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1.
Chin J Physiol ; 63(1): 7-14, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32056981

RESUMO

Chronic inflammation is a major risk factor for colitis-associated colorectal carcinoma (CRC). Macrophages play a key role in altering the tumor microenvironment by producing pro-inflammatory and anti-inflammatory cytokines. Our previous studies showed that glucose metabolism conferred death resistance for tumor progression and exerted anti-inflammatory effects in ischemic gut mucosa. However, the effect of glucose and cancer metabolites in modulating macrophage cytokine profiles remains poorly defined. We used an in vitro system to mimic intestinal microenvironment and to investigate the roles of glucose and cancer metabolites in the cross-talk between carcinoma cells and macrophages. Human monocyte-derived THP-1 macrophages were stimulated with bacterial lipopolysaccharide (LPS) in the presence of conditioned media (CM) collected from human CRC Caco-2 cells incubated in either glucose-free or glucose-containing media. Our results demonstrated that glucose modulated the macrophage cytokine production, including decreased LPS-induced pro-inflammatory cytokines (i.e., tumor necrosis factor [TNF]α and interleukin [IL]-6) and increased anti-inflammatory cytokine (i.e., IL-10), at resting state. Moreover, glucose-containing CM reduced the macrophage secretion of TNFα and IL-8 but elevated the IL-12 and IL-23 levels, showing an opposite pattern of distinct pro-inflammatory cytokines modulated by cancer glucose metabolites. In contrast, LPS-induced production of macrophage inflammatory protein-1 (a macrophage-derived chemoattractant for granulocytes) was not altered by glucose or CM, indicating that resident macrophages may play a more dominant role than infiltrating granulocytes for responding to cancer metabolites. In conclusion, glucose metabolites from CRC triggered distinct changes in the cytokine profiles in macrophages. The downregulation of death-inducing TNFα and upregulation of Th1/17-polarizing IL-12/IL-23 axis in macrophages caused by exposure to cancer-derived glucose metabolites may contribute to tumor progression.


Assuntos
Neoplasias do Colo , Células CACO-2 , Citocinas , Glucose , Humanos , Interleucina-12 , Interleucina-23 , Lipopolissacarídeos , Macrófagos , Microambiente Tumoral , Fator de Necrose Tumoral alfa
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 255-261, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027286

RESUMO

OBJECTIVE: To investigate the efficacy of bone marrow mesenchymal stem cells (BMMSC) on children with refractory graft-versus-host disease (GVHD) and to judge the efficacy of BMMSC by dynamically monitoring the changes of cytokines in children with GVHD before and after infusion of BMMSC, so as to provide a theoretical basis for clarifying the mechanism of BMMSC. METHODS: 17 children with refractory aGVHD including 7 of grade II, 6 cases of grade III and 4 cases of grade IV after allo-HSCT were enrolled. All the children with aGVHD, who received routine immunosuppressive therapy, but the state of disease not improved, were treated with immunosuppressive drugs combined with BMMSC infusion. Study endpoints included safety of BMMSC infusion, response to BMMSC, and overall response of aGVHD. The serum levels of IL-2α, IL-6, IL-10, IL-8 and TNF-α in aGVHD patients were measured by chemiluminescence before infusion of BMMSCs and Day 7, Day 14 after infusion of BMMSCs. RESULTS: The cumulative median dose of BMMSCs was 5.5 (3.4-11.1) × 106/kg for average of 3.7 times, and the median time of 16.5 (4-95) days for the first infusion of MSCs. In 17 cases of refractory GVHD, 14 responded to treatment, whereas 3 patients failed. The total effective rate was 82.4% and no adverse reactions occurred. Of the 14 survived cases (82.4%), the median follow-up time was 944 (559-1245) days from the first infusion of MSCs. The levels of TNF-α in children with grade II, III and IV GVHD before treatment were 9.5±4.3 pg/ml, 16.3±10.9 pg/ml and 35.8±21.2 pg/ml respectively. The difference between grade II and IV, III and IV was statistically significant (P<0.05). Compared with the ineffective group of BMMSC infusion, the serum TNF-αlevel in the BMMSCs treatment effective group was 10.8±5.6 pg/ml vs 40.6±14.8 pg/ml (t=-3.901, P<0.05) before treatment. In the effective group of BMMSCs infusion, IL-10 20±17.4 pg/ml of day 14 was significantly higher than that 7.3±3.1 pg/ml before the treatment (t=-2.850, P<0.05), while , the serum levels of IL-2α, IL-6, IL-8, TNF-α were not statistically significantly different (P>0.05). CONCLUSION: The infusion of BMMSC is safe and effective in the treatment of refractory GVHD in children. TNF-αlevel relates with the severity of GVHD. BMMSC may play an anti-GVHD role by up regulating the level of cytokine IL-10 in vivo.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Doença Aguda , Criança , Citocinas , Humanos , Transplante Homólogo
3.
Adv Exp Med Biol ; 1224: 63-77, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32036605

RESUMO

Mucosal-associated invariant T (MAIT) cells are innate T lymphocytes that circulate in blood and also reside in mucosal tissues. Blood MAIT cells are typically highly Th1-polarized, while those in mucosal tissues include both Th1- and Th17-polarized subsets. MAIT cells mount cytokine and cytolytic responses as a result of T cell receptor (TCR)-mediated recognition of microbially derived metabolites of riboflavin (vitamin B2) presented by the MR1 antigen-presenting molecule. Additionally, MAIT cells can be activated by inflammatory cytokines produced by antigen-presenting cells (APCs) that have been exposed to pathogen-associated molecular patterns (PAMPs). Since the antigenic metabolites of riboflavin recognized by MAIT cells are produced by many microorganisms, including pathogens as well as non-pathogenic colonists, the inflammatory state of the tissue may be a key feature that determines the nature of MAIT cell responses. Under normal conditions where inflammatory cytokines are not produced, MAIT cell responses to microbial metabolites may simply serve to help maintain a healthy balance between epithelial cells and microbial colonists. In contrast, in situations where inflammatory cytokines are produced (e.g., pathogenic infection or damage to epithelial tissue), MAIT cell responses may be more potently pro-inflammatory. Since chronic inflammation and microbial drivers are associated with tumorigenesis and also trigger MAIT cell responses, the nexus of MAIT cells, local microbiomes, and epithelial cells may play an important role in epithelial carcinogenesis. This chapter reviews current information about MAIT cells and epithelial tumors, where the balance of evidence suggests that enrichment of Th17-polarized MAIT cells at tumor sites associates with poor patient prognosis. Studying the role of MAIT cells and their interactions with resident microbes offers a novel view of the biology of epithelial tumor progression and may ultimately lead to new approaches to target MAIT cells clinically.


Assuntos
Células Epiteliais/patologia , Células T Invariáveis Associadas à Mucosa , Neoplasias/patologia , Citocinas/imunologia , Humanos , Células T Invariáveis Associadas à Mucosa/efeitos dos fármacos , Células T Invariáveis Associadas à Mucosa/imunologia , Neoplasias/tratamento farmacológico , Prognóstico , Receptores de Antígenos de Linfócitos T/imunologia
4.
Lancet ; 395(10221): 371-383, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32007172

RESUMO

Asthma is a disease of reversible airflow obstruction characterised clinically by wheezing, shortness of breath, and coughing. Increases in airway type 2 cytokine activity, including interleukin-4 (IL-4), IL-5, and IL-13, are now established biological mechanisms in asthma. Inhaled corticosteroids have been the foundation for asthma treatment, in a large part because they decrease airway type 2 inflammation. However, inhaled or systemic corticosteroids are ineffective treatments in many patients with asthma and few treatment options exist for patients with steroid resistant asthma. Although mechanisms for corticosteroid refractory asthma are likely to be numerous, the development of a new class of biologic agents that target airway type 2 inflammation has provided a new model for treating some patients with corticosteroid refractory asthma. The objective of this Therapeutic paper is to summarise the new type 2 therapeutics, with an emphasis on the biological rationale and clinical efficacy of this new class of asthma therapeutics.


Assuntos
Antiasmáticos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Adulto , Biomarcadores/metabolismo , Ensaios Clínicos Fase III como Assunto , Citocinas/antagonistas & inibidores , Citocinas/fisiologia , Eosinófilos/fisiologia , Previsões , Humanos , Ácidos Indolacéticos/uso terapêutico , Interleucina-4/antagonistas & inibidores , Interleucina-5/antagonistas & inibidores , Omalizumab/uso terapêutico , Piridinas/uso terapêutico , Células Th2/fisiologia , Resultado do Tratamento
5.
Adv Exp Med Biol ; 1224: 35-51, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32036603

RESUMO

CD4+ T helper (TH) cells are key regulators in the tumour immune microenvironment (TIME), mediating the adaptive immunological response towards cancer, mainly through the activation of cytotoxic CD8+ T cells. After antigen recognition and proper co-stimulation, naïve TH cells are activated, undergo clonal expansion, and release cytokines that will define the differentiation of a specific effector TH cell subtype. These different subtypes have different functions, which can mediate both anti- and pro-tumour immunological responses. Here, we present the dual role of TH cells restraining or promoting the tumour, the factors controlling their homing and differentiation in the TIME, their influence on immunotherapy, and their use as prognostic indicators.


Assuntos
Neoplasias/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Microambiente Tumoral/imunologia , Animais , Citocinas/metabolismo , Humanos , Linfócitos T Citotóxicos/imunologia
6.
Plast Reconstr Surg ; 145(2): 420-431, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31985635

RESUMO

BACKGROUND: Secondary lymphedema is a refractory disease, for which adipose-derived stem cells have shown some therapeutic potential. However, the mechanism of this action remains poorly understood. METHODS: The authors identified podoplanin-expressing adipose-derived stem cells, which allowed them to divide adipose-derived stem cells into podoplanin-positive and podoplanin-negative groups that they characterized in vitro. The authors then used a mouse hindlimb model for lymphedema to trace the fate of podoplanin-positive, podoplanin-negative, and unsorted adipose-derived stem cells in vivo. RESULTS: When induced in culture, podoplanin-positive cells were noted to up-regulate the expression of lymphatic endothelial cell markers, including LYVE-1, and assumed a cobblestone morphology. In addition, a substantial increase in lymphangiogenic cytokines was detected in the podoplanin-positive supernatant. The above findings were largely absent from the podoplanin-negative and unsorted groups. In the mouse model, the implanted cells relieved the limb lymphedema by promoting lymphangiogenesis, with the podoplanin-positive group showing the most significant effect. Immunocolocalization further revealed that the podoplanin-positive cells incorporated into lymphatic vessels were positive for LYVE-1. CONCLUSIONS: These data demonstrated that actions by means of both paracrine and differentiation pathways were involved in the adipose-derived stem cell-mediated therapeutic effects. The podoplanin-positive cells possessed lymphatic paracrine and differentiation abilities and may represent lymphatic endothelial cell precursor cells. The podoplanin-negative cells, which constitute a considerable proportion of the adipose-derived stem cells, may play an important paracrine role by secreting mesenchymal stem cell-related factors.


Assuntos
Linfangiogênese/fisiologia , Vasos Linfáticos/fisiologia , Glicoproteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/fisiologia , Animais , Biomarcadores/metabolismo , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/fisiologia , Feminino , Proteínas de Fluorescência Verde , Linfedema/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neovascularização Fisiológica/fisiologia , Fenótipo
7.
Rev Med Suisse ; 16(676-7): 28-30, 2020 Jan 15.
Artigo em Francês | MEDLINE | ID: mdl-31961078

RESUMO

Interleukin 17A is a key effector cytokine in numerous chronic inflammatory diseases. Its neutralization is therapeutically effective and approved in the treatment of chronic inflammatory conditions. Recently, five additional members of the IL-17 cytokine family have been identified, which also contribute to chronic inflammation. Innovative therapeutic strategies therefore aim to simultaneously block not one, but several members of this cytokine family in order to further increase therapeutic efficacy. This article reviews the current knowledge regarding the role of the IL-17 cytokine family in chronic inflammation.


Assuntos
Inflamação , Interleucina-17 , Anti-Inflamatórios , Citocinas , Humanos , Interleucina-17/fisiologia
8.
Life Sci ; 242: 117240, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31891722

RESUMO

Lycium barbarum polysaccharides (LBP) are derived from Wolfberry and have antioxidant activities. This study aimed to evaluate the efficacy of LBP for kidney injury in a rat model of sepsis. Male rats were divided randomly to control group (Con), LPS group (LPS), ulinastatin group (ULI), low dose LBP group (LBP-1), middle dose LBP group (LBP-2) and high dose LBP group (LBP-3). After intraperitoneal injection of LPS (5 mg/kg) to make sepsis model (LPS group), 10,000 U/kg ulinastatin were given in ULI group, and 200, 400 and 800 mg/kg LBP was given in LBP-1, -2, -3 group, respectively. Serum IL-1ß, IL-6, IL-8, TNF-α and NF-κB levels were measured by ELISA. Nrf2, Keap1, NF-κB, HO-1 and NQO1 expression levels were detected by PCR and Western blot analysis. We found that LBP decreased the levels of NF-κB and pro-inflammatory cytokines while attenuated kidney injury. In addition, LBP regulated Keap1-Nrf2/ARE signaling pathway in the kidney. In conclusion, LBP attenuates inflammation injury in the kidney via possible regulation of Keap1-Nrf2/ARE signaling.


Assuntos
Lesão Renal Aguda/prevenção & controle , Elementos de Resposta Antioxidante/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Sepse/complicações , Transdução de Sinais/efeitos dos fármacos , Animais , Western Blotting , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real
9.
Adv Exp Med Biol ; 1216: 55-64, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31894547

RESUMO

Chronic inflammation, which is called "inflamm-aging" , is characterized by an increased level of inflammatory cytokines in response to physiological and environmental stressors, and causes the immune system to function consistently at a low level, even though it is not effective. Possible causes of inflammaging include genetic susceptibility, visceral obesity, changes in gut microbiota and permeability, chronic infections and cellular senescence. Inflammation has a role in the development of many age-related diseases, such as frailty. Low grade chronic inflammation can also increase the risk of atherosclerosis and insulin resistance which are the leading mechanisms in the development of cardiovascular diseases (CVD). As it is well known that the risk of CVD is higher in older people with frailty and the risk of frailty is higher in patients with CVD, there may be relationship between inflammation and the development of CVD and frailty. Therefore, this important issue will be discussed in this chapter.


Assuntos
Doenças Cardiovasculares/complicações , Idoso Fragilizado , Fragilidade/complicações , Inflamação/complicações , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/imunologia , Envelhecimento/patologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/patologia , Senescência Celular , Citocinas/imunologia , Fragilidade/imunologia , Fragilidade/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia
10.
J Photochem Photobiol B ; 203: 111731, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31935633

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive and chronic inflammatory disease with a poor prognosis and very few available treatment options. Low-level laser therapy (LLLT) has been gaining prominence as a new and effective anti-inflammatory and immunomodulatory agent. Can lung inflammation and the airway remodeling be regulated by LLLT in an experimental model of IPF in C57Bl/6 mice? The present study investigated if laser attenuates cellular migration to the lungs, the airway remodeling as well as pro-fibrotic cytokines secretion from type II pneumocytes and fibroblasts. Mice were irradiated (780 nm and 30 mW) and then euthanized fifteen days after bleomycin-induced lung fibrosis. Lung inflammation and airway remodeling were evaluated through leukocyte counting in bronchoalveolar lavage fluid (BALF) and analysis of collagen in lung, respectively. Inflammatory cells in blood were also measured. For in vitro assays, bleomycin-activated fibroblasts and type II pneumocytes were irradiated with laser. The pro- and anti-inflammatory cytokines level in BALF as well as cells supernatant were measured by ELISA, and the TGFß in lung was evaluated by flow cytometry. Lung histology was used to analyze collagen fibers around the airways. LLLT reduced both migration of inflammatory cells and deposition of collagen fibers in the lungs. In addition, LLLT downregulated pro-inflammatory cytokines and upregulated the IL-10 secretion from fibroblasts and pneumocytes. Laser therapy greatly reduced total lung TGFß. Systemically, LLLT also reduced the inflammatory cells counted in blood. There is no statistical difference in inflammatory parameters studied between mice of the basal group and the laser-treated mice. Data obtained indicate that laser effectively attenuates the lung inflammation, and the airway remodeling in experimental pulmonary fibrosis is driven to restore the balance between the pro- and anti-inflammatory cytokines in lung and inhibit the pro-fibrotic cytokines secretion from fibroblasts.


Assuntos
Remodelação das Vias Aéreas , Citocinas/metabolismo , Fibrose Pulmonar Idiopática/radioterapia , Lasers , Animais , Líquido da Lavagem Broncoalveolar/química , Células Cultivadas , Citocinas/análise , Modelos Animais de Doenças , Regulação para Baixo/efeitos da radiação , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/efeitos da radiação , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Fibrose Pulmonar Idiopática/patologia , Terapia a Laser , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regulação para Cima/efeitos da radiação
11.
Isr Med Assoc J ; 22(1): 48-52, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31927806

RESUMO

BACKGROUND: Nasal polyps are three-dimensional structures arising from the mucosa of the upper airway. Due to their complexity, the reliability of single-layer cell cultures and animal systems as research models is limited. OBJECTIVES: To evaluate the feasibility of an ex vivo organ culture of human polyps, preserving tissue structure and function. METHODS: Nasal polyps were excised during routine endoscopic sinus surgery for chronic rhinosinusitis and polyposis. Fresh tissue samples were used for pathological evaluation and for the preparation of 250-500 µm sections, which were incubated in culture media. Tissue viability was assessed by visualisation of cilia motility, measurement of glucose uptake, and an infectivity assay. Cytokine secretion was evaluated by enzyme-linked immunosorbent assay and real-time polymerase chain reaction before and after the introduction of steroids. RESULTS: Polyp tissue viability was retained for 2-3 days as demonstrated by cilia motility, glucose uptake and preserved cellular composition. Tissue samples maintained their capacity to respond to infection by herpes simplex virus 1 and adenovirus. Introduction of dexamethasone to cultured tissue samples led to suppression of interferon-g production. CONCLUSIONS: The ex vivo nasal polyp organ culture reproduces the physiological, metabolic, and cellular features of nasal polyps. Furthermore, it shows a preserved capacity for viral infection and response to drugs. This system is a useful tool for the investigation nasal-polyps and for the development of novel therapies.


Assuntos
Pólipos Nasais/diagnóstico , Técnicas de Cultura de Órgãos/métodos , Adulto , Quimiocinas/metabolismo , Citocinas/metabolismo , Glucose/metabolismo , Humanos , Pólipos Nasais/metabolismo , Pólipos Nasais/patologia , Pólipos Nasais/cirurgia , Reação em Cadeia da Polimerase em Tempo Real
12.
Chem Pharm Bull (Tokyo) ; 68(1): 46-57, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902901

RESUMO

Over the past decade, a number of new 1,4-naphthoquinones have been isolated from natural sources and new 1,4-naphthoquinones with diverse structural features have been synthesized. Cardioprotective, anti-ischemic, hepatoprotective, neuroprotective and some other new properties were found for these compounds; their role in protecting against neurodegenerative diseases has been established. Their anti-inflammatory, antimicrobial and antitumor activities have been studied in more detail; new, previously unknown intracellular molecular targets and mechanisms of action have been discovered. Some compounds of this class are already being used as a medicinal drugs and some substances can be used as biochemical tools and probes for non-invasive detection of pathological areas in cells and tissues in myocardial infarction and neurodegenerative diseases using modern molecular imaging techniques.


Assuntos
Anti-Infecciosos/química , Anti-Inflamatórios/química , Naftoquinonas/química , Substâncias Protetoras/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Bactérias/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Naftoquinonas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Trypanosoma/efeitos dos fármacos
15.
Adv Clin Chem ; 94: 155-218, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31952571

RESUMO

Bone and skeletal muscle are integrated organs and their coupling has been considered mainly a mechanical one in which bone serves as attachment site to muscle while muscle applies load to bone and regulates bone metabolism. However, skeletal muscle can affect bone homeostasis also in a non-mechanical fashion, i.e., through its endocrine activity. Being recognized as an endocrine organ itself, skeletal muscle secretes a panel of cytokines and proteins named myokines, synthesized and secreted by myocytes in response to muscle contraction. Myokines exert an autocrine function in regulating muscle metabolism as well as a paracrine/endocrine regulatory function on distant organs and tissues, such as bone, adipose tissue, brain and liver. Physical activity is the primary physiological stimulus for bone anabolism (and/or catabolism) through the production and secretion of myokines, such as IL-6, irisin, IGF-1, FGF2, beside the direct effect of loading. Importantly, exercise-induced myokine can exert an anti-inflammatory action that is able to counteract not only acute inflammation due to an infection, but also a condition of chronic low-grade inflammation raised as consequence of physical inactivity, aging or metabolic disorders (i.e., obesity, type 2 diabetes mellitus). In this review article, we will discuss the effects that some of the most studied exercise-induced myokines exert on bone formation and bone resorption, as well as a brief overview of the anti-inflammatory effects of myokines during the onset pathological conditions characterized by the development a systemic low-grade inflammation, such as sarcopenia, obesity and aging.


Assuntos
Osso e Ossos/metabolismo , Citocinas/metabolismo , Músculo Esquelético/metabolismo , Envelhecimento/metabolismo , Animais , Exercício , Homeostase , Humanos , Inflamação/metabolismo , Obesidade/metabolismo
16.
Toxicol Lett ; 322: 50-57, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31958493

RESUMO

Allergic contact dermatitis (ACD) is an important occupational and environmental disease caused by topical exposure to chemical allergens. In the EU, it has been calculated that 4 % of animals are used in toxicity test for the assessment of skin sensitization (Peiser et al., 2012). To come a complete replacement of animals, evaluation of relative skin sensitization potency is necessary. The identification of mechanisms influencing allergen potency requires a better understanding of molecular events that trigger cell activation. Therefore, (i) the effects of selected allergens on surface markers expression and cytokines release in contact allergen-induced cell activation were assessed, and (ii) the role of Protein Kinase C (PKC) beta activation in contact allergen-induced cell activation was investigated. The human pro-myelocytic cell line THP-1 was used as experimental model surrogate of dendritic cells. Cells were exposed to select contact allergens of different potency and cell surface marker expression (CD80, CD86, HLA-DR) was determined by flow cytometry analysis. Cytokines production (IL-6, IL-8, IL-10, IL-12p40, IL-18) was evaluated with specific sandwich ELISA. The effective contribution of PKC beta in chemical allergen-induced cell activation was assessed by Western Blot analysis (PKC beta activation) and using a specific PKC beta inhibitor (PKC beta pseudosubstrate). In addition, to investigate if contact allergens are able to induce indeed dendritic cells (DCs) maturation, THP-1 cells were differentiated to immature DC and then exposed to contact allergen of different potency. Overall, our finding provides insights into the process of sensitization and strength of cell activation associated with allergens of different potency. Results obtained suggest that contact allergens of different potency are able to induce a different degree of activation of dendritic cells maturation involved in the process of ACD.


Assuntos
Alérgenos/classificação , Alternativas aos Testes com Animais , Células Dendríticas/efeitos dos fármacos , Dermatite Alérgica de Contato , Pele/efeitos dos fármacos , Xenobióticos/classificação , Alérgenos/toxicidade , Antígenos de Superfície/biossíntese , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Células Dendríticas/enzimologia , Células Dendríticas/imunologia , Dermatite Alérgica de Contato/enzimologia , Dermatite Alérgica de Contato/imunologia , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Humanos , Proteína Quinase C beta/metabolismo , Pele/enzimologia , Pele/imunologia , Xenobióticos/toxicidade
17.
Nat Commun ; 11(1): 557, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992699

RESUMO

Hydrogen sulfide (H2S) is involved in numerous pathophysiological processes and shares overlapping functions with CO and •NO. However, the importance of host-derived H2S in microbial pathogenesis is unknown. Here we show that Mtb-infected mice deficient in the H2S-producing enzyme cystathionine ß-synthase (CBS) survive longer with reduced organ burden, and that pharmacological inhibition of CBS reduces Mtb bacillary load in mice. High-resolution respirometry, transcriptomics and mass spectrometry establish that H2S stimulates Mtb respiration and bioenergetics predominantly via cytochrome bd oxidase, and that H2S reverses •NO-mediated inhibition of Mtb respiration. Further, exposure of Mtb to H2S regulates genes involved in sulfur and copper metabolism and the Dos regulon. Our results indicate that Mtb exploits host-derived H2S to promote growth and disease, and suggest that host-directed therapies targeting H2S production may be potentially useful for the management of tuberculosis and other microbial infections.


Assuntos
Sulfeto de Hidrogênio/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/patogenicidade , Animais , Cobre/metabolismo , Cistationina beta-Sintase/genética , Cistationina beta-Sintase/metabolismo , Citocinas/sangue , Modelos Animais de Doenças , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Metabolismo Energético , Feminino , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Homeostase , Pulmão/patologia , Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/genética , Células RAW 264.7 , Regulon , Enxofre/metabolismo , Transcriptoma , Tuberculose
18.
Int J Radiat Biol ; 96(1): 4-11, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30403905

RESUMO

Purpose: In the wake of a nuclear detonation, individuals with acute radiation syndrome will be a significant source of morbidity and mortality. Mathematical modeling can compare response strategies developed for real-world chaotic conditions after a nuclear blast in order to identify optimal strategies for administering effective treatment to these individuals. To maximize responders' abilities to save lives it is critical to understand how treatment efficacy is impacted by real-world conditions and levels of supportive care. To illustrate the importance of these factors, we developed a mathematical model of cytokine administration 24 h after the blast with varying levels of supportive care described in the primary literature.Conclusion: The results highlight the proportionally higher life-saving benefit of administering cytokines to individuals with a moderate to high dose of radiation exposure, compared to those with a lower dose. However, the fidelity of mathematical models is dependent on the primary data informing them. We describe the data needed to fully explore the impact of timing, dosage, and fractional benefit of cytokines and supportive care treatment in non-optimal situations that could be seen after a nuclear detonation. Studies addressing these types of knowledge gaps are essential to evaluating the relative efficacy of countermeasures to refine existing plans and help develop new strategies and priorities.


Assuntos
Contramedidas Médicas , Armas Nucleares , Exposição à Radiação/efeitos adversos , Tempo para o Tratamento , Síndrome Aguda da Radiação/etiologia , Síndrome Aguda da Radiação/metabolismo , Síndrome Aguda da Radiação/prevenção & controle , Síndrome Aguda da Radiação/terapia , Citocinas/metabolismo , Humanos
19.
Life Sci ; 241: 117120, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31825792

RESUMO

AIMS: The present study explored the function and regulatory mechanism of High mobility group box 1 (HMGB1) in asthma. MAIN METHODS: OVA (ovalbumin)-induced asthmatic mice model and LPS-treated cellular model were established in this study. Airway inflammation was measured through detecting the expression of IL-4, IL-5, IL-13 and Interferon-γ (IFN-γ) in serum and BALF (bronchoalveolar lavage fluid) by ELISA kits. Bioinformatics predictive analysis, ChIP assays, Luciferase reporter assay and Western blotting were used to explore the relation between HMGB1 and HSF1 (Heat shock factor 1). KEY FINDINGS: HMGB1 expression was increased in OVA-induced asthmatic mice. Silencing HMGB1 attenuated the increasing of IgE, inflammatory factors (IL-4, IL-5 and IL-13), and airway hyperresponsiveness that induced by OVA. In addition, our study found that HSF1 directly bind with the HMGB1 promoter and negatively regulation of HMGB1. HSF-1 were upregulated in OVA-induced asthmatic mice, and knockdown of HSF1 aggravated the OVA-induced airway inflammation and airway hyperreactivity in mice may through promoting the expression of HMGB1 and the activation of the Toll-like receptor 4 (TLR4)/Myeloid differentiation primary response 88 (MyD88)/Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signal pathway. SIGNIFICANCE: The expression of HMGB1 could be negatively regulated by HSF1, and the TLR4/MyD88/NF-κB signal pathway was involved in HSF1/HMGB1-mediated regulation of asthma.


Assuntos
Asma/patologia , Proteína HMGB1/metabolismo , Fatores de Transcrição de Choque Térmico/fisiologia , Inflamação/patologia , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Apoptose , Asma/induzido quimicamente , Asma/genética , Asma/metabolismo , Sequência de Bases , Hiper-Reatividade Brônquica/etiologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/patologia , Citocinas/metabolismo , Células HEK293 , Proteína HMGB1/genética , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/genética , Ovalbumina/toxicidade , Regiões Promotoras Genéticas , Transdução de Sinais , Receptor 4 Toll-Like/genética
20.
J Photochem Photobiol B ; 202: 111705, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31812087

RESUMO

The procurance of gold nanoparticles in the plant extracts is an excellent way to attain nanomaterials natural and eco-friendly nanomaterials. The Dehydrated roots of Chinese Euphorbia fischeriana flowering plant are called "Lang-Du". In this study, the retrieving of gold nanoparticles from Euphorbia fischeriana root was amalgamated by standard procedure. Fabricated gold nanoparticles were portrayed through the investigations of ultraviolet and visible spectrophotometry (UV-Vis), Fourier transform infrared spectroscopy (FTIR), High resolution transmission electron microscopy (HRTEM) and X-ray diffraction (XRD). The UV-Vis and FTIR results explicated the obtained particles were sphere-shaped and the terpenoids of Euphorbia fischeriana had strong communications with gold surface. The HRTEM and XRD images exposed the produced gold nanoparticles had an extreme composition of crystal arrangement and excellent uniformed size of particles. In our study, the Isoprenaline induced myocardial damage established the elevation in TBARS, LOOH of heart tissues and notable decline in antioxidant enzymes SOD, CAT, GPx, and GSH. This biochemical result was additionally proved by histopathological assessment. Remarkably, the pretreatment with EF-AuNps(50 mg/kg b.w) illustrated stabilized levels of serum creatine and cardiotropins in myocardial infarcted animals. And further we understood the essential function of NF-ƙB, TNF-α, IL-6 signaling molecules and its way progression in the development of vascular tenderness.


Assuntos
Euphorbia/química , Ouro/química , Nanopartículas Metálicas/uso terapêutico , Infarto do Miocárdio/prevenção & controle , Animais , Antioxidantes/química , Catalase/genética , Catalase/metabolismo , Creatina Quinase/sangue , Citocinas/metabolismo , Euphorbia/metabolismo , Química Verde , Isoproterenol/toxicidade , Nanopartículas Metálicas/química , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Extratos Vegetais/química , Raízes de Plantas/química , Ratos , ATPase Trocadora de Sódio-Potássio/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
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