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1.
Int J Mol Sci ; 24(4)2023 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-36835104

RESUMEN

Herein, we describe the synthesis and evaluation of anti-inflammatory activities of new curcumin derivatives. The thirteen curcumin derivatives were synthesized by Steglich esterification on one or both of the phenolic rings of curcumin with the aim of providing improved anti-inflammatory activity. Monofunctionalized compounds showed better bioactivity than the difunctionalized derivatives in terms of inhibiting IL-6 production, and known compound 2 presented the highest activity. Additionally, this compound showed strong activity against PGE2. Structure-activity relationship studies were carried out for both IL-6 and PGE2, and it was found that the activity of this series of compounds increases when a free hydroxyl group or aromatic ligands are present on the curcumin ring and a linker moiety is absent. Compound 2 remained the highest activity in modulating IL-6 production and showed strong activity against PGE2 synthesis.


Asunto(s)
Antiinflamatorios , Curcumina , Polifenoles , Antiinflamatorios/química , Antiinflamatorios/farmacología , Curcumina/análogos & derivados , Curcumina/farmacología , Interleucina-6 , Polifenoles/química , Relación Estructura-Actividad
2.
Molecules ; 28(23)2023 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-38067518

RESUMEN

Tetrahydrocurcumin, the most abundant curcumin transformation product in biological systems, can potentially be a new alternative therapeutic agent with improved anti-inflammatory activity and higher bioavailability than curcumin. In this article, we describe the synthesis and evaluation of the anti-inflammatory activities of tetrahydrocurcumin derivatives. Eleven tetrahydrocurcumin derivatives were synthesized via Steglich esterification on both sides of the phenolic rings of tetrahydrocurcumin with the aim of improving the anti-inflammatory activity of this compound. We showed that tetrahydrocurcumin (2) inhibited TNF-α and IL-6 production but not PGE2 production. Three tetrahydrocurcumin derivatives inhibited TNF-α production, five inhibited IL-6 production, and three inhibited PGE2 production. The structure-activity relationship analysis suggested that two factors could contribute to the biological activities of these compounds: the presence or absence of planarity and their structural differences. Among the tetrahydrocurcumin derivatives, cyclic compound 13 was the most active in terms of TNF-α production, showing even better activity than tetrahydrocurcumin. Acyclic compound 11 was the most effective in terms of IL-6 production and retained the same effect as tetrahydrocurcumin. Moreover, acyclic compound 12 was the most active in terms of PGE2 production, displaying better inhibition than tetrahydrocurcumin. A 3D-QSAR analysis suggested that the anti-inflammatory activities of tetrahydrocurcumin derivatives could be increased by adding bulky groups at the ends of compounds 2, 11, and 12.


Asunto(s)
Curcumina , Curcumina/química , Factor de Necrosis Tumoral alfa , Interleucina-6 , Antiinflamatorios/farmacología , Antiinflamatorios/química , Relación Estructura-Actividad
3.
J Immunol ; 205(10): 2795-2805, 2020 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-33037139

RESUMEN

Hemolysis causes an increase of intravascular heme, oxidative damage, and inflammation in which macrophages play a critical role. In these cells, heme can act as a prototypical damage-associated molecular pattern, inducing TLR4-dependent cytokine production through the MyD88 pathway, independently of TRIF. Heme promotes reactive oxygen species (ROS) generation independently of TLR4. ROS and TNF production contribute to heme-induced necroptosis and inflammasome activation; however, the role of ROS in proinflammatory signaling and cytokine production remains unknown. In this study, we demonstrate that heme activates at least three signaling pathways that contribute to a robust MAPK phosphorylation and cytokine expression in mouse macrophages. Although heme did not induce a detectable Myddosome formation, the TLR4/MyD88 axis was important for phosphorylation of p38 and secretion of cytokines. ROS generation and spleen tyrosine kinase (Syk) activation induced by heme were critical for most proinflammatory signaling pathways, as the antioxidant N-acetyl-l-cysteine and a Syk inhibitor differentially blocked heme-induced ROS, MAPK phosphorylation, and cytokine production in macrophages. Early generated mitochondrial ROS induced by heme was Syk dependent, selectively promoted the phosphorylation of ERK1/2 without affecting JNK or p38, and contributed to CXCL1 and TNF production. Finally, lethality caused by sterile hemolysis in mice required TLR4, TNFR1, and mitochondrial ROS, supporting the rationale to target these pathways to mitigate tissue damage of hemolytic disorders.


Asunto(s)
Hemo/metabolismo , Hemólisis/inmunología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/inmunología , Animales , Quimiocina CXCL1/metabolismo , Modelos Animales de Enfermedad , Humanos , Macrófagos/citología , Macrófagos/inmunología , Ratones , Ratones Noqueados , Mitocondrias/inmunología , Mitocondrias/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosforilación/inmunología , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Quinasa Syk/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
4.
Immunology ; 2018 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-29455451

RESUMEN

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. The cellular immune response to mycobacteria has been characterized extensively, but the antibody response remains underexplored. The present study aimed to examine whether host or bacterial phospholipids induce secretion of IgM, and specifically anti-phospholipid IgM, antibodies by B cells and to identify the responsible B-cell subset. Here we show that peritoneal B cells responded to lipid antigens by secreting IgM antibodies. Specifically, stimulation with M. tuberculosis H37Rv total lipids resulted in significant induction of total and anti-phosphatidylcholine IgM. Similarly, IgM antibody production increased significantly with stimulation by whole Mycobacterium bovis bacillus Calmette-Guérin. The B-1 subset was the dominant source of IgM antibodies after exposure to cardiolipin. Both CD5+ B-1a and CD5- B-1b cell subsets secreted total IgM antibodies after exposure to M. tuberculosis H37Rv total lipids in vitro. Overall, our results suggest that the poly-reactive B-1 cell repertoire contributes to non-specific anti-phospholipid IgM antibody secretion in response to M. tuberculosis lipids.

5.
Lung ; 195(4): 517-521, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28551717

RESUMEN

The cellular immune response to Mycobacterium tuberculosis infection has been well characterized, while the humoral antibody response remains underexplored. We aimed to examine the total and anti-phospholipid IgM levels in the pleural lavage from mice with Mycobacterium bovis BCG extrapulmonary infection. We found that the levels of total and anti-phosphatidylcholine IgM antibodies remained significantly higher in infected mice as compared to non-infected mice up to day 90 after BCG infection, while the anti-cardiolipin IgM antibody levels decreased with bacteria clearance. Our findings suggest that IgM antibodies are secreted and their composition vary during early and late immune response to BCG pleurisy.


Asunto(s)
Anticuerpos Antifosfolípidos/inmunología , Inmunidad Humoral , Inmunoglobulina M/inmunología , Mycobacterium tuberculosis/inmunología , Fosfatidilcolinas/inmunología , Tuberculosis Pleural/inmunología , Animales , Anticuerpos Anticardiolipina/inmunología , Carga Bacteriana , Modelos Animales de Enfermedad , Femenino , Interacciones Huésped-Patógeno , Masculino , Ratones Endogámicos C57BL , Factores de Tiempo , Tuberculosis Pleural/microbiología
6.
Proc Natl Acad Sci U S A ; 111(39): E4110-8, 2014 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-25225402

RESUMEN

The increase of extracellular heme is a hallmark of hemolysis or extensive cell damage. Heme has prooxidant, cytotoxic, and inflammatory effects, playing a central role in the pathogenesis of malaria, sepsis, and sickle cell disease. However, the mechanisms by which heme is sensed by innate immune cells contributing to these diseases are not fully characterized. We found that heme, but not porphyrins without iron, activated LPS-primed macrophages promoting the processing of IL-1ß dependent on nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3). The activation of NLRP3 by heme required spleen tyrosine kinase, NADPH oxidase-2, mitochondrial reactive oxygen species, and K(+) efflux, whereas it was independent of heme internalization, lysosomal damage, ATP release, the purinergic receptor P2X7, and cell death. Importantly, our results indicated the participation of macrophages, NLRP3 inflammasome components, and IL-1R in the lethality caused by sterile hemolysis. Thus, understanding the molecular pathways affected by heme in innate immune cells might prove useful to identify new therapeutic targets for diseases that have heme release.


Asunto(s)
Hemo/metabolismo , Hemólisis/fisiología , Inflamasomas/metabolismo , Animales , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Caspasa 1/deficiencia , Caspasa 1/genética , Caspasa 1/metabolismo , Hemo/química , Hemo/inmunología , Hemólisis/inmunología , Humanos , Inflamasomas/inmunología , Interleucina-1beta/metabolismo , Activación de Macrófagos , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , NADPH Oxidasa 2 , NADPH Oxidasas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR , Potasio/metabolismo , Protoporfirinas/química , Protoporfirinas/metabolismo , Especies Reactivas de Oxígeno/metabolismo
7.
Org Biomol Chem ; 14(29): 7053-60, 2016 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-27376396

RESUMEN

The influence of various structural patterns in a series of novel bi- and tricyclic N-heterocycles on the activity against Leishmania major and Leishmania panamensis has been studied and compounds that are active in the low micromolar region have been identified. Both quinolines and tetrahydrooxazinoindoles (TOI) proved to have significant antileishmanial activities, while substituted indoles were inactive. We have also showed that a chloroquine analogue induces Leishmania killing by modulating macrophage activation.


Asunto(s)
Antiprotozoarios/farmacología , Compuestos Heterocíclicos/farmacología , Leishmania/efectos de los fármacos , Macrófagos/efectos de los fármacos , Animales , Antiprotozoarios/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos/química , Interleucina-10/antagonistas & inhibidores , Interleucina-10/biosíntesis , Macrófagos/metabolismo , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad
8.
Molecules ; 21(6)2016 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-27338338

RESUMEN

Three new diterpenes, uprolide N (1), uprolide O (2), uprolide P (3) and a known one, dolabellane (4), were isolated from the CH2Cl2-MeOH extract of the gorgonian octocoral Eunicea succinea, collected from Bocas del Toro, on the Caribbean coast of Panama. Their structures were determined using spectroscopic analyses, including 1D and 2D NMR and high-resolution mass spectrometry (HRMS) together with molecular modeling studies. Compounds 1-3 displayed anti-inflammatory properties by inhibiting production of Tumor Necrosis Factor (TNF) and Interleukin (IL)-6 induced by lipopolysaccharide (LPS) in murine macrophages.


Asunto(s)
Antozoos/química , Diterpenos/química , Inflamación/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Animales , Diterpenos/administración & dosificación , Diterpenos/aislamiento & purificación , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/inducido químicamente , Inflamación/genética , Interleucina-6/biosíntesis , Interleucina-6/genética , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Moleculares , Panamá , Extractos Vegetales/química , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética
9.
Mediators Inflamm ; 2015: 263543, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26538822

RESUMEN

The inflammatory response is a highly regulated process, and its dysregulation can lead to the establishment of chronic inflammation and, in some cases, to death. Inflammation is the cause of several diseases, including rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, and asthma. The search for agents inhibiting inflammation is a great challenge as the inflammatory response plays an important role in the defense of the host to infections. Marine invertebrates are exceptional sources of new natural products, and among those diterpenoids secondary metabolites exhibit notable anti-inflammatory properties. Novel anti-inflammatory diterpenoids, exclusively produced by marine organisms, have been identified and synthetic molecules based on those structures have been obtained. The anti-inflammatory activity of marine diterpenoids has been attributed to the inhibition of Nuclear Factor-κB activation and to the modulation of arachidonic acid metabolism. However, more research is necessary to describe the mechanisms of action of these secondary metabolites. This review is a compilation of marine diterpenoids, mainly isolated from corals, which have been described as potential anti-inflammatory molecules.


Asunto(s)
Antozoos/química , Antiinflamatorios/farmacología , Diterpenos/farmacología , Inflamación/tratamiento farmacológico , Animales , Ácido Araquidónico/metabolismo , Productos Biológicos/farmacología , Glucocorticoides/química , Humanos , Ratones , FN-kappa B/metabolismo
10.
J Neuroinflammation ; 11: 48, 2014 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-24625061

RESUMEN

Alzheimer's disease (AD) is a major public health problem with substantial economic and social impacts around the world. The hallmarks of AD pathogenesis include deposition of amyloid ß (Aß), neurofibrillary tangles, and neuroinflammation. For many years, research has been focused on Aß accumulation in senile plaques, as these aggregations were perceived as the main cause of the neurodegeneration found in AD. However, increasing evidence suggests that inflammation also plays a critical role in the pathogenesis of AD. Microglia cells are the resident macrophages of the brain and act as the first line of defense in the central nervous system. In AD, microglia play a dual role in disease progression, being essential for clearing Aß deposits and releasing cytotoxic mediators. Aß activates microglia through a variety of innate immune receptors expressed on these cells. The mechanisms through which amyloid deposits provoke an inflammatory response are not fully understood, but it is believed that these receptors cooperate in the recognition, internalization, and clearance of Aß and in cell activation. In this review, we discuss the role of several receptors expressed on microglia in Aß recognition, uptake, and signaling, and their implications for AD pathogenesis.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Microglía/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Humanos
11.
Blood ; 119(10): 2368-75, 2012 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-22262768

RESUMEN

Diseases that cause hemolysis or myonecrosis lead to the leakage of large amounts of heme proteins. Free heme has proinflammatory and cytotoxic effects. Heme induces TLR4-dependent production of tumor necrosis factor (TNF), whereas heme cytotoxicity has been attributed to its ability to intercalate into cell membranes and cause oxidative stress. We show that heme caused early macrophage death characterized by the loss of plasma membrane integrity and morphologic features resembling necrosis. Heme-induced cell death required TNFR1 and TLR4/MyD88-dependent TNF production. Addition of TNF to Tlr4(-/-) or to Myd88(-/-) macrophages restored heme-induced cell death. The use of necrostatin-1, a selective inhibitor of receptor-interacting protein 1 (RIP1, also known as RIPK1), or cells deficient in Rip1 or Rip3 revealed a critical role for RIP proteins in heme-induced cell death. Serum, antioxidants, iron chelation, or inhibition of c-Jun N-terminal kinase (JNK) ameliorated heme-induced oxidative burst and blocked macrophage cell death. Macrophages from heme oxygenase-1 deficient mice (Hmox1(-/-)) had increased oxidative stress and were more sensitive to heme. Taken together, these results revealed that heme induces macrophage necrosis through 2 synergistic mechanisms: TLR4/Myd88-dependent expression of TNF and TLR4-independent generation of ROS.


Asunto(s)
Hemo/farmacología , Macrófagos/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Factores de Necrosis Tumoral/metabolismo , Animales , Western Blotting , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Imidazoles/farmacología , Indoles/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Macrófagos/citología , Macrófagos/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Células 3T3 NIH , Necrosis , Proteína Serina-Treonina Quinasas de Interacción con Receptores/antagonistas & inhibidores , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Factores de Necrosis Tumoral/farmacología
12.
J Vis Exp ; (203)2024 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-38345234

RESUMEN

Many protein-protein interactions involve the binding of short protein segments to peptide-binding domains. Usually, such interactions require the recognition of linear motifs with variable conservation. The combination of highly conserved and more variable regions in the same ligands often contributes to the multispecificity of binding, a common property of enzymes and cell signaling proteins. Characterization of amino acid preferences of peptide-binding domains is important for the design of mediators of protein-protein interactions (PPIs). Computational methods are an efficient alternative to the often costly and cumbersome experimental techniques, enabling the design of potential mediators that can be later validated in downstream experiments. Here, we described a methodology using the Pepspec application of the Rosetta molecular modeling package to predict the amino acid preferences of peptide-binding domains. This methodology is useful when the structure of the receptor protein and the nature of the peptide ligand are both known or can be inferred. The methodology starts with a well-characterized anchor from the ligand, which is extended by randomly adding amino acid residues. The binding affinity of peptides generated this way is then evaluated by flexible-backbone peptide docking in order to select the peptides with the best predicted binding scores. These peptides are then used to calculate amino acid preferences and to optionally compute a position-weight matrix (PWM) that can be used in further studies. To illustrate the application of this methodology, we used the interaction between subunits of human interferon regulatory factor 5 (IRF5), previously known to be multispecific but globally guided by a short conserved motif called pLxIS. The estimated amino acid preferences were consistent with previous knowledge about the IRF5 binding surface. Positions occupied by phosphorylatable serine residues exhibited a high frequency of aspartate and glutamate, likely because their negatively charged side chains are similar to phosphoserine.


Asunto(s)
Aminoácidos , Péptidos , Humanos , Secuencia de Aminoácidos , Aminoácidos/metabolismo , Ligandos , Péptidos/química , Proteínas/metabolismo , Factores Reguladores del Interferón/metabolismo , Unión Proteica , Sitios de Unión , Secuencias de Aminoácidos
13.
Toxicon ; 247: 107831, 2024 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-38936670

RESUMEN

Establishing humane endpoints to minimize animal suffering in studies on snake venom toxicity and antivenom potency tests is crucial. Our findings reveal that Swiss mice exhibit early temperature drop following exposure to different snake venoms and combinations of venoms and antivenoms, predicting later mortality. Evaluating temperature we can identify within 3 h post-inoculation, the animals that will not survive in a period of 48 h. Implementing temperature as a criterion would significantly reduce animal suffering in these studies without compromising the outcomes.


Asunto(s)
Antivenenos , Venenos de Serpiente , Animales , Ratones , Antivenenos/farmacología , Venenos de Serpiente/toxicidad , Temperatura Corporal/efectos de los fármacos , Temperatura , Masculino
15.
Toxins (Basel) ; 15(9)2023 08 26.
Artículo en Inglés | MEDLINE | ID: mdl-37755951

RESUMEN

Snake venom neutralization potency tests are required for quality control assessment by manufacturers and regulatory authorities. These assays require the use of large numbers of mice that manifest severe signs associated with pain and distress and long periods of suffering. Despite this, many animals make a full recovery; therefore, the observation of clinical signs as a predictor of animal death is highly subjective and could affect the accuracy of the results. The use of a more objective parameter such as body temperature measurement could help establish a humane endpoint that would contribute to significantly reducing the suffering of large numbers of animals. We determined the temperature drop in BALB/c mice exposed to the mixtures of Bothrops asper or Lachesis stenophrys venom and a polyvalent antivenom by using an infrared thermometer. Our data show that, based on the temperature change from baseline, it is possible to predict which animals will survive during the first 3 h after inoculation. The data provided in this study may contribute to future reductions in animal suffering, in concordance with general trends in the use of laboratory animals for the quality control of biologicals.


Asunto(s)
Temperatura Corporal , Venenos de Serpiente , Animales , Ratones , Pruebas de Neutralización , Venenos de Serpiente/toxicidad , Antivenenos , Bioensayo , Ratones Endogámicos BALB C
16.
Bioengineering (Basel) ; 10(8)2023 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-37627815

RESUMEN

Mesenchymal stromal cell (MSC)-derived products, such as trophic factors (MTFs), have anti-inflammatory properties that make them attractive for cell-free treatment. Three-dimensional (3D) culture can enhance these properties, and large-scale expansion using a bioreactor can reduce manufacturing costs. Three lots of MTFs were obtained from umbilical cord MSCs produced by either monolayer culture (Monol MTF) or using a 3D microcarrier in a spinner flask dynamic system (Bioreactor MTF). The resulting MTFs were tested and compared using anti-inflammatory potency assays in two different systems: (1) a phytohemagglutinin-activated peripheral blood mononuclear cell (PBMNC) system and (2) a lipopolysaccharide (LPS)-activated macrophage system. Cytokine expression by macrophages was measured via RT-PCR. The production costs of hypothetical units of anti-inflammatory effects were calculated using the percentage of TNF-α inhibition by MTF exposure. Bioreactor MTFs had a higher inhibitory effect on TNF (p < 0.01) than monolayer MTFs (p < 0.05). The anti-inflammatory effect of Bioreactor MTFs on IL-1ß, TNF-α, IL-8, IL-6, and MIP-1 was significantly higher than that of monolayer MTFs. The production cost of 1% inhibition of TNF-α was 11-40% higher using monolayer culture compared to bioreactor-derived MTFs. A 3D dynamic culture was, therefore, able to produce high-quality MTFs, with robust anti-inflammatory properties, more efficiently than monolayer static systems.

17.
Mar Drugs ; 10(11): 2608-17, 2012 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-23203281

RESUMEN

Two new eunicellin-based diterpenes, seco-briarellinone (1) and briarellin S (2), and a known seco-asbestinin (3) have been isolated from the methanolic extract of the common octocoral Briareum asbestinum collected in Bocas del Toro, Caribbean of Panama. The structures and relative stereochemistry of the compounds were defined using extensive spectroscopic analysis including 1D, 2D-nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). Compounds 1 and 2 displayed anti-inflammatory properties inhibiting nitric oxide (NO) production induced by lipopolisacharide (LPS) in macrophages with an Inhibitory concentration 50% (IC50) of 4.7 µM and 20.3 µM, respectively. This is the first report of briarellin diterpenes containing a ketone group at C-12.


Asunto(s)
Antozoos/química , Antiinflamatorios/farmacología , Diterpenos/farmacología , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/aislamiento & purificación , Diterpenos/administración & dosificación , Diterpenos/aislamiento & purificación , Concentración 50 Inhibidora , Lipopolisacáridos/toxicidad , Macrófagos/metabolismo , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico/metabolismo , Panamá
18.
Virulence ; 13(1): 1-4, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-34753390

RESUMEN

We highlight the need to include an analysis of the B-1 B cell subset to complement the characterization of the cell-mediated immune response to the Mycobacterium tuberculosis Beijing lineage. The literature describes the B-1 cell repertoire's involvement in the cell-mediated response within granulomas, which is different from the classic antibody response B cells are generally associated with. Specifically, the B-1 B cell subset migrates from other compartments along with other cells to the infection site. We provide details to complement the reported results from Cerezo-Cortes et al.


Asunto(s)
Subgrupos de Linfocitos B , Mycobacterium tuberculosis , Beijing , Genotipo
19.
J Biol Chem ; 285(52): 40714-23, 2010 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-20959459

RESUMEN

Pseudallescheria boydii (Scedosporium apiospermum) is a saprophytic fungus widespread in the environment, and has recently emerged as an agent of localized as well as disseminated infections, particularly mycetoma, in immunocompromised and immunocompetent hosts. We have previously shown that highly purified α-glucan from P. boydii activates macrophages through Toll-like receptor TLR2, however, the mechanism of P. boydii recognition by macrophage is largely unknown. In this work, we investigated the role of innate immune receptors in the recognition of P. boydii. Macrophages responded to P. boydii conidia and hyphae with secretion of proinflammatory cytokines. The activation of macrophages by P. boydii conidia required functional MyD88, TLR4, and CD14, whereas stimulation by hyphae was independent of TLR4 and TLR2 signaling. Removal of peptidorhamnomannans from P. boydii conidia abolished induction of cytokines by macrophages. A fraction highly enriched in rhamnomannans was obtained and characterized by NMR, high performance TLC, and GC-MS. Preparation of rhamnomannans derived from P. boydii triggered cytokine release by macrophages, as well as MAPKs phosphorylation and IκBα degradation. Cytokine release induced by P. boydii-derived rhamnomannans was dependent on TLR4 recognition and required the presence of non-reducing end units of rhamnose of the rhamnomannan, but not O-linked oligosaccharides from the peptidorhamnomannan. These results imply that TLR4 recognizes P. boydii conidia and this recognition is at least in part due to rhamnomannans expressed on the surface of P. boydii.


Asunto(s)
Activación de Macrófagos/inmunología , Macrófagos Peritoneales/inmunología , Mananos/inmunología , Pseudallescheria/inmunología , Esporas Fúngicas/inmunología , Receptor Toll-Like 4/inmunología , Animales , Citocinas/inmunología , Citocinas/metabolismo , Hifa/inmunología , Hifa/metabolismo , Inmunidad Innata/inmunología , Receptores de Lipopolisacáridos/inmunología , Receptores de Lipopolisacáridos/metabolismo , Macrófagos Peritoneales/metabolismo , Mananos/metabolismo , Ratones , Ratones Noqueados , Quinasas de Proteína Quinasa Activadas por Mitógenos/inmunología , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Factor 88 de Diferenciación Mieloide/inmunología , Factor 88 de Diferenciación Mieloide/metabolismo , Pseudallescheria/metabolismo , Esporas Fúngicas/metabolismo , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo
20.
J Biol Chem ; 285(43): 32844-32851, 2010 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-20729208

RESUMEN

Infectious diseases that cause hemolysis are among the most threatening human diseases, because of severity and/or global distribution. In these conditions, hemeproteins and heme are released, but whether heme affects the inflammatory response to microorganism molecules remains to be characterized. Here, we show that heme increased the lethality and cytokine secretion induced by LPS in vivo and enhanced the secretion of cytokines by macrophages stimulated with various agonists of innate immune receptors. Activation of nuclear factor κB (NF-κB) and MAPKs and the generation of reactive oxygen species were essential to the increase in cytokine production induced by heme plus LPS. This synergistic effect of heme and LPS was blocked by a selective inhibitor of spleen tyrosine kinase (Syk) and was abrogated in dendritic cells deficient in Syk. Moreover, inhibition of Syk and the downstream molecules PKC and PI3K reduced the reactive oxygen species generation by heme. Our results highlight a mechanism by which heme amplifies the secretion of cytokines triggered by microbial molecule activation and indicates possible pathways for therapeutic intervention during hemolytic infectious diseases.


Asunto(s)
Hemo/inmunología , Inmunidad Innata/fisiología , Péptidos y Proteínas de Señalización Intracelular/inmunología , Lipopolisacáridos/inmunología , Macrófagos Peritoneales/inmunología , Proteínas Tirosina Quinasas/inmunología , Especies Reactivas de Oxígeno/inmunología , Animales , Citocinas/inmunología , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Hemo/agonistas , Hemo/metabolismo , Hemo/farmacología , Humanos , Inmunidad Innata/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lipopolisacáridos/agonistas , Lipopolisacáridos/farmacología , Macrófagos Peritoneales/metabolismo , Ratones , Ratones Noqueados , FN-kappa B/genética , FN-kappa B/inmunología , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/inmunología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteína Quinasa C/genética , Proteína Quinasa C/inmunología , Proteína Quinasa C/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Quinasa Syk
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