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1.
Mol Cell ; 78(5): 850-861.e5, 2020 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-32348779

RESUMEN

Cas13 has demonstrated unique and broad utility in RNA editing, nucleic acid detection, and disease diagnosis; however, a constantly active Cas enzyme may induce unwanted effects. Bacteriophage- or prophage-region-encoded anti-CRISPR (acr) gene molecules provide the potential to control targeting specificity and potency to allow for optimal RNA editing and nucleic acid detection by spatiotemporally modulating endonuclease activities. Using integrated approaches to screen acrVI candidates and evaluate their effects on Cas13 function, we discovered a series of acrVIA1-7 genes that block the activities of Cas13a. These VI-A CRISPR inhibitors substantially attenuate RNA targeting and editing by Cas13a in human cells. Strikingly, type VI-A anti-CRISPRs (AcrVIAs) also significantly muffle the single-nucleic-acid editing ability of the dCas13a RNA-editing system. Mechanistically, AcrVIA1, -4, -5, and -6 bind LwaCas13a, while AcrVIA2 and -3 can only bind the LwaCas13-crRNA (CRISPR RNA) complex. These identified acr molecules may enable precise RNA editing in Cas13-based application and study of phage-bacterium interaction.


Asunto(s)
Proteínas Asociadas a CRISPR/antagonistas & inhibidores , Sistemas CRISPR-Cas/fisiología , Edición de ARN/fisiología , Animales , Bacterias/genética , Bacteriófagos/genética , Proteínas Asociadas a CRISPR/genética , Sistemas CRISPR-Cas/genética , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Edición Génica , Células HEK293 , Humanos , Leptotrichia/genética , Leptotrichia/metabolismo , ARN/genética , Edición de ARN/genética
2.
Proc Natl Acad Sci U S A ; 119(11): e2121180119, 2022 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-35254905

RESUMEN

SignificanceIn a polymicrobial battlefield where different species compete for nutrients and colonization niches, antimicrobial compounds are the sword and shield of commensal microbes in competition with invading pathogens and each other. The identification of an Escherichia coli-produced genotoxin, colibactin, and its specific targeted killing of enteric pathogens and commensals, including Vibrio cholerae and Bacteroides fragilis, sheds light on our understanding of intermicrobial interactions in the mammalian gut. Our findings elucidate the mechanisms through which genotoxins shape microbial communities and provide a platform for probing the larger role of enteric multibacterial interactions regarding infection and disease outcomes.


Asunto(s)
Cólera/microbiología , Microbioma Gastrointestinal , Interacciones Huésped-Patógeno , Interacciones Microbianas , Mutágenos/metabolismo , Vibrio cholerae/fisiología , Animales , Antibiosis , Cólera/mortalidad , Daño del ADN , Modelos Animales de Enfermedad , Escherichia coli/fisiología , Humanos , Ratones , Péptidos/metabolismo , Péptidos/farmacología , Policétidos/metabolismo , Policétidos/farmacología , Pronóstico , Especies Reactivas de Oxígeno , Vibrio cholerae/efectos de los fármacos
3.
PLoS Pathog ; 18(6): e1010581, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35714156

RESUMEN

Vibrio cholerae is the etiologic agent of the severe human diarrheal disease cholera. To colonize mammalian hosts, this pathogen must defend against host-derived toxic compounds, such as nitric oxide (NO) and NO-derived reactive nitrogen species (RNS). RNS can covalently add an NO group to a reactive cysteine thiol on target proteins, a process called protein S-nitrosylation, which may affect bacterial stress responses. To better understand how V. cholerae regulates nitrosative stress responses, we profiled V. cholerae protein S-nitrosylation during RNS exposure. We identified an S-nitrosylation of cysteine 235 of AphB, a LysR-family transcription regulator that activates the expression of tcpP, which activates downstream virulence genes. Previous studies show that AphB C235 is sensitive to O2 and reactive oxygen species (ROS). Under microaerobic conditions, AphB formed dimer and directly repressed transcription of hmpA, encoding a flavohemoglobin that is important for NO resistance of V. cholerae. We found that tight regulation of hmpA by AphB under low nitrosative stress was important for V. cholerae optimal growth. In the presence of NO, S-nitrosylation of AphB abolished AphB activity, therefore relieved hmpA expression. Indeed, non-modifiable aphBC235S mutants were sensitive to RNS in vitro and drastically reduced colonization of the RNS-rich mouse small intestine. Finally, AphB S-nitrosylation also decreased virulence gene expression via debilitation of tcpP activation, and this regulation was also important for V. cholerae RNS resistance in vitro and in the gut. These results suggest that the modulation of the activity of virulence gene activator AphB via NO-dependent protein S-nitrosylation is critical for V. cholerae RNS resistance and colonization.


Asunto(s)
Vibrio cholerae , Animales , Proteínas Bacterianas/metabolismo , Cisteína/metabolismo , Regulación Bacteriana de la Expresión Génica , Hempa/metabolismo , Mamíferos , Ratones , Regiones Promotoras Genéticas , Transactivadores/genética , Virulencia/genética
4.
Virol J ; 21(1): 179, 2024 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-39107822

RESUMEN

BACKGROUND: Epstein-Barr virus (EBV) can be reactivated and proliferated with fatal outcome in immuno-compromised people, but the clinical consequences of EBV infection in patients with severe fever with thrombocytopenia syndrome (SFTS) remain uncertain. In this study, we investigated the infection rate, the influence and the early predictors of EBV infection in SFTS patients. METHODS: In this retrospective study, SFTS patients who were treated in the First Affiliated Hospital of Nanjing Medical University from May 2011 to August 2021 were enrolled and divided into infected and non-infected groups. We compared the demographic characteristics, clinical manifestations and signs, laboratory tests and prognosis, and explored the risk factors of EBV infection by receiver operating characteristic (ROC) curve and logistic regression. RESULTS: A total of 120 hospitalized SFTS patients with EBV-DNA testing were enrolled in this study. Patients with EBV infection had statistically significant higher mortality rate (32.0% vs. 11.43%, P = 0.005). Compared with the non-infected group, the EBV-infected group had higher levels of C-reactive protein (CRP), creatine-kinase (CK), fasting blood glucose (FBG), blood urea nitrogen (BUN), D-dimer, and CD56+ cell counts, lower levels of immunoglobulin G (IgG), IgM, complement 3 (C3), and C4. The proportion of patients with age ≥ 60 years and ferritin > 1500.0 ng/ml in the EBV-infected group was significantly higher than that in the non-infected group. The results of ROC analysis showed that the cut-off values of CRP, IgG, C3, C4, and CD56+ cell counts to predict EBV infection were 13.2 mg/l, 12.5 g/l, 1.1 g/l, 0.6 g/l, 0.3 g/l, and 94.0 cells/µl. Multivariable logistic analysis showed that age ≥ 60 years old, CRP > 13.2 mg/l, BUN > 5.4 mmol/l, ferritin > 1500.0 ng/ml, IgG < 12.5 g/l, IgM < 1.1 g/l, C4 < 0.3 g/l, and CD56+ cell counts > 94.0 cells/µl were the independent risk factors of EBV infection in SFTS patients. CONCLUSIONS: SFTS combined with EBV infection is associated with high morbidity and mortality. It is necessary to strengthen screening for EBV infection and its early predictive markers after admission in SFTS patients.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Síndrome de Trombocitopenia Febril Grave , Humanos , Masculino , Femenino , Persona de Mediana Edad , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/virología , Estudios Retrospectivos , Síndrome de Trombocitopenia Febril Grave/virología , Síndrome de Trombocitopenia Febril Grave/sangre , Síndrome de Trombocitopenia Febril Grave/diagnóstico , Anciano , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Factores de Riesgo , Pronóstico , Adulto , Curva ROC , China/epidemiología , Anticuerpos Antivirales/sangre , ADN Viral/sangre
5.
BMC Infect Dis ; 24(1): 1018, 2024 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-39304813

RESUMEN

BACKGROUND: Cryptococcosis is progressively acknowledged among people, irrespective of the human with or without immunodeficiency virus (HIV). This change in epidemiology has been recorded in recent years, prompting closer examination and a broader understanding of the disease manifestations and risk factors. METHODS: The data of cryptococcal infections in China during 11 years were retrospectively analyzed. According to the position of infection, the patients were categorized into the pulmonary infection group and extrapulmonary infection group. The composition of the two groups was compared, and the potential risk factors of disseminated infection were analyzed. Logistic regression was used to analyze the prognostic risk factors of the disease. RESULTS: A total of 165 patients were enrolled. 113 (68.5%) were male, and the age was 47.49 (18-82) years. 101 cases (61.2%) had a normal immune function and 64 cases (38.8%) had impaired immune function. 45 patients had extrapulmonary infection, involving the central nervous system, bone and joint, skin and bloodstream, and 120 patients had simple pulmonary infection. The mortality of the extrapulmonary infection group (48.9%) was significantly higher than that of the pulmonary infection group (0.8%). According to univariate logistic regression analysis, immune status (hazard ratio [HR], 4.476; 95% confidence interval [CI], 1.725-11.618; P = 0.002), infection position ([HR], 113.826; [CI], 14.607-886.967; P < 0.001), white blood cell count, ([HR],1.209;[CI], 1.054-1.386; P = 0.007), hemoglobin ([HR], 0.970; [CI], 0.955-0.986; P < 0.001), platelet count ([HR], 0.993; [CI], 0.987-0.999; P = 0.026), neutrophil percentage ([HR], 1.115; [CI], 1.065-1.168; P < 0.001), lymphocyte percentage ([HR], 0.875; [CI], 0.827-0.927; P < 0.001), neutrophil-to-lymphocyte Ratio (NLR) ([HR], 1.144; [CI], 1.072-1.221; P < 0.001), monocyte percentage ([HR], 0.752; [CI], 0.618-0.915; P = 0.004) were related to the prognosis. Multivariate logistic regression analysis showed that the infection position was remained related to the prognosis with statistical significance ([HR], 0.018; [CI], 0.001-0.384; P = 0.001). CONCLUSION: Extrapulmonary infection of Cryptococcosis is an important risk factor for prognosis. High levels of neutrophils and NLR, and low levels of lymphocytes and monocytes may lead to disseminated infection of Cryptococcosis. Further studies are needed to reduce the occurrence rate of extrapulmonary infection and mortality.


Asunto(s)
Criptococosis , Enfermedades Pulmonares Fúngicas , Humanos , Criptococosis/epidemiología , Criptococosis/mortalidad , Masculino , Persona de Mediana Edad , Femenino , Adulto , Anciano , Pronóstico , Adolescente , Estudios Retrospectivos , Adulto Joven , China/epidemiología , Anciano de 80 o más Años , Factores de Riesgo , Enfermedades Pulmonares Fúngicas/epidemiología , Enfermedades Pulmonares Fúngicas/mortalidad , Enfermedades Pulmonares Fúngicas/microbiología
6.
Nucleic Acids Res ; 50(8): e47, 2022 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-35166837

RESUMEN

Gene-editing technologies, including the widespread usage of CRISPR endonucleases, have the potential for clinical treatments of various human diseases. Due to the rapid mutations of SARS-CoV-2, specific and effective prevention and treatment by CRISPR toolkits for coronavirus disease 2019 (COVID-19) are urgently needed to control the current pandemic spread. Here, we designed Type III CRISPR endonuclease antivirals for coronaviruses (TEAR-CoV) as a therapeutic to combat SARS-CoV-2 infection. We provided a proof of principle demonstration that TEAR-CoV-based RNA engineering approach leads to RNA-guided transcript degradation both in vitro and in eukaryotic cells, which could be used to broadly target RNA viruses. We report that TEAR-CoV not only cleaves SARS-CoV-2 genome and mRNA transcripts, but also degrades live influenza A virus (IAV), impeding viral replication in cells and in mice. Moreover, bioinformatics screening of gRNAs along RNA sequences reveals that a group of five gRNAs (hCoV-gRNAs) could potentially target 99.98% of human coronaviruses. TEAR-CoV also exerted specific targeting and cleavage of common human coronaviruses. The fast design and broad targeting of TEAR-CoV may represent a versatile antiviral approach for SARS-CoV-2 or potentially other emerging human coronaviruses.


Asunto(s)
COVID-19 , SARS-CoV-2 , Animales , Antivirales , COVID-19/terapia , Humanos , Ratones , Pandemias/prevención & control , Edición de ARN/genética , ARN Guía de Kinetoplastida/genética , SARS-CoV-2/genética
7.
J Bacteriol ; 205(6): e0013323, 2023 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-37195186

RESUMEN

The increasing prevalence of drug-resistant bacteria has significantly diminished the effectiveness of antibiotics in clinical settings, leading to the emergence of untreatable bacterial infections. To address this public health challenge, the gut microbiome represents a promising source of novel antimicrobial therapeutics. In this study, we screened mouse intestinal isolates for growth inhibitory activity against the human enteric pathogen Vibrio cholerae and identified a strain of spore-forming Bacillus velezensis, named BVM7, that produced a potent antibiotic with activity against V. cholerae and a broad spectrum of enteric and opportunistic pathogens. Characterization of the antimicrobial compounds produced by BVM7 revealed that they were primarily secreted antimicrobial peptides (AMPs) produced during stationary-phase growth. Furthermore, our results showed that introducing either BVM7 vegetative cells or spores into mice precolonized with V. cholerae or Enterococcus faecalis significantly reduced the burden of infection. Interestingly, we also observed that BVM7 was sensitive to a group of Lactobacillus probiotic strains and that inoculation of Lactobacilli could eliminate BVM7 and potentially restore the native gut microbiome. These findings highlight the potential of bacteria from the gut microbiome as a source for novel antimicrobial compounds and a tool for managing bacterial infections by in situ bio-delivery of multiple AMPs. IMPORTANCE The rise of antibiotic-resistant pathogens poses a challenge to public health. The gut microbiome presents a promising source of new antimicrobials and treatments. By screening murine gut commensals, we found a spore-forming Bacillus velezensis strain, BVM7, that exhibited antimicrobial activity toward a wide array of enteric and opportunistic bacterial pathogens. In addition to showing that this killing effect occurred through the action of secreted antimicrobial peptides (AMPs), we demonstrate that BVM7 vegetative cells and spores can be used to treat infections of both Gram-positive and Gram-negative pathogens in vivo. By expanding our knowledge of the antimicrobial properties of bacteria in the gut microbiome, we hope to contribute insights for developing novel drugs and therapeutic interventions.


Asunto(s)
Antiinfecciosos , Bacillus , Vibrio cholerae , Humanos , Animales , Ratones , Antibacterianos/farmacología , Bacterias , Péptidos Antimicrobianos
8.
J Immunol ; 207(1): 257-267, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-34135060

RESUMEN

Gut microbiota is increasingly linked to the development of various pulmonary diseases through a gut-lung axis. However, the mechanisms by which gut commensal microbes impact trafficking and functional transition of immune cells remain largely unknown. Using integrated microbiota dysbiosis approaches, we uncover that the gut microbiota directs the migration of group 2 innate lymphoid cells (ILC2s) from the gut to the lung through a gut-lung axis. We identify Proteobacteria as a critical species in the gut microbiome to facilitate natural ILC2 migration, and increased Proteobacteria induces IL-33 production. Mechanistically, IL-33-CXCL16 signaling promotes the natural ILC2 accumulation in the lung, whereas IL-25-CCL25 signals augment inflammatory ILC2 accumulation in the intestines upon abdominal infection, parabiosis, and cecum ligation and puncture in mice. We reveal that these two types of ILC2s play critical but distinct roles in regulating inflammation, leading to balanced host defense against infection. Overall results delineate that Proteobacteria in gut microbiota modulates ILC2 directional migration to the lung for host defense via regulation of select cytokines (IL-33), suggesting novel therapeutic strategies to control infectious diseases.


Asunto(s)
Microbioma Gastrointestinal/inmunología , Inmunidad Innata/inmunología , Inflamación/inmunología , Pulmón/inmunología , Linfocitos/inmunología , Animales , Femenino , Ratones , Ratones Endogámicos C57BL
9.
Immunology ; 166(3): 408-423, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35420160

RESUMEN

Cyclic GMP-AMP synthase (cGAS) is essential for fighting against viruses and bacteria, but how cGAS is involved in host immune response remains largely elusive. Here, we uncover the crucial role of cGAS in host immunity based on a Pseudomonas aeruginosa pulmonary infection model. cGAS-/- mice showed more heavy bacterial burdens and serious lung injury accompanied with exorbitant proinflammatory cytokines than wild-type mice. cGAS deficiency caused an accumulation of mitochondrial DNA in the cytoplasm, which, in turn, induced excessive secretion of proinflammatory factors by activating inflammasome and TLR9 signalling. Mechanistically, cGAS deficiency inhibited the recruitment of LC3 by reducing the binding capacity of TBK-1 to p62, leading to impaired mitophagy and augmented release of mitochondrial DNA. Importantly, cytoplasmic mitochondrial DNA also acted as a feedback signal that induced the activation of cGAS. Altogether, these findings identify protective and homeostasis functions of cGAS against Pseudomonas aeruginosa infection, adding significant insight into the pathogenesis of bacterial infectious diseases.


Asunto(s)
ADN Mitocondrial , Nucleotidiltransferasas/metabolismo , Infecciones por Pseudomonas , Animales , Citocinas/metabolismo , ADN Mitocondrial/genética , Inmunidad Innata , Ratones , Nucleotidiltransferasas/genética , Pseudomonas/genética , Pseudomonas/metabolismo
10.
J Immunol ; 205(8): 2231-2242, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-32929043

RESUMEN

The DNA repair enzyme 8-oxoguanine DNA glycosylase 1 (OGG1), which excises 8-oxo-7,8-dihydroguanine lesions induced in DNA by reactive oxygen species, has been linked to the pathogenesis of lung diseases associated with bacterial infections. A recently developed small molecule, SU0268, has demonstrated selective inhibition of OGG1 activity; however, its role in attenuating inflammatory responses has not been tested. In this study, we report that SU0268 has a favorable effect on bacterial infection both in mouse alveolar macrophages (MH-S cells) and in C57BL/6 wild-type mice by suppressing inflammatory responses, particularly promoting type I IFN responses. SU0268 inhibited proinflammatory responses during Pseudomonas aeruginosa (PA14) infection, which is mediated by the KRAS-ERK1-NF-κB signaling pathway. Furthermore, SU0268 induces the release of type I IFN by the mitochondrial DNA-cGAS-STING-IRF3-IFN-ß axis, which decreases bacterial loads and halts disease progression. Collectively, our results demonstrate that the small-molecule inhibitor of OGG1 (SU0268) can attenuate excessive inflammation and improve mouse survival rates during PA14 infection. This strong anti-inflammatory feature may render the inhibitor as an alternative treatment for controlling severe inflammatory responses to bacterial infection.


Asunto(s)
ADN Glicosilasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Macrófagos/inmunología , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/inmunología , Animales , ADN Glicosilasas/inmunología , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Sistema de Señalización de MAP Quinasas/inmunología , Macrófagos/microbiología , Macrófagos/patología , Ratones , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/patología
11.
PLoS Pathog ; 15(12): e1008198, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31790504

RESUMEN

The type VI secretion system (T6SS) is widely distributed in Gram-negative bacteria, whose function is known to translocate substrates to eukaryotic and prokaryotic target cells to cause host damage or as a weapon for interbacterial competition. Pseudomonas aeruginosa encodes three distinct T6SS clusters (H1-, H2-, and H3-T6SS). The H1-T6SS-dependent substrates have been identified and well characterized; however, only limited information is available for the H2- and H3-T6SSs since relatively fewer substrates for them have yet been established. Here, we obtained P. aeruginosa H2-T6SS-dependent secretomes and further characterized the H2-T6SS-dependent copper (Cu2+)-binding effector azurin (Azu). Our data showed that both azu and H2-T6SS were repressed by CueR and were induced by low concentrations of Cu2+. We also identified the Azu-interacting partner OprC, a Cu2+-specific TonB-dependent outer membrane transporter. Similar to H2-T6SS genes and azu, expression of oprC was directly regulated by CueR and was induced by low Cu2+. In addition, the Azu-OprC-mediated Cu2+ transport system is critical for P. aeruginosa cells in bacterial competition and virulence. Our findings provide insights for understanding the diverse functions of T6SSs and the role of metal ions for P. aeruginosa in bacteria-bacteria competition.


Asunto(s)
Proteínas Bacterianas/metabolismo , Cobre/metabolismo , Proteínas de Unión al ADN/metabolismo , Pseudomonas aeruginosa/patogenicidad , Sistemas de Secreción Tipo VI/metabolismo , Virulencia/fisiología , Animales , Ratones , Infecciones por Pseudomonas/metabolismo , Pseudomonas aeruginosa/metabolismo
12.
Adv Exp Med Biol ; 1303: 333-350, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33788201

RESUMEN

Acute and chronic lung inflammation is a risk factor for various diseases involving lungs and extrapulmonary organs. Intercellular and interorgan networks, including crosstalk between lung and brain, intestine, heart, liver, and kidney, coordinate host immunity against infection, protect tissue, and maintain homeostasis. However, this interaction may be counterproductive and cause acute or chronic comorbidities due to dysregulated inflammation in the lung. In this chapter, we review the relationship of the lung with other key organs during normal cell processes and disease development. We focus on how pneumonia may lead to a systemic pathophysiological response to acute lung injury and chronic lung disease through organ interactions, which can facilitate the development of undesirable and even deleterious extrapulmonary sequelae.


Asunto(s)
Lesión Pulmonar Aguda , Neumonía , Humanos , Inflamación , Hígado , Pulmón
13.
FASEB J ; 33(1): 1074-1085, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30067380

RESUMEN

Airway remodeling with progressive epithelial alterations in the respiratory tract is a severe consequence of asthma. Although dysfunctional signaling transduction is attributed to airway inflammation, the exact mechanism of airway remodeling remains largely unknown. TRPC1, a member of the transient receptor potential canonical Ca2+ channel family, possesses versatile functions but its role in airway remodeling remains undefined. Here, we show that ablation of TRPC1 in mice alleviates airway remodeling following house dust mite (HDM) challenge with decreases in mucus production, cytokine secretion, and collagen deposition. HDM challenge induces Ca2+ influx via the TRPC1 channel, resulting in increased levels of signal transducer and activator of transcription 3 (STAT3) and proinflammatory cytokines. In contrast, STAT3 expression was significantly decreased in TRPC1-/- mouse lungs compared with wild-type controls after HDM challenge. Mechanistically, STAT3 promotes epithelial-to-mesenchymal transition and increases mucin 5AC expression. Collectively, these findings identify TRPC1 as a modulator of HDM-induced airway remodeling via STAT3-mediated increase in mucus production, which provide new insight in our understanding of the molecular basis of airway remodeling, and identify novel therapeutic targets for intervention of severe chronic asthma.-Pu, Q., Zhao, Y., Sun, Y., Huang, T., Lin, P., Zhou, C., Qin, S., Singh, B. B., Wu, M. TRPC1 intensifies house dust mite-induced airway remodeling by facilitating epithelial-to-mesenchymal transition and STAT3/NF-κB signaling.


Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/fisiología , Transición Epitelial-Mesenquimal/fisiología , FN-kappa B/metabolismo , Pyroglyphidae , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Canales Catiónicos TRPC/fisiología , Animales , Bronquios/metabolismo , Calcio/metabolismo , Colágeno/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Células Epiteliales/metabolismo , Hipersensibilidad/fisiopatología , Inflamación/metabolismo , Transporte Iónico , Ratones , Ratones Noqueados , Moco , Canales Catiónicos TRPC/genética
14.
J Immunol ; 198(7): 2844-2853, 2017 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-28202616

RESUMEN

Oxygen is supplied as a supportive treatment for patients suffering from acute respiratory distress syndrome. Unfortunately, high oxygen concentration increases reactive oxygen species generation, which causes DNA damage and ultimately cell death in the lung. Although 8-oxoguanine-DNA glycosylase (OGG-1) is involved in repairing hyperoxia-mediated DNA damage, the underlying molecular mechanism remains elusive. In this study, we report that ogg-1-deficient mice exhibited a significant increase of proinflammatory cytokines (TNF-α, IL-6, and IFN-γ) in the lung after being exposed to 95% oxygen. In addition, we found that ogg-1 deficiency downregulated (macro)autophagy when exposed to hyperoxia both in vitro and in vivo, which was evident by decreased conversion of LC3-I to LC3-II, reduced LC3 punctate staining, and lower Atg7 expression compared with controls. Using a chromatin immunoprecipitation assay, we found that OGG-1 associated with the promoter of Atg7, suggesting a role for OGG1 in regulation of Atg7 activity. Knocking down OGG-1 decreased the luciferase reporter activity of Atg7. Further, inflammatory cytokine levels in murine lung epithelial cell line cells were downregulated following autophagy induction by starvation and rapamycin treatment, and upregulated when autophagy was blocked using 3-methyladenine and chloroquine. atg7 knockout mice and Atg7 small interfering RNA-treated cells exhibited elevated levels of phospho-NF-κB and intensified inflammatory cytokines, suggesting that Atg7 impacts inflammatory responses to hyperoxia. These findings demonstrate that OGG-1 negatively regulates inflammatory cytokine release by coordinating molecular interaction with the autophagic pathway in hyperoxia-induced lung injury.


Asunto(s)
Lesión Pulmonar Aguda/patología , Autofagia , ADN Glicosilasas/metabolismo , Reparación del ADN , Hiperoxia/patología , Pulmón/patología , Lesión Pulmonar Aguda/metabolismo , Animales , Western Blotting , Inmunoprecipitación de Cromatina , Ensayo Cometa , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Hiperoxia/metabolismo , Inmunoprecipitación , Inflamación/metabolismo , Inflamación/patología , Pulmón/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
15.
J Immunol ; 198(8): 3205-3213, 2017 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-28258192

RESUMEN

Sepsis is a severe and complicated syndrome that is characterized by dysregulation of host inflammatory responses and organ failure, with high morbidity and mortality. The literature implies that autophagy is a crucial regulator of inflammation in sepsis. In this article, we report that autophagy-related protein 7 (Atg7) is involved in inflammasome activation in Pseudomonas aeruginosa abdominal infection. Following i.p. challenge with P. aeruginosa, atg7fl/fl mice showed impaired pathogen clearance, decreased survival, and widespread dissemination of bacteria into the blood and lung tissue compared with wild-type mice. The septic atg7fl/fl mice also exhibited elevated neutrophil infiltration and severe lung injury. Loss of Atg7 resulted in increased production of IL-1ß and pyroptosis, consistent with enhanced inflammasome activation. Furthermore, we demonstrated that P. aeruginosa flagellin is a chief trigger of inflammasome activation in the sepsis model. Collectively, our results provide insight into innate immunity and inflammasome activation in sepsis.


Asunto(s)
Proteína 7 Relacionada con la Autofagia/inmunología , Inflamasomas/inmunología , Infecciones por Pseudomonas/inmunología , Piroptosis/inmunología , Sepsis/inmunología , Animales , Proteína 7 Relacionada con la Autofagia/deficiencia , Modelos Animales de Enfermedad , Inmunidad Innata/inmunología , Immunoblotting , Inflamasomas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Infecciones por Pseudomonas/metabolismo , Pseudomonas aeruginosa/inmunología , Sepsis/metabolismo
19.
Top Stroke Rehabil ; 21(2): 120-7, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24710972

RESUMEN

BACKGROUND: The commonly used therapeutic approach, the contemporary Bobath approach (CBA), is not sufficient to restore independent locomotion for individuals with severe motor deficit (SMD) after stroke. Therefore, we propose that the early sitting, standing, and walking in conjunction with the CBA (ECBA) be used to treat individuals with SMD after stroke. OBJECTIVE: To investigate whether ECBA may enhance mobility and balance in subjects with SMD after stroke. METHODS: Thirty-three men and 15 women, aged 60 to 74 years, with SMD after stroke were recruited for the study. CBA or ECBA was performed with the subjects 5 times per week in 50-minute sessions for 8 weeks. The Stroke Rehabilitation Assessment of Movement (STREAM) and the Berg Balance Scale were implemented before treatment and at 4 and 8 weeks after treatment, respectively. RESULTS: The STREAM scores indicated that ECBA was more efficient than the CBA intervention for lower extremity mobility, F(1, 46) = 24.0, P < .001, and basic mobility, F(1, 46) = 102.6, P < .001. Overall STREAM scores were higher in the ECBA group, F(1, 46) =24.1, P < .001, after 8 weeks of therapy. Balance scores of the ECBA subjects were higher than those of the CBA subjects after 8 weeks of therapy, F(1, 46) = 73.1, P < .001. However, there was no difference in upper extremity mobility between the 2 groups. CONCLUSION: ECBA is a valuable intervention to improve lower extremity mobility, basic mobility, and balance ability for individuals with SMD after stroke.


Asunto(s)
Intervención Médica Temprana/métodos , Trastornos del Movimiento/fisiopatología , Trastornos del Movimiento/rehabilitación , Postura , Rehabilitación de Accidente Cerebrovascular , Caminata , Anciano , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/etiología , Examen Neurológico , Modalidades de Fisioterapia , Equilibrio Postural , Recuperación de la Función , Accidente Cerebrovascular/complicaciones , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
20.
Front Microbiol ; 14: 1209705, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37455744

RESUMEN

Objectives: Invasive pulmonary aspergillosis (IPA) is common in immuno-compromised people, and a high incidence of IPA has been found in patients with severe fever with thrombocytopenia syndrome (SFTS). Our study aimed to determine the independent risk factors for IPA and the relationship between smoking status and the risk of IPA in SFTS patients. Methods: A retrospective analysis of SFTS patients in the First Affiliated Hospital of Nanjing Medical University from May 2011 to December 2021 was reviewed. The patients were divided into two groups: IPA and non-IPA groups. We compared demographic characteristics, clinical manifestation, laboratory parameters, treatment, and prognosis, and explored the risk factors of IPA using logistic regression and ROC curve. The dose-dependent effect of smoking on the risk of IPA was further estimated, including the age of smoking initiation, daily smoking amount, smoking duration, and pack-years of smoking. Results: In total, 189 individuals were included. Compared with the non-IPA group, the IPA group had higher levels of smoking, drinking, cough, dyspnea, aCCI scores, Dabie bandavirus (DBV) RNA load, ferritin, PCT, IL-6, APTT, LDH, BUN, creatinine, and lower levels of FT4 and TSH. The incidences of MODS, admission to ICU, ventilation, and broad-spectrum antibiotic treatment were significantly higher in the IPA group than in the non-IPA group. Multivariable logistic analysis showed that smoking history, cough, creatinine, admission to ICU, broad-spectrum, and corticosteroid therapies were the independent risk factors for IPA in SFTS patients. We further confirmed that the age of smoking initiation <30 years, smoking at least one pack per day, smoking for at least 40 years, and having at least 40 pack-years of smoking exposure were the independent risk factors for IPA among smokers. Conclusion: The prognosis of SFTS patients in the IPA group is worse than that of the non-IPA group. Attention should be paid to SFTS patients with a smoking history, cough, creatinine, admission to ICU, and broad-spectrum and corticosteroid therapies. There is a strong dose-dependent association between smoking and IPA development in SFTS patients. Prophylactic antifungal therapy should be considered for SFTS patients with these risk factors, but further studies are necessary to determine if it is beneficial for the prognosis of these patients.

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