RESUMEN
Dimethyl fumarate (DMF, Tecfidera) is an oral drug utilized to treat relapsing-remitting multiple sclerosis (MS). DMF treatment reduces disease activity in MS. Gastrointestinal discomfort is a common adverse effect of the treatment with DMF. This study aimed to investigate the effect of DMF administration in the gut draining lymph nodes cells of C57BL6/J female mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We have demonstrated that the treatment with DMF (7.5 mg/kg) significantly reduces the severity of EAE. This reduction of the severity is accompanied by the increase of both proinflammatory and anti-inflammatory mechanisms at the beginning of the treatment. As the treatment progressed, we observed an increasing number of regulatory Foxp3 negative CD4 T cells (Tr1), and anti-inflammatory cytokines such as IL-27, as well as the reduction of PGE2 level in the mesenteric lymph nodes of mice with EAE. We provide evidence that DMF induces a gradual anti-inflammatory response in the gut draining lymph nodes, which might contribute to the reduction of both intestinal discomfort and the inflammatory response of EAE. These findings indicate that the gut is the first microenvironment of action of DMF, which may contribute to its effects of reducing disease severity in MS patients.
Asunto(s)
Dimetilfumarato , Encefalomielitis Autoinmune Experimental , Ganglios Linfáticos , Ratones Endogámicos C57BL , Linfocitos T Reguladores , Animales , Dimetilfumarato/farmacología , Dimetilfumarato/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/efectos de los fármacos , Ratones , Femenino , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Mesenterio , Citocinas/metabolismo , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Modelos Animales de EnfermedadRESUMEN
PURPOSE: To assess the performance of computed tomography (CT) reconstruction in evaluating the response in metastatic lymph nodes after neoadjuvant chemotherapy (NAC) in breast cancer patients. METHODS: Patients undergoing pre-NAC and post-NAC CT were identified from the Peking University Cancer Hospital database. Axillary Lymph nodes (ALNs) that shrunk to < 5 mm in short-axis diameter after NAC on CT reconstruction images were classified as clinical complete response. Evaluations of CT reconstruction on ALNs were correlated with residual nodal disease in the final pathology. Overall, 53 invasive breast cancer patients between October 2016 and March 2018 were eligible for our study. The median age was 48 (range 35-70) years. Most women presented with T2 tumors (35/53, 66.0%). RESULTS: After NAC, 20 (37.7%) patients without residual nodal disease were defined as pCR. Of 53 patients, 18 (33.9%) showed negative conversion of ALNs on CT reconstruction evaluation; axillary pCR was present in 16/18 (88.9%) patients. Among 35 patients with abnormal nodes on post-NAC CT reconstruction, 31 (88.6%) had axillary metastasis on the final pathology. The sensitivity and specificity of CT reconstruction in predicting node-negative status were 80.0% and 93.9%, respectively. The positive predictive value was 84.9% for lymph node pCR. The area under the receiver operating characteristic curve of each imaging modality was 0.870 (95% confidence interval 0.755-0.984). CONCLUSIONS: CT reconstruction was useful for evaluating ALNs response following NAC and may be used to predict axillary nodes' pCR with adequate accuracy.
Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Ganglios Linfáticos/diagnóstico por imagen , Tomografía Computarizada Multidetector/métodos , Terapia Neoadyuvante/métodos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Área Bajo la Curva , Axila , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama , Quimioterapia Adyuvante/métodos , Ciclofosfamida/uso terapéutico , Epirrubicina/uso terapéutico , Femenino , Humanos , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/cirugía , Metástasis Linfática/diagnóstico por imagen , Metástasis Linfática/tratamiento farmacológico , Persona de Mediana Edad , Neoplasia Residual , Paclitaxel/uso terapéutico , Estudios Retrospectivos , Sensibilidad y Especificidad , Resultado del TratamientoRESUMEN
While Treg cells are responsible for self-tolerance and immune homeostasis, pathogenic autoreactive Th17 cells produce pro-inflammatory cytokines that lead to tissue damage associated with autoimmunity, as observed in multiple sclerosis. Therefore, the immunological balance between Th17 and Treg cells may represent a promising option for immune therapy. Statin drugs are used to treat dyslipidemia; however, besides their effects on preventing cardiovascular diseases, statins also have anti-inflammatory effects. Here, we investigated the role of pitavastatin on experimental autoimmune encephalomyelitis (EAE) and the differentiation of Treg and Th17 cells. EAE was induced by immunizing C57BL/6 mice with MOG35-55. EAE severity was determined by analyzing the clinical score and inflammatory parameters in the spinal cord. Naive CD4 T cells were cultured under Treg and Th17-skewing conditions in vitro in the presence of pitavastatin. We found that pitavastatin decreased EAE development, which was accompanied by a reduction of all parameters investigated. Pitavastatin also reduced the expression of IBA1 and pSTAT3 (Y705 and S727) in the spinal cords of EAE mice. Interestingly, the reduction of Th17 cell frequency in the draining lymph nodes of EAE mice treated with pitavastatin was followed by an increase of Treg cells. Indeed, pitavastatin directly affects T cell differentiation in vitro by decreasing Th17 and increasing Treg cell differentiation. Mechanistically, pitavastatin effects are dependent on mevalonate synthesis. Thus, our data show the potential anti-inflammatory effect of pitavastatin on the pathogenesis of the experimental neuroinflammation by modulating the Th17/Treg axis.
Asunto(s)
Antiinflamatorios/farmacología , Diferenciación Celular/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/prevención & control , Ácido Mevalónico/metabolismo , Quinolinas/farmacología , Médula Espinal/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacos , Animales , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Mediadores de Inflamación/metabolismo , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Masculino , Ratones Endogámicos C57BL , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos , Médula Espinal/inmunología , Médula Espinal/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Cyperus rotundus L. (Cyperaceae) is considered one of the most widely distributed plant species in the world, especially in tropical and subtropical regions. In addition, it is commonly used in India, China and Japan in traditional medicine to treat different diseases, including dermatitis and other skin disorders. AIM OF THE STUDY: To investigate the topical anti-inflammatory activity of C. rotundus rhizome ethanolic extract in models of acute and chronic dermatitis. MATERIALS AND METHODS: Phytochemical analysis was carried out using High-performance liquid chromatography-ultraviolet detection (HPLC/UV) to determine the presence of quercetin and chlorogenic acid in C. rotundus extract. Topical anti-inflammmatory effects of C. rotundus extract were evaluated on arachidonic acid (AA) and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in mice. Skin biopsies were collected and submitted to histological and enzymatic analysis to evaluate the C. rotundus effect in leukocyte migration into inflamed tissue. Antiproliferative activity of C. rotundus was confirmed by PCNA immunostained cell analysis. Systemic and possible adverse effects of topical treatment with C. rotundus were evaluated by the skin atrophy and same organ weights. In addition, the glucocorticoid receptor (GR) antagonist mifepristone was used to investigate possible GR-mediated mechanisms of action. RESULTS: The phytochemical analysis show that C. rotundus ethanol extract contains 45 µg/g of chlorogenic acid. Topical treatment with C. rotundus extract reduced ear edema and cellular infiltrate in acute and chronic skin inflammation models. Moreover, mice topically treated with C. rotundus exhibited decrease in TPA-induced keratinocyte hyperproliferation. Relevantly, topical treatment with C. rotundus did not caused skin atrophy or changes in lymphoid organ weight. The anti-inflammatory effect of C. rotundus was not influenced by the GR antagonist. CONCLUSION: The results here demonstrate for the first time the topical anti-inflammatory and antiproliferative efficacy of C. rotundus extract, suggesting that the extract could be a potential new therapeutic tool for the treatment of inflammatory skin disorders.
Asunto(s)
Antiinflamatorios/uso terapéutico , Cyperus , Dermatitis por Contacto/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Glándulas Suprarrenales/efectos de los fármacos , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Ácido Araquidónico , Atrofia/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Edema/tratamiento farmacológico , Edema/metabolismo , Femenino , Irritantes , Queratinocitos/efectos de los fármacos , Ganglios Linfáticos/efectos de los fármacos , Ratones , Fitoquímicos/análisis , Fitoquímicos/uso terapéutico , Fitoterapia , Extractos Vegetales/química , Extractos Vegetales/farmacología , Rizoma , Piel/efectos de los fármacos , Piel/patología , Bazo/efectos de los fármacos , Acetato de Tetradecanoilforbol , Timo/efectos de los fármacosRESUMEN
Staphylococcus aureus is one of the main causative agent of infections acquired in both community and hospital environment. In this context, photodynamic therapy (PDT) consists in using a photosensitizer that, activated by light, evokes the formation of reactive oxygen species (ROS), which lead to the death of microorganisms due to oxidative damage; it is useful tool since this action, harmful to pathogens, does not significantly injure human cells. In view of this, this work proposes a more in-depth study on the use of resveratrol (RSV) as a possible photosensitizer. It was observed, in the intradermal infection model in animals' ear dermis, that photoactivated resveratrol promotes an increase in myeloperoxidase expression with reduced bacterial load in the draining lymph node. Besides that, the draining lymph node of the animals treated with photoactivated RSV controls inflammation through IL-10 production. These are pioneers data and this work being a pilot study; then, other works must be conducted with the objective of elucidate the photoactivated resveratrol mechanism of action.
Asunto(s)
Luz , Resveratrol/efectos de la radiación , Resveratrol/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Animales , Carga Bacteriana/efectos de los fármacos , Cadherinas/metabolismo , Dermis/efectos de los fármacos , Dermis/enzimología , Oído/patología , Humanos , Inflamación/patología , Interleucina-10/biosíntesis , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/patología , Ratones Endogámicos BALB C , Peroxidasa/metabolismo , Proyectos Piloto , Resveratrol/farmacología , Staphylococcus aureus/efectos de los fármacosRESUMEN
BACKGROUND: Breast ultrasound and mammography were used in the detection of residual tumor after neoadjuvant chemotherapy. The aim of this study was to evaluate the correlation between clinical and pathological responses with breast density and IHC marker conversion to understand how this information might be used in the future to direct treatment. METHODS: We included 119 patients who underwent CNB and followed NACT. The breast density assessment was based on the mammography examination performed at the time of diagnosis. We evaluated the clinical and pathological responses to NACT by the UICC and Miller-Payne grading systems, respectively. RESULTS: Of 119 patients who met the inclusion criteria, patients with high pre-treatment IHC markers levels showed higher expression of IHC markers regardless of the post-treatment IHC marker level at baseline. However, breast and node tumor sizes before and after NACT were negatively correlated with hormone receptor conversion and positively correlated with Ki-67 conversion (P < 0.05). Patients with low BD were more likely to have a cCR, pCR, TNBC, and postmenopausal status than those with a high BD (P < 0.05). BD was significantly associated with PR and Ki67 conversion but not ER conversion. CONCLUSION: Our prospective observational study demonstrated that IHC marker conversion could be used to identify lesion size changes and BD. We also found that a high BD was linked to clinical and pathological responses, molecular subtype, and menopausal status. In the future, additional studies are required to validate the predictive value identified by this research.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Quimioterapia Adyuvante/métodos , Ganglios Linfáticos/patología , Imagen Molecular/métodos , Terapia Neoadyuvante/métodos , Adulto , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Ganglios Linfáticos/efectos de los fármacos , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismoRESUMEN
PURPOSE: To evaluate the effect of garlic on formation of postoperative adhesions in rats. METHODS: Twenty-four Sprague dawley rats were divided into three groups. In Group 1 (sham), laparotomy was performed and stitched up. In Group 2 (control), after laparotomy was performed, punctate hemorrhage was induced by cecal abrasion in the cecum and 2 cc of saline was intraperitoneally administered to each rat. In Group 3 (experimental), after laparotomy was performed, punctate hemorrhage was induced by cecal abrasion in the cecum and each rat was intraperitoneally administered a sterile Allium sativum derivative. The rats in all groups were re-laparotomized on postoperative day 7; samples were obtained from the peritoneal tissue surrounding the cecum. RESULTS: In Group 3, there was a statistically significant difference in terms of inflammation, lymph node size, and free oxygen radicals; these parameters tended to increase. In terms of fibrosis evaluated using H&E and MT, there was no significant difference between groups 2 and 3. CONCLUSIONS: No positive outcomes indicating that Allium sativum reduces intra-abdominal adhesions were obtained. However, it caused severe inflammation in the tissue. Additionally, in immunohistochemical analyses conducted to detect oxidative stress, allium sativum increased the production of free oxygen radicals in the tissue.
Asunto(s)
Ajo/química , Enfermedades Peritoneales/prevención & control , Animales , Fibrosis , Radicales Libres/análisis , Inmunohistoquímica , Laparotomía , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/patología , Estrés Oxidativo/efectos de los fármacos , Enfermedades Peritoneales/patología , Complicaciones Posoperatorias/patología , Complicaciones Posoperatorias/prevención & control , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Adherencias Tisulares/patología , Adherencias Tisulares/prevención & controlRESUMEN
Abstract Purpose: To evaluate the effect of garlic on formation of postoperative adhesions in rats. Methods: Twenty-four Sprague dawley rats were divided into three groups. In Group 1 (sham), laparotomy was performed and stitched up. In Group 2 (control), after laparotomy was performed, punctate hemorrhage was induced by cecal abrasion in the cecum and 2 cc of saline was intraperitoneally administered to each rat. In Group 3 (experimental), after laparotomy was performed, punctate hemorrhage was induced by cecal abrasion in the cecum and each rat was intraperitoneally administered a sterile Allium sativum derivative. The rats in all groups were re-laparotomized on postoperative day 7; samples were obtained from the peritoneal tissue surrounding the cecum Results: In Group 3, there was a statistically significant difference in terms of inflammation, lymph node size, and free oxygen radicals; these parameters tended to increase. In terms of fibrosis evaluated using H&E and MT, there was no significant difference between groups 2 and 3. Conclusions: No positive outcomes indicating that Allium sativum reduces intra-abdominal adhesions were obtained. However, it caused severe inflammation in the tissue. Additionally, in immunohistochemical analyses conducted to detect oxidative stress, allium sativum increased the production of free oxygen radicals in the tissue.
Asunto(s)
Animales , Enfermedades Peritoneales/prevención & control , Ajo/química , Enfermedades Peritoneales/patología , Complicaciones Posoperatorias/patología , Complicaciones Posoperatorias/prevención & control , Fibrosis , Inmunohistoquímica , Adherencias Tisulares/patología , Adherencias Tisulares/prevención & control , Reproducibilidad de los Resultados , Ratas Sprague-Dawley , Estrés Oxidativo/efectos de los fármacos , Radicales Libres/análisis , Laparotomía , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/patologíaRESUMEN
BACKGROUND: Ouabain (OUA) is a cardiotonic glycoside originally extracted from African plants. It has also been described as an endogenous component in mammals, being released in stress situations mainly by the adrenal gland. OUA has been reported to be capable of inhibiting mitogen-induced lymphocyte proliferation and also affects B and T lymphocytes. OBJECTIVES: The aim of this work is to show the effects of OUA in peripheral T lymphocytes. METHODS: In the in vivo experiments, mice were injected intraperitoneally for 3 consecutive days with RPMI medium (control group) or 0.56 mg/kg of OUA diluted in RPMI medium (OUA group). On the fourth day, spleen or mesenteric lymph nodes were removed. RESULTS: OUA significantly reduced the number of CD4+ T lymphocytes in the spleen, especially regulatory T cells (Tregs). In vitro OUA did not inhibit the proliferation of CD4+T lymphocytes stimulated with anti-CD3 neither was able to induce the apoptosis of CD4+ nor Tregs. There was no increase in the number or percentage of T lymphocytes in the mesenteric lymph nodes, suggesting that there was no preferential accumulation of these cells in this organ. Secretion of IL-2 by activated T lymphocytes was decreased by the OUA, explaining at least in part the reduction of Tregs, since this cytokine is involved in the peripheral conversion and maintenance of Tregs. CONCLUSION: The impact of this reduction in autoimmune diseases, allergy and cancer as well as the potential use of OUA as a therapeutic approach in tumor treatment still needs more investigation.
Asunto(s)
Cardiotónicos/farmacología , Interleucina-2/metabolismo , Ouabaína/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Animales , Femenino , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones , Bazo/efectos de los fármacos , Bazo/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
There is increasing evidence of the relevant connection and regulation between the gut and skin immune axis. In fact, oral administration of lipoteichoic acid (LTA) from Lactobacillus rhamnosus GG (LGG) prevents the development of UV-induced skin tumors in chronically exposed mice. Here we aim to evaluate whether this LTA is able to revert UV-induced immunosuppression as a mechanism involved in its anti-tumor effect and whether it has an immunotherapeutic effect against cutaneous squamous cell carcinoma. Using a mouse model of contact hypersensitivity, we demonstrate that LTA overcomes UV-induced skin immunosuppression. This effect was in part achieved by modulating the phenotype of lymph node resident dendritic cells (DC) and the homing of skin migratory DC. Importantly, oral LTA reduced significantly the growth of established skin tumors once UV radiation was discontinued, demonstrating that it has a therapeutic, besides the already demonstrated preventive antitumor effect. The data presented here strongly indicates that oral administration of LTA represents a promising immunotherapeutic approach for different conditions in which the skin immune system is compromised.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Lacticaseibacillus rhamnosus/química , Lipopolisacáridos/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Ácidos Teicoicos/farmacología , Rayos Ultravioleta/efectos adversos , Administración Oral , Animales , Antineoplásicos/aislamiento & purificación , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Movimiento Celular/efectos de la radiación , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/patología , Células Dendríticas/efectos de la radiación , Dermatitis por Contacto/genética , Dermatitis por Contacto/inmunología , Dermatitis por Contacto/patología , Femenino , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/patología , Tracto Gastrointestinal/efectos de la radiación , Lipopolisacáridos/aislamiento & purificación , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Ganglios Linfáticos/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Piel/efectos de los fármacos , Piel/inmunología , Piel/patología , Piel/efectos de la radiación , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Ácidos Teicoicos/aislamiento & purificaciónRESUMEN
Blomia tropicalis mite is highly prevalent in tropical and subtropical regions and it is associated with allergic diseases such as rhinitis and asthma. By using an OVA-model of allergic lung disease, we have previously shown that sensitization in the presence of toll like receptors (TLRs) agonists attenuates subsequent OVA-induced allergic responses. Here, we evaluated the effect of CpG-ODN, a specific synthetic TLR-9 agonist, on the development of experimental asthma induced by Blomia tropicalis extract, a relevant source of aeroallergens. Among different protocols of Blomia tropicalis extract sensitization, the subcutaneous sensitization in the presence of alum adjuvant induced the highest Th2 responses, including high IgE levels. Adsorption of CpG to Blomia tropicalis extract/Alum attenuated the airway hyperreactivity, the infiltration of inflammatory cells including eosinophils, and the IL-5 content in BAL. In addition, lung peribronchial inflammatory infiltrate, mucus production and IL-5-producing CD3+ CD4+ T cells were significantly reduced in the Blomia tropicalis extract/Alum+CpG group. Importantly, CpG inhibited total IgE production as well as active systemic or cutaneous anaphylaxis reactions. Inhibition of pulmonary Th2 responses was associated with increased IL-10 production but not with IFN-γ production. Notably, in IL-10-deficient mice, sensitization with OVA/Alum+CpG resulted in intense lung neutrophilia and IFN-γ production, indicating that IL-10 is necessary to inhibit subsequent Th1 immunity. Our work highlights the mechanisms of allergy attenuation by CpG and it indicates the potential use of Alum-based formulation with CpG to treat allergic processes.
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Compuestos de Alumbre/química , Asma/prevención & control , Asma/parasitología , Pyroglyphidae/fisiología , Receptor Toll-Like 9/agonistas , Adyuvantes Inmunológicos/farmacología , Adsorción , Anafilaxia/complicaciones , Anafilaxia/inmunología , Anafilaxia/parasitología , Animales , Asma/complicaciones , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Eosinófilos/patología , Femenino , Hipersensibilidad/complicaciones , Hipersensibilidad/inmunología , Hipersensibilidad/parasitología , Inmunidad/efectos de los fármacos , Inmunización , Interleucina-10/metabolismo , Interleucina-4/biosíntesis , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Subgrupos Linfocitarios/efectos de los fármacos , Subgrupos Linfocitarios/inmunología , Ratones Endogámicos C57BL , Neutrófilos/patología , Oligodesoxirribonucleótidos/farmacología , Pyroglyphidae/efectos de los fármacos , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th2/efectos de los fármacos , Células Th2/inmunología , Receptor Toll-Like 9/metabolismoRESUMEN
Fire ants are widely studied, invasive and venomous arthropod pests. There is significant biomedical interest in immunotherapy against fire ant stings. However, mainly due to practical reasons, the physiological effects of envenomation has remained poorly characterized. The present study takes advantage of a recently-described venom protein extract to delineate the immunological pathways underlying the allergic reaction to fire ant venom toxins. Mice were injected with controlled doses of venom protein extract. Following sensitization and a second exposure, a marked footpad swelling was observed. Based on eosinophil recruitment and production of Th2 cytokines, we hereby establish that fire ant proteins per se can lead to an allergic response, which casts a new light into the mechanism of action of these toxins.
Asunto(s)
Venenos de Hormiga/efectos adversos , Hipersensibilidad/etiología , Proteínas de Insectos/efectos adversos , Animales , Venenos de Hormiga/química , Venenos de Hormiga/inmunología , Hormigas/química , Citocinas/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Hipersensibilidad/inmunología , Mordeduras y Picaduras de Insectos/etiología , Mordeduras y Picaduras de Insectos/inmunología , Proteínas de Insectos/química , Proteínas de Insectos/inmunología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Masculino , Ratones Endogámicos BALB CRESUMEN
PURPOSE: To investigate the effects of pycnogenol on peritoneal adhesions and additionally to investigate the immunohistochemical effects of free oxygen radicals and reactive lymph nodes detected in the adhesive tissue that was sampled surrounding the cecum on intra-abdominal adhesions. METHODS: Twenty-seven Wistar Albino rats were divided into three groups. In group 1 (sham), laparotomy was performed and stitched up. In group 2 (control), after laparotomy was performed, punctate hemorrhage was induced by cecal abrasion in the cecum and each rat was intraperitoneally administered 2 cc of saline. In group 3 (experimental), after laparotomy was performed, punctate hemorrhage was induced by cecal abrasion in the cecum and each rat was intraperitoneally administered a sterile Pycnogenol derivative. The rats in all groups were re-laparotomized on postoperative day 7; samples were obtained from the peritoneal tissue surrounding the cecum, and the rats were sacrificed. RESULTS: In group 3, there was a statistically significant difference in terms of inflammation, lymph node size, and free oxygen radicals; these parameters tended to increase. In terms of fibrosis evaluated using H&E and MT, there was no significant difference between groups 2 and 3. CONCLUSIONS: No positive outcomes indicating that pycnogenol reduces intra-abdominal adhesions were obtained. However, it caused severe inflammation in the tissue. Moreover, a significant increase in lymph node size was detected secondary to inflammation. Additionally, in immunohistochemical analyses conducted to detect oxidative stress, pycnogenol increased the production of free oxygen radicals in the tissue.
Asunto(s)
Flavonoides/uso terapéutico , Ganglios Linfáticos/efectos de los fármacos , Enfermedades Peritoneales/prevención & control , Peritoneo/cirugía , Adherencias Tisulares/prevención & control , Animales , Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Modelos Animales de Enfermedad , Flavonoides/efectos adversos , Radicales Libres/análisis , Inmunohistoquímica , Inflamación/inducido químicamente , Inflamación/patología , Laparotomía , Ganglios Linfáticos/patología , Estrés Oxidativo/efectos de los fármacos , Enfermedades Peritoneales/etiología , Peritoneo/patología , Extractos Vegetales , Complicaciones Posoperatorias , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Adherencias Tisulares/etiología , Adherencias Tisulares/patologíaRESUMEN
Abstract Purpose: To investigate the effects of pycnogenol on peritoneal adhesions and additionally to investigate the immunohistochemical effects of free oxygen radicals and reactive lymph nodes detected in the adhesive tissue that was sampled surrounding the cecum on intra-abdominal adhesions. Methods: Twenty-seven Wistar Albino rats were divided into three groups. In group 1 (sham), laparotomy was performed and stitched up. In group 2 (control), after laparotomy was performed, punctate hemorrhage was induced by cecal abrasion in the cecum and each rat was intraperitoneally administered 2 cc of saline. In group 3 (experimental), after laparotomy was performed, punctate hemorrhage was induced by cecal abrasion in the cecum and each rat was intraperitoneally administered a sterile Pycnogenol derivative. The rats in all groups were re-laparotomized on postoperative day 7; samples were obtained from the peritoneal tissue surrounding the cecum, and the rats were sacrificed. Results: In group 3, there was a statistically significant difference in terms of inflammation, lymph node size, and free oxygen radicals; these parameters tended to increase. In terms of fibrosis evaluated using H&E and MT, there was no significant difference between groups 2 and 3. Conclusions: No positive outcomes indicating that pycnogenol reduces intra-abdominal adhesions were obtained. However, it caused severe inflammation in the tissue. Moreover, a significant increase in lymph node size was detected secondary to inflammation. Additionally, in immunohistochemical analyses conducted to detect oxidative stress, pycnogenol increased the production of free oxygen radicals in the tissue.
Asunto(s)
Animales , Ratas , Enfermedades Peritoneales/prevención & control , Peritoneo/cirugía , Flavonoides/uso terapéutico , Adherencias Tisulares/prevención & control , Enfermedades Peritoneales/etiología , Peritoneo/patología , Complicaciones Posoperatorias , Flavonoides/efectos adversos , Inmunohistoquímica , Extractos Vegetales , Adherencias Tisulares/etiología , Adherencias Tisulares/patología , Especies Reactivas de Oxígeno/metabolismo , Ratas Wistar , Estrés Oxidativo/efectos de los fármacos , Modelos Animales de Enfermedad , Radicales Libres/análisis , Inflamación/inducido químicamente , Inflamación/patología , Laparotomía , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/patología , Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéuticoRESUMEN
PURPOSE: Abdominal lymph node (ALN) recurrence in gastric cancer (GC) is rare and usually unresectable. We investigated the effects of integration of radiotherapy (RT) and chemotherapy against ALN recurrence in GC. METHODS: We retrospectively categorized GC patients with ALN recurrence treated between 2005 and 2013 into two groups: those treated with integration of RT and chemotherapy (RCT) and those who received systemic chemotherapy only (CT). The median follow-up period after ALN recurrence for all patients was 20 months. RESULTS: Of 53 patients, 31 and 22 were in the RCT and CT groups, respectively. Isolated distant failure (DF; 35.5%) without local progression (LP) was the dominant pattern of failure (POF) in the RCT group (median DF-free period, 26 months). LP followed by DF (31.8%) was the dominant POF in the CT group; LP (median LP-free period, 8 months) occurred 10 months earlier than DF (median DF-free period, 18 months). RCT patients had significantly longer median progression-free survival (PFS) compared to CT patients (25 vs. 8 months; P = 0.021). On multivariate analysis, treatment (CT vs. RCT) was an independent prognostic factor for PFS (hazard ratio 2.085; 95% confidence interval 1.073-4.050; P = 0.013). CONCLUSIONS: Integration of RT and chemotherapy achieved long-term local control and prolonged PFS in GC patients with ALN recurrence. Local RT is feasible for treating isolated ALN recurrences.
Asunto(s)
Adenocarcinoma/terapia , Carcinoma de Células en Anillo de Sello/terapia , Quimioradioterapia , Ganglios Linfáticos/patología , Recurrencia Local de Neoplasia/prevención & control , Neoplasias Gástricas/terapia , Adenocarcinoma/secundario , Adulto , Anciano , Carcinoma de Células en Anillo de Sello/secundario , Femenino , Estudios de Seguimiento , Humanos , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/efectos de la radiación , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/patología , Tasa de SupervivenciaRESUMEN
Abscopal effect is a rare phenomenon characterized by tumor regression of untreated metastatic lesions after a local therapy (eg, radiotherapy). We studied the probability of abscopal effect with radiotherapy associated with anti-programmed death cell 1 (PD1) therapy after progression on anti-PD1. This study is a retrospective analysis of patients treated with nivolumab or pembrolizumab for melanoma, non-small cell lung cancer (NSCLC) and renal cancer at Antônio Ermírio de Moraes Oncology Center, Brazil. To be eligible for this analysis, patients must have had unequivocal evidence of disease progression on anti-PD1 therapy and subsequent radiotherapy for any tumor site while still receiving anti-PD1. The abscopal effect was characterized as a response outside the irradiated field after radiotherapy plus anti-PD1. Sixteen patients were evaluated, including 12 metastatic melanoma, 2 metastatic NSCLC, and 2 metastatic renal cell carcinoma. The median time to disease progression on anti-PD1 was 3 months. The radiotherapy field included lung, lymph nodes, and bones, with a median total dose of 24 Gy (1-40 Gy), usually in 3 fractions (1-10 fractions). Three patients with melanoma developed an abscopal effect at a rate of 18.7% (25% among melanoma patients). Of note, one of them achieved a remarkable complete response lasting >6 months. Three patients with melanoma obtained a significant local response after radiotherapy, despite no response in distant metastases. Eleven patients presented disease progression after radiotherapy. No increased toxicity was observed. In conclusion, no patients with NSCLC or renal cancer showed abscopal effect, but 25% of patients with melanoma showed regression of nonirradiated lesions when anti-PD1 was continued after radiation to a tumor site that had progressed on anti-PD1 monotherapy.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inmunoterapia/métodos , Neoplasias Renales/tratamiento farmacológico , Pulmón/patología , Ganglios Linfáticos/patología , Melanoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/uso terapéutico , Brasil , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Femenino , Humanos , Neoplasias Renales/patología , Neoplasias Renales/radioterapia , Pulmón/efectos de la radiación , Ganglios Linfáticos/efectos de los fármacos , Masculino , Melanoma/patología , Melanoma/radioterapia , Persona de Mediana Edad , Metástasis de la Neoplasia , Nivolumab , Receptor de Muerte Celular Programada 1/inmunología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Ouabain (OUA) is a steroid hormone capable of inhibiting the protein Na+K+ATPase present in the plasma membrane of cells. Ouabain was initially extracted from the roots of African trees such as Acocanthera ouabaio and Strophantus gratus seeds and later described as an endogenous component found in higher mammals. The adrenal gland is the main site of synthesis of ouabain and it is released in stressful situations, conditions similar to those where there is secretion of corticosteroids. Immunological functions have been shown to be regulated by ouabain. In order to understand the effects of ouabain on B lymphocyte populations in different lymphoid organs, mice received intraperitoneal injections of ouabain for 3 consecutive days. Twenty-four hours after the last injection, cells were analyzed by flow cytometry. In the spleen, ouabain modulated especially follicular B cells, inducing a significant decrease in the percentage and absolute numbers of those cells. Ouabain also reduced the absolute number of marginal zone B lymphocytes. No difference in the percentage or absolute number of B lymphocytes in the spleen forty-eight hours after the last injection was observed. An increase in the number of B cells was seen in mesenteric lymph nodes and this retention appears to be directly related to increased expression of CXCR5 chemokine receptor and reduction of CD62L, which also explains the observed reduction of B cells in the spleen. Our results indicate that ouabain regulates the dynamics of B lymphocytes in peripheral organs but production of total IgM and IgG in the serum of animals treated in vivo with ouabain was not affected.
Asunto(s)
Subgrupos de Linfocitos B/efectos de los fármacos , Cardiotónicos/farmacología , Ganglios Linfáticos/efectos de los fármacos , Ouabaína/farmacología , Bazo/efectos de los fármacos , Animales , Subgrupos de Linfocitos B/citología , Subgrupos de Linfocitos B/inmunología , Femenino , Regulación de la Expresión Génica , Inmunoglobulina G/biosíntesis , Inmunoglobulina M/biosíntesis , Inmunofenotipificación , Inyecciones Intraperitoneales , Selectina L/genética , Selectina L/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Receptores CXCR5/genética , Receptores CXCR5/inmunología , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , ATPasa Intercambiadora de Sodio-Potasio/genética , ATPasa Intercambiadora de Sodio-Potasio/inmunología , Bazo/citología , Bazo/inmunologíaRESUMEN
Current therapies against malignant melanoma generally fail to increase survival in most patients, and immunotherapy is a promising approach as it could reduce the dosage of toxic therapeutic drugs. In the present study, we show that an immunotherapeutic approach based on the use of the Toll-like receptor (TLR)-5 ligand flagellin (Salmonella Typhimurium FliCi) combined with the major histocompatibility complex class II-restricted P10 peptide, derived from the Paracoccidioides brasiliensis gp43 major surface protein, reduced the number of lung metastasis in a murine melanoma model. Compounds were administered intranasally into C57Bl/6 mice intravenously challenged with syngeneic B16F10-Nex2 melanoma cells, aiming at the local (pulmonary) immune response modulation. Along with a marked reduction in the number of lung nodules, a significant increase in survival was observed. The immunization regimen induced both local and systemic proinflammatory responses. Lung macrophages were polarized towards a M1 phenotype, lymph node cells, and splenocytes secreted higher interleukin-12p40 and interferon (IFN)-γ levels when re-stimulated with tumor antigens. The protective effect of the FliCi+P10 formulation required TLR-5, myeloid differentiation primary response gene 88 and IFN-γ expression, but caspase-1 knockout mice were only partially protected, suggesting that intracellular flagellin receptors are not involved with the anti-tumor effect. The immune therapy resulted in the activation of tumor-specific CD4(+) T lymphocytes, which conferred protection to metastatic melanoma growth after adoptive transfer. Taken together, our results report a new immunotherapeutic approach based on TLR-5 activation and IFN-γ production capable to control the metastatic growth of B16F10-Nex2 melanoma, being a promising alternative to be associated with chemotherapeutic drugs for an effective anti-tumor responses.
Asunto(s)
Antígenos Bacterianos/inmunología , Vacunas contra el Cáncer/inmunología , Flagelina/inmunología , Glicoproteínas/inmunología , Inmunoterapia/métodos , Neoplasias Pulmonares/terapia , Melanoma Experimental/terapia , Fragmentos de Péptidos/inmunología , Administración Intranasal , Administración a través de la Mucosa , Animales , Antígenos Bacterianos/administración & dosificación , Antígenos Bacterianos/genética , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/genética , Caspasa 1/deficiencia , Caspasa 1/genética , Flagelina/administración & dosificación , Flagelina/genética , Expresión Génica , Glicoproteínas/administración & dosificación , Glicoproteínas/genética , Inyecciones Intravenosas , Interferón gamma/agonistas , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Subunidad p40 de la Interleucina-12/biosíntesis , Subunidad p40 de la Interleucina-12/inmunología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/patología , Masculino , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/inmunología , Metástasis de la Neoplasia , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/genética , Receptor Toll-Like 5/agonistas , Receptor Toll-Like 5/genética , Receptor Toll-Like 5/inmunologíaRESUMEN
BACKGROUND: In previous studies, we observed that thymulin 5cH could modulate BCG (Bacillus Calmette-Guerin) induced chronic inflammation by increasing peritoneal B1 stem cells differentiation into phagocytes and improving phagocytosis efficiency. METHODS: We used the same protocol to study the effects of thymulin 5cH in the experimental murine Leishmaniasis, in order to elucidate some aspects of the parasite-host relation under this homeopathic treatment. Male Balb/c mice were orally treated with thymulin 5cH or vehicle during 60 days, after the subcutaneous inoculation of 2 × 10(6) units of Leishmania (L.) amazonensis into the footpad. Washied inflammatory cell suspension from peritoneal cavity, spleen, local lymph node and infected subcutaneous tissue were harvested after 2 and 60 days from infection to quantify the inflammation cells by flow cytometry and histometry methods. RESULTS: After a transitory increase of peritoneal T reg cells, treated mice presented, chronically, increase in the peritoneal and spleen B1 cells percentage (p = 0.0001) in relation to other cell types; more organized and exuberant inflammation response in the infection site, and decrease in the number of parasites per field inside the primary lesion (p = 0.05). No difference was seen in local lymph node histology. CONCLUSIONS: Thymulin 5cH is able to improve B1 cell activation and Leishmania (L) amazonensis phagocytosis efficiency in mice, similarly to that observed previously in BCG experimental infection.
Asunto(s)
Homeopatía/métodos , Inflamación/tratamiento farmacológico , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/inmunología , Factor Tímico Circulante/administración & dosificación , Factor Tímico Circulante/inmunología , Administración Oral , Animales , Modelos Animales de Enfermedad , Interacciones Huésped-Parásitos/efectos de los fármacos , Inflamación/parasitología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/parasitología , Masculino , Ratones , Ratones Endogámicos BALB C , Bazo/efectos de los fármacos , Bazo/parasitologíaRESUMEN
Industrial growth has increased the exposition to endocrine disruptor compounds (EDC's), which are exogenous agents with agonist or antagonist action of endogenous steroid hormones that may affect the course of parasite infections. We wanted to determine if the exposure to diethylstilbestrol (DES), an estrogen agonist, to both male and female mice affected the immune response and their susceptibility to T. crassiceps cysticercosis. In all infected groups, females showed higher parasite loads than males, and neonatal DES administration did not modify this pattern. In the spleen, noninfected mice showed sex-related differences in the percentage of the CD8+ subpopulation, but DES decreased the percentage of CD3+, CD19+, and CD8+ subpopulations in infected mice. In the mesenteric lymphatic node (MNL), DES showed a dimorphic effect in the percentage of CD19+ cells. Regarding estrogen receptor alpha (ER-α) expression, DES treatment induced a reduction in the expression of this receptor in both noninfected female and male mice in the spleen, which was decreased only in males in CD3+ and CD8+ lymphocytes in MNL cell subpopulations. Our study is the first one to demonstrate that DES neonatal treatment in male and female mice affects the immune cell percentage, without effect on the susceptibility to T. crassiceps cysticercosis.