Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 75
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Mol Ther ; 32(4): 1033-1047, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38341613

RESUMO

As the world continues to confront severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial virus (RSV) is also causing severe respiratory illness in millions of infants, elderly individuals, and immunocompromised people globally. Exacerbating the situation is the fact that co-infection with multiple viruses is occurring, something which has greatly increased the clinical severity of the infections. Thus, our team developed a bivalent vaccine that delivered mRNAs encoding SARS-CoV-2 Omicron spike (S) and RSV fusion (F) proteins simultaneously, SF-LNP, which induced S and F protein-specific binding antibodies and cellular immune responses in BALB/c mice. Moreover, SF-LNP immunization effectively protected BALB/c mice from RSV infection and hamsters from SARS-CoV-2 Omicron infection. Notably, our study pointed out the antigenic competition problem of bivalent vaccines and provided a solution. Overall, our results demonstrated the potential of preventing two infectious diseases with a single vaccine and provided a paradigm for the subsequent design of multivalent vaccines.


Assuntos
COVID-19 , Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Vírus Sincicial Respiratório Humano , Humanos , Camundongos , Lactente , Cricetinae , Animais , Idoso , Vacinas de mRNA , Vacinas Combinadas , Anticorpos Antivirais , Vacinas contra Vírus Sincicial Respiratório/genética , Proteínas Virais de Fusão/genética , COVID-19/prevenção & controle , SARS-CoV-2/genética , Vírus Sincicial Respiratório Humano/genética , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Anticorpos Neutralizantes
2.
Nicotine Tob Res ; 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38602278

RESUMO

INTRODUCTION: Cigarette smoking greatly promotes the progression and poor prognosis of colorectal cancer (CRC) patients, with the molecular mechanism still not fully clear. METHODS: In this study, CRC cells were exposed to tobacco specific nitrosamine 4­(methylnitrosamino)­1­(3­pyridyl) 1­butanone (NNK), and the differentially expressed smoking-related genes were identified based on both NNK-induced CRC cells and a total of 763 CRC tissues from TCGA cohort. Cox regression analysis, ROC curve and Kaplan-Meier plot were used to establish the risk score model for CRC prognosis. Moreover, qRT-PCR, western blotting, colony formation, migration and invasion assays were performed to verify the core differentially expressed smoking-related gene and its molecular function in NNK-induced CRC progression. RESULTS: Results indicated NNK significantly enhanced CRC cell proliferation, migration and invasion. Moreover, a four-gene signature containing AKR1B10, CALB2, PLAC1, GNA15 was established as CRC prognosis marker. Among these four genes, AKR1B10 was further validated as the core gene, and its expression was significantly inhibited after NNK exposure in CRC cells. Results of gene enrichment analysis and western blotting suggested AKR1B10 might reduce the malignant progression of NNK-induced CRC cells through inhibiting Wnt signaling pathway by promoting E-Cadherin expression and inhibiting the expression of N-Cadherin, ß-Catenin, Vimentin and Snail. CONCLUSION: In conclusion, a new four smoking-related genes can be jointly used as prognostic markers for CRC. AKR1B10 served as a tumor suppressor, can be used as a potential target to inhibit NNK-induced CRC malignant progression through regulating Wnt signaling pathway. IMPLICATIONS: This study demonstrates tobacco-derived NNK dependence would promote the malignant progression of colorectal cancer through regulating the expressions of AKR1B10/Wnt signaling pathway. And a novel four-gene signature is established for the prognosis prediction of smoking CRC patients. These findings have important translational implications given the continued use of tobacco and the difficulty in smoking cessation worldwide, which can be applied to alleviate the adverse effects induced by tobacco dependence on colorectal cancer patients.

3.
World J Surg Oncol ; 22(1): 149, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840197

RESUMO

OBJECTIVE: The purpose of this study was to evaluate the efficacy and clinical value of US, FNAC,FNA-Tg and FNAC + FNA-Tg, as well as the cutoff values of FNA-Tg to evaluate LN metastasis. METHODS: We analyzed the diagnostic value of different US signs, the efficiency of US, FNAC, FNA-Tg and FNAC + FNA-Tg among the LN- and LN + groups, and the cutoff value of FNA-Tg to evaluate LN metastasis. We punctured LNs multiple times and measured the levels of FNA-Tg. Furthermore, the LNs were marked with immunohistochemical Tg and LCA to distinguish the presence of Tg in the para-cancerous tissue of the LNs. RESULTS: The s-Tg and FNA-Tg of the LN + group were higher than those of the LN- group (P = 0.018, ≤ 0.001). The LN + group had more abnormal US signs than the LN- group. The cutoff value of FNA-Tg was 3.2 ng/mL. US had a high sensitivity (92.42), but the specificity was not satisfactory (55.1). FNA-Tg had a higher sensitivity (92.42 vs. 89.39), specificity (100 vs. 93.88), and accuracy (92.42 vs. 83.27) than FNAC. However, the sensitivity of FNAC + FNA-Tg increased further, while the specificity and accuracy decreased slightly. The presence of Tg in the normal lymphocytes adjacent to the cancer was confirmed. CONCLUSION: Ultrasonography provides a noninvasive, dynamic, multidimensional assessment of LNs. With a cutoff value of 3.2 ng/mL, FNA-Tg has higher accuracy and a lower false-negative rate than various single diagnoses. However, FNAC combined with FNA-Tg does not cause additional pain to patients and offers a higher diagnostic efficacy and clinical value.


Assuntos
Metástase Linfática , Tireoglobulina , Neoplasias da Glândula Tireoide , Humanos , Biópsia por Agulha Fina/métodos , Feminino , Metástase Linfática/diagnóstico , Masculino , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/diagnóstico , Pessoa de Meia-Idade , Adulto , Tireoglobulina/análise , Tireoglobulina/metabolismo , Prognóstico , Citodiagnóstico/métodos , Carcinoma Papilar/patologia , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/cirurgia , Linfonodos/patologia , Idoso , Seguimentos , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Ultrassonografia/métodos , Adulto Jovem , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/cirurgia , Câncer Papilífero da Tireoide/diagnóstico
4.
BMC Genomics ; 24(1): 272, 2023 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-37208615

RESUMO

Macrophages are important effector cells in tumor progression and immune regulation. Previously, we demonstrated that the transcription suppressor homeobox containing 1(HMBOX1) exhibits immunosuppressive activity in LPS-induced acute liver injury by impeding macrophage infiltration and activation. We also observed a lower proliferation in HMBOX1-overexpressed RAW264.7 cells. However, the specific mechanism was unclear. Here, a work was performed to characterize HMBOX1 function related to cell proliferation from a metabolomics standpoint by comparing the metabolic profiles of HMBOX1-overexpressed RAW264.7 cells to those of the controls. Firstly, we assessed HMBOX1 anti-proliferation activity in RAW264.7 cells with CCK8 assay and clone formation. Then, we performed metabolomic analyses by ultra-liquid chromatography coupled with mass spectrometry to explore the potential mechanisms. Our results indicated that HMBOX1 inhibited the macrophage growth curve and clone formation ability. Metabolomic analyses showed significant changes in HMBOX1-overexpressed RAW264.7 metabolites. A total of 1312 metabolites were detected, and 185 differential metabolites were identified based on the criterion of OPLS-DA VIP > 1 and p value < 0.05. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that the elevated HMBOX1 in RAW264.7 inhibited the pathways of amino acid and nucleotide metabolism. Glutamine concentrations decreased significantly in HMBOX1-overexpressed macrophages, and glutamine-related transporter SLC1A5 was also downregulated. Furthermore, SLC1A5 overexpression reversed HMBOX1 inhibition of macrophage proliferation. This study demonstrated the potential mechanism of the HMBOX1/SLC1A5 pathway in cell proliferation by regulating glutamine transportation. The results may help provide a new direction for therapeutic interventions in macrophage-related inflammatory diseases.


Assuntos
Glutamina , Proteínas de Homeodomínio , Camundongos , Animais , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Cromatografia Líquida , Espectrometria de Massas em Tandem , Células RAW 264.7 , Metabolômica
5.
Physiol Plant ; 175(4): e13978, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37616012

RESUMO

The wounding-responsive KED gene, named for its coding for a lysine (K), glutamic acid (E), and aspartic acid (D)-rich protein, is widely present among land plants. However, little is known about its regulation or function. In this study, we found that transcription of the tomato (Solanum lycopersicum) KED gene, SlKED, was rapidly and transiently elevated by wounding or ethephon treatment. Compared to the wild-type plants, the CRISPR/Cas9-mediated SlKED knockout plants did not exhibit altered expression patterns for genes involved in hormone biosynthesis or stress signaling, suggesting a lack of pleiotropic effect on other stress-responsive genes. Conversely, jasmonic acid did not appear to directly regulate SlKED expression. Wounded leaves of the KED-lacking plants exhibited higher binding of Evans blue dye than the wild-type, indicating a possible role for KED in healing damaged tissues. The SlKED knockout plants showed a similar dietary effect as the wild-type on the larval growth of tobacco hornworm. But a higher frequency of larval mandible (mouth) movement was recorded during the first 2 minutes of feeding on the wounded KED-lacking SlKED knockout plants than on the wounded KED-producing wild-type plants, probably reflecting an initial differential response by the feeding larvae to the SlKED knockout plants. Our findings suggest that SlKED may be an ethylene-mediated early responder to mechanical stress in tomato, acting downstream of the wound stress response pathways. Although its possible involvement in response to other biotic and abiotic stresses is still unclear, we propose that SlKED may play a role in plant's rapid, short-term, early wounding responses, such as in cellular damage healing.


Assuntos
Solanum lycopersicum , Solanum lycopersicum/genética , Folhas de Planta/genética , Folhas de Planta/metabolismo , Estresse Fisiológico/genética , Expressão Gênica , Regulação da Expressão Gênica de Plantas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
6.
BMC Cancer ; 22(1): 635, 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35681154

RESUMO

BACKGROUND: The prognosis of Borrmann type III advanced gastric cancer (AGC) is known to vary significantly among patients. This study aimed to determine which differentially expressed genes (DEGs) are directly related to the survival time of Borrmann type III AGC patients and to construct a prognostic model. METHODS: We selected 25 patients with Borrmann type III AGC who underwent radical gastrectomy. According to the difference in overall survival (OS), the patients were divided into group A (OS<1 year, n=11) and group B (OS>3 years, n=14). DEGs related to survival time in patients with Borrmann type III AGC were determined by mRNA sequencing. The prognosis and functional differences of DEGs in different populations were determined by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) public databases. The expression of mRNA and protein in cell lines was detected by quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot (WB). Immunohistochemical (IHC) staining was used to detect protein expression in the paraffin-embedded tissues of 152 patients with Borrmann type III AGC who underwent radical gastrectomy. After survival analysis, nomograms were constructed to predict the prognosis of patients with Borrmann type III AGC. RESULTS: Arylacetamide deacetylase (AADAC) is a survival-related DEG in patients with Borrmann type III AGC. The higher the expression level of its mRNA and protein is, the better the prognosis of patients. Bioinformatics analysis found that AADAC showed significant differences in prognosis and function in European and American populations and Asian populations. In addition, the mRNA and protein expression levels of AADAC were high in differentiated gastric cancer (GC) cells. We also found that AADAC was an independent prognostic factor for patients with Borrmann type III AGC, and its high expression was significantly correlated with better OS and disease-free survival (DFS). Nomogram models of AADAC expression level combined with clinicopathological features can be used to predict the OS and DFS of Borrmann type III AGC. CONCLUSION: AADAC can be used as a biomarker to predict the prognosis of Borrmann type III AGC and has the potential to become a new therapeutic target for GC.


Assuntos
Hidrolases de Éster Carboxílico , Neoplasias Gástricas , Hidrolases de Éster Carboxílico/genética , Expressão Gênica , Humanos , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirurgia
7.
Phys Rev Lett ; 127(2): 026801, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34296892

RESUMO

We study quantum quenches of helical liquids with spin-flip inelastic scattering. Counterpropagating charge packets in helical edges can be created by an ultrashort electric pulse applied across a 2D topological insulator. Localized "hot spots" that form due to scattering enable two types of strongly nonlinear wave dynamics. First, propagating packets develop self-focusing shock fronts. Second, colliding packets with opposite charge can exhibit near-perfect retroreflection, despite strong dissipation. This leads to frequency doubling that could be detected experimentally from emitted terahertz radiation.

8.
Virol J ; 18(1): 230, 2021 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-34809668

RESUMO

BACKGROUND: In 2011, a new influenza virus, named Influenza D Virus (IDV), was isolated from pigs, and then cattle, presenting influenza-like symptoms. IDV is one of the causative agents of Bovine Respiratory Disease (BRD), which causes high morbidity and mortality in feedlot cattle worldwide. To date, the molecular mechanisms of IDV pathogenicity are unknown. Recent IDV outbreaks in cattle, along with serological and genetic evidence of IDV infection in humans, have raised concerns regarding the zoonotic potential of this virus. Influenza virus polymerase is a determining factor of viral pathogenicity to mammals. METHODS: Here we take a prospective approach to this question by creating a random mutation library about PB2 subunit of the IDV viral polymerase to test which amino acid point mutations will increase viral polymerase activity, leading to increased pathogenicity of the virus. RESULTS: Our work shows some exact sites that could affect polymerase activities in influenza D viruses. For example, two single-site mutations, PB2-D533S and PB2-G603Y, can independently increase polymerase activity. The PB2-D533S mutation alone can increase the polymerase activity by 9.92 times, while the PB2-G603Y mutation increments the activity by 8.22 times. CONCLUSION: Taken together, our findings provide important insight into IDV replication fitness mediated by the PB2 protein, increasing our understanding of IDV replication and pathogenicity and facilitating future studies.


Assuntos
Infecções por Orthomyxoviridae , Orthomyxoviridae , Thogotovirus , Aminoácidos/genética , Animais , Bovinos , Mutação , Suínos , Thogotovirus/genética , Replicação Viral
9.
Arch Virol ; 164(8): 2023-2029, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31111259

RESUMO

We previously obtained mouse-adapted variants of H1N2 avian influenza virus that contained PB2-L134H, PB2-I647L, PB2-D701N, HA-G228S, and M1-D231N mutations. Here, we analyzed the effects of these mutations on viral pathogenicity in a mammalian model. By evaluating the virulence of mouse-adapted H1N2 variants at different generations, we found that the PB2-D701N and HA-G228S mutations both contribute to the virulence of this virus in mammals. Furthermore, we found that the PB2-D701N and HA-G228S mutations both enhance the ability of the virus to replicate in vivo and in vitro and that the PB2-D701N substitution results in an expansion of viral tissue tropism. These results suggest that the PB2-D701N mutation and the HA-G228S mutation are the major mammalian determinants of H1N2 virus. These results help us to understand more about the mechanisms by which influenza viruses adapt to mammals, and monitoring of these mutations can be used in continuous influenza surveillance to assess the pandemic potential of avian influenza virus variants.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H1N2/genética , Influenza Aviária/virologia , Mutação/genética , Proteínas Virais/genética , Virulência/genética , Adaptação Biológica/genética , Substituição de Aminoácidos/genética , Animais , Aves , Linhagem Celular , Cães , Feminino , Células Madin Darby de Rim Canino , Mamíferos/virologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/virologia , Fenótipo , Replicação Viral/genética
10.
Arch Virol ; 163(2): 401-410, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29090366

RESUMO

H5 clade 2.3.4.4 influenza A viruses pose a potential threat to public health and are a cause of public concern. Here, we generated mouse-adapted viruses of a waterfowl-origin H5N5 virus (H5 clade 2.3.4.4) to identify adaptive changes that confer increased virulence in mammals. After two passages, we obtained a mouse-adapted H5N5 virus that contained single amino acid substitutions in the PB2 (E627K) and hemagglutinin (HA) (F430L) proteins. We then analyzed the impact of these individual amino acid substitutions on viral pathogenicity to mammals. The 50% mouse lethal dose (MLD50) of the H5N5 virus containing the PB2-E627K substitution or the HA-F430L substitution was reduced 1000-fold or 3.16-fold, respectively. Furthermore, we found that PB2-E627K enhanced viral replication kinetics in vitro and in vivo. These results suggest that the PB2-E627K and HA-F430L substitutions are important for adaptation of H5N5 AIVs to mammals. These findings emphasize the importance of continued surveillance of poultry for H5N5 AIVs with these amino acid substitutions.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A/genética , Vírus da Influenza A/patogenicidade , Influenza Aviária/virologia , RNA Polimerase Dependente de RNA/genética , Proteínas Virais/genética , Substituição de Aminoácidos , Animais , Anseriformes/virologia , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Vírus da Influenza A/enzimologia , Vírus da Influenza A/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Mutação de Sentido Incorreto , RNA Polimerase Dependente de RNA/metabolismo , Proteínas Virais/metabolismo , Virulência
11.
Proc Natl Acad Sci U S A ; 109(36): 14699-704, 2012 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-22915581

RESUMO

Secondary Wall-Associated NAC Domain 1s (SND1s) are transcription factors (TFs) known to activate a cascade of TF and pathway genes affecting secondary cell wall biosynthesis (xylogenesis) in Arabidopsis and poplars. Elevated SND1 transcriptional activation leads to ectopic xylogenesis and stunted growth. Nothing is known about the upstream regulators of SND1. Here we report the discovery of a stem-differentiating xylem (SDX)-specific alternative SND1 splice variant, PtrSND1-A2(IR), that acts as a dominant negative of SND1 transcriptional network genes in Populus trichocarpa. PtrSND1-A2(IR) derives from PtrSND1-A2, one of the four fully spliced PtrSND1 gene family members (PtrSND1-A1, -A2, -B1, and -B2). Each full-size PtrSND1 activates its own gene, and all four full-size members activate a common MYB gene (PtrMYB021). PtrSND1-A2(IR) represses the expression of its PtrSND1 member genes and PtrMYB021. Repression of the autoregulation of a TF family by its only splice variant has not been previously reported in plants. PtrSND1-A2(IR) lacks DNA binding and transactivation abilities but retains dimerization capability. PtrSND1-A2(IR) is localized exclusively in cytoplasmic foci. In the presence of any full-size PtrSND1 member, PtrSND1-A2(IR) is translocated into the nucleus exclusively as a heterodimeric partner with full-size PtrSND1s. Our findings are consistent with a model in which the translocated PtrSND1-A2(IR) lacking DNA-binding and transactivating abilities can disrupt the function of full-size PtrSND1s, making them nonproductive through heterodimerization, and thereby modulating the SND1 transcriptional network. PtrSND1-A2(IR) may contribute to transcriptional homeostasis to avoid deleterious effects on xylogenesis and plant growth.


Assuntos
Redes Reguladoras de Genes/genética , Homeostase/fisiologia , Modelos Biológicos , Populus/genética , Isoformas de Proteínas/genética , Fatores de Transcrição/genética , Western Blotting , Clonagem Molecular , Primers do DNA/genética , Dimerização , Eletroforese em Gel de Poliacrilamida , Plasmídeos/genética , Transporte Proteico , Reação em Cadeia da Polimerase em Tempo Real
12.
Drug Discov Today ; 29(7): 104026, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38762086

RESUMO

SARS-CoV-2 has triggered an international outbreak of the highly contagious acute respiratory disease known as COVID-19. Identifying key targets in the virus infection lifecycle is crucial for developing effective prevention and therapeutic strategies against it. Furin is a serine endoprotease that belongs to the family of proprotein convertases and plays a critical role in the entry of host cells by SARS-CoV-2. Furin can cleave a specific S1/S2 site, PRRAR, on the spike protein of SARS-CoV-2, which promotes viral transmission by facilitating membrane fusion. Hence, targeting furin could hold clinical implications for the prevention and treatment of COVID-19. This review offers an overview of furin's structure, substrates, function, and inhibitors, with a focus on its potential role in SARS-CoV-2 infection.


Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Furina , SARS-CoV-2 , Furina/metabolismo , Humanos , COVID-19/prevenção & controle , Antivirais/farmacologia , Antivirais/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Animais , Glicoproteína da Espícula de Coronavírus/metabolismo
13.
Artigo em Inglês | MEDLINE | ID: mdl-38971921

RESUMO

Resistant hypertension (RH) poses a significant health challenge, yet its underlying pathogenesis remains unclear. This study employs untargeted proteomic techniques to analyze the plasma of patients with RH and controlled hypertension (CH), identifying 157 differentially expressed proteins, with TGFB1 emerging as a key candidate. Through gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, Protein-Protein Interaction Networks (PPI) topological analysis, TGFB1's differential regulation in RH is established. ELISA verification solidifies TGFB1's role, marking it as a potential biological target for early RH diagnosis and treatment. The study underscores the importance of proteomic approaches in enhancing our understanding of RH and improving therapeutic strategies. These findings carry implications for advancing RH diagnostics and treatment modalities, addressing a critical gap in current knowledge.

14.
Nat Commun ; 15(1): 2987, 2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38582870

RESUMO

Nipah virus (NiV) is a World Health Organization priority pathogen and there are currently no approved drugs for clinical immunotherapy. Through the use of a naïve human phage-displayed Fab library, two neutralizing antibodies (NiV41 and NiV42) targeting the NiV receptor binding protein (RBP) were identified. Following affinity maturation, antibodies derived from NiV41 display cross-reactivity against both NiV and Hendra virus (HeV), whereas the antibody based on NiV42 is only specific to NiV. Results of immunogenetic analysis reveal a correlation between the maturation of antibodies and their antiviral activity. In vivo testing of NiV41 and its mature form (41-6) show protective efficacy against a lethal NiV challenge in hamsters. Furthermore, a 2.88 Å Cryo-EM structure of the tetrameric RBP and antibody complex demonstrates that 41-6 blocks the receptor binding interface. These findings can be beneficial for the development of antiviral drugs and the design of vaccines with broad spectrum against henipaviruses.


Assuntos
Infecções por Henipavirus , Vírus Nipah , Humanos , Anticorpos Neutralizantes/metabolismo , Vírus Nipah/metabolismo , Anticorpos Antivirais
15.
Nat Commun ; 15(1): 4330, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773072

RESUMO

The Hendra and Nipah viruses (HNVs) are highly pathogenic pathogens without approved interventions for human use. In addition, the interaction pattern between the attachment (G) and fusion (F) glycoproteins required for virus entry remains unclear. Here, we isolate a panel of Macaca-derived G-specific antibodies that cross-neutralize HNVs via multiple mechanisms. The most potent antibody, 1E5, confers adequate protection against the Nipah virus challenge in female hamsters. Crystallography demonstrates that 1E5 has a highly similar binding pattern to the receptor. In cryo-electron microscopy studies, the tendency of 1E5 to bind to the upper or lower heads results in two distinct quaternary structures of G. Furthermore, we identify the extended outer loop ß1S2-ß1S3 of G and two pockets on the apical region of fusion (F) glycoprotein as the essential sites for G-F interactions. This work highlights promising drug candidates against HNVs and contributes deeper insights into the viruses.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Microscopia Crioeletrônica , Infecções por Henipavirus , Proteínas Virais de Fusão , Animais , Anticorpos Neutralizantes/imunologia , Feminino , Anticorpos Antivirais/imunologia , Infecções por Henipavirus/virologia , Infecções por Henipavirus/imunologia , Proteínas Virais de Fusão/imunologia , Proteínas Virais de Fusão/química , Humanos , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/química , Vírus Nipah/imunologia , Internalização do Vírus/efeitos dos fármacos , Henipavirus/imunologia , Cricetinae , Reações Cruzadas/imunologia , Vírus Hendra/imunologia , Macaca , Mesocricetus , Cristalografia por Raios X
16.
JCI Insight ; 9(7)2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38587080

RESUMO

BACKGROUNDAs Omicron is prompted to replicate in the upper airway, neutralizing antibodies (NAbs) delivered through inhalation might inhibit early-stage infection in the respiratory tract. Thus, elucidating the prophylactic efficacy of NAbs via nasal spray addresses an important clinical need.METHODSThe applicable potential of a nasal spray cocktail containing 2 NAbs was characterized by testing its neutralizing potency, synergetic neutralizing mechanism, emergency protective and therapeutic efficacy in a hamster model, and pharmacokinetics/pharmacodynamic (PK/PD) in human nasal cavity.RESULTSThe 2 NAbs displayed broad neutralizing efficacy against Omicron, and they could structurally compensate each other in blocking the Spike-ACE2 interaction. When administrated through the intranasal mucosal route, this cocktail demonstrated profound efficacy in the emergency prevention in hamsters challenged with authentic Omicron BA.1. The investigator-initiated trial in healthy volunteers confirmed the safety and the PK/PD of the NAb cocktail delivered via nasal spray. Nasal samples from the participants receiving 4 administrations over a course of 16 hours demonstrated potent neutralization against Omicron BA.5 in an ex vivo pseudovirus neutralization assay.CONCLUSIONThese results demonstrate that the NAb cocktail nasal spray provides a good basis for clinical prophylactic efficacy against Omicron infections.TRIAL REGISTRATIONwww.chictr.org.cn, ChiCTR2200066525.FUNDINGThe National Science and Technology Major Project (2017ZX10202203), the National Key Research and Development Program of China (2018YFA0507100), Guangzhou National Laboratory (SRPG22-015), Lingang Laboratory (LG202101-01-07), Science and Technology Commission of Shanghai Municipality (YDZX20213100001556), and the Emergency Project from the Science & Technology Commission of Chongqing (cstc2021jscx-fyzxX0001).


Assuntos
Anticorpos Neutralizantes , Sprays Nasais , Animais , Cricetinae , Humanos , China , Traqueia , Voluntários Saudáveis
17.
Zhongguo Zhong Yao Za Zhi ; 38(6): 821-4, 2013 Mar.
Artigo em Zh | MEDLINE | ID: mdl-23717959

RESUMO

OBJECTIVE: To explore quantitative assessment indicators of Chrysanthemi Flos, and optimize the extraction process of Chrysanthemi Flos through orthogonal experimental design. METHOD: The concentration of ethanol, amount of ethanol, extraction time and extraction frequency were selected as factors in the L9 (3(4)) orthogonal experiment. A comprehensive assessment was conducted with the peak area of the eight major common peaks in the fingerprint of Chrysanthemi Flos as the indicators. RESULT: The optimum extraction process was selected as follows: using ultrasonic extraction method, adding 30-fold ethanol with 80% concentration, extracting for 2 times for extraction, 40 min for each time. CONCLUSION: The optimized extraction process is reliable, with controllable assessment indicators, which is significant to the standardization of the extraction process and quality control of Chrysanthemi Flos preparations.


Assuntos
Fracionamento Químico/métodos , Chrysanthemum/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/química , Etanol/química , Temperatura Alta , Controle de Qualidade , Reprodutibilidade dos Testes , Solubilidade , Fatores de Tempo
18.
Zhongguo Zhong Yao Za Zhi ; 38(13): 2155-8, 2013 Jul.
Artigo em Zh | MEDLINE | ID: mdl-24079245

RESUMO

To establish a fingerprint for Cimicifugae Rhizoma from different producing areas. Column kromasil (4.6 mm x 250 mm, 5 microm) was employed with acetonitrile-0.1% formic acid solution as the mobile phase for gradient elution. The flow rate was 1.0 mL x min(-1), the detection wavelength was 254 nm. Twenty chromatographic peaks were extracted as the common peaks of fingerprint, and 21 batches of samples were compared and classified with such methods as similarity evaluation, cluster analysis and principle component analysis. The results showed 12 common peaks and three categories of samples. The method was so highly reproducible, simple and reliable that it could provide basis for quality control and evaluation of Cimicifugae Rhizoma from different producing areas.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cimicifuga/química , Estabilidade de Medicamentos , Controle de Qualidade
19.
Zhongguo Zhong Yao Za Zhi ; 38(1): 26-31, 2013 Jan.
Artigo em Zh | MEDLINE | ID: mdl-23596870

RESUMO

Fingerprint technology is the key technology in modern Chinese medicine research, while spectrum-effect relationship research is the advanced stage of fingerprint research. Spectrum-effect relationship research can reveal the relationship between fingerprint and pharmacological effect through multiple statistical analyses, which can be used in Chinese medicine research. Spectrum-effect relationship has been used in many areas of Chinese medicine research, such as effective basis of single and compound Chinese medicine research, component compatibility research, processing mechanism research, pharmacological effect forecast research, technology optimization research, and so on. This paper systematically reviewed the application of spectrum-effect relationship in Chinese medicine research, and indicated some problems in spectrum-effect relationship research. At last, the authors give an outlook of the future of spectrum-effect relationship research.


Assuntos
Pesquisa Biomédica , Medicamentos de Ervas Chinesas/química , Animais , China , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Análise Espectral
20.
J Pathol Clin Res ; 9(1): 56-72, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36226731

RESUMO

Elastin (ELN) fibers are essential constituents of the tumor microenvironment of gastric cancer (GC). However, few studies have investigated the clinical prognostic significance of ELN in GC. We screened for molecular markers that were highly related to distant metastasis by transcriptome sequencing. The Cancer Genome Atlas (TCGA) and Harbin Medical University (HMU) validation cohorts were used to validate ELN expression and to explore molecular mechanisms. Immunohistochemistry for ELN, vimentin (VIM), and fibroblast activation protein, and elastic fiber-specific staining were used to evaluate the relationship between ELN and prognosis. R studio was used to construct a nomogram prognostic model. In this study, we found that ELN mRNA levels were significantly higher in cancer tissues and were associated with poor prognosis in TCGA and HMU patients. Gene set enrichment analysis showed that ELN was mainly enriched in the epithelial-mesenchymal transition (EMT) pathway. The mRNA expression of ELN was positively correlated with fibroblast molecular markers, especially VIM. For validation, we collected a tissue microarray containing 180 pairs of samples. We found that ELN was positively correlated with VIM expression in cancer tissue but not in paracancerous tissues by immunohistochemistry staining. Univariate and multivariate analyses showed that the expression of ELN and lymph node metastasis rate were independent predictors for overall survival. Moreover, a nomogram model was used to evaluate the risk of death by combining the expression of ELN and lymph node metastasis rate. ELN may play an important role in the progression of GC by regulating EMT and is a useful prognostic indicator in predicting the prognosis of GC.


Assuntos
Transição Epitelial-Mesenquimal , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Prognóstico , Metástase Linfática , Fibroblastos , RNA Mensageiro/genética , Microambiente Tumoral
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa