RESUMO
Histone Deacetylase- (HDAC-) dependent epigenetic mechanisms have been widely explored in the last decade in different types of malignancies in preclinical studies. This effort led to the discovery and development of a range of new HDAC inhibitors (iHDAC) with different chemical properties and selective abilities. In fact, hematological malignancies were the first ones to have new iHDACs approved for clinical use, such as Vorinostat and Romidepsin for cutaneous T cell lymphoma and panobinostat for multiple myeloma. Besides these promising already approved iHDACs, we highlight a range of studies focusing on the HDAC-dependent epigenetic control of B cell development, behavior, and/or function. Here, we highlight 21 iHDACs which have been studied in the literature in the context of B cell development and/or dysfunction mostly focused on B cell lymphomagenesis. Regardless, we have identified 55 clinical trials using 6 out of 21 iHDACs to approach their putative roles on B cell malignancies; none of them focuses on peritoneal B cell populations. Since cells belonging to this peculiar body compartment, named B1 cells, may contribute to the development of autoimmune pathologies, such as lupus, a better understanding of the HDAC-dependent epigenetic mechanisms that control its biology and behavior might shed light on iHDAC use to manage these immunological dysfunctions. In this sense, iHDACs might emerge as a promising new approach for translational studies in this field. In this review, we discuss a putative role of iHDACs in the modulation of peritoneal B cell subpopulation's balance as well as their role as therapeutic agents in the context of chronic diseases mediated by peritoneal B cells.
Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Epigênese Genética , Doenças do Sistema Imunitário/etiologia , Doenças do Sistema Imunitário/metabolismo , Imunomodulação , Terapia de Alvo Molecular , Animais , Linfócitos B/efeitos dos fármacos , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Imunomodulação/efeitos dos fármacos , Imunomodulação/genética , Cavidade Peritoneal/citologia , Cavidade Peritoneal/patologia , Pesquisa Translacional BiomédicaRESUMO
Fridericia chica, Bignoniaceae, is a tropical tree-creeper used as a traditional remedy for a number of diseases, highlighting inflammation. Our objective was to corroborate the popular anti-inflammatory use of the hydroethanolic extract from the leaves (HEFc) and of its isolated 4',6,7-trihydroxy-5-methoxyflavone (5-O-methylscutellarein) [1], described here for the first time. Quantitative analysis indicated 8.77 ± 0.23 mg/g of this compound in the extract. Neither HEFc nor [1] was cytotoxic in vitro. In LPS-induced peritonitis in mice, oral pre-treatment with HEFc or [1] led to decreased leukocyte migration to the peritoneal cavity and a reduction in the concentrations of pro-inflammatory cytokines (TNFα and IL-1ß). Also, the anti-inflammatory cytokine IL-10 was enhanced following treatment with [1]. Overall, these results validate the traditional use of Fridericia chica as anti-inflammatory, and indicate that the compound 5-O-methylscutellarein may participate in this effect.
Assuntos
Anti-Inflamatórios/isolamento & purificação , Bignoniaceae/química , Flavonas/isolamento & purificação , Inflamação/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Movimento Celular , Citocinas/análise , Citocinas/efeitos dos fármacos , Flavonas/farmacologia , Inflamação/induzido quimicamente , Leucócitos/citologia , Camundongos , Cavidade Peritoneal/patologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/químicaRESUMO
PURPOSE: To evaluate the effects of hyperbaric oxygenation on prevention of adhesions in the abdominal cavity after laparotomy. METHODS: Fifty four rats underwent laparotomy; stitches were made in the four quadrant parietal peritoneum and abdominal cavity closure. Animals were divided into three groups: 1 - control; 2 - subjected to high pressures and oxygenation; 3 - subjected to 100% hyperbaric oxygenation. The animals in groups 2 and 3 were daily submitted to oxygenation hyperbaric chamber after surgery. On the seventh day another laparotomy, registration of procedure, assessment of adhesions and biopsies of the peritoneum were held. Professionals analyzed the videos and the biopsies. RESULTS: Peritoneal cavity adhesions occurred in animals of three groups with no difference between them. In Group 3, the adhesions presented more fragile and vascular proliferation more pronounced, and there was no difference in comparison with the first and second groups. However, there was no significant difference in the evaluation of these parameters between the animals in groups 1 and 2. CONCLUSIONS: Postoperative hyperbaric oxygenation in rats submitted to laparotomy did not alter the frequency, but reduced the density of adhesions in the peritoneal cavity and promoted vascular proliferation. The change in atmospheric pressure alone had no influence on the results.
Assuntos
Oxigenoterapia Hiperbárica/métodos , Cavidade Peritoneal/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Aderências Teciduais/prevenção & controle , Animais , Modelos Animais de Doenças , Laparotomia , Cavidade Peritoneal/patologia , Ratos , Ratos WistarRESUMO
Abstract Purpose: To evaluate the effects of hyperbaric oxygenation on prevention of adhesions in the abdominal cavity after laparotomy. Methods: Fifty four rats underwent laparotomy; stitches were made in the four quadrant parietal peritoneum and abdominal cavity closure. Animals were divided into three groups: 1 - control; 2 - subjected to high pressures and oxygenation; 3 - subjected to 100% hyperbaric oxygenation. The animals in groups 2 and 3 were daily submitted to oxygenation hyperbaric chamber after surgery. On the seventh day another laparotomy, registration of procedure, assessment of adhesions and biopsies of the peritoneum were held. Professionals analyzed the videos and the biopsies. Results: Peritoneal cavity adhesions occurred in animals of three groups with no difference between them. In Group 3, the adhesions presented more fragile and vascular proliferation more pronounced, and there was no difference in comparison with the first and second groups. However, there was no significant difference in the evaluation of these parameters between the animals in groups 1 and 2. Conclusions: Postoperative hyperbaric oxygenation in rats submitted to laparotomy did not alter the frequency, but reduced the density of adhesions in the peritoneal cavity and promoted vascular proliferation. The change in atmospheric pressure alone had no influence on the results.
Assuntos
Animais , Ratos , Cavidade Peritoneal/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Aderências Teciduais/prevenção & controle , Oxigenoterapia Hiperbárica/métodos , Cavidade Peritoneal/patologia , Ratos Wistar , Modelos Animais de Doenças , LaparotomiaRESUMO
One of the hallmarks of acute inflammation is neutrophil infiltration of tissues. We investigated molecular mechanisms implicated in acute neutrophilic inflammation induced by the venom of a freshwater stingray (Potamotrygon cf. henlei) in mice. Ray venom induced early mobilization of neutrophil in the microvasculature of cremaster mice and infiltration of the peritoneal cavity 2 hours after injury, in a dose-response manner. IL-1ß, IL-6, TNF-α, and KC were produced. The neutrophilic infiltration did not occur in mice with ST2 receptor and MyD88 adapters neutralized, or in those with PI3K and p38 MAPK signaling blocked. Drastic reduction of neutrophil infiltration to peritoneal cavities was observed in ST2-/-, TLR2/TLR4-/-, MyD88-/-, TRIF-/- and IL-17A-/- mice, and a partial reduction was observed in IL-18R-/- mice. Mast cell Kit W(sh)/W(sh)-, AHR-, NLRP3-, ICE-, IL-1ß-, P2RX7-, CD39-, IL-17RA-, and TBX21 KO mice retain the ability to induce neutrophilia in peritoneal cavity after ray venom injection. IL-6 and TNF-α alone were insufficient for promote neutrophilia in the absence of ST2 signaling. Finally, abundant production of IL-33 by cardiomyocytes was observed. These results refine our understanding of the importance of the IL-33/ST2 axis and IL-33-producing cardiomyocytes in the early acute neutrophilia induced by freshwater stingray venoms.
Assuntos
Interleucina-33/metabolismo , Mastócitos/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Neutrófilos/imunologia , Venenos/toxicidade , Peçonhas/toxicidade , Animais , Citocinas/genética , Citocinas/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Camundongos , Camundongos Knockout , Cavidade Peritoneal/patologia , Intoxicação/patologia , Venenos/administração & dosagem , Transdução de Sinais , Rajidae , Peçonhas/administração & dosagemAssuntos
Humanos , Masculino , Adulto , Abdome Agudo/diagnóstico , Cavidade Peritoneal/patologia , Neoplasias Peritoneais , Diagnóstico por Imagem , Infarto , OmentoRESUMO
Background/Aims. The effects of cholecalciferol supplementation on the course of diabetes in humans and animals need to be better understood. Therefore, this study investigated the effect of short-term cholecalciferol supplementation on biochemical and hematological parameters in mice. Methods. Male diabetic (alloxan, 60 mg/kg i.v., 10 days) and nondiabetic mice were supplemented with cholecalciferol for seven days. The following parameters were determined: serum levels of 25-hydroxyvitamin D, phosphorus, calcium, urea, creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, red blood cell count, white blood cell count (WBC), hematocrit, hemoglobin, differential cell counts of peritoneal lavage (PeL), and bronchoalveolar lavage (BAL) fluids and morphological analysis of lung, kidney, and liver tissues. Results. Relative to controls, cholecalciferol supplementation increased serum levels of 25-hydroxyvitamin D, calcium, hemoglobin, hematocrit, and red blood cell counts and decreased leukocyte cell counts of PeL and BAL fluids in diabetic mice. Diabetic mice that were not treated with cholecalciferol had lower serum calcium and albumin levels and hemoglobin, WBC, and mononuclear blood cell counts and higher serum creatinine and urea levels than controls. Conclusion. Our results suggest that cholecalciferol supplementation improves the hematological parameters and reduces leukocyte migration into the PeL and BAL lavage of diabetic mice.
Assuntos
Colecalciferol/administração & dosagem , Diabetes Mellitus Experimental/dietoterapia , Suplementos Nutricionais , Vitamina D/metabolismo , Fosfatase Alcalina/sangue , Animais , Aspartato Aminotransferases/sangue , Movimento Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Contagem de Eritrócitos , Humanos , Contagem de Leucócitos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos NOD/metabolismo , Cavidade Peritoneal/patologia , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
Intraperitoneal free cancer cells in gastric adenocarcinoma are associated with a poor outcome. However, the true prognostic value of intraperitoneal free cancer cells is still unclear, leading to a lack of consensus in the management of gastric cancer. The aim of the present study is to perform a systematic review and meta-analysis to analyze intraperitoneal free cancer cells-positive patients with regard to tumor oncologic stage, recurrence, grade of cellular differentiation, and survival rates and to analyze the clinical significance of intraperitoneal free cancer cells with regard to prognosis. Databases were searched up to January 2016 for prognostic factors associated with intraperitoneal free cancer cells, including oncologic stage, depth of neoplasm invasion, lymph nodal spread, differentiation grade of the tumor, and recurrence and survival rates. A total of 100 studies were identified. Meta-analysis revealed a clear association between intraperitoneal free cancer cells and a poor prognosis. intraperitoneal free cancer cells -positive patients had higher rates of nodal spread (risk difference: 0.29; p<0.01), serosal invasion (risk difference: 0.43; p<0.01), recurrence (after 60 months of follow-up, risk difference: 0.44; p<0.01), and mortality (after 60 months of follow-up, risk difference: 0.34; p<0.01). Intraperitoneal free cancer cells are associated with a poor outcome in gastric cancer. This surrogate biomarker should be used to guide therapy both prior to and after surgery.
Assuntos
Humanos , Adenocarcinoma/patologia , Cavidade Peritoneal/patologia , Neoplasias Gástricas/patologia , Adenocarcinoma/mortalidade , Lavagem Gástrica , Metástase Linfática , Recidiva Local de Neoplasia , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Neoplasias Gástricas/mortalidadeRESUMO
Intraperitoneal free cancer cells in gastric adenocarcinoma are associated with a poor outcome. However, the true prognostic value of intraperitoneal free cancer cells is still unclear, leading to a lack of consensus in the management of gastric cancer. The aim of the present study is to perform a systematic review and meta-analysis to analyze intraperitoneal free cancer cells-positive patients with regard to tumor oncologic stage, recurrence, grade of cellular differentiation, and survival rates and to analyze the clinical significance of intraperitoneal free cancer cells with regard to prognosis. Databases were searched up to January 2016 for prognostic factors associated with intraperitoneal free cancer cells, including oncologic stage, depth of neoplasm invasion, lymph nodal spread, differentiation grade of the tumor, and recurrence and survival rates. A total of 100 studies were identified. Meta-analysis revealed a clear association between intraperitoneal free cancer cells and a poor prognosis. intraperitoneal free cancer cells -positive patients had higher rates of nodal spread (risk difference: 0.29; p<0.01), serosal invasion (risk difference: 0.43; p<0.01), recurrence (after 60 months of follow-up, risk difference: 0.44; p<0.01), and mortality (after 60 months of follow-up, risk difference: 0.34; p<0.01). Intraperitoneal free cancer cells are associated with a poor outcome in gastric cancer. This surrogate biomarker should be used to guide therapy both prior to and after surgery.
Assuntos
Adenocarcinoma/patologia , Lavagem Gástrica , Cavidade Peritoneal/patologia , Neoplasias Gástricas/patologia , Adenocarcinoma/mortalidade , Humanos , Metástase Linfática , Recidiva Local de Neoplasia , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Neoplasias Gástricas/mortalidadeRESUMO
Patients undergoing continuous ambulatory peritoneal dialysis are classified according to their peritoneal permeability as low transporter (low solute permeability) or High transporter (high solute permeability). Factors that determine the differences in permeability between them have not been fully disclosed. We investigated morphological features of cultured human peritoneal mesothelial cells from low or high transporter patients and its response to All trans retinoic Acid (ATRA, vitamin A active metabolite), as compared to non-uremic human peritoneal mesothelial cells. Control cells were isolated from human omentum. High or low transporter cells were obtained from dialysis effluents. Cells were cultured in media containing ATRA (0, 50, 100 or 200 nM). We studied length and distribution of microvilli and cilia (scanning electron microscopy), epithelial (cytokeratin, claudin-1, ZO-1 and occludin) and mesenchymal (vimentin and α-smooth muscle actin) transition markers by immunofluorescence and Western blot, and transforming growth factor ß1 expression by Western blot. Low and high transporter exhibited hypertrophic cells, reduction in claudin-1, occludin and ZO-1 expression, cytokeratin and vimentin disorganization and positive α-smooth muscle actin label. Vimentin, α-smooth muscle actin and transforming growth factor-ß1 were overexpressed in low transporter. Ciliated cells were diminished in low and high transporters. Microvilli number and length were severely reduced in high transporter. ATRA reduced hypertrophic cells number in low transporter. It also improved cytokeratin and vimentin organization, decreased vimentin and α-smooth muscle actin expression, and increased claudin 1, occludin and ZO-1 expression, in low and high transporter. In low transporter, ATRA reduced transforming growth factor-ß1 expression. ATRA augmented percentage of ciliated cells in low and high transporter. It also augmented cilia length in high transporter. Alterations in structure, epithelial mesenchymal markers and transforming growth factor-ß1 expression were differential between low and high transporter. Beneficial effects of ATRA were improved human peritoneal mesothelial cells morphology tending to normalize structures.
Assuntos
Cavidade Peritoneal/patologia , Diálise Peritoneal Ambulatorial Contínua , Tretinoína/farmacologia , Actinas/metabolismo , Adolescente , Adulto , Idoso , Transporte Biológico/efeitos dos fármacos , Contagem de Células , Células Cultivadas , Cílios/efeitos dos fármacos , Cílios/metabolismo , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Epitélio/patologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Microvilosidades/efeitos dos fármacos , Microvilosidades/metabolismo , Pessoa de Meia-Idade , Fator de Crescimento Transformador beta1/genética , Vimentina/metabolismo , Adulto JovemRESUMO
The effects of hypertonic saline solution (HSS) have been shown in several animal models of ischemia and shock. Literature has shown potential benefits of HSS modulating inflammatory response after sepsis in an animal model. We studied the HSS effects in sepsis through cecal ligation and puncture (CLP) in Balb-C mice. Groups studied: 1- CLP without treatment (CLP-C); 2- CLP treated with normal saline solution NaCl 0.9% - 34 ml/Kg (CLP-S); 3- CLP treated with HSS NaCl 7.5% - 4 ml/Kg (CLP-H); and 4- group (Basal) without no CLP or treatment. Volume infusion was always applied 30 min after CLP. Lung and peritoneal lavage were harvested after 6h and 24h of CLP to analyze cytokines amount, oxide nitric, lipid peroxidation and neutrophil infiltration. Neutrophil infiltration, ICAM-1, CXCR-2, and CXCL-1 in lung were reduced by HSS (CLP-H) compared to CLP-C or CLP-S. Neutrophil in peritoneal lavage was increased in 24h with HSS (CLP-H) compared to CLP and CLP-S. Peritoneal CXCR-2 was increased in CLP-C and CLP-S but presented a lower increase with HSS (CLP-H) after 6 hours. GRK-2 presented difference among the groups at 24 h, showing a profile similar to neutrophil infiltration. Pro-inflammatory cytokines (TNF-α and IL-6) were reduced by HSS treatment; CLP-S increased TNF-α. IL-10 was increased in lung tissue by the HSS treatment. The oxidative stress (TBARS and nitric oxide biochemistry markers) was reduced with HSS. Animal survival was 33.3% in CLP-C group, 46.6% in CLP-S group and 60% in the CLP-H group after the sixth day. The HSS protects the animal against sepsis. Our results suggest that the volume replacement modulate pro and anti-inflammatory mediators of an inflammatory response, but HSS presented a more effective and potent effect.
Assuntos
Infiltração de Neutrófilos/efeitos dos fármacos , Solução Salina Hipertônica/administração & dosagem , Sepse/patologia , Animais , Quimiocina CXCL1/metabolismo , Quimiotaxia de Leucócito/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Infiltração de Neutrófilos/imunologia , Estresse Oxidativo , Cavidade Peritoneal/patologia , Receptores de Interleucina-8B/metabolismo , Sepse/imunologia , Sepse/metabolismo , Sepse/microbiologia , Sepse/mortalidade , Sepse/terapia , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Inflammatory mediators are thought to be involved in the systemic and local immune response induced by the Tityus serrulatus scorpion envenomation. New functional aspects of lipid mediators have recently been described. Here, we examine the unreported role of lipid mediators in cell recruitment to the peritoneal cavity after an injection with Ts2 or Ts6 toxins isolated from the T. serrulatus scorpion venom. In this report, we demonstrate that following a single intraperitoneal (i.p.) injection of Ts2 or Ts6 (250 µg/kg) in mice, there was an induction of leukocytosis with a predominance of neutrophils observed at 4, 24, 48 and 96 h. Moreover, total protein, leukotriene (LT)B(4), prostaglandin (PG)E(2) and pro-inflammatory cytokine levels were increased. We also observed an increase of regulatory cytokines, including interleukin (IL)-10, after the Ts2 injection. Finally, we observed that Ts2 or Ts6 injection in 5-lipoxygenase (LO) deficient mice and in wild type (WT) 129sv mice pre-treated with LTs and PGs inhibitors (MK-886 and celecoxib, respectively) a reduction the influx of leukocytes occurs in comparison to WT. The recruitment of these cells demonstrated a phenotype characteristic of neutrophils, macrophages, CD4 and CD8 lymphocytes expressing GR1+, F4/80+, CD3+/CD4+ and CD3+/CD8+, respectively. In conclusion, our data demonstrate that Ts2 and Ts6 induce inflammation by mechanisms dependent on lipid mediators and cytokine production. Ts2 may play a regulatory role whereas Ts6 exhibits pro-inflammatory activity exclusively.
Assuntos
Citocinas/biossíntese , Mediadores da Inflamação/fisiologia , Inflamação/induzido quimicamente , Lipídeos/fisiologia , Venenos de Escorpião/toxicidade , Animais , Araquidonato 5-Lipoxigenase/metabolismo , Celecoxib , Movimento Celular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Imuno-Histoquímica , Indóis/farmacologia , Inflamação/patologia , Leucócitos/efeitos dos fármacos , Leucotrienos/biossíntese , Leucotrienos/fisiologia , Inibidores de Lipoxigenase/farmacologia , Masculino , Camundongos , Cavidade Peritoneal/patologia , Prostaglandinas/biossíntese , Prostaglandinas/fisiologia , Pirazóis/farmacologia , Sulfonamidas/farmacologiaRESUMO
Alginates are unbranched polymers of polysaccharide presented as the structural components of marine brown algae. The proinflammatory activity of SVHV, an alginate isolated from Sargassum vulgare, was investigated using models of paw edema, mast cells degranulation and neutrophil migration in vivo. SVHV induced a dose dependent paw edema, with a peak at 2 h, associated with an increased myeloperoxidase activity and production of TNF-α and IL-1ß. Pharmacological modulators, remarkably dexamethasone and indomethacin, inhibited the edema. SVHV (1.0 mg) also led to a significant induction of neutrophil migration in the peritoneal cavity of rats. This neutrophil migration was significantly reduced by peritoneal resident macrophages depletion, but was not affected by the depletion of mast cells. Our data suggest that SVHV has proinflammatory activity dependent of the activation of resident cells, being the macrophages the main cells involved.
Assuntos
Alginatos , Proliferação de Células/efeitos dos fármacos , Inflamação , Sargassum/química , Alginatos/química , Alginatos/isolamento & purificação , Alginatos/toxicidade , Animais , Edema/induzido quimicamente , Edema/patologia , Ácido Glucurônico/química , Ácido Glucurônico/isolamento & purificação , Ácido Glucurônico/toxicidade , Ácidos Hexurônicos/química , Ácidos Hexurônicos/isolamento & purificação , Ácidos Hexurônicos/toxicidade , Doenças do Sistema Imunitário/induzido quimicamente , Doenças do Sistema Imunitário/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/metabolismo , Transtornos Leucocíticos/induzido quimicamente , Transtornos Leucocíticos/patologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/patologia , Cavidade Peritoneal/citologia , Cavidade Peritoneal/patologia , Peroxidase/metabolismo , Ratos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Long-term nonsteroidal anti-inflammatory drugs (NSAIDs) therapy has been associated with several adverse effects such as gastric ulceration and cardiovascular events. Among the molecular modifications strategies, the prodrug approach is a useful tool to discover new safe NSAIDs. The 1-(2,6-dichlorophenyl)indolin-2-one is a diclofenac prodrug which demonstrated relevant anti-inflammatory properties without gastro ulceration effect. In addition, the prodrug decreases PGE(2) levels, COX-2 expression and cellular influx into peritoneal cavity induced by carrageenan treatment. Preliminary pharmacokinetic studies have shown in vivo bioconversion of prodrug to diclofenac. This prodrug is a new nonulcerogenic NSAID useful to treat inflammatory events by long-term therapy.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Diclofenaco/farmacologia , Pró-Fármacos , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Carragenina/efeitos adversos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Diclofenaco/administração & dosagem , Diclofenaco/efeitos adversos , Diclofenaco/análogos & derivados , Diclofenaco/química , Diclofenaco/farmacocinética , Dinoprostona/biossíntese , Modelos Animais de Doenças , Edema/induzido quimicamente , Edema/tratamento farmacológico , Leucócitos/metabolismo , Masculino , Camundongos , Estrutura Molecular , Cavidade Peritoneal/patologia , Ratos , Úlcera Gástrica/induzido quimicamenteRESUMO
The mdx (X chromosome-linked muscular dystrophy) mouse develops a multi-staged disorder characterized by muscle degeneration and reactive fibrosis. Skeletal muscles of mdx mice are not equally susceptible to degeneration. The aim of this study was to verify whether the intense remodeling of the mdx diaphragm could be attributed to influences from the peritoneal microenvironment and omentum, a lymphohematopoietic tissue rich in progenitor cells and trophic factors. At ages corresponding to increased muscular regeneration (12 weeks) and activation of fibrosis (24 weeks), the mdx omentum exhibited (1) morphological and functional characteristics of activation with enlarged milk-spots, an accumulation of CD4(+), CD8(+) and CD19(+)B220(+) B lymphocytes; (2) the formation of clusters positive for proliferating cell nuclear antigen, mainly in B220(+)-rich areas organized in a follicular structure with a germinative center without any challenge by external antigen inducers; (3) clusters with cells positive for fibroblast growth factor-2, numerous Sca-1(+)CD3(-)CD19(-)Mac-1(-) progenitor cells and increased CD4(+), CD8(+) and CD3(+)NK1.1(+) cells in the peritoneal cavity. Omentectomy reduced areas with F4/80(+) inflammatory infiltrate the activity of matrix metalloproteases 9 and 2, collagen deposition and areas with regenerating myofibers in the diaphragm. Thus, persistent activation of the omentum influences the pattern of inflammation and regeneration of the mdx diaphragm partly via the activation of progenitor cells and the production of growth factors that influence the physiopathology of the muscular tissue remodeling.
Assuntos
Diafragma/patologia , Distrofia Muscular Animal/patologia , Omento/patologia , Animais , Citometria de Fluxo , Linfócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Omento/imunologia , Omento/cirurgia , Cavidade Peritoneal/patologia , Células-Tronco/citologiaRESUMO
Prolonged survival of long-lived antibody-secreting cells in the BM has been implicated as a key component of long-term humoral immunity. The current study was designed to uncover the extrinsic signals required for the generation and maintenance of ASC in several niches (peritoneum, spleen and bone-marrow). Our results show that protein mixture of the Thalassophryne nattereri venom induced a chronic Th2 humoral response that is characterized by splenic hyperplasia with GC formation and venom retention by follicular DCs. Retention of B1a in the BM were observed. In the late phase (120d) of chronic venom-response the largest pool of ASC into the peritoneal cavity consisted of B220(neg)CD43(high) phenotype; the largest pool of ASC into spleen was constituted by B220 positive cells (B220(high) and B220(low)), whereas the largest pool of ASC into in the BM was constituted by the B220(high)CD43(low) phenotype; and finally, terminally differentiated cells (B220(neg)CD43(high)) were only maintained in the inflamed peritoneal cavity in late phase. After 120d a sustained production of cytokines (KC, IL-5, TNF-α, IL-6, IL-17A and IL-23) and leukocytes recruitment (eosinophils, mast cells, and neutrophils) were induced. IL-5- and IL-17A-producing CD4+ CD44+ CD40L+ Ly6C+ effector memory T cells were also observed in peritoneal cavity. Finally, treatment of venom-mice with anti-IL-5- and anti-IL17A-neutralizing mAbs abolished the synthesis of specific IgE, without modifying the splenic hyperplasia or GC formation. In addition, IL-5 and IL-17A negatively regulated the expansion of B1a in peritoneal cavity and BM, and promoted the differentiation of these cells in spleen. And more, IL-5 and IL-17A are sufficient for the generation of ASC B220(neg) in the peritoneal cavity and negatively regulate the number of ASC B220(pos), confirming that the hierarchical process of ASC differentiation triggered by venom needs the signal derived from IL-5 and IL-17A.
Assuntos
Células Produtoras de Anticorpos/imunologia , Células Produtoras de Anticorpos/patologia , Diferenciação Celular/imunologia , Imunoglobulina E/imunologia , Inflamação/patologia , Interleucina-17/imunologia , Interleucina-5/imunologia , Animais , Formação de Anticorpos/efeitos dos fármacos , Especificidade de Anticorpos/efeitos dos fármacos , Especificidade de Anticorpos/imunologia , Antígenos/imunologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Imunidade Humoral/efeitos dos fármacos , Imunoglobulina E/biossíntese , Memória Imunológica/efeitos dos fármacos , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Masculino , Toxinas Marinhas/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Especificidade de Órgãos/efeitos dos fármacos , Cavidade Peritoneal/patologia , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Fatores de TempoRESUMO
In an effort to develop an effective and affordable oral vaccine against porcine Taenia solium cysticercosis, the S3Pvac anti-cysticercosis vaccine was expressed in papaya calli. Taenia pisiformis experimental rabbit cysticercosis was used as a model to compare the efficacy of the oral vaccine vs. the injectable S3Pvac-synthetic and S3Pvac-phage versions. Oral S3Pvac-papaya significantly reduced the expected number of hepatic lesions and peritoneal cysticerci to a similar extent than the injectable vaccines. This study reports for the first time an effective oral vaccine against T. pisiformis cysticercosis, possibly useful against porcine T. solium cysticercosis.
Assuntos
Cisticercose/prevenção & controle , Vacinas Protozoárias , Taenia/imunologia , Animais , Sequência de Bases , Cisticercose/patologia , Cysticercus/imunologia , Feminino , Inflamação/imunologia , Inflamação/patologia , Proteínas de Insetos/genética , Fígado/imunologia , Fígado/patologia , Dados de Sequência Molecular , NADH Desidrogenase/genética , Cavidade Peritoneal/parasitologia , Cavidade Peritoneal/patologia , Vacinas Protozoárias/administração & dosagem , Vacinas Protozoárias/imunologia , Coelhos , Alinhamento de Sequência , Taenia/genéticaRESUMO
The aim was to analyze the effect of leukotriene synthesis inhibitor administered intraperitoneally in vasopressin release during sepsis. Male Wistar rats received injections of MK-886 (1.0, 2.0 or 4.0 mg/kg) or vehicle (DMSO 5%) 1 h before cecal ligation and puncture. There was some variation on the survival rate depending on the dose used but the drug did not modify the hematocrit, osmolality, serum sodium and nitrate, plasma protein, and neutrophil recruitment, in any dose. Nevertheless, vasopressin (AVP) release decreased in a dose-response manner in the early phase of sepsis. These results support the suggestion that leukotrienes (LTs) are involved in AVP release during sepsis.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Indóis/uso terapêutico , Sepse/tratamento farmacológico , Sepse/metabolismo , Vasopressinas/metabolismo , Animais , Ceco/cirurgia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Modelos Animais de Doenças , Hematócrito/métodos , Leucotrienos/metabolismo , Ligadura/métodos , Inibidores de Lipoxigenase/toxicidade , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Neutrófilos/fisiologia , Nitratos/sangue , Concentração Osmolar , Cavidade Peritoneal/patologia , Proteínas/metabolismo , Punções/efeitos adversos , Radioimunoensaio , Ratos , Ratos Wistar , Sepse/etiologia , Sepse/patologia , Sódio/sangueRESUMO
Mast cell number and reactivity have been shown to be down-regulated under diabetic conditions. This study was undertaken in order to investigate the role of the advanced glycation end products in the reduction of mast cell number and reactivity in diabetic rats. The effect of aminoguanidine on mast cell apoptosis was also evaluated. Diabetes was induced by intravenous injection of alloxan into fasted rats and aminoguanidine was administered after 3 days of diabetes induction, once daily for 18 consecutive days. Mast cell apoptosis and levels of Bax, a pro-apoptotic member of Bcl-2 family, were evaluated by TUNEL and western blot, respectively. Diabetes led to increased levels of fructosamine and AGEs in the plasma, an effect prevented by aminoguanidine. Treatment with aminoguanidine restored mast cell numbers in the pleural cavity and in mesenteric tissue of diabetic rats. Aminoguanidine also significantly reversed the diabetes-induced reduction in histamine release, as measured by fluorescence, following activation with substance P or antigen in vitro. Increased apoptosis and levels of Bax in mast cells from diabetic rats were inhibited by aminoguanidine. In conclusion, our findings showed that aminoguanidine restored the number and reactivity of mast cells in diabetic rats, accompanied by suppression of apoptosis, evidencing that advanced glycation end product formation has a critical role in mast cell behavior of diabetic rats.
Assuntos
Diabetes Mellitus Experimental/imunologia , Inibidores Enzimáticos/farmacologia , Produtos Finais de Glicação Avançada/imunologia , Guanidinas/farmacologia , Mastócitos/efeitos dos fármacos , Animais , Antígenos/farmacologia , Apoptose/efeitos dos fármacos , Glicemia/análise , Contagem de Células , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Produtos Finais de Glicação Avançada/sangue , Insulina/sangue , Masculino , Mastócitos/imunologia , Mesentério/imunologia , Cavidade Peritoneal/patologia , Cavidade Pleural/imunologia , Ratos , Ratos Wistar , Substância P/farmacologia , Proteína X Associada a bcl-2/imunologiaRESUMO
BACKGROUND AND AIMS: Schistosomiasis is an intravascular parasitic disease associated with inflammation. Endothelial cells control leukocyte transmigration and vascular permeability being modulated by pro-inflammatory mediators. Recent data have shown that endothelial cells primed in vivo in the course of a disease keep the information in culture. Herein, we evaluated the impact of schistosomiasis on endothelial cell-regulated events in vivo and in vitro. METHODOLOGY AND PRINCIPAL FINDINGS: The experimental groups consisted of Schistosoma mansoni-infected and age-matched control mice. In vivo infection caused a marked influx of leukocytes and an increased protein leakage in the peritoneal cavity, characterizing an inflamed vascular and cellular profile. In vitro leukocyte-mesenteric endothelial cell adhesion was higher in cultured cells from infected mice as compared to controls, either in the basal condition or after treatment with the pro-inflammatory cytokine tumor necrosis factor (TNF). Nitric oxide (NO) donation reduced leukocyte adhesion to endothelial cells from control and infected groups; however, in the later group the effect was more pronounced, probably due to a reduced NO production. Inhibition of control endothelial NO synthase (eNOS) increased leukocyte adhesion to a level similar to the one observed in the infected group. Besides, the adhesion of control leukocytes to endothelial cells from infected animals is similar to the result of infected animals, confirming that schistosomiasis alters endothelial cells function. Furthermore, NO production as well as the expression of eNOS were reduced in cultured endothelial cells from infected animals. On the other hand, the expression of its repressor protein, namely caveolin-1, was similar in both control and infected groups. CONCLUSION/SIGNIFICANCE: Schistosomiasis increases vascular permeability and endothelial cell-leukocyte interaction in vivo and in vitro. These effects are partially explained by a reduced eNOS expression. In addition, our data show that the disease primes endothelial cells in vivo, which keep the acquired phenotype in culture.