Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.204
Filtrar
1.
Int J Mol Sci ; 22(17)2021 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-34502274

RESUMO

Heat shock proteins (HSPs) are a large group of chaperones found in most eukaryotes and bacteria. They are responsible for the correct protein folding, protection of the cell against stressors, presenting immune and inflammatory cytokines; furthermore, they are important factors in regulating cell differentiation, survival and death. Although the biological function of HSPs is to maintain cell homeostasis, some of them can be used by viruses both to fold their proteins and increase the chances of survival in unfavorable host conditions. Folding viral proteins as well as replicating many different viruses are carried out by, among others, proteins from the HSP70 and HSP90 families. In some cases, the HSP70 family proteins directly interact with viral polymerase to enhance viral replication or they can facilitate the formation of a viral replication complex and/or maintain the stability of complex proteins. It is known that HSP90 is important for the expression of viral genes at both the transcriptional and the translational levels. Both of these HSPs can form a complex with HSP90 and, consequently, facilitate the entry of the virus into the cell. Current studies have shown the biological significance of HSPs in the course of infection SARS-CoV-2. A comprehensive understanding of chaperone use during viral infection will provide new insight into viral replication mechanisms and therapeutic potential. The aim of this study is to describe the molecular basis of HSP70 and HSP90 participation in some viral infections and the potential use of these proteins in antiviral therapy.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Viroses/patologia , COVID-19/metabolismo , COVID-19/patologia , COVID-19/virologia , Vírus de DNA/fisiologia , Humanos , Isoformas de Proteínas/metabolismo , Vírus de RNA/fisiologia , SARS-CoV-2/isolamento & purificação , Viroses/metabolismo , Viroses/virologia
2.
Int J Mol Sci ; 22(16)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34445766

RESUMO

The endosomal sorting complex required for transport (ESCRT) system consists of peripheral membrane protein complexes ESCRT-0, -I, -II, -III VPS4-VTA1, and ALIX homodimer. This system plays an important role in the degradation of non-essential or dangerous plasma membrane proteins, the biogenesis of lysosomes and yeast vacuoles, the budding of most enveloped viruses, and promoting membrane shedding of cytokinesis. Recent results show that exosomes and the ESCRT pathway play important roles in virus infection. This review mainly focuses on the roles of exosomes and the ESCRT pathway in virus assembly, budding, and infection of enveloped viruses. The elaboration of the mechanism of exosomes and the ESCRT pathway in some enveloped viruses provides important implications for the further study of the infection mechanism of other enveloped viruses.


Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Exossomos/metabolismo , Envelope Viral/fisiologia , Viroses/metabolismo , Liberação de Vírus , Animais , Humanos , Corpos Multivesiculares/metabolismo
3.
Viruses ; 13(7)2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34372572

RESUMO

Human APOBEC3 (apolipoprotein B mRNA-editing catalytic polypeptide-like 3) enzymes are capable of inhibiting a wide range of endogenous and exogenous viruses using deaminase and deaminase-independent mechanisms. These enzymes are essential components of our innate immune system, as evidenced by (a) their strong positive selection and expansion in primates, (b) the evolution of viral counter-defense mechanisms, such as proteasomal degradation mediated by HIV Vif, and (c) hypermutation and inactivation of a large number of integrated HIV-1 proviruses. Numerous APOBEC3 single nucleotide polymorphisms, haplotypes, and splice variants have been identified in humans. Several of these variants have been reported to be associated with differential antiviral immunity. This review focuses on the current knowledge in the field about these natural variations and their roles in infectious diseases.


Assuntos
Desaminases APOBEC/genética , Desaminases APOBEC/metabolismo , Viroses/genética , Citidina Desaminase/genética , Citosina Desaminase/genética , HIV-1/fisiologia , Vírus da Hepatite B/fisiologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/imunologia , Polimorfismo Genético/genética , Isoformas de Proteínas/genética , Viroses/metabolismo , Replicação Viral/genética
4.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360716

RESUMO

Oxygen is essential for aerobic cells, and thus its sensing is critical for the optimal maintenance of vital cellular and tissue processes such as metabolism, pH homeostasis, and angiogenesis, among others. Hypoxia-inducible factors (HIFs) play central roles in oxygen sensing. Under hypoxic conditions, the α subunit of HIFs is stabilized and forms active heterodimers that translocate to the nucleus and regulate the expression of important sets of genes. This process, in turn, will induce several physiological changes intended to adapt to these new and adverse conditions. Over the last decades, numerous studies have reported a close relationship between viral infections and hypoxia. Interestingly, this relation is somewhat bidirectional, with some viruses inducing a hypoxic response to promote their replication, while others inhibit hypoxic cellular responses. Here, we review and discuss the cellular responses to hypoxia and discuss how HIFs can promote a wide range of physiological and transcriptional changes in the cell that modulate numerous human viral infections.


Assuntos
Fator 1 Induzível por Hipóxia/metabolismo , Consumo de Oxigênio , Viroses/metabolismo , Replicação Viral , Vírus/metabolismo , Hipóxia Celular , Humanos , Viroses/patologia
5.
J Gen Virol ; 102(8)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34424156

RESUMO

Viruses may exploit the cardiovascular system to facilitate transmission or within-host dissemination, and the symptoms of many viral diseases stem at least in part from a loss of vascular integrity. The microvascular architecture is comprised of an endothelial cell barrier ensheathed by perivascular cells (pericytes). Pericytes are antigen-presenting cells (APCs) and play crucial roles in angiogenesis and the maintenance of microvascular integrity through complex reciprocal contact-mediated and paracrine crosstalk with endothelial cells. We here review the emerging ways that viruses interact with pericytes and pay consideration to how these interactions influence microvascular function and viral pathogenesis. Major outcomes of virus-pericyte interactions include vascular leakage or haemorrhage, organ tropism facilitated by barrier disruption, including viral penetration of the blood-brain barrier and placenta, as well as inflammatory, neurological, cognitive and developmental sequelae. The underlying pathogenic mechanisms may include direct infection of pericytes, pericyte modulation by secreted viral gene products and/or the dysregulation of paracrine signalling from or to pericytes. Viruses we cover include the herpesvirus human cytomegalovirus (HCMV, Human betaherpesvirus 5), the retrovirus human immunodeficiency virus (HIV; causative agent of acquired immunodeficiency syndrome, AIDS, and HIV-associated neurocognitive disorder, HAND), the flaviviruses dengue virus (DENV), Japanese encephalitis virus (JEV) and Zika virus (ZIKV), and the coronavirus severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2; causative agent of coronavirus disease 2019, COVID-19). We touch on promising pericyte-focussed therapies for treating the diseases caused by these important human pathogens, many of which are emerging viruses or are causing new or long-standing global pandemics.


Assuntos
Fenômenos Fisiológicos Celulares , Suscetibilidade a Doenças , Interações Hospedeiro-Patógeno , Pericitos/virologia , Viroses/metabolismo , Viroses/virologia , Animais , Comunicação Celular , Vírus da Dengue/fisiologia , Gerenciamento Clínico , Células Endoteliais/virologia , Endotélio/metabolismo , Endotélio/virologia , HIV/fisiologia , Humanos , Comunicação Parácrina , SARS-CoV-2/fisiologia , Viroses/diagnóstico , Viroses/terapia , Fenômenos Fisiológicos Virais
6.
Nutrients ; 13(7)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34371920

RESUMO

Nutraceuticals, including vitamin D, vitamin A, zinc, lactoferrin, polyphenols coenzyme Q, magnesium, and selenium, are implicated in the modulation of the complex molecular pathways involved in the immune response against viral pathogens. A common element of the activity of nutraceuticals is their ability to enhance the innate immune response against pathogens by acting on the major cellular subsets and inducing the release of pro-inflammatory cytokines and antimicrobial peptides. In some cases, this action is accompanied by a direct antimicrobial effect, as evidenced in the specific case of lactoferrin. Furthermore, nutraceuticals act through complex molecular mechanisms to minimize the damage caused by the activation of the immune system against pathogens, reducing the oxidative damage, influencing the antigen presentation, enhancing the differentiation and proliferation of regulatory T cells, driving the differentiation of lymphocyte subsets, and modulating the production of pro-inflammatory cytokines. In this paper, we review the main molecular mechanisms responsible for the immunomodulatory function of nutraceuticals, focusing on the most relevant aspects for the prevention and treatment of viral infections.


Assuntos
Antivirais/uso terapêutico , Suplementos Nutricionais , Sistema Imunitário/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Viroses/tratamento farmacológico , Vírus/efeitos dos fármacos , Animais , Antivirais/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Interações Hospedeiro-Patógeno , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Sistema Imunitário/virologia , Fatores Imunológicos/efeitos adversos , Resultado do Tratamento , Viroses/imunologia , Viroses/metabolismo , Viroses/virologia , Vírus/imunologia , Vírus/patogenicidade
7.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360945

RESUMO

Mitochondria are vital intracellular organelles that play an important role in regulating various intracellular events such as metabolism, bioenergetics, cell death (apoptosis), and innate immune signaling. Mitochondrial fission, fusion, and membrane potential play a central role in maintaining mitochondrial dynamics and the overall shape of mitochondria. Viruses change the dynamics of the mitochondria by altering the mitochondrial processes/functions, such as autophagy, mitophagy, and enzymes involved in metabolism. In addition, viruses decrease the supply of energy to the mitochondria in the form of ATP, causing viruses to create cellular stress by generating ROS in mitochondria to instigate viral proliferation, a process which causes both intra- and extra-mitochondrial damage. SARS-COV2 propagates through altering or changing various pathways, such as autophagy, UPR stress, MPTP and NLRP3 inflammasome. Thus, these pathways act as potential targets for viruses to facilitate their proliferation. Autophagy plays an essential role in SARS-COV2-mediated COVID-19 and modulates autophagy by using various drugs that act on potential targets of the virus to inhibit and treat viral infection. Modulated autophagy inhibits coronavirus replication; thus, it becomes a promising target for anti-coronaviral therapy. This review gives immense knowledge about the infections, mitochondrial modulations, and therapeutic targets of viruses.


Assuntos
Autofagia , COVID-19/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/virologia , Animais , Autofagia/efeitos dos fármacos , COVID-19/tratamento farmacológico , Humanos , Dinâmica Mitocondrial/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Viroses/tratamento farmacológico , Viroses/metabolismo
8.
Int J Mol Sci ; 22(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299043

RESUMO

Bombyx mori nucleopolyhedrovirus (BmNPV) is a pathogen that causes great economic losses in sericulture. Many genes play a role in viral infection of silkworms, but silkworm metabolism in response to BmNPV infection is unknown. We studied BmE cells infected with BmNPV. We performed liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS)-based non-targeted metabolomics analysis of the cytosolic extract and identified 36, 76, 138, 101, 189, and 166 different molecules at 3, 6, 12, 24, 48, and 72 h post BmNPV infection (hpi) compared with 0 hpi. Compounds representing different areas of metabolism were increased in cells post BmNPV infection. These areas included purine metabolism, aminoacyl-tRNA biosynthesis, and ABC transporters. Glycerophosphocholine (GPC), 2-hydroxyadenine (2-OH-Ade), gamma-glutamylcysteine (γ-Glu-Cys), hydroxytolbutamide, and 5-pyridoxolactone glycerophosphocholine were continuously upregulated in BmE cells post BmNPV infection by heat map analysis. Only 5-pyridoxolactone was found to strongly inhibit the proliferation of BmNPV when it was used to treat BmE cells. Fewer infected cells were detected and the level of BmNPV DNA decreased with increasing 5-pyridoxolactone in a dose-dependent manner. The expression of BmNPV genes ie1, helicase, GP64, and VP39 in BmE cells treated with 5-pyridoxolactone were strongly inhibited in the BmNPV infection stage. This suggested that 5-pyridoxolactone may suppress the entry of BmNPV. The data in this study characterize the metabolism changes in BmNPV-infected cells. Further analysis of 5-pyridoxolactone, which is a robust antiviral molecule, may increase our understanding of antiviral immunity.


Assuntos
Antivirais/farmacologia , Bombyx/crescimento & desenvolvimento , Lactonas/farmacologia , Metaboloma , Nucleopoliedrovírus/efeitos dos fármacos , Viroses/tratamento farmacológico , Animais , Bombyx/efeitos dos fármacos , Bombyx/virologia , Viroses/metabolismo , Viroses/virologia
9.
Biochim Biophys Acta Mol Basis Dis ; 1867(11): 166218, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34311080

RESUMO

Throughout history, pandemics of infectious diseases caused by emerging viruses have spread worldwide. Evidence from previous outbreaks demonstrated that pregnant women are at high risk of contracting the diseases and suffering from adverse outcomes. However, while some viruses can cause major health complications for the mother and her fetus, others do not appear to affect pregnancy. Viral surface proteins bind to specific receptors on the cellular membrane of host cells and begin therewith the infection process. During pregnancy, the molecular features of these proteins may determine specific target cells in the placenta, which may explain the different outcomes. In this review, we display information on Variola, Influenza, Zika and Corona viruses focused on their surface proteins, effects on pregnancy, and possible target placental cells. This will contribute to understanding viral entry during pregnancy, as well as to develop strategies to decrease the incidence of obstetrical problems in current and future infections.


Assuntos
Placenta/virologia , Complicações Infecciosas na Gravidez/virologia , Proteínas do Envelope Viral/metabolismo , Viroses/virologia , Feminino , Humanos , Placenta/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Vírus da Varíola/metabolismo , Vírus da Varíola/patogenicidade , Viroses/metabolismo , Zika virus/metabolismo , Zika virus/patogenicidade
10.
Molecules ; 26(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209713

RESUMO

Antiviral action of various photosensitizers is already summarized in several comprehensive reviews, and various mechanisms have been proposed for it. However, a critical consideration of the matter of the area is complicated, since the exact mechanisms are very difficult to explore and clarify, and most publications are of an empirical and "phenomenological" nature, reporting a dependence of the antiviral action on illumination, or a correlation of activity with the photophysical properties of the substances. Of particular interest is substance-assisted photogeneration of highly reactive singlet oxygen (1O2). The damaging action of 1O2 on the lipids of the viral envelope can probably lead to a loss of the ability of the lipid bilayer of enveloped viruses to fuse with the lipid membrane of the host cell. Thus, lipid bilayer-affine 1O2 photosensitizers have prospects as broad-spectrum antivirals against enveloped viruses. In this short review, we want to point out the main types of antiviral photosensitizers with potential affinity to the lipid bilayer and summarize the data on new compounds over the past three years. Further understanding of the data in the field will spur a targeted search for substances with antiviral activity against enveloped viruses among photosensitizers able to bind to the lipid membranes.


Assuntos
Antivirais , Lipídeos de Membrana/metabolismo , Fármacos Fotossensibilizantes , Envelope Viral/metabolismo , Viroses , Vírus/metabolismo , Animais , Antivirais/química , Antivirais/farmacocinética , Antivirais/uso terapêutico , Humanos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/uso terapêutico , Oxigênio Singlete , Viroses/tratamento farmacológico , Viroses/metabolismo
11.
Lancet Digit Health ; 3(8): e507-e516, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34325854

RESUMO

BACKGROUND: Acute febrile illness is one of the main reasons for outpatient hospital visits worldwide. However, differential diagnosis between bacterial and viral causes is challenging and misdiagnosis can result in antimicrobial overuse and hinder prompt treatment. We aimed to build and validate a diagnostic model to discriminate bacterial from viral infection in acute febrile illness by evaluating the expression of potential classifier host genes. METHODS: In this multicentre discovery and validation study, we included patients aged 14-85 years with acute febrile illness (fever for ≤14 days, axillary temperature of ≥38°C, and confirmed bacterial infection, viral infection, or non-infectious inflammatory disease), and healthy control participants (no significant medical history and no fever within the past 90 days) from four hospitals in Shandong province, China. Patients from the first hospital were divided into the screening, discovery, and internal validation groups, and patients from the three other hospitals comprised the external validation group. We measured expression of candidate genes in peripheral blood by RT-PCR, and patients for whom a successful RT-PCT result was recorded were included in the next-step analysis. For patients from the first hospital, those enrolled during the early phase of the study were assigned to the screening group, which was used to identify the optimal transcripts (IFI44L and PI3) for discrimination between bacterial and viral infections by screening four candidate genes (FAM89A, IFI44L, PI3, and ITGB2) by RT-PCR. The remaining patients were then randomly assigned (1:1) to discovery and internal validation groups by time of admission and blood drawing via the equidistant random sampling method. A logistic regression model integrating the mRNA levels of IFI44L and PI3 was built by use of the discovery group, and the diagnostic performance of the model was evaluated in the internal and external validation groups using area under the receiver operating curve (AUC), sensitivity, and specificity. FINDINGS: Between March 1, 2018, and Aug 31, 2019, we assessed 1658 individuals for inclusion in the study. After exclusion of ineligible participants, 458 participants were enrolled (178 patients with acute febrile illness caused by bacterial infection, 212 with acute febrile illness caused by viral infection, 38 with non-infectious inflammatory diseases, and 30 healthy controls). The 390 patients with bacterial or viral infections were assigned to one of four groups: screening (n=64, 33 with bacterial infections and 31 with viral infections), discovery (n=124, 55 with bacterial infections and 69 with viral infections), internal validation (n=124, 55 with bacterial infections and 69 with viral infections), and external validation (n=78, 35 with bacterial infections and 43 with viral infections). Of the four candidate host genes (FAM89A, IFI44L, PI3, and ITGB2), IFI44L and PI3 showed the most discriminative expression pattern and were used to build the logistic regression model. We established the optimal cutoff of the bacterial infection likelihood score to be 0·547598. With the diagnostic result from the gold standard tests (culture and PCR) as the reference, the two-transcript classifier model had an AUC of 0·969 (95% CI 0·937-1·000), sensitivity of 0·891 (0·782-0·949), and specificity of 0·971 (0·900-0·992) to discriminate bacterial and viral infections in the internal validation group. The model showed similar results in the external validation group (AUC 0·986, 95% CI 0·968-1·000; sensitivity 0·857, 0·706-0·937; and specificity 0·954, 0·845-0·987). INTERPRETATION: IFI44L and PI3 transcripts, measured by RT-PCR, are robust classifiers to discriminate bacterial from viral infection in acute febrile illness. This two-transcript biomarker has the potential to be transformed into a commercial panel and applied universally. FUNDING: None.


Assuntos
Bactérias , Infecções Bacterianas/diagnóstico , Febre/diagnóstico , Programas de Rastreamento/métodos , Modelos Biológicos , Viroses/diagnóstico , Vírus , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Bactérias/crescimento & desenvolvimento , Infecções Bacterianas/metabolismo , Infecções Bacterianas/microbiologia , Biomarcadores/metabolismo , China , Diagnóstico Diferencial , Feminino , Febre/metabolismo , Febre/microbiologia , Febre/virologia , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Reprodutibilidade dos Testes , Viroses/metabolismo , Viroses/virologia , Vírus/crescimento & desenvolvimento , Adulto Jovem
12.
Biochimie ; 189: 76-86, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34153376

RESUMO

Soluble resistance-related calcium-binding protein (sorcin), a 22 kDa penta-EF-hand protein, has been intensively studied in cancers and multidrug resistance over a prolonged period. Sorcin is widely distributed in tissues and participates in the regulation of Ca2+ homeostasis and Ca2+-dependent signaling. Protein-protein interactions (PPIs) are essential for regulating protein functions in almost all biological processes. Sorcin interaction partners tend to vary in type, including Ca2+ receptors, Ca2+ transporters, endoplasmic reticulum stress markers, transcriptional regulatory elements, immunomodulation-related factors, and viral proteins. Recent studies have shown that sorcin is involved in a broad range of pathological conditions, such as cardiomyopathy, type 2 diabetes mellitus, neurodegenerative diseases, liver diseases, and viral infections. As a multifunctional cellular protein, in these diseases, sorcin has a role by interacting with or regulating the expression of other proteins, such as sarcoplasmic reticulum/endoplasmic reticulum Ca2+ ATPase, ryanodine receptors, presenilin 2, L-type Ca2+ channels, carbohydrate-responsive element-binding protein, tau, α-synuclein, signal transducer and activator of transcription 3, HCV nonstructural 5A protein, and viral capsid protein 1. This review summarizes the roles that sorcin plays in various diseases, mainly via different PPIs, and focuses principally on non-neoplastic diseases to help acquire a more comprehensive understanding of sorcin's multifunctional characteristics.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Cálcio/metabolismo , Cardiomiopatias/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hepatopatias/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Viroses/metabolismo , Proteínas de Ligação ao Cálcio/genética , Cardiomiopatias/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Hepatopatias/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Doenças Neurodegenerativas/genética , Viroses/genética
13.
Viruses ; 13(5)2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064347

RESUMO

Viral infections are responsible for several chronic and acute diseases in both humans and animals. Despite the incredible progress in human medicine, several viral diseases, such as acquired immunodeficiency syndrome, respiratory syndromes, and hepatitis, are still associated with high morbidity and mortality rates in humans. Natural products from plants or other organisms are a rich source of structurally novel chemical compounds including antivirals. Indeed, in traditional medicine, many pathological conditions have been treated using plant-derived medicines. Thus, the identification of novel alternative antiviral agents is of critical importance. In this review, we summarize novel phytochemicals with antiviral activity against human viruses and their potential application in treating or preventing viral disease.


Assuntos
Antivirais/farmacologia , Produtos Biológicos/farmacologia , Descoberta de Drogas , Animais , Antivirais/química , Antivirais/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/uso terapêutico , Vírus de DNA/efeitos dos fármacos , Vírus de DNA/fisiologia , Desenvolvimento de Medicamentos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Vírus de RNA/efeitos dos fármacos , Vírus de RNA/fisiologia , Viroses/diagnóstico , Viroses/tratamento farmacológico , Viroses/etiologia , Viroses/metabolismo , Replicação Viral/efeitos dos fármacos
14.
Genes Immun ; 22(3): 141-160, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34140652

RESUMO

When surveying the current literature on COVID-19, the "cytokine storm" is considered to be pathogenetically involved in its severe outcomes such as acute respiratory distress syndrome, systemic inflammatory response syndrome, and eventually multiple organ failure. In this review, the similar role of DAMPs is addressed, that is, of those molecules, which operate upstream of the inflammatory pathway by activating those cells, which ultimately release the cytokines. Given the still limited reports on their role in COVID-19, the emerging topic is extended to respiratory viral infections with focus on influenza. At first, a brief introduction is given on the function of various classes of activating DAMPs and counterbalancing suppressing DAMPs (SAMPs) in initiating controlled inflammation-promoting and inflammation-resolving defense responses upon infectious and sterile insults. It is stressed that the excessive emission of DAMPs upon severe injury uncovers their fateful property in triggering dysregulated life-threatening hyperinflammatory responses. Such a scenario may happen when the viral load is too high, for example, in the respiratory tract, "forcing" many virus-infected host cells to decide to commit "suicidal" regulated cell death (e.g., necroptosis, pyroptosis) associated with release of large amounts of DAMPs: an important topic of this review. Ironically, although the aim of this "suicidal" cell death is to save and restore organismal homeostasis, the intrinsic release of excessive amounts of DAMPs leads to those dysregulated hyperinflammatory responses-as typically involved in the pathogenesis of acute respiratory distress syndrome and systemic inflammatory response syndrome in respiratory viral infections. Consequently, as briefly outlined in this review, these molecules can be considered valuable diagnostic and prognostic biomarkers to monitor and evaluate the course of the viral disorder, in particular, to grasp the eventual transition precociously from a controlled defense response as observed in mild/moderate cases to a dysregulated life-threatening hyperinflammatory response as seen, for example, in severe/fatal COVID-19. Moreover, the pathogenetic involvement of these molecules qualifies them as relevant future therapeutic targets to prevent severe/ fatal outcomes. Finally, a theory is presented proposing that the superimposition of coronavirus-induced DAMPs with non-virus-induced DAMPs from other origins such as air pollution or high age may contribute to severe and fatal courses of coronavirus pneumonia.


Assuntos
Alarminas/imunologia , COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome do Desconforto Respiratório/imunologia , SARS-CoV-2/imunologia , Viroses/imunologia , Alarminas/metabolismo , COVID-19/metabolismo , COVID-19/virologia , Síndrome da Liberação de Citocina/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Modelos Imunológicos , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/metabolismo , SARS-CoV-2/fisiologia , Viroses/complicações , Viroses/metabolismo
15.
Biomed Pharmacother ; 140: 111596, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34126315

RESUMO

Flavonoids are natural phytochemicals known for their antiviral activity. The flavonoids acts at different stages of viral infection, such as viral entrance, replication and translation of proteins. Viruses cause various diseases such as SARS, Hepatitis, AIDS, Flu, Herpes, etc. These, and many more viral diseases, are prevalent in the world, and some (i.e. SARS-CoV-2) are causing global chaos. Despite much struggle, effective treatments for these viral diseases are not available. The flavonoid class of phytochemicals has a vast number of medicinally active compounds, many of which are studied for their potential antiviral activity against different DNA and RNA viruses. Here, we reviewed many flavonoids that showed antiviral activities in different testing environments such as in vitro, in vivo (mice model) and in silico. Some flavonoids had stronger inhibitory activities, showed no toxicity & the cell proliferation at the tested doses are not affected. Some of the flavonoids used in the in vivo studies also protected the tested mice prophylactically from lethal doses of virus, and effectively prevented viral infection. The glycosides of some of the flavonoids increased the solubility of some flavonoids, and therefore showed increased antiviral activity as compared to the non-glycoside form of that flavonoid. These phytochemicals are active against different disease-causing viruses, and inhibited the viruses by targeting the viral infections at multiple stages. Some of the flavonoids showed more potent antiviral activity than the market available drugs used to treat viral infections.


Assuntos
Antivirais/farmacologia , Antivirais/uso terapêutico , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Viroses/tratamento farmacológico , Vírus/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Glicosídeos/metabolismo , Humanos , Viroses/metabolismo
16.
Int J Mol Sci ; 22(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063096

RESUMO

Programmed cell death protein 1 (PD-1), a receptor on T cells, and its ligand, PD-L1, have been a topic of much interest in cancer research. Both tumour and virus-infected cells can upregulate PD-L1 to suppress cytotoxic T-cell killing. Research on the PD-1/PD-L1 axis has led to the development of anti-PD-1/PD-L1 immune checkpoint blockades (ICBs) as promising cancer therapies. Although effective in some cancer patients, for many, this form of treatment is ineffective due to a lack of immunogenicity in the tumour microenvironment (TME). Despite the development of therapies targeting the PD-1/PD-L1 axis, the mechanisms and pathways through which these proteins are regulated are not completely understood. In this review, we discuss the latest research on molecules of inflammation and innate immunity that regulate PD-L1 expression, how its expression is regulated during viral infection, and how it is modulated by different cancer therapies. We also highlight existing research on the development of different combination therapies with anti-PD-1/PD-L1 antibodies. This information can be used to develop better cancer immunotherapies that take into consideration the pathways involved in the PD-1/PD-L1 axis, so these molecules do not reduce their efficacy, which is currently seen with some cancer therapies. This review will also assist in understanding how the TME changes during treatment, which will provide further rationale for combination therapies.


Assuntos
Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Viroses/metabolismo , Animais , Autoimunidade , Antígeno B7-H1/metabolismo , Humanos , Modelos Biológicos , Neoplasias/patologia , Neoplasias/terapia
17.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073389

RESUMO

The aetiology of Kawasaki disease (KD), an acute inflammatory disorder of childhood, remains unknown despite various triggers of KD having been proposed. Host 'omic profiles offer insights into the host response to infection and inflammation, with the interrogation of multiple 'omic levels in parallel providing a more comprehensive picture. We used differential abundance analysis, pathway analysis, clustering, and classification techniques to explore whether the host response in KD is more similar to the response to bacterial or viral infections at the transcriptomic and proteomic levels through comparison of 'omic profiles from children with KD to those with bacterial and viral infections. Pathways activated in patients with KD included those involved in anti-viral and anti-bacterial responses. Unsupervised clustering showed that the majority of KD patients clustered with bacterial patients on both 'omic levels, whilst application of diagnostic signatures specific for bacterial and viral infections revealed that many transcriptomic KD samples had low probabilities of having bacterial or viral infections, suggesting that KD may be triggered by a different process not typical of either common bacterial or viral infections. Clustering based on the transcriptomic and proteomic responses during KD revealed three clusters of KD patients on both 'omic levels, suggesting heterogeneity within the inflammatory response during KD. The observed heterogeneity may reflect differences in the host response to a common trigger, or variation dependent on different triggers of the condition.


Assuntos
Infecções Bacterianas , Perfilação da Expressão Gênica , Síndrome de Linfonodos Mucocutâneos , Proteômica , Viroses , Adolescente , Infecções Bacterianas/classificação , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/metabolismo , Criança , Pré-Escolar , Biologia Computacional , Feminino , Humanos , Masculino , Síndrome de Linfonodos Mucocutâneos/classificação , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/metabolismo , Viroses/classificação , Viroses/diagnóstico , Viroses/metabolismo
18.
Int J Mol Sci ; 22(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064510

RESUMO

The nuclear factor of activated T cells 5 (NFAT5) is well known for its sensitivity to cellular osmolarity changes, such as in the kidney medulla. Accumulated evidence indicates that NFAT5 is also a sensitive factor to stress signals caused by non-hypertonic stimuli such as heat shock, biomechanical stretch stress, ischaemia, infection, etc. These osmolality-related and -unrelated stimuli can induce NFAT5 upregulation, activation and nuclear accumulation, leading to its protective role against various detrimental effects. However, dysregulation of NFAT5 expression may cause pathological conditions in different tissues, leading to a variety of diseases. These protective or pathogenic effects of NFAT5 are dictated by the regulation of its target gene expression and activation of its signalling pathways. Recent studies have found a number of kinases that participate in the phosphorylation/activation of NFAT5 and related signal proteins. Thus, this review will focus on the NFAT5-mediated signal transduction pathways. As for the stimuli that upregulate NFAT5, in addition to the stresses caused by hyperosmotic and non-hyperosmotic environments, other factors such as miRNA, long non-coding RNA, epigenetic modification and viral infection also play an important role in regulating NFAT5 expression; thus, the discussion in this regard is another focus of this review. As the heart, unlike the kidneys, is not normally exposed to hypertonic environments, studies on NFAT5-mediated cardiovascular diseases are just emerging and rapidly progressing. Therefore, we have also added a review on the progress made in this field of research.


Assuntos
Doenças Cardiovasculares/genética , Epigênese Genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Viroses/genética , Proteínas de Ancoragem à Quinase A/genética , Proteínas de Ancoragem à Quinase A/metabolismo , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Metilação de DNA , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Resposta ao Choque Térmico/genética , Histonas/genética , Histonas/metabolismo , Humanos , Medula Renal/metabolismo , Medula Renal/patologia , MicroRNAs/metabolismo , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Concentração Osmolar , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Viroses/metabolismo , Viroses/patologia , Viroses/virologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Cells ; 10(5)2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064516

RESUMO

Sphingolipids are important structural membrane components and, together with cholesterol, are often organized in lipid rafts, where they act as signaling molecules in many cellular functions. They play crucial roles in regulating pathobiological processes, such as cancer, inflammation, and infectious diseases. The bioactive metabolites ceramide, sphingosine-1-phosphate, and sphingosine have been shown to be involved in the pathogenesis of several microbes. In contrast to ceramide, which often promotes bacterial and viral infections (for instance, by mediating adhesion and internalization), sphingosine, which is released from ceramide by the activity of ceramidases, kills many bacterial, viral, and fungal pathogens. In particular, sphingosine is an important natural component of the defense against bacterial pathogens in the respiratory tract. Pathologically reduced sphingosine levels in cystic fibrosis airway epithelial cells are normalized by inhalation of sphingosine, and coating plastic implants with sphingosine prevents bacterial infections. Pretreatment of cells with exogenous sphingosine also prevents the viral spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) from interacting with host cell receptors and inhibits the propagation of herpes simplex virus type 1 (HSV-1) in macrophages. Recent examinations reveal that the bactericidal effect of sphingosine might be due to bacterial membrane permeabilization and the subsequent death of the bacteria.


Assuntos
Infecções Bacterianas/imunologia , Micoses/imunologia , Transdução de Sinais/imunologia , Esfingosina/metabolismo , Viroses/imunologia , Animais , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/metabolismo , Infecções Bacterianas/microbiologia , Parede Celular/efeitos dos fármacos , Ceramidas/metabolismo , Modelos Animais de Doenças , Herpesvirus Humano 1/imunologia , Humanos , Lisofosfolipídeos/metabolismo , Microdomínios da Membrana/imunologia , Microdomínios da Membrana/metabolismo , Micoses/tratamento farmacológico , Micoses/metabolismo , Micoses/microbiologia , SARS-CoV-2/imunologia , Esfingolipídeos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Esfingosina/uso terapêutico , Viroses/tratamento farmacológico , Viroses/metabolismo , Viroses/virologia
20.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073578

RESUMO

Ceramide is a lipid messenger at the heart of sphingolipid metabolism. In concert with its metabolizing enzymes, particularly sphingomyelinases, it has key roles in regulating the physical properties of biological membranes, including the formation of membrane microdomains. Thus, ceramide and its related molecules have been attributed significant roles in nearly all steps of the viral life cycle: they may serve directly as receptors or co-receptors for viral entry, form microdomains that cluster entry receptors and/or enable them to adopt the required conformation or regulate their cell surface expression. Sphingolipids can regulate all forms of viral uptake, often through sphingomyelinase activation, and mediate endosomal escape and intracellular trafficking. Ceramide can be key for the formation of viral replication sites. Sphingomyelinases often mediate the release of new virions from infected cells. Moreover, sphingolipids can contribute to viral-induced apoptosis and morbidity in viral diseases, as well as virus immune evasion. Alpha-galactosylceramide, in particular, also plays a significant role in immune modulation in response to viral infections. This review will discuss the roles of ceramide and its related molecules in the different steps of the viral life cycle. We will also discuss how novel strategies could exploit these for therapeutic benefit.


Assuntos
Ceramidas/metabolismo , HIV-1/metabolismo , Vírus da Influenza A/metabolismo , SARS-CoV-2/metabolismo , Viroses/metabolismo , Viroses/virologia , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Ceramidas/química , Regulação Viral da Expressão Gênica , HIV-1/patogenicidade , Humanos , Imunomodulação , Vírus da Influenza A/patogenicidade , SARS-CoV-2/patogenicidade , Vírion/crescimento & desenvolvimento , Viroses/imunologia , Internalização do Vírus , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...