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1.
Prior upregulation of interferon pathways in the nasopharynx impacts viral shedding following live attenuated influenza vaccine challenge in children.
Costa-Martins, AG, Mane, K, Lindsey, BB, Ogava, RLT, Castro, Í, Jagne, YJ, Sallah, HJ, Armitage, EP, Jarju, S, Ahadzie, B, et al
Cell reports. Medicine. 2021;(12):100465
Abstract
In children lacking influenza-specific adaptive immunity, upper respiratory tract innate immune responses may influence viral replication and disease outcome. We use trivalent live attenuated influenza vaccine (LAIV) as a surrogate challenge model in children aged 24-59 months to identify pre-infection mucosal transcriptomic signatures associated with subsequent viral shedding. Upregulation of interferon signaling pathways prior to LAIV is significantly associated with lower strain-specific viral loads (VLs) at days 2 and 7. Several interferon-stimulated genes are differentially expressed in children with pre-LAIV asymptomatic respiratory viral infections and negatively correlated with LAIV VLs. Upregulation of genes enriched in macrophages, neutrophils, and eosinophils is associated with lower VLs and found more commonly in children with asymptomatic viral infections. Variability in pre-infection mucosal interferon gene expression in children may impact the course of subsequent influenza infections. This variability may be due to frequent respiratory viral infections, demonstrating the potential importance of mucosal virus-virus interactions in children.
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2.
Aristocratic human papillomavirus drove cervical cancer: a study of the therapeutic potential of the combination of interferon with zinc.
Gao, YH, Yu, L, Liu, ZS, Li, YF
Molecular and cellular biochemistry. 2021;(2):757-765
Abstract
Human papillomavirus (HPV) infection is related to cancer growth of vaginal, cervical, vulva, penile, anogenital, and non-genital oropharyngeal sites. HPV, as a sexually transmitted virus, infects all sexes similarly but with more significant pathological risks in women. This accounts for high mortality due to late detection and poor prognosis. The initial development and eventual progress of this cancer type depend entirely on three main oncogenes E5, E6 and E7, constitutively expressed to lead to carcinogenesis. Despite an opportunity for pharmacological therapy, there is still a shortage of medical treatment that may remove HPV from infected lesions. This study offers a concise summary of the nature of the issue and the current status of work on potential lead molecules and therapeutic approaches that show the capacity of HPV therapies to counteract the roles of deregulation of E5, E6, and E7.
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3.
Prevention and treatment of COVID-19: Focus on interferons, chloroquine/hydroxychloroquine, azithromycin, and vaccine.
Bakadia, BM, He, F, Souho, T, Lamboni, L, Ullah, MW, Boni, BO, Ahmed, AAQ, Mukole, BM, Yang, G
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;:111008
Abstract
The ongoing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has drawn the attention of researchers and clinicians from several disciplines and sectors who are trying to find durable solutions both at preventive and treatment levels. To date, there is no approved effective treatment or vaccine available to control the coronavirus disease-2019 (COVID-19). The preliminary in vitro studies on viral infection models showed potential antiviral activities of type I and III interferons (IFNs), chloroquine (CQ)/hydroxychloroquine (HCQ), and azithromycin (AZM); however, the clinical studies on COVID-19 patients treated with CQ/HCQ and AZM led to controversies in different regions due to their adverse side effects, as well as their combined treatment could prolong the QT interval. Interestingly, the treatment with type I IFNs showed encouraging results. Moreover, the different preliminary reports of COVID-19 candidate vaccines showcase promising results by inducing the production of a high level of neutralizing antibodies (NAbs) and specific T cell-mediated immune response in almost all participants. The present review aims to summarize and analyze the recent progress evidence concerning the use of IFNs, CQ/HCQ, and AZM for the treatment of COVID-19. The available data on immunization options to prevent the COVID-19 are also analyzed with the aim to present the promising options which could be investigated in future for sustainable control of the pandemic.
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4.
The Dramatic Role of IFN Family in Aberrant Inflammatory Osteolysis.
Deng, Z, Hu, W, Ai, H, Chen, Y, Dong, S
Current gene therapy. 2021;(2):112-129
Abstract
Skeletal system has been considered a highly dynamic system, in which bone-forming osteoblasts and bone-resorbing osteoclasts go through a continuous remodeling cycle to maintain homeostasis of bone matrix. It has been well acknowledged that interferons (IFNs), acting as a subgroup of cytokines, not only have crucial effects on regulating immunology but also could modulate the dynamic balance of bone matrix. In the light of different isoforms, IFNs have been divided into three major categories in terms of amino acid sequences, recognition of specific receptors and biological activities. Currently, type I IFNs consist of a multi-gene family with several subtypes, of which IFN-α exerts pro-osteoblastogenic effects to activate osteoblast differentiation and inhibits osteoclast fusion to maintain bone matrix integrity. Meanwhile, IFN-β suppresses osteoblast-mediated bone remodeling as well as exhibits inhibitory effects on osteoclast differentiation to attenuate bone resorption. Type II IFN constitutes the only type, IFN-γ, which exerts regulatory effects on osteoclastic bone resorption and osteoblastic bone formation by biphasic ways. Interestingly, type III IFNs are regarded as new members of IFN family composed of four members, including IFN-λ1 (IL-29), IFN-λ2 (IL-28A), IFN-λ3 (IL-28B) and IFN-λ4, which have been certified to participate in bone destruction. However, the direct regulatory mechanisms underlying how type III IFNs modulate the metabolic balance of bone matrix, remains poorly elucidated. In this review, we have summarized functions of IFN family during physiological and pathological conditions and described the mechanisms by which IFNs maintain bone matrix homeostasis via affecting the osteoclast-osteoblast crosstalk. In addition, the potential therapeutic effects of IFNs on inflammatory bone destruction diseases such as rheumatoid arthritis (RA), osteoarthritis (OA) and infectious bone diseases are also well displayed, which are based on the predominant role of IFNs in modulating the dynamic equilibrium of bone matrix.
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5.
Vitamin D, zinc and glutamine: Synergistic action with OncoTherad immunomodulator in interferon signaling and COVID‑19 (Review).
Name, JJ, Vasconcelos, AR, Souza, ACR, Fávaro, WJ
International journal of molecular medicine. 2021;(3)
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Abstract
Coronavirus disease 2019 (COVID‑19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), was identified in December, 2019 in Wuhan, China. Since then, it has continued to spread rapidly in numerous countries, while the search for effective therapeutic options persists. Coronaviruses, including SARS‑CoV‑2, are known to suppress and evade the antiviral responses of the host organism mediated by interferon (IFN), a family of cytokines that plays an important role in antiviral defenses associated with innate immunity, and has been used therapeutically for chronic viral diseases and cancer. On the other hand, OncoTherad, a safe and effective immunotherapeutic agent in the treatment of non‑muscle invasive bladder cancer (NMIBC), increases IFN signaling and has been shown to be a promising therapeutic approach for COVID‑19 in a case report that described the rapid recovery of a 78‑year‑old patient with NMIBC with comorbidities. The present review discusses the possible synergistic action of OncoTherad with vitamin D, zinc and glutamine, nutrients that have been shown to facilitate immune responses mediated by IFN signaling, as well as the potential of this combination as a therapeutic option for COVID‑19.
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Treatment and re-treatment results of HCV patients in the DAA era.
Piecha, F, Gänßler, JM, Ozga, AK, Wehmeyer, MH, Dietz, J, Kluwe, J, Laschtowitz, A, von Felden, J, Sterneck, M, Jordan, S, et al
PloS one. 2020;(5):e0232773
Abstract
BACKGROUND Re-treatment in patients with a chronic hepatitis C virus (HCV) infection and a previous failure to direct-acting antiviral (DAA) treatment remains a challenge. Therefore, we investigated the success rate of treatment and re-treatment regimens used at our center from October 2011 to March 2018. METHODS A retrospective analysis of DAA-based HCV therapies of 1096 patients was conducted. Factors associated with a virological relapse were identified by univariable and multivariable logistic regression, treatment success of the re-treatment regimens was evaluated by an analysis of sustained virological response (SVR) rates in patients with a documented follow-up 12 weeks after the end of treatment. RESULTS Of 1096 patients treated with DAA-based regimens, 91 patients (8%) were lost to follow-up, 892 of the remaining 1005 patients (89%) achieved an SVR12. Most patients (65/113, 58%) who experienced a virological relapse received an interferon-based DAA regimen. SVR rates were comparable in special cohorts like liver transplant recipients (53/61, 87%) and people with a human immunodeficiency virus (HIV) coinfection (41/45, 91%). On multivariable analysis, interferon-based DAA therapy was associated with treatment failure (odds ratio 0.111, 95%-confidence interval 0.054-0.218) among others. One hundred seventeen patients with multiple DAA treatment courses were identified, of which 97 patients (83%) experienced a single relapse, but further relapses after two (18/117, 15%) or even three (2/117, 2%) treatment courses were also observed. Eighty-two of 96 (85%) re-treatment attempts with all-oral DAA regimens were successful after an initial treatment failure. CONCLUSION Overall, DAA re-treatments were highly effective in this real-world cohort and only a minority of patients failed more than two treatment courses. Switching to-or addition of-a new drug class seem to be valid options for the re-treatment of patients especially after failure of an interferon-based regimen.
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Viral Infections and Interferons in the Development of Obesity.
Tian, Y, Jennings, J, Gong, Y, Sang, Y
Biomolecules. 2019;(11)
Abstract
Obesity is now a prevalent disease worldwide and has a multi-factorial etiology. Several viruses or virus-like agents including members of adenoviridae, herpesviridae, slow virus (prion), and hepatitides, have been associated with obesity; meanwhile obese patients are shown to be more susceptible to viral infections such as during influenza and dengue epidemics. We examined the co-factorial role of viral infections, particularly of the persistent cases, in synergy with high-fat diet in induction of obesity. Antiviral interferons (IFNs), as key immune regulators against viral infections and in autoimmunity, emerge to be a pivotal player in the regulation of adipogenesis. In this review, we examine the recent evidence indicating that gut microbiota uphold intrinsic IFN signaling, which is extensively involved in the regulation of lipid metabolism. However, the prolonged IFN responses during persistent viral infections and obesogenesis comprise reciprocal causality between virus susceptibility and obesity. Furthermore, some IFN subtypes have shown therapeutic potency in their anti-inflammation and anti-obesity activity.
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8.
Deferasirox drives ROS-mediated differentiation and induces interferon-stimulated gene expression in human healthy haematopoietic stem/progenitor cells and in leukemia cells.
Tataranni, T, Mazzoccoli, C, Agriesti, F, De Luca, L, Laurenzana, I, Simeon, V, Ruggieri, V, Pacelli, C, Della Sala, G, Musto, P, et al
Stem cell research & therapy. 2019;(1):171
Abstract
BACKGROUND Administration of the iron chelator deferasirox (DFX) in transfusion-dependent patients occasionally results in haematopoiesis recovery by a mechanism remaining elusive. This study aimed to investigate at a molecular level a general mechanism underlying DFX beneficial effects on haematopoiesis, both in healthy and pathological conditions. METHODS Human healthy haematopoietic stem/progenitor cells (HS/PCs) and three leukemia cell lines were treated with DFX. N-Acetyl cysteine (NAC) and fludarabine were added as antioxidant and STAT1 inhibitor, respectively. In vitro colony-forming assays were assessed both in healthy and in leukemia cells. Intracellular and mitochondrial reactive oxygen species (ROS) as well as mitochondrial content were assessed by cytofluorimetric and confocal microscopy analysis; mtDNA was assessed by qRT-PCR. Differentiation markers were monitored by cytofluorimetric analysis. Gene expression analysis (GEA) was performed on healthy HS/PCs, and differently expressed genes were validated in healthy and leukemia cells by qRT-PCR. STAT1 expression and phosphorylation were assessed by Western blotting. Data were compared by an unpaired Student t test or one-way ANOVA. RESULTS DFX, at clinically relevant concentrations, increased the clonogenic capacity of healthy human CD34+ HS/PCs to form erythroid colonies. Extension of this analysis to human-derived leukemia cell lines Kasumi-1, K562 and HL60 confirmed DFX capacity to upregulate the expression of specific markers of haematopoietic commitment. Notably, the abovementioned DFX-induced effects are all prevented by the antioxidant NAC and accompanied with overproduction of mitochondria-generated reactive oxygen species (ROS) and increase of mitochondrial content and mtDNA copy number. GEA unveiled upregulation of genes linked to interferon (IFN) signalling and tracked back to hyper-phosphorylation of STAT1. Treatment of leukemic cell lines with NAC prevented the DFX-mediated phosphorylation of STAT1 as well as the expression of the IFN-stimulated genes. However, STAT1 inhibition by fludarabine was not sufficient to affect differentiation processes in leukemic cell lines. CONCLUSIONS These findings suggest a significant involvement of redox signalling as a major regulator of multiple DFX-orchestrated events promoting differentiation in healthy and tumour cells. The understanding of molecular mechanisms underlying the haematological response by DFX would enable to predict patient's ability to respond to the drug, to extend treatment to other patients or to anticipate the treatment, regardless of the iron overload.
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Interleukin 28 Polymorphisms and Hepatocellular Carcinoma Development after Direct Acting Antiviral Therapy for Chronic Hepatitis C.
Simili, A, Mazzella, G, Ravaioli, F, Festi, D, Bacchi-Reggiani, ML, Porro, A, Bazzoli, F, Azzaroli, F
Journal of gastrointestinal and liver diseases : JGLD. 2019;(4):449-456
Abstract
BACKGROUND AND AIMS Cirrhotic patients with hepatitis C virus (HCV) infection remain at risk of developing hepatocellular carcinoma (HCC) even after the sustained virologic response (SVR). We aimed to evaluate whether the IL28 (rs12979860) single nucleotide polymorphism (SNP) may constitute a predisposing genetic factor and to identify the SVR patients at risk of HCC. METHODS Two hundred patients undergoing DAAs treatment for chronic hepatitis C with advanced fibrosis (F3- F4) were consecutively enrolled. Besides normal routine laboratory testing for HCV, patients' sera were evaluated also for retinol, retinol-binding protein 4 and the following SNPs: PNPLA3 (rs738409), TM6SF2 (rs58542926), MBOAT7 (rs641738), IL28B (rs12979860), TIMP-1 (rs4898), TIMP-2 (rs8179090), NF-kB promoter (rs28362491). Statistical analyses were conducted using Stata/SE 14.2 statistical software (Stata Corp, College Station, TX). RESULTS Almost all patients (197/200) obtained SVR24. Seventeen patients had a previous history of treated HCC before DAAs. Six patients developed HCC recurrence and five patients developed de novo HCC after a mean period of 18 months since EOT. All these patients had SVR. A significant association between IL28B - TT genotype and HCC development after DAAs therapy was observed (OR 4.728, CI 95% 1.222 - 18.297, p=0.024). CONCLUSION IL28B rs12979860 polymorphism was significantly associated with HCC development after DAAs. Assessment of this SNP may better identify patients at risk of developing HCC after treatment. Further prospective studies are required to confirm these hypotheses.
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10.
Probiotic supplements containing Lactobacillus reuteri does not affect the levels of matrix metalloproteinases and interferons in oral wound healing.
Twetman, S, Pedersen, AML, Yucel-Lindberg, T
BMC research notes. 2018;(1):759
Abstract
OBJECTIVE The use of beneficial bacteria may stimulate wound healing. We performed a randomized, placebo-controlled double-blind cross-over study comprising ten healthy volunteers. The aim was to investigate the impact of topical and systemic applications of probiotic lactobacilli (Lactobacillus reuteri) on the healing of standardized wounds (punch biopsies) in the oral mucosa. The expression of selected matrix metalloproteinases (MMP'S) and interferons (IFN's) was analyzed with multiplex immunoassays in the wound exudate during the first healing week (day 2, 5 and 8). RESULTS All participants completed the study and in all cases, the healing after the punch biopsies was uneventful. The concentrations of MMP-1, MMP-2, MMP-3 decreased with time in both the test- and control group. The MMP levels were consistently lower during the probiotic intervention when compared with placebo but the differences were not statistically significant. Likewise, the concentrations if IFN-alpha2, IFN-beta and IFN-gamma decreased with time with no significant differences between the test and placebo interventions. Within the limitations of this pilot study, we were unable to demonstrate an influence of probiotic supplements containing L. reuteri on the concentrations of selected matrix metalloproteinases and interferons from mucosal wounds within 1 week after a standardized punch biopsy. Trial registration ClinicalTrials.gov Identifier NCT03210779. Date of registration: July 7, 2017.