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1.
Nat Commun ; 12(1): 1209, 2021 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-33619282

RESUMEN

Fructose intake has increased substantially throughout the developed world and is associated with obesity, type 2 diabetes and non-alcoholic fatty liver disease. Currently, our understanding of the metabolic and mechanistic implications for immune cells, such as monocytes and macrophages, exposed to elevated levels of dietary fructose is limited. Here, we show that fructose reprograms cellular metabolic pathways to favour glutaminolysis and oxidative metabolism, which are required to support increased inflammatory cytokine production in both LPS-treated human monocytes and mouse macrophages. A fructose-dependent increase in mTORC1 activity drives translation of pro-inflammatory cytokines in response to LPS. LPS-stimulated monocytes treated with fructose rely heavily on oxidative metabolism and have reduced flexibility in response to both glycolytic and mitochondrial inhibition, suggesting glycolysis and oxidative metabolism are inextricably coupled in these cells. The physiological implications of fructose exposure are demonstrated in a model of LPS-induced systemic inflammation, with mice exposed to fructose having increased levels of circulating IL-1ß after LPS challenge. Taken together, our work underpins a pro-inflammatory role for dietary fructose in LPS-stimulated mononuclear phagocytes which occurs at the expense of metabolic flexibility.


Asunto(s)
Fructosa/farmacología , Glutamina/metabolismo , Inflamación/metabolismo , Inflamación/patología , Lipopolisacáridos/toxicidad , Ácidos/metabolismo , Animales , Ciclo del Ácido Cítrico/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Glucosa/farmacología , Glucólisis/efectos de los fármacos , Marcaje Isotópico , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Análisis de Flujos Metabólicos , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Oxidación-Reducción , Fosforilación Oxidativa/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Fenotipo , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo
2.
Medicine (Baltimore) ; 100(3): e23986, 2021 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-33545988

RESUMEN

ABSTRACT: Rosacea is a facial chronic inflammatory skin disease with immune and vascular system dysfunction. Paeoniflorin (PF) is a traditional Chinese medicine with anti-inflammatory properties. However, its effects on rosacea remain unknown. Here, we investigated the mechanisms through which PF inhibits the macrophage-related rosacea-like inflammatory response. Immunohistochemical methods were used to detect differences in the inflammatory response and degree of macrophage infiltration in granulomatous rosacea lesions and their peripheral areas. Cell Counting Kit-8 was used to determine the cytotoxicity of PF towards RAW 264.7 cells. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to measure the influence of PF on mRNA and protein expression levels of suppressor of cytokine signaling 3 (SOCS3), apoptosis signal-regulating kinase 1 (ASK1)-p38, Toll-like receptor 2, and cathelicidin antimicrobial peptide ( or LL37) in the lipopolysaccharide (LPS)-induced macrophage-related rosacea-like inflammatory response of RAW 264.7 cells. Inflammatory cell infiltration was more pronounced in granulomatous rosacea lesions than in peripheral areas. LL37 expression increased significantly, and the infiltration of a large number of CD68+ macrophages was observed in the lesions. PF promoted SOCS3 expression in RAW 264.7 cells and inhibited the LPS-induced increase in toll-like receptor 2 and LL37 expression through the ASK1-p38 cascade, thereby alleviating the macrophage-related rosacea-like inflammatory response. These changes could be abrogated by SOCS3 siRNA in vitro.In conclusion, the pathogenesis of rosacea involves abnormal macrophage infiltration within the lesions. PF inhibits the macrophage-related rosacea-like inflammatory response through the SOCS3-ASK1-p38 pathway, demonstrating its potential application as a novel drug for rosacea therapy.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Glucósidos/farmacología , MAP Quinasa Quinasa Quinasa 5/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Monoterpenos/farmacología , Rosácea/tratamiento farmacológico , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Animales , Técnicas de Cultivo de Célula , Humanos , Macrófagos/metabolismo , Ratones , Células RAW 264.7 , Piel/citología
3.
Nat Commun ; 12(1): 879, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33563986

RESUMEN

Salmonella Typhimurium establishes systemic infection by replicating in host macrophages. Here we show that macrophages infected with S. Typhimurium exhibit upregulated glycolysis and decreased serine synthesis, leading to accumulation of glycolytic intermediates. The effects on serine synthesis are mediated by bacterial protein SopE2, a type III secretion system (T3SS) effector encoded in pathogenicity island SPI-1. The changes in host metabolism promote intracellular replication of S. Typhimurium via two mechanisms: decreased glucose levels lead to upregulated bacterial uptake of 2- and 3-phosphoglycerate and phosphoenolpyruvate (carbon sources), while increased pyruvate and lactate levels induce upregulation of another pathogenicity island, SPI-2, known to encode virulence factors. Pharmacological or genetic inhibition of host glycolysis, activation of host serine synthesis, or deletion of either the bacterial transport or signal sensor systems for those host glycolytic intermediates impairs S. Typhimurium replication or virulence.


Asunto(s)
Proteínas Bacterianas/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Macrófagos/metabolismo , Salmonella typhimurium/crecimiento & desarrollo , Salmonella typhimurium/patogenicidad , Sistemas de Secreción Tipo III/metabolismo , Animales , Proteínas Bacterianas/genética , Regulación Bacteriana de la Expresión Génica , Islas Genómicas , Glucosa/metabolismo , Ácidos Glicéricos/metabolismo , Glucólisis , Factores de Intercambio de Guanina Nucleótido/genética , Macrófagos/microbiología , Ratones , Células RAW 264.7 , Salmonella typhimurium/metabolismo , Serina/biosíntesis , Transducción de Señal , Sistemas de Secreción Tipo III/genética , Virulencia
4.
Nat Commun ; 12(1): 759, 2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33536421

RESUMEN

The malignancy of colorectal cancer (CRC) is connected with inflammation and tumor-associated macrophages (TAMs), but effective therapeutics for CRC are limited. To integrate therapeutic targeting with tumor microenvironment (TME) reprogramming, here we develop biocompatible, non-covalent channel-type nanoparticles (CNPs) that are fabricated through host-guest complexation and self-assemble of mannose-modified γ-cyclodextrin (M-γ-CD) with Regorafenib (RG), RG@M-γ-CD CNPs. In addition to its carrier role, M-γ-CD serves as a targeting device and participates in TME regulation. RG@M-γ-CD CNPs attenuate inflammation and inhibit TAM activation by targeting macrophages. They also improve RG's anti-tumor effect by potentiating kinase suppression. In vivo application shows that the channel-type formulation optimizes the pharmacokinetics and bio-distribution of RG. In colitis-associated cancer and CT26 mouse models, RG@M-γ-CD is proven to be a targeted, safe and effective anti-tumor nanomedicine that suppresses tumor cell proliferation, lesions neovascularization, and remodels TME. These findings indicate RG@M-γ-CD CNPs as a potential strategy for CRC treatment.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Nanopartículas/administración & dosificación , Neoplasias Experimentales/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Piridinas/administración & dosificación , gamma-Ciclodextrinas/administración & dosificación , Animales , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HT29 , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Manosa/química , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Nanopartículas/química , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Compuestos de Fenilurea/química , Piridinas/química , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética , gamma-Ciclodextrinas/química
5.
Nat Commun ; 12(1): 773, 2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33536439

RESUMEN

Macrophages are plastic and, in response to different local stimuli, can polarize toward multi-dimensional spectrum of phenotypes, including the pro-inflammatory M1-like and the anti-inflammatory M2-like states. Using a high-throughput phenotypic screen in a library of ~4000 FDA-approved drugs, bioactive compounds and natural products, we find ~300 compounds that potently activate primary human macrophages toward either M1-like or M2-like state, of which ~30 are capable of reprogramming M1-like macrophages toward M2-like state and another ~20 for the reverse repolarization. Transcriptional analyses of macrophages treated with 34 non-redundant compounds identify both shared and unique targets and pathways through which the tested compounds modulate macrophage activation. One M1-activating compound, thiostrepton, is able to reprogram tumor-associated macrophages toward M1-like state in mice, and exhibit potent anti-tumor activity. Our compound-screening results thus help to provide a valuable resource not only for studying the macrophage biology but also for developing therapeutics through modulating macrophage activation.


Asunto(s)
Antiinflamatorios/farmacología , Productos Biológicos/farmacología , Ensayos Analíticos de Alto Rendimiento/métodos , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Animales , Antiinflamatorios/química , Productos Biológicos/química , Línea Celular Tumoral , Células Cultivadas , Expresión Génica/efectos de los fármacos , Ontología de Genes , Humanos , Macrófagos/clasificación , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Neoplasias Experimentales/prevención & control , Fenotipo , Células THP-1 , Tioestreptona/química , Tioestreptona/farmacología
6.
Clin Transl Gastroenterol ; 12(1): e00293, 2021 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-33438988

RESUMEN

INTRODUCTION: Coronavirus disease (COVID-19) has spread from Wuhan, China, and become a worldwide pandemic. Most patients display respiratory symptoms but up to 50% report gastrointestinal symptoms. Neopterin is a surrogate marker for viral inflammation, and its production by macrophages is driven by interferon-γ. METHODS: We measured fecal neopterin in 37 hospitalized COVID-19 patients not requiring intensive care measures and 22 healthy controls. RESULTS: Fecal neopterin was elevated in stool samples from COVID-19 patients compared with that in samples from healthy controls. Especially, patients reporting gastrointestinal symptoms exhibited increased fecal neopterin values. DISCUSSION: COVID-19 is associated with an inflammatory immune response in the gastrointestinal tract.


Asunto(s)
/complicaciones , Heces/química , Enfermedades Gastrointestinales/metabolismo , Enfermedades Gastrointestinales/virología , Neopterin/análisis , Adulto , Anciano , Austria/epidemiología , /epidemiología , Estudios de Casos y Controles , Femenino , Enfermedades Gastrointestinales/diagnóstico , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/patología , Tracto Gastrointestinal/virología , Humanos , Inflamación/inmunología , Inflamación/virología , Pacientes Internos , Interferón gamma/metabolismo , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , /genética
7.
Nat Commun ; 12(1): 102, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397994

RESUMEN

Pro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.


Asunto(s)
Tejido Adiposo/metabolismo , Sistemas de Liberación de Medicamentos , Macrófagos/metabolismo , Mitocondrias/metabolismo , Obesidad/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Animales , Peso Corporal/efectos de los fármacos , Hígado Graso/genética , Hígado Graso/patología , Inflamación/genética , Inflamación/patología , Resistencia a la Insulina , Hígado/metabolismo , Hígado/patología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Obesidad/genética , Obesidad/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células RAW 264.7 , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Pérdida de Peso/efectos de los fármacos
8.
Nat Commun ; 12(1): 308, 2021 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-33436632

RESUMEN

Accumulating evidence shows that RAGE has an important function in the pathogenesis of sepsis. However, the mechanisms by which RAGE transduces signals to downstream kinase cascades during septic shock are not clear. Here, we identify SLP76 as a binding partner for the cytosolic tail of RAGE both in vitro and in vivo and demonstrate that SLP76 binds RAGE through its sterile α motif (SAM) to mediate downstream signaling. Genetic deficiency of RAGE or SLP76 reduces AGE-induced phosphorylation of p38 MAPK, ERK1/2 and IKKα/ß, as well as cytokine release. Delivery of the SAM domain into macrophages via the TAT cell-penetrating peptide blocks proinflammatory cytokine production. Furthermore, administration of TAT-SAM attenuates inflammatory cytokine release and tissue damage in mice subjected to cecal ligation and puncture (CLP) and protects these mice from the lethality of sepsis. These findings reveal an important function for SLP76 in RAGE-mediated pro-inflammatory signaling and shed light on the development of SLP76-targeted therapeutics for sepsis.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Terapia Molecular Dirigida , Fosfoproteínas/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Sepsis/tratamiento farmacológico , Animales , Bacteriófago T7/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Células HEK293 , Humanos , Inflamación/metabolismo , Inflamación/patología , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Péptidos/metabolismo , Unión Proteica , Dominios Proteicos , Células RAW 264.7 , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor para Productos Finales de Glicación Avanzada/química , Sepsis/patología , Transducción de Señal
9.
Aquat Toxicol ; 231: 105739, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33434705

RESUMEN

Cadmium (Cd) with no known functional role in any life-form has myriad of harmful effects. The present study was designed to elucidate the mechanism of Cd-induced oxystress generation and its impact on antioxidant and apoptosis signaling pathways in head kidney macrophage (HKM) of Channa punctatus Bloch. Fish were sampled and acclimatized with one group treated with cadmium chloride (CdCl2) (1.96 mg/L) and another as untreated control group, both kept under observation for 7 days. Exposure to Cd caused ultrastructural changes along with reduced head kidney somatic index (HKSI). Significantly increased levels of reactive oxygen species (ROS), respiratory burst activity, lipid peroxidation, DNA fragmentation and superoxide dismutase were found in the HKM from the treated group as compared to control. In contrast, antioxidant enzymes like catalase and reduced glutathione activity decreased in the Cd exposed group. The suppressed antioxidant activity was further confirmed and corroborated from the altered expression of Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) genes, the major player of antioxidant pathway. Cd induced alteration in Nrf2-Keap1 signaling pathway was also validated by the diminished levels of Nrf2 dependent expression of protein like heme oxygenase-1 (HO-1). The flow cytometry analysis supported the event of apoptosis in Cd exposed group as compared to control, which was further confirmed by the upregulated expression of caspase-3, caspase-8, caspase-9, TNF-α and p53 genes from the real-time gene expression study. In addition, altered protein level of cytochrome C validates the incidence of apoptosis. Altogether, our results demonstrate that exposure to Cd caused oxidative stress in HKM of Channa punctatus Bloch. by compromising the antioxidant enzyme activities via the down regulation of expression of genes related to antioxidant signaling pathway besides encouraging apoptosis via both mitochondrial and death receptor pathway.


Asunto(s)
Apoptosis , Cadmio/toxicidad , Peces/metabolismo , Riñón Cefálico/citología , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Macrófagos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Catalasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/ultraestructura , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Receptores de Muerte Celular/metabolismo , Transducción de Señal/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Contaminantes Químicos del Agua/toxicidad
10.
BMC Genomics ; 22(1): 67, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33472590

RESUMEN

BACKGROUND: Avian infectious bronchitis virus (IBV) is a gamma coronavirus that severely affects the poultry industry worldwide. Long non-coding RNAs (lncRNAs), a subset of non-coding RNAs with a length of more than 200 nucleotides, have been recently recognized as pivotal factors in the pathogenesis of viral infections. However, little is known about the function of lncRNAs in host cultured cells in response to IBV infection. RESULTS: We used next-generation high throughput sequencing to reveal the expression profiles of mRNAs and lncRNAs in IBV-infected HD11 cells. Compared with the uninfected cells, we identified 153 differentially expressed (DE) mRNAs (106 up-regulated mRNAs, 47 down-regulated mRNAs) and 181 DE lncRNAs (59 up-regulated lncRNAs, 122 down-regulated lncRNAs) in IBV-infected HD11 cells. Moreover, gene ontology (GO) and pathway enrichment analyses indicated that DE mRNAs and lncRNAs were mainly involved in cellular innate immunity, amino acid metabolism, and nucleic acid metabolism. In addition, 2640 novel chicken lncRNAs were identified, and a competing endogenous RNA (ceRNAs) network centered on gga-miR-30d and miR-146a-5p was established. CONCLUSIONS: We identified expression profiles of mRNAs and lncRNAs during IBV infection that provided new insights into the pathogenesis of IBV.


Asunto(s)
Pollos/genética , Perfilación de la Expresión Génica/métodos , Macrófagos/metabolismo , ARN Largo no Codificante/genética , ARN Mensajero/genética , Transcriptoma/genética , Animales , Línea Celular , Pollos/virología , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/virología , Ontología de Genes , Virus de la Bronquitis Infecciosa/patogenicidad , Macrófagos/virología , Enfermedades de las Aves de Corral/genética , Enfermedades de las Aves de Corral/virología , Transducción de Señal/genética , Virulencia
11.
Mediators Inflamm ; 2021: 6699560, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33505216

RESUMEN

Licorice extract is a Chinese herbal medication most often used as a demulcent or elixir. The extract usually consists of many components but the key ingredients are glycyrrhizic (GL) and glycyrrhetinic acid (GA). GL and GA function as potent antioxidants, anti-inflammatory, antiviral, antitumor agents, and immuneregulators. GL and GA have potent activities against hepatitis A, B, and C viruses, human immunodeficiency virus type 1, vesicular stomatitis virus, herpes simplex virus, influenza A, severe acute respiratory syndrome-related coronavirus, respiratory syncytial virus, vaccinia virus, and arboviruses. Also, GA was observed to be of therapeutic valve in human enterovirus 71, which was recognized as the utmost regular virus responsible for hand, foot, and mouth disease. The anti-inflammatory mechanism of GL and GA is realized via cytokines like interferon-γ, tumor necrotizing factor-α, interleukin- (IL-) 1ß, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, and IL-17. They also modulate anti-inflammatory mechanisms like intercellular cell adhesion molecule 1 and P-selectin, enzymes like inducible nitric oxide synthase (iNOS), and transcription factors such as nuclear factor-kappa B, signal transducer and activator of transcription- (STAT-) 3, and STAT-6. Furthermore, DCs treated with GL were capable of influencing T-cell differentiation toward Th1 subset. Moreover, GA is capable of blocking prostaglandin-E2 synthesis via blockade of cyclooxygenase- (COX-) 2 resulting in concurrent augmentation nitric oxide production through the enhancement of iNOS2 mRNA secretion in Leishmania-infected macrophages. GA is capable of inhibiting toll-like receptors as well as high-mobility group box 1.


Asunto(s)
Antiinflamatorios/farmacocinética , Ácido Glicirretínico/farmacocinética , Ácido Glicirrínico/farmacocinética , Factores Inmunológicos/farmacocinética , Animales , Citocinas/metabolismo , Medicamentos Herbarios Chinos/farmacocinética , Glycyrrhiza/química , Humanos , Inflamación , Interferones/metabolismo , Interleucinas/metabolismo , Leishmania/metabolismo , Sistema de Señalización de MAP Quinasas , Macrófagos/metabolismo , Macrófagos/parasitología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Prostaglandinas/metabolismo , ARN Mensajero/metabolismo , Células TH1/citología , Receptores Toll-Like/metabolismo
12.
Anticancer Res ; 41(2): 719-730, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33517276

RESUMEN

BACKGROUND/AIM: The purpose of this study was to evaluate the effect of extracellular vesicles derived from canine M1-polarized macrophages (M1EVs) on canine tumor cells, such as D17 (osteosarcoma cells) and LMeC (melanoma cells). MATERIALS AND METHODS: Protein expression was determined by western blot analysis. Gene expression was determined by RT-qPCR. In addition, cell apoptosis was analyzed by Annexin V/PI staining. RESULTS: In the case of M1EV, the levels of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1ß were increased, and nitrate/nitrite levels were also increased. M1EV induced apoptosis of tumor cells by increasing caspase-3 and caspase-7 activation. In addition, M1EVs decreased expression of CCR4, Foxp3 and CTLA-4 in canine peripheral mononuclear cells cocultured with tumor cells. CONCLUSION: M1EV could be an effective anti-cancer therapeutic approach in melanoma and osteosarcoma and M1EVs can be used as immunomodulators in the tumor microenvironment for cancer treatment.


Asunto(s)
Apoptosis , Neoplasias Óseas/patología , Vesículas Extracelulares/metabolismo , Macrófagos/metabolismo , Melanoma/patología , Osteosarcoma/patología , Neoplasias Cutáneas/patología , Animales , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Técnicas de Cocultivo , Perros , Melanoma/metabolismo , Osteosarcoma/metabolismo , Fenotipo , Transducción de Señal , Neoplasias Cutáneas/metabolismo , Microambiente Tumoral
13.
Nutrients ; 13(1)2021 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-33440736

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) has reached pandemic proportions worldwide. We have previously reported that the probiotic strains Bifidobacterium breve CNCM I-4035, Lactobacillus paracasei CNCM I-4034 and Lactobacillus rhamnosus CNCM I-4036 exert anti-inflammatory effects in the intestine of Zucker-Lepr fa/fa rats. In this work, we focused on their hepatic effects. M1 macrophages are related to inflammation and NAFLD pathogenesis, whereas M2 macrophages release anti-inflammatory mediators. We evaluated the effects of these 3 strains on macrophage polarization, inflammation and liver damage of Zucker-Lepr fa/fa rats. The animals received either a placebo or 1010 CFU of probiotics orally for 30 days. Nos2 and Cd86 mRNA levels were determined as markers of M1 macrophages, and Cd163 and Arg1 as M2 markers, respectively, by qRT-PCR. Liver damage was determined by lipid peroxidation, leukocyte infiltration and myeloperoxidase activity. We evaluated a panoply of circulating chemokines, the hepatic ratio P-Akt/Akt, NF-kB and P-NF-kB protein levels. All 3 probiotic strains modulated macrophage polarization in liver and circulating levels of inflammation-related mediators. L. paracasei CNCM I-4034 increased the ratio P-Akt/Akt and NF-kB protein levels. B. breve CNCM I-4035, L. paracasei CNCM I-4034 and L. rhamnosus CNCM I-4036 decreased both pro-inflammatory macrophage gene expression and leukocyte infiltration in the liver.


Asunto(s)
Bifidobacterium breve , Regulación de la Expresión Génica , Lactobacillus rhamnosus , Hepatopatías/metabolismo , Hígado/metabolismo , Macrófagos/metabolismo , Probióticos/farmacología , Animales , Biomarcadores/metabolismo , Hígado/patología , Hepatopatías/patología , Macrófagos/patología , Masculino , Ratas , Ratas Zucker
14.
Nat Commun ; 12(1): 648, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33510170

RESUMEN

Controlling nanocarrier interactions with the immune system requires a thorough understanding of the surface properties that modulate protein adsorption in biological fluids, since the resulting protein corona redefines cellular interactions with nanocarrier surfaces. Albumin is initially one of the dominant proteins to adsorb to nanocarrier surfaces, a process that is considered benign or beneficial by minimizing opsonization or inflammation. Here, we demonstrate the surface chemistry of a model nanocarrier can be engineered to stabilize or denature the three-dimensional conformation of adsorbed albumin, which respectively promotes evasion or non-specific clearance in vivo. Interestingly, certain common chemistries that have long been considered to convey stealth properties denature albumin to promote nanocarrier recognition by macrophage class A1 scavenger receptors, providing a means for their eventual removal from systemic circulation. We establish that the surface chemistry of nanocarriers can be specified to modulate adsorbed albumin structure and thereby tune clearance by macrophage scavenger receptors.


Asunto(s)
Macrófagos/metabolismo , Nanopartículas/química , Pliegue de Proteína , Albúmina Sérica Bovina/química , Adsorción , Animales , Bovinos , Microscopía por Crioelectrón , Humanos , Cinética , Ratones , Ratones Endogámicos C57BL , Microscopía Electrónica de Transmisión , Nanopartículas/ultraestructura , Corona de Proteínas/química , Corona de Proteínas/metabolismo , Células RAW 264.7 , Receptores Depuradores/química , Receptores Depuradores/metabolismo , Albúmina Sérica Bovina/metabolismo , Propiedades de Superficie
15.
Nat Commun ; 12(1): 650, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33510172

RESUMEN

Hepatic inflammation is the driving force for the development and progression of NASH. Treatment targeting inflammation is believed to be beneficial. In this study, adoptive transfer of CD4+ T cells converted double negative T cells (cDNT) protects mice from diet-induced liver fat accumulation, lobular inflammation and focal necrosis. cDNT selectively suppress liver-infiltrating Th17 cells and proinflammatory M1 macrophages. IL-10 secreted by M2 macrophages decreases the survival and function of cDNT to protect M2 macrophages from cDNT-mediated lysis. NKG2A, a cell inhibitory molecule, contributes to IL-10 induced apoptosis and dampened suppressive function of cDNT. In conclusion, ex vivo-generated cDNT exert potent protection in diet induced obesity, type 2 diabetes and NASH. The improvement of outcome is due to the inhibition on liver inflammatory cells. This study supports the concept and the feasibility of potentially utilizing this autologous immune cell-based therapy for the treatment of NASH.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Inflamación/metabolismo , Hígado/metabolismo , Macrófagos/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Traslado Adoptivo/métodos , Animales , Linfocitos T CD4-Positivos/inmunología , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Dieta Alta en Grasa/efectos adversos , Progresión de la Enfermedad , Perfilación de la Expresión Génica/métodos , Inflamación/genética , Interleucina-10/metabolismo , Hígado/patología , Macrófagos/clasificación , Macrófagos/inmunología , Masculino , Ratones Endogámicos C57BL , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/terapia , Obesidad/etiología , Obesidad/metabolismo , Obesidad/terapia
16.
Science ; 371(6527): 400-405, 2021 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-33479153

RESUMEN

Key to the success of intracellular pathogens is the ability to sense and respond to a changing host cell environment. Macrophages exposed to microbial products undergo metabolic changes that drive inflammatory responses. However, the role of macrophage metabolic reprogramming in bacterial adaptation to the intracellular environment has not been explored. Here, using metabolic profiling and dual RNA sequencing, we show that succinate accumulation in macrophages is sensed by intracellular Salmonella Typhimurium (S. Tm) to promote antimicrobial resistance and type III secretion. S Tm lacking the succinate uptake transporter DcuB displays impaired survival in macrophages and in mice. Thus, S Tm co-opts the metabolic reprogramming of infected macrophages as a signal that induces its own virulence and survival, providing an additional perspective on metabolic host-pathogen cross-talk.


Asunto(s)
Interacciones Huésped-Patógeno , Macrófagos/metabolismo , Salmonella typhimurium/metabolismo , Salmonella typhimurium/patogenicidad , Ácido Succínico/metabolismo , Sistemas de Secreción Tipo III/metabolismo , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Supervivencia Celular , Transportadores de Ácidos Dicarboxílicos/genética , Transportadores de Ácidos Dicarboxílicos/metabolismo , Modelos Animales de Enfermedad , Femenino , Macrófagos/microbiología , Ratones , Ratones Endogámicos C57BL , RNA-Seq , Salmonella typhimurium/genética , Virulencia
17.
Nat Commun ; 12(1): 301, 2021 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-33436596

RESUMEN

Macrophages are innate immune cells that contribute to fighting infections, tissue repair, and maintaining tissue homeostasis. To enable such functional diversity, macrophages resolve potentially conflicting cues in the microenvironment via mechanisms that are unclear. Here, we use single-cell RNA sequencing to explore how individual macrophages respond when co-stimulated with inflammatory stimuli LPS and IFN-γ and the resolving cytokine IL-4. These co-stimulated macrophages display a distinct global transcriptional program. However, variable negative cross-regulation between some LPS + IFN-γ-specific and IL-4-specific genes results in cell-to-cell heterogeneity in transcription. Interestingly, negative cross-regulation leads to mutually exclusive expression of the T-cell-polarizing cytokine genes Il6 and Il12b versus the IL-4-associated factors Arg1 and Chil3 in single co-stimulated macrophages, and single-cell secretion measurements show that these specialized functions are maintained for at least 48 h. This study suggests that increasing functional diversity in the population is one strategy macrophages use to respond to conflicting environmental cues.


Asunto(s)
Polaridad Celular , Macrófagos/citología , Animales , Arginasa/metabolismo , Polaridad Celular/efectos de los fármacos , Polaridad Celular/genética , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Interferón gamma/farmacología , Interleucina-12/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/farmacología , Aprendizaje Automático , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Redes Neurales de la Computación , Oportunidad Relativa , Análisis de la Célula Individual , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacos
18.
Metabolism ; 114: 154404, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33069810

RESUMEN

BACKGROUND: Recent studies have considered the obesity-related lipid environment as the potential cause for M1 macrophage polarization in type 2 diabetes. However, the specific regulatory mechanism is still unclear. Here, we investigated the role and molecular mechanism of histone methyltransferases G9a in lipids-induced M1 macrophage polarization in type 2 diabetes. METHODS: We used saturated fatty acid palmitate to induce macrophage polarization, and performed real-time PCR, western blot, flow cytometry and CHIP assay to study the function and molecular mechanism of G9a. Additionally, we isolated the peripheral blood mononuclear cells (PBMCs) from 187 patients with type 2 diabetes and 68 healthy individuals, and analyzed the expression level of G9a. RESULTS: The palmitate treatment induced the macrophage M1 polarization, and decreased the expression of G9a. The deficiency of G9a could promote the palmitate-induced M1 macrophage polarization, whereas, over-expressing G9a notably suppressed this process. Meanwhile, we observed the regulatory role of G9a on the ER stress which could contribute to M1 macrophage. Furthermore, we identified the fatty acid transport protein CD36 as the potential target of G9a. Dependent on the methyltransferase activity, G9a could negatively regulate the expression of CD36 induced by palmitate. The CD36 inhibitor SSO could significantly attenuate the regulatory effect of G9a on M1 macrophage polarization and ER stress. Importantly, G9a was decreased, and suppressed CD36 and M1 macrophage genes in the PBMCs from individuals with type 2 diabetes. CONCLUSIONS: Our studies demonstrate that G9a plays critical roles in lipid-induced M1 macrophage polarization via negatively regulating CD36.


Asunto(s)
Antígenos CD36/metabolismo , Polaridad Celular/fisiología , Diabetes Mellitus Tipo 2/metabolismo , Histona Metiltransferasas/metabolismo , Macrófagos/metabolismo , Animales , Polaridad Celular/efectos de los fármacos , Citometría de Flujo , Humanos , Leucocitos Mononucleares/metabolismo , Macrófagos/efectos de los fármacos , Ratones , Ácido Palmítico/farmacología , Células RAW 264.7
19.
Environ Pollut ; 269: 116075, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33316494

RESUMEN

Polystyrene nanoparticles (PS NPs), originated from breakdown of large plastic wastes, have already caused much concern for their environmental risks on health. This current study was aimed to reveal the toxicological mechanism of PS NPs on developing zebrafish and macrophage cells. To fulfill this purpose, 42 nm PS NPs were exposed to the early development stage of zebrafish for 5 days, the decreased heart rate and locomotor activity of zebrafish larvae were observed. The fluorescent PS NPs were used to precisely assess the accumulation of PS NPs in zebrafish larvae, and the results indicated that PS NPs not only accumulated in digestive system, but also infiltrated into the liver. More importantly, the transcriptomic analysis revealed that a total of 356 genes were differentially expressed and the KEGG class map showed significant differences in the MAPK pathway upon PS NPs treatment. Meanwhile, the induction of oxidative stress and inflammation were also observed in zebrafish larvae. Furthermore, PS NPs also induced oxidative damage and inflammatory response in RAW 264.7 cells, which activated p38 MAPK signal pathway and finally induced cell apoptosis. Our study provides a new understanding of MAPK signaling pathway involved in toxicity mechanism.


Asunto(s)
Nanopartículas , Poliestirenos , Animales , Apoptosis , Macrófagos/metabolismo , Nanopartículas/toxicidad , Estrés Oxidativo , Poliestirenos/metabolismo , Pez Cebra/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
20.
Phytomedicine ; 80: 153398, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33130474

RESUMEN

BACKGROUND: Celastrol, a pentacyclic triterpenoid quinonemethide isolated from several spp. of Celastraceae family, exhibits anti-inflammatory activities in a variety of diseases including arthritis. PURPOSE: This study aims to investigate whether the inhibition of NLRP3 inflammasome is engaged in the anti-inflammatory activities of celastrol and delineate the underlying mechanism. METHODS: The influence of celastrol on NLRP3 inflammasome activation was firstly studied in lipopolysaccharide (LPS)-primed mouse bone marrow-derived macrophages (BMDMs) and phorbol 12-myristate 13-acetate (PMA)-primed THP-1 cells treated with nigericin. Reconstituted inflammasome was also established by co-transfecting NLRP3, ASC, pro-caspase-1 and pro-IL-1ß in HEK293T cells. The changes of inflammasome components including NLRP3, ASC, pro-caspase-1/caspase-1 and pro-IL-1ß/IL-1ß were examined by enzyme-linked immunosorbent assay (ELISA), western blotting and immunofluorescence. Furthermore, Propionibacterium acnes (P. acnes)/LPS-induced liver injury and monosodium urate (MSU)-induced gouty arthritis in mice were employed in vivo to validate the inhibitory effect of celastrol on NLRP3 inflammasome. RESULTS: Celastrol significantly suppressed the cleavage of pro-caspase-1 and pro-IL-1ß, while not affecting the protein expressions of NLRP3, ASC, pro-caspase-1 and pro-IL-1ß in THP-1 cells, BMDMs and HEK293T cells. Celastrol suppressed NLRP3 inflammasome activation and alleviated P. acnes/LPS-induced liver damage and MSU-induced gouty arthritis. Mechanism study revealed that celastrol could interdict K63 deubiquitination of NLRP3, which may concern interaction of celastrol and BRCA1/BRCA2-containing complex subunit 3 (BRCC3), and thereby prohibited the formation of NLRP3, ASC and pro-caspase-1 complex to block the generation of mature IL-1ß. CONCLUSION: Celastrol suppresses NLRP3 inflammasome activation in P. acnes/LPS-induced liver damage and MSU-induced gouty arthritis via inhibiting K63 deubiquitination of NLRP3, which presents a novel insight into inhibition of celastrol on NLRP3 inflammasome and provides more evidences for its application in the therapy of inflammation-related diseases.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Artritis Gotosa/tratamiento farmacológico , Hígado/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Triterpenos/farmacología , Animales , Artritis Gotosa/inducido químicamente , Artritis Gotosa/metabolismo , Células HEK293 , Humanos , Inflamasomas/efectos de los fármacos , Inflamasomas/metabolismo , Lipopolisacáridos/toxicidad , Hígado/microbiología , Hígado/patología , Lisina/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Mutantes , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Propionibacterium acnes/patogenicidad , Células THP-1 , Ubiquitinación/efectos de los fármacos , Ácido Úrico/toxicidad
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