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1.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673372

RESUMO

One of the most severe effects of coronavirus disease 2019 (COVID-19) is lung disorders such as acute respiratory distress syndrome. In the absence of effective treatments, it is necessary to search for new therapies and therapeutic targets. Platelets play a fundamental role in respiratory disorders resulting from viral infections, being the first line of defense against viruses and essential in maintaining lung function. The direct application of platelet lysate (PL) obtained from the platelet-rich plasma of healthy donors could help in the improvement of the patient due its anti-inflammatory, immunomodulatory, antifibrotic, and repairing effects. This work evaluates PL nebulization by analyzing its levels of growth factors and its biological activity on lung fibroblast cell cultures, besides describing a scientific basis for its use in this kind of pathology. The data of the work suggest that the molecular levels and biological activity of the PL are maintained after nebulization. Airway administration would allow acting directly on the lung tissue modulating inflammation and stimulating reparative processes on key structures such as the alveolocapillary barrier, improving the disease and sequels. The protocol developed in this work is a first step for the study of nebulized PL both in animal experimentation and in clinical trials.


Assuntos
Anti-Inflamatórios/farmacologia , Fatores Imunológicos/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Plasma Rico em Plaquetas , Adulto , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/imunologia , Plaquetas/imunologia , Linhagem Celular , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Masculino , Nebulizadores e Vaporizadores , Plasma Rico em Plaquetas/imunologia , Resultado do Tratamento
3.
Methods Mol Biol ; 2225: 227-239, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33108666

RESUMO

Severe inflammatory disease initiated by neurotrauma and stroke is of primary concern in these intractable pathologies as noted in recent studies and understanding of the pathogenesis of spinal cord injury (SCI) in the rat model. Successful anti-inflammatory treatments should result in neuroprotection and limit the loss of neurological function to injury caused by the initial damage. Continuous subdural infusion offers direct access to the cavity of injury (COI) that forms after balloon crush SCI deep in the spinal cord. Some anti-inflammatory compounds are not likely capable of crossing the blood-spinal cord barrier. Subdural infusion of myxoma virus-derived Serp-1, an anti-thrombotic/anti-thrombolytic, and also of M-T7, a chemokine inhibitor, improved the locomotor scores and pain sensation scores as well as reduced the numbers of macrophages in the COI by 50 and 80%, respectively, while intraperitoneal infusion of either protein had little effect. Injection of a chitosan hydrogel loaded with Serp-1 into the dorsal spinal column crush also resulted in improved neurological deficits and in reduction of the size of the crush lesion 4 weeks after injury. While neurological scores in a simplified hind-end (HE) locomotor test together with a toe-pinch withdrawal test demonstrated improvement in all balloon crush injury and dorsal spinal crush injury rats, a severe inflammation is induced by the injury indicating additional damage to the spinal cord. Thus neurological function testing can be contradictory, rather than corresponding, to the pathogenesis of SCI. The count of macrophages in the COI offers a precise, reliable method of measuring the effectiveness of a neuroprotective treatment of SCI in preclinical studies.


Assuntos
Anti-Inflamatórios/farmacologia , Fatores Imunológicos/farmacologia , Myxoma virus/química , Fármacos Neuroprotetores/farmacologia , Traumatismos da Medula Espinal/tratamento farmacológico , Proteínas Virais/farmacologia , Animais , Anti-Inflamatórios/imunologia , Quitosana/química , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Hidrogéis/química , Fatores Imunológicos/imunologia , Injeções Epidurais , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/imunologia , Ratos , Ratos Long-Evans , Receptores de Interferon/imunologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/patologia , Proteínas Virais/imunologia
4.
Methods Mol Biol ; 2225: 257-273, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33108668

RESUMO

Solid tissue transplant is a growing medical need that is further complicated by a limited donor organ supply. Acute and chronic rejection occurs in nearly all transplants and reduces long-term graft survival, thus increasing the need for repeat transplantation. Viruses have evolved highly adapted responses designed to evade the host's immune defenses. Immunomodulatory proteins derived from viruses represent a novel class of potential therapeutics that are under investigation as biologics to attenuate immune-mediated rejection and damage. These immune-modulating proteins have the potential to reduce the need for traditional posttransplant immune suppressants and improve graft survival. The myxoma virus-derived protein M-T7 is a promising biologic that targets chemokine and glycosaminoglycan pathways central to kidney transplant rejection. Orthotopic transplantations in mice are prohibitively difficult and costly and require a highly trained microsurgeon to successfully perform the procedure. Here we describe a kidney-to-kidney subcapsular transplant model as a practical and simple method for studying transplant rejection, a model that requires fewer mice. One kidney can be used as a donor for transplants into six or more recipient mice. Using this model there is lower morbidity, pain, and mortality for the mice. Subcapsular kidney transplantation provides a first step approach to testing virus-derived proteins as new potential immune-modulating therapeutics to reduce transplant rejection and inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Fatores Imunológicos/farmacologia , Transplante de Rim/métodos , Myxoma virus/química , Proteínas Virais/farmacologia , Animais , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/metabolismo , Biomarcadores/análise , Quimiocinas/biossíntese , Complemento C4b/genética , Complemento C4b/imunologia , Feminino , Expressão Gênica , Rejeição de Enxerto/genética , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Fatores Imunológicos/biossíntese , Fatores Imunológicos/imunologia , Rim/imunologia , Rim/cirurgia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Receptores de Interferon/biossíntese , Receptores de Interferon/imunologia , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Transplante Homólogo , Proteínas Virais/biossíntese , Proteínas Virais/imunologia
5.
Methods Mol Biol ; 2225: 275-292, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33108669

RESUMO

Ischemia-reperfusion injury (IRI) drives early and long-term damage to organs as well as compounding damage from acute transplant rejection and surgical trauma. IRI initiates an aggressive and prolonged inflammation leading to tissue injury, organ failure, and death. However, there are few effective therapeutic interventions for IRI. The destructive inflammatory cell activity in IRI is part of an aberrant innate immune response that triggers multiple pathways. Hence, immune-modulating treatments to control pathways triggered by IRI hold great therapeutic potential. Viruses, especially large DNA viruses, have evolved highly effective immune-modulating proteins for the purpose of immune evasion and to protect the virus from the host immune defenses. A number of these immune-modulating proteins have proven therapeutically effective in preclinical models, many with function targeting pathways known to be involved in IRI. The use of virus-derived immune-modulating proteins thus represents a promising source for new treatments to target ischemia-reperfusion injury. Laboratory small animal models of IRI are well established and are able to reproduce many aspects of ischemia-reperfusion injury seen in humans. This chapter will discuss the methods used to perform the IRI procedure in mice, as well as clinically relevant diagnostic tests to evaluate liver injury and approaches for assessing histological damage while testing novel immune modulating protein treatments.


Assuntos
Anti-Inflamatórios/farmacologia , Hepatite/prevenção & controle , Fatores Imunológicos/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Proteínas Virais/farmacologia , Isquemia Quente/métodos , Alanina Transaminase/genética , Alanina Transaminase/metabolismo , Animais , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/metabolismo , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Biomarcadores/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Hepatite/genética , Hepatite/imunologia , Hepatite/patologia , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/biossíntese , Fatores Imunológicos/imunologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/imunologia , Fígado/patologia , Camundongos , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Coloração e Rotulagem/métodos , Proteínas Virais/biossíntese , Proteínas Virais/imunologia
6.
Mol Immunol ; 126: 40-45, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32750537

RESUMO

Oxidative stress-related injury is a negative state caused by the imbalance between oxidation and antioxidant effects in the internal environment of the body. Oxidative stress has been confirmed to be an important factor in aging and a variety of diseases and the inhibition of inappropriate oxidative stress responses are important for maintaining normal physiological functions. Recently, considerable attention has been focused on specialized pro-resolving mediators(SPMs). SPMs are endogenous mediators derived from polyunsaturated fatty acids, which have multiple protective effects such as anti-inflammation, pro-resolution, and promoting tissue damage repair, etc. Moreover, the role of SPMs on oxidative stress has been extensively researched and provides a possible treatment method. In the current study, we review the positive role of SPMs in oxidative stress-related disease and outline the possible involved mechanism, thus providing the theoretical support for a better understanding of the roles of SPMs in oxidative stress and the theoretical basis for finding targets for the oxidative stress-related diseases.


Assuntos
Anti-Inflamatórios/metabolismo , Ácidos Graxos Insaturados/metabolismo , Inflamação/imunologia , Estresse Oxidativo/imunologia , Animais , Anti-Inflamatórios/imunologia , Modelos Animais de Doenças , Ácidos Graxos Insaturados/imunologia , Humanos , Espécies Reativas de Oxigênio/metabolismo
7.
Am J Respir Crit Care Med ; 202(6): 830-842, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32520577

RESUMO

Rationale: Sepsis is characterized by a dysregulated immune response to infection. Norepinephrine, the cornerstone vasopressor used in septic shock, may contribute to immune dysregulation and impact host defense.Objectives: To investigate effects of norepinephrine and the alternative vasopressor vasopressin on the immune response and host defense.Methods: Leukocytes from six to nine donors were stimulated in the presence or absence of norepinephrine and vasopressin. A total of 190 C57BL/6J mice received a continuous infusion of norepinephrine or vasopressin via microosmotic pumps and were challenged with LPS or underwent cecal ligation and puncture. Thirty healthy volunteers were randomized to a 5-hour infusion of norepinephrine, vasopressin, or saline and intravenously challenged with LPS. The relationship between the norepinephrine infusion rate and the use of ß-blockers and plasma cytokines was assessed in 195 patients with septic shock.Measurements and Main Results: Norepinephrine attenuated the production of proinflammatory mediators and reactive oxygen species and augmented antiinflammatory IL-10 production both in vitro and in LPS-challenged mice. Norepinephrine infusion during cecal ligation and puncture resulted in increased bacterial dissemination to the spleen, liver, and blood. In LPS-challenged volunteers, norepinephrine enhanced plasma IL-10 concentrations and attenuated the release of the proinflammatory cytokine IFN-γ-induced protein 10. Vasopressin exerted no immunomodulatory effects across these experimental setups. In patients, higher norepinephrine infusion rates were correlated with a more antiinflammatory cytokine balance, whereas ß-blocker use was associated with a more proinflammatory cytokine balance.Conclusions: Norepinephrine dysregulates the immune response in mice and humans and compromises host defense. Therefore, it may significantly contribute to sepsis-induced immunoparalysis, whereas vasopressin does not have untoward immunologic effects.


Assuntos
Imunidade Ativa/efeitos dos fármacos , Norepinefrina/efeitos adversos , Norepinefrina/imunologia , Choque Séptico/tratamento farmacológico , Choque Séptico/imunologia , Vasoconstritores/efeitos adversos , Vasoconstritores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/uso terapêutico , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Modelos Animais , Países Baixos , Norepinefrina/uso terapêutico , Kit de Reagentes para Diagnóstico , Vasoconstritores/uso terapêutico
11.
Cell Mol Life Sci ; 77(2): 289-303, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31432236

RESUMO

CD4 T-helper (Th) cells secret a variety of inflammatory cytokines and play critical roles in host defense against invading foreign pathogens. On the other hand, uncontrolled inflammatory responses mediated by Th cells may result in tissue damage and inflammatory disorders including autoimmune and allergic diseases. Thus, the induction of anti-inflammatory cytokine expression becomes an important "brake" to repress and/or terminate aberrant and/or unnecessary immune responses. Interleukin-10 (IL-10) is one of the most important anti-inflammatory cytokines to limit inflammatory Th cells and immunopathology and to maintain tissue homeostasis. Many studies have indicated that Th cells can be a major source of IL-10 under specific conditions both in mouse and human and that extracellular signals and cell intrinsic molecular switches are required to turn on and off Il10 expression in different Th cells. In this review, we will highlight the recent findings that have enhanced our understanding on the mechanisms of IL-10 induction in distinct Th-cell subsets, including Th1, Th2, and Th17 cells, as well as the importance of these IL-10-producing anti-inflammatory Th cells in immunity and inflammation.


Assuntos
Anti-Inflamatórios/imunologia , Diferenciação Celular/imunologia , Inflamação/imunologia , Interleucina-10/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Humanos
12.
Immunol Invest ; 49(3): 317-332, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31298595

RESUMO

Along years, the advent of biological therapy widely modified treatment of rheumatic diseases and other disorders. However, many agents may elicit in anti-drug antibodies (ADAbs) upon consecutive infusions, with a loss of response. For the right strategy of a personalized medicine, the therapeutic monitoring of TNF-α inhibitors and ADAbs represents an important effort in diagnostic-therapeutic pathway, to improve overall patient management and favoring an appropriate clinical approach. A raising number of diagnostic tests have been designed to elucidate the efficacy and/or safety of a specific drug or class of drugs for a targeted patient's group. Our paper reviewed the current understanding of the immunogenicity of biological drugs employed in the treatment of inflammatory diseases underlying the laboratory role.


Assuntos
Anti-Inflamatórios/uso terapêutico , Terapia Biológica , Serviços de Laboratório Clínico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anti-Inflamatórios/imunologia , Biomarcadores/sangue , Doença Crônica , Monitoramento de Medicamentos , Humanos , Inflamação/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/imunologia , Fator de Necrose Tumoral alfa/metabolismo
13.
Cytokine Growth Factor Rev ; 49: 32-41, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31672283

RESUMO

Allergic diseases are ubiquitous diseases with detrimental effects on the quality of life of people worldwide. Common allergic diseases include asthma, allergic rhinitis (AR) and allergic dermatitis (AD). Recently, studies have shown that interleukin (IL)-37, a novel cytokine in the IL-1 family, exhibits broad protective properties in various diseases, such as autoimmune diseases and cancer. IL-37 displays its anti-inflammatory effect on diseases by curbing innate and acquired immunity as well as inflammatory reactions. IL-37 functions by forming a complex with IL-18Rα and IL-1R8 extracellularly and can be translocated to the nucleus upon forming a complex with mothers against decapentaplegic homolog 3 (Smad3) intracellularly, thereby affecting gene transcription and signaling pathway activation. In addition, increasing evidence confirms that IL-37 expression is aberrant in asthma, AR and AD, which indicates that IL-37 may also play essential roles in allergic diseases. Furthermore, accumulating data obtained from recombinant IL-37 (rIL-37)-treated mice and from IL-37 transgenic (IL-37tg) mice suggest a protective role for IL-37. This review will detail the role of IL-37 in the occurrence and development of allergic diseases and discuss the potential of IL-37 as a therapeutic target in allergic diseases.


Assuntos
Hipersensibilidade , Interleucina-1/genética , Interleucina-1/imunologia , Animais , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/uso terapêutico , Asma/genética , Asma/imunologia , Humanos , Hipersensibilidade/imunologia , Hipersensibilidade/terapia , Inflamação/terapia , Interleucina-1/uso terapêutico , Camundongos , Transdução de Sinais
14.
Sci Adv ; 5(11): eaay1971, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31723606

RESUMO

Enhancing the therapeutic efficacy of drugs for inflammatory diseases is of high demand. One possible approach is targeting drugs to the extracellular matrix of the inflamed area. Here, we target collagens in the matrix, which are inaccessible in most tissues yet are exposed to the bloodstream in the inflamed area because of vascular hyperpermeability. We conferred collagen affinity to anti-tumor necrosis factor-α (α-TNF) antibody by conjugating a collagen-binding peptide (CBP) derived from the sequence of decorin. CBP-α-TNF accumulated in the inflamed paw of the arthritis model, and arthritis development was significantly suppressed by treatment with CBP-α-TNF compared with the unmodified antibody. Similarly, CBP-anti-transforming growth factor-ß (α-TGF-ß) accumulated in the inflamed lung of pulmonary fibrosis model and significantly suppressed pulmonary fibrosis compared with the unmodified antibody. Together, collagen affinity enables the anticytokine antibodies to target arthritis and pulmonary fibrosis accompanied by inflammation, demonstrating a clinically translational approach to treat inflammatory diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos/uso terapêutico , Colágeno/antagonistas & inibidores , Inflamação/tratamento farmacológico , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Animais , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/metabolismo , Anticorpos/imunologia , Anticorpos/metabolismo , Colágeno/imunologia , Colágeno/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Pulmão/imunologia , Pulmão/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular/métodos , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/metabolismo , Sialoglicoproteínas/imunologia , Sialoglicoproteínas/metabolismo , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
15.
Eur J Gastroenterol Hepatol ; 31(10): 1228-1233, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31498282

RESUMO

BACKGROUND: Loss of response in pediatric inflammatory bowel disease patients treated with biologic medications can be due to development of anti-drug antibodies. Natural history of anti-drug antibodies development has not been well described in pediatric inflammatory bowel disease. The primary aim of this study was to describe a single-center experience for the temporal onset of anti-drug antibodies detection. METHODS: We performed a retrospective, single-center chart review of pediatric inflammatory bowel disease patients at the Division of Pediatric Gastroenterology, Hepatology, and Nutrition at Rainbow Babies and Children's Hospital from 2010 to 2015. Patients were treated with infliximab or adalimumab and had at least two evaluations for anti-drug antibodies with the homogenous mobility shift assay. Demographics, laboratory and medication data, and clinical disease activity were collected. RESULTS: A total of 75 subjects are included in the analysis. Eighty-one percent of subjects were treated with infliximab. Eleven subjects developed anti-drug antibodies; average time to anti-drug antibodies detection was 13.2 ± 7.3 months. Longer duration of inflammatory bowel disease, L1 location in Crohn's disease, and not having immunomodulatory therapy before biologic was associated with higher risk of antibody detection. Antibody detection occurred more frequently with infliximab vs. adalimumab. Time-to-antibody detection for infliximab and adalimumab was 14.83 and 23.48 months, respectively. CONCLUSION: Chances of anti-drug antibodies detection in the infliximab group were higher than the adalimumab group. Time-to-antibody detection was 8.65 months longer in patients who received adalimumab when compared to infliximab. These results may have implications for long-term therapy and help guide use of concomitant immunomodulators.


Assuntos
Adalimumab/imunologia , Anti-Inflamatórios/imunologia , Anticorpos/sangue , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Tolerância a Medicamentos/imunologia , Infliximab/imunologia , Adalimumab/uso terapêutico , Adolescente , Anti-Inflamatórios/uso terapêutico , Criança , Colite Ulcerativa/sangue , Colite Ulcerativa/imunologia , Doença de Crohn/sangue , Doença de Crohn/imunologia , Feminino , Seguimentos , Humanos , Infliximab/uso terapêutico , Masculino , Estudos Retrospectivos , Fatores de Tempo
16.
Front Immunol ; 10: 1504, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379807

RESUMO

Autoimmune diseases are characterized by an aberrantly activated immune system, resulting in tissue damage and functional disability in patients. An important therapeutic goal is to restore the deregulated immunological balance between pro- and anti-inflammatory T cells. This imbalance is illustrated by elevated levels and activity of memory Th17 cell populations, such as Th17, Th1/Th17, and Th17.1 cells, in various autoimmune diseases. These cells are characterized by the chemokine receptor CCR6, RORC expression and production of IL-17A, IFNγ, and TNFα. Using rheumatoid arthritis (RA) as a model of autoimmune disease, we here demonstrate that pro-inflammatory memory CCR6+ Th cells can switch into anti-inflammatory cells with regulatory capacity using the active vitamin D metabolite 1,25(OH)2D3. Memory CCR6+ Th cells, excluding Tregs, were sorted from healthy controls or treatment-naïve patients with early rheumatoid arthritis (RA) and cultured with or without 1,25(OH)2D3. Treatment with 1,25(OH)2D3 inhibited pro-inflammatory cytokines such as IL-17A, IL-17F, IL-22 and IFNγ in memory CCR6+ Th cells from both healthy controls and RA patients. This was accompanied by induction of anti-inflammatory factors, including IL-10 and CTLA4. Interestingly, these formerly pathogenic cells suppressed proliferation of autologous CD3+ T cells similar to classical Tregs. Importantly, the modulated memory cells still migrated toward inflammatory milieus in vitro, modeled by RA synovial fluid, and retained their suppressive capacity in this environment. These data show the potential to reset the pathogenic profile of human memory Th cells into non-pathogenic cells with regulatory capacity.


Assuntos
Anti-Inflamatórios/imunologia , Memória Imunológica/imunologia , Células Th17/imunologia , Vitamina D/imunologia , Adulto , Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Complexo CD3/imunologia , Células Cultivadas , Feminino , Humanos , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Receptores CCR6/imunologia , Fator de Necrose Tumoral alfa/imunologia
17.
Life Sci ; 234: 116773, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31422095

RESUMO

AIMS: NLRP3 inflammasome activation is essential for the development and prognosis of diabetic cardiomyopathy (DCM). The anti-aging protein Klotho is suggested to modulate tissue inflammatory responses. The aim of the present study was to examine the protective effects of Klotho on DCM. MAIN METHODS: A streptozotocin-induced diabetes mouse model was established to assess the effects of Klotho in vivo, which was administered for 12 weeks. The characteristics of type 1 DCM were evaluated by general status, echocardiography, and histopathology. The expression of associated factors was determined by RT-qPCR and western blotting. Parallel experiments to determine the molecular mechanism through which Klotho prevents DCM were performed using H9C2 cells exposed to high glucose (35 mM). KEY FINDINGS: Diabetes-induced increases in serum creatine kinase-muscle/brain and lactate dehydrogenase levels, cardiac fibrosis, cardiomyocyte apoptosis, and cardiac dysfunction were ameliorated by Klotho. Additionally, Klotho suppressed TXNIP expression, NLRP3 inflammasome activation, and expression of the inflammatory cytokines tumor necrosis factor ɑ, interleukin-1ß, and interleukin-18 in vivo. In high glucose-cultured cardiomyocytes, Klotho and N-acetylcysteine significantly downregulated intracellular reactive oxygen species generation and TXNIP/NLRP3 inflammasome activation. Pretreatment of H9C2 cells with NLRP3 siRNA or Klotho prevented high glucose-induced inflammation and apoptosis in H9C2 cells. SIGNIFICANCE: Our results demonstrate that the protective effect of Klotho on diabetes-induced cardiac injury is associated with inhibition of the NLRP3 inflammasome pathway, suggesting its therapeutic potential for DCM.


Assuntos
Diabetes Mellitus Experimental/imunologia , Cardiomiopatias Diabéticas/imunologia , Glucuronidase/imunologia , Inflamassomos/imunologia , Inflamação/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Animais , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/uso terapêutico , Cardiotônicos/imunologia , Cardiotônicos/uso terapêutico , Linhagem Celular , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/patologia , Glucuronidase/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Ratos , Espécies Reativas de Oxigênio/imunologia
18.
Gastroenterology ; 157(4): 985-996.e2, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31194979

RESUMO

BACKGROUND & AIMS: Proactive monitoring of drug trough concentrations and antibodies against drugs might help determine whether patients are likely to respond to treatment and increase efficacy. We investigated whether proactive drug monitoring is associated with higher rates of clinical remission in pediatric patients with Crohn's disease (CD). METHODS: We performed a nonblinded, randomized controlled trial of 78 children with CD (6-18 years old; 29% female; mean age, 14.3 ± 2.6 years) who had not received prior treatment with a biologic agent but had responded to adalimumab induction therapy, under scheduled monitoring of clinical and biologic measures (based on clinical factors and levels of C-reactive protein and fecal calprotectin), at pediatric gastroenterology units in Israel from July 2015 through December 2018. The patients were randomly assigned to groups that received proactive monitoring (trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72, n = 38) or reactive monitoring (physicians were informed of trough concentrations after loss of response, n = 40). In both groups, doses and intervals of adalimumab were adjusted to achieve trough concentrations of 5 µg/mL. The primary endpoint was sustained corticosteroid-free clinical remission at all visits (week 8 through week 72). RESULTS: The primary endpoint was achieved by 31 children (82%) in the proactive group and 19 children (48%) in the reactive group (P = .002). Sixteen patients in the proactive monitoring group (42%) achieved a composite outcome of sustained corticosteroid-free remission, C-reactive protein ≤0.5 mg/dL, and level of fecal calprotectin ≤150 µg/g compared with 5 patients in the reactive monitoring group (12%) (P = .003). By week 72 of treatment, 33 patients in the proactive monitoring group had received adalimumab intensification (87%) compared with 24 patients in the reactive monitoring group (60%) (P = .001). CONCLUSIONS: In a randomized controlled trial of pediatric patients with CD, we found that proactive monitoring of adalimumab trough concentrations and adjustment of doses and intervals resulted in significantly higher rates corticosteroid-free clinical remission than reactive monitoring (measuring trough concentration after loss of response). Clinicaltrials.gov no.: NCT02256462.


Assuntos
Adalimumab/sangue , Adalimumab/uso terapêutico , Anti-Inflamatórios/sangue , Anti-Inflamatórios/uso terapêutico , Anticorpos/sangue , Doença de Crohn/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Fármacos Gastrointestinais/sangue , Fármacos Gastrointestinais/uso terapêutico , Adalimumab/imunologia , Adalimumab/farmacocinética , Adolescente , Corticosteroides/uso terapêutico , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/farmacocinética , Biomarcadores/sangue , Criança , Doença de Crohn/sangue , Doença de Crohn/diagnóstico , Doença de Crohn/imunologia , Feminino , Fármacos Gastrointestinais/imunologia , Fármacos Gastrointestinais/farmacocinética , Humanos , Israel , Masculino , Modelos Biológicos , Valor Preditivo dos Testes , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento
19.
Curr Top Microbiol Immunol ; 421: 139-158, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123888

RESUMO

Infectious diseases have been paramount among the threats to human health and survival throughout evolutionary history. Bacterial cell-surface molecules are key factors in the microorganism-host crosstalk, as they can interact with host pattern-recognition receptors (PRRs) of the gastrointestinal mucosa. The best-studied PRRs are toll-like receptors (TLRs). Because TLRs play an important key role in host defense, they have received increasing interest in the evolutionary and population genetics literature, and their variation represents a potential target of adaptive evolution. Helicobacter pylori is one of the commensal bacteria in our body and can have pathogenic properties in a subset of infected people. The history of H. pylori research indicated that humans and bacteria co-evolved during evolution. A genome-wide association study (GWAS) has opened the way for investigating the genomic evolution of bacterial pathogens during the colonization and infection of humans. Recent GWAS research emphasized the importance of TLRs, especially TLR10 during pathogenesis in H. pylori infection. We demonstrated that TLR10, whose ligand was unknown for a long time, can recognize H. pylori LPS. Our results of H. pylori research suggest that TLR10 might play an important role to also recognize other commensal bacteria. In this review, we discuss the importance of TLRs in pro-inflammatory and anti-inflammatory responses by H. pylori infection. Especially, we highlight the TLR10 interaction with H. pylori infection, providing new insights about TLR10 signaling.


Assuntos
Anti-Inflamatórios/imunologia , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Helicobacter pylori/patogenicidade , Mediadores da Inflamação/imunologia , Receptores Toll-Like/imunologia , Evolução Molecular , Estudo de Associação Genômica Ampla , Infecções por Helicobacter/genética , Humanos , Receptores Toll-Like/genética
20.
Psychopharmacology (Berl) ; 236(5): 1653-1670, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31119329

RESUMO

RATIONALE: Mycobacterium vaccae (NCTC 11659) is an environmental saprophytic bacterium with anti-inflammatory, immunoregulatory, and stress resilience properties. Previous studies have shown that whole, heat-killed preparations of M. vaccae prevent allergic airway inflammation in a murine model of allergic asthma. Recent studies also demonstrate that immunization with M. vaccae prevents stress-induced exaggeration of proinflammatory cytokine secretion from mesenteric lymph node cells stimulated ex vivo, prevents stress-induced exaggeration of chemically induced colitis in a model of inflammatory bowel disease, and prevents stress-induced anxiety-like defensive behavioral responses. Furthermore, immunization with M. vaccae induces anti-inflammatory responses in the brain and prevents stress-induced exaggeration of microglial priming. However, the molecular mechanisms underlying anti-inflammatory effects of M. vaccae are not known. OBJECTIVES: Our objective was to identify and characterize novel anti-inflammatory molecules from M. vaccae NCTC 11659. METHODS: We have purified and identified a unique anti-inflammatory triglyceride, 1,2,3-tri [Z-10-hexadecenoyl] glycerol, from M. vaccae and evaluated its effects in freshly isolated murine peritoneal macrophages. RESULTS: The free fatty acid form of 1,2,3-tri [Z-10-hexadecenoyl] glycerol, 10(Z)-hexadecenoic acid, decreased lipopolysaccharide-stimulated secretion of the proinflammatory cytokine IL-6 ex vivo. Meanwhile, next-generation RNA sequencing revealed that pretreatment with 10(Z)-hexadecenoic acid upregulated genes associated with peroxisome proliferator-activated receptor alpha (PPARα) signaling in lipopolysaccharide-stimulated macrophages, in association with a broad transcriptional repression of inflammatory markers. We confirmed using luciferase-based transfection assays that 10(Z)-hexadecenoic acid activated PPARα signaling, but not PPARγ, PPARδ, or retinoic acid receptor (RAR) α signaling. The effects of 10(Z)-hexadecenoic acid on lipopolysaccharide-stimulated secretion of IL-6 were prevented by PPARα antagonists and absent in PPARα-deficient mice. CONCLUSION: Future studies should evaluate the effects of 10(Z)-hexadecenoic acid on stress-induced exaggeration of peripheral inflammatory signaling, central neuroinflammatory signaling, and anxiety- and fear-related defensive behavioral responses.


Assuntos
Anti-Inflamatórios/imunologia , Anti-Inflamatórios/isolamento & purificação , Mycobacterium/imunologia , Mycobacterium/isolamento & purificação , Estresse Psicológico/imunologia , Estresse Psicológico/prevenção & controle , Animais , Ansiedade/induzido quimicamente , Ansiedade/imunologia , Ansiedade/prevenção & controle , Colite/induzido quimicamente , Colite/imunologia , Colite/prevenção & controle , Medo/efeitos dos fármacos , Medo/fisiologia , Inflamação/imunologia , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/imunologia , Microbiologia do Solo , Estresse Psicológico/induzido quimicamente
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