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1.
Nanotechnology ; 35(36)2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38848693

RESUMEN

Aqueous aluminum-ion batteries have many advantages such as their safety, environmental friendliness, low cost, high reserves and the high theoretical specific capacity of aluminum. So aqueous aluminum-ion batteries are potential substitute for lithium-ion batteries. In this paper, the current research status and development trends of cathode and anode materials and electrolytes for aqueous aluminum-ion batteries are described. Aiming at the problem of passivation, corrosion and hydrogen evolution reaction of aluminum anode and dissolution and irreversible change of cathode after cycling in aqueous aluminum-ion batteries. Solutions of different research routes such as ASEI (artificial solid electrolyte interphase), alloying, amorphization, elemental doping, electrolyte regulation, etc and different transformation mechanisms of anode and cathode materials during cycling have been summarized. Moreover, it looks forward to the possible research directions of aqueous aluminum-ion batteries in the future. We hope that this review can provide some insights and support for the design of more suitable electrode materials and electrolytes for aqueous aluminum-ion batteries.

2.
J Cell Mol Med ; 27(24): 4093-4106, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37830762

RESUMEN

Tumour necrosis factor-α (TNF-α) is a cytokine involved in systemic inflammation. TNF-α slows down osteogenic differentiation, which may contribute to poor bone development in the inflammatory microenvironment. TNF-α inhibits osteogenic differentiation by activating the JAK-STAT3 pathway, of which Signal transducer and activator of transcription 3 (STAT3)-interacting protein 1 (StIP1, also known as elongator complex protein 2, ELP2) is a key protein in the JAK-STAT3 pathway. We investigated whether and how ELP2 activation mediates the TNF-α-induced pyroptosis during osteoblastic differentiation. Using in vitro cell cultures of preosteoblastic MC3T3-E1 cells, we found that TNF-α exposure causes cell pyroptosis in an inflammatory microenvironment during osteoblastic differentiation. Bioinformatics, protein docking model and co-immunoprecipitation analysis revealed an association between ELP2, STAT3 and NLRP3. Forced ELP2 expression promoted MC3T3-E1 cells pyroptosis, with an increase in the expression of STAT3, NLRP3 inflammasome, GSDMD/GSDME, osteoblast marker genes, and the activity of alkaline phosphatase. In contrast, ELP2 silencing ameliorated MC3T3-E1 cells pyroptosis, and osteogenic differentiation, especially after TNF-α stimulation. The TNF-α-induced cells pyroptosis during osteoblastic differentiation was therefore mediated by ELP2. These results suggest that ELP2 is upregulated at the pyroptosis of MC3T3-E1 cells and inhibits osteogenic differentiation in response to TNF-α through NLRP3-GSDMD/GSDME activation.


Asunto(s)
Osteogénesis , Factor de Necrosis Tumoral alfa , Diferenciación Celular , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Osteoblastos/metabolismo , Piroptosis , Factor de Necrosis Tumoral alfa/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Ratones
3.
Biol Reprod ; 107(3): 765-778, 2022 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-35639638

RESUMEN

In oocytes, mRNA decay is essential for maturation and subsequent events, such as maternal-zygotic transition, zygotic genomic activation, and embryo development. Reversible N6-methyladenosine RNA methylation directly regulates transcription, pre-mRNA splicing, mRNA export, mRNA stability, and translation. Here, we identified that downregulation of N6-methyladenosine modification by microinjecting a methyltransferase-like 3 (Mettl3)-specific small interfering RNA into mouse germinal vesicle oocytes led to defects in meiotic spindles and the first polar body extrusion during maturation in vitro. By further quantitative real-time polymerase chain reaction and Poly(A)-tail assay analysis, we found that N6-methyladenosine methylation mainly acts by reducing deadenylation of mRNAs mediated by the carbon catabolite repression 4-negative on TATA less system, thereby causing mRNA accumulation in oocytes. Meanwhile, transcriptome analysis of germinal vesicle oocytes revealed the downregulation of transcripts of several genes encoding ribosomal subunits proteins in the Mettl3 small interfering RNA-treated group, suggesting that N6-methyladenosine modification might affect translation. Together, our results indicate that RNA methylation accelerates mRNA decay, confirming the critical role of RNA clearance in oocyte maturation.


Asunto(s)
Metiltransferasas , Oocitos , Cuerpos Polares , Adenosina/metabolismo , Animales , Regulación hacia Abajo , Metiltransferasas/genética , Metiltransferasas/metabolismo , Ratones , Oocitos/metabolismo , Estabilidad del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo
4.
J Virol ; 95(6)2021 02 24.
Artículo en Inglés | MEDLINE | ID: mdl-33408175

RESUMEN

Guanylate-binding protein 7 (GBP7) belongs to the GBP family, which plays key roles in mediating innate immune responses to intracellular pathogens. Thus far, GBP7 has been reported to be a critical cellular factor against bacterial infection. However, the relationship between GBP7 and influenza A virus (IAV) replication is unknown. Here, we showed that GBP7 expression was significantly upregulated in the lungs of mice, human peripheral blood mononuclear cells (PBMCs), and A549 cells during IAV infection. Using the CRISPR-Cas9 system and overexpression approaches, it was found that GBP7 knockout inhibited IAV replication by enhancing the expression of IAV-induced type I interferon (IFN), type III IFN, and proinflammatory cytokines. Conversely, overexpression of GBP7 facilitated IAV replication by suppressing the expression of those factors. Furthermore, GBP7 knockout enhanced IAV-induced nuclear factor-κB (NF-κB) activation and phosphorylation of stat1 and stat2; overexpression of GBP7 had the opposite effect. Our data indicated that GBP7 suppresses innate immune responses to IAV infection via NF-κB and JAK-STAT signaling pathways. Taken together, upon IAV infection, the induced GBP7 facilitated IAV replication by suppressing innate immune responses to IAV infection, which suggested that GBP7 serves as a therapeutic target for controlling IAV infection.IMPORTANCE So far, few studies have mentioned the distinct function of guanylate-binding protein 7 (GBP7) on virus infection. Here, we reported that GBP7 expression was significantly upregulated in the lungs of mice, human PBMCs, and A549 cells during IAV infection. GBP7 facilitated IAV replication by suppressing the expression of type I interferon (IFN), type III IFN, and proinflammatory cytokines. Furthermore, it was indicated that GBP7 suppresses innate immune responses to IAV infection via NF-κB and JAK-STAT signaling pathways. Taken together, our results elucidate a critical role of GBP7 in the host immune system during IAV infection.


Asunto(s)
Proteínas de Unión al GTP/inmunología , Virus de la Influenza A/fisiología , Subunidad alfa del Factor 3 de Genes Estimulados por el Interferón/metabolismo , FN-kappa B/metabolismo , Infecciones por Orthomyxoviridae/inmunología , Replicación Viral , Animales , Células Cultivadas , Citocinas/genética , Citocinas/inmunología , Proteínas de Unión al GTP/genética , Proteínas de Unión al GTP/metabolismo , Humanos , Evasión Inmune , Inmunidad Innata , Virus de la Influenza A/inmunología , Interferones/genética , Interferones/inmunología , Pulmón/metabolismo , Pulmón/virología , Ratones , Infecciones por Orthomyxoviridae/virología , Fosforilación , Transducción de Señal/inmunología
5.
Biochem Biophys Res Commun ; 526(4): 1143-1149, 2020 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-32327257

RESUMEN

In this study, we examined the impact of roscovitine, a cyclin-dependent kinase inhibitor (CDKI) that has entered phase I and II clinical trials, on influenza A viruses (IAVs) and its antiviral mechanism. The results illustrated that roscovitine inhibited multiple subtypes of influenza strains dose-dependently, including A/WSN/1933(H1N1), A/Aichi/2/68 (H3N2) and A/FM1/47 (H1N1) with IC50 value of 3.35 ± 0.39, 7.01 ± 1.84 and 5.99 ± 1.89 µM, respectively. Moreover, roscovitine suppressed the gene transcription and genome replication steps in the viral life cycle. Further mechanistic studies indicated that roscovitine reduced viral polymerase activity and bound specifically to the viral PB2cap protein by fluorescence polarization assay (FP) and surface plasmon resonance (SPR). Therefore, we believed roscovitine, as a PB2cap inhibitor, was a prospective antiviral agent to be developed as therapeutic treatment against influenza A virus infection.


Asunto(s)
Antivirales/farmacología , Virus de la Influenza A/fisiología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas de Unión a Caperuzas de ARN/metabolismo , ARN Polimerasa Dependiente del ARN/metabolismo , Roscovitina/farmacología , Proteínas Virales/metabolismo , Replicación Viral/efectos de los fármacos , Animales , ARN Polimerasas Dirigidas por ADN/metabolismo , Perros , Genoma Viral , Humanos , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/genética , Células de Riñón Canino Madin Darby , Inhibidores de Proteínas Quinasas/química , Roscovitina/química , Transcripción Genética/efectos de los fármacos , Internalización del Virus/efectos de los fármacos , Replicación Viral/genética
6.
J Biol Chem ; 293(1): 271-284, 2018 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-29118187

RESUMEN

The hypoxic response is a stress response triggered by low oxygen tension. Hypoxia-inducible factors (HIFs) play a prominent role in the pathobiology of hypoxia-associated conditions, including pulmonary hypertension (PH) and polycythemia. The c-Jun N-terminal protein kinase (JNK), a stress-activated protein kinase that consists of two ubiquitously expressed isoforms, JNK1 and JNK2, and a tissue-specific isoform, JNK3, has been shown to be activated by hypoxia. However, the physiological role of JNK1 and JNK2 in the hypoxic response remains elusive. Here, using genetic knockout cells and/or mice, we show that JNK2, but not JNK1, up-regulates the expression of HIF-1α and HIF-2α and contributes to hypoxia-induced PH and polycythemia. Knockout or silencing of JNK2, but not JNK1, prevented the accumulation of HIF-1α in hypoxia-treated cells. Loss of JNK2 resulted in a decrease in HIF-1α and HIF-2α mRNA levels under resting conditions and in response to hypoxia. Consequently, hypoxia-treated Jnk2-/- mice had reduced erythropoiesis and were less prone to polycythemia because of decreased expression of the HIF target gene erythropoietin (Epo). Jnk2-/- mice were also protected from hypoxia-induced PH, as indicated by lower right ventricular systolic pressure, a process that depends on HIF. Taken together, our results suggest that JNK2 is a positive regulator of HIFs and therefore may contribute to HIF-dependent pathologies.


Asunto(s)
Hipoxia de la Célula/fisiología , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Proteína Quinasa 9 Activada por Mitógenos/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Eritropoyesis/fisiología , Eritropoyetina/genética , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína Quinasa 8 Activada por Mitógenos/fisiología , Proteína Quinasa 9 Activada por Mitógenos/fisiología , Policitemia/metabolismo , ARN Mensajero/genética , Activación Transcripcional , Regulación hacia Arriba
7.
Biochim Biophys Acta Biomembr ; 1860(3): 784-791, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29229526

RESUMEN

BACKGROUND AND OBJECTIVES: Recently influenza pandemic outbreaks were caused by emerging H5N1, H7N9 and H1N1 viruses. However, virucidal disinfectants are mainly unspecific and toxic. It is tactical to discover specific virucidal compounds. METHODS: The inhibitory potency was determined in H5N1 pseudovirus system; Interactions of compounds with hemagglutinin (HA) were detected with surface plasmon resonance (SPR) and further calculated with molecular docking. Virucidal effect was also estimated in influenza virus A/Puerto Rico/8/34(H1N1). Prevention efficacy was further estimated in mice model. RESULTS: Oligothiophene compound 4sc was potently virucidal against H5N1 pseudovirus with selective index>1169 (IC50=0.17±0.01µM). Pseudovirus assay revealed 4sc may interact with HA. However, HA inhibition test indicated 4sc did not interact with receptor pocket in HA. SPR detection revealed 4sc interacted directly with HA and its HA2 subunits. Molecular docking analysis revealed that 4sc interacted with the cavity of HA2 stem region and HA1-HA2 interface which consist of 7 residues: L22, K262, G472 and F1102 in HA2; M241, E251 and N271 in HA1. 4sc also potently and irreversibly neutralized PR8 (H1N1) virus, causing 105.06±0.26 fold decrease of virus titer after exposure for 10min. 4sc blocked PR8 transmission to MDCK cells. Amazingly, virucidal effect of 4sc was not significantly reduced even at 4°C. Furthermore, 4sc blocked viral transmission to mice. CONCLUSION: Oligothiophene compound 4sc is a novel selective virucide of influenza virus, which blocks entry by interfering viral hemagglutinin. Due to promising safety profile and stable virucidal effect at 4°C, 4sc may be useful in disinfecting H5N1 and H1N1 influenza virus.


Asunto(s)
Antivirales/farmacología , Glicoproteínas Hemaglutininas del Virus de la Influenza/efectos de los fármacos , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Animales , Antivirales/síntesis química , Perros , Evaluación Preclínica de Medicamentos , Células HEK293 , Humanos , Células de Riñón Canino Madin Darby , Masculino , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Estructura Molecular , Organismos Libres de Patógenos Específicos , Internalización del Virus/efectos de los fármacos
8.
Mol Carcinog ; 57(9): 1181-1190, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29745440

RESUMEN

Gliomas are common, aggressive central nervous system tumors with poor overall survival rates. Despite improvements in neurosurgery, chemotherapy, and radiotherapy, the outcomes of patients with malignant gliomas remain poor. Therefore, increased knowledge of the molecular mechanisms that regulate glioma progression is crucial to identify novel therapeutic targets. Here, we reported that SHCBP1, a member of Src homolog and collagen homolog (Shc) family, was significantly overexpressed in glioma tissues and glioma cell lines compared to the corresponding normal tissues and cells. Ectopic overexpression of SHCBP1 promoted glioma cell migration and invasion, whereas knockdown of endogenous SHCBP1 had the opposite effects. Importantly, we demonstrated that SHCBP1 promoted aggressiveness in gliomas by activating the NF-κB signaling pathway. Collectively, our study indicates that SHCBP1 plays a pivotal role to promote progression in gliomas and targeting the oncogenic effects of SHCBP1 may provide a clinical strategy to treat gliomas.


Asunto(s)
Neoplasias Encefálicas/genética , Regulación Neoplásica de la Expresión Génica , Glioma/genética , FN-kappa B/inmunología , Invasividad Neoplásica/genética , Proteínas Adaptadoras de la Señalización Shc/genética , Regulación hacia Arriba , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Glioma/inmunología , Glioma/patología , Humanos , Invasividad Neoplásica/inmunología , Invasividad Neoplásica/patología , Proteínas Adaptadoras de la Señalización Shc/inmunología , Transducción de Señal
9.
Cell Immunol ; 327: 26-35, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29525181

RESUMEN

The persistent inflammation aggravated by a disordered immune response is considered to be the major cause of CD4+ T cell depletion in lymphoid tissue, which impels the progression of AIDS. Here, we report that heat shock factor 1 (HSF1) works as an innate repressor of HIV-induced inflammation. The activation of HSF1 was found to accompany inflammation during HIV infection. Further research uncovered that HSF1 activation inhibited HIV-induced inflammation. In addition, HSF1 overexpression suppressed the inflammatory response induced by HIV, while HSF1 deficiency exacerbated that inflammation. Mechanistically, HSF1 was found to compete with nuclear factor-κB (NF-κB) in the nucleus. Generally, our report highlights that HSF1 is an important host factor in regulating HIV-induced inflammation and may work as a potential target for curing AIDS.


Asunto(s)
Infecciones por VIH/metabolismo , Factores de Transcripción del Choque Térmico/metabolismo , Factores de Transcripción del Choque Térmico/fisiología , Adulto , Proteínas de Unión al ADN , Femenino , Células HEK293 , VIH/metabolismo , VIH/patogenicidad , Proteínas HSP70 de Choque Térmico , Voluntarios Sanos , Respuesta al Choque Térmico , Humanos , Inflamación , Masculino , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Transducción de Señal , Células THP-1 , Factores de Transcripción , Factor de Necrosis Tumoral alfa
10.
Mol Ther ; 25(9): 2129-2139, 2017 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-28571917

RESUMEN

A major challenge for cancer chemotherapy is the development of safe and clinically effective chemotherapeutic agents. With its low toxicity profile, sophocarpine (SC), a naturally occurring tetracyclic quinolizidine alkaloid derived from Sophora alopecuroides L, has shown promising therapeutic properties, including anti-inflammatory, anti-nociceptive, and antivirus activities. However, the antitumor efficacy of SC and its underlying mechanisms have not been completely delineated. In the present study, the inhibitory effect of SC on head and neck squamous cell carcinoma (HNSCC) progression and possible mechanisms for this effect involving microRNA-21 (miR-21) regulation were investigated. By cell viability, Transwell, and wound healing assays, we show that SC effectively inhibited proliferation, invasion, and migration of HNSCC cells. Moreover, SC exerted its growth-inhibitory effect via the downregulation of miR-21 expression by blocking Dicer-mediated miR-21 maturation. Furthermore, SC treatment led to the increased expression of PTEN and p38MAPK phosphorylation as well as the reversal of epithelial-mesenchymal transition (EMT), which was rescued by ectopic expression of miR-21 in cells. Notably, SC dramatically repressed tumor growth without observable tissue cytotoxicity in a mouse xenograft model of HNSCC. Our findings offer a preclinical proof of concept for SC as a leading natural agent for HNSCC cancer therapy.


Asunto(s)
Alcaloides/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , MicroARNs/genética , Alcaloides/química , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Ratones , MicroARNs/química , Mutación , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
11.
World J Surg Oncol ; 15(1): 231, 2017 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-29284526

RESUMEN

BACKGROUND: Glioblastoma is the most common primary malignant brain tumor. Extraneural metastases are rarely reported in the literature. CASE PRESENTATION: We report a case of a 38-year-old patient who was diagnosed with glioblastoma in 2015. Four months after surgery, local relapse was found and the patient received a second surgery. After another 4 months, we found a hard mass in the right posterior neck when she admitted to our department for fourth cycle of adjuvant chemotherapy. Immunohistochemical investigation supported the diagnosis of glioblastoma metastases to the neck after resection of the right neck mass. A few days later, spinal vertebral magnetic resonance imaging (MRI) confirmed multiple metastases in the thoracic, lumbar, sacral, and bilateral iliac bones. CONCLUSIONS: Glioblastoma is the most common primary malignant brain tumor. Whole tumor resection and early radiotherapy and chemotherapy can delay recurrence and prolong survival. Extracranial metastases are extremely rare. We report this case with the aim of bringing attention to extracranial metastasis of brain glioma.


Asunto(s)
Neoplasias Encefálicas/cirugía , Glioblastoma/cirugía , Neoplasias de Cabeza y Cuello/etiología , Procedimientos Neuroquirúrgicos/efectos adversos , Complicaciones Posoperatorias , Adulto , Neoplasias Encefálicas/patología , Femenino , Glioblastoma/patología , Neoplasias de Cabeza y Cuello/secundario , Humanos , Pronóstico , Recurrencia
12.
Biochim Biophys Acta ; 1848(10 Pt A): 2344-50, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26092189

RESUMEN

Influenza A viruses (IAV) are significant pathogens that result in millions of human infections and impose a substantial health and economic burdens worldwide. Due to the limited anti-influenza A therapeutics available and the emergence of drug resistant viral strains, it is imperative to develop potent anti-IAV agents with different mode of action. In this study, by applying a pseudovirus based screening approach, two super short membrane-active lipopeptides of C12-KKWK and C12-OOWO were identified as effective anti-IAV agents with IC50 value of 7.30±1.57 and 8.48±0.74 mg/L against A/Puerto Rico/8/34 strain, and 6.14±1.45 and 7.22±0.67 mg/L against A/Aichi/2/68 strain, respectively. The mechanism study indicated that the anti-IAV activity of these peptides would result from the inhibition of virus entry by interacting with HA2 subunit of hemagglutinin (HA). Thus, these peptides may have potentials as lead peptides for the development of new anti-IAV therapeutics to block the entry of virus into host cells.


Asunto(s)
Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/fisiología , Lipopéptidos/administración & dosificación , Lipopéptidos/síntesis química , Internalización del Virus/efectos de los fármacos , Animales , Antivirales/administración & dosificación , Antivirales/química , Perros , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Dosificación Letal Mediana , Células de Riñón Canino Madin Darby , Peso Molecular
13.
Virology ; 600: 110249, 2024 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-39303344

RESUMEN

Influenza is an acute viral respiratory infection that causes mild to severe illness in humans and animals. Current studies show that glucose-regulated protein 78 (GRP78) can exert crucial functions during viral infection; however, the mechanism by which GRP78 regulates influenza A virus (IAV) infection remains unclear. In the present study, we found that IAV infection increased GRP78 expression. Overexpression of GRP78 significantly inhibited IAV replication, as indicated by reduced viral mRNA levels, protein levels, and viral titers. Mechanistically, Type I interferon (IFN) response signaling is upregulated during IAV infection by GRP78. Further study showed that GRP78 interacts with tyrosine kinase 2 (TYK2) and enhances its phosphorylation, thereby activating downstream STAT1/2 and antiviral IFN-stimulated gene (ISG) expression. Collectively, these results demonstrate an important mechanism by which GRP78 exerts in innate antiviral effect in IAV infection. This mechanism could be used as a therapeutic target for anti-influenza treatment.

14.
Sci Signal ; 17(831): eadg7867, 2024 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-38593156

RESUMEN

Type I interferons (IFNs) are critical for the antiviral immune response, and fine-tuning type I IFN production is critical to effectively clearing viruses without causing harmful immunopathology. We showed that the transcription factor Miz1 epigenetically repressed the expression of genes encoding type I IFNs in mouse lung epithelial cells by recruiting histone deacetylase 1 (HDAC1) to the promoters of Ifna and Ifnb. Loss of function of Miz1 resulted in augmented production of these type I IFNs during influenza A virus (IAV) infection, leading to improved viral clearance in vitro and in vivo. IAV infection induced Miz1 accumulation by promoting the cullin-4B (CUL4B)-mediated ubiquitylation and degradation of the E3 ubiquitin ligase Mule (Mcl-1 ubiquitin ligase E3; also known as Huwe1 or Arf-BP1), which targets Miz1 for degradation. As a result, Miz1 accumulation limited type I IFN production and favored viral replication. This study reveals a previously unrecognized function of Miz1 in regulating antiviral defense and a potential mechanism for influenza viruses to evade host immune defense.


Asunto(s)
Virus de la Influenza A , Gripe Humana , Interferón Tipo I , Ratones , Animales , Humanos , Virus de la Influenza A/fisiología , Ubiquitinación , Células Epiteliales/metabolismo , Regulación de la Expresión Génica , Replicación Viral , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , Gripe Humana/genética , Interferones/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Inhibidoras de STAT Activados/genética , Proteínas Inhibidoras de STAT Activados/metabolismo
15.
J Hazard Mater ; 446: 130617, 2023 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-36623344

RESUMEN

Microplastics (MPs) are emerging pollutants which exist in various environments and pose a potential threat to human health. However, the effect of MP on respiratory pathogens-infected organisms is unknown. In order to explore the effect of MP on respiratory pathogen infection, we studied the effect of polystyrene microplastics (PS) on influenza A virus (IAV)-infected A549 cells. Western blot, qPCR, and viral plaque assay demonstrated that PS could promote IAV infection. Further study by bioluminescence imaging showed that a large number of IAV could be enriched on PS and entered cells through endocytosis. Meanwhile, the expression of IFITM3 in cells was significantly reduced. In addition, our results showed that PS down-regulated IRF3 and its active form P-IRF3 by down-regulating RIG-I and inhibiting TBK1 phosphorylation activation, which then significantly reduced IFN-ß expression and affected the cellular innate antiviral immune system. Taken together, our results indicate the potential threat of MPs to respiratory diseases caused by IAV and provide new insights into human health protection.


Asunto(s)
Virus de la Influenza A , Gripe Humana , Humanos , Microplásticos/toxicidad , Plásticos , Poliestirenos/toxicidad , Virus de la Influenza A/fisiología , Proteínas de la Membrana , Proteínas de Unión al ARN
16.
Microbes Infect ; 25(3): 105062, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36280208

RESUMEN

With the prevalence of novel strains and drug-resistant influenza viruses, there is an urgent need to develop effective and low-toxicity anti-influenza therapeutics. Regulation of the type I interferon antiviral response is considered an attractive therapeutic strategy for viral infection. Pterostilbene, a 3,5-dimethoxy analog of resveratrol, is known for its remarkable pharmacological activity. Here, we found that pterostilbene effectively inhibited influenza A virus infection and mainly affected the late stages of viral replication. A mechanistic study showed that the antiviral activity of pterostilbene might promote the induction of antiviral type I interferon and expression of its downstream interferon-stimulated genes during viral infection. The same effect of pterostilbene was also observed in the condition of polyinosinic-polycytidylic acid (poly I:C) transfection. Further study showed that pterostilbene interacted with influenza non-structural 1 (NS1) protein, inhibited ubiquitination mediated degradation of RIG-I and activated the downstream antiviral pathway, orchestrating an antiviral state against influenza virus in the cell. Taken together, pterostilbene could be a promising anti-influenza agent for future antiviral drug exploitation and compounds with similar structures may provide new options for the development of novel inhibitors against influenza A virus (IAV).


Asunto(s)
Virus de la Influenza A , Gripe Humana , Interferón Tipo I , Virosis , Humanos , Virus de la Influenza A/genética , Gripe Humana/tratamiento farmacológico , Antivirales/farmacología , Antivirales/metabolismo , Interferón Tipo I/metabolismo , Replicación Viral , Proteínas no Estructurales Virales/genética
17.
Heliyon ; 8(9): e10588, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-36132175

RESUMEN

Coiled coils (CCs) are protein structural motifs universally found in proteins and mediate a plethora of biological interactions, and thus their reliable annotation is crucial for studies of protein structure and function. Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is a large double-stranded DNA (dsDNA) virus and encodes 154 proteins. In this study, genome-wide scans of previously uncharacterized CC motifs throughout AcMNPV was conducted using CC prediction software. In total, 24 CC motifs in 19 CC proteins with high confidence were identified. The characteristic of viral CC motifs were analyzed. The CC proteins could be divided into 12 viral structural proteins and 7 non-structural proteins, including viral membrane fusion proteins, enzymes, and transcription factors. Moreover, CC motifs are conserved in the baculoviral orthologs of 14 of the 19 proteins. It is noted that five CC proteins, including Ac51, Ac66, Exon0, Ac13, and GP16, were previously identified to function in the nuclear egress of nucleocapsids, and Ac66 contains multiple CC motifs, the longest of which comprises 252 amino acids, suggesting a role of CC motifs in this process. Taken together, the CC motifs identified in this study are valuable resource for studying protein function and protein interaction networks during virus replication.

18.
Front Cell Infect Microbiol ; 12: 904775, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35873150

RESUMEN

Given the frequent emergence of drug-resistant influenza virus strains and new highly pathogenic influenza virus strains, there is an urgent need to identify new antiviral drugs and targets. We found that influenza A virus (IAV) infection caused a significant decrease of microRNA let-7 expression in host cells; that overexpression of let-7 increased interferon expression and effectively inhibit IAV infection; and that let-7 targets the 3'-untranslated region (UTR) of the ribosomal protein 16 (RPS16) gene, decreasing its expression. Knocking down the expression of RPS16 increased the expression of type I interferon and inhibited viral replication. The present study uncovered the regulatory effect of let-7b and let-7f on influenza A infection, which is a potential biomarker of IAV infection. In addition, let-7 may be a promising therapeutic agent against influenza A.


Asunto(s)
Gripe Humana , Interferón Tipo I , MicroARNs , Antivirales/farmacología , Interacciones Huésped-Patógeno , Humanos , Virus de la Influenza A , Gripe Humana/tratamiento farmacológico , Gripe Humana/genética , Interferón Tipo I/metabolismo , MicroARNs/genética , Proteínas Ribosómicas/metabolismo , Replicación Viral
19.
J Inflamm Res ; 15: 2745-2759, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35509324

RESUMEN

Introduction: Osteomyelitis is characterized by intensive inflammatory bone disease and remains a clinical challenge in orthopedic surgery, despite the advances made in medical and surgical therapies. Staphylococcus aureusis a major causative agent of osteomyelitis, causing the progressive inflammatory destruction of bone. Prophylaxis of osteomyelitis during orthopedic surgery is necessary. NFκB essential modulator-binding domain (NBD) peptides are cell-permeable peptide inhibitors of the IκB-kinase complex. The prophylactic effect of NBD peptides in relieving inflammation and inhibiting bone defects in osteomyelitis is still under investigation. Our purpose was to determine the preventive effect of NBD peptides in S. aureus infection-induced bone defects in osteomyelitis. Methods: An S. aureus osteomyelitis rabbit model was used in this study. The rabbits were divided into four groups: NBD, cefazolin, control, and PBS. Clinical and laboratory indicators of erythrocyte-sedimentation rate, CRP, and TNFα levels were assessed to monitor systemic reactions. The efficacy of NBD peptides in S. aureus-induced osteomyelitis was evaluated by radiological, histological, and microbiological examinations, immunohistochemistry, immunofluorescence, and micro-CT scans. Results: In general, NBD peptides effectively reduced clinical signs in rabbits when compared with the control group. Radiography indicated that there was more severe osteomyelitis in the bacterium-infection control group. There was no significance between cefazolin- and NBD-group average scores. The histological results of the lesion slices further confirmed different severity among the groups. Additionally, significant pathological differences were found between the cefazolin and NBD groups, and the PBS group showed no obvious pathological changes. Conclusion: Prophylactic administration of NBD peptides to bone-defect areas inhibited bacterial spread and promoted bone regeneration, making NBD peptides a possible treatment option for prophylaxis in bone infections.

20.
Biomed Res Int ; 2021: 3664564, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34853789

RESUMEN

Tumor necrosis factor-α is a common cytokine that increases in inflammatory processes, slows the differentiation of bone formation, and induces osteodystrophy in the long-term inflammatory microenvironment. Our previous study confirmed that the Elongation protein 2 (ELP2) plays a significant role in osteogenesis and osteogenic differentiation, which is considered a drug discovery target in diseases related to bone formation and differentiation. In this study, we applied an in silico virtual screening method to select molecules that bind to the ELP2 protein from a chemical drug molecule library and obtained 95 candidates. Then, we included 11 candidates by observing the docking patterns and the noncovalent bonds. The binding affinity of the ELP2 protein with the candidate compounds was examined by SPR analysis, and 5 out of 11 compounds performed good binding affinity to the mouse ELP2 protein. After in vitro cell differentiation assay, candidates 2# and 5# were shown to reduce differentiation inhibition after tumor necrosis factor-α stimulation, allowing further optimization and development for potential clinical treatment of inflammation-mediated orthopedic diseases.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Osteogénesis/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacología , Células 3T3 , Animales , Calcificación Fisiológica/efectos de los fármacos , Calcificación Fisiológica/fisiología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Línea Celular , Bases de Datos Farmacéuticas , Evaluación Preclínica de Medicamentos , Marcadores Genéticos , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intracelular/química , Ligandos , Ratones , Modelos Moleculares , Simulación del Acoplamiento Molecular , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteogénesis/genética , Osteogénesis/fisiología , Unión Proteica , Relación Estructura-Actividad , Resonancia por Plasmón de Superficie , Interfaz Usuario-Computador
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