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1.
Molecules ; 27(3)2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35164164

RESUMO

Interleukin-1 beta (IL-1ß) has diverse physiological functions and plays important roles in health and disease. In this report, we focus on its function in the production of pro-inflammatory cytokines, including IL-6 and IL-8, which are implicated in several autoimmune diseases and host defense against infection. IL-1ß activity is markedly dependent on the binding affinity toward IL-1 receptors (IL-1Rs). Several studies have been conducted to identify suitable small molecules that can modulate the interactions between 1L-1ß and 1L-1R1. Based on our previous report, where DPIE [2-(1,2-Diphenyl-1H-indol-3-yl)ethanamine] exhibited such modulatory activity, three types of DPIE derivatives were synthesized by introducing various substituents at the 1, 2, and 3 positions of the indole group in DPIE. To predict a possible binding pose in complex with IL-1R1, a docking simulation was performed. The effect of the chemicals was determined in human gingival fibroblasts (GFs) following IL-1ß induction. The DPIE derivatives affected different aspects of cytokine production. Further, a group of the derivatives enabled synergistic pro-inflammatory cytokine production, while another group caused diminished cytokine production compared to DPIE stimulation. Some groups displayed no significant difference after stimulation. These findings indicate that the modification of the indole site could modulate IL-1ß:IL1R1 binding affinity to reduce or enhance pro-inflammatory cytokine production.


Assuntos
Citocinas/agonistas , Citocinas/antagonistas & inibidores , Indóis/farmacologia , Mediadores da Inflamação/agonistas , Mediadores da Inflamação/antagonistas & inibidores , Fenetilaminas/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Células Cultivadas , Citocinas/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Indóis/química , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-1beta/agonistas , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Fenetilaminas/química
2.
Inflammopharmacology ; 29(4): 1201-1210, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34241784

RESUMO

Marine sponges and their associated microbiota are multicellular animals known to produce metabolites with interesting pharmacological properties playing a pivotal role against a plethora of pathologic disorders such as inflammation, cancer and infections. Characellide A and B belong to a novel class of glycolipopeptides isolated from the deep sea marine sponge Characella pachastrelloides. In this study, we have evaluated the effects of characellide A and B on cytokine and chemokine release from human peripheral blood mononuclear cells (PBMC). Characellide A induces a concentration- and time-dependent CXCL8, IL-6 and TNF-α release from PBMC. This production is mediated by the induction of gene transcription. Moreover, cytokine/chemokine release induced by characellide A from PBMC is CD1d-dependent because a CD1d antagonist, 1,2-bis(diphenylphosphino)ethane [DPPE]-polyethylene glycolmonomethylether [PEG], specifically inhibits characellide A-induced activation of PBMC. In conclusion, characellide A is a novel modulator of adaptative/innate immune responses. Further studies are needed to understand its potential pharmacological application.


Assuntos
Fatores Biológicos/farmacologia , Agentes de Imunomodulação/farmacologia , Mediadores da Inflamação/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Poríferos , Animais , Fatores Biológicos/isolamento & purificação , Relação Dose-Resposta a Droga , Humanos , Agentes de Imunomodulação/isolamento & purificação , Imunomodulação/efeitos dos fármacos , Imunomodulação/fisiologia , Mediadores da Inflamação/agonistas , Mediadores da Inflamação/imunologia , Leucócitos Mononucleares/imunologia
3.
Fertil Steril ; 115(2): 483-489, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33032814

RESUMO

OBJECTIVE: To evaluate the effect of testosterone treatment on metabolic and inflammation parameters and leukocyte-endothelium interactions in transgender men (TGM). DESIGN: Prospective observational study. SETTING: University hospital. PATIENT(S): One hundred fifty-seven TGM. INTERVENTION(S): Administration of testosterone undecanoate (1,000 mg, intramuscular) every 12 weeks. MAIN OUTCOME MEASURE(S): Endocrine parameters, adhesion molecules (vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1, and E-selectin), proinflammatory cytokines interleukin-6, and tumor necrosis factor alpha were evaluated in serum before and after treatment using Luminex's xMAP technology. In addition, interactions between human umbilical vein endothelial cells and polymorphonuclear leukocytes were assessed by flow chamber microscopy. RESULT(S): Testosterone treatment led to an increase in leukocyte-endothelium interactions due to an increase in polymorphonuclear leukocytes rolling and adhesion and decreased rolling velocity. It also boosted levels of vascular cell adhesion molecule-1, E-selectin, interleukin-6, and tumor necrosis factor alpha. As expected, testosterone also produced a significant increase in free androgenic index, androstenedione, total testosterone, and atherogenic index of plasma and a decrease in sex hormone-binding globulin and high-density lipoprotein cholesterol. CONCLUSION(S): Treatment of TGM with testosterone induces an increase in leukocyte-endothelium interactions and adhesion molecules and proinflammatory cytokines. These effects are a reason to monitor cardiovascular risk in these patients.


Assuntos
Androgênios/efeitos adversos , Endotélio Vascular/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Leucócitos/efeitos dos fármacos , Testosterona/análogos & derivados , Pessoas Transgênero , Adulto , Androgênios/administração & dosagem , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/agonistas , Injeções Subcutâneas , Leucócitos/metabolismo , Masculino , Estudos Prospectivos , Testosterona/administração & dosagem , Testosterona/efeitos adversos , Adulto Jovem
4.
Pharmacol Res ; 161: 105117, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32768626

RESUMO

BACKGROUND AND PURPOSE: Formyl peptide receptor 2 (FPR2) is a Class A G protein-coupled receptor (GPCR) that interacts with multiple ligands and transduces both proinflammatory and anti-inflammatory signals. These ligands include weak agonists and modulators that are produced during inflammation. The present study investigates how prolonged exposure to FPR2 modulators influence receptor signaling. EXPERIMENTAL APPROACH: Fluorescent biosensors of FPR2 were constructed based on single-molecule fluorescent resonance energy transfer (FRET) and used for measurement of ligand-induced receptor conformational changes. These changes were combined with FPR2-mediated signaling events and used as parameters for the conformational states of FPR2. Ternary complex models were developed to interpret ligand concentration-dependent changes in FPR2 conformational states. KEY RESULTS: Incubation with Ac2-26, an anti-inflammatory ligand of FPR2, decreased FRET intensity at picomolar concentrations. In comparison, WKYMVm (W-pep) and Aß42, both proinflammatory agonists of FPR2, increased FRET intensity. Preincubation with Ac2-26 at 10 pM diminished W-pep-induced Ca2+ flux but potentiated W-pep-stimulated ß-arrestin2 membrane translocation and p38 MAPK phosphorylation. The opposite effects were observed with 10 pM of Aß42. Neither Ac2-26 nor Aß42 competed for W-pep binding at the picomolar concentrations. CONCLUSIONS AND IMPLICATIONS: The results support the presence of two allosteric binding sites on FPR2, each for Ac2-26 and Aß42, with high and low affinities. Sequential binding of the two allosteric ligands at increasing concentrations induce different conformational changes in FPR2, providing a novel mechanism by which biased allosteric modulators alter receptor conformations and generate pro- and anti-inflammatory signals.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Anexina A1/farmacologia , Mediadores da Inflamação/agonistas , Fragmentos de Peptídeos/farmacologia , Peptídeos/farmacologia , Receptores de Formil Peptídeo/agonistas , Receptores de Lipoxinas/agonistas , Técnicas Biossensoriais , Sinalização do Cálcio , Linhagem Celular Tumoral , AMP Cíclico/metabolismo , Transferência Ressonante de Energia de Fluorescência , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Mediadores da Inflamação/metabolismo , Ligantes , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Modelos Moleculares , Fosforilação , Conformação Proteica , Receptores de Formil Peptídeo/genética , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/genética , Receptores de Lipoxinas/metabolismo , Proteínas Recombinantes de Fusão , Relação Estrutura-Atividade , beta-Arrestina 2/metabolismo
5.
Respir Res ; 21(1): 67, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164736

RESUMO

BACKGROUND: The use of electronic cigarettes (ECIGs) is increasing, but the impact of ECIG-vapor on cellular processes like inflammation or host defense are less understood. The aim of the present study was to compare the acute effects of traditional cigarettes (TCIGs) and ECIG-exposure on host defense, inflammation, and cellular activation of cell lines and primary differentiated human airway epithelial cells (pHBE). METHODS: We exposed pHBEs and several cell lines to TCIG-smoke or ECIG-vapor. Epithelial host defense and barrier integrity were determined. The transcriptome of airway epithelial cells was compared by gene expression array analysis. Gene interaction networks were constructed and differential gene expression over all groups analyzed. The expression of several candidate genes was validated by qRT-PCR. RESULTS: Bacterial killing, barrier integrity and the expression of antimicrobial peptides were not affected by ECIG-vapor compared to control samples. In contrast, TCIGs negatively affected host defense and reduced barrier integrity in a significant way. Furthermore ECIG-exposure significantly induced IL-8 secretion from Calu-3 cells but had no effect on NCI-H292 or primary cells. The gene expression based on array analysis distinguished TCIG-exposed cells from ECIG and room air-exposed samples. CONCLUSION: The transcriptome patterns of host defense and inflammatory genes are significantly distinct between ECIG-exposed and TCIG-treated cells. The overall effects of ECIGs on epithelial cells are less in comparison to TCIG, and ECIG-vapor does not affect host defense. Nevertheless, although acute exposure to ECIG-vapor induces inflammation, and the expression of S100 proteins, long term in vivo data is needed to evaluate the chronic effects of ECIG use.


Assuntos
Fumar Cigarros/efeitos adversos , Sistemas Eletrônicos de Liberação de Nicotina , Mediadores da Inflamação/metabolismo , Mucosa Respiratória/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversos , Vaping/efeitos adversos , Linhagem Celular Tumoral , Células Cultivadas , Humanos , Mediadores da Inflamação/agonistas , Mucosa Respiratória/efeitos dos fármacos
6.
Inflammation ; 43(3): 916-936, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31981062

RESUMO

Osteoarthritis (OA) is considered the most frequent degenerative disease and is characterized by cartilage degradation and synovial inflammation. Fibroblast-like synoviocytes (FLSs) are vital to synovial inflammation in OA. Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and hyperinsulinemia (HINS) and has been demonstrated to be an independent risk factor for OA. Autophagy is involved in the processes of various inflammatory diseases, and autophagy inhibition can stimulate OA development. Thus, we aimed to investigate the role of insulin in the inflammatory phenotype and autophagy of FLSs in OA. The data showed that cell viability and proinflammatory cytokine production in FLSs were both increased after insulin stimulation. We also found that high insulin could promote macrophage infiltration and chemokine production but inhibited autophagy in FLSs. To further explore the potential mechanisms, the effects of insulin on PI3K/Akt/mTOR and NF-ĸB signaling activation were evaluated. The results indicated that insulin activated PI3K/Akt/mTOR/NF-ĸB signaling, and the above-mentioned inflammatory responses, including autophagy inhibition, were notably attenuated by specific signaling inhibitors in the presence of high insulin. Moreover, the data showed that a positive feedback loop existed between proinflammatory cytokines (e.g., IL-1ß, IL-6, and TNF-α) and PI3K/mTOR/Akt/NF-ĸB signaling in FLSs, and insulin enhanced this feedback loop to accelerate OA progression. Our study suggests that insulin may be a novel therapeutic strategy for OA prevention and treatment in the future.


Assuntos
Fibroblastos/metabolismo , Mediadores da Inflamação/metabolismo , Insulina/toxicidade , Osteoartrite/metabolismo , Sinoviócitos/metabolismo , Idoso , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Mediadores da Inflamação/agonistas , Masculino , Pessoa de Meia-Idade , Osteoartrite/patologia , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/patologia
7.
J Neuroimmune Pharmacol ; 15(2): 280-291, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31863333

RESUMO

Histamine is a major peripheral inflammatory mediator and a neurotransmitter in the central nervous system. We have reported that histamine induces microglia activation and releases proinflammatory factors in primary cultured microglia. Whether histamine has similar effects in vivo is unknown. In the present study, we aimed to investigate the role of histamine and its receptors in the release of inflammatory mediators and activation of microglia in rat brain. We site-directed injected histamine, histamine receptor agonists or histamine receptor antagonists in the rat lateral ventricle using stereotaxic techniques. Flow cytometry was employed to determine histamine receptor expression in rat microglia. Microglia activation was assessed by Iba1 immunohistochemistry. The levels of tumour necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1ß) and interleukin-10 (IL-10) were measured with commercial enzyme-linked immunosorbent assay (ELISA) kits, TNF-α, IL-1ß and IL-10 mRNA expressions were determined with Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). We found that all four types of histamine receptors were expressed in rat brain microglia. Histamine was able to induce microglia activation and subsequent production of the inflammatory factors TNF-α, IL-1ß and IL-10, and these effects were partially abolished by H1R and H4R antagonists. However, H2R and H3R antagonists significantly increased production of TNF-α and IL-1ß, and decreased IL-10 levels. The H1R or H4R agonists stimulated the production of TNF-α and IL-1ß, while the H2R or H3R agonists increased IL-10 release. Our results demonstrate that histamine induces microglia activation and the release of both proinflammatory and anti-inflammatory factors in rat brain, thus contributing to the development of inflammation in the brain. Graphical Abstract Histamine induces microglia activation and the release of both proinflammatory (TNF-α and IL-1ß) and anti-inflammatory factors (IL-10) in rat brain, thus contributing to the development of inflammation in the brain.


Assuntos
Encéfalo/metabolismo , Histamina/farmacologia , Mediadores da Inflamação/metabolismo , Microglia/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H4/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Mediadores da Inflamação/agonistas , Masculino , Microglia/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H4/antagonistas & inibidores
8.
Sci Rep ; 9(1): 16893, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729440

RESUMO

Cytokines of the interleukin (IL)-1 family regulate immune and inflammatory responses. The recently discovered IL-36 family members are involved in psoriasis, rheumatoid arthritis, and pulmonary diseases. Here, we show that IL-36α interacts with heme thereby contributing to its regulation. Based on in-depth spectroscopic analyses, we describe two heme-binding sites in IL-36α that associate with heme in a pentacoordinated fashion. Solution NMR analysis reveals structural features of IL-36α and its complex with heme. Structural investigation of a truncated IL-36α supports the notion that the N-terminus is necessary for association with its cognate receptor. Consistent with our structural studies, IL-36-mediated signal transduction was negatively regulated by heme in synovial fibroblast-like synoviocytes from rheumatoid arthritis patients. Taken together, our results provide a structural framework for heme-binding proteins and add IL-1 cytokines to the group of potentially heme-regulated proteins.


Assuntos
Heme/metabolismo , Interleucina-1/metabolismo , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Células Cultivadas , Citocinas/agonistas , Citocinas/química , Citocinas/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Mediadores da Inflamação/agonistas , Mediadores da Inflamação/química , Mediadores da Inflamação/metabolismo , Interleucina-1/agonistas , Interleucina-1/química , Modelos Moleculares , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , Psoríase/metabolismo , Psoríase/patologia , Relação Estrutura-Atividade , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia
9.
J Neuroinflammation ; 16(1): 173, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31470863

RESUMO

BACKGROUND: Disturbances in clock genes affect almost all patients with Alzheimer's disease (AD), as evidenced by their altered sleep/wake cycle, thermoregulation, and exacerbation of cognitive impairment. As microglia-mediated neuroinflammation proved to be a driver of AD rather than a result of the disease, in this study, we evaluated the relationship between clock gene disturbance and neuroinflammation in microglia and their contribution to the onset of AD. METHODS: In this study, the expression of clock genes and inflammatory-related genes was examined in MACS microglia isolated from 2-month-old amyloid precursor protein knock-in (APP-KI) and wild-type (WT) mice using cap analysis gene expression (CAGE) deep sequencing and RT-PCR. The effects of clock gene disturbance on neuroinflammation and relevant memory changes were examined in 2-month-old APP-KI and WT mice after injection with SR9009 (a synthetic agonist for REV-ERB). The microglia morphology was studied by staining, neuroinflammation was examined by Western blotting, and cognitive changes were examined by Y-maze and novel object recognition tests. RESULTS: CLOCK/BMAL1-driven transcriptional negative feedback loops were impaired in the microglia from 2-month-old APP-KI mice. Pro-inflammatory genes in microglia isolated from APP-KI mice were significantly higher than those isolated from WT mice at Zeitgeber time 14. The expression of pro-inflammatory genes was positively associated with NF-κB activation and negatively associated with the BMAL1 expression. SR9009 induced the activation of microglia, the increased expression of pro-inflammatory genes, and cognitive decline in 2-month-old APP-KI mice. CONCLUSION: Clock gene disturbance in microglia is involved in the early onset of AD through the induction of chronic neuroinflammation, which may be a new target for preventing or slowing AD.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Proteínas CLOCK/metabolismo , Técnicas de Introdução de Genes/métodos , Mediadores da Inflamação/metabolismo , Microglia/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/efeitos dos fármacos , Proteínas CLOCK/antagonistas & inibidores , Proteínas CLOCK/genética , Inflamação/genética , Inflamação/metabolismo , Mediadores da Inflamação/agonistas , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Pirrolidinas/toxicidade , Tiofenos/toxicidade
10.
Toxicol Appl Pharmacol ; 382: 114713, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31437494

RESUMO

INTRODUCTION: Cannabidiol (CBD) containing products are available in a plethora of flavors in oral, sublingual, and inhalable forms. Immunotoxicological effects of CBD containing liquids were assessed by hypothesizing that CBD regulates oxidative stress and lipopolysaccharide (LPS) induced inflammatory responses in macrophages, epithelial cells, and fibroblasts. METHODS: Epithelial cells (BEAS-2B and NHBE), macrophages (U937), and lung fibroblast cells (HFL-1) were treated with varying CBD concentrations or exposed to CBD aerosols. Generated reactive oxygen species (ROS) and inflammatory mediators were measured. Furthermore, monocytes and epithelial cells were stimulated with LPS in combination with CBD or dexamethasone to understand the anti-inflammatory effects of CBD. RESULTS: CBD showed differential effects on IL-8 and MCP-1, and acellular and cellular ROS levels. CBD significantly attenuated LPS-induced NF-κB activity, IL-8, and MCP-1 release from macrophages. Cytokine array data depicted a differential cytokine response due to CBD. Inflammatory mediators, IL-8, serpin E1, CXCL1, IL-6, MIF, IFN-γ, MCP-1, RANTES, and TNF-α were induced, whereas MCP-1/CCL2, CCL5, eotaxin, and IL-2 were reduced. CBD and dexamethasone treatments reduced the IL-8 level induced by LPS when the cells were treated individually, but showed antagonistic effects when used in combination via MCPIP (monocytic chemotactic protein-induced protein). CONCLUSION: CBD differentially regulated basal pro-inflammatory response and attenuated both LPS-induced cytokine release and NF-κB activity in monocytes, similar to dexamethasone. Thus, CBD has a differential inflammatory response and acts as an anti-inflammatory agent in pro-inflammatory conditions but acts as an antagonist with steroids, overriding the anti-inflammatory potential of steroids when used in combination.


Assuntos
Canabidiol/farmacologia , Fibroblastos/efeitos dos fármacos , Mediadores da Inflamação/antagonistas & inibidores , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Mucosa Respiratória/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Fibroblastos/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/agonistas , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , Células U937
11.
J Biochem Mol Toxicol ; 32(11): e22213, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30152906

RESUMO

We investigated the effect of apigenin, a dietary flavonoid, on isoproterenol hydrochloride (ISO)-induced apoptotic signaling in cardiomyoblast H9C2 cells. The results showed that apigenin treatment (10 µM) prevented ISO (31.25 µM)-induced lipid peroxidative levels and antioxidants status in H9C2 cells. Furthermore, apigenin inhibited expression of inflammatory markers in ISO-treated cells. In addition, apigenin prevented ISO-induced DNA damage and apoptotic signaling through modulating the expression of Bax, caspase-3, -8 and -9, cytochrome c, and Fas proteins in H9C2 cells. It is concluded that apigenin prevents ISO-induced antioxidants depletion, oxidative DNA damage, inflammatory, and apoptotic signaling in H9C2 cells. Thus, the present results demonstrated that apigenin has a cardioprotective effect on cardiomyoblasts cells.


Assuntos
Antioxidantes/farmacologia , Apigenina/farmacologia , Apoptose/efeitos dos fármacos , Cardiotônicos/efeitos adversos , Isoproterenol/efeitos adversos , Mioblastos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Biomarcadores/metabolismo , Cardiotônicos/antagonistas & inibidores , Linhagem Celular , Dano ao DNA/efeitos dos fármacos , Mediadores da Inflamação/agonistas , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Isoproterenol/antagonistas & inibidores , Peroxidação de Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/imunologia , Mitocôndrias Cardíacas/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/imunologia , Membranas Mitocondriais/metabolismo , Mioblastos Cardíacos/citologia , Mioblastos Cardíacos/imunologia , Mioblastos Cardíacos/metabolismo , Ratos , Proteína X Associada a bcl-2/agonistas , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/metabolismo , Receptor fas/agonistas , Receptor fas/antagonistas & inibidores , Receptor fas/metabolismo
12.
Biol Pharm Bull ; 41(9): 1355-1361, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29910215

RESUMO

The intestinal barrier dysfunction is a critical pathological change in irritable bowel syndrome (IBS). The objective of this study was to evaluate the effect of Prim-O-glucosylcimifugin (POG) on intestinal barrier dysfunction and reveal possible molecular mechanisms. Human colon adenocarcinoma cell line (Caco-2) cell monolayers induced by tryptase (TRYP) were used to establish an intestinal barrier dysfunction model. Caco-2 cell monolayers from both functional and dysfunctional samples were treated with POG (30, 60 and 120 µg/mL) for 2, 8, 24, 36, 48 and 72 h. The Caco-2 cell monolayers were assessed by measurement of trans-epithelial electrical resistance (TEER) and percentage of fluorescein permeation (PFP). The expression of Protease Activated Receptor 2 (PAR-2) and myosin light chain kinase (MLCK) mRNA was analyzed by RT-PCR and the level of Zonula Occludens-1 (ZO-1) protein expression was determined by Western blot. In addition, the impact of POG on the distribution of the tight juction protein of Occludin was performed by immunofluorescence. Our results showed that POG elevated the TEER and decreased the PFP of the functional Caco-2 cell monolayers, as well as the dysfunctional Caco-2 cell monolayers. Furthermore, POG inhibited the expression of PAR-2 mRNA and MLCK mRNA and increased the level of ZO-1 protein expression in dysfunctional Caco-2 cells. The distribution of the Occludin proteins was ameliorated simultaneously. This study demonstrates that POG can enhance the intestinal barrier function of Caco-2 cell monolayers by inhibiting the expression of PAR-2 and MLCK and up-regulating the expression of ZO-1 protein, and ameliorated the distribution of Occludin protein.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Monossacarídeos/farmacologia , Triptases/toxicidade , Xantenos/farmacologia , Anti-Inflamatórios não Esteroides/química , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Mediadores da Inflamação/agonistas , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Absorção Intestinal/fisiologia , Mucosa Intestinal/metabolismo , Monossacarídeos/química , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/fisiologia , Xantenos/química
13.
Int J Cardiol ; 255: 92-98, 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29425570

RESUMO

BACKGROUND: Emerging evidence indicates gut microbes and their products could activate the autonomic nervous system (ANS), which plays important roles in the initiation and maintenance of atrial fibrillation (AF). Trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes, is associated with cardiovascular diseases. The present study aimed to investigate the role of TMAO in the progression of AF. METHODS: In part 1: TMAO or saline was locally injected into 4 major atrial ganglionated plexi (GP) to clarify its effect on cardiac ANS and AF inducibility in normal canines. In part 2: TMAO or saline was injected into 4 major atrial GP to test its effect on AF progression in a rapid atrial pacing (RAP)-induced AF model. RESULTS: In part 1: Local injection of TMAO significantly increased anterior right GP (ARGP) function and neural activity, shortened ERP values. In part 2, compared with the control group, 6-hour RAP significantly shortened the ERP, widened the ∑WOV, enhanced the ARGP function and neural activity, increased the NGF and c-fos expression, and up-regulated the inflammatory cytokines. TMAO aggravated all of these changes by activating the proinflammatory p65 NF-κB signaling pathway. CONCLUSIONS: TMAO could increase the instability of atrial electrophysiology in normal canines and aggravate the acute electrical remodeling in a RAP-induced AF model by exacerbating autonomic remodeling. The increased inflammatory cytokines in the GP due to the activation of p65 NF-κB signaling may contribute to these effects.


Assuntos
Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/metabolismo , Progressão da Doença , Microbioma Gastrointestinal/efeitos dos fármacos , Metilaminas/toxicidade , Oxidantes/toxicidade , Animais , Fibrilação Atrial/fisiopatologia , Cães , Microbioma Gastrointestinal/fisiologia , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Mediadores da Inflamação/agonistas , Mediadores da Inflamação/metabolismo , Distribuição Aleatória
14.
J Biol Chem ; 292(45): 18699-18712, 2017 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-28972143

RESUMO

In the CNS, microglia are activated in response to injury or infection and in neurodegenerative diseases. The endocytic and cell signaling receptor, LDL receptor-related protein-1 (LRP1), is reported to suppress innate immunity in macrophages and oppose microglial activation. The goal of this study was to identify novel mechanisms by which LRP1 may regulate microglial activation. Using primary cultures of microglia isolated from mouse brains, we demonstrated that LRP1 gene silencing increases expression of proinflammatory mediators; however, the observed response was modest. By contrast, the LRP1 ligand, receptor-associated protein (RAP), robustly activated microglia, and its activity was attenuated in LRP1-deficient cells. An important element of the mechanism by which RAP activated microglia was its ability to cause LRP1 shedding from the plasma membrane. This process eliminated cellular LRP1, which is anti-inflammatory, and generated a soluble product, shed LRP1 (sLRP1), which is potently proinflammatory. Purified sLRP1 induced expression of multiple proinflammatory cytokines and the mRNA encoding inducible nitric-oxide synthase in both LRP1-expressing and -deficient microglia. LPS also stimulated LRP1 shedding, as did the heat-shock protein and LRP1 ligand, calreticulin. Other LRP1 ligands, including α2-macroglobulin and tissue-type plasminogen activator, failed to cause LRP1 shedding. Treatment of microglia with a metalloproteinase inhibitor inhibited LRP1 shedding and significantly attenuated RAP-induced cytokine expression. RAP and sLRP1 both caused neuroinflammation in vivo when administered by stereotaxic injection into mouse spinal cords. Collectively, these results suggest that LRP1 shedding from microglia may amplify and sustain neuroinflammation in response to proinflammatory stimuli.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Córtex Cerebral/metabolismo , Mediadores da Inflamação/agonistas , Microglia/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores de LDL/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Animais Recém-Nascidos , Calreticulina/genética , Calreticulina/metabolismo , Micropartículas Derivadas de Células/efeitos dos fármacos , Micropartículas Derivadas de Células/imunologia , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Proteína Associada a Proteínas Relacionadas a Receptor de LDL/metabolismo , Ligantes , Lipopolissacarídeos/toxicidade , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/imunologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Óxido Nítrico Sintase Tipo II/química , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Interferência de RNA , Receptores de LDL/agonistas , Receptores de LDL/antagonistas & inibidores , Receptores de LDL/genética , Proteínas Recombinantes/metabolismo , Proteínas Supressoras de Tumor/agonistas , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética
15.
Biochem Soc Trans ; 45(4): 953-62, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28687714

RESUMO

Termed 'master gene regulators' long ncRNAs (lncRNAs) have emerged as the true vanguard of the 'noncoding revolution'. Functioning at a molecular level, in most if not all cellular processes, lncRNAs exert their effects systemically. Thus, it is not surprising that lncRNAs have emerged as important players in human pathophysiology. As our body's first line of defense upon infection or injury, inflammation has been implicated in the etiology of several human diseases. At the center of the acute inflammatory response, as well as several pathologies, is the pleiotropic transcription factor NF-κß. In this review, we attempt to capture a summary of lncRNAs directly involved in regulating innate immunity at various arms of the NF-κß pathway that have also been validated in human disease. We also highlight the fundamental concepts required as lncRNAs enter a new era of diagnostic and therapeutic significance.


Assuntos
Doença Crônica , Regulação da Expressão Gênica no Desenvolvimento , Imunidade Inata , Modelos Imunológicos , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Animais , Predisposição Genética para Doença , Humanos , Mediadores da Inflamação/agonistas , Mediadores da Inflamação/metabolismo , NF-kappa B/agonistas , NF-kappa B/genética , NF-kappa B/metabolismo , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética
16.
Artigo em Inglês | MEDLINE | ID: mdl-28163255

RESUMO

This study investigated the effects of caffeine in the behavioral and inflammatory alterations caused by copper in zebrafish larvae, attempting to correlate these changes with the modulation of adenosine receptors. To perform a survival curve, 7dpf larvae were exposed to 10µM CuSO4, combined to different concentrations of caffeine (100µM, 500µM and 1mM) for up to 24h. The treatment with copper showed lower survival rates only when combined with 500µM and 1mM of caffeine. We selected 4 and 24h as treatment time-points. The behavior evaluation was done by analyzing the traveled distance, the number of entries in the center, and the length of permanence in the center and the periphery of the well. The exposure to 10µM CuSO4 plus 500µM caffeine at 4 and 24h changed the behavioral parameters. To study the inflammatory effects of caffeine, we assessed the PGE2 levels by using UHPLC-MS/MS, and TNF, COX-2, IL-6 and IL-10 gene expression by RT-qPCR. The expression of adenosine receptors was also evaluated with RT-qPCR. When combined to copper, caffeine altered inflammatory markers depending on the time of exposure. Adenosine receptors expression was significantly increased, especially after 4h exposure to copper and caffeine together or separately. Our results demonstrated that caffeine enhances the inflammation induced by copper by decreasing animal survival, altering inflammatory markers and promoting behavioral changes in zebrafish larvae. We also conclude that alterations in adenosine receptors are related to those effects.


Assuntos
Cafeína/efeitos adversos , Cobre/toxicidade , Larva/efeitos dos fármacos , Antagonistas de Receptores Purinérgicos P1/efeitos adversos , Receptores Purinérgicos P1/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Cafeína/agonistas , Cafeína/antagonistas & inibidores , Cobre/agonistas , Cobre/química , Sulfato de Cobre/administração & dosagem , Dinoprostona/agonistas , Dinoprostona/antagonistas & inibidores , Dinoprostona/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Mediadores da Inflamação/agonistas , Mediadores da Inflamação/metabolismo , Larva/crescimento & desenvolvimento , Larva/imunologia , Larva/metabolismo , Concentração Osmolar , Agonistas do Receptor Purinérgico P1/química , Agonistas do Receptor Purinérgico P1/toxicidade , Antagonistas de Receptores Purinérgicos P1/química , Receptores Purinérgicos P1/química , Receptores Purinérgicos P1/genética , Análise de Sobrevida , Poluentes Químicos da Água/agonistas , Poluentes Químicos da Água/antagonistas & inibidores , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/imunologia , Proteínas de Peixe-Zebra/agonistas , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
17.
J Physiol Biochem ; 73(1): 49-57, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27718123

RESUMO

Excessive exercise induces an inflammatory response caused by oxidative stress, which delays recovery of damaged muscle fibers. The reduction of inflammatory response is important for skeletal muscle homeostasis. Peroxisome proliferator-activated receptor gamma (PPARγ) is an anti-inflammatory molecule, but the role of PPARγ in skeletal muscle as anti-inflammatory activity is not clear. Thus, this study examined the anti-inflammatory role of PPARγ against H2O2-induced oxidative stress in skeletal muscle. Sprague Dawley (SD) rats were exercised on a treadmill to induce oxidative stress. In vitro oxidative stress was evaluated in differentiated C2C12 cells stimulated using 200 µM H2O2. Inflammation-related molecules were determined by immunohistochemistry and Western blot analysis. Expressions of the inflammatory molecules tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), cyclooxygenase-2 (COX-2), and matrix metalloproteinase-2 (MMP-2) in muscles of the acute exercise group were highly increased. PPARγ was also highly expressed in these muscles. These inflammatory molecules were also markedly increased in C2C12 cells with H2O2 stimulation. However, PPARγ overexpression in C2C12 transfected by Ad/PPARγ dramatically reduced the inflammatory molecules. PPARγ also enhanced the anti-oxidants molecules like Cu/Zn-SOD, Mn-SOD, and hemeoxygenase-1 by reducing the generation of ROS, even in the presence of H2O2. PPARγ displayed dual anti-inflammatory and anti-oxidant roles by inhibiting the mitogen-activated protein kinase (MAPK) pathway and translocation of nuclear transcriptional factor-κB (NF-κB) from the cytosol to the nucleus. These results demonstrate a potential role of PPARγ in protecting muscle fibers against oxidative stress caused by excessive acute exercise due to its anti-inflammatory and anti-oxidant activity exerted by inhibition of the MAPK/NF-κB pathway.


Assuntos
Sistema de Sinalização das MAP Quinases , Músculo Esquelético/metabolismo , Mioblastos Esqueléticos/metabolismo , Miosite/metabolismo , NF-kappa B/antagonistas & inibidores , PPAR gama/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Linhagem Celular , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Humanos , Mediadores da Inflamação/agonistas , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 2 da Matriz/química , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Atividade Motora , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/imunologia , Mioblastos Esqueléticos/efeitos dos fármacos , Mioblastos Esqueléticos/imunologia , Miosite/induzido quimicamente , Miosite/etiologia , Miosite/imunologia , NF-kappa B/metabolismo , Oxidantes/toxicidade , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/agonistas , PPAR gama/genética , Esforço Físico , Distribuição Aleatória , Ratos Sprague-Dawley , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo
18.
J Nutr Biochem ; 36: 21-30, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27560195

RESUMO

The bioactivity of trans-resveratrol (RSV), an important wine polyphenol, and of its metabolites was investigated in a more relevant setup comprising an in vitro coculture cell model that combines intestinal absorption and conjugation with changes in endothelial function, which is primarily affected in cardiovascular diseases. Caco-2 and endothelial EA.hy926 cells were grown in a coculture, and Caco-2 cells were treated with RSV in the coculture and in two different sequential setups for 4 h and 24 h. Transported metabolites were investigated by UPLC-MS/MSE, and the effects on NO production, ROS inhibition and secretion of vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and intercellular adhesion molecule-1 (ICAM-1) were evaluated in TNF-α-activated and nonactivated endothelial cells. RSV and four conjugated metabolites, two sulfates and two glucuronides, were identified after intestinal transport. In both coculture and sequential systems, RSV at 20 µM strongly induced NO production. Changes in ROS and NO levels demonstrated a clear effect of crosstalk between cells in the coculture. The secretion of proinflammatory cytokines and VEGF was largely increased by treatment with TNF-α (inflammatory condition). The polyphenol intervention significantly reduced the levels of VEGF, ROS, IL-8 and ICAM-1, with a more pronounced effect in TNF-α-activated endothelial cells. In conclusion, RSV and its metabolites showed accentuated bioactivity on TNF-α-induced inflammation, and the metabolism of endothelial cells as a biological target was not only influenced by these phenolics but also by the communication between distinct cell lines, showing a new perspective for investigations on polyphenol intervention and its biological outcomes.


Assuntos
Anti-Inflamatórios não Esteroides/metabolismo , Antioxidantes/metabolismo , Endotélio Vascular/metabolismo , Enterócitos/metabolismo , Estresse Oxidativo , Estilbenos/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/química , Antioxidantes/química , Biomarcadores/metabolismo , Células CACO-2 , Comunicação Celular , Linhagem Celular , Técnicas de Cocultura , Endotélio Vascular/imunologia , Enterócitos/imunologia , Glucuronídeos/metabolismo , Humanos , Mediadores da Inflamação/agonistas , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/química , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-8/agonistas , Interleucina-8/antagonistas & inibidores , Interleucina-8/metabolismo , Absorção Intestinal , Óxido Nítrico/agonistas , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Resveratrol , Estilbenos/química , Sulfatos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fatores de Crescimento do Endotélio Vascular/agonistas , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fatores de Crescimento do Endotélio Vascular/metabolismo
19.
Toxicon ; 118: 54-60, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27090011

RESUMO

Although deoxynivalenol (DON) suppresses food intake and subsequent weight gain, its contribution to anorexia mechanisms has not been fully clarified. Thus, we investigated the anorexic actions of DON in the hypothalamus and intestine, both organs related to appetite. When female B6C3F1 mice were orally exposed to different doses of DON, a drastic anorexic action was observed at a dose of 12.5 mg/kg body weight (bw) from 0 to 3 h after administration. Exposure to DON (12.5 mg/kg bw) for 3 h significantly increased the hypothalamic mRNA levels of anorexic pro-opiomelanocortin (POMC) and its downstream targets, including melanocortin 4 receptor, brain-derived neurotrophic factor, and tyrosine kinase receptor B; at the same time, orexigenic hormones were not affected. In addition, exposure to DON significantly elevated the hypothalamic mRNA levels of proinflammatory cytokines (IL-1ß, TNF-α, and IL-6) and activated nuclear factor-kappa B (NF-κB), an upstream factor of POMC. These results suggest that DON-induced proinflammatory cytokines increased the POMC level via NF-κB activation. Moreover, exposure to DON significantly enhanced the gastrointestinal mRNA levels of anorexic cholecystokinin (CCK) and transient receptor potential ankyrin-1 channel (TRPA1), a possible target of DON; these findings suggest that DON induced anorexic action by increasing CCK production via TRPA1. Taken together, these results suggest that DON induces anorexic POMC, perhaps via NF-κB activation, by increasing proinflammatory cytokines in the hypothalamus and brings about CCK production, possibly through increasing intestinal TRPA1 expression, leading to anorexic actions.


Assuntos
Anorexia/induzido quimicamente , Depressores do Apetite/toxicidade , Poluentes Ambientais/toxicidade , Trato Gastrointestinal/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Tricotecenos/toxicidade , Administração Oral , Animais , Anorexia/imunologia , Anorexia/metabolismo , Depressores do Apetite/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/agonistas , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Ingestão de Energia/efeitos dos fármacos , Poluentes Ambientais/administração & dosagem , Feminino , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo/imunologia , Hipotálamo/metabolismo , Mediadores da Inflamação/agonistas , Mediadores da Inflamação/metabolismo , Camundongos , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/imunologia , Neurônios/metabolismo , Pró-Opiomelanocortina/agonistas , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , RNA Mensageiro/metabolismo , Receptor Tipo 4 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Receptor trkB/agonistas , Receptor trkB/genética , Receptor trkB/metabolismo , Tricotecenos/administração & dosagem
20.
Toxicon ; 118: 13-20, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27085306

RESUMO

Cyanobacterial blooms caused by water eutrophication have become a worldwide problem. Microcystins (MCs), especially microcystin-LR (MC-LR), released during cyanobacterial blooms exert great toxicity on fish and even lead to massive death. The present study mainly investigated the pathological damage and immune response of spleen, gut and gill in zebrafish exposed to MC-LR. Fish were exposed to 0, 1, 5 and 20 µg/L of MC-LR for 30 d. In zebrafish exposed to 5 and 20 µg/L MC-LR, edematous mitochondria, deformation of the nucleus and compaction of chromatin were observed in lymphocyte of spleen; frayed gut villi, exfoliation of epithelial cells and widespread cell lyses were observed in intestines; hyperemia in gill lamellae, epithelial tissue edema and uplift and lamellar fusion were observed in gill. Varied changed gene expression was observed in spleen, intestine and gill of zebrafish. The transcriptional levels of IFN-1 and IL-8 in spleen significantly up-regulated in 20 µg/L group, and the transcription of IL-1ß and TNFα in spleen increased in 1 µg/L MC-LR treated fish. In addition, the mRNA levels of IFN-1, IL-1ß, IL-8, TGF-ß and TNF-α dramatically increased in intestine and gill in all MC-LR treated groups. The present studies indicated that MC-LR exposure caused marked pathological damage, however, fish could adjust actively the expression of innate immune-related genes to resist the tissue damage. Our findings provided strong evidence of the recovery potential of fish exposed to microcystins.


Assuntos
Toxinas Bacterianas/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Mediadores da Inflamação/agonistas , Microcistinas/toxicidade , Poluentes Químicos da Água/toxicidade , Proteínas de Peixe-Zebra/agonistas , Animais , Resistência a Medicamentos , Brânquias/efeitos dos fármacos , Brânquias/imunologia , Brânquias/metabolismo , Brânquias/ultraestrutura , Imunidade nas Mucosas/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/ultraestrutura , Toxinas Marinhas , Microscopia Eletrônica de Varredura , Microvilosidades/efeitos dos fármacos , Microvilosidades/imunologia , Microvilosidades/metabolismo , Microvilosidades/ultraestrutura , Especificidade de Órgãos , Concentração Osmolar , RNA Mensageiro/metabolismo , Distribuição Aleatória , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , Baço/ultraestrutura , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
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