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1.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(10): 871-876, 2020 Oct.
Artículo en Chino | MEDLINE | ID: mdl-33148380

RESUMEN

Objective To investigate the effects of inorganic arsenic exposure on the differentiation of renal CD4+T lymphocytes and the possible mechanism. Methods Female C57BL/6 mice were randomly divided into control group, (2.5, 5, 10) mg/kg NaAsO2 exposure groups, 10 mice in each group. As was administered once intragastrically for 24 hours, and control mice were treated with normal saline. Real-time fluorescence quantitative PCR was used to detect T helper type 1 (Th1) cell-specific transcription factor T-box expressed in T cells (T-bet) and IFN-γ, Th2 cell-specific transcription factor GATA-binding protein 3 (GATA3) and interleukin 4 (IL-4), Th17 cell-specific transcription factor retinoic acid related orphan nuclear receptor γt (ROR-γt) and cytokine IL-22, regulatory T cells (Tregs)-specific transcription factor forkhead box P3 (FOXP3) and cytokine transforming growth factor-ß (TGF-ß) mRNA levels. We used commercial kits to detect catalase (CAT) activity and total antioxidant capacity (T-AOC) in serum as well as renal malondialdehyde (MDA) and superoxide dismutase (SOD). Results Compared with the control group, the body mass, renal mass and kidney index of the mice in all arsenic-treated groups have no significant changes. The levels of the master transcription factors T-bet, GATA3, ROR-γt and FOXP3 as well as related cytokines IFN-γ, IL-4, IL-22 and TGF-ß of Th1, Th2, Th17 cells and Tregs decreased in the arsenic-treated groups. Serum CAT activity and T-AOC level in the arsenic-treated mice dropped greatly. In addition, arsenic markedly increased renal MDA level while decreased SOD activity. Conclusion Inorganic arsenic exposure can suppress renal T cell subpopulation function and induce renal oxidative injure.


Asunto(s)
Arsénico/toxicidad , Riñón/efectos de los fármacos , Estrés Oxidativo , Linfocitos T Reguladores/efectos de los fármacos , Células TH1/efectos de los fármacos , Células Th2/efectos de los fármacos , Animales , Citocinas/metabolismo , Femenino , Factores de Transcripción Forkhead/metabolismo , Factor de Transcripción GATA3/metabolismo , Riñón/inmunología , Ratones , Ratones Endogámicos C57BL
2.
BMC Infect Dis ; 20(1): 832, 2020 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-33176697

RESUMEN

BACKGROUND: Carvacrol, as the major components of aromatic plants used for treating human skin diseases including origanum, Satureja, thymus, and coridothymus species, presented a kind of antiviral activity. To explore the mechanisms of carvacrol against herpes simplex virus (HSV) in vitro. METHOD: The BSC-1 cells model of HSV infection was established, and from the two aspects of viral replication level and cell death pathway, the antiviral effects of carvacrol on HSV infected cells were also evaluated by plaque assay under the three modes including prevention, treatment, and direct inactivation. RESULTS: In the three ways, the half-maximal effective concentration (EC50) of 2% true carvacrol solution on HSV-2 infected cells were severally 0.43, 0.19 and 0.51 mmol/L, and the corresponding therapeutic index (TI) were 4.02, 9.11 and 3.39, respectively. It's the opposite of the increased levels caused by HSV-2 infection, that both the expressions at the transcription genes and protein levels of virus own replication key factors (including ICP4, ICP27, VP16, gB, and UL30) and cytokines (including RIP3, TNF-α, and MLKL) of infected cells treated with carvacrol were dose-dependently inhibited. Besides, HSV-2 infection can cause the decrease of intracellular protein ubiquitination level, and carvacrol can reverse the ubiquitination decrease level caused by HSV-2 infection. CONCLUSION: Carvacrol exhibits significant antiviral activity by inhibiting the HSV-2 proliferation process and HSV-2-induced TNF-α increasing levels, decreasing RIP3 and MLKL protein expressions through the intracellular RIP3-mediated programmed cell necrosis pathway. In addition, carvacrol also may exhibit anti-HSV-2 activity by reversing the ubiquitination decrease level caused by HSV-2 infection on the ubiquitin-proteasome system, which provides insights into the molecular mechanism.


Asunto(s)
Antivirales/farmacología , Apoptosis/efectos de los fármacos , Cimenos/farmacología , Células Epiteliales/virología , Herpes Simple/metabolismo , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 2/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Ubiquitina/metabolismo , Animales , Chlorocebus aethiops , Citocinas/metabolismo , Herpes Simple/virología , Transducción de Señal/efectos de los fármacos , Células Vero , Replicación Viral/efectos de los fármacos
3.
BMC Infect Dis ; 20(1): 823, 2020 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-33176722

RESUMEN

BACKGROUND: The highly pathogenic avian influenza A/H5N1 virus is one of the causative agents of acute lung injury (ALI) with high mortality rate. Studies on therapeutic administration of bone marrow-derived mesenchymal stem cells (MSCs) in ALI caused by the viral infection have been limited in number and have shown conflicting results. The aim of the present investigation is to evaluate the therapeutic potential of MSC administration in A/H5N1-caused ALI, using a mouse model. METHODS: MSCs were prepared from the bone marrow of 9 to 12 week-old BALB/c mice. An H5N1 virus of A/turkey/East Java/Av154/2013 was intranasally inoculated into BALB/c mice. On days 2, 4, and 6 after virus inoculation, MSCs were intravenously administered into the mice. To evaluate effects of the treatment, we examined for lung alveolar protein as an indicator for lung injury, PaO2/FiO2 ratio for lung functioning, and lung histopathology. Expressions of NF-κB, RAGE (transmembrane receptor for damage associated molecular patterns), TNFα, IL-1ß, Sftpc (alveolar cell type II marker), and Aqp5+ (alveolar cell type I marker) were examined by immunohistochemistry. In addition, body weight, virus growth in lung and brain, and duration of survival were measured. RESULTS: The administration of MSCs lowered the level of lung damage in the virus-infected mice, as shown by measuring lung alveolar protein, PaO2/FiO2 ratio, and histopathological score. In the MSC-treated group, the expressions of NF-κB, RAGE, TNFα, and IL-1ß were significantly suppressed in comparison with a mock-treated group, while those of Sftpc and Aqp5+ were enhanced. Body weight, virus growth, and survival period were not significantly different between the groups. CONCLUSION: The administration of MSCs prevented further lung injury and inflammation, and enhanced alveolar cell type II and I regeneration, while it did not significantly affect viral proliferation and mouse morbidity and mortality. The results suggested that MSC administration was a promissing strategy for treatment of acute lung injuries caused by the highly pathogenic avian influenza A/H5N1 virus, although further optimization and combination use of anti-viral drugs will be obviously required to achieve the goal of reducing mortality.


Asunto(s)
Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/cirugía , Subtipo H5N1 del Virus de la Influenza A , Trasplante de Células Madre Mesenquimatosas , Infecciones por Orthomyxoviridae/complicaciones , Neumonía/etiología , Neumonía/cirugía , Lesión Pulmonar Aguda/prevención & control , Lesión Pulmonar Aguda/virología , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Pulmón/metabolismo , Pulmón/virología , Masculino , Ratones , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/virología , Neumonía/prevención & control , Neumonía/virología , Resultado del Tratamiento
4.
mSphere ; 5(6)2020 11 11.
Artículo en Inglés | MEDLINE | ID: mdl-33177214

RESUMEN

Viral shedding patterns and their correlations with immune responses are still poorly characterized in mild coronavirus (CoV) disease 2019 (COVID-19). We monitored shedding of viral RNA and infectious virus and characterized the immune response kinetics of the first five patients quarantined in Geneva, Switzerland. High viral loads and infectious virus shedding were observed from the respiratory tract despite mild symptoms, with isolation of infectious virus and prolonged positivity by reverse transcriptase PCR (RT-PCR) until days 7 and 19 after symptom onset, respectively. Robust innate responses characterized by increases in activated CD14+ CD16+ monocytes and cytokine responses were observed as early as 2 days after symptom onset. Cellular and humoral severe acute respiratory syndrome (SARS)-CoV-2-specific adaptive responses were detectable in all patients. Infectious virus shedding was limited to the first week after symptom onset. A strong innate response, characterized by mobilization of activated monocytes during the first days of infection and SARS-CoV-2-specific antibodies, was detectable even in patients with mild disease.IMPORTANCE This work is particularly important because it simultaneously assessed the virology, immunology, and clinical presentation of the same subjects, whereas other studies assess these separately. We describe the detailed viral and immune profiles of the first five patients infected by SARS-CoV-2 and quarantined in Geneva, Switzerland. Viral loads peaked at the very beginning of the disease, and infectious virus was shed only during the early acute phase of disease. No infectious virus could be isolated by culture 7 days after onset of symptoms, while viral RNA was still detectable for a prolonged period. Importantly, we saw that all patients, even those with mild symptoms, mount an innate response sufficient for viral control (characterized by early activated cytokines and monocyte responses) and develop specific immunity as well as cellular and humoral SARS-CoV-2-specific adaptive responses, which already begin to decline a few months after the resolution of symptoms.


Asunto(s)
Inmunidad Adaptativa , Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Inmunidad Innata , Neumonía Viral/inmunología , Neumonía Viral/virología , Carga Viral , Esparcimiento de Virus , Adulto , Anciano , Anticuerpos Antivirales/metabolismo , Betacoronavirus/aislamiento & purificación , Biomarcadores/metabolismo , Técnicas de Laboratorio Clínico , Infecciones por Coronavirus/diagnóstico , Citocinas/metabolismo , Humanos , Cinética , Persona de Mediana Edad , Pandemias , Neumonía Viral/diagnóstico , Índice de Severidad de la Enfermedad
5.
Nat Commun ; 11(1): 5777, 2020 11 13.
Artículo en Inglés | MEDLINE | ID: mdl-33188170

RESUMEN

Vibrio parahaemolyticus is the leading cause of seafood-borne diarrheal diseases. Experimental overproduction of a type 3 secretion system (T3SS1) in this pathogen leads to decreased intestinal colonization, which suggests that T3SS1 repression is required for maximal virulence. However, the mechanisms by which T3SS1 is repressed in vivo are unclear. Here, we show that host-derived nitrite modifies the activity of a bacterial histidine kinase and mediates T3SS1 repression. More specifically, nitrite activates histidine kinase sensor VbrK through S-nitrosylation on cysteine 86, which results in downregulation of the entire T3SS1 operon through repression of its positive regulator exsC. Replacement of cysteine 86 with a serine (VbrK C86S mutant) leads to increased expression of inflammatory cytokines in infected Caco-2 cells. In an infant rabbit model of infection, the VbrK C86S mutant induces a stronger inflammatory response at the early stage of infection, and displays reduced intestinal colonization and virulence at the later stage of infection, in comparison with the parent strain. Our results indicate that the pathogen V. parahaemolyticus perceives nitrite as a host-derived signal and responds by downregulating a proinflammatory factor (T3SS1), thus enhancing intestinal colonization and virulence.


Asunto(s)
Proteínas Bacterianas/metabolismo , Histidina Quinasa/metabolismo , Sistemas de Secreción Tipo III/metabolismo , Vibrio parahaemolyticus/metabolismo , Vibrio parahaemolyticus/patogenicidad , Anaerobiosis , Animales , Secuencia de Bases , Sitios de Unión , Células CACO-2 , Citocinas/metabolismo , Regulación hacia Abajo/genética , Regulación Bacteriana de la Expresión Génica , Interacciones Huésped-Patógeno/genética , Humanos , Modelos Biológicos , Nitratos/metabolismo , Nitritos/metabolismo , Nitrosación , Fosforilación , Regiones Promotoras Genéticas/genética , Unión Proteica , Conejos , Transcripción Genética , Vibrio parahaemolyticus/genética , Virulencia/genética
6.
An Acad Bras Cienc ; 92(4): e20200012, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33206789

RESUMEN

Professional athletes conduct high-intensitive hypoxic training often accompanied by the increase of many inflammatory-related cytokines and immunosuppression. Cucurbitacin E (CucE), as a triterpenoid isolated from Cucurbitaceae plants, exert potential anti-cancer and anti-inflammatory. However, it is unknown whether that the CucE could be used as dietary supplement for athletes to improve inflammatory response and immunosuppression. In this study, we established the simulative hypoxic training rat and monkey models and evaluated the effects of CucE on immune- and inflammation-related factors. Obvious improvement on pro-inflammatory factors and pro-lymphocyte proliferation activities were showed in CucE treated rats compared with the control. Further supplement of CucE in professional meals for cynomolgus monkeys with 4-weeks high-intensitive hypoxic training also exert effects on altitude-induced oxidative stress, inflammation and immunologic function. Furtherly, we explored the underlying mechanism of CucE in human Jurkat T cells and results showed that CucE may exhibit immunosuppressive effect by attenuating critical cytokine expression through down-regulating the NF-κB signaling pathway. In conclusion, CucE is expected to be a potential dietary supplement for athletes to ameliorate the inflammation and immunosuppression caused by high-intensitive exercise.


Asunto(s)
Altitud , Triterpenos , Animales , Citocinas/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Estrés Oxidativo , Ratas , Triterpenos/farmacología
7.
J Toxicol Sci ; 45(11): 701-711, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33132244

RESUMEN

We aimed to investigate the role of programmed cell death protein 1 (PD-1) and T lymphocytes in the proliferation, apoptosis and secretion of cells from patients and mice with Graves' disease (GD). The levels of serum hormones, related antibodies and inflammatory cytokines in GD patients were determined by electrochemiluminescence immunoassay and ELISA. The percentages of CD4 and CD8 T-lymphocytes and PD-1 expression were examined by flow cytometry. A GD mouse model, a thyroid follicular epithelial cell, and a CD4+PD-1+, CD4+PD-1- and CD8+PD-1+, CD8+PD-1- T lymphocyte co-culture system were constructed. The viability, apoptosis-related markers, serum hormones, related antibodies and inflammatory cytokines in thyroid follicular epithelial cells were determined by CCK-8, Western blot, qTR-PCR, electrochemiluminescence immunoassay and ELISA. Elevated free thyroid hormones (FT3, FT4), thyroid hormone antibodies (TRAb, TPOAb and TGAb), inflammatory cytokines, and inhibited TSH were observed in GD patients. The percentage of CD4+ T cells was increased, while that of CD8+ T cells was reduced in GD patients. PD-1 expression level was lifted in both CD4+ and CD8+ cells from GD patients. In mouse thyroid follicular epithelial cells co-cultured with CD4+PD-1+ and CD8+PD-1+ T lymphocytes, the cell viability, TH and TRAb levels and inflammatory cytokines level were the highest, while the TSH level and apoptosis were the lowest. PD-1 positive T lymphocytes were able to promote viability and inhibit apoptosis of thyroid follicular epithelial cells, which further caused a more accelerated development of GD.


Asunto(s)
Antígeno B7-H1/inmunología , Antígeno B7-H1/fisiología , Proliferación Celular , Citocinas/metabolismo , Células Epiteliales/inmunología , Células Epiteliales/fisiología , Enfermedad de Graves/genética , Enfermedad de Graves/inmunología , Mediadores de Inflamación/metabolismo , Linfocitos/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/fisiología , Glándula Tiroides/citología , Adulto , Animales , Apoptosis , Células Cultivadas , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Enfermedad de Graves/patología , Humanos , Masculino , Ratones Endogámicos BALB C , Persona de Mediana Edad
8.
Cell Death Dis ; 11(11): 957, 2020 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-33159040

RESUMEN

A global effort is currently undertaken to restrain the COVID-19 pandemic. Host immunity has come out as a determinant for COVID-19 clinical outcomes, and several studies investigated the immune profiling of SARS-CoV-2 infected people to properly direct the clinical management of the disease. Thus, lymphopenia, T-cell exhaustion, and the increased levels of inflammatory mediators have been described in COVID-19 patients, in particular in severe cases1. Age represents a key factor in COVID-19 morbidity and mortality2. Understanding age-associated immune signatures of patients are therefore important to identify preventive and therapeutic strategies. In this study, we investigated the immune profile of COVID-19 hospitalized patients identifying a distinctive age-dependent immune signature associated with disease severity. Indeed, defined circulating factors - CXCL8, IL-10, IL-15, IL-27, and TNF-α - positively correlate with older age, longer hospitalization, and a more severe form of the disease and may thus represent the leading signature in critical COVID-19 patients.


Asunto(s)
Infecciones por Coronavirus/patología , Citocinas/metabolismo , Neumonía Viral/patología , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Betacoronavirus/inmunología , Betacoronavirus/aislamiento & purificación , Análisis por Conglomerados , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Femenino , Humanos , Inmunoglobulina G/sangre , Interleucina-10/metabolismo , Interleucina-8/metabolismo , Tiempo de Internación , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/virología , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/metabolismo
9.
Int J Nanomedicine ; 15: 8411-8426, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33149584

RESUMEN

Background: Gold nanoparticles with high biocompatibility and immunomodulatory properties have potential applications in the development of new diagnostic and therapeutic strategies for nanomedicine. Nanoparticles targeting macrophages can manipulate or control immunological diseases. This study assessed the activity of dendrimer-encapsulated gold nanodots (AuNDs) with three surface modifications [ie, outfacing groups with primary amine (AuNDs-NH2), hydroxyl (AuNDs-OH), and quaternary ammonium ions (AuNDs-CH3)] regulated macrophage function and antioxidant response through Nrf2-dependent pathway. Methods: AuNDs were prepared and characterized. Intracellular distribution of AuNDs in human macrophages was observed through confocal microscopy. The activity of AuNDs was evaluated using macrophage functions and antioxidant response in the human macrophage cell line THP-1. Results: AuNDs-NH2 and AuNDs-CH3, but not AuNDs-OH, drove the obvious Nrf2-antioxidant response element pathway in THP-1 cells. Of the three, AuNDs-NH2 considerably increased mRNA levels and antioxidant activities of heme oxygenase 1 and NAD(P)H quinone dehydrogenase 1 in THP-1 cells. IL-6 mRNA and protein expression was mediated through Nrf2 activation in AuNDs-NH2-treated macrophages. Furthermore, Nrf2 activation by AuNDs-NH2 increased the phagocytic ability of THP-1 macrophages. Conclusion: AuNDs-NH2 had immunomodulatory activities in macrophages. The findings of the present work suggested that AuNDs have potential effects against chronic inflammatory diseases via the Nrf2 pathway.


Asunto(s)
Aminas/química , Antioxidantes/metabolismo , Oro/química , Macrófagos/metabolismo , Nanopartículas del Metal/química , Terapia Molecular Dirigida , Factor 2 Relacionado con NF-E2/metabolismo , Citocinas/metabolismo , Endotoxinas/metabolismo , Hemo-Oxigenasa 1/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Estrés Oxidativo , Fagocitosis , Fosforilación , Especies Reactivas de Oxígeno/metabolismo , Células THP-1
10.
Cell Transplant ; 29: 963689720965980, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33040594

RESUMEN

Novel therapies are urgently needed to combat the severe cytokine storm syndromes induced by coronavirus disease 2019 (COVID-19). An increasing number of preclinical and clinical investigations of stem cell and derivatives therapy for COVID-19 were being carried out, among which several studies have preliminarily demonstrated the safety and possible efficacy of stem cell transplantation therapy, providing a hint to solve the tricky situation of anti-COVID-19.


Asunto(s)
Infecciones por Coronavirus/terapia , Citocinas/metabolismo , Trasplante de Células Madre Mesenquimatosas , Neumonía Viral/terapia , Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Humanos , Linfocitos/citología , Linfocitos/metabolismo , Pandemias , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/patología , Neumonía Viral/virología , Cordón Umbilical/citología
11.
Toxicol Lett ; 334: 66-77, 2020 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-33002524

RESUMEN

Although colchicine (COL) has been used to treat gout for more than a thousand years, it has been shrouded in a dark history for a long time due to its high toxicity, especially for the gastrointestinal tract. With the widespread clinical application of COL, COL's toxicity to the gastrointestinal tract has raised concerns. This study's objective was to address the exact intestinal toxicity of COL, with particular attention to the effects of COL on gut microbiota homeostasis. The mice were exposed to various dosages of COL (0.1, 0.5, and 2.5 mg kg-1 body weight per day) for a week, and the results showed that COL exposure caused serious intestinal injuries, reducing the relative expression levels of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and tight junction proteins (zo-1, claudin-1, and occludin) in the ileum and colon tissue. The 16S rRNA gene sequencing analysis of mice feces samples revealed that the composition and diversity of intestinal microbiome underwent a profound remodeling at the dosage of 2.5 mg kg-1 body weight per day, which may increase the toxic load in the gut. In addition, elevated levels of diamine oxidase (DAO) and lipopolysaccharide (LPS) in serum indicated that COL increased intestinal permeability, impairing intestinal barrier. In conclusion, our results demonstrate that COL's toxicity to the gut microbiome is compatible with intestinal injuries, inflammatory pathway inhibition, and increased intestinal permeability; our results also represent a novel insight to uncover the adverse reactions of COL in the gastrointestinal tract.


Asunto(s)
Colchicina/toxicidad , Citocinas/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Proteínas de Uniones Estrechas/metabolismo , Animales , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Masculino , Ratones , Ratones Endogámicos , Permeabilidad
12.
Nat Microbiol ; 5(11): 1439-1448, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33028965

RESUMEN

SARS-CoV-2 is causing a pandemic of COVID-19, with high infectivity and significant mortality1. Currently, therapeutic options for COVID-19 are limited. Historically, metal compounds have found use as antimicrobial agents, but their antiviral activities have rarely been explored. Here, we test a set of metallodrugs and related compounds, and identify ranitidine bismuth citrate, a commonly used drug for the treatment of Helicobacter pylori infection, as a potent anti-SARS-CoV-2 agent, both in vitro and in vivo. Ranitidine bismuth citrate exhibited low cytotoxicity and protected SARS-CoV-2-infected cells with a high selectivity index of 975. Importantly, ranitidine bismuth citrate suppressed SARS-CoV-2 replication, leading to decreased viral loads in both upper and lower respiratory tracts, and relieved virus-associated pneumonia in a golden Syrian hamster model. In vitro studies showed that ranitidine bismuth citrate and its related compounds exhibited inhibition towards both the ATPase (IC50 = 0.69 µM) and DNA-unwinding (IC50 = 0.70 µM) activities of the SARS-CoV-2 helicase via an irreversible displacement of zinc(II) ions from the enzyme by bismuth(III) ions. Our findings highlight viral helicase as a druggable target and the clinical potential of bismuth(III) drugs or other metallodrugs for the treatment of SARS-CoV-2 infection.


Asunto(s)
Antivirales/farmacología , Betacoronavirus/efectos de los fármacos , Bismuto/farmacología , Infecciones por Coronavirus/virología , Neumonía Viral/virología , Ranitidina/análogos & derivados , Replicación Viral/efectos de los fármacos , Animales , Betacoronavirus/fisiología , Quimiocinas/metabolismo , Chlorocebus aethiops , Infecciones por Coronavirus/tratamiento farmacológico , Citocinas/metabolismo , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Pulmón/patología , Pulmón/virología , Mesocricetus , Pandemias , Neumonía Viral/tratamiento farmacológico , ARN Helicasas/metabolismo , Ranitidina/farmacología , Células Vero , Carga Viral
13.
Chem Biol Interact ; 331: 109282, 2020 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-33031791

RESUMEN

The novel human coronavirus-2 (HCoV-2), called SARS-CoV-2, is the causative agent of Coronavirus Induced Disease (COVID-19) and has spread causing a global pandemic. Currently, there is no vaccine to prevent infection nor any approved drug for the treatment. The development of a new drug is time-consuming and cannot be relied on as a solution in combatting the immediate global challenge. In such a situation, the drug repurposing becomes an attractive solution to identify the potential of COVID-19 treatment by existing drugs, which are approved for other indications. Here, we review the potential use of rapamycin, an mTOR (Mammalian Target of Rapamycin) inhibitor that can be repurposed at low dosages for the treatment of COVID-19. Rapamycin inhibits protein synthesis, delays aging, reduces obesity in animal models, and inhibits activities or expression of pro-inflammatory cytokines such as IL-2, IL-6 and, IL-10. Overall, the use of rapamycin can help to control viral particle synthesis, cytokine storms and contributes to fight the disease by its anti-aging and anti-obesity effects. Since, rapamycin targets the host factors and not viral machinery, it represents a potent candidate for the treatment of COVID-19 than antiviral drugs as its efficacy is less likely to be dampened with high mutation rate of viral RNA. Additionally, the inhibitory effect of rapamycin on cell proliferation may aid in reducing viral replication. Therefore, by drug repurposing, low dosages of rapamycin can be tested for the potential treatment of COVID-19/SARS-CoV-2 infection.


Asunto(s)
Infecciones por Coronavirus/tratamiento farmacológico , Reposicionamiento de Medicamentos , Neumonía Viral/tratamiento farmacológico , Sirolimus/uso terapéutico , Betacoronavirus/aislamiento & purificación , Betacoronavirus/fisiología , Proliferación Celular/efectos de los fármacos , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Citocinas/metabolismo , Expresión Génica/efectos de los fármacos , Humanos , Pandemias , Neumonía Viral/patología , Neumonía Viral/virología , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Replicación Viral/efectos de los fármacos
14.
Anatol J Cardiol ; 24(4): 224-234, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33001051

RESUMEN

Coronavirus disease 2019 (COVID-19) caused by 'Severe Acute Respiratory Syndrome Coronavirus-2' (SARS-CoV-2) infection emerged in Wuhan, a city of China, and spread to the entire planet in early 2020. The virus enters the respiratory tract cells and other tissues via ACE2 receptors. Approximately 20% of infected subjects develop severe or critical disease. A cytokine storm leads to over inflammation and thrombotic events. The most common clinical presentation in COVID-19 is pneumonia, typically characterized by bilateral, peripheral, and patchy infiltrations in the lungs. However multi-systemic involvement including peripheral thromboembolic skin lesions, central nervous, gastrointestinal, circulatory, and urinary systems are reported. The disease has a higher mortality compared to other viral agents causing pneumonia and unfortunately, no approved specific therapy, nor vaccine has yet been discovered. Several clinical trials are ongoing with hydroxychloroquine, remdesivir, favipiravir, and low molecular weight heparins. This comprehensive review aimed to summarize coagulation abnormalities reported in COVID-19, discuss the thrombosis, and inflammation-driven background of the disease, emphasize the impact of thrombotic and inflammatory processes on the progression and prognosis of COVID-19, and to provide evidence-based therapeutic guidance, especially from antithrombotic and anti-inflammatory perspectives.


Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/complicaciones , Inflamación/virología , Neumonía Viral/complicaciones , Trombosis/virología , Trastornos de la Coagulación Sanguínea/terapia , Trastornos de la Coagulación Sanguínea/virología , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/terapia , Infecciones por Coronavirus/virología , Citocinas/metabolismo , Trastornos Hemostáticos/virología , Humanos , Inmunomodulación/fisiología , Inflamación/terapia , Pandemias , Neumonía Viral/mortalidad , Neumonía Viral/terapia , Neumonía Viral/virología , Pronóstico , Trombosis/terapia
15.
Nat Commun ; 11(1): 5163, 2020 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-33057020

RESUMEN

Parkinson's disease-associated kinase LRRK2 has been linked to IFN type II (IFN-γ) response in infections and to dopaminergic neuronal loss. However, whether and how LRRK2 synergizes with IFN-γ remains unclear. In this study, we employed dopaminergic neurons and microglia differentiated from patient-derived induced pluripotent stem cells carrying LRRK2 G2019S, the most common Parkinson's disease-associated mutation. We show that IFN-γ enhances the LRRK2 G2019S-dependent negative regulation of AKT phosphorylation and NFAT activation, thereby increasing neuronal vulnerability to immune challenge. Mechanistically, LRRK2 G2019S suppresses NFAT translocation via calcium signaling and possibly through microtubule reorganization. In microglia, LRRK2 modulates cytokine production and the glycolytic switch in response to IFN-γ in an NFAT-independent manner. Activated LRRK2 G2019S microglia cause neurite shortening, indicating that LRRK2-driven immunological changes can be neurotoxic. We propose that synergistic LRRK2/IFN-γ activation serves as a potential link between inflammation and neurodegeneration in Parkinson's disease.


Asunto(s)
Neuronas Dopaminérgicas/inmunología , Interferón gamma/metabolismo , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Microglía/inmunología , Enfermedad de Parkinson/inmunología , Señalización del Calcio/genética , Diferenciación Celular , Citocinas/metabolismo , Neuronas Dopaminérgicas/metabolismo , Técnicas de Inactivación de Genes , Glucólisis/genética , Células HEK293 , Humanos , Células Madre Pluripotentes Inducidas/fisiología , Interferón gamma/inmunología , Microscopía Intravital , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Microglía/metabolismo , Microtúbulos/metabolismo , Mutación , Factores de Transcripción NFATC/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Cultivo Primario de Células , Transducción de Señal/genética , Transducción de Señal/inmunología , Células THP-1
16.
Signal Transduct Target Ther ; 5(1): 240, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-33060566

RESUMEN

The COVID-19 pandemic has emerged as a global health emergency due to its association with severe pneumonia and relative high mortality. However, the molecular characteristics and pathological features underlying COVID-19 pneumonia remain largely unknown. To characterize molecular mechanisms underlying COVID-19 pathogenesis in the lung tissue using a proteomic approach, fresh lung tissues were obtained from newly deceased patients with COVID-19 pneumonia. After virus inactivation, a quantitative proteomic approach combined with bioinformatics analysis was used to detect proteomic changes in the SARS-CoV-2-infected lung tissues. We identified significant differentially expressed proteins involved in a variety of fundamental biological processes including cellular metabolism, blood coagulation, immune response, angiogenesis, and cell microenvironment regulation. Several inflammatory factors were upregulated, which was possibly caused by the activation of NF-κB signaling. Extensive dysregulation of the lung proteome in response to SARS-CoV-2 infection was discovered. Our results systematically outlined the molecular pathological features in terms of the lung response to SARS-CoV-2 infection, and provided the scientific basis for the therapeutic target that is urgently needed to control the COVID-19 pandemic.


Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/genética , Lesión Pulmonar/genética , Neumonía Viral/genética , Proteoma/genética , Proteómica/métodos , Síndrome Respiratorio Agudo Grave/genética , Anciano , Autopsia , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Citocinas/genética , Citocinas/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ontología de Genes , Humanos , Pulmón/metabolismo , Pulmón/patología , Pulmón/virología , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Lesión Pulmonar/virología , Masculino , Redes y Vías Metabólicas , Anotación de Secuencia Molecular , FN-kappa B/genética , FN-kappa B/metabolismo , Pandemias , Neumonía Viral/metabolismo , Neumonía Viral/patología , Neumonía Viral/virología , Proteoma/metabolismo , Síndrome Respiratorio Agudo Grave/metabolismo , Síndrome Respiratorio Agudo Grave/patología , Síndrome Respiratorio Agudo Grave/virología , Índice de Severidad de la Enfermedad , Transducción de Señal
18.
Nat Commun ; 11(1): 5086, 2020 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-33033248

RESUMEN

Coronavirus Disease 19 (COVID-19) is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has grown to a worldwide pandemic with substantial mortality. Immune mediated damage has been proposed as a pathogenic factor, but immune responses in lungs of COVID-19 patients remain poorly characterized. Here we show transcriptomic, histologic and cellular profiles of post mortem COVID-19 (n = 34 tissues from 16 patients) and normal lung tissues (n = 9 tissues from 6 patients). Two distinct immunopathological reaction patterns of lethal COVID-19 are identified. One pattern shows high local expression of interferon stimulated genes (ISGhigh) and cytokines, high viral loads and limited pulmonary damage, the other pattern shows severely damaged lungs, low ISGs (ISGlow), low viral loads and abundant infiltrating activated CD8+ T cells and macrophages. ISGhigh patients die significantly earlier after hospitalization than ISGlow patients. Our study may point to distinct stages of progression of COVID-19 lung disease and highlights the need for peripheral blood biomarkers that inform about patient lung status and guide treatment.


Asunto(s)
Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Neumonía Viral/inmunología , Neumonía Viral/patología , Anciano , Anciano de 80 o más Años , Betacoronavirus/patogenicidad , Betacoronavirus/fisiología , Linfocitos T CD8-positivos/inmunología , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/virología , Citocinas/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Interferones/metabolismo , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Macrófagos/inmunología , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/mortalidad , Neumonía Viral/virología , Carga Viral
19.
Biol Direct ; 15(1): 19, 2020 10 16.
Artículo en Inglés | MEDLINE | ID: mdl-33066821

RESUMEN

The spike glycoprotein of the SARS-CoV-2 virus, which causes COVID-19, has attracted attention for its vaccine potential and binding capacity to host cell surface receptors. Much of this research focus has centered on the ectodomain of the spike protein. The ectodomain is anchored to a transmembrane region, followed by a cytoplasmic tail. Here we report a distant sequence similarity between the cysteine-rich cytoplasmic tail of the coronavirus spike protein and the hepcidin protein that is found in humans and other vertebrates. Hepcidin is thought to be the key regulator of iron metabolism in humans through its inhibition of the iron-exporting protein ferroportin. An implication of this preliminary observation is to suggest a potential route of investigation in the coronavirus research field making use of an already-established literature on the interplay of local and systemic iron regulation, cytokine-mediated inflammatory processes, respiratory infections and the hepcidin protein. The question of possible homology and an evolutionary connection between the viral spike protein and hepcidin is not assessed in this report, but some scenarios for its study are discussed.


Asunto(s)
Betacoronavirus/genética , Infecciones por Coronavirus/virología , Hepcidinas/genética , Hierro/metabolismo , Neumonía Viral/virología , Glicoproteína de la Espiga del Coronavirus/genética , Animales , Proteínas de Transporte de Catión/metabolismo , Cisteína/química , Citocinas/metabolismo , Citoplasma/metabolismo , Hepcidinas/química , Humanos , Hipoxia , Inflamación , Interleucina-6/metabolismo , Pandemias , Dominios Proteicos , Procesamiento Proteico-Postraduccional , Alineación de Secuencia , Glicoproteína de la Espiga del Coronavirus/química , Tetraodontiformes
20.
J Pharmacol Sci ; 144(4): 189-196, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33070837

RESUMEN

Pneumonia is a common illness that continues to be the major killer of remaining to be a significant source of morbidity and mortality in the patient population. Many microorganisms cause pneumonia, and now concern is turning to the importance of the cause the new therapies for viral pneumonia. In the current study, we report the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on poly I: C-induced pneumonia. Andrographolide sulfonate was administrated through intraperitoneal injection to mice with poly I: C-induced pneumonia. Recruitment of airway inflammatory cells, alteration of lung histological induced by Poly I: C were significantly ameliorated by andrographolide sulfonate. The protein levels of pro-inflammatory cytokines in bronchoalveolar fluid (BALF) and serum were reduced by andrographolide sulfonate treatment. The levels of MUC5AC and MUC5B in lung tissue were also suppressed. These results reveal that andrographolide sulfate remarkably alleviated pneumonia induced by poly I:C in mice. Moreover, andrographolide sulfonate markedly inhibited the activation of nuclear factor-κB (NF-κB). Taken together, we demonstrated that andrographolide sulfonate ameliorated poly I: C-induced pneumonia in mice, suggesting the possible use of andrographolide sulfonate for virus-induced pneumonia in clinical.


Asunto(s)
Diterpenos/administración & dosificación , Diterpenos/farmacología , FN-kappa B/metabolismo , Fitoterapia , Neumonía/tratamiento farmacológico , Neumonía/metabolismo , Poli I-C/efectos adversos , Animales , Citocinas/sangre , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Inyecciones Intraperitoneales , Masculino , Ratones Endogámicos C57BL , Mucina 5AC/metabolismo , Mucina 5B/metabolismo , Neumonía/inducido químicamente , Neumonía/patología , Neumonía Viral/tratamiento farmacológico
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