scholarly journals Coumarin Derivative N6 as a Novel anti-hantavirus Infection Agent Targeting AKT

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhoupeng Li ◽  
Fang Wang ◽  
Yongsheng Liu ◽  
Dongshen Zhai ◽  
Xiaoxiao Zhang ◽  
...  
Keyword(s):  
Early Stage ◽  
Specific Treatment ◽  
Hemorrhagic Fever ◽  
Coumarin Derivative ◽  
Hantaan Virus ◽  
Hantavirus Infection ◽  
Amino Acid Residues ◽  
Coumarin Derivatives ◽  
Newborn Mice

Hantaviruses are globally emerging zoonotic viruses that can cause hemorrhagic fever with renal syndrome (HFRS) in Asia and Europe, which is primarily caused by Hantaan virus (HTNV) infection, results in profound morbidity and mortality. However, no specific treatment is available for this disease. Coumarin derivatives have been reported as antiviral molecules, while studies about the bioactivity of coumarin derivatives against HTNV infection are limited. To study the potential antiviral activity of coumarin derivatives, 126 coumarin derivatives are synthesized, and their inhibitory activity against HTNV is analyzed in vitro. Among these compounds, N6 inhibits HTNV with relatively high selectivity index at 10.9, and the viral titer of HTNV is reduced significantly after 5, 10, and 20 μM N6 treatments. Furthermore, the administration of N6 at the early stage of HTNV infection can inhibit the replication and production of infectious HTNV in host cell, this therapeutic efficacy is confirmed in HTNV-infected newborn mice at the early stage of infection. The molecular docking results show that N6 forms interactions with the key amino acid residues at its active site, and reveals several molecular interactions responsible for the observed affinity, and the treatment of N6 can inhibit the expression of p (Ser473)Akt and HTNV nucleocapsid protein significantly. As such, these observations demonstrate that coumarin derivative N6 might be used as a potential agent against HTNV infection.

scholarly journals Hantavirus Infection of Dendritic Cells

2002 ◽  
Vol 76 (21) ◽  
pp. 10724-10733 ◽  
Author(s):  
Martin J. Raftery ◽  
Annette A. Kraus ◽  
Rainer Ulrich ◽  
Detlev H. Krüger ◽  
Günther Schönrich
Keyword(s):  
Dendritic Cells ◽  
Hemorrhagic Fever ◽  
Hantaan Virus ◽  
Hantavirus Infection ◽  
Necrosis Factor Alpha ◽  
Antigen Uptake ◽  
Antiviral Immune Response ◽  
Factor Alpha ◽  
Antigen Presenting

ABSTRACT Dendritic cells (DCs) play a pivotal role as antigen-presenting cells in the antiviral immune response. Here we show that Hantaan virus (HTNV), which belongs to the Bunyaviridae family (genus Hantavirus) and causes hemorrhagic fever with renal syndrome, productively infects human DCs in vitro. In the course of HTNV infection, DCs did not show any cytopathic effect and viral replication did not induce cell lysis or apoptosis. Furthermore, HTNV did not affect apoptosis-inducing signals that are important for the homeostatic control of mature DCs. In contrast to immunosuppressive viruses, e.g., human cytomegalovirus, HTNV activated immature DCs, resulting in upregulation of major histocompatibility complex (MHC), costimulatory, and adhesion molecules. Intriguingly, strong upregulation of MHC class I molecules and an increased intercellular cell adhesion molecule type 1 expression was also detected on HTNV-infected endothelial cells. In addition, antigen uptake by HTNV-infected DCs was reduced, another characteristic feature of DC maturation. Consistent with these findings, we observed that HTNV-infected DCs stimulated T cells as efficiently as did mature DCs. Finally, infection of DCs with HTNV induced the release of the proinflammatory cytokines tumor necrosis factor alpha and alpha interferon. Taken together, our findings indicate that hantavirus-infected DCs may significantly contribute to hantavirus-associated pathogenesis.

Hemorrhagic fever with renal syndrome with concurrent aortic dissection: a case report

2020 ◽  
Author(s):  
Fengqi Qiu ◽  
Congcong Li ◽  
Jianya Zhou
Keyword(s):  
Acute Kidney Injury ◽  
Aortic Dissection ◽  
Kidney Injury ◽  
Hemorrhagic Fever ◽  
Sudden Onset ◽  
High Fever ◽  
Hantaan Virus ◽  
Hantavirus Infection ◽  
Microvascular Damage ◽  
Stanford B

Abstract Background Hemorrhagic fever with renal syndrome (HFRS) is caused by hantaviruses presenting with high fever, hemorrhage, acute kidney injury. Microvascular injury and hemorrhage in mucus was often observed in patients with hantavirus infection. Infection with bacterial and virus related aortic aneurysm or dissection occurs sporadically. We present a previously unreported case of hemorrhagic fever with concurrent Stanford B aortic dissection. Case presentation: A 56-year-old man complained of high fever, generalized body ache, with decreased platelet counts of 10 × 10^9/L and acute kidney injury. The ELISA test for Hantaan virus of IgM and IgG antibodies were both positive. During the convalescent period, he complained sudden onset acute chest pain radiating to the back and the CTA revealed an aortic dissection of the descending aorta extending to iliac artery. He was diagnosed with Hemorrhagic fever with renal syndrome and Stanford B aortic dissection. The patient recovered completely after surgery with other support treatments. Conclusion We present a case of HFRS complicated with aortic dissection,and no study has reported the association of HFRS with aortic disease. However, we suppose that hantavirus infection not only cause microvascular damage but may be risk factor for acute macrovascular detriment. A causal relationship has yet to be confirmed.

scholarly journals Chloroquine, an Anti-Malaria Drug as Effective Prevention for Hantavirus Infections

2021 ◽  
Vol 11 ◽  
Author(s):  
Valentijn Vergote ◽  
Lies Laenen ◽  
Raf Mols ◽  
Patrick Augustijns ◽  
Marc Van Ranst ◽  
...  
Keyword(s):  
Virus Infection ◽  
Syrian Hamster ◽  
Osmotic Pump ◽  
Hantaan Virus ◽  
Dependent Manner ◽  
Prophylactic Effect ◽  
Hamster Model ◽  
Newborn Mice ◽  
Andes Virus

We investigated whether chloroquine can prevent hantavirus infection and disease in vitro and in vivo, using the Hantaan virus newborn C57BL/6 mice model and the Syrian hamster model for Andes virus. In vitro antiviral experiments were performed using Vero E6 cells, and Old World and New World hantavirus species. Hantavirus RNA was detected using quantitative RT-PCR. For all hantavirus species tested, results indicate that the IC50 of chloroquine (mean 10.2 ± 1.43 μM) is significantly lower than the CC50 (mean 260 ± 2.52 μM) yielding an overall selectivity index of 25.5. We also investigated the potential of chloroquine to prevent death in newborn mice after Hantaan virus infection and its antiviral effect in the hantavirus Syrian hamster model. For this purpose, C57Bl/6 mother mice were treated subcutaneously with daily doses of chloroquine. Subsequently, 1-day-old suckling mice were inoculated intracerebrally with 5 x 102 Hantaan virus particles. In litters of untreated mothers, none of the pups survived challenge. The highest survival rate (72.7% of pups) was found when mother mice were administered a concentration of 10 mg/kg chloroquine. Survival rates declined in a dose-dependent manner, with 47.6% survival when treated with 5 mg/kg chloroquine, and 4.2% when treated with 1 mg/kg chloroquine. Assessing the antiviral therapeutic and prophylactic effect of chloroquine in the Syrian hamster model was done using two different administration routes (intraperitoneally and subcutaneously using an osmotic pump system). Evaluating the prophylactic effect, a delay in onset of disease was noted and for the osmotic pump, 60% survival was observed. Our results show that chloroquine can be highly effective against Hantaan virus infection in newborn mice and against Andes virus in Syrian hamsters.

scholarly journals Hantavirus RdRp Requires a Host Cell Factor for Cap Snatching

2018 ◽  
Vol 93 (5) ◽  
Author(s):  
Subbiah Jeeva ◽  
Sheema Mir ◽  
Adrain Velasquez ◽  
Brandy A. Weathers ◽  
Aljona Leka ◽  
...  
Keyword(s):  
Host Cell ◽  
Virus Replication ◽  
Umbilical Vein ◽  
Hemorrhagic Fever ◽  
Hantavirus Infection ◽  
Early Event ◽  
N Protein ◽  
Host Cell Factor ◽  
Endonuclease Domain

ABSTRACTThe hantavirus RNA-dependent RNA polymerase (RdRp) snatches 5′ capped mRNA fragments from the host cell transcripts and uses them as primers to initiate transcription and replication of the viral genome in the cytoplasm of infected cells. Hantavirus nucleocapsid protein (N protein) binds to the 5′ caps of host cell mRNA and protects them from the attack of cellular decapping machinery. N protein rescues long capped mRNA fragments in cellular P bodies that are later processed by an unknown mechanism to generate 10- to 14-nucleotide-long capped RNA primers with a 3′ G residue. Hantavirus RdRp has an N-terminal endonuclease domain and a C-terminal uncharacterized domain that harbors a binding site for the N protein. The purified endonuclease domain of RdRp nonspecifically degraded RNAin vitro. It is puzzling how such nonspecific endonuclease activity generates primers of appropriate length and specificity during cap snatching. We fused the N-terminal endonuclease domain with the C-terminal uncharacterized domain of the RdRp. The resulting NC mutant, with the assistance of N protein, generated capped primers of appropriate length and specificity from a test mRNA in cells. Bacterially expressed and purified NC mutant and N protein required further incubation with the lysates of human umbilical vein endothelial cells (HUVECs) for the specific endonucleolytic cleavage of a test mRNA to generate capped primers of appropriate length and defined 3′ terminusin vitro. Our results suggest that an unknown host cell factor facilitates the interaction between N protein and NC mutant and brings the N protein-bound capped RNA fragments in close proximity to the endonuclease domain of the RdRp for specific cleavage at a precise length from the 5′ cap. These studies provide critical insights into the cap-snatching mechanism of cytoplasmic viruses and have revealed potential new targets for their therapeutic intervention.IMPORTANCEHumans acquire hantavirus infection by the inhalation of aerosolized excreta of infected rodent hosts. Hantavirus infections cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS), with mortality rates of 15% and 50%, respectively (1). Annually 150,000 to 200,000 cases of hantavirus infections are reported worldwide, for which there is no treatment at present. Cap snatching is an early event in the initiation of virus replication in infected hosts. Interruption in cap snatching will inhibit virus replication and will likely improve the prognosis of the hantavirus disease. Our studies provide mechanistic insight into the cap-snatching mechanism and demonstrate the requirement of a host cell factor for successful cap snatching. Identification of this host cell factor will reveal a novel therapeutic target for combating this viral illness.

scholarly journals Detection and Typing of Human Pathogenic Hantaviruses by Real-Time Reverse Transcription-PCR and Pyrosequencing

2007 ◽  
Vol 53 (11) ◽  
pp. 1899-1905 ◽  
Author(s):  
Marit Kramski ◽  
Helga Meisel ◽  
Boris Klempa ◽  
Detlev H Krüger ◽  
Georg Pauli ◽  
...  
Keyword(s):  
Real Time ◽  
Reverse Transcription ◽  
Hantaan Virus ◽  
Hantavirus Infection ◽  
Sequence Information ◽  
Rt Pcr ◽  
Clinical Specimens ◽  
Reverse Transcription Pcr ◽  
Pcr Assays

Abstract Background: Because the clinical course of human infections with hantaviruses can vary from subclinical to fatal, rapid and reliable detection of hantaviruses is essential. To date, the diagnosis of hantavirus infection is based mainly on serologic assays, and the detection of hantaviral RNA by the commonly used reverse transcription (RT)-PCR is difficult because of high sequence diversity of hantaviruses and low viral loads in clinical specimens. Methods: We developed 5 real-time RT-PCR assays, 3 of which are specific for the individual European hantaviruses Dobrava, Puumala, or Tula virus. Two additional assays detect the Asian species Hantaan virus together with Seoul virus and the American species Andes virus together with Sin Nombre virus. Pyrosequencing was established to provide characteristic sequence information of the amplified hantavirus for confirmation of the RT-PCR results or for a more detailed virus typing. Results: The real-time RT-PCR assays were specific for the respective hantavirus species and optimized to run on 2 different platforms, the LightCycler and the ABI 7900/7500. Each assay showed a detection limit of 10 copies of a plasmid containing the RT-PCR target region, and pyrosequencing was possible with 10 to 100 copies per reaction. With this assay, viral genome could be detected in 16 of 552 (2.5%) specimens of suspected hantavirus infections of humans and mice. Conclusions: The new assays detect, differentiate, and quantify hantaviruses in clinical specimens from humans and from their natural hosts and may be useful for in vitro studies of hantaviruses.

scholarly journals The Pathogenic NY-1 Hantavirus G1 Cytoplasmic Tail Inhibits RIG-I- and TBK-1-Directed Interferon Responses

2006 ◽  
Vol 80 (19) ◽  
pp. 9676-9686 ◽  
Author(s):  
Peter J. Alff ◽  
Irina N. Gavrilovskaya ◽  
Elena Gorbunova ◽  
Karen Endriss ◽  
YuSon Chong ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Active Form ◽  
Cytoplasmic Tail ◽  
Hemorrhagic Fever ◽  
Hantaan Virus ◽  
Hantavirus Infection ◽  
Dependent Manner ◽  
Human Endothelial Cells ◽  
Transcriptional Responses ◽  
Interferon Responses

ABSTRACT Hantaviruses cause two diseases with prominent vascular permeability defects, hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. All hantaviruses infect human endothelial cells, although it is unclear what differentiates pathogenic from nonpathogenic hantaviruses. We observed dramatic differences in interferon-specific transcriptional responses between pathogenic and nonpathogenic hantaviruses at 1 day postinfection, suggesting that hantavirus pathogenesis may in part be determined by viral regulation of cellular interferon responses. In contrast to pathogenic NY-1 virus (NY-1V) and Hantaan virus (HTNV), nonpathogenic Prospect Hill virus (PHV) elicits early interferon responses following infection of human endothelial cells. We determined that PHV replication is blocked in human endothelial cells and that RNA and protein synthesis by PHV, but not NY-1V or HTNV, is inhibited at 2 to 4 days postinfection. The addition of antibodies to beta interferon (IFN-β) blocked interferon-directed MxA induction by >90% and demonstrated that hantavirus infection induces the secretion of IFN-β from endothelial cells. Coinfecting endothelial cells with NY-1V and PHV resulted in a 60% decrease in the induction of interferon-responsive MxA transcripts by PHV and further suggested the potential for NY-1V to regulate early IFN responses. Expression of the NY-1V G1 cytoplasmic tail inhibited by >90% RIG-I- and downstream TBK-1-directed transcription from interferon-stimulated response elements or β-interferon promoters in a dose-dependent manner. In contrast, expression of the NY-1V nucleocapsid or PHV G1 tail had no effect on RIG-I- or TBK-1-directed transcriptional responses. Further, neither the NY-1V nor PHV G1 tails inhibited transcriptional responses directed by a constitutively active form of interferon regulatory factor 3 (IRF-3 5D), and IRF-3 is a direct target of TBK-1 phosphorylation. These findings indicate that the pathogenic NY-1V G1 protein regulates cellular IFN responses upstream of IRF-3 phosphorylation at the level of the TBK-1 complex. These findings further suggest that the G1 cytoplasmic tail contains a virulence element which determines the ability of hantaviruses to bypass innate cellular immune responses and delineates a mechanism for pathogenic hantaviruses to successfully replicate within human endothelial cells.

scholarly journals Fibroblast membrane-camouflaged nanoparticles for inflammation treatment in the early stage

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Lizhong Sun ◽  
Libang He ◽  
Wei Wu ◽  
Li Luo ◽  
Mingyue Han ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Immune Cell ◽  
Early Stage ◽  
Specific Treatment ◽  
Cell Types ◽  
Loss Of Function ◽  
Tissue Repair And Regeneration ◽  
Inflammatory Conditions

AbstractUnrestrained inflammation is harmful to tissue repair and regeneration. Immune cell membrane-camouflaged nanoparticles have been proven to show promise as inflammation targets and multitargeted inflammation controls in the treatment of severe inflammation. Prevention and early intervention of inflammation can reduce the risk of irreversible tissue damage and loss of function, but no cell membrane-camouflaged nanotechnology has been reported to achieve stage-specific treatment in these conditions. In this study, we investigated the prophylactic and therapeutic efficacy of fibroblast membrane-camouflaged nanoparticles for topical treatment of early inflammation (early pulpitis as the model) with the help of in-depth bioinformatics and molecular biology investigations in vitro and in vivo. Nanoparticles have been proven to act as sentinels to detect and competitively neutralize invasive Escherichia coli lipopolysaccharide (E. coli LPS) with resident fibroblasts to effectively inhibit the activation of intricate signaling pathways. Moreover, nanoparticles can alleviate the secretion of multiple inflammatory cytokines to achieve multitargeted anti-inflammatory effects, attenuating inflammatory conditions in the early stage. Our work verified the feasibility of fibroblast membrane-camouflaged nanoparticles for inflammation treatment in the early stage, which widens the potential cell types for inflammation regulation.

scholarly journals Altered expression of Armet and Mrlp51 in the oocyte, preimplantation embryo, and brain of mice following oocyte in vitro maturation but postnatal brain development and cognitive function are normal

Reproduction ◽  
2011 ◽  
Vol 142 (3) ◽  
pp. 401-408 ◽  
Author(s):  
Ning Wang ◽  
Liya Wang ◽  
Fang Le ◽  
Qitao Zhan ◽  
Yingming Zheng ◽  
...  
Keyword(s):  
Brain Development ◽  
Early Stage ◽  
Suppressive Subtractive Hybridization ◽  
Control Group ◽  
Newborn Mice ◽  
Altered Expression ◽  
Developmental Potential ◽  
The Brain

Despite the efforts to recapitulate the follicle environment, oocytes from in vitro maturation (IVM) have poorer developmental potential than those matured in vivo and the effects on the resultant offspring are of concern. The aim of this study was to determine altered gene expression in oocytes following IVM and to evaluate the expression of the arginine rich, mutated in early stage of tumors gene (Armet) and mitochondrial ribosomal protein L51 (Mrpl51) in embryos and brains of fetal/postnatal mice and the brain development of IVM offspring. An IVM mouse model was established while oocytes matured in vivo were used as the controls. Suppressive subtractive hybridization (SSH) and RT-PCR/western blot were used to analyze the differential expression of genes/proteins between IVM and the control group. HE staining and water maze were used to assess the histological changes in brain tissue and cognition of the offspring. The rates of fertilization, cleavage, and live birth were significantly decreased in IVM group. Thirteen genes were upregulated in IVM oocytes compared with the control, including Armet and Mrpl51. The higher level of Armet in IVM oocytes was retained in brain of newborn mice, which could be related to the upregulation of activating transcription factor 6 (Atf6) and X-box binding protein 1 (Xbp1), while Mrpl51 was expressed normally in brain of postnatal mice. No significant differences were detected in brain weight, neuronal counts, and the cognition in the offspring between the two groups. The present results suggested that IVM could affect the pregnancy outcome and the Armet and Mrpl51 gene/protein expression. The change in Armet expression lasted while the change of Mrpl51 disappeared after birth. However, the brain development of the offspring seemed to be unaffected by IVM.

scholarly journals Urinary genome detection and tracking of Hantaan virus from hemorrhagic fever with renal syndrome patients using multiplex PCR-based next-generation sequencing

2021 ◽  
Vol 15 (9) ◽  
pp. e0009707
Author(s):  
Seungchan Cho ◽  
Won-Keun Kim ◽  
Jin Sun No ◽  
Seung-Ho Lee ◽  
Jaehun Jung ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Multiplex Pcr ◽  
Phylogenetic Analyses ◽  
Hemorrhagic Fever ◽  
Hantaan Virus ◽  
Hantavirus Infection ◽  
Next Generation ◽  
Genome Sequences ◽  
Generation Sequencing ◽  
Urine Specimens

Background Hantavirus infection occurs through the inhalation of aerosolized excreta, including urine, feces, and saliva of infected rodents. The presence of Hantaan virus (HTNV) RNA or infectious particles in urine specimens of patient with hemorrhagic fever with renal syndrome (HFRS) remains to be investigated. Methodology/Principal findings We collected four urine and serum specimens of Republic of Korea Army (ROKA) patients with HFRS. We performed multiplex PCR-based next-generation sequencing (NGS) to obtain the genome sequences of clinical HTNV in urine specimens containing ultra-low amounts of viral genomes. The epidemiological and phylogenetic analyses of HTNV demonstrated geographically homogenous clustering with those in Apodemus agrarius captured in highly endemic areas, indicating that phylogeographic tracing of HTNV genomes reveals the potential infection sites of patients with HFRS. Genetic exchange analyses showed a genetic configuration compatible with HTNV L segment exchange in nature. Conclusion/Significance Our results suggest that whole or partial genome sequences of HTNV from the urine enabled to track the putative infection sites of patients with HFRS by phylogeographically linking to the zoonotic HTNV from the reservoir host captured at endemic regions. This report raises awareness among physicians for the presence of HTNV in the urine of patients with HFRS.

Does the melatonin supplementation decrease the severity of the outcomes in COVID-19 patients? A mini review of observational data in the in vivo and in vitro studies

2021 ◽  
Vol 4 (2) ◽  
pp. 348-359
Author(s):  
Mohammad Gholizadeh ◽  
Faezeh Abaj ◽  
Hossein Hasani ◽  
Atieh Mirzababaei ◽  
Khadijeh Mirzaei
Keyword(s):  
Molecular Level ◽  
Antioxidant Activities ◽  
Early Stage ◽  
Specific Treatment ◽  
Case Series ◽  
Lung Damage ◽  
In Vivo Studies ◽  
Critical Conditions

The Coronavirus Disease 2019 (COVID-19) is a global pandemic and there is no specific treatment for reducing the severity of this disease up to date. The majority of the treatments remain supportive and empirical. The aim of present study is to assess the relationship between melatonin supplementation and its effect on the severity of the outcomes in covid-19 patients. All published studies up to April 4 of 2021 were searched by using the databases of PubMed, ISI Web of Science, SCOPUS and Google Scholar.  Finally, 201 studies have been acquired.      After screening titles, abstracts and justifying the inclusion criteria, eight studies were finally selected in our study. Four studies were observational and case series with total 216,792 participants. Three studies performed on laboratory in the molecular level and one was carried out in mice. The results have suggested that melatonin decreases the severity of the outcomes of COVID-19 patients in their early stage or even in their critical conditions. Furthermore, the melatonin decreases pneumonia and reduces the ground glass lung damage observed in the image findings. Also, it plays an important role as anti-inflammatory, anti-viral and antioxidant activities. Melatonin inhibits the main protease of sares-cov-2 virus and decreases the viral load in molecular level. Regarding the in vivo studies, melatonin is more effective for reducing acute lung injury than other treatments. Although, further clinical studies are required.

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