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1.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445510

RESUMO

Microglia are resident immune cells of the central nervous system that act as brain-specific macrophages and are also known to regulate the innate immune functions of astrocytes through secretory molecules. This communication plays an important role in brain functions and homeostasis as well as in neuropathologic disease. In this study, we aimed to elucidate whether astrocytes and microglia could crosstalk to induce microglial polarization and proliferation, which can be further regulated under a microenvironment mimicking that of brain stroke. Microglia in a mixed glial culture showed increased survival and proliferation and were altered to M2 microglia; CD11b-GFAP+ astrocytes resulted in an approximately tenfold increase in microglial cell proliferation after the reconstitution of astrocytes. Furthermore, GM-CSF stimulated microglial proliferation approximately tenfold and induced them to become CCR7+ M1 microglia, which have a phenotype that could be suppressed by anti-inflammatory cytokines such as IL-4, IL-10, and substance P. In addition, the astrocytes in the microglial co-culture showed an A2 phenotype; they could be activated to A1 astrocytes by TNF-α and IFN-γ under the stroke-mimicking condition. Altogether, astrocytes in the mixed glial culture stimulated the proliferation of the microglia and M2 polarization, possibly through the acquisition of the A2 phenotype; both could be converted to M1 microglia and A1 astrocytes under the inflammatory stroke-mimicking environment. This study demonstrated that microglia and astrocytes could be polarized to M2 microglia and A2 astrocytes, respectively, through crosstalk in vitro and provides a system with which to explore how microglia and astrocytes may behave in the inflammatory disease milieu after in vivo transplantation.


Assuntos
Astrócitos/citologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Macrófagos/citologia , Microglia/citologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Comunicação Celular , Polaridade Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Microglia/efeitos dos fármacos , Microglia/imunologia , Ratos
2.
J Immunol ; 207(5): 1401-1410, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34380646

RESUMO

PI3Kδ is critical in generating humoral and regulatory immune responses. In this study, we determined the impact of PI3Kδ in immunity to Trypanosoma congolense, an African trypanosome that can manipulate and evade Ab responses critical for protection. Upon infection with T. congolense, PI3KδD910A mice lacking PI3Kδ activity paradoxically show a transient enhancement in early control of parasitemia, associated with impaired production of regulatory IL-10 by B cells in the peritoneum. C57BL/6 wild-type (WT) mice treated with the PI3Kδ inhibitor (PI3Kδi) Idelalisib showed a similar transient decrease in parasitemia associated with reduced IL-10. Strikingly, however, we find that PI3KδD910A mice were ultimately unable to control this infection, resulting in uncontrolled parasitemia and death within 2 wk. Assessment of humoral responses revealed delayed B cell activation, impaired germinal center responses, and compromised Ab responses to differing degrees in PI3KδD910A and PI3Kδi-treated mice. To test the role of Abs, we administered serum from WT mice to PI3KδD910A mice and found that lethality was prevented by postinfection serum. Interestingly, serum from naive WT mice provided partial protection to PI3KδD910A mutants, indicating an additional role for natural Abs. Together our findings suggest that although PI3Kδ drives immune regulatory responses that antagonize early control of parasite growth in the peritoneum, it is also required for generation of Abs that are critical for protection from systemic trypanosome infection. The essential role of PI3Kδ for host survival of African trypanosome infection contrasts with findings for other pathogens such as Leishmania, underlining the critical importance of PI3Kδ-dependent humoral immunity in this disease.


Assuntos
Linfócitos B/imunologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Trypanosoma congolense/fisiologia , Tripanossomíase Africana/imunologia , Animais , Classe I de Fosfatidilinositol 3-Quinases/genética , Imunidade Humoral , Imunomodulação , Interleucina-10/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Parasitemia
3.
Immunity ; 54(7): 1374-1376, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34260885

RESUMO

In a recent issue of Nature, Hoeffel et al. describe a novel pathway of sterile tissue repair utilizing a mouse model of sunburn. This wound healing pathway is coordinated by sensory neuron-derived TAFA4 that induces IL-10 production from Tim4+ dermal macrophages to prevent sustained inflammation and the emergence of tissue fibrosis.


Assuntos
Células Receptoras Sensoriais/patologia , Queimadura Solar/patologia , Cicatrização/fisiologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Fibrose/metabolismo , Fibrose/patologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-10/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Transdução de Sinais/fisiologia , Pele/metabolismo , Pele/patologia , Queimadura Solar/metabolismo
4.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206987

RESUMO

Hepatitis C virus (HCV) is one of the main triggers of chronic liver disease. Despite tremendous progress in the HCV field, there is still no vaccine against this virus. Potential vaccines can be based on its recombinant proteins. To increase the humoral and, especially, cellular immune response to them, more effective adjuvants are needed. Here, we evaluated a panel of compounds as potential adjuvants using the HCV NS5B protein as an immunogen. These compounds included inhibitors of polyamine biosynthesis and urea cycle, the mTOR pathway, antioxidants, and cellular receptors. A pronounced stimulation of cell proliferation and interferon-γ (IFN-γ) secretion in response to concanavalin A was shown for antioxidant N-acetylcysteine (NAC), polyamine biosynthesis inhibitor 2-difluoromethylornithine (DFMO), and TLR9 agonist CpG ODN 1826 (CpG). Their usage during the immunization of mice with the recombinant NS5B protein significantly increased antibody titers, enhanced lymphocyte proliferation and IFN-γ production. NAC and CpG decreased relative Treg numbers; CpG increased the number of myeloid-derived suppressor cells (MDSCs), whereas neither NAC nor DFMO affected MDSC counts. NAC and DFMO suppressed NO and interleukin 10 (IL-10) production by splenocytes, while DFMO increased the levels of IL-12. This is the first evidence of immunomodulatory activity of NAC and DFMO during prophylactic immunization against infectious diseases.


Assuntos
Acetilcisteína/farmacologia , Adjuvantes Imunológicos/farmacologia , Eflornitina/farmacologia , Hepatite C/imunologia , Imunidade Ativa/efeitos dos fármacos , Proteínas não Estruturais Virais/imunologia , Animais , Proliferação de Células , Células Cultivadas , Feminino , Imunogenicidade da Vacina/efeitos dos fármacos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Óxido Nítrico/metabolismo , Oligodesoxirribonucleotídeos/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Vacinas contra Hepatite Viral/imunologia
5.
Molecules ; 26(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34206998

RESUMO

BACKGROUND: N-octadecanoyl-5-hydroxytryptamide (C18-5HT) is an amide that can be obtained by the coupling of serotonin and octadecanoic acid. This study aims to characterize the in vivo and in vitro anti-inflammatory activity of C18-5HT. METHODS: A subcutaneous air pouch model (SAP) was used. The exudates were collected from SAP after carrageenan injection to assess cell migration and inflammatory mediators production. RAW 264.7 cells were used for in vitro assays. RESULTS: C18-5HT significantly inhibited leukocyte migration into the SAP as well as nitric oxide (NO) and cytokines production and protein extravasation. We also observed an reduction in some cytokines and an increase in IL-10 production. Assays conducted with RAW 264.7 cells indicated that C18-5HT inhibited NO and cytokine produced. CONCLUSIONS: Taken together, our data suggest that C18-5HT presents a significant effect in different cell types (leukocytes collected from exudate, mainly polumorphonuclear leukocytes and cell culture macrophages) and is a promising compound for further studies for the development of a new anti-inflammatory drug.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Serotonina/farmacologia , Animais , Carragenina/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-10/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Óxido Nítrico/metabolismo , Células RAW 264.7
6.
J Immunol ; 207(3): 902-912, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34301845

RESUMO

Myeloid cells are critical for systemic inflammation, microbial control, and organ damage during sepsis. MicroRNAs are small noncoding RNAs that can dictate the outcome of sepsis. The role of myeloid-based expression of microRNA-21 (miR-21) in sepsis is inconclusive. In this study, we show that sepsis enhanced miR-21 expression in both peritoneal macrophages and neutrophils from septic C57BL/6J mice, and the deletion of miR-21 locus in myeloid cells (miR-21Δmyel mice) enhanced animal survival, decreased bacterial growth, decreased systemic inflammation, and decreased organ damage. Resistance to sepsis was associated with a reduction of aerobic glycolysis and increased levels of the anti-inflammatory mediators PGE2 and IL-10 in miR-21Δmyel in vivo and in vitro. Using blocking Abs and pharmacological tools, we discovered that increased survival and decreased systemic inflammation in septic miR-21Δmyel mice is dependent on PGE2/IL-10-mediated inhibition of glycolysis. Together, these findings demonstrate that expression of miR-21 in myeloid cells orchestrates the balance between anti-inflammatory mediators and metabolic reprogramming that drives cytokine storm during sepsis.


Assuntos
Dinoprostona/metabolismo , Interleucina-10/metabolismo , Macrófagos Peritoneais/fisiologia , MicroRNAs/genética , Neutrófilos/fisiologia , Sepse/imunologia , Animais , Células Cultivadas , Reprogramação Celular , Glicólise , Humanos , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sepse/genética
7.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299256

RESUMO

To investigate the effect of leptin in childhood ITP, we measured plasma leptin in 39 children with acute ITP, after treatment and in remission, and in 33 healthy age/BMI-matched controls. We also cultured ITP and control peripheral blood mononuclear cells (PBMCs) with recombinant leptin to assess its direct effect on pro/anti-inflammatory cytokine gene expression. A significant increase in leptin was observed in children with active disease compared to controls. A significant inverse correlation of leptin with platelet count was also observed in children with acute ITP. Leptin remained high after treatment with IVIg, whereas steroid treatment lowered leptin below control levels. In remission, leptin was in the control range. Cytokine gene expression was significantly increased in children with acute ITP compared with controls, with highest expression for IFN-γ and IL-10. IVIg/steroid treatment significantly decreased IFN-γ and IL-10 expression. In remission, IFN-γ and IL-10 expression remained low. Addition of leptin to PBMCs isolated from patients in remission resulted in a significant increase in IL-10 gene expression compared to controls. Further experiments with purified T-cells and monocytes identified monocytes as the source of leptin-induced IL-10. We suggest that leptin acts as an active anti-inflammatory agent in childhood ITP by promoting IL-10 secretion by monocytes.


Assuntos
Leptina/análise , Púrpura Trombocitopênica Idiopática/metabolismo , Adolescente , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Criança , Pré-Escolar , Citocinas/efeitos dos fármacos , Citocinas/imunologia , Feminino , Expressão Gênica , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Interferon gama/metabolismo , Interleucina-10/metabolismo , Leptina/sangue , Leptina/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Monócitos/metabolismo , Plasma/química , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/fisiopatologia , Células Th2/imunologia
8.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299013

RESUMO

Mucosal CD4+ T lymphocytes display a potent opioid-mediated analgesic activity in interleukin (IL)-10 knockout mouse model of inflammatory bowel diseases (IBD). Considering that endogenous opioids may also exhibit anti-inflammatory activities in the periphery, we examined the consequences of a peripheral opioid receptor blockade by naloxone-methiodide, a general opioid receptor antagonist unable to cross the blood-brain barrier, on the development of piroxicam-accelerated colitis in IL-10-deficient (IL-10-/-) mice. Here, we show that IL-10-deficient mice treated with piroxicam exhibited significant alterations of the intestinal barrier function, including permeability, inflammation-related bioactive lipid mediators, and mucosal CD4+ T lymphocyte subsets. Opioid receptor antagonization in the periphery had virtually no effect on colitis severity but significantly worsened epithelial cell apoptosis and intestinal permeability. Thus, although the endogenous opioid tone is not sufficient to reduce the severity of colitis significantly, it substantially contributes to the protection of the physical integrity of the epithelial barrier.


Assuntos
Colite/metabolismo , Interleucina-10/genética , Mucosa Intestinal/efeitos dos fármacos , Naloxona/análogos & derivados , Antagonistas de Entorpecentes/administração & dosagem , Piroxicam/farmacologia , Receptores Opioides/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linfócitos T CD4-Positivos/efeitos dos fármacos , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Citocinas/genética , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Interleucina-10/metabolismo , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Naloxona/farmacologia , Permeabilidade/efeitos dos fármacos , Compostos de Amônio Quaternário/farmacologia , Índice de Gravidade de Doença
9.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199160

RESUMO

Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study was aimed at evaluating the in vitro and in vivo effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories) in an experimental model of colitis in rats. A set of experiments evaluated the ability of FA5 to activate AMPK and to compare the efficacy of FA5 with ACA in an experimental model of colitis. The effects of FA-5, ACA, or dexamethasone were tested in rats with 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis to assess systemic and tissue inflammatory parameters. In in vitro experiments, FA5 induced phosphorylation, and thus the activation, of AMPK, contextually to the activation of SIRT-1. In vivo, FA5 counteracted the increase in spleen weight, improved the colon length, ameliorated macroscopic damage score, and reduced TNF and MDA tissue levels in DNBS-treated rats. Of note, FA-5 displayed an increased anti-inflammatory efficacy as compared with ACA. The novel AMPK activator FA-5 displays an improved anti-inflammatory efficacy representing a promising pharmacological tool against bowel inflammation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Benzofuranos/uso terapêutico , Desenvolvimento de Medicamentos , Ativadores de Enzimas/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Benzofuranos/farmacologia , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Colo/efeitos dos fármacos , Colo/patologia , Dinitrofluorbenzeno/análogos & derivados , Eletroforese em Gel Bidimensional , Ontologia Genética , Doenças Inflamatórias Intestinais/patologia , Interleucina-10/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
11.
Int Immunopharmacol ; 97: 107828, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34091116

RESUMO

In various pathological conditions, cellular immunity plays an important role in immune responses. Amongimmunecells, T lymphocytes pdomotecellular and humoralresponses as well as innate immunity. Therefore, careful investigation of these cells has a significant impact on accurate knowledge in COVID-19diseasepathogenesis. In current research, the frequency and function of various T lymphocytes involved in immune responses examined in SARS-CoV-2 patients with various disease severity compared to normal subjects. In order to make an accurate comparison among patients with various disease severity, this study was performed on asymptomatic recovered cases (n = 20), ICU hospitalized patients (n = 30), non-ICU hospitalized patients (n = 30), and normal subjects (n = 20). To precisely evaluate T cells activity following purification, their cytokine secretion activity was examined. Similarly, immediately after purification of Treg cells, their inhibitory activity on T cells was investigated. The results showed that COVID-19 patients with severe disease (ICU hospitalized patients) not only had a remarkable increase in Th1 and Th17 but also a considerable decrease in Th2 and Treg cells. More importantly, as the IL-17 and IFN-γ secretion was sharply increased in severe disease, the secretion of IL-10 and IL-4 was decreased. Furthermore, the inhibitory activity of Treg cells was reduced in severe disease patients in comparison to other groups. In severe COVID-19 disease, current findings indicate when the inflammatory arm of cellular immunity is significantly increased, a considerable reduction in anti-inflammatory and regulatory arm occurred.


Assuntos
COVID-19/sangue , COVID-19/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/virologia , Adulto , Idoso , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Imunidade Celular , Inflamação/metabolismo , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-4/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Adulto Jovem
12.
Biomed Pharmacother ; 140: 111797, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34098193

RESUMO

Sodium Thiosulfate (STS) is already reported as an antioxidant, anti-inflammatory agent with antiseptic, antifungal properties. The search for an ideal antiseptic still continues, which is lethal to all types of bacteria and their spores and sustain the activity for a longer time without any harm to the host tissue. The aim of the present study is to evaluate the effect of STS on curing of wounds in rats when compared to Betadine. We developed topical gels having 6% and 12% STS. The effects of STS on wound healing rate of Rats were evaluated against Betadine as positive control. Wounds of control group, selected as Group 1 was treated with normal saline (0.2 ml), twice a day. Reference standard control, designated as Group 2 rats were given with 0.2 ml Betadine twice a day. Rats in Groups 3 and 4 were treated with 0.2 ml of STS gel (6% or 12% respectively) twice a day. In our study, STS formulation has proved to be a safe and efficient wound healing product. It has a neutral pH and longer half life (>12 months). Higher STS dose of 12% proved to have a wound curing rate equivalent to that of Betadine. On 11th Day, 97 ± 0.79% healing was achieved with Betadine and 98 ± 0.67% with 12% STS Gel (∗P < 0.05). Microscopic images of H&E stained skin tissue from animals treated with Betadine and 12% STS formulation showed a reduction in scar size, lesser amount of inflammatory cells, higher fibroblasts and blood vessels, with considerable collagen accumulation. Furthermore, a significant enhancement in the levels of GPx, CAT and SOD was observed in the tissue at the wound site of the treated group. The IL 10 levels in both groups of STS-treated rats was increased, whereas, TNF-α levels were reduced significantly in tissue homogenate compared with control. Thus, this study shows the wound-healing performance of STS formulation. Further studies are necessary to understand the real mechanism of how STS formulation heals wounds.


Assuntos
Anti-Infecciosos Locais/uso terapêutico , Tiossulfatos/uso terapêutico , Cicatrização/efeitos dos fármacos , Animais , Catalase/metabolismo , Géis , Glutationa Peroxidase/metabolismo , Interleucina-10/metabolismo , Masculino , Povidona-Iodo/uso terapêutico , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
13.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067047

RESUMO

Mast cells (MCs) play critical roles in Th2 immune responses, including the defense against parasitic infections and the initiation of type I allergic reactions. In addition, MCs are involved in several immune-related responses, including those in bacterial infections, autoimmune diseases, inflammatory bowel diseases, cancers, allograft rejections, and lifestyle diseases. Whereas antigen-specific IgE is a well-known activator of MCs, which express FcεRI on the cell surface, other receptors for cytokines, growth factors, pathogen-associated molecular patterns, and damage-associated molecular patterns also function as triggers of MC stimulation, resulting in the release of chemical mediators, eicosanoids, and various cytokines. In this review, we focus on the role of interleukin (IL)-10, an anti-inflammatory cytokine, in MC-mediated immune responses, in which MCs play roles not only as initiators of the immune response but also as suppressors of excessive inflammation. IL-10 exhibits diverse effects on the proliferation, differentiation, survival, and activation of MCs in vivo and in vitro. Furthermore, IL-10 derived from MCs exerts beneficial and detrimental effects on the maintenance of tissue homeostasis and in several immune-related diseases including contact hypersensitivity, auto-immune diseases, and infections. This review introduces the effects of IL-10 on various events in MCs, and the roles of MCs in IL-10-related immune responses and as a source of IL-10.


Assuntos
Anti-Inflamatórios/metabolismo , Inflamação/metabolismo , Interleucina-10/metabolismo , Mastócitos/metabolismo , Animais , Humanos , Doenças do Sistema Imunitário/patologia , Mastócitos/citologia , Modelos Biológicos
14.
Biomed Res Int ; 2021: 5585077, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33997019

RESUMO

Background: Fibrinogen and interleukin-1ß as a proinflammatory cytokine and interleukin-10 and nesfatin-1 as an anti-inflammatory cytokine have an important role in the development and prevention of systemic inflammation and incidence of obesity-induced diseases. Thus, this study is aimed at the interaction effects of aerobic training and oak husk hydroalcoholic extract consumption on plasma levels of fibrinogen, interleukin-1ß, nesfatin-1, and interleukin-10 in obese elderly male mice. Materials and Methods: In this experimental study, 40 fat male mice were fed a high-fat diet for 4 weeks to induce obesity, and subsequently, they were divided randomly into four groups: control, supplement, exercise-placebo, and exercise-supplement. The training groups performed aerobic exercise 5 days a week for 6 weeks (approximately 80-75% VOmax 2). The supplement groups received a solution of oak husk hydroalcoholic extract at a dose of 20 milligram per kilogram of body weight for 6 weeks. Blood samples were taken 48 h after the last training session, and the levels of IL-10, fibrinogen, IL-1ß, and nesfatin-1 were measured. Data were analyzed using one-way ANOVA and LSD post hoc tests. Results: The results showed that six-week training and oak husk hydroalcoholic extract consumption significantly increased the levels of IL-10 and nesfatin-1 in experimental groups (P < 0.001). Also, the levels of fibrinogen and IL-1ß decreased significantly in training groups. Averages between group variations of all indicators were statistically significant, and they were more meaningfully pronounced in the exercise-supplement group than other groups (P ≤ 0.05). Conclusions: Considering the results of the present study, the use of moderate aerobic exercise and oak husk hydroalcoholic extract is recommended to reduce the risk of obesity; it may also have a positive effect on inflammatory factors.


Assuntos
Envelhecimento/patologia , Etanol/química , Inflamação/terapia , Obesidade/terapia , Condicionamento Físico Animal , Extratos Vegetais/uso terapêutico , Quercus/química , Água/química , Animais , Peso Corporal/efeitos dos fármacos , Fibrinogênio/metabolismo , Inflamação/complicações , Inflamação/tratamento farmacológico , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos Obesos , Nucleobindinas/metabolismo , Obesidade/complicações , Obesidade/tratamento farmacológico , Extratos Vegetais/farmacologia
15.
Nature ; 594(7861): 94-99, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34012116

RESUMO

Inflammation is a defence response to tissue damage that requires tight regulation in order to prevent impaired healing. Tissue-resident macrophages have a key role in tissue repair1, but the precise molecular mechanisms that regulate the balance between inflammatory and pro-repair macrophage responses during healing remain poorly understood. Here we demonstrate a major role for sensory neurons in promoting the tissue-repair function of macrophages. In a sunburn-like model of skin damage in mice, the conditional ablation of sensory neurons expressing the Gαi-interacting protein (GINIP) results in defective tissue regeneration and in dermal fibrosis. Elucidation of the underlying molecular mechanisms revealed a crucial role for the neuropeptide TAFA4, which is produced in the skin by C-low threshold mechanoreceptors-a subset of GINIP+ neurons. TAFA4 modulates the inflammatory profile of macrophages directly in vitro. In vivo studies in Tafa4-deficient mice revealed that TAFA4 promotes the production of IL-10 by dermal macrophages after UV-induced skin damage. This TAFA4-IL-10 axis also ensures the survival and maintenance of IL-10+TIM4+ dermal macrophages, reducing skin inflammation and promoting tissue regeneration. These results reveal a neuroimmune regulatory pathway driven by the neuropeptide TAFA4 that promotes the anti-inflammatory functions of macrophages and prevents fibrosis after tissue damage, and could lead to new therapeutic perspectives for inflammatory diseases.


Assuntos
Citocinas/metabolismo , Macrófagos/metabolismo , Regeneração , Células Receptoras Sensoriais/metabolismo , Cicatrização , Animais , Sobrevivência Celular , Citocinas/deficiência , Modelos Animais de Doenças , Feminino , Fibrose/etiologia , Fibrose/metabolismo , Fibrose/patologia , Fibrose/prevenção & controle , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Interleucina-10/biossíntese , Interleucina-10/metabolismo , Macrófagos/efeitos da radiação , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Receptoras Sensoriais/efeitos da radiação , Pele/patologia , Pele/efeitos da radiação , Queimadura Solar/complicações , Queimadura Solar/etiologia , Queimadura Solar/metabolismo , Queimadura Solar/patologia , Raios Ultravioleta/efeitos adversos
16.
Medicine (Baltimore) ; 100(21): e25868, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032699

RESUMO

RATIONALE: Infantile inflammatory bowel disease (IBD) is an extremely rare subgroup of IBD that includes patients whose age of onset is younger than 2 years old. These patients can have more surgical interventions, and a severe and refractory disease course with higher rates of conventional treatment failure. Monogenic defects play an important role in this subgroup of IBD, and identification of the underlying defect can guide the therapeutic approach. PATIENT CONCERNS: In 2007, a 4-month-old girl from a nonconsanguineous family presenting with anal fistula, chronic diarrhea, and failure to thrive. She underwent multiple surgical repairs but continued to have persistent colitis and perianal fistulas. DIAGNOSIS: Crohn's disease was confirmed by endoscopic and histologic finding. INTERVENTION: Conventional pediatric IBD therapy including multiple surgical interventions and antitumor necrosis factor alpha agents were applied. OUTCOMES: The patient did not respond to conventional pediatric IBD therapy. Interleukin-10 (IL-10) receptor mutation was discovered by whole-exome sequencing and defective IL-10 signaling was proved by functional test of IL-10 signaling pathway by the age of 12. The patient is currently awaiting hematopoietic stem cell transplantation. LESSONS: Early detection of underlying genetic causes of patients with infantile-IBD is crucial, since it may prevent patients from undergoing unnecessary surgeries and adverse effects from ineffective medical therapies. Moreover, infantile-IBD patients with complex perianal disease, intractable early onset enterocolitis and extraintestinal manifestations including oral ulcers and skin folliculitis, should undergo genetic and functional testing for IL-10 pathway defect.


Assuntos
Doença de Crohn/diagnóstico , Diarreia/genética , Insuficiência de Crescimento/genética , Subunidade alfa de Receptor de Interleucina-10/genética , Fístula Retal/genética , Criança , Pré-Escolar , Colectomia , Doença de Crohn/complicações , Doença de Crohn/genética , Doença de Crohn/terapia , Diagnóstico Tardio , Diarreia/terapia , Diagnóstico Precoce , Insuficiência de Crescimento/terapia , Feminino , Seguimentos , Testes Genéticos , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunossupressores/administração & dosagem , Interleucina-10/metabolismo , Subunidade alfa de Receptor de Interleucina-10/metabolismo , Mutação de Sentido Incorreto , Fístula Retal/terapia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Falha de Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Sequenciamento Completo do Exoma
17.
Exp Parasitol ; 225: 108112, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33964315

RESUMO

Matrix metalloproteinases (MMPs), are implicated in the pathogenesis of multiple sclerosis (MS) and in its animal model, experimental autoimmune encephalomyelitis (EAE). Our aim was to investigate whether amelioration of EAE in Dark Agouti (DA) rats, induced by Trichinella spiralis muscle larvae excretory-secretory products (ES L1), could be related to the level and activity of gelatinases, MMP-9 and MMP-2. Serum levels of MMP-9, MMP-2, NGAL/MMP-9, TIMP-1, and cytokines, evaluated by gel-zymography or ELISA, as well as gelatinases and TIMP-1 expression in the spinal cord (SC), were determined in: i) EAE induced, ii) ES L1-treated EAE induced animals. Milder clinical signs in ES L1-treated EAE induced DA rats were accompanied with lower serum levels of MMP-9 and NGAL/MMP-9 complex. However, the correlation between the severity of EAE and the level of serum MMP-9 was found only in the peak of the disease, with MMP-9/TIMP-1 ratio higher in EAE animals without ES L1 treatment. Lower expression of MMP-9 in SC of ES L1-treated, EAE induced rats, correlated with the reduced number of SC infiltrating cells. In SC infiltrates, in the effector and the recovery phase, production of anti-inflammatory cytokines IL-4 and IL-10 was higher in animals treated with ES L1 prior to EAE induction, compared to untreated EAE animals. Reduced expression of MMP-9 in SC tissue, which correlated with the reduced number of infiltrating cells, might be ascribed to regulatory mechanisms, among which is IL-10.


Assuntos
Antígenos de Helmintos/uso terapêutico , Encefalomielite Autoimune Experimental/metabolismo , Proteínas de Helminto/uso terapêutico , Metaloproteinase 9 da Matriz/metabolismo , Trichinella spiralis/metabolismo , Animais , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Inflamação , Interleucina-10/metabolismo , Ratos , Índice de Gravidade de Doença , Medula Espinal/imunologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo
18.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33947017

RESUMO

Platelets (PLTs) can modulate the immune system through the release of soluble mediators or through interaction with immune cells. Monocytes are the main immune cells that bind with PLTs, and this interaction is increased in several inflammatory and autoimmune conditions, including systemic lupus erythematosus (SLE). Our aim was to characterize the phenotypic and functional consequences of PLT binding to monocytes in healthy donors (HD) and in SLE and to relate it to the pathogenesis of SLE. We analyzed the phenotypic and functional features of monocytes with non-activated and activated bound PLTs by flow cytometry. We observed that monocytes with bound PLTs and especially those with activated PLTs have an up-regulated HLA-DR, CD86, CD54, CD16 and CD64 expression. Monocytes with bound PLTs also have an increased capacity for phagocytosis, though not for efferocytosis. In addition, monocytes with bound PLTs have increased IL-10, but not TNF-α, secretion. The altered phenotypic and functional features are comparable in SLE and HD monocytes and in bound PLTs. However, the percentages of monocytes with bound PLTs are significantly higher in SLE patients and are associated with undetectable levels of anti-dsDNA antibodies and hematuria, and with normal C3 and albumin/creatinine levels. Our results suggest that PLTs have a modulatory influence on monocytes and that this effect may be highlighted by an increased binding of PLTs to monocytes in autoimmune conditions.


Assuntos
Plaquetas/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Monócitos/metabolismo , Adulto , Idoso , Anticorpos Antinucleares/sangue , Antígenos CD/biossíntese , Apoptose , Feminino , Citometria de Fluxo , Antígenos HLA-DR/biossíntese , Humanos , Interleucina-10/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Masculino , Glicoproteínas de Membrana/biossíntese , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Neutrófilos/patologia , Fagocitose , Fenótipo , Fator de Necrose Tumoral alfa/metabolismo
19.
PLoS Pathog ; 17(4): e1009531, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33878120

RESUMO

Most individuals who consume foods contaminated with the bacterial pathogen Listeria monocytogenes (Lm) develop mild symptoms, while others are susceptible to life-threatening systemic infections (listeriosis). Although it is known that the risk of severe disease is increased in certain human populations, including the elderly, it remains unclear why others who consume contaminated food develop listeriosis. Here, we used a murine model to discover that pulmonary coinfections can impair the host's ability to adequately control and eradicate systemic Lm that cross from the intestines to the bloodstream. We found that the resistance of mice to oral Lm infection was dramatically reduced by coinfection with Streptococcus pneumoniae (Spn), a bacterium that colonizes the respiratory tract and can also cause severe infections in the elderly. Exposure to Spn or microbial products, including a recombinant Lm protein (L1S) and lipopolysaccharide (LPS), rendered otherwise resistant hosts susceptible to severe systemic Lm infection. In addition, we show that this increase in susceptibility was dependent on an increase in the production of interleukin-10 (IL-10) from Ncr1+ cells, including natural killer (NK) cells. Lastly, the ability of Ncr1+ cell derived IL-10 to increase disease susceptibility correlated with a dampening of both myeloid cell accumulation and myeloid cell phagocytic capacity in infected tissues. These data suggest that efforts to minimize inflammation in response to an insult at the respiratory mucosa render the host more susceptible to infections by Lm and possibly other pathogens that access the oral mucosa.


Assuntos
Listeria monocytogenes/imunologia , Listeriose/imunologia , Pneumonia/imunologia , Animais , Progressão da Doença , Suscetibilidade a Doenças , Feminino , Interleucina-10/metabolismo , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/fisiologia , Lipopolissacarídeos , Listeria monocytogenes/patogenicidade , Listeriose/complicações , Listeriose/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doenças da Boca/complicações , Doenças da Boca/imunologia , Doenças da Boca/microbiologia , Doenças da Boca/patologia , Pneumonia/complicações , Pneumonia/etiologia , Pneumonia/patologia
20.
Brain Behav Immun ; 95: 344-361, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33862171

RESUMO

Gabapentinoids are recommended first-line treatments for neuropathic pain. They are neuronal voltage-dependent calcium channel α2δ-1 subunit ligands and have been suggested to attenuate neuropathic pain via interaction with neuronal α2δ-1 subunit. However, the current study revealed their microglial mechanisms underlying antineuropathic pain. Intrathecal injection of gabapentin, pregabalin and mirogabalin rapidly inhibited mechanical allodynia and thermal hyperalgesia, with projected ED50 values of 30.3, 6.2 and 1.5 µg (or 176.9, 38.9 and 7.2 nmol) and Emax values of 66%, 61% and 65% MPE respectively for mechanical allodynia. Intrathecal gabapentinoids stimulated spinal mRNA and protein expression of IL-10 and ß-endorphin (but not dynorphin A) in neuropathic rats with the time point parallel to their inhibition of allodynia, which was observed in microglia but not astrocytes or neurons in spinal dorsal horns by using double immunofluorescence staining. Intrathecal gabapentin alleviated pain hypersensitivity in male/female neuropathic but not male sham rats, whereas it increased expression of spinal IL-10 and ß-endorphin in male/female neuropathic and male sham rats. Treatment with gabapentin, pregabalin and mirogabalin specifically upregulated IL-10 and ß-endorphin mRNA and protein expression in primary spinal microglial but not astrocytic or neuronal cells, with EC50 values of 41.3, 11.5 and 2.5 µM and 34.7, 13.3 and 2.8 µM respectively. Pretreatment with intrathecal microglial metabolic inhibitor minocycline, IL-10 antibody, ß-endorphin antiserum or µ-opioid receptor antagonist CTAP (but not κ- or δ-opioid receptor antagonists) suppressed spinal gabapentinoids-inhibited mechanical allodynia. Immunofluorescence staining exhibited specific α2δ-1 expression in neurons but not microglia or astrocytes in the spinal dorsal horns or cultured primary spinal cells. Thus the results illustrate that gabapentinoids alleviate neuropathic pain through stimulating expression of spinal microglial IL-10 and consequent ß-endorphin.


Assuntos
Gabapentina/farmacologia , Interleucina-10 , Microglia/metabolismo , Neuralgia , beta-Endorfina , Animais , Feminino , Hiperalgesia/tratamento farmacológico , Interleucina-10/metabolismo , Masculino , Neuralgia/tratamento farmacológico , Ratos , Ratos Wistar , Medula Espinal , beta-Endorfina/metabolismo
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