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1.
Nat Commun ; 11(1): 4966, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009404

RESUMO

Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy in adults, with an unknown etiology. A hallmark of TLE is the characteristic loss of layer 3 neurons in the medial entorhinal area (MEA) that underlies seizure development. One approach to intervention is preventing loss of these neurons through better understanding of underlying pathophysiological mechanisms. Here, we show that both neurons and glia together give rise to the pathology that is mitigated by the amino acid D-serine whose levels are potentially diminished under epileptic conditions. Focal administration of D-serine to the MEA attenuates neuronal loss in this region thereby preventing epileptogenesis in an animal model of TLE. Additionally, treatment with D-serine reduces astrocyte counts in the MEA, alters their reactive status, and attenuates proliferation and/or infiltration of microglia to the region thereby curtailing the deleterious consequences of neuroinflammation. Given the paucity of compounds that reduce hyperexcitability and neuron loss, have anti-inflammatory properties, and are well tolerated by the brain, D-serine, an endogenous amino acid, offers new hope as a therapeutic agent for refractory TLE.


Assuntos
Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/patologia , Serina/uso terapêutico , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Comportamento Animal , Encéfalo/patologia , Córtex Entorrinal/efeitos dos fármacos , Córtex Entorrinal/patologia , Gliose/patologia , Inflamação/patologia , Microglia/efeitos dos fármacos , Microglia/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos Sprague-Dawley , Serina/administração & dosagem , Serina/farmacologia
2.
Lancet Oncol ; 21(9): e419-e430, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888471

RESUMO

Notable advances have been achieved in the treatment of cancer since the advent of immunotherapy, and immune checkpoint inhibitors have shown clinical benefit across a wide variety of tumour types. Nevertheless, most patients still progress on these treatments, highlighting the importance of unravelling the underlying mechanisms of primary resistance to immunotherapy. A well described biomarker of non-responsiveness to immune checkpoint inhibitors is the absence or low presence of lymphocytes in the tumour microenvironment, so-called cold tumours. There are five mechanisms of action that have the potential to turn cold tumours into so-called hot and inflamed tumours, hence increasing the tumour's responsiveness to immunotherapy-increasing local inflammation, neutralising immunosuppression at the tumour site, modifying the tumour vasculature, targeting the tumour cells themselves, or increasing the frequency of tumour-specific T cells. In this Review, we discuss preclinical data that serves as the basis for ongoing immunotherapy clinical trials for the treatment of non-immunoreactive tumours, as well as reviewing clinical and translational data where available. We explain how improving our understanding of the underlying mechanisms of primary resistance to immunotherapy will help elucidate an increasingly granular view of the tumour microenvironment cellular composition, functional status, and cellular localisation, with the goal of further therapy refinement.


Assuntos
Resistencia a Medicamentos Antineoplásicos/imunologia , Imunoterapia/efeitos adversos , Inflamação/terapia , Neoplasias/terapia , Microambiente Tumoral/efeitos dos fármacos , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Quinase 1 do Ponto de Checagem/imunologia , Ensaios Clínicos como Assunto , Humanos , Imunidade Celular/imunologia , Inflamação/imunologia , Inflamação/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Microambiente Tumoral/imunologia
4.
Medicine (Baltimore) ; 99(38): e22241, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957369

RESUMO

BACKGROUND: Quercetin, a major flavonol, wildly exists in plantage, which has been reported to have an anti-apoptosis and anti-inflammation effects on vascular endothelial cells, but its underlying molecular mechanisms remain unclear. OBJECTIVE: The aim of this study was to investigate the mechanisms of how quercetin inhibits tumor necrosis factor alpha (TNF-α) induced human umbilical vein endothelial cells (HUVECs) apoptosis and inflammation. METHODS AND RESULTS: HUVECs were preconditioned with quercetin for 18 hours, and subsequently treated with TNF-α for 6 hours to induce apoptosis. The expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin, ß-actin mRNA was then detected by RT-PCR. Flow cytometry was used to estimate the apoptosis rates, and the expression of activator protein 1 (AP-1) and nuclear factor kappa B (NF-κB) was measured by Western blot. TNF-α induced elevated apoptosis rates and upregulation of VCAM-1, ICAM-1, and E-selectin were meaningfully reduced in HUVECs by pretreatment with quercetin. In addition, quercetin also inhibited the activation of AP-1and NF-κB. CONCLUSION: Results indicate that quercetin could suppress TNF-α induced apoptosis and inflammation by blocking NF-κB and AP-1 signaling pathway in HUVECs, which might be one of the underlying mechanisms in treatment of coronary heart disease.


Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Inflamação/prevenção & controle , NF-kappa B/metabolismo , Quercetina/farmacologia , Fator de Transcrição AP-1/metabolismo , Regulação para Baixo , Selectina E/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Molécula 1 de Adesão Intercelular/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/farmacologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
5.
Nat Commun ; 11(1): 4596, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929083

RESUMO

Earlier studies indicate that either the canonical or non-canonical pathways of inflammasome activation have a limited role on malaria pathogenesis. Here, we report that caspase-8 is a central mediator of systemic inflammation, septic shock in the Plasmodium chabaudi-infected mice and the P. berghei-induced experimental cerebral malaria (ECM). Importantly, our results indicate that the combined deficiencies of caspases-8/1/11 or caspase-8/gasdermin-D (GSDM-D) renders mice impaired to produce both TNFα and IL-1ß and highly resistant to lethality in these models, disclosing a complementary, but independent role of caspase-8 and caspases-1/11/GSDM-D in the pathogenesis of malaria. Further, we find that monocytes from malaria patients express active caspases-1, -4 and -8 suggesting that these inflammatory caspases may also play a role in the pathogenesis of human disease.


Assuntos
Caspase 8/metabolismo , Inflamação/patologia , Malária Cerebral/enzimologia , Animais , Encéfalo/patologia , Caspase 1/metabolismo , Células Dendríticas/metabolismo , Ativação Enzimática , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Humanos , Interferon gama/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos , Malária Cerebral/genética , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Plasmodium chabaudi/fisiologia , Baço/metabolismo , Receptores Toll-Like/metabolismo
6.
Open Biol ; 10(9): 200160, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32961074

RESUMO

Coronavirus disease 2019 (COVID-19) has swept the world, unlike any other pandemic in the last 50 years. Our understanding of the disease has evolved rapidly since the outbreak; disease prognosis is influenced mainly by multi-organ involvement. Acute respiratory distress syndrome, heart failure, renal failure, liver damage, shock and multi-organ failure are strongly associated with morbidity and mortality. The COVID-19 disease pathology is plausibly linked to the hyperinflammatory response of the body characterized by pathological cytokine levels. The term 'cytokine storm syndrome' is perhaps one of the critical hallmarks of COVID-19 disease severity. In this review, we highlight prominent cytokine families and their potential role in COVID-19, the type I and II interferons, tumour necrosis factor and members of the Interleukin family. We address various changes in cellular components of the immune response corroborating with changes in cytokine levels while discussing cytokine sources and biological functions. Finally, we discuss in brief potential therapies attempting to modulate the cytokine storm.


Assuntos
Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/patologia , Citocinas/sangue , Pneumonia Viral/patologia , Betacoronavirus/imunologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/tratamento farmacológico , Humanos , Inflamação/patologia , Pandemias
7.
Adv Exp Med Biol ; 1274: 71-99, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32894508

RESUMO

Bioactive lipid mediators resulting from the metabolism of polyunsaturated fatty acids (PUFA) are controlled by many pathways that regulate the levels of these mediators and maintain homeostasis to prevent disease. PUFA metabolism is driven primarily through three pathways. Two pathways, the cyclooxygenase (COX) and lipoxygenase (LO) enzymatic pathways, form metabolites that are mostly inflammatory, while the third route of metabolism results from the oxidation by the cytochrome P450 enzymes to form hydroxylated PUFA and epoxide metabolites. These epoxygenated fatty acids (EpFA) demonstrate largely anti-inflammatory and beneficial properties, in contrast to the other metabolites formed from the degradation of PUFA. Dysregulation of these systems often leads to chronic disease. Pharmaceutical targets of disease focus on preventing the formation of inflammatory metabolites from the COX and LO pathways, while maintaining the EpFA and increasing their concentration in the body is seen as beneficial to treating and preventing disease. The soluble epoxide hydrolase (sEH) is the major route of metabolism of EpFA. Inhibiting its activity increases concentrations of beneficial EpFA, and often disease states correlate to mutations in the sEH enzyme that increase its activity and decrease the concentrations of EpFA in the body. Recent approaches to increasing EpFA include synthetic mimics that replicate biological activity of EpFA while preventing their metabolism, while other approaches focus on developing small molecule inhibitors to the sEH. Increasing EpFA concentrations in the body has demonstrated multiple beneficial effects in treating many diseases, including inflammatory and painful conditions, cardiovascular disease, neurological and disease of the central nervous system. Demonstration of efficacy in so many disease states can be explained by the fundamental mechanism that EpFA have of maintaining healthy microvasculature and preventing mitochondrial and endoplasmic reticulum stress. While there are no FDA approved methods that target the sEH or other enzymes responsible for metabolizing EpFA, current clinical efforts to test for efficacy by increasing EpFA that include inhibiting the sEH or administration of EpFA mimics that block metabolism are in progress.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Estresse do Retículo Endoplasmático , Ácidos Graxos/metabolismo , Inflamação/tratamento farmacológico , Mitocôndrias/patologia , Terapia de Alvo Molecular , Manejo da Dor , Doenças Cardiovasculares/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Inflamação/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Dor
8.
Nat Commun ; 11(1): 4766, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958778

RESUMO

Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Inflamação/patologia , Telômero/patologia , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antibacterianos/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Caspase 1/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Criança , Colo/metabolismo , Colo/microbiologia , Colo/patologia , Gastroenteropatias/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/microbiologia , Interleucina-18/genética , Interleucina-18/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Mutantes , Fosforilação , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Transdução de Sinais , Telomerase/genética , Telomerase/metabolismo
9.
Mol Cell ; 80(1): 43-58.e7, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32937100

RESUMO

Immune cell function depends on specific metabolic programs dictated by mitochondria, including nutrient oxidation, macromolecule synthesis, and post-translational modifications. Mitochondrial adaptations have been linked to acute and chronic inflammation, but the metabolic cues and precise mechanisms remain unclear. Here we reveal that histone deacetylase 3 (HDAC3) is essential for shaping mitochondrial adaptations for IL-1ß production in macrophages through non-histone deacetylation. In vivo, HDAC3 promoted lipopolysaccharide-induced acute inflammation and high-fat diet-induced chronic inflammation by enhancing NLRP3-dependent caspase-1 activation. HDAC3 configured the lipid profile in stimulated macrophages and restricted fatty acid oxidation (FAO) supported by exogenous fatty acids for mitochondria to acquire their adaptations and depolarization. Rather than affecting nuclear gene expression, HDAC3 translocated to mitochondria to deacetylate and inactivate an FAO enzyme, mitochondrial trifunctional enzyme subunit α. HDAC3 may serve as a controlling node that balances between acquiring mitochondrial adaptations and sustaining their fitness for IL-1ß-dependent inflammation.


Assuntos
Ácidos Graxos/metabolismo , Histona Desacetilases/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Mitocôndrias/metabolismo , Adulto , Animais , Caspase 1/metabolismo , Feminino , Humanos , Inflamação/patologia , Metabolismo dos Lipídeos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Mitocôndrias/ultraestrutura , Subunidade alfa da Proteína Mitocondrial Trifuncional/metabolismo , Células Mieloides/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Oxirredução , Fosforilação Oxidativa , Adulto Jovem
10.
Int J Nanomedicine ; 15: 4811-4824, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32753867

RESUMO

Purpose: Magnetic resonance imaging (MRI) contrast agents are pharmaceuticals that enable a better visualization of internal body structures. In this study, we present the synthesis, MRI signal enhancement capabilities, in vitro as well as in vivo cytotoxicity results of gold-coated iron oxide nanoparticles (Fe3O4@AuNPs) as potential contrast agents. Methods: Fe3O4@AuNPs were obtained by synthesizing iron oxide nanoparticles and gradually coating them with gold. The obtained Fe3O4@AuNPs were characterized by spectroscopies, transmission electron microscopy (TEM) and energy dispersive X-ray diffraction. The effect of the nanoparticles on the MRI signal was tested using a 7T Bruker PharmaScan system. Cytotoxicity tests were made in vitro on Fe3O4@AuNP-treated retinal pigment epithelium cells by WST-1 tests and in vivo by following histopathological changes in rats after injection of Fe3O4@AuNPs. Results: Stable Fe3O4@AuNPs were successfully prepared following a simple and fast protocol (<1h worktime) and identified using TEM. The cytotoxicity tests on cells have shown biocompatibility of Fe3O4@AuNPs at small concentrations of Fe (<1.95×10-8 mg/cell). Whereas, at higher Fe concentrations (eg 7.5×10-8 mg/cell), cell viability decreased to 80.88±5.03%, showing a mild cytotoxic effect. MRI tests on rats showed an optimal Fe3O4@AuNPs concentration of 6mg/100g body weight to obtain high-quality images. The histopathological studies revealed significant transient inflammatory responses in the time range from 2 hours to 14 days after injection and focal cellular alterations in several organs, with the lung being the most affected organ. These results were confirmed by hyperspectral microscopic imaging of the same, but unstained tissues. In most organs, the inflammatory responses and sublethal cellular damage appeared to be transitory, except for the kidneys, where the glomerular damage indicated progression towards glomerular sclerosis. Conclusion: The obtained stable, gold covered, iron oxide nanoparticles with reduced cytotoxicity, gave a negative T2 signal in the MRI, which makes them suitable for candidates as contrast agent in small animal MRI applications.


Assuntos
Meios de Contraste/química , Compostos Férricos/química , Ouro/química , Imagem por Ressonância Magnética , Nanopartículas Metálicas/química , Animais , Sobrevivência Celular , Endocitose , Inflamação/patologia , Masculino , Nanopartículas Metálicas/ultraestrutura , Ratos Wistar , Difração de Raios X
11.
Diagn Pathol ; 15(1): 103, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32799894

RESUMO

BACKGROUND: The world is currently witnessing a major devastating pandemic of Coronavirus disease-2019 (COVID-19). This disease is caused by a novel coronavirus named Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). It primarily affects the respiratory tract and particularly the lungs. The virus enters the cell by attaching its spike-like surface projections to the angiotensin-converting enzyme-2 (ACE-2) expressed in various tissues. Though the majority of symptomatic patients have mild flu-like symptoms, a significant minority develop severe lung injury with acute respiratory distress syndrome (ARDS), leading to considerable morbidity and mortality. Elderly patients with previous cardiovascular comorbidities are particularly susceptible to severe clinical manifestations. BODY: Currently, our limited knowledge of the pathologic findings is based on post-mortem biopsies, a few limited autopsies, and very few complete autopsies. From these reports, we know that the virus can be found in various organs but the most striking tissue damage involves the lungs resulting almost always in diffuse alveolar damage with interstitial edema, capillary congestion, and occasional interstitial lymphocytosis, causing hypoxia, multiorgan failure, and death. A few pathology studies have also reported intravascular microthrombi and pulmonary thrombembolism. Although the clinical presentation of this disease is fairly well characterized, knowledge of the pathologic aspects remains comparatively limited. CONCLUSION: In this review, we discuss clinical, pathologic, and genomic features of COVID-19, review current hypotheses regarding the pathogenesis, and briefly discuss the clinical characteristics. We also compare the salient features of COVID-19 with other coronavirus-related illnesses that have posed significant public health issues in the past, including SARS and the Middle East Respiratory Syndrome (MERS).


Assuntos
Betacoronavirus , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Humanos , Inflamação/patologia , Inflamação/virologia , Pandemias , Peptidil Dipeptidase A/metabolismo
12.
Orv Hetil ; 161(35): 1456-1465, 2020 08.
Artigo em Húngaro | MEDLINE | ID: mdl-32822324

RESUMO

INTRODUCTION: Fatty liver can develop as a result of diseases, surgical procedures, medicaments, malnutrition or excessive alcohol consumption, however, fat and poor fiber feeding can be attributed as the primary cause. Non-alcoholic fatty liver can be found in 20-30% of the population. Generally, alimentary-induced fatty liver in early state is described as uncomplicated liver injury. AIM: The aim of our research was to study the effect of fat rich nutrition on the gut-liver axis by routine laboratory, analytical and histological methods in rats. METHODS: We also examined the redox parameters of the liver and of the bowel. Fatty acid composition and element content of liver were measured. RESULTS: Significant changes were found in parameters of redox homeostasis as well as alterations in liver enzymes and metabolites. The changes could be detected in the liver, blood and bowel parts. The development of fatty liver is associated with the decrease of transmethylation capacity. Fatty acid composition and metal ion homeostasis were also altered in liver. Histological examinations showed that hepatocytes were swollen in the central part of the liver lobules, showed droplets and pycnotic nuclei, which were characterized by fatty degeneration. Small and large bowel enterocytes were damaged, sometimes pushed from the surface, and sometimes inflammatory reactions in the mucous membrane were observed. CONCLUSION: Our results suggest that alimentary fatty liver in early state is not considered simply as a reversible alteration because it alters the entire body's redox homeostasis and establishes heart and serious metabolic diseases as well as hasten the development of gastrointestinal tumors. Orv Hetil. 2020; 161(35): 1456-1465.


Assuntos
Dieta Hiperlipídica , Inflamação/patologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica , Animais , Ácidos Graxos , Hepatócitos , Intestinos/patologia , Síndrome Metabólica/complicações , Ratos
14.
Open Biol ; 10(8): 200208, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32847471

RESUMO

COVID-19 management guidelines have largely attributed critically ill patients who develop acute respiratory distress syndrome, to a systemic overproduction of pro-inflammatory cytokines. Cardiovascular dysfunction may also represent a primary phenomenon, with increasing data suggesting that severe COVID-19 reflects a confluence of vascular dysfunction, thrombosis and dysregulated inflammation. Here, we first consolidate the information on localized microvascular inflammation and disordered cytokine release, triggering vessel permeability and prothrombotic conditions that play a central role in perpetuating the pathogenic COVID-19 cascade. Secondly, we seek to clarify the gateways which SARS-CoV-2, the causative COVID-19 virus, uses to enter host vascular cells. Post-mortem examinations of patients' tissues have confirmed direct viral endothelial infection within several organs. While there have been advances in single-cell RNA sequencing, endothelial cells across various vascular beds express low or undetectable levels of those touted SARS-CoV-2 entry factors. Emerging studies postulate alternative pathways and the apicobasal distribution of host cell surface factors could influence endothelial SARS-CoV-2 entry and replication. Finally, we provide experimental considerations such as endothelial polarity, cellular heterogeneity in organoids and shear stress dynamics in designing cellular models to facilitate research on viral-induced endothelial dysfunctions. Understanding the vascular underpinning of COVID-19 pathogenesis is crucial to managing outcomes and mortality.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/patologia , Células Endoteliais/patologia , Inflamação/patologia , Pneumonia Viral/patologia , Trombose/patologia , Permeabilidade Capilar/fisiologia , Comorbidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Citocinas/sangue , Células Endoteliais/virologia , Humanos , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/patologia , Índice de Gravidade de Doença , Internalização do Vírus
15.
Science ; 369(6506)2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820093

RESUMO

In developed countries, the leading causes of blindness such as diabetic retinopathy are characterized by disorganized vasculature that can become fibrotic. Although many such pathological vessels often naturally regress and spare sight-threatening complications, the underlying mechanisms remain unknown. Here, we used orthogonal approaches in human patients with proliferative diabetic retinopathy and a mouse model of ischemic retinopathies to identify an unconventional role for neutrophils in vascular remodeling during late-stage sterile inflammation. Senescent vasculature released a secretome that attracted neutrophils and triggered the production of neutrophil extracellular traps (NETs). NETs ultimately cleared diseased endothelial cells and remodeled unhealthy vessels. Genetic or pharmacological inhibition of NETosis prevented the regression of senescent vessels and prolonged disease. Thus, clearance of senescent retinal blood vessels leads to reparative vascular remodeling.


Assuntos
Envelhecimento/patologia , Retinopatia Diabética/patologia , Armadilhas Extracelulares/imunologia , Vasos Retinianos/patologia , Animais , Senescência Celular , Retinopatia Diabética/imunologia , Modelos Animais de Doenças , Células Endoteliais/imunologia , Células Endoteliais/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Vasos Retinianos/imunologia
16.
Inflamm Res ; 69(11): 1077-1085, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32767095

RESUMO

BACKGROUND: Decline in mitochondrial function occurs with aging and may increase mortality. We discuss mitochondrial contribution to Covid-19 sepsis, specifically the complex interaction of innate immune function, viral replication, hyper-inflammatory state, and HIF-α/Sirtuin pathways. METHODS: Articles from PubMed/Medline searches were reviewed using the combination of terms "SARS-CoV-2, Covid-19, sepsis, mitochondria, aging, and immunometabolism". RESULTS: Evidence indicates that mitochondria in senescent cells may be dysfunctional and unable to keep up with hypermetabolic demands associated with Covid-19 sepsis. Mitochondrial proteins may serve as damage-associated molecular pattern (DAMP) activating innate immunity. Disruption in normal oxidative phosphorylation pathways contributes to elevated ROS which activates sepsis cascade through HIF-α/Sirtuin pathway. Viral-mitochondrial interaction may be necessary for replication and increased viral load. Hypoxia and hyper-inflammatory state contribute to increased mortality associated with Covid-19 sepsis. CONCLUSIONS: Aging is associated with worse outcomes in sepsis. Modulating Sirtuin activity is emerging as therapeutic agent in sepsis. HIF-α, levels of mitochondrial DNA, and other mitochondrial DAMP molecules may also serve as useful biomarker and need to be investigated. These mechanisms should be explored specifically for Covid-19-related sepsis. Understanding newly discovered regulatory mechanisms may lead to the development of novel diagnostic and therapeutic targets.


Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Inflamação/etiologia , Inflamação/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/etiologia , Doenças Mitocondriais/patologia , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Sepse/etiologia , Sepse/patologia , Envelhecimento , Infecções por Coronavirus/mortalidade , Humanos , Inflamação/mortalidade , Doenças Mitocondriais/mortalidade , Pandemias , Pneumonia Viral/mortalidade , Sepse/mortalidade
17.
Yonsei Med J ; 61(8): 660-669, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32734729

RESUMO

PURPOSE: Neonatal hypoxic ischemic encephalopathy (HIE) is an essential factor underlying neonatal death and disability. This study sought to explore the role of miR-146b-5p in regulating neonatal HIE. MATERIALS AND METHODS: In vitro and in vivo HIE models were established in PC12 cells and 10-day neonatal Sprague Dawley rats, respectively. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to assess miR-146b-5p expression and inflammatory factors [interleukin (IL)-6 and tumor necrosis factor (TNF)-α] in brain lesions and PC12 cells, while enzyme-linked immunosorbent assay was employed to detect the expression of oxidative stress factors (SOD and GSH-Px). Gain- and loss-assays of miR-146b-5p were conducted to verify its role in modulating the viability and apoptosis of PC12 cells under oxygen-glucose deprivation (OGD) treatment. Expression of TLR4, IRAK1, TRAF6, TAK1, and NF-κB were examined by qRT-PCR and/or Western blot. Dual luciferase activity assay was conducted to identify relationships between miR-146b-5p and IRAK1. RESULTS: In the HIE models, significant oxidative stress and inflammatory responses emerged upon upregulation of TLR4/IRAK1/TRAF6/TAK1/NF-κB signaling. Overexpression of miR-146b-5p greatly inhibited OGD-induced PC12 cell injury, inflammatory responses, and oxidative stress. Inhibiting miR-146b-5p, however, had the opposite effects. IRAK1 was found to be a target of miR-146b-5p, and miR-146b-5p overexpression suppressed the activation of IRAK1/TRAF6/TAK1/NF-κB signaling. CONCLUSION: This study demonstrated that miR-146b-5p overexpression alleviates HIE-induced neuron injury by inhibiting the IRAK1/TRAF6/TAK1/NF-κB pathway.


Assuntos
Hipóxia-Isquemia Encefálica/genética , Quinases Associadas a Receptores de Interleucina-1/metabolismo , MAP Quinase Quinase Quinases/metabolismo , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/genética , Sequência de Bases , Modelos Animais de Doenças , Regulação para Baixo/genética , Glucose/deficiência , Inflamação/patologia , MicroRNAs/genética , Estresse Oxidativo , Oxigênio , Células PC12 , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
18.
J Nutr Health Aging ; 24(7): 685-691, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32744561

RESUMO

A new coronavirus, called SARS-CoV-2, was identified in Wuhan, China, in December 2019. The SARS-CoV-2 spread very rapidly, causing a global pandemic, Coronavirus Disease 2019 (COVID-19). Older adults have higher peak of viral load and, especially those with comorbidities, had higher COVID-19-related fatality rates than younger adults. In this Perspective paper, we summarize current knowledge about SARS-CoV-2 and aging, in order to understand why older people are more affected by COVID-19. We discuss about the possibility that the so-called "immunosenescence" and "inflammaging" processes, already present in a fraction of frail older adults, could allow the immune escape of SARS-CoV-2 leading to COVID-19 serious complications. Finally, we propose to use geroscience approaches to the field of COVID-19.


Assuntos
Envelhecimento , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Geriatria , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Virologia , Idoso , Envelhecimento/imunologia , Envelhecimento/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Pandemias
19.
Nat Commun ; 11(1): 3984, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770009

RESUMO

The epsin family of endocytic adapter proteins are widely expressed, and interact with both proteins and lipids to regulate a variety of cell functions. However, the role of epsins in atherosclerosis is poorly understood. Here, we show that deletion of endothelial epsin proteins reduces inflammation and attenuates atherosclerosis using both cell culture and mouse models of this disease. In atherogenic cholesterol-treated murine aortic endothelial cells, epsins interact with the ubiquitinated endoplasmic reticulum protein inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), which triggers proteasomal degradation of this calcium release channel. Epsins potentiate its degradation via this interaction. Genetic reduction of endothelial IP3R1 accelerates atherosclerosis, whereas deletion of endothelial epsins stabilizes IP3R1 and mitigates inflammation. Reduction of IP3R1 in epsin-deficient mice restores atherosclerotic progression. Taken together, epsin-mediated degradation of IP3R1 represents a previously undiscovered biological role for epsin proteins and may provide new therapeutic targets for the treatment of atherosclerosis and other diseases.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Aterosclerose/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Proteólise , Proteínas Adaptadoras de Transporte Vesicular/química , Animais , Aorta/metabolismo , Aorta/patologia , Aterosclerose/patologia , Cálcio/metabolismo , Colesterol/metabolismo , Células Endoteliais/metabolismo , Feminino , Deleção de Genes , Células HEK293 , Homeostase , Humanos , Inflamação/patologia , Masculino , Camundongos Knockout , Ligação Proteica , Domínios Proteicos , Ubiquitinação
20.
Int J Nanomedicine ; 15: 4763-4778, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32753865

RESUMO

Introduction: Methotrexate exhibits poor cutaneous bioavailability and systemic side effects on topical administration, so there is an unmet need for a novel carrier and its optimized therapy. Methotrexate-loaded nanostructured lipid carriers (MTXNLCs) were formulated and characterized to determine in vitro drug release and evaluate the role of MTXNLC gel in the topical treatment of psoriasis. Methods: A solvent diffusion technique was employed to prepare MTXNLCs, which was optimized using 32 full factorial designs. The mean diameter and surface morphology of MTXNLCs was evaluated. The crystallinity of lyophilized MTXNLCs was characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD). MTXNLCs were integrated in 1% w/w Carbopol 934 P gel base, and in vitro skin deposition studies in human cadaver skin (HCS) were carried out. Results: The optimized MTXNLCs were rod-shaped, with an average particle size of 253 ± 8.65 nm, a zeta potential of -26.4±0.86 mV, and EE of 54.00±1.49%. DSC and XRD data confirmed the formation of NLCs. Significantly higher deposition of MTX was found in HCS from MTXNLC gel (71.52 ±1.13%) as compared to MTX plain gel (38.48±0.96%). In vivo studies demonstrated significant improvement in therapeutic response and reduction in local side effects with MTXNLCs-loaded gel in the topical treatment of psoriasis. Anti-psoriatic efficacy of MTXNLCs 100 ug/cm2 compared with plain MTX gel was evaluated using imiquimod (IMQ)-induced psoriasis in BALB/c mice. The topical application of MTXNLCs to the mouse ear resulted in a significant reduction of psoriatic area and severity index, oxidative stress, inflammatory cytokines like TNF-α, IL-1ß, and IL-6 and IMQ-induced histopathological alterations in mouse ear samples. Conclusion: Developed formulation of MTXNLC gel demonstrated better anti-psoriatic activity and also displayed prolonged and sustained release effect, which shows that it can be a promising alternative to existing MTX formulation for the treatment of psoriasis.


Assuntos
Composição de Medicamentos , Géis/química , Imiquimode/uso terapêutico , Inflamação/tratamento farmacológico , Lipídeos/química , Metotrexato/uso terapêutico , Nanoestruturas/química , Psoríase/tratamento farmacológico , Administração Cutânea , Administração Tópica , Animais , Catalase/metabolismo , Citocinas/metabolismo , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Glutationa/metabolismo , Humanos , Inflamação/patologia , Malondialdeído/metabolismo , Camundongos Endogâmicos BALB C , Nanoestruturas/ultraestrutura , Tamanho do Órgão , Superóxido Dismutase/metabolismo
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