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1.
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
2.
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
3.
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
4.
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
5.
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
6.
Food Chem ; 340: 127931, 2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-32871358

RESUMEN

Thinned peach is abundant in polyphenols, and has been shown to exhibit various bioactivities. In this study, we evaluated the underlying immunomodulatory activity of polyphenol extracts of thinned peach (PETP) via the NF-κB and Nrf2 signaling pathways in RAW264.7 macrophages. The results demonstrated that the PETP efficiently activated the nuclear translocation of NF-κB and Nrf2, as well as downstream cytokines (IL-1ß, IL-6, TNF-α and IFN-γ), SOD activity and ROS levels in RAW264.7 cells. Specifically, the PETP of natural drying and hot air drying exhibited less efficacy than that of freeze drying in NF-κB pathway. Interestingly, the PETP of hot air drying at 50 °C was more effective than freeze-dried PETP in activating Nrf2 nuclear translocation. Additionally, 50 µg/mL PETP enhanced immune responses, whereas 800 µg/mL PETP inhibited inflammatory development in macrophages. These findings indicated that different PETP affected the immunomodulation effects differently, which associated with the drying methods and incubation concentrations.


Asunto(s)
Desecación/métodos , Factores Inmunológicos/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Polifenoles/farmacología , Prunus persica/química , Animales , Citocinas/metabolismo , Liofilización , Factores Inmunológicos/química , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Polifenoles/química , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos
7.
Food Chem ; 336: 127539, 2021 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-32763730

RESUMEN

Hesperidin hydrolysates (HHS) was produced by the hydrolysis of hesperidin (HDN) in previous studies. The potential components in HHS were identified by LC-MS, and minor components (MCS) in HHS were isolated. Antioxidant activities by radical-scavenging capacities, reducing capacity and ß-carotene-linoleate assay, anti-inflammatory effects by inhibiting NO production of RAW 264.7 cells, and α-glucosidase inhibitory effects of HDN, HHS, MCS and henperetin (HTN) were investigated in present study. HHS showed higher radical scavenging activities, higher reducing capacity, and higher inhibitory activity in the ß-carotene-linoleate assay than HDN. HHS inhibited the production of NO and pro-inflammatory cytokines of RAW 264.7 cells more strongly than HDN. HHS also intensively inhibited α-glucosidase activity whereas HDN showed little activity. In addition, the effects of MCS on above activities showed it play a synergistic part with HTN. This work suggested that hydrolyzation of HDN enhance the activities, and provided valuable information on effective utilization of HDN.


Asunto(s)
Antiinflamatorios/química , Antioxidantes/química , Citrus/química , Inhibidores Enzimáticos/química , Hesperidina/análisis , Animales , Antiinflamatorios/farmacología , Catálisis , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Citrus/metabolismo , Inhibidores Enzimáticos/metabolismo , Hesperidina/metabolismo , Hesperidina/farmacología , Hidrólisis , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Espectrometría de Masas , Ratones , Óxido Nítrico/metabolismo , Células RAW 264.7 , alfa-Glucosidasas/química , alfa-Glucosidasas/metabolismo
8.
Food Chem ; 336: 127744, 2021 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-32781352

RESUMEN

Cardoon (Cynara cardunculus L.) bracts were collected at different maturation stages to investigate seasonal changes in the phenolic compounds profile and in vitro bioactivities. Among the 12 phenolic compounds tentatively identified, 3,5-O-dicaffeoylquinic acid (21.83 mg/g extract) and apigenin-7-O-glucuronide (10.6 mg/g extract) were the most abundant. Immature bracts (C1: principal growth stage (PGS) 5) had the highest phenolic compounds content, and anti-inflammatory (IC50 = 72 µg/mL) and cytotoxic (GI50 of 30-79 µg/mL) activities. Moreover, extract C1 inhibited efficiently the formation of thiobarbituric acid reactive substances (TBARS; IC50 = 26.8 µg/mL), while extract C8 (PGS 8/9) was more effective against oxidative haemolysis (IC50 38 and 75 µg/mL). The highest antibacterial and antifungal activities were attributed to samples C1 and C6 (PGS 7/8) and samples C2 (PGS 5/6) and C4 (PGS 6/7), respectively. Overall, the obtained results suggest the seasonal changes of polyphenolic composition and bioactivity of cardoon bracts of variable maturity.


Asunto(s)
Cynara/química , Fenoles/química , Animales , Antiinfecciosos/química , Antiinfecciosos/farmacología , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antioxidantes/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cynara/crecimiento & desarrollo , Cynara/metabolismo , Hongos/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Óxido Nítrico/metabolismo , Fenoles/análisis , Extractos Vegetales/química , Extractos Vegetales/farmacología , Hojas de la Planta/química , Hojas de la Planta/metabolismo , Células RAW 264.7 , Estaciones del Año
9.
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
10.
Phytomedicine ; 80: 153400, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33157413

RESUMEN

BACKGROUND: Vascular Endothelial Growth Factors (VEGFs) are a group of growth factor in regulating development and maintenance of blood capillary. The VEGF family members include VEGF-A, placenta growth factor (PGF), VEGF-B, VEGF-C and VEGF-D. VEGF receptor activation leads to multiple complex signaling pathways, particularly in inducing angiogenesis. Besides, VEGF is produced by macrophages and T cells, which is playing roles in inflammation. In macrophages, VEGF receptor-3 (VEGFR-3) and its ligand VEGF-C are known to attenuate the release of pro-inflammatory cytokines. METHODS: Immunoprecipitation and molecular docking assays showed the binding interaction of kaempferol-3-O-rutinoside and VEGF-C. Western blotting and qRT-PCR methods were applied to explore the potentiating effect of kaempferol-3-O-rutinoside in VEGF-C-mediated expressions of proteins and genes in endothelial cells and LPS-induced macrophages. Enzyme-linked immunosorbent assay (ELISA) was employed to reveal the release of proinflammatory cytokines in LPS-induced macrophages. Immunofluorescence assay was performed to determine the effect of kaempferol-3-O-rutinoside in regulating nuclear translocation of NF-κB p65 subunit in the VEGF-C-treated cultures. In addition, Transwell® motility assay was applied to detect the ability of cell migration after drug treatment in LPS-induced macrophages. RESULTS: We identified kaempferol-3-O-rutinoside, a flavonoid commonly found in vegetable and fruit, was able to act on cultured macrophages in inhibiting inflammatory response, and the inhibition was mediated by its specific binding to VEGF-C. The kaempferol-3-O-rutinoside-bound VEGF-C showed high potency to trigger the receptor activation. In LPS-treated cultured macrophages, applied kaempferol-3-O-rutinoside potentiated inhibitory effects of exogenous applied VEGF-C on the secretions of pro-inflammatory cytokines, i.e. IL-6 and TNF-α, as well as expressions of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). This inhibition was in parallel to transcription and translocation of NF-κB. Moreover, the binding of kaempferol-3-O-rutinoside with VEGF-C suppressed the LPS-induced migration of macrophage. CONCLUSION: Taken together, our results suggested the pharmacological roles of kaempferol-3-O-rutinoside in VEGF-C-mediated anti-inflammation.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Quempferoles/metabolismo , Quempferoles/farmacología , Factor C de Crecimiento Endotelial Vascular/metabolismo , Factor C de Crecimiento Endotelial Vascular/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Quempferoles/química , Lipopolisacáridos/toxicidad , Macrófagos/efectos de los fármacos , Ratones , Simulación del Acoplamiento Molecular , FN-kappa B/genética , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Células RAW 264.7
11.
Phytomedicine ; 80: 153377, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33126167

RESUMEN

BACKGROUND: Osteoporosis is a threat to aged people who have excessive osteoclast activation and bone resorption, subsequently causing fracture and even disability. Inhibiting osteoclast differentiation and absorptive functions has become an efficient approach to treat osteoporosis, but osteoclast-targeting inhibitors available clinically remain rare. Kirenol (Kir), a bioactive diterpenoid derived from an antirheumatic Chinese herbal medicine Herba Siegesbeckiae, can treat collagen-induced arthritis in vivo and promote osteoblast differentiation in vitro, while the effects of Kir on osteoclasts are still unclear. PURPOSE: We explore the role of Kir on RANKL-induced osteoclastogenesis in vitro and bone loss in vivo. METHODS: The in vitro effects of Kir on osteoclast differentiation, bone resorption and the underlying mechanisms were evaluated with bone marrow-derived macrophages (BMMs). In vivo experiments were performed using an ovariectomy (OVX)-induced osteoporosis model. RESULTS: We found that Kir remarkably inhibited osteoclast generation and bone resorption in vitro. Mechanistically, Kir significantly inhibited F-actinring formation and repressed RANKL-induced NF-κB p65 activation and p-p38, p-ERK and c-Fos expression. Moreover, Kir inhibited both the expression and nuclear translocation of NFATc1. Ca2+ oscillation and caveolin-1 (Cav-1) were also reduced by Kir during osteoclastogenesis in vitro. Consistent with these findings, 2-10 mg/kg Kir attenuated OVX-induced osteoporosis in vivo as evidenced by decreased osteoclast numbers and downregulated Cav-1 and NFATc1 expression. CONCLUSIONS: Kir suppresses osteoclastogenesis and the Cav-1/NFATc1 signaling pathway both in vitro and in vivo and protects against OVX-induced osteoporosis. Our findings reveal Kir as a potential safe oral treatment for osteoporosis.


Asunto(s)
Caveolina 1/metabolismo , Diterpenos/farmacología , Factores de Transcripción NFATC/metabolismo , Osteogénesis/efectos de los fármacos , Osteoporosis/prevención & control , Administración Oral , Animales , Resorción Ósea/prevención & control , Calcio/metabolismo , Diferenciación Celular/efectos de los fármacos , Diterpenos/administración & dosificación , Femenino , Macrófagos/efectos de los fármacos , Ratones Endogámicos C57BL , Osteoclastos/efectos de los fármacos , Osteoporosis/etiología , Ovariectomía/efectos adversos , Ligando RANK/metabolismo , Ligando RANK/farmacología , Transducción de Señal/efectos de los fármacos
12.
J Ethnopharmacol ; 265: 113236, 2021 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-32750462

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Rhynchosia nulubilis (black soybean) has many applications in oriental medicine. It is traditionally used to treat disease related with high blood pressure, diabetes, inflammation, and osteoporosis. Furthermore, fermented soybean foods have traditionally been used for immunity enhancement in East Asia. However, the anti-inflammatory effects of germinated R. nulubilis (GR) against delayed-type hypersensitivity (DTH) are not fully understood. AIM OF STUDY: This study aimed to investigate the anti-inflammatory effects of germinated Rhynchosia nulubilis (GR) fermented with the lactic acid bacterium Lactobacillus pentosus SC65 (GR-SC65) isolated from pickled burdock. MATERIALS AND METHODS: We investigated the effects of GR-SC65 (300 mg/kg/day) on ear thickness and immune cell infiltration in DNFB-induced DTH in mice. We used dexamethasone (3 mg/kg) as a reference drug. Changes in infiltration of CD4+ and CD8+ T cells and NK cells were examined by immunohistochemistry. In addition, we investigated cytokine and chemokine production related to DTH using reverse transcription-polymerase chain reaction. We also investigated DTH-related cytokine production using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. RESULTS: Two lactic acid bacterial strains (Lactobacillus pentosus SC65 and Pediococcus pentosaceus ON81A) were selected for fermenting GR due to their high 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity. The total polyphenol contents (TPCs) in GR-SC65 and GR-ON81A were higher than that in unfermented GR (∗∗∗P < 0.001 vs. GR). Content of daidzein, glycitein, and genistein, the deglycosylated form of isoflavonoids, was higher in GR-SC65 than in unfermented GR. The ethanol extracts of GR-SC65 exerted a stronger anti-inflammatory activity than GR by inhibiting pro-inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) in LPS-induced RAW264.7 macrophages. GR-SC65 reduced 1-fluoro-2,4-dinitrofluorobenzene (DNFB)-induced ear swelling and hyperplasia as well as vascular permeability. Fewer infiltrated CD4+ and CD8+ T cells were observed in the ear tissue of the GR-SC65-treated mice than those of the unfermented GR-treated mice. Furthermore, fewer infiltrated NK cells were observed in the GR-SC65 treated mice, than in the GR-treated mice. GR-SC65 significantly diminished the levels of CCL5 and COX-2 mRNAs and increased the level of IL-10 mRNA. CONCLUSIONS: These data suggest that GR-SC65 can be used as a health supplement or a prophylactic against delayed-type hypersensitive inflammatory disease.


Asunto(s)
Antiinflamatorios/farmacología , Hipersensibilidad Retardada/prevención & control , Lactobacillus pentosus , Soja/química , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/metabolismo , Dexametasona/farmacología , Dinitrofluorobenceno , Femenino , Fermentación , Inflamación/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Células RAW 264.7
13.
Biomed Pharmacother ; 134: 111171, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33383312

RESUMEN

Periodontitis is a multifactorial chronic infectious disease leading to a host immune response involving inflammatory cytokines, especially IL-1ß, which is the main reason for further developing this disease. IL-1 receptor antagonist (IL-1ra) binds IL-1 receptor, inhibiting IL-1ß signaling and reducing the levels of other cytokines closely related to periodontitis, such as IL-6 and TNF-α. Therefore, the use of IL-1ra to inhibit periodontitis development in a system, ensuring its sustained release, might be an effective way to combat this disease. Hence, in this study, a novel IL-1ra-loaded dextran/PLGA microsphere was developed to allow the sustained release of IL-1ra and enhance the anti-inflammatory properties. Therefore, this study's purposes were to develop a novel periodontal treatment for inhibition and treatment of periodontitis and evaluate the sustained-release effect and anti-inflammatory properties of IL-1ra-loaded dextran/PLGA microspheres in vitro by cell experiments and in vivo by animal experiments. The results showed that IL-1ra-loaded dextran/PLGA microspheres were non-toxic both in vitro and in vivo and could be used as a safe and effective treatment. In addition, these microspheres could significantly prolong the half-life of IL-1ra drug, exerting a useful anti-inflammatory effect in macrophages stimulated with P. gingivalis lipopolysaccharide and in rats with periodontitis. In conclusion, IL-1ra-loaded dextran/PLGA microsphere might be a useful tool to combat periodontal disease.


Asunto(s)
Antiinflamatorios/farmacología , Dextranos/química , Portadores de Fármacos , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Periodontitis/prevención & control , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Animales , Antiinflamatorios/química , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Composición de Medicamentos , Proteína Antagonista del Receptor de Interleucina 1/química , Lipopolisacáridos/aislamiento & purificación , Lipopolisacáridos/toxicidad , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Microesferas , Periodontitis/inmunología , Periodontitis/metabolismo , Porphyromonas gingivalis/química , Células RAW 264.7 , Ratas Sprague-Dawley
14.
Cytokine ; 137: 155312, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33128927

RESUMEN

BACKGROUND: COVID-19, as a newly-emerged viral infection has now spread all over the world after originating in Wuhan, China. Pneumonia is the hallmark of the disease, with dyspnea in half of the patients and acute respiratory distress syndrome (ARDS) in up to one -third of the cases. Pulmonary edema, neutrophilic infiltration, and inflammatory cytokine release are the pathologic signs of this disease. The anti-inflammatory effect of the photobiomodulation (PBM) has been confirmed in many previous studies. Therefore, this review study was conducted to evaluate the direct effect of PBM on the acute lung inflammation or ARDS and also accelerating the regeneration of the damaged tissues. The indirect effects of PBM on modulation of the immune system, increasing the blood flow and oxygenation in other tissues were also considered. METHODOLOGY: The databases of PubMed, Cochrane library, and Google Scholar were searched to find the relevant studies. Keywords included the PBM and related terms, lung inflammation, and COVID-19 -related signs. Studies were categorized with respect to the target tissue, laser parameters, and their results. RESULTS: Seventeen related papers were included in this review. All of them were in animal models. They showed that the PBM could significantly decrease the pulmonary edema, neutrophil influx, and generation of pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), intracellular adhesion molecule (ICAM), reactive oxygen species (ROS), isoform of nitric oxide synthase (iNOS), and macrophage inflammatory protein 2 (MIP-2)). CONCLUSION: Our findings revealed that the PBM could be helpful in reducing the lung inflammation and promoting the regeneration of the damaged tissue. PBM can increase the oxygenation indirectly in order to rehabilitate the affected organs. Thus, the infra-red lasers or light-emitting diodes (LEDs) are recommended in this regard.


Asunto(s)
/radioterapia , Terapia por Luz de Baja Intensidad , Pulmón/efectos de la radiación , Neumonía/radioterapia , /sangre , Citocinas/metabolismo , Humanos , Pulmón/fisiopatología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neumonía/inmunología , Neumonía/fisiopatología , PubMed , Edema Pulmonar/inmunología , Edema Pulmonar/fisiopatología , Edema Pulmonar/radioterapia , Especies Reactivas de Oxígeno/metabolismo , /radioterapia
15.
Life Sci ; 266: 118906, 2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-33338502

RESUMEN

AIMS: The aim of this study was to investigate the role of TRPA1 in the pathogenesis of AD. MAIN METHODS: The experimental atopic dermatitis (AD)-like skin lesions were established using 2,4-dinitrochlorobenzene (DNCB). Mice were divided into three groups: TRPA1-/- and WT groups were treated with DNCB dissolved in a 3:1 mixture of acetone and olive oil; the negative control group was treated with 3:1 mixture of acetone and olive oil without DNCB. The treatment lasted for 21 days, after which the animals were sacrificed and their blood, ears and dorsal skin tissue samples were collected for analysis. KEY FINDINGS: Lower dermatitis score, ear thickness, pruritus score, and epidermal hyperplasia were observed in mice in TRPA1-/- mice compared to the WT group. Besides, lower dermal mast cell infiltration, proinflammatory cytokines, Th2 cytokines and the infiltration of macrophages were observed in the TRPA1-/- mice compared to the WT group. Furthermore, we demonstrated that TRPA1 antagonist HC-030031 could alleviate AD-like symptoms and reduce the degree of epidermal hyperplasia in mice. SIGNIFICANCE: TRPA1 has a crucial role during the AD pathogenesis in mice, thus may be used as a potential new target for treating patients with chronic skin inflammatory disease.


Asunto(s)
Dermatitis Atópica/complicaciones , Inflamación/prevención & control , Macrófagos/inmunología , Mastocitos/inmunología , Prurito/prevención & control , Canal Catiónico TRPA1/fisiología , Acetanilidas/farmacología , Animales , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/patología , Dinitroclorobenceno/toxicidad , Inflamación/etiología , Inflamación/patología , Macrófagos/efectos de los fármacos , Mastocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Prurito/etiología , Prurito/patología , Purinas/farmacología , Canal Catiónico TRPA1/antagonistas & inhibidores
16.
J Ethnopharmacol ; 266: 113406, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-32979410

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Eryngium carlinae F. Delaroche (Apiaceae) is an herb used in folk medicine as a diuretic, analgesic, and anti-inflammatory agent. AIM OF THE STUDY: This work assessed the diuretic, antinociceptive, and anti-inflammatory actions of an ethanol extract from the leaves and stems of Eryngium carlinae (ECE). These ethnomedicinal properties of ECE were scientifically validated using in vitro and in vivo assays. MATERIALS AND METHODS: The antinociceptive and diuretic actions of ECE (10-200 mg/kg p.o.) were assessed with the acetic acid-induced writhing test and by using metabolic cages to house mice, respectively. The in vitro anti-inflammatory actions of ECE (1-500 µg/ml) were evaluated using LPS-stimulated primary murine macrophages, and the in vivo anti-inflammatory actions were assessed using the TPA-induced ear edema test (2 mg/ear) and carrageenan-induced paw edema test (50-200 mg/kg p.o.). The production of inflammatory mediators was estimated using in vitro and in vivo assays. RESULTS: ECE lacked antinociceptive and diuretic effects. ECE increased the production of IL-10 in LPS-stimulated macrophages (EC50 = 37.8 pg/ml) and the carrageenan-induced paw edema test (ED50 = 82.6 mg/kg). ECE showed similar in vivo anti-inflammatory actions compared to those observed with indomethacin. CONCLUSION: ECE exerts in vitro and in vivo anti-inflammatory effects by increasing the release of IL-10.


Asunto(s)
Antiinflamatorios/farmacología , Eryngium/química , Inflamación/tratamiento farmacológico , Extractos Vegetales/farmacología , Analgésicos/farmacología , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/aislamiento & purificación , Carragenina , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Edema/tratamiento farmacológico , Etanol/química , Indometacina/farmacología , Inflamación/patología , Mediadores de Inflamación/metabolismo , Interleucina-10/metabolismo , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Componentes Aéreos de las Plantas , Extractos Vegetales/administración & dosificación
17.
J Ethnopharmacol ; 266: 113425, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33010405

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia Miltiorrhiza Radix et Rhizoma (Danshen) and Chuanxiong Rhizoma (Chuanxiong) are both traditional Chinese medicines with vascular protective effects, and their combination is widely used in China to treat occlusive or ischemic diseases of the cerebrovascular or cardiovascular system. Although it is widely accepted that these diseases have high relevance to inflammation, little is known about the anti-inflammatory effect of Danshen, Chuanxiong, and their combination. AIM OF STUDY: We aimed to investigate the complex mode of action of Danshen, Chuanxiong, and their combination and the molecular mechanisms underlying their anti-inflammatory activity. Specifically, toll-like receptor (TLR1/2, 3, and 4)-triggered macrophages and endothelial cells, the two major cell players in atherosclerosis as well as in related cardiovascular and cerebrovascular injuries, were emphasized. METHODS: TLR1/2-, TLR3-, and TLR4-induced bone marrow macrophages (BMMs) and human umbilical vein endothelial cells (HUVECs) were treated with Danshen extract (S. miltiorrhiza extract, SME), ligustrazine (2, 3, 5, 6-tetramethylpyrazine, TMP), and their combination (S. miltiorrhiza and TMP injection, SLI), respectively. The proinflammatory cytokines interleukin 6 (IL-6), IL-12, and tumor necrosis factor alpha (TNF-α) were detected as the preliminary indicators of inflammation. In addition, RNA sequencing (RNA-seq)-based transcriptional profiling analyses were conducted for TLR2-activated BMMs to determine the molecular mode of action of SLI as well as the contribution of SME to SLI activity. RESULTS: SLI mitigated inflammation in both BMMs and HUVECs. Refer to the combination, SME had pronounced anti-inflammatory effect on BMMs but had only a slight effect on HUVECs. In contrast, TMP had considerable anti-inflammatory effect on HUVECs but not on BMMs. Bioinformatic analysis identified a broad spectrum of regulatory genes, in addition to IL-6 gene, and C-X-C motif chemokine ligand 10 (CXCL10) appeared to be another key molecule involved in the mechanism underlying SLI and SME effects. At the molecular level, SME was a major contributor of the anti-inflammatory activity of SLI. CONCLUSIONS: In TLR-activated inflammation, SLI exhibits a "multiple ingredient-multiple target" effect, with SME primarily affecting macrophages and TMP affecting HUVECs. Our study provides evidence for the clinical application of SLI in treating complex diseases involving inflammation-induced injury of both macrophages and epithelial cells. Further bioinformatics studies are required to reveal the entire molecular network involved in TMP, SME, and SLI activity.


Asunto(s)
Antiinflamatorios/farmacología , Medicamentos Herbarios Chinos/farmacología , Inflamación/tratamiento farmacológico , Pirazinas/farmacología , Animales , Antiinflamatorios/administración & dosificación , Citocinas/metabolismo , Quimioterapia Combinada , Medicamentos Herbarios Chinos/administración & dosificación , Femenino , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Inflamación/patología , Mediadores de Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Pirazinas/administración & dosificación
18.
Life Sci ; 266: 118851, 2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-33310032

RESUMEN

AIMS: Macrophage is known to readily engulf any particulate material they encounter, including invading microbes and nano- or micro-particles. While recent studies show that some microparticles (MP) are immunogenic even without drug-cargo, the mechanism underlying this phenomenon is yet unclear. Phagocytosis induces NADPH oxidase-2 (NOX-2) mediated ROS generation that is reported to regulate antibacterial autophagy. We therefore, investigated the role of NOX-2 derived ROS in phagosomal maturation and autophagy induction in response to phagocytic uptake of two kinds of polymeric biodegradable and biocompatible microparticles: yeast-derived ß-glucan particles (YDGP) and poly-(D, L-Lactic Acid) microparticles (PMP). MAIN METHODS: J774A.1 macrophage wereas exposed to polymeric particles and the immune responses: ROS, phagosomal maturation and autophagy induction, were examined by assays including NBT, DCFH-DA, NADPH-Oxidase activity, Lysotracker and Acridine Orange. Further, the LC3 and NOX-2 expression were validated by RT-PCR, immunofluorescence assay and Western blotting. Antimicrobial activity of both MP was examined by CFU counting after administration to Mycobacterium tuberculosis and Salmonella typhimurium infected macrophage. KEY FINDINGS: YDGP induces phagosomal maturation and acidic vesicle accumulation at 30 min and 24 h post-exposure, much more proficiently than that by PMP. YDGP exposure also induced NOX-2 dependent expression of light chain 3 (LC3-II), further confirmed as autophagy activation via autophagic flux assay with autophagolysosome inhibitor bafilomycin A1. Additionally, YDGP displayed superior anti-microbial activity than that by PMP. SIGNIFICANCE: The induction of NOX-2-dependent autophagy and antimicrobial activity exhibited by particulate glucans has significant implications in harnessing these drug delivery vehicles as potential 'value-added' autophagy-mediated therapeutics in future.


Asunto(s)
Autofagia , Macrófagos/patología , Mycobacterium tuberculosis/efectos de los fármacos , NADPH Oxidasa 2/metabolismo , Fagocitosis , beta-Glucanos/farmacología , Animales , Células Cultivadas , Lisosomas/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , NADPH Oxidasa 2/genética , Oxidación-Reducción , Especies Reactivas de Oxígeno/metabolismo
19.
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
20.
PLoS One ; 15(12): e0242543, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33326419

RESUMEN

Clinical studies using a range of omega-3 supplements have yielded conflicting results on their efficacy to control inflammation. Omega-3 fatty acids are substrate for the formation of potent immune-protective mediators, termed as specialized pro-resolving mediators (SPM). Herein, we investigated whether observed differences in the potencies of distinct omega-3 supplements were linked with their ability to upregulate SPM formation. Using lipid mediator profiling we found that four commercially available supplements conferred a unique SPM signature profile to human macrophages, with the overall increases in SPM concentrations being different between the four supplements. These increases in SPM concentrations were linked with an upregulation of macrophage phagocytosis and a decreased uptake of oxidized low-density lipoproteins. Pharmacological inhibition of two key SPM biosynthetic enzymes 5-Lipoxygenase or 15-Lipoxygenase reversed the macrophage-directed actions of each of the omega-3 supplements. Furthermore, administration of the two supplements that most potently upregulated macrophage SPM formation and reprogrammed their responses in vitro, to APOE-/- mice fed a western diet, increased plasma SPM concentrations and reduced vascular inflammation. Together these findings support the utility of SPM as potential prognostic markers in determining the utility of a given supplement to regulate macrophage responses and inflammation.


Asunto(s)
Aterosclerosis/prevención & control , Suplementos Dietéticos , Ácidos Grasos Omega-3/administración & dosificación , Leucotrienos/biosíntesis , Lipoxinas/biosíntesis , Macrófagos/efectos de los fármacos , Prostaglandinas/biosíntesis , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Apolipoproteínas E/inmunología , Araquidonato 15-Lipooxigenasa/genética , Araquidonato 15-Lipooxigenasa/inmunología , Araquidonato 5-Lipooxigenasa/genética , Araquidonato 5-Lipooxigenasa/inmunología , Aterosclerosis/etiología , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Dieta Occidental/efectos adversos , Ácidos Grasos Omega-3/metabolismo , Femenino , Expresión Génica , Humanos , Leucotrienos/inmunología , Lipoproteínas LDL/antagonistas & inhibidores , Lipoproteínas LDL/farmacología , Lipoxinas/inmunología , Inhibidores de la Lipooxigenasa/farmacología , Macrófagos/citología , Macrófagos/inmunología , Masculino , Ratones , Ratones Noqueados para ApoE , Fagocitosis/efectos de los fármacos , Cultivo Primario de Células , Análisis de Componente Principal , Prostaglandinas/inmunología
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