory state and schizophrenia are an enduring finding of psychiatry, with elevated cytokine concentrations correlated with psychotic symptom severity. Most importantly, persons with schizophrenia and a history of childhood trauma demonstrate increased cytokine levels...
December 19, 2018: Psychiatry Research
Valentina Profumo, Barbara Forte, Stefano Percio, Federica Rotundo, Valentina Doldi, Elena Ferrari, Nicola Fenderico, Matteo Dugo, Dario Romagnoli, Matteo Benelli, Riccardo Valdagni, Diletta Dolfini, Nadia Zaffaroni, Paolo Gandellini
Though miR-205 function has been largely characterized, the nature of its host gene, MIR205HG, is still completely unknown. Here, we show that only lowly expressed alternatively spliced MIR205HG transcripts act as de facto pri-miRNAs, through a process that involves Drosha to prevent unfavorable splicing and directly mediate miR-205 excision. Notably, MIR205HG-specific processed transcripts revealed to be functional per se as nuclear long noncoding RNA capable of regulating differentiation of human prostate basal cells through control of the interferon pathway...
January 18, 2019: Nature Communications
Yu Xiong, Linli Li, Liting Zhang, Yangyang Cui, Chengyong Wu, Hui Li, Kai Chen, Qiuyuan Yang, Rong Xiang, Yiguo Hu, Shile Huang, Yuquan Wei, Shengyong Yang
Necroptosis is a programmed form of necrotic cell death, which is tightly regulated by the necroptotic signaling pathway containing receptor-interacting protein (RIP)1, RIP3, and mixed-lineage kinase domain-like (MLKL) protein. In addition to the RIP1-RIP3-MLKL axis, other factors regulating necroptosis are still largely unknown. Here a cell-based small-molecule screening led to the finding that BET inhibitors protected cells from necroptosis in the TNFα/Smac-mimetic/Z-VAD-FMK (TSZ)-induced cell necroptosis model...
January 15, 2019: Cell Death and Differentiation
Anna Wiszniewsky, Manuel Ritter, Vanessa Krupp, Sandy Schulz, Kathrin Arndts, Heike Weighardt, Samuel Wanji, Achim Hoerauf, Laura E Layland
Worldwide approximately 68 million people are infected with lymphatic filariasis (Lf), provoked by Wuchereria bancrofti, Brugia malayi and Brugia timori. This disease can lead to massive swelling of the limbs (elephantiasis) and disfigurement of the male genitalia (hydrocele). Filarial induced immune regulation is characterised by dominant type 2 helper T cell and regulatory immune responses. In vitro studies have provided evidence that signalling via Toll-like receptor-mediated pathways is triggered by filarial associated factors...
January 15, 2019: Parasitology Research
Min Hong, Zuoyang Zhang, Qing Chen, Yanxia Lu, Jianming Zhang, Chun Lin, Fan Zhang, Wenjuan Zhang, Xiaomin Li, Wei Zhang, Xuenong Li
Background: Interferon regulatory factor 1 (IRF1) plays a role in the immune response, cellular necrosis, DNA damage, and DNA repair, offering an attractive target for anticancer treatment. However, little is known about the role of IRF1 in the regulation of CRC progression. Methods: Quantitative reverse transcription-PCR, Western blot, and immunohistochemistry were used to examine the expression level of IRF1; Cell Counting Kit-8, migration assay, and xenograft mouse models were used to examine the function of IRF1 in CRC cell lines; a ChIP assay was used to examine the binding between IRF1 and Ras association domain-containing protein 5 (RASSF5)...
2019: Cancer Management and Research
Yahui Gao, Jianping Jiang, Shaohua Yang, Jie Cao, Bo Han, Yachun Wang, Yi Zhang, Ying Yu, Shengli Zhang, Qin Zhang, Lingzhao Fang, Bonnie Cantrell, Dongxiao Sun
BACKGROUND: Paratuberculosis is a contagious, chronic and enteric disease in ruminants, which is caused by Mycobacterium avium subspecies paratuberculosis (MAP) infection, resulting in enormous economic losses worldwide. There is currently no effective cure for MAP infection or a vaccine, it is thus important to explore the genetic variants that contribute to host susceptibility to infection by MAP, which may provide a better understanding of the mechanisms of paratuberculosis and benefit animal genetic improvement...
December 27, 2018: BMC Genomics
Cheng Peng, Qianwen Hu, Fang Yang, Heng Zhang, Fubin Li, Chuanxin Huang
The programmed cell death protein 1 (PD-1) ligands PD-L1 and PD-L2 on germinal center (GC) B cells deliver coinhibitory signals to follicular T cells. The PD-L1/L2-PD-1 axis modulates the quality and quantity of follicular T cells and has been shown to influence the GC responses. However, the transcriptional control of PD-1 ligands on GC B cells remains largely unknown. In this study, we report that the transcription factor BCL6 is a key negative regulator of the PD-1 ligands PD-L1 and PD-L2 in GC B cells. Acute deletion of Bcl6 in mature GC B cells resulted in marked upregulation of mRNA and protein abundance of PD-1 ligands...
December 19, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Anne-Kathrin Knuth, Stefanie Rösler, Barbara Schenk, Lisa Kowald, Sjoerd J L van Wijk, Simone Fulda
Interferons (IFNs) are key players in the tumor immune response and act by inducing the expression of IFN-stimulated genes (ISGs). Here, we identify the mixed-lineage kinase domain-like pseudokinase (MLKL) as an ISG in various cancer cell lines. Both type I and type II IFNs increase the expression of MLKL indicating that MLKL up-regulation is a general feature of IFN signaling. IFNγ up-regulates mRNA as well as protein levels of MLKL demonstrating that IFNγ transcriptionally regulates MLKL. This notion is further supported by Actinomycin D chase experiments showing that IFNγ-stimulated up-regulation of MLKL is prevented in the presence of the transcriptional inhibitor Actinomycin D...
December 3, 2018: Neoplasia: An International Journal for Oncology Research
Lucy A Eddowes, Kinda Al-Hourani, Narayan Ramamurthy, Jamie Frankish, Hannah T Baddock, Cynthia Sandor, John D Ryan, Dahlene N Fusco, João Arezes, Eleni Giannoulatou, Sara Boninsegna, Stephane Chevaliez, Benjamin M J Owens, Chia Chi Sun, Paolo Fabris, Maria Teresa Giordani, Diego Martines, Slobodan Vukicevic, John Crowe, Herbert Y Lin, Jan Rehwinkel, Peter J McHugh, Marco Binder, Jodie L Babitt, Raymond T Chung, Matthew W Lawless, Andrew E Armitage, Caleb Webber, Paul Klenerman, Hal Drakesmith
Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity...
December 3, 2018: Nature Microbiology
Benoit Briard, Rajendra Karki, R K Subbarao Malireddi, Anannya Bhattacharya, David E Place, Jayadev Mavuluri, Jennifer L Peters, Peter Vogel, Masahiro Yamamoto, Thirumala-Devi Kanneganti
Invasive pulmonary aspergillosis causes substantial mortality in immunocompromised individuals. Recognition of Aspergillus fumigatus by the host immune system leads to activation of the inflammasome, which provides protection against infection. However, regulation of inflammasome activation at the molecular level is poorly understood. Here, we describe two distinct pathways that coordinately control inflammasome activation during A. fumigatus infection. The C-type lectin receptor pathway activates both MAPK and NF-κB signalling, which leads to induction of downstream mediators, such as the transcription factor IRF1, and also primes the inflammasomes...
December 3, 2018: Nature Microbiology
Na Yu, Min Xue, Weilong Wang, Dongxue Xia, Yajie Li, Xiaofeng Zhou, Dan Pang, Kui Lu, Jinghan Hou, Aijia Zhang, Ting Zhuang, Lidong Wang, Tingmin Chang, Xiumin Li
Oesophageal cancer ranks as one of the most common malignancy in China and worldwide. Although genome-wide association studies and molecular biology studies aim to elucidate the driver molecules in oesophageal cancer progression, the detailed mechanisms remain to be identified. Interestingly, RNF168 (RING finger protein 168) shows a high frequency of gene amplification in oesophageal cancer from TCGA database. Here, we report an important function for RNF168 protein in supporting oesophageal cancer growth and invasion by stabilizing STAT1 protein...
December 3, 2018: Journal of Cellular and Molecular Medicine
Yuzhen Zhou, Qi Wang, Li Chu, Weixing Dai, Xiaozhou Zhang, Jianfeng Chen, Long Zhang, Peipei Ding, Xin Zhang, Hongyu Gu, Pingzhao Zhang, Ling Li, Wei Zhang, Luying Li, Xinyue Lv, Danlei Zhou, Guoxiang Cai, Liang Chen, Kuaile Zhao, Weiguo Hu
OBJECTIVES: We aimed to elucidate the role and molecular mechanisms of FOXM1 in regulating metastasis in oesophageal squamous cell carcinoma (ESCC) as well as its clinical implications. MATERIALS AND METHODS: The expression levels of four isoforms of FOXM1 were analysed by real-time PCR. Next, genetically modification using overexpression and RNAi systems and transwell were employed to examine FOXM1c function in invasion and migration. Dual luciferase and ChIP assays were performed to decipher the underlying mechanism for transcriptional regulation...
November 28, 2018: Cell Proliferation
Gabriel Rodrigo Fries, Sarwar Khan, Sydney Stamatovich, Elena Dyukova, Consuelo Walss-Bass, Scott D Lane, Joy M Schmitz, Margaret C Wardle
Treatments for Cocaine Use Disorder (CUD) are variably effective, and there are no FDA-approved medications. One approach to developing new treatments for CUD may be to investigate and target poor prognostic signs. One such sign is anhedonia (i.e. a loss of pleasure or interest in non-drug rewards), which predicts worse outcomes in existing CUD treatments. Inflammation is thought to underlie anhedonia in many other disorders, but the relationship between anhedonia and inflammation has not been investigated in CUD...
2018: PloS One
Ailing Wu, Qingzhe Wu, Yujie Deng, Yuning Liu, Jinqiu Lu, Liansheng Liu, Xiaoling Li, Cheng Liao, Bin Zhao, Hai Song
Targeting immune checkpoints, such as PD-L1 and its receptor PD-1, has opened a new avenue for treating cancers. Understanding the regulatory mechanism of PD-L1 and PD-1 will improve the clinical response rate and efficacy of PD-1/PD-L1 blockade in cancer patients and the development of combinatorial strategies. VGLL4 inhibits YAP-induced cell proliferation and tumorigenesis through competition with YAP for binding to TEADs. However, whether VGLL4 has a role in anti-tumor immunity is largely unknown. Here, we found that disruption of Vgll4 results in potent T cell-mediated tumor regression in murine syngeneic models...
January 3, 2019: EMBO Journal
Che Wang, Honghui Yang, Chuanyu Gao
In this study, we identified candidate biomarkers for heart failure (HF). The gene expression profile GSE57338, containing 117 ischemic cardiomyopathic HF and 136 control samples, was downloaded and analyzed using various bioinformatics approaches. In total, 376 differentially expressed genes (DEGs) were identified, and four modules were explored in protein-protein interaction networks. DEGs (including ankyrin repeat and SOCS box-containing 14 [ASB14]) in the modules were mainly categorized by the function...
October 28, 2018: Journal of Cellular Physiology
Richa Rani, Sudhir Kumar, Akanksha Sharma, Sujit K Mohanty, Bryan Donnelly, Gregory M Tiao, Chandrashekhar Gandhi
Mice depleted of hepatic stellate cells (HSCs) are protected from concanavalin A (ConA)-induced liver injury that is mediated by the activation of interferon regulatory factor 1 (IRF1). The aim of this study was to determine the mechanisms of ConA-mediated signaling and synthesis/release of mediators by HSCs that damage hepatocytes. Primary cultures of wild type (WT) and IRF1-knockout (KO) HSCs and hepatocytes were used, and ConA-induced liver damage in IFNαβ receptor-deficient (IFNαβR-KO) mice was determined...
October 22, 2018: Journal of Biological Chemistry
Jiawen Qian, Chen Wang, Bo Wang, Jiao Yang, Yuedi Wang, Feifei Luo, Junying Xu, Chujun Zhao, Ronghua Liu, Yiwei Chu
BACKGROUND: PD-L1 is an immune inhibitory receptor ligand that leads to T cell dysfunction and apoptosis by binding to its receptor PD-1, which works in braking inflammatory response and conspiring tumor immune evasion. However, in gliomas, the cause of PD-L1 expression in the tumor microenvironment is not yet clear. Besides, auxiliary biomarkers are urgently needed for screening possible responsive glioma patients for anti-PD-1/PD-L1 therapies. METHODS: The distribution of tumor-infiltrating T cells and PD-L1 expression was analyzed via immunofluorescence in orthotopic murine glioma model...
October 17, 2018: Journal of Neuroinflammation
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