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1.
Cell ; 183(3): 771-785.e12, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33125892

RESUMO

Trained innate immunity, induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Here, we investigated whether anti-tumor immunity can be enhanced through induction of trained immunity. Pre-treatment of mice with ß-glucan, a fungal-derived prototypical agonist of trained immunity, resulted in diminished tumor growth. The anti-tumor effect of ß-glucan-induced trained immunity was associated with transcriptomic and epigenetic rewiring of granulopoiesis and neutrophil reprogramming toward an anti-tumor phenotype; this process required type I interferon signaling irrespective of adaptive immunity in the host. Adoptive transfer of neutrophils from ß-glucan-trained mice to naive recipients suppressed tumor growth in the latter in a ROS-dependent manner. Moreover, the anti-tumor effect of ß-glucan-induced trained granulopoiesis was transmissible by bone marrow transplantation to recipient naive mice. Our findings identify a novel and therapeutically relevant anti-tumor facet of trained immunity involving appropriate rewiring of granulopoiesis.


Assuntos
Granulócitos/imunologia , Imunidade Inata , Neoplasias/imunologia , Imunidade Adaptativa , Transferência Adotiva , Animais , Epigênese Genética , Interferon Tipo I/metabolismo , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Neoplasias/patologia , Neutrófilos/metabolismo , Fenótipo , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/metabolismo , Transcrição Gênica , Transcriptoma/genética , beta-Glucanas/metabolismo
2.
FASEB J ; 35(3): e21425, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33566443

RESUMO

Histamine-induced vascular leakage is a core process of allergic pathologies, including anaphylaxis. Here, we show that glycolysis is integral to histamine-induced endothelial barrier disruption and hyperpermeability. Histamine rapidly enhanced glycolysis in endothelial cells via a pathway that involved histamine receptor 1 and phospholipase C beta signaling. Consistently, partial inhibition of glycolysis with 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) prevented histamine-induced hyperpermeability in human microvascular endothelial cells, by abolishing the histamine-induced actomyosin contraction, focal adherens junction formation, and endothelial barrier disruption. Pharmacologic blockade of glycolysis with 3PO in mice reduced histamine-induced vascular hyperpermeability, prevented vascular leakage in passive cutaneous anaphylaxis and protected from systemic anaphylaxis. In conclusion, we elucidated the role of glycolysis in histamine-induced disruption of endothelial barrier integrity. Our data thereby point to endothelial glycolysis as a novel therapeutic target for human pathologies related to excessive vascular leakage, such as systemic anaphylaxis.


Assuntos
Permeabilidade Capilar/fisiologia , Células Endoteliais/efeitos dos fármacos , Glicólise/fisiologia , Histamina/farmacologia , Junções Aderentes/efeitos dos fármacos , Junções Aderentes/metabolismo , Anafilaxia/metabolismo , Anafilaxia/patologia , Animais , Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Camundongos , Fosfolipase C beta/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Circulation ; 139(24): 2778-2792, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-30922078

RESUMO

BACKGROUND: Enhancers are genomic regulatory elements conferring spatiotemporal and signal-dependent control of gene expression. Recent evidence suggests that enhancers can generate noncoding enhancer RNAs, but their (patho)biological functions remain largely elusive. METHODS: We performed chromatin immunoprecipitation-coupled sequencing of histone marks combined with RNA sequencing of left ventricular biopsies from experimental and genetic mouse models of human cardiac hypertrophy to identify transcripts revealing enhancer localization, conservation with the human genome, and hypoxia-inducible factor 1α dependence. The most promising candidate, hypoxia-inducible enhancer RNA ( HERNA)1, was further examined by investigating its capacity to modulate neighboring coding gene expression by binding to their gene promoters by using chromatin isolation by RNA purification and λN-BoxB tethering-based reporter assays. The role of HERNA1 and its neighboring genes for pathological stress-induced growth and contractile dysfunction, and the therapeutic potential of HERNA1 inhibition was studied in gapmer-mediated loss-of-function studies in vitro using human induced pluripotent stem cell-derived cardiomyocytes and various in vivo models of human pathological cardiac hypertrophy. RESULTS: HERNA1 is robustly induced on pathological stress. Production of HERNA1 is initiated by direct hypoxia-inducible factor 1α binding to a hypoxia-response element in the histoneH3-lysine27acetylation marks-enriched promoter of the enhancer and confers hypoxia responsiveness to nearby genes including synaptotagmin XVII, a member of the family of membrane-trafficking and Ca2+-sensing proteins and SMG1, encoding a phosphatidylinositol 3-kinase-related kinase. Consequently, a substrate of SMG1, ATP-dependent RNA helicase upframeshift 1, is hyperphoshorylated in a HERNA1- and SMG1-dependent manner. In vitro and in vivo inactivation of SMG1 and SYT17 revealed overlapping and distinct roles in modulating cardiac hypertrophy. Finally, in vivo administration of antisense oligonucleotides targeting HERNA1 protected mice from stress-induced pathological hypertrophy. The inhibition of HERNA1 postdisease development reversed left ventricular growth and dysfunction, resulting in increased overall survival. CONCLUSIONS: HERNA1 is a novel heart-specific noncoding RNA with key regulatory functions in modulating the growth, metabolic, and contractile gene program in disease, and reveals a molecular target amenable to therapeutic exploitation.


Assuntos
Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/prevenção & controle , Cardiomiopatia Hipertrófica/prevenção & controle , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Miócitos Cardíacos/metabolismo , Oligonucleotídeos Antissenso/administração & dosagem , RNA não Traduzido/metabolismo , Animais , Sítios de Ligação , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica/patologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Células HEK293 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/deficiência , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/patologia , Regiões Promotoras Genéticas , RNA não Traduzido/genética , Transdução de Sinais , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
4.
Z Naturforsch C J Biosci ; 71(11-12): 415-421, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27197132

RESUMO

In this study, a comparative liquid chromatography/mass spectroscopy (LC/ESI-MS/MS) profiling of different fractions of Ulmus parvifolia leaves and stems was performed. Identification of compounds was based on comparing the mass spectrometric information obtained including m/z values and individual compound fragmentation pattern to tandem mass spectral library search and literature data. Eleven compounds were tentatively identified in the different analyzed fractions. One of the major constituents of this plant was isolated and identified as Icariside E4 [dihydro-dehydro-diconiferyl alcohol-4-O-α-L-rhamnopyranoside] (5). The evaluation of anti-inflammatory activity of the total methanolic extract using nitric oxide inhibition on LPS-stimulated RAW 264.7 cells model strong anti-inflammatory activity with 17.5% inhibition of nitric oxide production versus 10% inhibition for dexamethasone. The cytotoxic activity of the methanolic extract and Icariside E4 was evaluated against four types of human cell lines using MTT assay. Icariside E4 showed cytotoxic effect against Hep-G2, MCF-7, and CACO-2 cell lines compared to a negligible activity for the total extract. The same extract showed a moderate antioxidant activity with SC50=362.5 µg/mL.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Cromatografia Líquida/métodos , Extratos Vegetais/farmacologia , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Ulmus/química , Anti-Inflamatórios/química , Antineoplásicos Fitogênicos/química , Antioxidantes/química , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos , Extratos Vegetais/química
5.
Cell Rep ; 42(6): 112616, 2023 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-37289585

RESUMO

Combined inhibition of oxidative phosphorylation (OXPHOS) and glycolysis has been shown to activate a PP2A-dependent signaling pathway, leading to tumor cell death. Here, we analyze highly selective mitochondrial complex I or III inhibitors in vitro and in vivo to elucidate the molecular mechanisms leading to cell death following OXPHOS inhibition. We show that IACS-010759 treatment (complex I inhibitor) induces a reactive oxygen species (ROS)-dependent dissociation of CIP2A from PP2A, leading to its destabilization and degradation through chaperone-mediated autophagy. Mitochondrial complex III inhibition has analogous effects. We establish that activation of the PP2A holoenzyme containing B56δ regulatory subunit selectively mediates tumor cell death, while the arrest in proliferation that is observed upon IACS-010759 treatment does not depend on the PP2A-B56δ complex. These studies provide a molecular characterization of the events subsequent to the alteration of critical bioenergetic pathways and help to refine clinical studies aimed to exploit metabolic vulnerabilities of tumor cells.


Assuntos
Autofagia Mediada por Chaperonas , Complexo I de Transporte de Elétrons , Neoplasias , Humanos , Autoantígenos/metabolismo , Linhagem Celular Tumoral , Metabolismo Energético , Neoplasias/patologia , Fosforilação Oxidativa , Proteína Fosfatase 2/antagonistas & inibidores , Proteína Fosfatase 2/metabolismo , Transdução de Sinais , Complexo I de Transporte de Elétrons/antagonistas & inibidores
6.
Elife ; 122023 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-37449973

RESUMO

The hypothalamus-pituitary-adrenal (HPA) axis is activated in response to inflammation leading to increased production of anti-inflammatory glucocorticoids by the adrenal cortex, thereby representing an endogenous feedback loop. However, severe inflammation reduces the responsiveness of the adrenal gland to adrenocorticotropic hormone (ACTH), although the underlying mechanisms are poorly understood. Here, we show by transcriptomic, proteomic, and metabolomic analyses that LPS-induced systemic inflammation triggers profound metabolic changes in steroidogenic adrenocortical cells, including downregulation of the TCA cycle and oxidative phosphorylation, in mice. Inflammation disrupts the TCA cycle at the level of succinate dehydrogenase (SDH), leading to succinate accumulation and disturbed steroidogenesis. Mechanistically, IL-1ß reduces SDHB expression through upregulation of DNA methyltransferase 1 (DNMT1) and methylation of the SDHB promoter. Consequently, increased succinate levels impair oxidative phosphorylation and ATP synthesis and enhance ROS production, leading to reduced steroidogenesis. Together, we demonstrate that the IL-1ß-DNMT1-SDHB-succinate axis disrupts steroidogenesis. Our findings not only provide a mechanistic explanation for adrenal dysfunction in severe inflammation, but also offer a potential target for therapeutic intervention.


Assuntos
Proteômica , Ácido Succínico , Camundongos , Animais , Glucocorticoides/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Inflamação/metabolismo
7.
Sci Transl Med ; 13(623): eabi7964, 2021 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-34878823

RESUMO

Endoreplication, duplication of the nuclear genome without cell division, occurs in disease to drive morphologic growth, cell fate, and function. Despite its criticality, the metabolic underpinnings of disease-induced endoreplication and its link to morphologic growth are unknown. Heart disease is characterized by endoreplication preceding cardiac hypertrophy. We identify ATP synthase as a central control node and determinant of cardiac endoreplication and hypertrophy by rechanneling free mitochondrial ADP to methylenetetrahydrofolate dehydrogenase 1 L (MTHFD1L), a mitochondrial localized rate-limiting enzyme of formate and de novo nucleotide biosynthesis. Concomitant activation of the adenosine monophosphate­activated protein kinase (AMPK)­retinoblastoma protein (Rb)-E2F axis co-opts metabolic products of MTHFD1L function to support DNA endoreplication and pathologic growth. Gain- and loss-of-function studies in genetic and surgical mouse heart disease models and correlation in individuals confirm direct coupling of deregulated energetics with endoreplication and pathologic overgrowth. Together, we identify cardiometabolic endoreplication as a hitherto unknown mechanism dictating pathologic growth progression in the failing myocardium.


Assuntos
Endorreduplicação , Cardiopatias , Animais , Ciclo Celular , Divisão Celular , Replicação do DNA , Camundongos
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