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1.
Nature ; 633(8029): 426-432, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38977017

RESUMO

Highly pathogenic H5N1 avian influenza (HPAI H5N1) viruses occasionally infect, but typically do not transmit, in mammals. In the spring of 2024, an unprecedented outbreak of HPAI H5N1 in bovine herds occurred in the USA, with virus spread within and between herds, infections in poultry and cats, and spillover into humans, collectively indicating an increased public health risk1-4. Here we characterize an HPAI H5N1 virus isolated from infected cow milk in mice and ferrets. Like other HPAI H5N1 viruses, the bovine H5N1 virus spread systemically, including to the mammary glands of both species, however, this tropism was also observed for an older HPAI H5N1 virus isolate. Bovine HPAI H5N1 virus bound to sialic acids expressed in human upper airways and inefficiently transmitted to exposed ferrets (one of four exposed ferrets seroconverted without virus detection). Bovine HPAI H5N1 virus thus possesses features that may facilitate infection and transmission in mammals.


Assuntos
Doenças dos Bovinos , Virus da Influenza A Subtipo H5N1 , Infecções por Orthomyxoviridae , Virulência , Animais , Bovinos , Feminino , Humanos , Camundongos , Furões/virologia , Virus da Influenza A Subtipo H5N1/imunologia , Virus da Influenza A Subtipo H5N1/isolamento & purificação , Virus da Influenza A Subtipo H5N1/patogenicidade , Virus da Influenza A Subtipo H5N1/fisiologia , Influenza Humana/transmissão , Influenza Humana/virologia , Influenza Humana/epidemiologia , Glândulas Mamárias Animais/virologia , Camundongos Endogâmicos BALB C , Leite/virologia , Infecções por Orthomyxoviridae/epidemiologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/transmissão , Infecções por Orthomyxoviridae/veterinária , Infecções por Orthomyxoviridae/virologia , Ácidos Siálicos/metabolismo , Tropismo Viral , Doenças dos Bovinos/epidemiologia , Doenças dos Bovinos/transmissão , Doenças dos Bovinos/virologia , Estados Unidos/epidemiologia , Zoonoses Virais , Soroconversão , Máscaras Laríngeas/virologia
2.
Plant J ; 118(6): 1793-1814, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38461478

RESUMO

Flavan-3-ols are prominent phenolic compounds found abundantly in the young leaves of tea plants. The enzymes involved in flavan-3-ol biosynthesis in tea plants have been extensively investigated. However, the localization and associations of these numerous functional enzymes within cells have been largely neglected. In this study, we aimed to investigate the synthesis of flavan-3-ols in tea plants, particularly focusing on epigallocatechin gallate. Our analysis involving the DESI-MSI method to reveal a distinct distribution pattern of B-ring trihydroxylated flavonoids, primarily concentrated in the outer layer of buds. Subcellular localization showed that CsC4H, CsF3'H, and CsF3'5'H localizes endoplasmic reticulum. Protein-protein interaction studies demonstrated direct associations between CsC4H, CsF3'H, and cytoplasmic enzymes (CHS, CHI, F3H, DFR, FLS, and ANR), highlighting their interactions within the biosynthetic pathway. Notably, CsF3'5'H, the enzyme for B-ring trihydroxylation, did not directly interact with other enzymes. We identified cytochrome b5 isoform C serving as an essential redox partner, ensuring the proper functioning of CsF3'5'H. Our findings suggest the existence of distinct modules governing the synthesis of different B-ring hydroxylation compounds. This study provides valuable insights into the mechanisms underlying flavonoid diversity and efficient synthesis and enhances our understanding of the substantial accumulation of B-ring trihydroxylated flavan-3-ols in tea plants.


Assuntos
Camellia sinensis , Catequina , Citocromos b5 , Flavonoides , Proteínas de Plantas , Flavonoides/metabolismo , Flavonoides/biossíntese , Camellia sinensis/metabolismo , Camellia sinensis/genética , Catequina/metabolismo , Catequina/análogos & derivados , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Citocromos b5/metabolismo , Citocromos b5/genética , Folhas de Planta/metabolismo , Hidroxilação , Retículo Endoplasmático/metabolismo
3.
Opt Express ; 31(18): 28830-28849, 2023 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-37710694

RESUMO

A new thin plane mirror with an Archimedes spiral structure (Archimedes-structure thin plane mirror - ATPM) that implements an elastic support boundary is proposed in this study. An optimal structure of ATPM is developed to achieve a linear displacement response with respect to optical forces. The displacement response of the optimized ATPM is analyzed by considering the combined effects of optical force and gravity. The distribution of the optical force density is calculated based on a tilted Gaussian laser beam. Experimental results demonstrate that the optimized ATPM can produce a steady-state displacement of 24.18 nm on average in a normal-gravity environment when subjected to an average optical force of 132.17 nN. When the optical force exceeds 133 nN, the nonlinearity of the displacement response of the optimized ATPM is less than 6.28%. An amplification of the optical force-induced displacement is achieved by more than 15 times compared with that for an unstructured mirror of the same size. The results of this study can assist the development of a miniaturized macroscale optical force platform based on an ATPM for practical applications including the in-situ laser power measurement and nN level force source in the atomic and close-to-atomic scale manufacturing.

4.
Plant J ; 107(5): 1466-1477, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34174125

RESUMO

Rubus chingii Hu (Fu-Pen-Zi), a perennial woody plant in the Rosaceae family, is a characteristic traditional Chinese medicinal plant because of its unique pharmacological effects. There are abundant hydrolyzable tannin (HT) components in R. chingii that provide health benefits. Here, an R. chingii chromosome-scale genome and related functional analysis provide insights into the biosynthetic pathway of HTs. In total, sequence data of 231.21 Mb (155 scaffolds with an N50 of 8.2 Mb) were assembled into seven chromosomes with an average length of 31.4 Mb, and 33 130 protein-coding genes were predicted, 89.28% of which were functionally annotated. Evolutionary analysis showed that R. chingii was most closely related to Rubus occidentalis, from which it was predicted to have diverged 22.46 million years ago (Table S8). Comparative genomic analysis showed that there was a tandem gene cluster of UGT, carboxylesterase (CXE) and SCPL genes on chromosome 02 of R. chingii, including 11 CXE, eight UGT, and six SCPL genes, which may be critical for the synthesis of HTs. In vitro enzyme assays indicated that the proteins encoded by the CXE (LG02.4273) and UGT (LG02.4102) genes have tannin hydrolase and gallic acid glycosyltransferase functions, respectively. The genomic sequence of R. chingii will be a valuable resource for comparative genomic analysis within the Rosaceae family and will be useful for understanding the biosynthesis of HTs.


Assuntos
Vias Biossintéticas , Cromossomos de Plantas/genética , Genoma de Planta/genética , Taninos Hidrolisáveis/metabolismo , Rubus/genética , Evolução Molecular , Genômica , Família Multigênica , Rubus/metabolismo
7.
J Virol ; 94(1)2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31597771

RESUMO

Efficient human-to-human transmission is a prerequisite for a novel influenza virus to cause an influenza pandemic; however, the genetic determinants of influenza virus transmission are still not fully understood. In this study, we compared the respiratory droplet transmissibilities of four H7N9 viruses that are genetic closely related and found that these viruses have dissimilar transmissibilities in guinea pigs: A/Anhui/1/2013 (AH/1) transmitted efficiently, whereas the other three viruses did not transmit. The three nontransmissible viruses have one to eight amino acid differences compared with the AH/1 virus. To investigate which of these amino acids is important for transmission, we used reverse genetics to generate a series of reassortants and mutants in the AH/1 background and tested their transmissibility in guinea pigs. We found that the neuraminidase (NA) of the nontransmissible virus A/chicken/Shanghai/S1053/2013 had low enzymatic activity that impaired the transmission of AH/1 virus, and three amino acid mutations-V292I and K627E in PB2 and D156E in M1-independently abolished the transmission of the AH/1 virus. We further found that an NA reassortant and three single-amino-acid mutants replicated less efficiently than the AH/1 virus in A549 cells and that the amino acid at position 156 of M1 affected the morphology of H7N9 viruses. Our study identifies key amino acids in PB2 and M1 that play important roles in H7N9 influenza virus transmission and provides new insights into the transmissibility of influenza virus.IMPORTANCE Efficient transmission is a prerequisite for a novel influenza virus to cause an influenza pandemic; however, the genetic determinants of influenza virus transmission remain poorly understood. H7N9 influenza viruses, which emerged in 2013 in China, have caused over 1,560 human infection cases, showing clear pandemic potential. Previous studies have shown that the H7N9 viruses differ in their transmissibility in animal models. In this study, we found two amino acids in PB2 (292V and 627K) and one in M1 (156D) that are extremely important for H7N9 virus transmission. Of note, PB2 292V and M1 156D appear in most H7N9 viruses, and the PB2 627K mutation could easily occur when the H7N9 virus replicates in humans. Our study thus identifies new amino acids that are important for influenza virus transmission and suggests that just a few key amino acid changes can render the H7N9 virus transmissible in mammals.


Assuntos
Subtipo H7N9 do Vírus da Influenza A/genética , Neuraminidase/genética , Infecções por Orthomyxoviridae/transmissão , RNA Polimerase Dependente de RNA/genética , Vírus Reordenados/genética , Proteínas da Matriz Viral/genética , Proteínas Virais/genética , Células A549 , Substituição de Aminoácidos , Animais , Expressão Gênica , Cobaias , Humanos , Subtipo H7N9 do Vírus da Influenza A/metabolismo , Subtipo H7N9 do Vírus da Influenza A/patogenicidade , Mutação , Neuraminidase/metabolismo , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , RNA Polimerase Dependente de RNA/metabolismo , Vírus Reordenados/metabolismo , Vírus Reordenados/patogenicidade , Genética Reversa , Relação Estrutura-Atividade , Proteínas da Matriz Viral/metabolismo , Proteínas Virais/metabolismo , Replicação Viral
8.
Proc Natl Acad Sci U S A ; 113(2): 392-7, 2016 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-26711995

RESUMO

Pigs are important intermediate hosts for generating novel influenza viruses. The Eurasian avian-like H1N1 (EAH1N1) swine influenza viruses (SIVs) have circulated in pigs since 1979, and human cases associated with EAH1N1 SIVs have been reported in several countries. However, the biologic properties of EAH1N1 SIVs are largely unknown. Here, we performed extensive influenza surveillance in pigs in China and isolated 228 influenza viruses from 36,417 pigs. We found that 139 of the 228 strains from pigs in 10 provinces in China belong to the EAH1N1 lineage. These viruses formed five genotypes, with two distinct antigenic groups, represented by A/swine/Guangxi/18/2011 and A/swine/Guangdong/104/2013, both of which are antigenically and genetically distinct from the current human H1N1 viruses. Importantly, the EAH1N1 SIVs preferentially bound to human-type receptors, and 9 of the 10 tested viruses transmitted in ferrets by respiratory droplet. We found that 3.6% of children (≤10 y old), 0% of adults, and 13.4% of elderly adults (≥60 y old) had neutralization antibodies (titers ≥40 in children and ≥80 in adults) against the EAH1N1 A/swine/Guangxi/18/2011 virus, but none of them had such neutralization antibodies against the EAH1N1 A/swine/Guangdong/104/2013 virus. Our study shows the potential of EAH1N1 SIVs to transmit efficiently in humans and suggests that immediate action is needed to prevent the efficient transmission of EAH1N1 SIVs to humans.


Assuntos
Furões/genética , Furões/virologia , Vírus da Influenza A Subtipo H1N1/fisiologia , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/virologia , Adulto , Animais , Antígenos Virais/imunologia , China/epidemiologia , Evolução Molecular , Genótipo , Hemaglutininas/genética , Humanos , Imunidade , Vigilância Imunológica , Vírus da Influenza A Subtipo H1N1/patogenicidade , Pulmão/patologia , Pulmão/virologia , Camundongos , Pessoa de Meia-Idade , Infecções por Orthomyxoviridae/epidemiologia , Infecções por Orthomyxoviridae/transmissão , Prevalência , Suínos , Virulência , Replicação Viral
9.
J Virol ; 90(21): 9797-9805, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27558424

RESUMO

The H5N1 avian influenza viruses emerged in Southeast Asia in the late 20th century and have evolved into multiple phylogenetic clades based on their hemagglutinin (HA)-encoding genes. The clade 7.2 viruses were first detected in chickens in northern China in 2006, and vaccines specifically targeted to the clade were developed and have been used in poultry in China since 2006. During routine surveillance and disease diagnosis, we isolated seven H5 viruses between 2011 and 2014 that bear the clade 7.2 HA genes. Here, we performed extensive studies to understand how the clade 7.2 H5 viruses have evolved in chickens in China. Full genome sequence analysis revealed that the seven viruses formed two subtypes (four H5N1 viruses and three H5N2 viruses) and four genotypes by deriving genes from other influenza viruses. All of the viruses had antigenically drifted from the clade 7.2 viruses that were isolated in 2006. Pathogenicity studies of four viruses, one from each genotype, revealed that all of the viruses are highly pathogenic in chickens, but none of them could replicate in ducks. The four viruses exclusively bound to avian-type receptors and replicated only in the turbinates and/or lungs of mice; none of them were lethal to mice at a dosage of 106 50% egg infective doses (EID50). Our study indicates that although the clade 7.2 viruses have not been eradicated from poultry through vaccination, they have not become more dangerous to other animals (e.g., ducks and mice) and humans. IMPORTANCE: Animal influenza viruses can acquire the ability to infect and kill humans. The H5N1 viruses have been a concern in recent decades because of their clear pandemic potential. We sorted H5N1 influenza viruses into different phylogenetic clades based on their HA genes. The clade 7.2 viruses were detected in chickens in several provinces of northern China in 2006. Vaccines for these viruses were subsequently developed and have been used ever since to control infection of poultry. Here, we analyzed the genetic and biologic properties of seven clade 7.2 viruses that were isolated from chickens between 2011 and 2014. We found that after nearly 9 years of circulation in chickens, the clade 7.2 viruses still exclusively bind to avian-type receptors and are of low pathogenicity to mice, suggesting that these H5 viruses pose a low risk to human public health.


Assuntos
Virus da Influenza A Subtipo H5N1/genética , Vírus da Influenza A Subtipo H5N2/genética , Influenza Aviária/epidemiologia , Influenza Aviária/virologia , Animais , Galinhas , China/epidemiologia , Patos/virologia , Genoma Viral/genética , Genótipo , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Virus da Influenza A Subtipo H5N1/imunologia , Vírus da Influenza A Subtipo H5N2/imunologia , Vacinas contra Influenza/imunologia , Influenza Aviária/imunologia , Filogenia , Aves Domésticas , Vacinação/métodos
10.
J Virol ; 90(3): 1455-69, 2016 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-26581996

RESUMO

UNLABELLED: H4 avian influenza virus (AIV) is one of the most prevalent influenza virus subtypes in the world. However, whether H4 AIVs pose a threat to public health remains largely unclear. Here, we analyzed the phylogenetic relationships, receptor binding properties, replication, and transmissibility in mammals of H4 AIVs isolated from live poultry markets in China between 2009 and 2012. Genomic sequence analysis of 36 representative H4 viruses revealed 32 different genotypes, indicating that these viruses are undergoing complex and frequent reassortment events. All 32 viruses tested could replicate in the respiratory organs of infected mice without prior adaptation. Receptor binding analysis demonstrated that the H4 AIVs bound to α-2,6-linked glycans, although they retained the binding preference for α-2,3-linked glycans. When we tested the direct-contact transmission of 10 H4 viruses in guinea pigs, we found that three viruses did not transmit to any of the contact animals, one virus transmitted to one of three contact animals, and six viruses transmitted to all three contact animals. When we further tested the respiratory droplet transmissibility of four of the viruses that transmitted efficiently via direct contact, we found that three of them could transmit to one or two of the five exposed animals. Our study demonstrates that the current circulating H4 AIVs can infect, replicate in, and transmit to mammalian hosts, thereby posing a potential threat to human health. These findings emphasize the continual need for enhanced surveillance of H4 AIVs. IMPORTANCE: Numerous surveillance studies have documented the wide distribution of H4 AIVs throughout the world, yet the biological properties of H4 viruses have not been well studied. In this study, we found that multiple genotypes of H4 viruses are cocirculating in the live poultry markets of China and that H4 viruses can replicate in mice, possess human-type receptor binding specificity, and transmit between guinea pigs via direct contact. Strikingly, some H4 strains also can transmit via respiratory droplet, albeit with limited efficiency. These results clearly show the potential threat posed by H4 viruses to public health.


Assuntos
Vírus da Influenza A/crescimento & desenvolvimento , Vírus da Influenza A/isolamento & purificação , Influenza Aviária/virologia , Infecções por Orthomyxoviridae/veterinária , Aves Domésticas/virologia , Ligação Viral , Replicação Viral , Animais , China , Análise por Conglomerados , Feminino , Genoma Viral , Cobaias , Vírus da Influenza A/genética , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Infecções por Orthomyxoviridae/transmissão , Filogenia , RNA Viral/genética , Receptores Virais/análise , Análise de Sequência de DNA , Homologia de Sequência
11.
PLoS Pathog ; 10(11): e1004508, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25411973

RESUMO

H9N2 subtype influenza viruses have been detected in different species of wild birds and domestic poultry in many countries for several decades. Because these viruses are of low pathogenicity in poultry, their eradication is not a priority for animal disease control in many countries, which has allowed them to continue to evolve and spread. Here, we characterized the genetic variation, receptor-binding specificity, replication capability, and transmission in mammals of a series of H9N2 influenza viruses that were detected in live poultry markets in southern China between 2009 and 2013. Thirty-five viruses represented 17 genotypes on the basis of genomic diversity, and one specific "internal-gene-combination" predominated among the H9N2 viruses. This gene combination was also present in the H7N9 and H10N8 viruses that have infected humans in China. All of the 35 viruses preferentially bound to the human-like receptor, although two also retained the ability to bind to the avian-like receptor. Six of nine viruses tested were transmissible in ferrets by respiratory droplet; two were highly transmissible. Some H9N2 viruses readily acquired the 627K or 701N mutation in their PB2 gene upon infection of ferrets, further enhancing their virulence and transmission in mammals. Our study indicates that the widespread dissemination of H9N2 viruses poses a threat to human health not only because of the potential of these viruses to cause an influenza pandemic, but also because they can function as "vehicles" to deliver different subtypes of influenza viruses from avian species to humans.


Assuntos
Variação Genética , Vírus da Influenza A Subtipo H9N2 , Influenza Aviária , Influenza Humana , Animais , Sequência de Bases , Galinhas , China , Cães , Furões , Humanos , Vírus da Influenza A Subtipo H9N2/genética , Vírus da Influenza A Subtipo H9N2/isolamento & purificação , Vírus da Influenza A Subtipo H9N2/patogenicidade , Influenza Aviária/genética , Influenza Aviária/transmissão , Influenza Humana/genética , Influenza Humana/transmissão , Células Madin Darby de Rim Canino , Dados de Sequência Molecular , Doenças das Aves Domésticas/genética , Doenças das Aves Domésticas/transmissão , Doenças das Aves Domésticas/virologia
12.
Oncogene ; 43(40): 3003-3017, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39232218

RESUMO

Hepatocellular carcinoma (HCC) stands as one of the most aggressively advancing and lethal malignancies. Sorafenib is presently endorsed as a primary therapy for advanced liver cancer, but its resistance presents a formidable challenge. Previous studies have implicated a connection between post-sorafenib discontinuation rebound and the development of drug resistance, yet the underlying mechanism remains elusive. In this study, we discerned that Sorafenib induced a senescent phenotype in HCC cells and caused a cleavage of ubiquitin-binding protein p62. Mechanistic studies establish that truncated p62 drives cellular senescence by promoting proteasome-dependent degradation of 4EBP1. Furthermore, truncated p62 induced specific ubiquitination of 4EBP1. Crucially, virtual drug screening uncovered that dacinostat inhibited cellular senescence by blocking sorafenib-induced p62 cleavage. In summary, our findings imply that truncated p62 from sorafenib cleavage promotes senescence via 4EBP1 degradation. The prevention of p62 cleavage could emerge as a crucial strategy for impeding the sorafenib-induced cellular senescence.


Assuntos
Carcinoma Hepatocelular , Senescência Celular , Neoplasias Hepáticas , Sorafenibe , Sorafenibe/farmacologia , Humanos , Senescência Celular/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linhagem Celular Tumoral , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteína Sequestossoma-1/metabolismo , Proteína Sequestossoma-1/genética , Fosfoproteínas/metabolismo , Camundongos , Animais , Proteólise/efeitos dos fármacos , Ubiquitinação/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Ligação a RNA
13.
Redox Biol ; 75: 103277, 2024 09.
Artigo em Inglês | MEDLINE | ID: mdl-39059206

RESUMO

Sepsis is a common complication of infections that significantly impacts the survival of critically patients. Currently, effective pharmacological treatment strategies are lacking. Auranofin, known as an inhibitor of Thioredoxin reductase (TrxR), exhibits anti-inflammatory activity, but its role in sepsis is not well understood. Here, we demonstrate the significant inhibitory effect of Auranofin on sepsis in a cecal ligation and puncture (CLP) mouse model. In vitro, Auranofin inhibits pyroptosis triggered by Caspase-11 activation. Further investigations reveal that inhibiting TrxR1 suppresses macrophage pyroptosis induced by E. coli, while TrxR2 does not exhibit this effect. TrxR1, functioning as a reductase, regulates the oxidative-reductive status of Thioredoxin-1 (Trx-1). Mechanistically, the modulation of Trx-1's reductive activity by TrxR1 may be involved in Caspase-11 activation-induced pyroptosis. Additionally, inhibiting TrxR1 maintains Trx-1 in its oxidized state. The oxidized form of Trx-1 interacts with Caveolin-1 (CAV1), regulating outer membrane vesicle (OMV) internalization. In summary, our study suggests that inhibiting TrxR1 suppresses OMV internalization by maintaining the oxidized form of Trx-1, thereby restricting Caspase-11 activation and alleviating sepsis.


Assuntos
Auranofina , Oxirredução , Piroptose , Sepse , Tiorredoxinas , Tiorredoxinas/metabolismo , Tiorredoxinas/genética , Animais , Camundongos , Oxirredução/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Auranofina/farmacologia , Sepse/metabolismo , Humanos , Caspases Iniciadoras/metabolismo , Tiorredoxina Redutase 1/metabolismo , Tiorredoxina Redutase 1/genética , Modelos Animais de Doenças , Masculino , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos
14.
Acta Pharm Sin B ; 14(4): 1677-1692, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38572095

RESUMO

Chemotherapy-induced mucositis represents a severe adverse outcome of cancer treatment, significantly curtailing the efficacy of these treatments and, in some cases, resulting in fatal consequences. Despite identifying intestinal epithelial cell damage as a key factor in chemotherapy-induced mucositis, the paucity of effective treatments for such damage is evident. In our study, we discovered that Eubacterium coprostanoligenes promotes mucin secretion by goblet cells, thereby fortifying the integrity of the intestinal mucus barrier. This enhanced barrier function serves to resist microbial invasion and subsequently reduces the inflammatory response. Importantly, this effect remains unobtrusive to the anti-tumor efficacy of chemotherapy drugs. Mechanistically, E. copr up-regulates the expression of AUF1, leading to the stabilization of Muc2 mRNA and an increase in mucin synthesis in goblet cells. An especially significant finding is that E. copr activates the AhR pathway, thereby promoting the expression of AUF1. In summary, our results strongly indicate that E. copr enhances the intestinal mucus barrier, effectively alleviating chemotherapy-induced intestinal mucositis by activating the AhR/AUF1 pathway, consequently enhancing Muc2 mRNA stability.

15.
EBioMedicine ; 101: 105034, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38408394

RESUMO

BACKGROUND: In 2022 and 2023, novel reassortant H3N8 influenza viruses infected three people, marking the first human infections with viruses of this subtype. METHODS: Here, we generated one of these viruses (A/Henan/4-10CNIC/2022; hereafter called A/Henan/2022 virus) by using reverse genetics and characterized it. FINDINGS: In intranasally infected mice, reverse genetics-generated A/Henan/2022 virus caused weight loss in all five animals (one of which had to be euthanized) and replicated efficiently in the respiratory tract. Intranasal infection of ferrets resulted in minor weight loss and moderate fever but no mortality. Reverse genetics-generated A/Henan/2022 virus replicated efficiently in the upper respiratory tract of ferrets but was not detected in the lungs. Virus transmission via respiratory droplets occurred in one of four pairs of ferrets. Deep-sequencing of nasal swab samples from inoculated and exposed ferrets revealed sequence polymorphisms in the haemagglutinin protein that may affect receptor-binding specificity. We also tested 90 human sera for neutralizing antibodies against reverse genetics-generated A/Henan/2022 virus and found that some of them possessed neutralizing antibody titres, especially sera from older donors with likely exposure to earlier human H3N2 viruses. INTERPRETATION: Our data demonstrate that reverse genetics-generated A/Henan/2022 virus is a low pathogenic influenza virus (of avian influenza virus descent) with some antigenic resemblance to older human H3N2 viruses and limited respiratory droplet transmissibility in ferrets. FUNDING: This work was supported by the Japan Program for Infectious Diseases Research and Infrastructure (JP23wm0125002), and the Japan Initiative for World-leading Vaccine Research and Development Centers (JP233fa627001) from the Japan Agency for Medical Research and Development (AMED).


Assuntos
Vírus da Influenza A Subtipo H3N8 , Influenza Humana , Infecções por Orthomyxoviridae , Humanos , Animais , Camundongos , Vírus da Influenza A Subtipo H3N2/genética , Furões , Pulmão/patologia , Redução de Peso
16.
Vaccine ; 42(24): 126269, 2024 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-39241354

RESUMO

Recombinant influenza virus neuraminidase (NA) is a promising broadly protective influenza vaccine candidate. However, the recombinant protein alone is not sufficient to induce durable and protective immune responses and requires the coadministration of immunostimulatory molecules. Here, we evaluated the immunogenicity and cross-protective potential of a recombinant influenza virus N2 neuraminidase vaccine construct, adjuvanted with a toll-like receptor 9 (TLR9) agonist (CpG 1018® adjuvant), and alum. The combination of CpG 1018 adjuvant and alum induced a balanced and robust humoral and T-cellular immune response against the NA, which provided protection and reduced morbidity against homologous and heterologous viral challenges in mouse and hamster models. This study supports Syrian hamsters as a useful complementary animal model to mice for pre-clinical evaluation of influenza virus vaccines.


Assuntos
Adjuvantes Imunológicos , Anticorpos Antivirais , Vacinas contra Influenza , Neuraminidase , Infecções por Orthomyxoviridae , Animais , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Neuraminidase/imunologia , Neuraminidase/genética , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/imunologia , Camundongos , Adjuvantes Imunológicos/administração & dosagem , Feminino , Cricetinae , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/administração & dosagem , Adjuvantes de Vacinas , Camundongos Endogâmicos BALB C , Proteção Cruzada/imunologia , Mesocricetus , Oligodesoxirribonucleotídeos/administração & dosagem , Oligodesoxirribonucleotídeos/imunologia , Compostos de Alúmen/administração & dosagem , Modelos Animais de Doenças , Imunidade Celular
17.
EBioMedicine ; 103: 105103, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38574407

RESUMO

BACKGROUND: World Health Organisation (WHO) and USA Centers for Disease Control and Prevention (U.S. CDC) recommendations now allow simultaneous administration of COVID-19 and other vaccines. We compared antibody responses after coadministration of influenza and bivalent COVID-19 vaccines in the same (ipsilateral) arm vs. different (contralateral) arms. METHODS: Pre- and post-vaccination serum samples from individuals in the Prospective Assessment of COVID-19 in a Community (PACC) cohort were used to conduct haemaglutination inhibition (HI) assays with the viruses in the 2022-2023 seasonal influenza vaccine and focus reduction neutralisation tests (FRNT) using a BA.5 SARS-CoV-2 virus. The effect of ipsilateral vs. contralateral vaccination on immune responses was inferred in a model that accounted for higher variance in vaccine responses at lower pre-vaccination titers. FINDINGS: Ipsilateral vaccination did not cause higher influenza vaccine responses compared to contralateral vaccination. The response to SARS-CoV-2 was slightly increased in the ipsilateral group, but equivalence was not excluded. INTERPRETATION: Coadministration of influenza and bivalent COVID-19 vaccines in the same arm or different arms did not strongly influence the antibody response to either vaccine. FUNDING: This work was supported by the U.S. CDC (grant number: 75D30120C09259).


Assuntos
Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Vacinas contra Influenza , Influenza Humana , SARS-CoV-2 , Humanos , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , COVID-19/imunologia , SARS-CoV-2/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Influenza Humana/prevenção & controle , Influenza Humana/imunologia , Adulto , Formação de Anticorpos/imunologia , Vacinação/métodos , Idoso , Estudos Prospectivos , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia
18.
Br J Pharmacol ; 180(8): 1072-1089, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36455594

RESUMO

BACKGROUND AND PURPOSE: Liver fibrosis is a critical risk factor for the progression from chronic liver injury to hepatocellular carcinoma. Clinically, there is a lack of therapeutic drugs for liver fibrosis. Previous studies have confirmed that GL-V9, a newly synthesized flavonoid derivative, exhibits anti-inflammatory activity, but whether it has anti-hepatic fibrosis actions remains unclear. This study aimed to investigate the anti-fibrotic activities and potential mechanisms of GL-V9. EXPERIMENTAL APPROACH: Bile duct ligation (BDL) and carbon tetrachloride (CCl4 ) challenges were used to assess the anti-fibrotic effects of GL-V9 in vivo. Mouse primary hepatic stellate cells (pHSCs) and the human HSC line LX2 also served as a liver fibrosis model in vitro. Cellular functions and molecular mechanism were analysed using senescence-associated beta-galactosidase staining, real-time PCR, western blotting, immunofluorescence, and co-immunoprecipitation. KEY RESULTS: GL-V9 attenuated hepatic histopathological injury and collagen accumulation, as well as decreasing the expression of fibrotic genes in vivo. GL-V9 promoted senescence and inhibited the expression of fibrogenic genes in HSCs in vitro. Mechanistic studies revealed that GL-V9 induced senescence by upregulating GATA4 expression in HSCs. Further studies confirmed that GL-V9 stabilized GATA4 by promoting autophagic degradation of P62. CONCLUSION AND IMPLICATIONS: GL-V9 exerted potent anti-fibrotic effects both in vivo and in vitro by stabilizing GATA4, thereby promoting the senescence of HSCs, and by avoiding its activation and ultimately inhibiting liver fibrosis. This action indicated that the flavonoid GL-V9 is a potential therapeutic candidate for the treatment of liver fibrosis.


Assuntos
Flavonoides , Células Estreladas do Fígado , Camundongos , Animais , Humanos , Flavonoides/farmacologia , Fator de Transcrição GATA4/metabolismo , Fator de Transcrição GATA4/farmacologia , Cirrose Hepática/metabolismo , Fígado/metabolismo , Fibrose
19.
Front Plant Sci ; 14: 1134993, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36968391

RESUMO

Rubus chingii Hu is a berry plant of the genus Rubus of the Rosaceae family, which has high nutritional and medicinal value and is rich in flavonoids. Flavonol synthase (FLS) and dihydroflavonol 4-reductase (DFR) compete for the common substrate dihydroflavonols to regulate the metabolic flux of flavonoids. However, the competition between FLS and DFR based on enzyme is rarely reported. Here, we isolated and identified two FLS genes (RcFLS1 and RcFLS2) and one DFR gene (RcDFR) from Rubus chingii Hu. RcFLSs and RcDFR were highly expressed in stems, leaves, and flowers, although the flavonol accumulation in these organs was significantly higher than that of proanthocyanidins (PAs). The recombinant RcFLSs demonstrated bifunctional activities via hydroxylation and desaturation at the C-3α position having a lower Michaelis constant (Km) for dihydroflavonols than RcDFR. We also found that a low concentration of flavonols could significantly inhibit RcDFR activity. To investigate the competitive relationship between RcFLSs and RcDFR, we used a prokaryotic expression system (E. coli) to co-express these proteins. The transgenic cells expressing recombinant proteins were incubated with substrates, and the reaction products were analyzed. Furthermore, two transient expression systems (tobacco leaves and strawberry fruits) and a stable genetic system (Arabidopsis thaliana) were used to co-express these proteins in vivo. The results showed that RcFLS1 was dominant in the competition with RcDFR. Our results demonstrated that the competition between FLS and DFR regulated the metabolic flux distribution of flavonols and PAs, which will be of great significance for the molecular breeding of Rubus plants.

20.
Viruses ; 15(5)2023 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-37243179

RESUMO

Routine surveillance in live poultry markets in the northern regions of Vietnam from 2016 to 2017 resulted in the isolation of 27 highly pathogenic avian H5N1 and H5N6 viruses of 3 different clades (2.3.2.1c, 2.3.4.4f, and 2.3.4.4g). Sequence and phylogenetic analysis of these viruses revealed reassortment with various subtypes of low pathogenic avian influenza viruses. Deep-sequencing identified minor viral subpopulations encoding variants that may affect pathogenicity and sensitivity to antiviral drugs. Interestingly, mice infected with two different clade 2.3.2.1c viruses lost body weight rapidly and succumbed to virus infection, whereas mice infected with clade 2.3.4.4f or 2.3.4.4g viruses experienced non-lethal infections.


Assuntos
Virus da Influenza A Subtipo H5N1 , Influenza Aviária , Animais , Camundongos , Galinhas/virologia , Influenza Aviária/epidemiologia , Filogenia , Aves Domésticas/virologia , Vietnã/epidemiologia
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