Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.700
Filtrar
1.
Int J Mol Sci ; 22(9)2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33923272

RESUMO

The mechanisms of lymphedema development are not well understood, but emerging evidence highlights the crucial role the immune system plays in driving its progression. It is well known that lymphatic function deteriorates as lymphedema progresses; however, the connection between this progressive loss of function and the immune-driven changes that characterize the disease has not been well established. In this study, we assess changes in leukocyte populations in lymph nodes within the lymphatic drainage basin of the tissue injury site (draining lymph nodes, dLNs) using a mouse tail model of lymphedema in which a pair of draining collecting vessels are left intact. We additionally quantify lymphatic pump function using established near infrared (NIR) lymphatic imaging methods and lymph-draining nanoparticles (NPs) synthesized and employed by our team for lymphatic tissue drug delivery applications to measure lymphatic transport to and resulting NP accumulation within dLNs associated with swelling following surgery. When applied to assess the effects of the anti-inflammatory drug bestatin, which has been previously shown to be a possible treatment for lymphedema, we find lymph-draining NP accumulation within dLNs and lymphatic function to increase as lymphedema progresses, but no significant effect on leukocyte populations in dLNs or tail swelling. These results suggest that ameliorating this loss of lymphatic function is not sufficient to reverse swelling in this surgically induced disease model that better recapitulates the extent of lymphatic injury seen in human lymphedema. It also suggests that loss of lymphatic function during lymphedema may be driven by immune-mediated mechanisms coordinated in dLNs. Our work indicates that addressing both lymphatic vessel dysfunction and immune cell expansion within dLNs may be required to prevent or reverse lymphedema when partial lymphatic function is sustained.


Assuntos
Modelos Animais de Doenças , Leucina/análogos & derivados , Leucócitos/imunologia , Leucotrieno B4/antagonistas & inibidores , Linfonodos/imunologia , Vasos Linfáticos/imunologia , Linfedema/imunologia , Animais , Feminino , Cinética , Leucina/farmacologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Leucócitos/patologia , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Linfonodos/patologia , Vasos Linfáticos/efeitos dos fármacos , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patologia , Linfedema/tratamento farmacológico , Linfedema/metabolismo , Linfedema/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Proteases/farmacologia
2.
Molecules ; 26(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802855

RESUMO

Inflammatory bowel disease (IBD) is an immune disorder that develops due to chronic inflammation in several cells. It is known that colorectal and T cells are mainly involved in the pathogenesis of IBD. Chrysophanol is an anthraquinone family member that possesses several bioactivities, including anti-diabetic, anti-tumor, and inhibitory effects on T cell activation. However, it is unknown whether chrysophanol suppresses the activity of colorectal cells. In this study, we found that chrysophanol did not induce cytotoxicity in HT-29 colorectal cells. Pre-treatment with chrysophanol inhibited the mRNA levels of pro-inflammatory cytokines in tumor necrosis factor-α (TNF-α)-stimulated HT-29 cells. Western blot analysis revealed that pre-treatment with chrysophanol mitigates p65 translocation and the mitogen-activated protein kinase (MAPK) pathway in activated HT-29 cells. Results from the in vivo experiment confirmed that oral administration of chrysophanol protects mice from dextran sulfate sodium (DSS)-induced IBD. Chrysophanol administration attenuates the expression of pro-inflammatory cytokines in colon tissues of the DSS-induced IBD model. In addition, we found that oral administration of chrysophanol systemically decreased the expression of effector cytokines from mesenteric lymph nodes. Therefore, these data suggest that chrysophanol has a potent modulatory effect on colorectal cells as well as exhibiting a beneficial potential for curing IBD in vivo.


Assuntos
Antraquinonas/administração & dosagem , Antraquinonas/farmacologia , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Administração Oral , Animais , Antraquinonas/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Colo/citologia , Colo/efeitos dos fármacos , Colo/metabolismo , Neoplasias Colorretais/patologia , Citocinas/genética , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Feminino , Células HT29 , Humanos , Doenças Inflamatórias Intestinais/induzido quimicamente , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
3.
Int J Mol Sci ; 22(8)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924467

RESUMO

Kurarinone is a flavanone, extracted from Sophora flavescens Aiton, with multiple biological effects. Here, we determine the therapeutic potential of kurarinone and elucidate the interplay between kurarinone and the autoimmune disease rheumatoid arthritis (RA). Arthritis was recapitulated by induction of bovine collagen II (CII) in DBA/1 mice as a collagen-induced arthritis (CIA) model. After the establishment of the CIA, kurarinone was given orally from day 21 to 42 (100 mg/kg/day) followed by determination of the severity based on a symptom scoring scale and with histopathology. Levels of cytokines, anti-CII antibodies, and the proliferation and lineages of T cells from the draining lymph nodes were measured using ELISA and flow cytometry, respectively. The expressional changes, including STAT1, STAT3, Nrf2, KEAP-1, and heme oxygenase-1 (HO-1) changes in the paw tissues, were evaluated by Western blot assay. Oxidative stress featured with malondiadehyde (MDA) and hydrogen peroxide (H2O2) activities in paw tissues were also evaluated. Results showed that kurarinone treatment reduced arthritis severity of CIA mice, as well as their levels of proinflammatory cytokines, TNF-α, IL-6, IFN-γ, and IL-17A, in the serum and paw tissues. T cell proliferation was also reduced by kurarinone even under the stimulation of CII and anti-CD3 antibody. In addition, kurarinone reduced STAT1 and STAT3 phosphorylation and the proportions of Th1 and Th17 cells in lymph nodes. Moreover, kurarinone suppressed the production of MDA and H2O2. All while promoting enzymatic activities of key antioxidant enzymes, SOD and GSH-Px. In the paw tissues, upregulation of Nrf-2 and HO-1, and downregulation of KEAP-1 were observed. Overall, kurarinone showed an anti-inflammatory effect by inhibiting Th1 and Th17 cell differentiation and an antioxidant effect exerted in part through activating the Nrf-2/KEAP-1 pathway. These beneficial effects in CIA mice contributed to the amelioration of their arthritis, indicating that kurarinone might be an adjunct treatment option for rheumatoid arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Flavonoides/uso terapêutico , Animais , Antioxidantes/metabolismo , Bovinos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Galinhas , Colágeno Tipo II , Citocinas/sangue , Citocinas/metabolismo , Feminino , Flavonoides/farmacologia , Glutationa Peroxidase/metabolismo , Peróxido de Hidrogênio/metabolismo , Mediadores da Inflamação/metabolismo , Articulações/efeitos dos fármacos , Articulações/patologia , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Malondialdeído/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Superóxido Dismutase/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
5.
Carbohydr Polym ; 255: 117370, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33436203

RESUMO

Natural polysaccharides have attracted considerable interests due to diverse biological activities. Succinoglycan is an extracellular polysaccharide produced by most Agrobacterium strains. Here, we confirmed riclin was a typical succinoglycan by NMR and methylation analysis, and investigated the antitumor effects of riclin in sarcoma 180 tumor-bearing mice. The results showed that riclin inhibited the tumor growth significantly as well as cyclophosphamide (CTX). While CTX caused serious damage to spleen structure, riclin increased the spleen index and promoted lymphocytes proliferation in peripheral blood, spleen and lymph nodes. Riclin decreased splenocytes apoptosis as evidenced by alterations of B-cell lymphoma-2 family proteins and Cleaved Caspase-3 protein. Moreover, 1H nuclear magnetic resonance (NMR)-based metabolomics analysis revealed that riclin partially altered the metabolic profiles of splenocytes. In conclusion, riclin is a succinoglycan that performed strong immunogenicity and suppressed sarcoma growth in mice. Succinoglycan riclin could be a potential antitumor agent for functional food and pharmaceutical purpose.


Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica , Fatores Imunológicos/farmacologia , Linfócitos/efeitos dos fármacos , Polissacarídeos Bacterianos/farmacologia , Sarcoma 180/tratamento farmacológico , Agrobacterium/química , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Apoptose/genética , Sequência de Carboidratos , Caspase 3/genética , Caspase 3/imunologia , Proliferação de Células/efeitos dos fármacos , Ciclofosfamida/farmacologia , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfonodos/patologia , Linfócitos/imunologia , Linfócitos/patologia , Masculino , Metaboloma/imunologia , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Polissacarídeos Bacterianos/química , Polissacarídeos Bacterianos/isolamento & purificação , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Sarcoma 180/genética , Sarcoma 180/imunologia , Sarcoma 180/patologia , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Carga Tumoral/efeitos dos fármacos
6.
Proc Natl Acad Sci U S A ; 118(3)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33431676

RESUMO

Pathogen interactions arising during coinfection can exacerbate disease severity, for example when the immune response mounted against one pathogen negatively affects defense of another. It is also possible that host immune responses to a pathogen, shaped by historical evolutionary interactions between host and pathogen, may modify host immune defenses in ways that have repercussions for other pathogens. In this case, negative interactions between two pathogens could emerge even in the absence of concurrent infection. Parasitic worms and tuberculosis (TB) are involved in one of the most geographically extensive of pathogen interactions, and during coinfection worms can exacerbate TB disease outcomes. Here, we show that in a wild mammal natural resistance to worms affects bovine tuberculosis (BTB) severity independently of active worm infection. We found that worm-resistant individuals were more likely to die of BTB than were nonresistant individuals, and their disease progressed more quickly. Anthelmintic treatment moderated, but did not eliminate, the resistance effect, and the effects of resistance and treatment were opposite and additive, with untreated, resistant individuals experiencing the highest mortality. Furthermore, resistance and anthelmintic treatment had nonoverlapping effects on BTB pathology. The effects of resistance manifested in the lungs (the primary site of BTB infection), while the effects of treatment manifested almost entirely in the lymph nodes (the site of disseminated disease), suggesting that resistance and active worm infection affect BTB progression via distinct mechanisms. Our findings reveal that interactions between pathogens can occur as a consequence of processes arising on very different timescales.


Assuntos
Búfalos/imunologia , Resistência à Doença , Hemoncose/microbiologia , Pulmão/imunologia , Linfonodos/imunologia , Tricostrongilose/microbiologia , Tuberculose Bovina/microbiologia , Animais , Antinematódeos/farmacologia , Búfalos/microbiologia , Búfalos/parasitologia , Bovinos , Coinfecção , Progressão da Doença , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/microbiologia , Eosinófilos/parasitologia , Fezes/parasitologia , Feminino , Fenbendazol/farmacologia , Hemoncose/tratamento farmacológico , Hemoncose/mortalidade , Hemoncose/parasitologia , Haemonchus/efeitos dos fármacos , Haemonchus/genética , Haemonchus/patogenicidade , Imunoglobulina A/sangue , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/parasitologia , Linfonodos/efeitos dos fármacos , Linfonodos/microbiologia , Linfonodos/parasitologia , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/microbiologia , Mastócitos/parasitologia , Mycobacterium bovis/crescimento & desenvolvimento , Mycobacterium bovis/patogenicidade , Índice de Gravidade de Doença , Análise de Sobrevida , Tricostrongilose/tratamento farmacológico , Tricostrongilose/mortalidade , Tricostrongilose/parasitologia , Trichostrongylus/efeitos dos fármacos , Trichostrongylus/genética , Trichostrongylus/patogenicidade , Tuberculose Bovina/tratamento farmacológico , Tuberculose Bovina/mortalidade , Tuberculose Bovina/parasitologia
7.
Toxicology ; 451: 152694, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33493553

RESUMO

OBJECTIVE: This study was aimed to explore the possible mechanism of environmental metal cadmium (Cd) inducing apoptosis of pig lymph nodes. METHOD: 10 healthy 6-week-old weaned piglets were randomly divided into two groups (n = 5 pigs/group). The control group was fed with a basic diet, and the test group was fed with a basic diet of 20 mg/kg CdCl2. RESULTS: The Cd deposition in mesenteric lymph nodes (MLN), inguinal lymph nodes (ILN) and submaxillary lymph nodes (SLN) after Cd exposure was 2.37 folds, 1.4 folds and 1.8 folds of the control group, respectively. And the rate of MLN and ILN apoptotic cells in the Cd group was 4.11 folds and 9.18 folds of the control group, respectively. The mRNA levels of SOD1, SOD2, CAT, GPX1 and GSH in the Cd group were reduced. Similarly, the two-phase detoxification enzymes had a significant downward trend. Cd exposure decreased the activities of GSH, GSH-Px, SOD, CAT, and increased H2O2 and MDA levels. The mRNA and protein levels of Drp1 and Mff in the Cd group were higher than the corresponding control group, and the mRNA and protein levels of Mfn1 and Mfn2 were lower than those in the control group. In addition, the mRNA and protein levels of pro-apoptotic genes in the Cd group were lower than those in the control group. Cd can significantly reduce the expression of PI3K, AKT and HIF-1α in the three lymph nodes. In summary, Cd induces oxidative stress and regulates the PI3K/AKT/HIF-1α signal transduction pathway to cause mitochondrial dynamics disorder, which leads to the apoptosis of pig lymph nodes, suggesting that Cd-induced mitochondrial pathway apoptosis is related to Cd pig lymph nodes play an important role in the toxicity mechanism.


Assuntos
Cádmio/toxicidade , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Suínos
8.
Int Immunopharmacol ; 91: 107278, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33341737

RESUMO

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.


Assuntos
Anti-Inflamatórios/farmacologia , Diferenciação Celular/efeitos dos fármacos , Encefalomielite Autoimune Experimental/prevenção & controle , Ácido Mevalônico/metabolismo , Quinolinas/farmacologia , Medula Espinal/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Mediadores da Inflamação/metabolismo , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfonodos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos , Medula Espinal/imunologia , Medula Espinal/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th17/metabolismo
9.
Methods Mol Biol ; 2223: 37-47, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33226585

RESUMO

Wheat allergy is a pathological event involving immunocompetent cells against ingested wheat allergen and is clearly associated with transdermal sensitization. However, the molecular mechanisms involved in the disease etiology are not completely understood. A complex cellular and tissue network linking to food allergy makes it difficult to understand the molecular mechanism of allergenicity. Animal models are valuable tools to deduce basic principles of human disease without invasive intervention trials. A mouse model of wheat allergy has provided insights into effects of skin exposure to wheat protein; it is a plausible route of human sensitization for wheat anaphylaxis. Further investigation of this model will capture the essential occurrence and flow of events, bringing useful clues to develop effective treatment and control strategies against wheat allergy. Here, we describe a method for analyzing the expression of cell surface molecules in single cells isolated from lymphoid tissue with flow cytometry. Sensitization by wheat extracts significantly increases antigen-specific T cells in the spleen. Collecting information regarding the contribution of immune cells to allergic sensitization in the development of wheat allergy would be useful in preventing and treating food allergies.


Assuntos
Modelos Animais de Doenças , Imunofenotipagem/métodos , Linfócitos/efeitos dos fármacos , Extratos Vegetais/imunologia , Triticum/imunologia , Hipersensibilidade a Trigo/imunologia , Administração Cutânea , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Biomarcadores/metabolismo , Feminino , Farinha/análise , Citometria de Fluxo , Expressão Gênica , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Interferon gama/genética , Interferon gama/imunologia , Linfonodos/citologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfócitos/citologia , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/administração & dosagem , Análise de Célula Única , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Adesivo Transdérmico , Triticum/química , Hipersensibilidade a Trigo/sangue , Hipersensibilidade a Trigo/genética , Hipersensibilidade a Trigo/patologia
10.
Methods Mol Biol ; 2223: 49-65, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33226586

RESUMO

Egg allergy is one of the most common food allergies in children, being the most important allergenic proteins found in the egg white (EW). Allergy to EW shows a complex phenotype that involves a multifaceted reaction that can only be assessed in vivo. Although other routes of sensitization have been described, oral exposure to food antigens is one of the most suitable in humans. In mice, oral administration of allergenic proteins results in the development of tolerance, and the use of adjuvants, such as cholera toxin (CT), is required to promote Th2-biased immune responses over tolerogenic responses. In this regard, among the mouse strains that readily display Th2 responses, Balb/c has been widely used. Here, we describe a frequently used protocol of oral EW sensitization by using CT as an adjuvant and we explain in detail the methods that we have developed to analyze the sensitizing and eliciting capacity of EW proteins including evaluation of signs, measurement of serum levels of specific immunoglobulins, mast cell degranulation, cytokine secretion profile of allergen-reactive T cells, phenotyping of mesenteric lymph node- and spleen-derived dendritic and T cells by flow cytometry, and quantification of intestinal gene expression.


Assuntos
Células Dendríticas/efeitos dos fármacos , Modelos Animais de Doenças , Hipersensibilidade a Ovo/imunologia , Clara de Ovo/química , Imunofenotipagem/métodos , Células Th2/efeitos dos fármacos , Adjuvantes Imunológicos/administração & dosagem , Administração Oral , Animais , Biomarcadores/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Galinhas , Toxina da Cólera/administração & dosagem , Células Dendríticas/citologia , Células Dendríticas/imunologia , Hipersensibilidade a Ovo/sangue , Hipersensibilidade a Ovo/genética , Hipersensibilidade a Ovo/patologia , Feminino , Citometria de Fluxo , Expressão Gênica , Humanos , Imunoglobulinas/sangue , Imunoglobulinas/classificação , Imunoglobulinas/imunologia , Interleucinas/genética , Interleucinas/imunologia , Linfonodos/citologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Células Th2/citologia , Células Th2/imunologia
11.
Nanotoxicology ; 14(8): 1096-1117, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32909489

RESUMO

Gold nanoparticles (AuNP) are largely biocompatible; however, many studies have demonstrated their potential to modulate various immune cell functions. The potential allergenicity of AuNP remains unclear despite the recognition of gold as a common contact allergen. In these studies, AuNP (29 nm) dermal sensitization potential was assessed via Local Lymph Node Assay (LLNA). Soluble gold (III) chloride (AuCl3) caused lymph node (LN) expansion (SI 10.9), whereas bulk particles (Au, 942 nm) and AuNP did not. Next, the pulmonary immune effects of AuNP (10, 30, 90 µg) were assessed 1, 4, and 8 days post-aspiration. All markers of lung injury and inflammation remained unaltered, but a dose-responsive increase in LN size was observed. Finally, mice were dermally-sensitized to AuCl3 then aspirated once, twice, or three times with Au or AuNP in doses normalized for mass or surface area (SA) to assess the impact of existing contact sensitivity to gold on lung immune responses. Sensitized animals exhibited enhanced responsivity to the metal, wherein subsequent immune alterations were largely conserved with respect to dose SA. The greatest increase in bronchoalveolar lavage (BAL) lymphocyte number was observed in the high dose group - simultaneous to preferential expansion of BAL/LN CD8+ T-cells. Comparatively, the lower SA-based doses of Au/AuNP caused more modest elevations in BAL lymphocyte influx (predominantly CD4+ phenotype), exposure-dependent increases in serum IgE, and selective expansion/activation of LN CD4+ T-cells and B-cells. Overall, these findings suggest that AuNP are unlikely to cause sensitization; however, established contact sensitivity to gold may increase immune responsivity following pulmonary AuNP exposure.


Assuntos
Alérgenos/toxicidade , Compostos de Ouro/toxicidade , Ouro/toxicidade , Pulmão/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Pele/efeitos dos fármacos , Animais , Proteínas Sanguíneas/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Ensaio Local de Linfonodo , Pulmão/imunologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Pele/imunologia , Propriedades de Superfície
12.
Nat Commun ; 11(1): 3858, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737343

RESUMO

Checkpoint blockade therapy has provided noteworthy benefits in multiple cancers in recent years; however, its clinical benefits remain confined to 10-40% of patients with extremely high costs. Here, we design an ultrafast, low-temperature, and universal self-assembly route to integrate immunology-associated large molecules into metal-organic-framework (MOF)-gated mesoporous silica (MS) as cancer vaccines. Core MS nanoparticles, acting as an intrinsic immunopotentiator, provide the niche, void, and space to accommodate antigens, soluble immunopotentiators, and so on, whereas the MOF gatekeeper protects the interiors from robust and off-target release. A combination of MOF-gated MS cancer vaccines with systemic programmed cell death 1 (PD-1) blockade therapy generates synergistic effects that potentiate antitumour immunity and reduce the effective dose of an anti-PD-1 antibody to as low as 1/10 of that for PD-1 blockade monotherapy in E.G7-OVA tumour-bearing mice, with eliciting the robust adaptive OVA-specific CD8+ T-cell responses, reversing the immunosuppressive pathway and inducing durable tumour suppression.


Assuntos
Anticorpos Neutralizantes/farmacologia , Vacinas Anticâncer/farmacologia , Linfoma/terapia , Estruturas Metalorgânicas/farmacologia , Nanopartículas/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/química , Citotoxicidade Imunológica , Composição de Medicamentos , Feminino , Humanos , Imunidade Inata/efeitos dos fármacos , Imunoterapia/métodos , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfoma/imunologia , Linfoma/mortalidade , Linfoma/patologia , Estruturas Metalorgânicas/síntese química , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Receptor de Morte Celular Programada 1/imunologia , Dióxido de Silício/química , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Nutr ; 150(8): 2120-2130, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32510141

RESUMO

BACKGROUND: Folate is essential for DNA synthesis, DNA repair, cell proliferation, development, and morphogenesis. Folic acid (FA) is a nutritional supplement used to fortify human diets. OBJECTIVES: We investigated the effects of dietary FA on early mammary gland (MG) development and hyperplasia. METHODS: Study 1: nulliparous female FVB wild-type (WT) mice were fed control (Con; 2 mg FA/kg), deficient (Def; 0 mg FA/kg), excess (Ex; 5 mg FA/kg), or super excess (S-Ex; 20 mg FA/kg) diets for 8 wk before mating to WT or heterozygous FVB/N-Tg[mouse mammary tumor virus long terminal repeat (MMTV)-polyomavirus middle T antigen (PyVT)]634Mul/J (MMTV-PyMT+/-) transgenic males. Dams were fed these diets until they weaned WT or MMTV-PyMT+/- pups, which were fed the dam's diet from postnatal day (PND) 21 to 42. Tissues were collected from female progeny at PNDs 1, 21, and 42. Study 2: Con or Def diets were fed to WT intact females and males from PND 21 to 56, or to ovariectomized females from PND 21 to 77; tissues were collected at PND 56 or 77. Growth of all offspring, development of MGs, MG hyperplasia, supramammary lymph nodes, thymus and spleen, cell proliferation, and expression of MG growth factors were measured. RESULTS: Study 1: Ex or S-Ex did not affect postnatal MG development or hyperplasia. The rate of isometric MG growth (PND 1-21) was reduced by 69% in Def female progeny (P < 0.0001). Similarly, hyperplastic growth in MGs of Def MMTV-PyMT+/- offspring was 18% of Con (P < 0.05). The Def diet reduced supramammary lymph node size by 20% (P < 0.0001) and increased MG insulin-like growth factor 2 mRNA by 200% (P < 0.05) and protein by 130%-150% (P < 0.05). Study 2: the Def diet did not affect MG growth, but it did reduce supramammary lymph node size (P < 0.05), spleen weight (P < 0.001), and thymic medulla area (P < 0.05). CONCLUSIONS: In utero and postnatal folate deficiency reduced the isometric development of the MGs and early MG hyperplasia. Postnatal folate deficiency reduced the development of lymphatic tissues.


Assuntos
Deficiência de Ácido Fólico , Ácido Fólico/administração & dosagem , Linfonodos/efeitos dos fármacos , Linfonodos/crescimento & desenvolvimento , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/crescimento & desenvolvimento , Animais , Dieta , Feminino , Masculino , Camundongos , Ovariectomia
14.
Rev Mal Respir ; 37(5): 399-411, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32386802

RESUMO

A paradoxical reaction is the worsening of prior existing, or the appearance of, new tuberculous lesions, following the initiation of treatment with anti-tuberculous drugs, after the exclusion of poor compliance, malabsorption, drug interaction or multiresistant mycobacteria. Well known and well managed in the context of HIV coinfection, it is not well known outside this context. An increasing number of publications have described this syndrome. This review aims to describe the pathogenic, epidemiological, clinical, prognostic and therapeutic elements of non-HIV-associated paradoxical reactions. It involves a reversal of the Mycobacterium tuberculosis-induced immunodepression along with a heightened detrimental pro-inflammatory profile caused by efficient drug treatment. Extra-thoracic locations, especially lymph nodes and neurological, malnutrition and initial lymphopenia are the principal risk factors. The median delay is 40±20 days after the onset of treatment. Corticosteroids are the mainstay of the management. Anti-TNF-α drugs show good results in corticosteroid refractory cases. The prognosis is good overall except in neurological forms. The place of preventive methods remains to be established.


Assuntos
Antituberculosos/uso terapêutico , Progressão da Doença , Tuberculose/tratamento farmacológico , Tuberculose/patologia , Antituberculosos/efeitos adversos , Humanos , Linfonodos/efeitos dos fármacos , Linfonodos/microbiologia , Linfonodos/patologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/fisiologia , Fatores de Risco , Tuberculose/epidemiologia
15.
Toxicology ; 441: 152474, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32380031

RESUMO

2-Methoxy-4-nitroaniline (MNA), an intermediate in the synthesis of azo dyes used in textiles and paints, is structurally similar to carcinogenic anilines. Human exposure occurs primarily in the occupational setting through handling of dye dust, and through use and disposal of MNA-containing products. MNA has been reported to induce contact hypersensitivity in a human, myocardial necrosis in rats, and bacterial mutagenicity. This study assessed the subacute toxicity, genotoxicity, contact hypersensitivity, and reproductive toxicity of MNA in rodents in an effort to more fully characterize its toxicological profile. B6C3F1/N mice were exposed to 0, 650, 1250, 2500, 5000, or 10,000 ppm MNA by dosed feed for 14-days to evaluate subacute toxicity and histopathological endpoints. In female mice, decreased body weight (13.5 %) and absolute kidney weight (14.8 %), compared to control, were observed at 10,000 ppm MNA; increased relative liver weight (10-12 %), compared to control, occurred at 5,000-10,000 ppm MNA. In male mice, absolute (15 %) and relative liver weights (9-13 %) were increased at 2,500-5,000 ppm and 1250-10,000 ppm MNA, compared to control, respectively. In both sexes of mice, minimal elevations of hemosiderin pigmentation (a breakdown product of erythrocytes), relative to control, were observed in the liver (10,000 ppm); minimal to moderate elevations of hemosiderin pigmentation (5,000-10,000 ppm) and minimal increases in hematopoietic cell proliferation occurred in the spleen (≥ 1250 ppm). In a reproductive toxicity study, timed-mated female Harlan Sprague Dawley rats were exposed to 0-10,000 ppm MNA by dosed feed from gestation day 6 through postnatal day (PND) 21. Decreases in mean litter weights were observed at 5000 ppm MNA, compared to control, beginning at PND1. To evaluate potential contact hypersensitivity, MNA (2.5-50 %, in dimethylformamide) was applied to the dorsa of both ears of female Balb/c mice once daily for three days. The increase observed in lymph node cell proliferation (10-50 % increase in thymidine uptake compared to control) did not reproducibly achieve the Sensitization Index (SI) 3 level, and there was no ear swelling evident following sensitization with 10-50 % MNA and challenge with 25 % MNA in the mouse ear swelling test. In bacterial mutagenicity assays, MNA (250-1000 µg/plate) induced significant increases, compared to control, in mutant colonies with and without metabolic activation enzymes in Salmonella typhimurium strains TA100 and TA98. These data indicate that MNA is genotoxic, and may induce erythrocyte damage and reactive phagocytosis by macrophages in the liver and spleen.


Assuntos
Compostos de Anilina/toxicidade , Dermatite de Contato/etiologia , Nitrocompostos/toxicidade , Reprodução/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Ensaio Cometa , Relação Dose-Resposta a Droga , Feminino , Fígado/efeitos dos fármacos , Linfonodos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Testes para Micronúcleos , Testes de Mutagenicidade , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
16.
Dis Colon Rectum ; 63(6): 758-768, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32384406

RESUMO

BACKGROUND: Metformin may reduce cancer risk and mortality and improve radiotherapy responses in several malignancies. OBJECTIVE: This study aimed to compare tumor responses and prognoses of metformin and nonmetformin groups of diabetic patients receiving neoadjuvant concurrent chemoradiotherapy for rectal cancer. DESIGN: This is a retrospective study. SETTING: This study was conducted at a single institution in the Republic of Korea. PATIENTS: Between January 2000 and November 2017, 104 patients with rectal cancer who were taking diabetes medication and treated with neoadjuvant concurrent chemoradiotherapy followed by radical surgery were reviewed. Patients were divided into those taking (n = 62) and not taking metformin (n = 42). Tumor responses, survival, and other outcomes were analyzed. MAIN OUTCOME MEASURES: Tumor response, rectal cancer-specific survival, and disease-free survival rates were measured. RESULTS: Tumor regression grade (p = 0.002), pathological complete response (p = 0.037), and N downstaging (p < 0.001) after neoadjuvant concurrent chemoradiotherapy were significantly higher in the metformin group than in the nonmetformin group. In analysis of cancer-specific mortality, metformin use, differentiation (well, moderate vs poor), pathological Union for International Cancer Control stage (3 vs 1-2), ypN stage (1-2 vs 0), and N downstaging (HR, 0.256 (95% CI, 0.082-0.794), p = 0.018; HR, 0.147 (95% CI, 0.031-0.697), p = 0.016; HR, 3.693 (95% CI, 1.283-10.635), p = 0.015; HR, 3.181 (95% CI, 1.155-8.759), p = 0.025, and HR, 0.175 (95% CI, 0.040-0.769), p = 0.021) were significant factors related to mortality in diabetic patients with rectal cancer. In addition, in the multivariate analysis of cancer recurrence, the interaction between metformin use and lymph node downstaging was a significant predictive factor (HR, 0.222 (95% CI, 0.077-0.639); p = 0.005). LIMITATIONS: This was a small retrospective study conducted at a single institution. CONCLUSIONS: Metformin use was associated with better tumor responses and cancer-specific survival, as well as a lower risk of cancer recurrence, in patients with diabetes mellitus who had lymph node downstaging after neoadjuvant concurrent chemoradiotherapy in rectal cancer. See Video Abstract at http://links.lww.com/DCR/B185. BENEFICIO EN SUPERVIVENCIA CON METFORMINA A TRAVÉS DE UNA MEJOR RESPUESTA TUMORAL CON QUIMIORRADIOTERAPIA CONCURRENTE NEOADYUVANTE EN CÁNCER RECTAL: La metformina puede reducir el riesgo de cáncer y la mortalidad y mejorar las respuestas a la radioterapia en varios tumores malignos.Comparar las respuestas tumorales y los pronósticos de los grupos con metformina y sin metformina de pacientes diabéticos que reciben quimiorradioterapia concurrente neoadyuvante para cáncer de recto.Estudio retrospectivo.Institución única en la República de Corea.Se revisaron 104 pacientes entre enero de 2000 y noviembre de 2017, con cáncer rectal que tomaban medicamentos para diabetes y que fueron tratados con quimiorradioterapia concurrente neoadyuvante seguida de cirugía radical. Los pacientes se dividieron en aquellos que tomaban (n = 62) y los que no tomaban metformina (n = 42). Se analizaron las respuestas tumorales, la supervivencia y otros resultados.Se midieron las tasas de la respuesta tumoral, la supervivencia específica de cáncer rectal y de la supervivencia libre de enfermedad.El grado de regresión tumoral (p = 0.002), la remisión patológica completa (p = 0.037) y la reducción de la etapa N (p < 0.001) después de la quimiorradioterapia concurrente neoadyuvante fueron significativamente mayores en el grupo de metformina que en el grupo sin metformina. En el análisis de la mortalidad específica por cáncer, el uso de metformina, la diferenciación (bien, moderada vs pobre), el estadio patológico UICC (3 vs 1-2), el estadio ypN (1-2 vs 0) y la disminución de la etapa N (hazard ratios [intervalos de confianza 95%]: 0.256 [0.082-0.794], p = 0.018; 0.147 [0.031-0.697], p = 0.016; 3.693 [1.283-10.635], p = 0.015; 3.181 [1.155-8.759], p = 0.025 y 0.175 [0.040-0.769], p = 0.021, respectivamente) fueron factores significativos relacionados con la mortalidad en pacientes diabéticos con cáncer rectal. Adicionalmente, en el análisis multivariado de la recurrencia del cáncer, la interacción entre el uso de metformina y la disminución de la etapa ganglionar (N) fue un factor predictivo significativo (hazard ratios [intervalos de confianza del 95%]: 0.222 [0.077-0.639]; p = 0.005).Este fue un estudio retrospectivo pequeño realizado en un solo instituto.El uso de metformina se asoció con mejores respuestas tumorales y supervivencia específica de cáncer, así como un menor riesgo de recurrencia del cáncer, en pacientes con disminución de la etapa ganglionar (N) después de quimiorradioterapia concurrente neoadyuvante en pacientes con cáncer rectal y diabetes. Consulte Video Resumen en http://links.lww.com/DCR/B185. (Traducción-Dr. Jorge Silva Velazco).


Assuntos
Quimiorradioterapia/efeitos adversos , Terapia Neoadjuvante/métodos , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/mortalidade , Adulto , Idoso , Estudos de Casos e Controles , Diabetes Mellitus/tratamento farmacológico , Intervalo Livre de Doença , Feminino , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Masculino , Metformina/farmacologia , Metformina/uso terapêutico , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Estadiamento de Neoplasias/estatística & dados numéricos , Prognóstico , Neoplasias Retais/radioterapia , Neoplasias Retais/cirurgia , República da Coreia/epidemiologia , Estudos Retrospectivos
17.
J Surg Oncol ; 122(3): 373-381, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32436217

RESUMO

BACKGROUND AND OBJECTIVES: This study mainly explored the factors that influence non-sentinel lymph node (NSLN) metastasis in patients with breast cancer (BC) whose axillary lymph nodal status changed from clinically node positive (cN+) to clinically node negative (cN0) after neoadjuvant chemotherapy (NAC). METHODS: We retrospectively analyzed the clinicopathological factors affecting NSLN metastasis in a total of 179 patients with cN+ BC downstaged to cN0 (120 in the training set and 59 in the validation set) who underwent both sentinel lymph node (SLN) biopsy and axillary lymph node dissection following NAC. RESULTS: Among 179 patients enrolled, the overall NSLN metastatic rate was 24.0% (95% confidence interval [CI]: 17.7%-30.3%). In multivariate logistic regression analysis, the number of positive SLNs achieving a pathological complete remission of the breast and clinical node staging was independent predictors of NSLN metastasis. A nomogram was established based on these factors and displayed a good discriminatory capability, with an area under the curve of 0.919 (95% CI: 0.865-0.973) for the training set and 0.900 (95% CI: 0.812-0.988) for the validation set and its clinical utility was confirmed by the decision curve analysis. CONCLUSIONS: The nomogram established showed the ability to predict NSLN metastases in patients with initial cN+ BC that downstaged to cN0 after NAC.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linfonodos/patologia , Nomogramas , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Feminino , Humanos , Excisão de Linfonodo , Linfonodos/efeitos dos fármacos , Metástase Linfática , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Estudos Retrospectivos , Linfonodo Sentinela/patologia , Linfonodo Sentinela/cirurgia
18.
Breast Cancer Res ; 22(1): 54, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32460816

RESUMO

INTRODUCTION: Neoadjuvant endocrine therapy (NET) has demonstrated efficacy in post-menopausal patients with hormone-responsive breast cancer. This trial was designed to compare the efficacy of neoadjuvant chemotherapy (NCT) with NET in pre-menopausal breast cancer. PATIENTS AND METHODS: In this prospective, randomised, phase III study, oestrogen receptor (ER)-positive, HER2-negative, and lymph node-positive pre-menopausal breast cancer patients were recruited from 7 hospitals in South Korea. Enrolled patients were randomly assigned (1:1) to receive 24 weeks of either NCT or NET with goserelin and tamoxifen. The primary purpose was to evaluate the non-inferiority of NET compared to NCT using clinical response, assessed by MRI. Besides, pathological complete response rate (pCR), changes in Ki-67 expression, breast conservation surgery (BCS) rate, and quality of life were included as secondary endpoints. RESULTS: A total of 187 patients were assigned to receive NCT (n = 95) or NET (n = 92), and 87 patients in each group completed treatments. More NCT patients had complete response or partial response than NET patients using MRI (NCT 83.7% vs. NET 52.9%, 95% CI 17.6-44.0, p < 0.001) and callipers (NCT 83.9% vs. NET 71.3%, 95% CI 0.4-24.9, p = 0.046). Three NCT patients (3.4%) and one NET patient (1.2%) showed pCR (p < 0.005). No difference existed in the conversion rate of BCS (13.8% for NCT vs. 11.5% for NET, p = 0.531) and Ki-67 change (p = 0.114) between the two groups. Nineteen NCT patients had treatment-related grade 3 or worse events compared with none in the NET group. CONCLUSIONS: Better clinical responses were observed in pre-menopausal patients after 24 weeks of NCT compared to those observed after NET. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01622361. Registration June 19, 2012.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linfonodos/patologia , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Adulto , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Terapia Combinada , Ciclofosfamida/administração & dosagem , Docetaxel/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Gosserrelina/administração & dosagem , Humanos , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Pessoa de Meia-Idade , Pré-Menopausa , Prognóstico , Estudos Prospectivos , Receptores de Progesterona/metabolismo , Trastuzumab/administração & dosagem
19.
Cancer Control ; 27(1): 1073274820915947, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32268796

RESUMO

Lymphatic metastasis is a major determinant of the outcome of resected pancreatic cancer. Gemcitabine-based adjuvant chemotherapy can improve the outcome of resected pancreatic cancer. However, the efficacy of gemcitabine against pancreatic cancer stratified by nodal involvement is unclear. In this study, patients who had undergone curative resection of pancreatic adenocarcinoma (612 cases) were included. The efficacy of adjuvant gemcitabine-based regimen, stratified by nodal status (negative, positive) or N substage (N0, no nodal involvement; N1, 1-3-node involvement; N2, ≥4-node involvement), was examined. Both the node-negative (hazard ratio [HR] = 0.62, 95% confidence interval [CI], 0.44-0.87, P = .006) and node-positive subgroups (HR = 0.45, 95% CI, 0.33-0.62, P < .001) benefited from gemcitabine-based adjuvant chemotherapy. Patients with N0 (ie, the node-negative subgroup) or N1 (HR = 0.36, 95% CI, 0.25-0.52, P < .001) disease benefited from gemcitabine-based chemotherapy. However, patients with N2 tumors (HR = 0.95, 95% CI, 0.50-1.78, P = .867) had poor response to gemcitabine-based treatment. Therefore, we postulate that resected pancreatic cancer with N2 node involvement is refractory to gemcitabine-based adjuvant chemotherapy. A more intensive adjuvant regimen may be required for N2 subgroup patients.


Assuntos
Quimioterapia Adjuvante/métodos , Desoxicitidina/análogos & derivados , Linfonodos/efeitos dos fármacos , Metástase Linfática/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade
20.
J Acquir Immune Defic Syndr ; 83(5): 530-537, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32168200

RESUMO

BACKGROUND: Most HIV-infected cells during antiretroviral therapy (ART) persist in lymphoid tissues. Studies disagree on whether suboptimal tissue ART concentrations contribute to ongoing HIV replication during viral suppression. METHODS: We performed a cross-sectional study in virally-suppressed HIV+ participants measuring lymphoid tissue ART [darunavir (DRV), atazanavir (ATV), and raltegravir (RAL)] concentrations by LC-MS/MS assay. Tissue and plasma ART concentrations were used to estimate TPRs and drug-specific tissue:inhibitory concentration ratios (TICs). HIV DNA and sequentially produced HIV RNA transcripts were quantified from rectal biopsies using droplet digital PCR (ddPCR) assays. RESULTS: Tissue samples were collected in duplicate from 19 participants: 38 rectal, 8 ileal (4 RAL, 2 DRV, 2 ATV), and 6 lymph node (4 RAL, 2 DRV) samples. Overall, median TICs were higher for RAL than DRV or ATV (both P = 0.006). Median TICs were lower in lymph nodes vs. ileum (0.49 vs. 143, P = 0.028) or rectum (33, P = 0.019), and all ART levels were below target concentrations. Higher rectal TICs were associated with lower HIV RNA transcripts (read-through, long LTR, and Nef, P all < 0.026) and a lower long LTR RNA/long LTR DNA ratio (P = 0.021). CONCLUSIONS: We observed higher tissue ART concentrations in ileum and rectum compared with lymph nodes. We observed higher HIV transcription in participants with lower rectal ART concentrations. These findings add to the limited data supporting the idea that viral transcription may be influenced by ART concentrations in lymphoid tissues. Further exploration of tissue pharmacokinetics is needed in future HIV eradication strategies.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Trato Gastrointestinal/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Linfonodos/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Adulto , Terapia Antirretroviral de Alta Atividade , Sulfato de Atazanavir/uso terapêutico , Biópsia , Linfócitos T CD4-Positivos , Estudos Transversais , Darunavir/uso terapêutico , Feminino , Trato Gastrointestinal/patologia , Infecções por HIV/virologia , HIV-1/genética , Humanos , Íleo/efeitos dos fármacos , Íleo/patologia , Linfonodos/patologia , Masculino , Raltegravir Potássico/uso terapêutico , São Francisco , Replicação Viral/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...