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1.
Biochim Biophys Acta Mol Cell Res ; 1869(1): 119134, 2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34520816

RESUMO

Actin-based, finger-like cell protrusions such as microvilli and filopodia play important roles in epithelial cells. Several proteins have been identified to regulate cell protrusion formation, which helps us to learn about the underlying mechanism of this process. FCH domain and double SH3 domains containing protein 2 (FCHSD2) belongs to the FCH and Bin-Amphiphysin-Rvs (F-BAR) protein family, containing an N-terminal F-BAR domain, two SH3 domains, and a C-terminal PDZ domain-binding interface (PBI). Previously, we found that FCHSD2 interacts with WASP/N-WASP and stimulates ARP2/3-mediated actin polymerization in vitro. In the present work, we show that FCHSD2 promotes the formation of apical and lateral cell protrusions in cultured cells. Our data suggest that FCHSD2 cooperates with CDC42 and N-WASP in regulating apical cell protrusion formation. In line with this, biochemical studies reveal that FCHSD2 and CDC42 simultaneously bind to N-WASP, forming a protein complex. Interestingly, the F-BAR domain of FCHSD2 induces lateral cell protrusion formation independently of N-WASP. Furthermore, we show that the ability of FCHSD2 to induce cell protrusion formation requires its plasma membrane-binding ability. In summary, our present work suggests that FCHSD2 cooperates with CDC42 and N-WASP to regulate cell protrusion formation in a membrane-dependent manner.

2.
PLoS Pathog ; 17(9): e1009897, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34492082

RESUMO

The key to battling the COVID-19 pandemic and its potential aftermath is to develop a variety of vaccines that are efficacious and safe, elicit lasting immunity, and cover a range of SARS-CoV-2 variants. Recombinant viral receptor-binding domains (RBDs) are safe vaccine candidates but often have limited efficacy due to the lack of virus-like immunogen display pattern. Here we have developed a novel virus-like nanoparticle (VLP) vaccine that displays 120 copies of SARS-CoV-2 RBD on its surface. This VLP-RBD vaccine mimics virus-based vaccines in immunogen display, which boosts its efficacy, while maintaining the safety of protein-based subunit vaccines. Compared to the RBD vaccine, the VLP-RBD vaccine induced five times more neutralizing antibodies in mice that efficiently blocked SARS-CoV-2 from attaching to its host receptor and potently neutralized the cell entry of variant SARS-CoV-2 strains, SARS-CoV-1, and SARS-CoV-1-related bat coronavirus. These neutralizing immune responses induced by the VLP-RBD vaccine did not wane during the two-month study period. Furthermore, the VLP-RBD vaccine effectively protected mice from SARS-CoV-2 challenge, dramatically reducing the development of clinical signs and pathological changes in immunized mice. The VLP-RBD vaccine provides one potentially effective solution to controlling the spread of SARS-CoV-2.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Imunogenicidade da Vacina , Nanopartículas/uso terapêutico , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Modelos Animais de Doenças , Desenho de Fármacos , Feminino , Células HEK293 , Humanos , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Domínios Proteicos/imunologia
3.
Cell Mol Immunol ; 18(10): 2293-2306, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34497376

RESUMO

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) initiates the infection process by binding to the viral cellular receptor angiotensin-converting enzyme 2 through the receptor-binding domain (RBD) in the S1 subunit of the viral spike (S) protein. This event is followed by virus-cell membrane fusion mediated by the S2 subunit, which allows virus entry into the host cell. Therefore, the SARS-CoV-2 S protein is a key therapeutic target, and prevention and treatment of coronavirus disease 2019 (COVID-19) have focused on the development of neutralizing monoclonal antibodies (nAbs) that target this protein. In this review, we summarize the nAbs targeting SARS-CoV-2 proteins that have been developed to date, with a focus on the N-terminal domain and RBD of the S protein. We also describe the roles that binding affinity, neutralizing activity, and protection provided by these nAbs play in the prevention and treatment of COVID-19 and discuss the potential to improve nAb efficiency against multiple SARS-CoV-2 variants. This review provides important information for the development of effective nAbs with broad-spectrum activity against current and future SARS-CoV-2 strains.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , SARS-CoV-2/química , Glicoproteína da Espícula de Coronavírus/química , Animais , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Neutralizantes/química , Anticorpos Antivirais/química , Ensaios Clínicos como Assunto , Aprovação de Drogas , Combinação de Medicamentos , Humanos
4.
Nat Commun ; 12(1): 5377, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34508089

RESUMO

Beyond the scope of Hermitian physics, non-Hermiticity fundamentally changes the topological band theory, leading to interesting phenomena, e.g., non-Hermitian skin effect, as confirmed in one-dimensional systems. However, in higher dimensions, these effects remain elusive. Here, we demonstrate the spin-polarized, higher-order non-Hermitian skin effect in two-dimensional acoustic higher-order topological insulators. We find that non-Hermiticity drives wave localizations toward opposite edges upon different spin polarizations. More interestingly, for finite systems with both edges and corners, the higher-order non-Hermitian skin effect leads to wave localizations toward two opposite corners for all the bulk, edge and corner states in a spin-dependent manner. We further show that such a skin effect enables rich wave manipulation by configuring the non-Hermiticity. Our study reveals the intriguing interplay between higher-order topology and non-Hermiticity, which is further enriched by the pseudospin degree of freedom, unveiling a horizon in the study of non-Hermitian physics.

5.
Phytomedicine ; 91: 153701, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34438230

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by limited airflow due to pulmonary and alveolar abnormalities from exposure to cigarette smoke (CS). Current therapeutic drugs are limited and the development of novel treatments to prevent disease progression is challenging. Isoforskolin (ISOF) from the plant Coleus forskohlii is an effective activator of adenylyl cyclase (AC) isoforms. Previously we found ISOF could attenuate acute lung injury in animal models, while the effect of ISOF on COPD has not been elucidated. PURPOSE: In this study, we aimed to evaluate the efficacy of ISOF on COPD and reveal its potential mechanisms. METHODS: A rat model of COPD was established by long-term exposure to CS, then the rats were orally administered with ISOF (0.5, 1 and 2 mg/kg). The pulmonary function, lung morphology, inflammatory cells and cytokines in serum or bronchoalveolar lavage fluid (BALF) were evaluated. Transcriptomics, proteomics and network pharmacology analysis were utilized to identify potential mechanisms of ISOF. Droplet digital PCR was used to detect the mRNA expression of AC1-10 in donor lung tissues. AC activation was determined in recombinant human embryonic kidney 293 (HEK293) cells stably expressing human AC isoforms. In addition, ISOF caused trachea relaxation ex vivo were assessed in isolated trachea rings from guinea pigs. RESULTS: ISOF significantly ameliorated pathological damage of lung tissue and improved pulmonary function in COPD rats. ISOF treatment decreased the number of inflammatory cells in peripheral blood, and also the levels of pro-inflammatory cytokines in serum and BALF. Consistent with omics-based analyses, ISOF markedly downregulated the mTOR level in lung tissue. Flow cytometry analysis revealed that ISOF treatment reduced the ratio of Th17/Treg cells in peripheral blood. Furthermore, the expression levels of AC1 and AC2 are relatively higher than other AC isoforms in normal lung tissues, and ISOF could potently activate AC1 and AC2 in vitro and significantly relax isolated guinea pig trachea. CONCLUSION: Collectively, our studies suggest that ISOF exerts its anti-COPD effect by improving lung function, anti-inflammation and trachea relaxation, which may be related to AC activation, mTOR signaling and Th17/Treg balance.


Assuntos
Adenilil Ciclases , Colforsina/farmacologia , Doença Pulmonar Obstrutiva Crônica , Fumaça , Animais , Coleus/química , Cobaias , Células HEK293 , Humanos , Compostos Fitoquímicos/farmacologia , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Ratos , Fumaça/efeitos adversos , Fumar
6.
Vet Microbiol ; 261: 109188, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34365051

RESUMO

Porcine Parvovirus (PPV) is a pathogen causing porcine reproductive disorders. Non-structural protein NS1 appears diverse functions acting as a predominant regulator in promoting PPV replication. In this study, we identified a PPV NS1 binding protein coatomer subunit epsilon (COPƐ), and found that COPƐ is a critical regulator during PPV replication. In NS1 transfected or PPV infected cells, COPƐ was interacted with NS1 and translocated into nucleus together with NS1. Knockout of COPƐ could inhibit PPV production by increasing the expression levels of IFN-ß, while overexpression of COPƐ enhanced PPV production by reducing the expression levels of IFN-ß. Furthermore, the domain mapping assay showed that the N-terminal amino acids domain of NS1 (25-EAFSYVF-31) were required for the interaction of COPƐ with NS1. Sequence alignment result displays that parvovirus NS1 (EAFSYVF) amino acids domain is highly conservative among PPV, CPV, FPV and MEV, and down-regulation of COPƐ could also significantly reduce the replication of these viruses. Notably, we found that the interaction of COPƐ with NS1 play an important role in promoting the production of type I interferon during PPV or CPV infection, which affect the replication of these viruses. Taken together, the results presented here show a novel function of NS1 interaction with COPƐ that regulates the parvovirus replication through modulating the type I interferons signaling pathway, provided a potential target for the control of parvovirus-associated diseases.

7.
Br J Ophthalmol ; 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34340973

RESUMO

BACKGROUND: The impacts of social restrictions for COVID-19 on children's vision and lifestyle remain unknown. AIMS: To investigate myopia incidence, spherical equivalent refraction (SER) and lifestyle changes among schoolchildren during the COVID-19 pandemic. METHODS: Two separate longitudinal cohorts of children aged 6-8 years in Hong Kong were included. The COVID-19 cohort was recruited at the beginning of the COVID-19 outbreak, whereas the pre-COVID-19 cohort was recruited before the COVID-19 pandemic. All children received ocular examinations, and answered a standardised questionnaire relating to their lifestyle, including time spent on outdoor activities and near work, both at baseline and at follow-up visits. RESULTS: A total of 1793 subjects were recruited, of whom 709 children comprised the COVID-19 cohort with 7.89±2.30 months of follow-up, and 1084 children comprised the pre-COVID-19 cohort with 37.54±3.12 months of follow-up. The overall incidence was 19.44% in the COVID-19 cohort, and 36.57% in pre-COVID-19 cohort. During the COVID-19 pandemic, the change in SER and axial length was -0.50±0.51 D and 0.29±0.35 mm, respectively; the time spent on outdoor activities decreased from 1.27±1.12 to 0.41±0.90 hours/day (p<0.001), while screen time increased from 2.45±2.32 to 6.89±4.42 hours/day (p<0.001). CONCLUSIONS: We showed a potential increase in myopia incidence, significant decrease in outdoor time and increase in screen time among schoolchildren in Hong Kong during the COVID-19 pandemic. Our results serve to warn eye care professionals, and also policy makers, educators and parents, that collective efforts are needed to prevent childhood myopia-a potential public health crisis as a result of COVID-19.

8.
Foodborne Pathog Dis ; 18(8): 599-606, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34403268

RESUMO

Salmonella is a global foodborne pathogen that causes human diseases ranging from mild gastroenteritis to severe systemic infections. Recently, antimicrobial blue light (aBL) showed effective bactericidal activity against a variety of bacteria (e.g., Salmonella) with varying efficiency. However, the antimicrobial mechanism of aBL has not been fully elucidated. Our previous report showed that the outer membrane (OM) is a key target of aBL. The major component of the OM, lipopolysaccharide (LPS), may play a role in aBL bactericidal effect. Therefore, the influence of LPS truncation on the sensitivity of Salmonella Typhimurium SL1344 to aBL was investigated for the first time. First, the rfaC gene in the SL1344 strain likely involved in linking lipid A to the core region of LPS was inactivated and the influence on LPS structure was verified in the mutant strain SL1344ΔrfaC. SL1344ΔrfaC showed a significant increase in sensitivity to aBL, and the bactericidal efficiency exceeded 8 log CFU at an aBL dose of 383 J/cm2, while that of its parental SL1344 strain approached 4 log CFU. To discover the possible mechanism of higher sensitivity, the permeability of OM was determined. Compared to SL1344, SL1344ΔrfaC showed 2.7-fold higher permeability of the OM at 20 J/cm2, this may explain the higher vulnerability of the OM to aBL. Furthermore, the fatty acid profile was analyzed to reveal the detailed changes in the OM and inner membrane of the mutant. Results showed that the membrane lipids of SL1344ΔrfaC were markedly different to SL1344, indicating that change in fatty acid profile might mediate the enhancement of OM permeability and the increased sensitivity to aBL in SL1344ΔrfaC. Hence, we concluded that disruption of rfaC in Salmonella Typhimurium led to the formation of truncated LPS and thus enhanced the permeability of the OM, which contributed to the increased sensitivity to aBL.

9.
Cell Rep ; 36(8): 109607, 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34433035

RESUMO

The interrelation between hypoxia and immune response has pivotal roles in the pathogenesis of chronic metabolic diseases. However, the role of macrophage HIF-2α in NLRP3 inflammasome activation remains unclear. Here, we show that deficiency of HIF-2α in macrophages results in excessive activation of the NLRP3 inflammasome in a manner dependent on CPT1A-mediated enhancement of fatty acid oxidation (FAO). Mechanistically, HIF-2α binds directly to the Cpt1a promoter and is involved in the regulation of H3K27me3 methylation during NLRP3 inflammasome activation. Myeloid-specific Hif2α knockout mice exhibit exacerbated insulin resistance and increased activation of NLRP3 inflammasome in macrophages. Overexpression of the Hif2α gene or stabilization of the protein by FG-4592 ameliorates insulin resistance and reduces NLRP3 inflammasome activation in macrophages. Taken together, our results suggest that macrophage HIF-2α inhibits FAO-mediated activation of the NLRP3 inflammasome and alleviates insulin resistance.

10.
Sci Rep ; 11(1): 13749, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215790

RESUMO

Choroidal thickness is associated with many ocular conditions, interchangeability among different generations of optical coherence tomography is therefore important for both research purpose and clinical application. Hence, we compared choroidal thickness measurements between spectral-domain optical coherence tomography (SD-OCT) and swept-source optical coherence tomography (SS-OCT) in healthy paediatric eyes. A total of 114 children from the population-based Hong Kong Children Eye Study with mean age of 7.38 ± 0.82 years were included. Choroidal thickness of the right eye was measured by both devices. The central foveal choroidal thickness (CFCT) measured by SD-OCT and SS-OCT was 273.24 ± 54.29 µm and 251.84 ± 47.12 µm respectively. Inter-device correlation coefficient was 0.840 (95% CI 0.616-0.918). However, choroidal thickness obtained by SD-OCT was significantly thicker than that measured by SS-OCT with a mean difference of 21.40 ± 33.13 µm (P < 0.001). Bland-Altman limit of agreement on the relative difference scale for SD-OCT/SS-OCT was 86.33 µm. Validated conversion equation for translating SD-OCT CFCT measurement into SS-OCT was SS-OCT = 35.261 + 0.810 × SD-OCT. In conclusion, intra-class correlation coefficient (ICC) shows an acceptable agreement between SD-OCT and SS-OCT, however, there was a significant inter-device difference of choroidal thickness measurements in normal children eyes. Therefore, the measurements are not interchangeable.

11.
J Tissue Viability ; 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34312030

RESUMO

BACKGROUND: Pressure injuries presently has been a serious healthcare problem all over the world. Children were recognized as the high-risk population of pressure injuries in the latest prevention and treatment of pressure injuries clinical practice guideline. However, the estimates of incidence, and prevalence of pressure injuries in hospitalized children patients vary considerable in relevant published studies. OBJECTIVE: To systematically quantify the incidence and prevalence of pressure injuries (PIs) in hospitalized children and the most affected PIs sites. METHODS: A systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Electronic databases searches of the Cochrane Library, Pubmed, Web of Science, Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, China Knowledge Resource Integrated Database (CNKI), Wanfang Database, Chinese Biomedical Database (CBM), and Weipu Database (VIP), and hand-search through references were conducted to find relevant articles. Studies were evaluated independently by two researchers and audited by a third researcher. The data were extracted and presented in tables. The risk of bias was assessed using Hoy's tool. The I2 statistic and random-effects model were used to assess the heterogeneity. Meta-regression analysis and subgroup analysis were conducted to examine between-study heterogeneity. RESULTS: A total of 6, 672 articles were screened, and 30 studies with 251, 501 participants were ultimately included in this review. The pooled incidence of PIs for 3, 205 children was 13.5% (95% CI: 10.5-16.5); and the pooled prevalence of PIs for 4, 639 children was 12.2% (95% CI: 8.0-16.3). The most affected body sites were occiput, ears, and nose. Meta-regression and subgroup analysis showed that the inpatient ward, and region were the sources of heterogeneity. CONCLUSIONS: The incidence and prevalence of PIs was significantly higher than the adults. Our discoveries recommended that healthcare givers ought to pay more consideration to diminish the happens of PIs. Additionally, more research may be needed to improve our understanding of the characteristics of PIs among children and to identify PIs risk factors to prevent and treat it in children effectively.

12.
Medicine (Baltimore) ; 100(24): e26309, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34128869

RESUMO

RATIONALE: The Schaaf-Yang syndrome (SYS) is an autosomal dominant multi-system genetic disease caused by melanoma antigen L2 (MAGEL2) gene mutations imprinted by mothers and expressed by fathers on the 15q11-15q13 chromosomes in the critical region of Prader-Willi. MAGEL2 is a single exon gene and one of the protein-coding genes of the Prader-Willi domain. MAGEL2 is a matrilineal imprinted gene (i.e., the maternal chromosome is methylated). It is only expressed by unmethylated paternal alleles, and the individual is affected only when the variation occurs on the paternal allele. PATIENT CONCERNS: We reported a patient with MAGEL2 gene new site mutation who had mild intellectual disability, social fear, small hands and feet, obesity issues, dyskinesia, growth retardation, language lag and sexual development disorder. DIAGNOSIS: Whole-exome sequencing showed a heterozygous variation in the MAGEL2 gene, NM_019066.4:c.1687C > T (p.Q563X) and diagnosed as Schaaf-Yang syndrome. INTERVENTIONS: Patient was advised to reduce weight, control blood lipids, blood glucose through appropriate strengthening of exercise and diet control in the future. At the same time, the family members were advised to provide mental training to the patient to strengthen the contact and communication with the outside world and improve the autistic symptoms. Because of the patient's bilateral cryptorchidism, it is recommended that the patient should be treated with bilateral cryptorchidism reduction fixation. OUTCOMES: After a follow-up of the patient for 2 months, the patient is still walking unsteadily and requires an auxiliary reference material to walk normally. There is no significant change in height compared to before, and the weight has dropped by about 2 kg in the past 2 months. The symptoms of autism have improved slightly. The patient is willing to communicate with outsiders; his intelligence has not improved significantly, and his academic performance in school is still at the middle and lower levels. LESSONS: The pathogenesis of SYS is complex, involving multiple pathways such as Leptin-POMC, MAGEL2-USP7-TRIM27 complex and oxytocin. Our study has also found that certain fatal phenotypes such as respiratory distress have a high incidence at individual sites, and early detection and timely intervention may prolong the life span of patients. Therefore, for patients in whom SYS is highly suspected, gene detection should be carried out as soon as possible.


Assuntos
Transtornos Cromossômicos/genética , Proteínas/genética , Adolescente , Humanos , Masculino , Mutação , Fenótipo , Sequenciamento Completo do Exoma
13.
FEBS Open Bio ; 2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34176242

RESUMO

Previous studies have found follicle-stimulating hormone (FSH) receptors on chondrocytes (cartilage cells), but the mechanism of FSH action on chondrocytes is not clear. The purpose of this experiment is to study whether FSH affects chondrocytes and how it causes changes in these cells. Our results show that osteoarthritis became worse after FSH injection in the knee joint of mice. After the stimulation of chondrocytes by FSH, a total of 664 up-regulated genes, such as Col12a1 and Col1a1, and 644 down-regulated genes, such as MGP, were screened by transcriptomics. A subset of extracellular matrix (ECM)-related genes and pathways underwent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and the downregulation of MGP, the upregulation of EGR1 and Col1a1, and the increase of IL-6 were verified. It was also observed that FSH can inhibit the cAMP/PKA and MKK4/JNK signaling pathway. In conclusion, we demonstrated that FSH can increase cartilage inflammatory response and promote chondrocyte dedifferentiation by inhibiting the cAMP/PKA and MKK4/JNK signaling pathways.

14.
Sci Rep ; 11(1): 10036, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976344

RESUMO

Triglyceride glucose (TyG) index and inflammatory markers are reported to have a positive association with metabolic syndrome (MetS). However, no previous study has assessed the value of TyG index and inflammatory markers as predictors of metabolic syndrome in the same study. This study looks at the comparison of the triglyceride index and blood leukocyte indices as predictors of metabolic syndrome in the Chinese population. The study cohort involved 1542 Chinese population without metabolic syndrome. The subjects underwent comprehensive routine health examination in 2011 and returned for a follow-up examination in 2016. Metabolic syndrome was defined according to Chinese Diabetes Society criteria, using body mass index for the replacement of waist circumference. TyG index, total leukocytes, neutrophils, lymphocytes, and neutrophil-to-lymphocyte ratio (NLR) were measured. Adjust d logistic models were used to assess the relationship between TyG index, blood leukocyte indices, and incident MetS. Receiver operating characteristic (ROC) curves were performed to determine the predictive value of TyG index and blood leukocyte indices for MetS. Results from multivariate logistic regression analysis showed that, in the adjusted model, the subjects with the highest quartile of TyG index and neutrophils had a 3.894- and 1.663-fold increased incidence of MetS (P < 0.0001 and P = 0.027), respectively. No significant association was observed between total leukocytes, lymphocytes, NLR with incident MetS. ROC analysis showed that the AUC of TyG index and neutrophils were 0.674 and 0.568 for incident MetS, respectively. TyG index rather than blood leukocyte indices may have the strongest predictive value in MetS development over a 5-year period.

15.
BMC Cancer ; 21(1): 483, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931030

RESUMO

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignant head and neck tumor, and more than 70% of new cases are in East and Southeast Asia. However, association between NPC and pseudogenes playing important roles in genesis of multiple tumor types is still not clear and needs to be investigated. METHODS: Using RNA-Sequencing (RNA-seq) technology, we analyzed pseudogene expression in 13 primary NPC and 6 recurrent NPC samples as well as their paracancerous counterparts. Quantitative PCR was used to validate the differentially expressed pseudogenes. RESULTS: We found 251 differentially expressed pseudogenes including 73 up-regulated and 178 down-regulated ones between primary NPC and paracancerous tissues. Enrichment analysis of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were conducted to filter out the key pseudogenes. We reported that pseudogenes from cytochrome P450 (CYP) family, such as CYP2F2P, CYP2G1P, CYP4F24P, CYP2B7P and CYP2G2P were significantly down-regulated in NPC compared to paracancerous tissues, while IGHV1OR15-2, IGHV3-11, FCGR1CP and IGHV3-69-1 belonging to Fc gamma receptors were significantly up-regulated. CYP2B7P, CYP2F2P and CYP4F26P were enriched in arachidonic acid metabolism pathway. The qRT-PCR analysis validated the lower expression of pseudogenes CYP2F2P and CYP2B7P in NPC tissues and cell lines compared to paracancerous tissues and normal human nasopharyngeal epithelial cell line. CYP2B7P overexpression weakened migratory and invasive capacity of NPC cell line. Moreover, the expression pattern of those pseudogenes in recurrent NPC tissues was different from the primary NPC. CONCLUSION: This study suggested the role of pseudogenes in tumorigenesis and progression, potentially functioning as therapeutic targets to NPC.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Recidiva Local de Neoplasia/genética , Pseudogenes , Receptores de IgG/genética , Análise de Sequência de RNA , Adulto , Idoso , Ácido Araquidônico/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Família 2 do Citocromo P450/genética , Regulação para Baixo , Feminino , Ontologia Genética , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Invasividade Neoplásica , Pseudogenes/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Transfecção/métodos , Regulação para Cima
16.
Vet Res ; 52(1): 73, 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34034820

RESUMO

Porcine Parvovirus (PPV), a pathogen causing porcine reproductive disorders, encodes two capsid proteins (VP1 and VP2) and three nonstructural proteins (NS1, NS2 and SAT) in infected cells. The PPV NS2 mRNA is from NS1 mRNA after alternative splicing, yet the corresponding mechanism is unclear. In this study, we identified a PPV NS1 mRNA binding protein SYNCRIP, which belongs to the hnRNP family and has been identified to be involved in host pre-mRNA splicing by RNA-pulldown and mass spectrometry approaches. SYNCRIP was found to be significantly up-regulated by PPV infection in vivo and in vitro. We confirmed that it directly interacts with PPV NS1 mRNA and is co-localized at the cytoplasm in PPV-infected cells. Overexpression of SYNCRIP significantly reduced the NS1 mRNA and protein levels, whereas deletion of SYNCRIP significantly reduced NS2 mRNA and protein levels and the ratio of NS2 to NS1, and further impaired replication of the PPV. Furthermore, we found that SYNCRIP was able to bind the 3'-terminal site of NS1 mRNA to promote the cleavage of NS1 mRNA into NS2 mRNA. Taken together, the results presented here demonstrate that SYNCRIP is a critical molecule in the alternative splicing process of PPV mRNA, while revealing a novel function for this protein and providing a potential target of antiviral intervention for the control of porcine parvovirus disease.


Assuntos
DNA Viral/fisiologia , Ribonucleoproteínas Nucleares Heterogêneas/genética , Infecções por Parvoviridae/veterinária , Parvovirus Suíno/fisiologia , RNA Mensageiro/genética , Doenças dos Suínos/genética , Proteínas não Estruturais Virais/genética , Processamento Alternativo , Animais , Replicação do DNA , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Infecções por Parvoviridae/genética , Infecções por Parvoviridae/metabolismo , Parvovirus Suíno/genética , RNA Mensageiro/metabolismo , Sus scrofa , Suínos , Doenças dos Suínos/metabolismo , Proteínas não Estruturais Virais/metabolismo
17.
Cell Rep ; 35(6): 109107, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33979612

RESUMO

As vaccine-induced non-neutralizing antibodies may cause antibody-dependent enhancement of Zika virus (ZIKV) infection, we test a vaccine that induces only specific cytotoxic T lymphocytes (CTLs) without specific antibodies. We construct a DNA vaccine expressing a ubiquitinated and rearranged ZIKV non-structural protein 3 (NS3). The protein is immediately degraded and processed in the proteasome for presentation via major histocompatibility complex (MHC) class I for CTL generation. We immunize Ifnar1-/- adult mice with the ubiquitin/NS3 vaccine, impregnate them, and challenge them with ZIKV. Our data show that the vaccine greatly reduces viral titers in reproductive organs and other tissues of adult mice. All mice immunized with the vaccine survived after ZIKV challenge. The vaccine remarkably reduces placenta damage and levels of pro-inflammatory cytokines, and it fully protects fetuses from damage. CD8+ CTLs are essential in protection, as demonstrated via depletion experiments. Our study provides a strategy to develop safe and effective vaccines against viral infections.

18.
J Neurosci ; 41(26): 5620-5637, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34016714

RESUMO

The adult olfactory epithelium (OE) regenerates sensory neurons and nonsensory supporting cells from resident stem cells after injury. How supporting cells contribute to OE regeneration remains largely unknown. In this study, we elucidated a novel role of Ym2 (also known as Chil4 or Chi3l4), a chitinase-like protein expressed in supporting cells, in regulating regeneration of the injured OE in vivo in both male and female mice and cell proliferation/differentiation in OE colonies in vitro We found that Ym2 expression was enhanced in supporting cells after OE injury. Genetic knockdown of Ym2 in supporting cells attenuated recovery of the injured OE, while Ym2 overexpression by lentiviral infection accelerated OE regeneration. Similarly, Ym2 bidirectionally regulated cell proliferation and differentiation in OE colonies. Furthermore, anti-inflammatory treatment reduced Ym2 expression and delayed OE regeneration in vivo and cell proliferation/differentiation in vitro, which were counteracted by Ym2 overexpression. Collectively, this study revealed a novel role of Ym2 in OE regeneration and cell proliferation/differentiation of OE colonies via interaction with inflammatory responses, providing new clues to the function of supporting cells in these processes.SIGNIFICANCE STATEMENT The mammalian olfactory epithelium (OE) is a unique neural tissue that regenerates sensory neurons and nonsensory supporting cells throughout life and postinjury. How supporting cells contribute to this process is not entirely understood. Here we report that OE injury causes upregulation of a chitinase-like protein, Ym2, in supporting cells, which facilitates OE regeneration. Moreover, anti-inflammatory treatment reduces Ym2 expression and delays OE regeneration, which are counteracted by Ym2 overexpression. This study reveals an important role of supporting cells in OE regeneration and provides a critical link between Ym2 and inflammation in this process.

19.
Mol Genet Genomic Med ; 9(6): e1682, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33822487

RESUMO

BACKGROUND: Joubert syndrome (JBTS) is a rare genetic disorder that is characterized by midbrain-hindbrain malformations. Multiple variants in genes that affect ciliary function contribute to the genetic and clinical heterogeneity of JBTS and its subtypes. However, the correlation between genotype and phenotype has not been elucidated due to the limited number of patients available. METHODS: In this study, we observed different clinical features in two siblings from the same family. The older sibling was classified as a pure JBTS patient, whereas her younger sibling displayed oral-facial-digital defects and was therefore classified as an oral-facial-digital syndrome type VI (OFD VI) patient. Next, we performed human genetic tests to identify the potential pathogenic variants in the two siblings. RESULTS: Genetic sequencing indicated that both siblings harbored compound heterozygous variants of a missense variant (c.1067C>T, p.S356F) and a frameshift variant (c.8377_8378del, p.E2793Lfs*24) in CPLANE1 (NM_023073.3). CONCLUSION: This study reports that two novel CPLANE1 variants are associated with the occurrence of JBTS and OFD VI. These results help elucidate the intrafamilial phenotypic variability associated with CPLANE1 variants.

20.
Artigo em Inglês | MEDLINE | ID: mdl-33855386

RESUMO

OBJECTIVE: 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) was one of the newly found lipokines. The goal of this study was to investigate whether the 12,13-diHOME was associated with related metabolic markers of nonalcoholic fatty liver disease (NAFLD) in a Chinese population with type 2 diabetes (T2DM) and obesity. METHODS: This cross-sectional study enrolled 202 subjects with T2DM. Anthropometric parameters, 12,13-diHOME, serum lipids levels, fasting blood-glucose (FBG), serum glycosylated hemoglobin (HbA1c), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), liver and kidney function parameters were collected. NAFLD was diagnosed based on abdominal ultrasonography examination results. A computer-aided ultrasound quantitative method was applied to evaluate the liver fat content (LFC). RESULTS: The number of the patients with fatty liver was 139 (68.81%) and those with non-fatty liver was 63 (31.19%). Subjects with NAFLD had a higher body mass index (BMI), diastolic blood pressure, serum alanine aminotransferase (ALT), triglyceride (TG), HOMA-IR, LFC, p<0.05 for all. But no significant difference was found in plasma 12,13-diHOME level (p=0.967), though its level trend was higher in non-NAFLD group. Plasma 12,13-diHOME was positively correlated with aspartate aminotransferase (AST), total cholesterol (TC), high density lipoprotein cholesterol (HDLC), blood urea nitrogen (BUN), free fatty acid (FFA), C-peptide, FINS and HOMAIR. It was negatively correlated with height, body weight, glomerular filtration rate (eGFR) and HbA1c. CONCLUSIONS: Although 12,13-diHOME was correlated with AST, TC, HDL-C, BUN, FFA, C-peptide, FINS, HOMA-IR, eGFR and HbA1c, there was no significant difference in 12,13-diHOME level between the two groups. However, more research should be carried on about this newly found lipokine.

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