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1.
Front Immunol ; 13: 791267, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35529872

RESUMO

Host cholesterol metabolism remodeling is significantly associated with the spread of human pathogenic coronaviruses, suggesting virus-host relationships could be affected by cholesterol-modifying drugs. Cholesterol has an important role in coronavirus entry, membrane fusion, and pathological syncytia formation, therefore cholesterol metabolic mechanisms may be promising drug targets for coronavirus infections. Moreover, cholesterol and its metabolizing enzymes or corresponding natural products exert antiviral effects which are closely associated with individual viral steps during coronavirus replication. Furthermore, the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 infections are associated with clinically significant low cholesterol levels, suggesting cholesterol could function as a potential marker for monitoring viral infection status. Therefore, weaponizing cholesterol dysregulation against viral infection could be an effective antiviral strategy. In this review, we comprehensively review the literature to clarify how coronaviruses exploit host cholesterol metabolism to accommodate viral replication requirements and interfere with host immune responses. We also focus on targeting cholesterol homeostasis to interfere with critical steps during coronavirus infection.


Assuntos
COVID-19 , Antivirais/uso terapêutico , Colesterol/metabolismo , Humanos , Replicação Viral
2.
J Orthop Surg Res ; 17(1): 200, 2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35379285

RESUMO

BACKGROUND: The diagnostic value of platelet indices has been evaluated in various infectious diseases but not in infected nonunion. The purpose of this study was to assess the usefulness of platelet indices for diagnosis of infected nonunion after open reduction and internal fixation. METHODS: This retrospective study was performed in patients who underwent primary fracture nonunion revision surgeries from January 2016 to December 2021. A total of 297 patients were included in the study: 96 with infected nonunion (group A) and 201 with aseptic nonunion (group B). Receiver operator characteristic (ROC) curve analysis was performed to evaluate diagnostic value of each index. Area under the curve (AUC), sensitivity, specificity, and positive and negative predictive values were calculated and compared. RESULTS: Demographic characteristics were comparable between the two groups. White blood cell (WBC) count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), plasma fibrinogen, plasma D-dimer, platelet count (PC), plateletcrit, and ratio of platelet count to mean platelet volume (PC/MPV) were significantly higher, and MPV and platelet distribution width (PDW) significantly lower, in group A than in group B (P < 0.05). ROC analysis showed PC/MPV and plasma fibrinogen to have better diagnostic value than the other coagulation indicators (AUC of 0.801 and 0.807, respectively). The combination of ESR, plasma fibrinogen, and PC/MPV had good sensitivity and specificity for diagnosis of infected nonunion. PC/MPV had better diagnostic value than ESR and plasma fibrinogen in the subgroup of patients with coagulation-related comorbidities. CONCLUSIONS: Plasma fibrinogen and PC/MPV ratio might be useful parameters for early diagnosis of infected nonunion.


Assuntos
Volume Plaquetário Médio , Área Sob a Curva , Sedimentação Sanguínea , Humanos , Contagem de Plaquetas , Estudos Retrospectivos
3.
Exp Ther Med ; 23(4): 302, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35340882

RESUMO

Adipogenesis and fat accumulation are closely associated with the development of obesity. Sleeve gastrectomy (SG) is an effective treatment for obesity and associated metabolic disorders. Leptin is downregulated after SG and Src homology phosphatase 2 (Shp2) has an important role in leptin signaling. The role of Shp2 in SG and the mechanisms of fat reduction following SG were further investigated in the current study. Sham and SG operations were performed on obese type-2 diabetes model Sprague-Dawley rats. Primary pre-adipocytes were isolated from the inguinal white adipose tissue (ingWAT) of the rats. Shp2 expression in ingWAT pre-adipocytes was silenced using small interfering RNA transfection. Shp2 function was inhibited using the specific inhibitor, SHP099. In addition, Shp2 was overexpressed using lentivirus. Gene and protein expression analysis was performed after adipocyte differentiation. Furthermore, Shp2-overexpressing ingWAT pre-adipocytes treated with the ß-catenin inhibitor, PNU-74654, were also used for gene and protein expression analysis. Adipogenic markers, including triglycerides, peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (Cebpα), adiponectin, fatty acid-binding protein 4 and leptin, were examined. Compared with the sham, triglyceride, leptin, PPARγ and Cebpα levels were significantly reduced in the ingWAT from the SG group. Shp2 expression levels were reduced following leptin treatment. Moreover, genetic analysis demonstrated depot-specific adipogenesis following Shp2 silencing or inhibition in ingWAT pre-adipocytes. Conversely, Shp2 overexpression decreased the expression of adipogenic markers by enhancing ß-catenin expression. PNU-74654 treatment abolished the downregulation of adipogenic markers caused by Shp2 overexpression. SG decreased leptin levels in ingWAT, which in turn upregulated Shp2, and Shp2 suppressed fat accumulation and adipogenic differentiation by activating the Wnt/ß-catenin signaling pathway. Overall, this may represent a potential mechanism of fat reduction in SG, and Shp2 may serve as a potential therapeutic target for the treatment of obesity and type-2 diabetes.

5.
J Virol ; 96(2): e0162921, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-34705566

RESUMO

The Newcastle disease virus (NDV) matrix (M) protein is the pivotal element for viral assembly, budding, and proliferation. It traffics through the cellular nucleus but performs its primary function in the cytoplasm. To investigate the biological importance of M protein nuclear-cytoplasmic trafficking and the mechanism involved, the regulatory motif nuclear export signal (NES) and nuclear localization signal (NLS) were analyzed. Here, two types of combined NLSs and NESs were identified within the NDV-M protein. The Herts/33-type M protein was found to mediate efficient nuclear export and stable virus-like particle (VLP) release, while the LaSota-type M protein was retained mostly in the nuclei and showed retarded VLP production. Two critical residues, namely, 247 and 263, within the motif were identified and associated with nuclear export efficiency. We identified, for the first time, residue 247 as an important monoubiquitination site, of which its modification regulates the nuclear-cytoplasmic trafficking of NDV-M. Subsequently, mutant LaSota strains were rescued via reverse genetics, which contained either single or double amino acid substitutions that were similar to the M of Herts/33. The rescued LaSota (rLaSota) strains rLaSota-R247K, -S263R, and -double mutation (DM) showed about 2-fold higher hemagglutination (HA) titers and 10-fold higher 50% egg infective dose (EID50) titers than wild-type (wt) rLaSota. Furthermore, the mean death time (MDT) and intracerebral pathogenicity index (ICPI) values of those recombinant viruses were slightly higher than those of wt rLaSota probably due to their higher proliferation rates. Our findings contribute to a better understanding of the molecular mechanism of the replication and pathogenicity of NDV and even those of all other paramyxoviruses. This information is beneficial for the development of vaccines and therapies for paramyxoviruses. IMPORTANCE Newcastle disease virus (NDV) is a pathogen that is lethal to birds and causes heavy losses in the poultry industry worldwide. The World Organization for Animal Health (OIE) ranked Newcastle disease (ND) as the third most significant poultry disease and the eighth most important wildlife disease in the World Livestock Disease Atlas in 2011. The matrix (M) protein of NDV is very important for viral assembly and maturation. It is interesting that M proteins enter the cellular nucleus before performing their primary function in the cytoplasm. We found that NDV-M has a combined nuclear import and export signal. The ubiquitin modification of a lysine residue within this signal is critical for quick, efficient nuclear export and subsequent viral production. Our findings shed new light on viral replication and open up new possibilities for therapeutics against NDV and other paramyxoviruses; furthermore, we demonstrate a novel approach for improving paramyxovirus vaccines.


Assuntos
Núcleo Celular/metabolismo , Vírus da Doença de Newcastle/fisiologia , Vírus da Doença de Newcastle/patogenicidade , Ubiquitinação , Proteínas da Matriz Viral/metabolismo , Replicação Viral , Animais , Galinhas , Citoplasma/metabolismo , Lisina , Modelos Moleculares , Mutação , Doença de Newcastle/metabolismo , Doença de Newcastle/virologia , Vírus da Doença de Newcastle/metabolismo , Sinais de Exportação Nuclear , Sinais de Localização Nuclear , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/genética , Virulência , Liberação de Vírus
6.
Foot Ankle Surg ; 28(2): 251-257, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33832815

RESUMO

OBJECTIVE: The purpose of this study was to retrospectively evaluate patients who had open reduction, external fixation and bone cement implantation of open calcaneal fractures. METHODS: The records of 14 patients with open calcaneus fractures from January 2015 to January 2019 were reviewed retrospectively. Clinical evaluations consisting of AOFAS, MFS and EQ-5D VAS scores and radiological evaluations consisting of the height, width and length of the calcaneus as well as Bohler's and Gissane angle performed at 3 months, 1 year and the last follow-up postoperatively. Time to surgery, wound complications were recorded. RESULTS: Our study sample consisted of 9 males and 5 females with a mean age of 38.5 ± 9.8 years and a mean follow-up of 31.4 ± 7.7 months. The mean period from injury to surgery was 5.4 ± 1.9 days and the mean duration of hospitalization was 13.2 ± 4.5 days. The AOFAS, MFS and EQ-5D VAS scores were 92.5 ± 10.3, 84.1 ± 9.7 and 86.4 ± 15.1 respectively at the final follow-up. The Bohler's angle increased from (12.9 ± 3.1)° preoperatively to (28.5 ± 6.3)° at the final follow-up (P < 0.001), with the Gissane's angle from (104.5 ± 9.7)° to (116.4 ± 8.9)° (P < 0.001). One patients (7.1%) developed pin infections and one patient (7.1%) suffered from dorso-lateral hindfoot hypoaesthesia. There was complete fracture healing without secondary loss of reduction in all cases. CONCLUSION: External fixation with bone cement implantation is a valid alternative treatment for the management of displaced open calcaneal fractures with a low rate of complications. LEVEL OF EVIDENCE: IV, retrospective case series.


Assuntos
Calcâneo , Fraturas Ósseas , Fraturas Expostas , Fraturas Intra-Articulares , Adulto , Cimentos Ósseos , Placas Ósseas , Calcâneo/diagnóstico por imagem , Calcâneo/cirurgia , Fixadores Externos , Feminino , Fixação de Fratura , Fixação Interna de Fraturas , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/cirurgia , Fraturas Expostas/diagnóstico por imagem , Fraturas Expostas/cirurgia , Humanos , Fraturas Intra-Articulares/diagnóstico por imagem , Fraturas Intra-Articulares/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
7.
Viruses ; 13(12)2021 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-34960678

RESUMO

The chicken is a model animal for the study of evolution, immunity and development. In addition to their use as a model organism, chickens also represent an important agricultural product. Pathogen invasion has already been shown to modulate the expression of hundreds of genes, but the role of alternative splicing in avian virus infection remains unclear. We used RNA-seq data to analyze virus-induced changes in the alternative splicing of Gallus gallus, and found that a large number of alternative splicing events were induced by virus infection both in vivo and in vitro. Virus-responsive alternative splicing events preferentially occurred in genes involved in metabolism and transport. Many of the alternatively spliced transcripts were also expressed from genes with a function relating to splicing or immune response, suggesting a potential impact of virus infection on pre-mRNA splicing and immune gene regulation. Moreover, exon skipping was the most frequent AS event in chickens during virus infection. This is the first report describing a genome-wide analysis of alternative splicing in chicken and contributes to the genomic resources available for studying host-virus interaction in this species. Our analysis fills an important knowledge gap in understanding the extent of genome-wide alternative splicing dynamics occurring during avian virus infection and provides the impetus for the further exploration of AS in chicken defense signaling and homeostasis.


Assuntos
Processamento Alternativo , Galinhas/genética , Galinhas/virologia , Interações entre Hospedeiro e Microrganismos , Doenças das Aves Domésticas/genética , Viroses/veterinária , Regiões 3' não Traduzidas , Animais , Células Cultivadas , Doença de Newcastle/genética , Doença de Newcastle/virologia , Vírus da Doença de Newcastle/genética , Vírus da Doença de Newcastle/fisiologia , Poliadenilação , Doenças das Aves Domésticas/virologia , Fatores de Processamento de RNA/genética , RNA-Seq , Spliceossomos/genética , Transcriptoma , Viroses/virologia
8.
Autophagy ; : 1-19, 2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34720029

RESUMO

Lacking a self-contained metabolism network, viruses have evolved multiple mechanisms for rewiring the metabolic system of their host to hijack the host's metabolic resources for replication. Newcastle disease virus (NDV) is a paramyxovirus, as an oncolytic virus currently being developed for cancer treatment. However, how NDV alters cellular metabolism is still far from fully understood. In this study, we show that NDV infection reprograms cell metabolism by increasing glucose utilization in the glycolytic pathway. Mechanistically, NDV induces mitochondrial damage, elevated mitochondrial reactive oxygen species (mROS) and ETC dysfunction. Infection of cells depletes nucleotide triphosphate levels, resulting in elevated AMP:ATP ratios, AMP-activated protein kinase (AMPK) phosphorylation, and MTOR crosstalk mediated autophagy. In a time-dependent manner, NDV shifts the balance of mitochondrial dynamics from fusion to fission. Subsequently, PINK1-PRKN-dependent mitophagy was activated, forming a ubiquitin chain with MFN2 (mitofusin 2), and molecular receptor SQSTM1/p62 recognized damaged mitochondria. We also found that NDV infection induces NAD+-dependent deacetylase SIRT3 loss via mitophagy to engender HIF1A stabilization, leading to the switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis. Overall, these studies support a model that NDV modulates host cell metabolism through PINK1-PRKN-dependent mitophagy for degrading SIRT3.Abbreviations: AMPK: AMP-activated protein kinase; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ECAR: extracellular acidification rate; hpi: hours post infection LC-MS: liquid chromatography-mass spectrometry; mito-QC: mCherry-GFP-FIS1[mt101-152]; MFN2: mitofusin 2; MMP: mitochondrial membrane potential; mROS: mitochondrial reactive oxygen species; MOI: multiplicity of infection; 2-NBDG: 2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino)-2-deoxyglucose; NDV: newcastle disease virus; OCR: oxygen consumption rate; siRNA: small interfering RNA; SIRT3: sirtuin 3; TCA: tricarboxylic acid; TCID50: tissue culture infective doses.

9.
iScience ; 24(8): 102837, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34368653

RESUMO

A number of new cell death processes have been discovered in recent years, including ferroptosis, which is characterized by the accumulation of lipid peroxidation products derived from iron metabolism. The evidence suggests that ferroptosis has a tumor-suppressor function. However, the mechanism by which ferroptosis mediates the response of tumor cells to oncolytic viruses remains poorly understood. The Newcastle disease virus (NDV) can selectively replicate in tumor cells. We show that NDV-induced ferroptosis acts through p53-SLC7A11-GPX4 pathway. Meanwhile, the levels of intracellular reactive oxygen species and lipid peroxides increased in tumor cells. Ferritinophagy was induced by NDV promotion of ferroptosis through the release of ferrous iron and an enhanced Fenton reaction. Collectively, these observations demonstrated that the NDV can kill tumor cells through ferroptosis. Our study provides novel insights into the mechanisms of NDV-induced ferroptosis and highlights the critical role of viruses in treating therapy-resistant cancers.

10.
J Orthop Surg Res ; 16(1): 530, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433474

RESUMO

BACKGROUND: Volar locking plating remains a popular method for the surgical management of distal radius fractures. Dorsal metaphyseal comminution (DMC) is a common fracture pattern which weakens the stability during fracture fixation. In this study, we aimed to compare the radiographic and functional outcome of the intra- and extra-articular distal radius fractures with DMC following single volar locking plate fixation. MATERIALS AND METHODS: Patients suffered from a distal radius fracture with DMC were reviewed in the clinical database of the authors' institution between Jan 2016 and Jan 2020. The included patients were classified into the extra-articular (A3) group or the intra-articular (C2 and C3) group according to the AO/OTA system. The radiological parameters, wrist range of motion, and functional outcomes were evaluated following open reduction and volar locking plate fixation. RESULTS: A total of 130 patients were included in this study with a mean follow-up length of 17.2 months. Compared with the A3 fracture group, no significant fracture re-displacement or reduced wrist ROMs was observed in the C2 fractures after 12-month's follow-up. However, significantly decreased volar tilt (P = 0.003) as well as the extension/flexion ROMs were observed in the C3 fractures comparing to the A3 fractures. Most of the patients achieved an excellent (n = 75) or good (n = 51) Gartland and Werley wrist score. Four patients with C3 fractures resulted in a fair functional outcome due to a significant loss of volar tilt during follow-up. CONCLUSIONS: The single volar locking plate fixation provided sufficient stability for distal radius fractures with DMC, and resulted in similar radiological and functional outcomes in the intra-articular distal radius fractures with a simple articular component (C2 fractures) as those in the extra-articular fractures. Considering the intra-articular fractures with multifragmentary articular component (C3 fracture), despite of the subsequent loss of volar tilt, the majority of the patients achieved good to excellent wrist function following single volar locking plating. TRIAL REGISTRATION: This study has been registered on the ClinicalTrials.gov.


Assuntos
Fraturas Cominutivas , Fraturas do Rádio , Placas Ósseas , Fixação Interna de Fraturas , Humanos , Fraturas do Rádio/diagnóstico por imagem , Fraturas do Rádio/cirurgia , Amplitude de Movimento Articular/fisiologia , Resultado do Tratamento
12.
Poult Sci ; 100(8): 101267, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34237546

RESUMO

The genotype VII Newcastle disease virus (NDV) vaccine has begun to replace the traditional genotype II NDV vaccine and is widely used in the commercial poultry of China. However, the effect of homologous and heterogeneous anti-NDV serum on the evolution of prevalent NDV is unknown. To understand the effect of genotype II and VII anti-NDV serum on the evolution of genotype VII NDV strains, ZJ1 (waterfowl origin) and CH/SD/2008/128 (ND128; chicken origin) were used for serial passage of 30 generations in DF-1 cells without anti-NDV serum or with genotype II and VII anti-NDV serum independently. The F and HN genes of the 2 viruses were amplified for the 10th, 20th, and 30th generations of each serial passage group and compared with their respective original viruses. We found that there was only one mutation at position 248 in the F gene of ZJ1 due to the serum pressure of genotype VII anti-NDV. Similarly, mutations at residue 527 of the F gene, and position 9 and 319 of the HN gene of ND128 were noted in both anti-NDV serum groups. The results show that the nonsynonymous (NS)-to-synonymous (S) ratio of the F gene of ZJ1 virus was 1.6, and for the HN gene, it was 2.5 in the anti-II serum group. In the anti-VII serum group, the NS/S ratio for the F gene was 2.1, and for the HN gene, it was 2.5. The NS/S ratio of the F gene of the ND128 virus was 0.8, and for the HN gene, it was 3 in the anti-II serum group. Furthermore, the NS/S ratio of the F gene was 0.8, and the HN gene was 2.3 in the anti-VII group. Taken together, our findings highlight that there was no significant difference in the variation of protective antigens in genotype VII NDV under the selection pressure of homologous and heterogeneous genotype NDV inactivated vaccines.


Assuntos
Doença de Newcastle , Doenças das Aves Domésticas , Vacinas Virais , Animais , Galinhas , China , Genótipo , Doença de Newcastle/prevenção & controle , Vírus da Doença de Newcastle/genética , Doenças das Aves Domésticas/prevenção & controle
13.
mBio ; 12(3): e0100521, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34125604

RESUMO

DEAD (Glu-Asp-Ala-Glu) box RNA helicases have been proven to contribute to antiviral innate immunity. The DDX21 RNA helicase was identified as a nuclear protein involved in rRNA processing and RNA unwinding. DDX21 was also proven to be the scaffold protein in the complex of DDX1-DDX21-DHX36, which senses double-strand RNA and initiates downstream innate immunity. Here, we identified that DDX21 undergoes caspase-dependent cleavage after virus infection and treatment with RNA/DNA ligands, especially for RNA virus and ligands. Caspase-3/6 cleaves DDX21 at D126 and promotes its translocation from the nucleus to the cytoplasm in response to virus infection. The cytoplasmic cleaved DDX21 negatively regulates the interferon beta (IFN-ß) signaling pathway by suppressing the formation of the DDX1-DDX21-DHX36 complex. Thus, our data identify DDX21 as a regulator of immune balance and most importantly uncover a potential role of DDX21 cleavage in the innate immune response to virus. IMPORTANCE Innate immunity serves as the first barrier against virus infection. DEAD (Glu-Asp-Ala-Glu) box RNA helicases, originally considered to be involved in RNA processing and RNA unwinding, have been shown to play an important role in antiviral innate immunity. The precise regulation of innate immunity is critical for the host because the aberrant production of cytokines leads to unexpected pathological consequences. Here, we identified that DDX21 was cleaved at D126 by virus infection and treatment with RNA/DNA ligands via the caspase-3/6-dependent pathway. The cytoplasmic cleaved DDX21 negatively regulates the IFN-ß signaling pathway by suppressing the formation of the DDX1-DDX21-DHX36 complex. In sum, our data identify DDX21 as a regulator of immune balance and most importantly uncover a potential role of DDX21 cleavage in the innate immune response to virus.


Assuntos
Caspases/metabolismo , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/imunologia , Imunidade Inata , Viroses/imunologia , Células A549 , Caspases/classificação , Caspases/genética , Linhagem Celular , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Células HEK293 , Células HeLa , Humanos , Interferon beta/imunologia , Ligação Proteica , Transdução de Sinais/imunologia , Células THP-1
15.
BMC Musculoskelet Disord ; 22(1): 379, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33892699

RESUMO

BACKGROUNDS: Theaim of this study was to assess the efficacy of a modified intrafocal pinningtechnique with three-dimensional (3D) planning to facilitate volar plating in dorsally comminuted intra-articular distal radius fractures. METHODS: Intotal 35 AO/OTA type C2 and C3 fractures were finally included.The 3D digital model of the fracture was reconstructed based on preoperative computedtomographic (CT) images, with the displacement of the comminuted dorsalfragment and the intra-articular fragment analyzed for preoperative planning. During operation, amodified intrafocal pinning technique was applied percutaneously from thedorsal aspect of the radius to reduce the collapsed intra-articular fragmentfollowing volar plating. Adequate reduction was confirmed in all of patientsconsidering radial height, radial inclination and volar tilt in postoperativeradiographs. RESULTS: No significant fracture re-displacement wasobserved in most of the cases during a mean follow-up period of 17.4 months, exceptfor two patients withthe C3 fracture. All of the patients achieved adequate clinicalROMs at 12 months postoperatively, with a mean DASH score of 12.0. Most of the patients achievedan excellent (n = 21) or good (n = 12) Gartland and Werley wrist score. CONCLUSIONS: Ourmodified intrafocal pinning technique with 3D planning contributes to a satisfactoryclinical and radiological outcome in dorsally comminuted intra-articular distalradius fractures fixed with a volar locking plate. TRIALREGISTRATION: Notapplicable because the design of the study is retrospective.


Assuntos
Fraturas Cominutivas , Fraturas do Rádio , Placas Ósseas , Fixação Interna de Fraturas , Fraturas Cominutivas/diagnóstico por imagem , Fraturas Cominutivas/cirurgia , Humanos , Fraturas do Rádio/diagnóstico por imagem , Fraturas do Rádio/cirurgia , Amplitude de Movimento Articular , Estudos Retrospectivos , Resultado do Tratamento
16.
Genes (Basel) ; 12(4)2021 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805275

RESUMO

Newcastle disease virus (NDV) causes a highly contagious and devastating disease in poultry. ND causes heavy economic losses to the global poultry industry by decreasing the growth rate, decrease in egg production high morbidity and mortality. Although significant advances have been made in the vaccine development, outbreaks are reported in vaccinated birds. In this study, we report the damage caused by NDV infection in the pancreatic tissues of vaccinated and specific-pathogen-free chickens. The histopathological examination of the pancreas showed severe damage in the form of partial depletion of zymogen granules, acinar cell vacuolization, necrosis, apoptosis, congestion in the large and small vessels, sloughing of epithelial cells of the pancreatic duct, and mild perivascular edema. Increased plasma levels of corticosterone and somatostatin were observed in NDV-infected chicken at three- and five- days post infection (DPI). A slight decrease in the plasma concentrations of insulin was noticed at 5 DPI. Significant changes were not observed in the plasma levels of glucagon. Furthermore, NDV infection decreased the activity and mRNA expression of amylase, lipase, and trypsin from the pancreas. Taken together, our findings highlight that NDV induces extensive tissue damage in the pancreas, decreases the activity and expression of pancreatic enzymes, and increases plasma corticosterone and somatostatin. These findings provide new insights that a defective pancreas may be one of the reasons for decreased growth performance after NDV infection in chickens.


Assuntos
Ilhotas Pancreáticas/patologia , Doença de Newcastle/complicações , Vírus da Doença de Newcastle/isolamento & purificação , Pâncreas Exócrino/patologia , Pancreatite/veterinária , Doenças das Aves Domésticas/patologia , Animais , Galinhas , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/virologia , Doença de Newcastle/metabolismo , Doença de Newcastle/virologia , Pâncreas Exócrino/metabolismo , Pâncreas Exócrino/virologia , Pancreatite/patologia , Pancreatite/virologia , Doenças das Aves Domésticas/epidemiologia , Doenças das Aves Domésticas/virologia
17.
PLoS Pathog ; 17(2): e1008690, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33635931

RESUMO

Cytoplasmic stress granules (SGs) are generally triggered by stress-induced translation arrest for storing mRNAs. Recently, it has been shown that SGs exert anti-viral functions due to their involvement in protein synthesis shut off and recruitment of innate immune signaling intermediates. The largest RNA viruses, coronaviruses, impose great threat to public safety and animal health; however, the significance of SGs in coronavirus infection is largely unknown. Infectious Bronchitis Virus (IBV) is the first identified coronavirus in 1930s and has been prevalent in poultry farm for many years. In this study, we provided evidence that IBV overcomes the host antiviral response by inhibiting SGs formation via the virus-encoded endoribonuclease nsp15. By immunofluorescence analysis, we observed that IBV infection not only did not trigger SGs formation in approximately 80% of the infected cells, but also impaired the formation of SGs triggered by heat shock, sodium arsenite, or NaCl stimuli. We further demonstrated that the intrinsic endoribonuclease activity of nsp15 was responsible for the interference of SGs formation. In fact, nsp15-defective recombinant IBV (rIBV-nsp15-H238A) greatly induced the formation of SGs, along with accumulation of dsRNA and activation of PKR, whereas wild type IBV failed to do so. Consequently, infection with rIBV-nsp15-H238A strongly triggered transcription of IFN-ß which in turn greatly affected rIBV-nsp15-H238A replication. Further analysis showed that SGs function as an antiviral hub, as demonstrated by the attenuated IRF3-IFN response and increased production of IBV in SG-defective cells. Additional evidence includes the aggregation of pattern recognition receptors (PRRs) and signaling intermediates to the IBV-induced SGs. Collectively, our data demonstrate that the endoribonuclease nsp15 of IBV interferes with the formation of antiviral hub SGs by regulating the accumulation of viral dsRNA and by antagonizing the activation of PKR, eventually ensuring productive virus replication. We further demonstrated that nsp15s from PEDV, TGEV, SARS-CoV, and SARS-CoV-2 harbor the conserved function to interfere with the formation of chemically-induced SGs. Thus, we speculate that coronaviruses employ similar nsp15-mediated mechanisms to antagonize the host anti-viral SGs formation to ensure efficient virus replication.


Assuntos
COVID-19/virologia , Grânulos Citoplasmáticos/metabolismo , Endorribonucleases/imunologia , Endorribonucleases/metabolismo , SARS-CoV-2/fisiologia , Proteínas não Estruturais Virais/imunologia , Proteínas não Estruturais Virais/metabolismo , COVID-19/metabolismo , Linhagem Celular , Coronavirus/imunologia , Grânulos Citoplasmáticos/imunologia , Grânulos Citoplasmáticos/virologia , Humanos , Interferon beta/imunologia , Interferon beta/metabolismo , SARS-CoV-2/metabolismo , Transdução de Sinais , Replicação Viral/fisiologia
18.
Vet Res ; 52(1): 7, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431056

RESUMO

Elucidating virus-cell interactions is fundamental to understanding viral replication and identifying targets for therapeutic control of viral infection. The extracellular signal-regulated kinase (ERK) pathway has been shown to regulate pathogenesis during many viral infections, but its role during coronavirus infection is undetermined. Infectious bronchitis virus is the representative strain of Gammacoronavirus, which causes acute and highly contagious diseases in the poultry farm. In this study, we investigated the role of ERK1/2 signaling pathway in IBV infection. We found that IBV infection activated ERK1/2 signaling and the up-regulation of phosphatase DUSP6 formed a negative regulation loop. Pharmacological inhibition of MEK1/2-ERK1/2 signaling suppressed the expression of DUSP6, promoted cell death, and restricted virus replication. In contrast, suppression of DUSP6 by chemical inhibitor or siRNA increased the phosphorylation of ERK1/2, protected cells from apoptosis, and facilitated IBV replication. Overexpression of DUSP6 decreased the level of phospho-ERK1/2, promoted apoptosis, while dominant negative mutant DUSP6-DN lost the regulation function on ERK1/2 signaling and apoptosis. In conclusion, these data suggest that MEK-ERK1/2 signaling pathway facilitates IBV infection, probably by promoting cell survival; meanwhile, induction of DUSP6 forms a negative regulation loop to restrict ERK1/2 signaling, correlated with increased apoptosis and reduced viral load. Consequently, components of the ERK pathway, such as MEK1/2 and DUSP6, represent excellent targets for the development of antiviral drugs.


Assuntos
Apoptose/fisiologia , Fosfatases de Especificidade Dupla/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Vírus da Bronquite Infecciosa/fisiologia , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Animais , Butadienos/farmacologia , Linhagem Celular , Galinhas , Chlorocebus aethiops , Fosfatases de Especificidade Dupla/antagonistas & inibidores , Fosfatases de Especificidade Dupla/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Fosfatases da Proteína Quinase Ativada por Mitógeno/antagonistas & inibidores , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Nitrilas/farmacologia , Regulação para Cima , Replicação Viral
19.
Infect Drug Resist ; 13: 4003-4008, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33177850

RESUMO

BACKGROUND: The timely and accurate diagnosis of infected nonunion is challenging, and there is a need for more efficient biomarkers. Previous studies have shown that fibrinogen plays an important role in mediating inflammation in bacterial infections and, therefore, could be a valuable biomarker for infected nonunion. The purpose of this study was to evaluate and compare the performance of plasma fibrinogen and other traditional blood markers for the diagnosis of infected nonunion. MATERIALS AND METHODS: We retrospectively studied 146 patients who underwent surgery for primary nonunion between January 2018 and January 2020. The patients were divided into those with infected nonunion (n = 55) and those with aseptic nonunion (n = 91). The preoperatively analyzed parameters were plasma fibrinogen, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and white blood cell (WBC) count. Receiver operating characteristic (ROC) curve analysis was used to assess the sensitivity and specificity of the biomarkers, and Youden's index was calculated to determine their optimal cut-off values. RESULTS: The plasma fibrinogen values were significantly higher (p < 0.001) in the patients with infected nonunion than in those with aseptic nonunion. ROC curve analysis showed that plasma fibrinogen had a high value of area under the curve (0.816), which indicated that it had good diagnostic ability. Further, at the optimal threshold value of 2.75 g/L, plasma fibrinogen had the highest sensitivity (78.2%; 95% CI = 64.6-87.8) and good specificity (82.4%; 95% CI, 72.7-89.3). CONCLUSION: In comparison to the traditional markers of infection, plasma fibrinogen showed good diagnostic ability for the detection of infected nonunion. It may have potential as a practical and cost-efficient biomarker for the diagnosis of infected nonunion.

20.
Vaccines (Basel) ; 8(4)2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33019497

RESUMO

Newcastle disease (ND) and infectious bronchitis (IB) are two highly contagious diseases that severely threaten the poultry industry. The goal of this study is to prevent these two diseases and reduce the vaccine costs during storage and transportation. In this study, we design a thermostable recombinant Newcastle disease virus (NDV) candidate live vaccine strain designated as rLS-T-HN-T/B, which expresses the multiple epitope cassette of the identified infectious bronchitis virus (IBV) (S-T/B). The rLS-T-HN-T/B strain was found to possess similar growth kinetics, passage stability, morphological characteristics, and virulence to the parental LaSota strain. After incubation at 56 °C at the indicated time points, the rLS-T-HN-T/B strain was determined by the hemagglutination (HA), and 50% embryo infectious dose (EID50) assays demonstrated that it accords with the criteria for thermostability. The thermostable rLS-T-HN-T/B and parental LaSota vaccines were stored at 25 °C for 16 days prior to immunizing the one-day-old specific pathogen-free (SPF) chicks. Three weeks postimmunization, the virus challenge results suggested that the chicks vaccinated with the rLS-T-HN-T/B vaccine were protected by 100% and 90% against a lethal dose of NDV and IBV, respectively. Furthermore, the trachea ciliary activity assay indicated that the mean ciliostasis score of the chicks vaccinated with thermostable rLS-T-HN-T/B vaccine was significantly superior to that of the LaSota and PBS groups (p < 0.05). The rLS-T-HN-T/B vaccine stored at 25 °C for 16 days remained capable of eliciting the immune responses and protecting against IBV and NDV challenges. However, the same storage conditions had a great impact on the parental LaSota strain vaccinated chicks, and the NDV challenge protection ratio was only 20%. We conclude that the thermostable rLS-T-HN-T/B strain is a hopeful bivalent candidate vaccine to control both IB and ND and provides an alternative strategy for the development of cost-effective vaccines for village chickens, especially in the rural areas of developing countries.

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