RESUMEN
Germline-encoded pattern recognition receptors (PRRs) recognize molecules frequently found in pathogens (pathogen-associated molecular patterns [PAMPs]) during viral infection. This process induces production of IFNs, leading to expression of IFN-stimulated genes to establish a cellular antiviral state against viral infection. However, aberrant activation of the IFN system may cause immunopathological damage and systemic autoimmune diseases such as systemic lupus erythematosus. Stringent control of IFN signaling activation is critical for maintaining homoeostasis of the immune system; yet, the mechanisms responsible for its precise regulation remain to be elucidated. In this study, we identified that ring finger protein 215 (RNF215), a zinc finger protein, was upregulated by viral infection in human macrophages. In addition, we demonstrated that RNF215 inhibited the production of type I IFNs at least in part via interacting with p65, a subunit of NF-κB, and repressed the accumulation of NF-κB in the promoter region of IFNB1. Moreover, we found that the expression of RNF215 negatively correlated with type I IFNs in patients with systemic lupus erythematosus, indicating that RNF215 plays an important role in the pathogenesis of autoimmune diseases. Collectively, our data identified RNF215 as a key negative regulator of type I IFNs and suggested RNF215 as a potential target for intervention in diseases with aberrant IFN production.
Asunto(s)
Enfermedades Autoinmunes , Lupus Eritematoso Sistémico , Humanos , Interferón Tipo I/biosíntesis , FN-kappa B , Moléculas de Patrón Molecular Asociado a Patógenos , Transducción de SeñalRESUMEN
The Zika virus (ZIKV) is a mosquito-borne virus that already poses a danger to worldwide human health. Patients infected with ZIKV generally have mild symptoms like a low-grade fever and joint pain. However, severe symptoms can also occur, such as Guillain-Barré syndrome, neuropathy, and myelitis. Pregnant women infected with ZIKV may also cause microcephaly in newborns. To date, we still lack conventional antiviral drugs to treat ZIKV infections. Marine natural products have novel structures and diverse biological activities. They have been discovered to have antibacterial, antiviral, anticancer, and other therapeutic effects. Therefore, marine products are important resources for compounds for innovative medicines. In this study, we identified a marine natural product, harzianopyridone (HAR), that could inhibit ZIKV replication with EC50 values from 0.46 to 2.63 µM while not showing obvious cytotoxicity in multiple cellular models (CC50 > 45 µM). Further, it also reduced the expression of viral proteins and protected cells from viral infection. More importantly, we found that HAR directly bound to the ZIKV RNA-dependent RNA polymerase (RdRp) and suppressed its polymerase activity. Collectively, our findings provide HAR as an option for the development of anti-ZIKV drugs.
Asunto(s)
Productos Biológicos , Piridonas , Infección por el Virus Zika , Virus Zika , Animales , Humanos , Femenino , Recién Nacido , Embarazo , Antivirales/farmacología , ARN Polimerasa Dependiente del ARN/metabolismo , Productos Biológicos/farmacología , Replicación ViralRESUMEN
Enterovirus A71 (EV-A71) is a highly contagious virus that poses a major threat to global health, representing the primary etiological agent for hand-foot and mouth disease (HFMD) and neurological complications. It has been established that interferon signaling is critical to establishing a robust antiviral state in host cells, mainly mediated through the antiviral effects of numerous interferon-stimulated genes (ISGs). The host restriction factor SHFL is a novel ISG with broad antiviral activity against various viruses through diverse underlying molecular mechanisms. Although SHFL is widely acknowledged for its broad-spectrum antiviral activity, it remains elusive whether SHFL inhibits EV-A71. In this work, we validated that EV-A71 triggers the upregulation of SHFL both in cell lines and in a mouse model. Knockdown and overexpression of SHFL in EVA71-infected cells suggested that this factor could markedly suppress EV-A71 replication. Our findings further revealed an intriguing mechanism of SHFL that it could interact with the nonstructural proteins 3Dpol of EV-A71 and promoted the degradation of 3Dpol through the ubiquitin-proteasome pathway. Furthermore, the zinc-finger domain and the 36 amino acids (164-199) of SHFL were crucial to the interaction between SHFL and EV-A71 3Dpol . Overall, these findings broadened our understanding of the pivotal roles of SHFL in the interaction between the host and EV-A71.
Asunto(s)
Enterovirus Humano A , Infecciones por Enterovirus , Enterovirus , Enfermedad de Boca, Mano y Pie , Animales , Ratones , Enterovirus Humano A/genética , Complejo de la Endopetidasa Proteasomal , Productos del Gen pol , Antígenos Virales/genética , Antivirales , Interferones , UbiquitinasRESUMEN
Mounting evidence has associated Zika virus (ZIKV) infection with congenital malformations, including microcephaly, which raises global alarm. Nonetheless, mechanisms by which ZIKV disrupts neurogenesis and causes microcephaly are far from being understood. In this study, we discovered direct effects of ZIKV on neural progenitor cell development by inducing caspase-1- and gasdermin D (GSDMD)-mediated pyroptotic cell death, linking ZIKV infection with the development of microcephaly. Importantly, caspase-1 depletion or its inhibitor VX-765 treatment reduced ZIKV-induced inflammatory responses and pyroptosis, and substantially attenuated neuropathology and brain atrophy in vivo. Collectively, our data identify caspase-1- and GSDMD-mediated pyroptosis in neural progenitor cells as a previously unrecognized mechanism for ZIKV-related pathological effects during neural development, and also provide treatment options for ZIKV-associated diseases.
Asunto(s)
Encefalopatías , Células-Madre Neurales , Piroptosis/fisiología , Infección por el Virus Zika , Virus Zika , Animales , Encéfalo/citología , Encéfalo/metabolismo , Encéfalo/virología , Encefalopatías/metabolismo , Encefalopatías/virología , Células Cultivadas , Humanos , Ratones , Microcefalia/metabolismo , Microcefalia/virología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/virología , Infección por el Virus Zika/metabolismo , Infección por el Virus Zika/virologíaRESUMEN
BACKGROUND: Zika virus (ZIKV) infection is a global health problem, and its complications, including congenital Zika syndrome and Guillain-Barré syndrome, constitute a continued threat to humans. Unfortunately, effective therapeutics against ZIKV infection are not available thus far. METHODS: We screened the compounds collection consisting of 1789 FDA-approved drugs by a computational docking method to obtain anti-ZIKV candidate compounds targeting ZIKV RNA-dependent RNA polymerase (RdRp). SPR (BIAcore) assay was employed to demonstrate the candidate compounds' direct binding to ZIKV RdRp, and polymerase activity assay was used to determine the inhibitory effect on ZIKV RdRp-catalyzed RNA synthesis. The antiviral effects on ZIKV in vitro and in vivo were detected in infected cultured cells and in Ifnar1-/- mice infected by ZIKV virus using plaque assay, western blotting, tissue immunofluorescence, and immunohistochemistry. RESULTS: Here, we report that a first-in-class macrocyclic antibiotic, which has been clinically used to treat Clostridium difficile infection, fidaxomicin, potently inhibits ZIKV replication in vitro and in vivo. Our data showed that fidaxomicin was effective against African and Asian lineage ZIKV in a wide variety of cell lines of various tissue origins, and prominently suppressed ZIKV infection and significantly improved survival of infected mice. In addition, fidaxomicin treatment reduced the virus load in the brains and testes, and alleviated ZIKV-associated pathological damages, such as paralysis, hunching, and neuronal necrosis in the cerebra. Furthermore, our mechanistic study showed that fidaxomicin directly bound ZIKV NS5 protein and inhibited the RNA synthesis-catalyzing activity of ZIKV RdRp. CONCLUSIONS: Our data suggest that fidaxomicin may represent an effective anti-ZIKV agent. In the light that fidaxomicin is already a clinically used drug, there might be a promising prospect in the development of fidaxomicin to be an antiviral therapeutic.
Asunto(s)
Fidaxomicina/uso terapéutico , ARN Polimerasa Dependiente del ARN/uso terapéutico , Infección por el Virus Zika/tratamiento farmacológico , Animales , Línea Celular Tumoral , Chlorocebus aethiops , Femenino , Fidaxomicina/farmacología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , ARN Polimerasa Dependiente del ARN/farmacología , Células Vero , Infección por el Virus Zika/patologíaRESUMEN
Long noncoding RNAs (lncRNAs) are involved in the pathology of various tumours, including non-small cell lung cancer (NSCLC). However, the underlying molecular mechanisms of their specific association with NSCLC have not been fully elucidated. Here, we report that a cytoplasmic lncRNA, DUXAP9-206 is overexpressed in NSCLC cells and closely related to NSCLC clinical features and poor patient survival. We reveal that DUXAP9-206 induced NSCLC cell proliferation and metastasis by directly interacting with Cbl-b, an E3 ubiquitin ligase, and reducing the degradation of epidermal growth factor receptor (EGFR) and thereby augmenting EGFR signaling in NSCLC. Notably, correlations between DUXAP9-206 and activated EGFR signaling were also validated in NSCLC patient specimens. Collectively, our findings reveal the novel molecular mechanisms of DUXAP9-206 in mediating the progression of NSCLC and DUXAP9-206 may serve as a potential target for NSCLC therapy.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/secundario , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas c-cbl/metabolismo , ARN Largo no Codificante/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Apoptosis , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Movimiento Celular , Proliferación Celular , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Pronóstico , Proteínas Proto-Oncogénicas c-cbl/genética , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Zika virus (ZIKV) is a mosquito-borne virus that has been identified as a cause of several severe disease manifestations, including congenital microcephaly and Guillain-Barré syndrome, meningoencephalitis, and myelitis. Previous studies showed that ZIKV-infected patients exhibited elevated plasma levels of interleukin 1ß (IL-1ß), indicating that ZIKV may activate inflammasomes. However, the molecular basis for its viral pathogenesis remains poorly understood. In this current study, we found that ZIKV infection caused severe inflammatory pathological changes and promoted IL-1ß production in vitro and in vivo. We here demonstrate that the maturation and secretion of IL-1ß during ZIKV infection was mediated by NLRP3 inflammasome activation and that ZIKV nonstructural protein 5 (NS5) facilitated the assembly of the NLRP3 inflammasome complex, leading to IL-1ß activation through interaction with NLRP3 and induction of reactive oxygen species production. Collectively, our data identify NLRP3 inflammasome-derived IL-1ß production as a critical feature of inflammation during ZIKV infection. These findings offer new insights into inflammasome-mediated diseases and may provide new therapeutic options for ZIKV-associated diseases.
Asunto(s)
Inflamasomas/metabolismo , Inflamación/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Infección por el Virus Zika/metabolismo , Virus Zika/patogenicidad , Animales , Proteínas Portadoras/metabolismo , Línea Celular , Células HEK293 , Humanos , Inflamación/virología , Interleucina-1beta/metabolismo , Ratones , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismo , Proteínas no Estructurales Virales/metabolismoRESUMEN
The hepatitis B core antigen (HBcAg) is an important target for antiviral response in chronic hepatitis B (CHB) patients. However, the correlation between HBcAg in the hepatocyte nucleus and nucleos(t)ide analogue (NA) therapeutic response is unclear. We sought to evaluate the role of HBcAg by analysing liver biopsies for viral response in NA-naïve hepatitis B e antigen (HBeAg) positive (+) CHB patients via immunohistochemistry (IHC). A total of 48 HBcAg-negative (-) patients and 48 HBcAg (+) patients with matching baseline characteristics were retrospectively analysed for up to 288 weeks. Virological response (VR) rates of patients in the HBcAg (-) group were significantly higher at week 48 and 96 than the HBcAg (+) group (77.1% versus 45.8% at week 48, respectively, P = 0.002 and 95.3% versus 83.3% at week 96, respectively, P = 0.045). The serological negative conversion rate of HBeAg was significantly higher in the HBcAg (-) than in the HBcAg (+) group from week 96 to 288 (35.4 % versus 14.6% at week 96, respectively, P = 0.018; 60.4% versus 14.6%, respectively, P < 0.001 at week 144; 72.9% versus 35.4%, respectively, P < 0.001 at week 288). The cumulative frequencies of VR and lack of HBeAg were higher in the HBcAg (-) group (both P < 0.05). Binary logistic regression analysis showed that HBcAg (-) was the predictor for the lack of HBeAg (OR 4.482, 95% CI: 1.58-12.68). In summary, the absence of HBcAg in the hepatocyte nucleus could be an independent predictor for HBeAg seroconversion rates during NA-naïve treatment in HBeAg (+) CHB patients.
Asunto(s)
Antivirales/uso terapéutico , Antígenos del Núcleo de la Hepatitis B/biosíntesis , Hepatitis B Crónica/tratamiento farmacológico , Hígado/efectos de los fármacos , Adulto , Biopsia , Femenino , Antígenos e de la Hepatitis B/biosíntesis , Hepatitis B Crónica/patología , Hepatitis B Crónica/virología , Humanos , Inmunohistoquímica , Hígado/patología , Hígado/virología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
UNLABELLED: Dengue virus (DENV) is the most common mosquito-borne virus infecting humans and is currently a serious global health challenge. To establish infection in its host cells, DENV must subvert the production and/or antiviral effects of interferon (IFN). The aim of this study was to understand the mechanisms by which DENV suppresses IFN production. We determined that DENV NS4A interacts with mitochondrial antiviral signaling protein (MAVS), which was previously found to activate NF-κB and IFN regulatory factor 3 (IRF3), thus inducing type I IFN in the mitochondrion-associated endoplasmic reticulum membranes (MAMs). We further demonstrated that NS4A is associated with the N-terminal CARD-like (CL) domain and the C-terminal transmembrane (TM) domain of MAVS. This association prevented the binding of MAVS to RIG-I, resulting in the repression of RIG-I-induced IRF3 activation and, consequently, the abrogation of IFN production. Collectively, our findings illustrate a new molecular mechanism by which DENV evades the host immune system and suggest new targets for anti-DENV strategies. IMPORTANCE: Type I interferon (IFN) constitutes the first line of host defense against invading viruses. To successfully establish infection, dengue virus (DENV) must counteract either the production or the function of IFN. The mechanism by which DENV suppresses IFN production is poorly understood and characterized. In this study, we demonstrate that the DENV NS4A protein plays an important role in suppressing interferon production through binding MAVS and disrupting the RIG-I-MAVS interaction in mitochondrion-associated endoplasmic reticulum membranes (MAMs). Our study reveals that MAVS is a novel host target of NS4A and provides a molecular mechanism for DENV evasion of the host innate immune response. These findings have important implications for understanding the pathogenesis of DENV and may provide new insights into using NS4A as a therapeutic and/or prevention target.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Virus del Dengue/inmunología , Dengue/inmunología , Interacciones Huésped-Patógeno/inmunología , Inmunidad Innata/inmunología , Interferón Tipo I/metabolismo , Proteínas no Estructurales Virales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Antivirales/metabolismo , Western Blotting , Células Cultivadas , Dengue/metabolismo , Dengue/virología , Retículo Endoplásmico/metabolismo , Técnica del Anticuerpo Fluorescente , Células HEK293 , Células HeLa , Humanos , Técnicas para Inmunoenzimas , Inmunoprecipitación , Factor 3 Regulador del Interferón/antagonistas & inhibidores , Factor 3 Regulador del Interferón/genética , Factor 3 Regulador del Interferón/metabolismo , Monocitos/citología , Monocitos/metabolismo , Monocitos/virología , FN-kappa B/genética , FN-kappa B/metabolismo , Unión Proteica , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Proteínas no Estructurales Virales/genéticaRESUMEN
Interferon-inducible transmembrane proteins 1, 2 and 3 (IFITM1, IFITM2 and IFITM3) have recently been identified as potent antiviral effectors that function to suppress the entry of a broad range of enveloped viruses and modulate cellular tropism independent of viral receptor expression. However, the antiviral effect and mechanisms of IFITMs in response to viral infections remain incompletely understood and characterized. In this work, we focused our investigation on the function of the extracellular IFITM3 protein. In cell models of DENV-2 infection, we found that IFITM3 contributed to both the baseline and interferon-induced inhibition of DENV entry. Most importantly, our study for the first time demonstrated the presence of IFITM-containing exosome in the extracellular environment, and identified an ability of cellular exosome to intercellularly deliver IFITM3 and thus transmit its antiviral effect from infected to non-infected cells. Thus, our findings provide new insights in the basic mechanisms underlying the actions of IFITM3, which might lead to future development of exosome-mediated anti-viral strategies using IFITM3 as a therapeutic agent. Conceivably, variations in the basal and inducible levels of IFITMs, as well as in intracellular and extracellular levels of IFITMs, might predict the severity of dengue virus infections among individuals or across species.
Asunto(s)
Antivirales/metabolismo , Virus del Dengue/inmunología , Dengue/inmunología , Exosomas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Unión al ARN/metabolismo , Virus del Dengue/fisiología , Internalización del VirusRESUMEN
Multiple nodes in the one-carbon metabolism pathway play important regulatory roles in cancer cell growth and tumorigenesis. The specific biological functions of metabolic enzymes in regulating the signaling pathways that are associated with tumor cell growth and survival, however, remain unclear. Our current study found that phosphoserine aminotransferase 1 (PSAT1), an enzyme catalyzing serine biosynthesis, was significantly up-regulated in non-small cell lung cancer (NSCLC) and was involved in the regulation of E2F activity. Loss- and gain-of-function experiments demonstrated that PSAT1 promoted cell cycle progression, cell proliferation and tumorigenesis. Mechanistic study suggested that elevated PSAT1 led to inhibition of cyclin D1 degradation and subsequently an alteration in Rb-E2F pathway activity, which in turn enhanced G1 progression and proliferation of NSCLC cells. Moreover, phosphorylation of cyclin D1 at threonine 286 by GSK-3ß was required for PSAT1-induced blockage of cyclin D1 degradation. We also found that the activity of p70S6K mediated the effects of PSAT1 on GSK-3ß phosphorylation and cyclin D1 degradation. We further identified that PSAT1 was over-expressed in NSCLC and predicted poor clinical outcome of patients with the disease. Correlation analysis showed that PSAT1 expression positively correlated with the levels of phosphorylated GSK-3ß, cyclin D1 and phosphorylated Rb in NSCLC primary tumors. These findings uncover a mechanism for constitutive activation of E2F via which unrestrained cell cycle progression occurs in NSCLC and may represent a prognostic biomarker and therapeutic target.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/enzimología , Proliferación Celular , Ciclina D1/metabolismo , Neoplasias Pulmonares/enzimología , Transaminasas/fisiología , Animales , Línea Celular Tumoral , Factores de Transcripción E2F/metabolismo , Puntos de Control de la Fase G1 del Ciclo Celular , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Fosforilación , Pronóstico , Procesamiento Proteico-Postraduccional , Proteolisis , Transducción de Señal , Transcriptoma , Carga TumoralRESUMEN
BACKGROUND: Currently, a licensed vaccine for Dengue Virus (DENV) is not yet available. Virus-like particles (VLP) have shown considerable promise for use as vaccines and have many advantages compared to many other types of viral vaccines. VLPs have been found to have high immunogenic potencies, providing protection against various pathogens. RESULTS: In the current study, four DENV-VLP serotypes were successfully expressed in Pichia pastoris, based on co-expression of the prM and E proteins. The effects of a tetravalent VLP vaccine were also examined. Immunization with purified, recombinant, tetravalent DENV1-4 VLPs induced specific antibodies against all DENV1-4 antigens in mice. The antibody titers were higher after immunization with the tetravalent VLP vaccine compared to titers after immunization with any of the dengue serotype VLPs alone. Indirect immunofluorescence assay (IFA) results indicated that sera from VLP immunized mice recognized the native viral antigens. TNF-α and IL-10 were significantly higher in mice immunized with tetravalent DENV-VLP compared to those mice received PBS. The tetravalent VLP appeared to stimulate neutralizing antibodies against each viral serotype, as shown by PRNT50 analysis (1:32 against DENV1 and 2, and 1:16 against DENV3 and 4). The highest titers with the tetravalent VLP vaccine were still a little lower than the monovalent VLP against the corresponding serotype. The protection rates of tetravalent DENV-VLP immune sera against challenges with DENV1 to 4 serotypes in suckling mice were 77, 92, 100, and 100%, respectively, indicating greater protective efficacy compared with monovalent immune sera. CONCLUSIONS: Our results provide an important basis for the development of the dengue VLP as a promising non-infectious candidate vaccine for dengue infection.
Asunto(s)
Vacunas contra el Dengue/inmunología , Dengue/prevención & control , Vacunas de Partículas Similares a Virus/inmunología , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Dengue/inmunología , Vacunas contra el Dengue/administración & dosificación , Vacunas contra el Dengue/genética , Vacunas contra el Dengue/aislamiento & purificación , Virus del Dengue/genética , Virus del Dengue/inmunología , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Expresión Génica , Inmunización Pasiva , Interleucina-10/metabolismo , Ratones Endogámicos BALB C , Pruebas de Neutralización , Pichia/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/metabolismo , Análisis de Supervivencia , Factor de Necrosis Tumoral alfa/metabolismo , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/aislamiento & purificación , Vacunas de Partículas Similares a Virus/administración & dosificación , Vacunas de Partículas Similares a Virus/genética , Vacunas de Partículas Similares a Virus/aislamiento & purificación , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/metabolismoRESUMEN
Zika virus (ZIKV), belonging to the Flavivirus family and mainly transmitted by mosquitoes, causes a variety of adverse outcomes, including Guillain-Barré syndrome, microcephaly, and meningoencephalitis. However, there are no approved vaccines or drugs available for ZIKV. The discovery and research on drugs for ZIKV are still essential. In this study, we identified doramectin, an approved veterinary antiparasitic drug, as a novel anti-ZIKV agent (EC50 value from 0.85 µM to 3.00 µM) with low cytotoxicity (CC50 > 50 µM) in multiple cellular models. The expression of ZIKV proteins also decreased significantly under the treatment of doramectin. Further study showed that doramectin directly interacted with the key enzyme for ZIKV genome replication, RNA-dependent RNA polymerase (RdRp), with a stronger affinity (Kd = 16.9 µM), which may be related to the effect on ZIKV replication. These results suggested that doramectin might serve as a promising drug candidate for anti-ZIKV.
Asunto(s)
Infección por el Virus Zika , Virus Zika , Animales , Virus Zika/genética , Reposicionamiento de Medicamentos , Infección por el Virus Zika/tratamiento farmacológico , Replicación Viral , Antivirales/farmacología , Antivirales/uso terapéuticoRESUMEN
The major severe complications linked to Zika virus (ZIKV) cause the global public health problems, including microcephaly and other congenital abnormalities in newborns, and Guillain-Barré syndrome, meningoencephalitis, multi-organ failure in adults. However, neither approved vaccines nor drugs are available for ZIKV. In this study, we describe the design, synthesis and the anti-ZIKV activities of a series of anthraquinone analogs. Most of the newly synthesized compounds demonstrated moderate to excellent potency against ZIKV. Among all, compound 22, showed the most potent anti-ZIKV activity (EC50 value from 1.33 µM to 5.72 µM) with low cytotoxicity (CC50ï¼50 µM) in multiple cellular model. Importantly, 22 significantly improved the survival of ZIKV-infected mice (Ifnar1-/-), alleviated ZIKV-associated pathological damages and suppressed the excessive inflammatory response and pyroptosis induced by ZIKV in vivo and in vitro. Furthermore, the molecular docking simulation analysis and the surface plasmon resonance results demonstrated the direct binding between 22 and ZIKV RdRp, and the mechanistic study revealed that 22 suppressed viral RNA synthesis by ZIKV NS5 in cells. Taken together, this study highlights that 22 may be a novel anti-ZIKV drug candidate and provides treatment options for ZIKV-associated diseases.
Asunto(s)
Infección por el Virus Zika , Virus Zika , Animales , Ratones , Antivirales/química , Simulación del Acoplamiento Molecular , Replicación Viral , Infección por el Virus Zika/tratamiento farmacológicoRESUMEN
OBJECTIVES: This study aimed to determine the epidemiological and genetic features of human metapneumovirus (HMPV) infection in children in southern China, and the effect of meteorological factors on infection. METHODS: 14,817 children (≤14 years) with acute respiratory tract infections from 2010 to 2019 were examined for HMPV and other respiratory viruses by real-time quantitative polymerase chain reaction. Full-length F gene of 54 positive samples were sequenced and subjected to phylogenetic analysis. The correlation between the HMPV-positive rate and meteorological factors was analyzed by linear regression analysis. RESULTS: HMPV was detected in 524 (3.5%) children, who were mostly younger than 1 year. The seasonal peak of HMPV prevalence mainly occurred in spring. Respiratory syncytial virus was the most common virus coinfected with HMPV (5.3%). Phylogenetic analysis revealed that the sequenced HMPV strains belonged to four sublineages, including A2b (1.9%), A2c (31.5%), B1 (50.0%), and B2 (16.7%). After adjusting for all meteorological factors, sunshine duration was inversely correlated with the HMPV-positive rate. CONCLUSION: HMPV is an important respiratory pathogen that causes acute respiratory tract infections in children in southern China, particularly in children ≤5 years old. The prevalence peak of HMPV in this area appeared in spring, and the predominant subtype was B1. Meteorological factors, especially long sunshine duration, might decrease the HMPV prevalence.
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Metapneumovirus , Infecciones por Paramyxoviridae , Infecciones del Sistema Respiratorio , Niño , Humanos , Lactante , Preescolar , Metapneumovirus/genética , Estudios Retrospectivos , Epidemiología Molecular , Filogenia , Infecciones por Paramyxoviridae/epidemiología , Infecciones del Sistema Respiratorio/epidemiología , China/epidemiología , Conceptos MeteorológicosRESUMEN
Cytoskeleton has been reported to play an essential role in facilitating the viral life cycle. However, whether the host can exert its antiviral effects by modulating the cytoskeleton is not fully understood. In this study, we identified that host factor DUSP5 was upregulated after dengue virus (DENV) infection. In addition, we demonstrated that overexpression of DUSP5 remarkably inhibited DENV replication. Conversely, the depletion of DUSP5 led to an increase in viral replication. Moreover, DUSP5 was found to restrain viral entry into host cells by suppressing F-actin rearrangement via negatively regulating the ERK-MLCK-Myosin IIB signaling axis. Depletion of dephosphorylase activity of DUSP5 abolished its above inhibitory effects. Furthermore, we also revealed that DUSP5 exhibited broad-spectrum antiviral effects against DENV and Zika virus. Taken together, our studies identified DUSP5 as a key host defense factor against viral infection and uncovered an intriguing mechanism by which the host exerts its antiviral effects through targeting cytoskeleton rearrangement.
Asunto(s)
Virus del Dengue , Dengue , Infección por el Virus Zika , Virus Zika , Humanos , Replicación Viral , Citoesqueleto , Antivirales/farmacología , Dengue/tratamiento farmacológico , Fosfatasas de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/farmacologíaRESUMEN
Identification of endogenous angiogenesis inhibitors has led to development of an increasingly attractive strategy for cancer therapy and other angiogenesis-driven diseases. Vascular endothelial growth inhibitor (VEGI), a potent and relatively nontoxic endogenous angiogenesis inhibitor, has been intensively studied, and this work shed new light on developing promising anti-angiogenic strategies. It is well-documented that the RGD (Arg-Gly-Asp) motif exhibits high binding affinity to integrin α(v)ß(3), which is abundantly expressed in cancer cells and specifically associated with angiogenesis on tumors. Here, we designed a fusion protein containing the special RGD-4C motif sequence and VEGI-192, aimed at offering more effective multiple targeting to tumor cells and tumor vasculature, and higher anti-angiogenic and antitumor efficacy. Functional tests demonstrated that the purified recombinant human RGD-VEGI-192 protein (rhRGD-VEGI-192) potently inhibited endothelial growth in vitro and suppressed neovascularization in chicken chorioallantoic membrane in vivo, to a higher degree as compared with rhVEGI-192 protein. More importantly, rhRGD-VEGI-192, but not rhVEGI-192 protein, could potentially target MDA-MB-435 breast tumor cells, significantly inhibiting growth of MDA-MB-435 cells in vitro, triggered apoptosis in MDA-MB-435 cells by activation of caspase-8 as well as caspase-3, which was mediated by activating the JNK signaling associated with upregulation of pro-apoptotic protein Puma, and consequently led to the observed significant antitumor effect in vivo against a human breast cancer xenograft. Our study indicated that the RGD-VEGI-192 fusion protein might represent a novel anti-angiogenic and antitumor strategy.
Asunto(s)
Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Oligopéptidos/metabolismo , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/farmacología , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Pollos , Membrana Corioalantoides/irrigación sanguínea , Membrana Corioalantoides/efectos de los fármacos , Femenino , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ratones , Ratones Endogámicos BALB C , Transducción de Señal/efectos de los fármacos , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Breast cancer remains a major health problem worldwide. While chemotherapy represents an important therapeutic modality against breast cancer, limitations in the clinical use of chemotherapy remain formidable because of chemoresistance. The HER2/PI-3K/Akt pathway has been demonstrated to play a causal role in conferring a broad chemoresistance in breast cancer cells and thus justified to be a target for enhancing the effects of anti-breast cancer chemotherapies, such as adriamycin (ADR). Agents that can either enhance the effects of chemotherapeutics or overcome chemoresistance are urgently needed for the treatment of breast cancer. In this context, SZ-685C, an agent that has been previously shown, as such, to suppress Akt signaling, is expected to increase the efficacy of chemotherapy. Our current study investigated whether SZ-685C can override chemoresistance through inhibiting Akt signaling in human breast cancer cells. ADR-resistant cells derived from human breast cancer cell lines MCF-7, MCF-7/ADR and MCF-7/Akt, were used as models to test the effects of SZ-685C. We found that SZ-685C suppressed the Akt pathway and induced apoptosis in MCF-7/ADR and MCF-7/Akt cells that are resistant to ADR treatment, leading to antitumor effects both in vitro and in vivo. Our data suggest that use of SZ-685C might represent a potentially promising approach to the treatment of ADR-resistant breast cancer.