RESUMO
Chronic rhinosinusitis (CRS), especially with nasal polyps, continues to elude precise pathogenesis and effective treatment. Prior work in our laboratory demonstrated interleukin-33 (IL-33) and Substance P (SP) activation of mast cells, and inhibitory effect of interleukin-37 (IL-37). Our objective is to study the expression of these neurohormonal mediators in mast cell stimulation of nasal polyposis. This was a prospective research study involving collection of nasal lavage fluid and nasal polyp tissue from adult patients with CRS. The study was divided into two arms. First, nasal lavage fluid was collected from normal controls, and patients with allergic rhinitis, CRS, or CRS with nasal polyposis. The second arm was collection of nasal tissue from normal controls undergoing inferior turbinoplasty, or patients with nasal polyposis. Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction techniques were used to determine levels in the lavage fluid and relative gene expression in the tissue of SP, IL-33, and IL-37. In total, 70 lavage and 23 tissue specimens were obtained. The level of SP was highest in patients with polyps; however, gene expression was reduced compared to normal controls. The level of IL-33 was reduced in patients with polyps as compared to patients with allergy and sinusitis, and its gene expression was not significantly different from normal controls. IL-37 was elevated in the lavage fluid of patients with nasal polyps and its gene expression was increased in the polyp tissue. Levels of SP and IL-37 were elevated in the lavage fluid of patients with nasal polyps as compared to normal controls and other sinonasal pathologies, and gene expression of IL-37 was significantly increased in the polyp tissue itself. These findings implicate these neurohormonal molecules in the pathophysiology of nasal polyposis and provide possible novel therapeutic targets.
Assuntos
Pólipos Nasais , Rinite , Sinusite , Adulto , Doença Crônica , Humanos , Estudos ProspectivosRESUMO
The COVID-19 pandemic necessitated the rapid production of vaccines aimed at the production of neutralizing antibodies against the COVID-19 spike protein required for the corona virus binding to target cells. The best well-known vaccines have utilized either mRNA or an adenovirus vector to direct human cells to produce the spike protein against which the body produces mostly neutralizing antibodies. However, recent reports have raised some skepticism as to the biologic actions of the spike protein and the types of antibodies produced. One paper reported that certain antibodies in the blood of infected patients appear to change the shape of the spike protein so as to make it more likely to bind to cells, while other papers showed that the spike protein by itself (without being part of the corona virus) can damage endothelial cells and disrupt the blood-brain barrier. These findings may be even more relevant to the pathogenesis of long-COVID syndrome that may affect as many as 50% of those infected with SARS-CoV-2. In COVID-19, a response to oxidative stress is required by increasing anti-oxidant enzymes. In this regard, it is known that polyphenols are natural anti-oxidants with multiple health effects. Hence, there are even more reasons to intervene with the use of anti-oxidant compounds, such as luteolin, in addition to available vaccines and anti-inflammatory drugs to prevent the harmful actions of the spike protein.
Assuntos
COVID-19 , Glicoproteína da Espícula de Coronavírus , COVID-19/complicações , Células Endoteliais , Humanos , Pandemias , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética , Síndrome de COVID-19 Pós-AgudaRESUMO
Infection with SARS-CoV2 leads to COVID-19, the severity of which derives from the host's immune response, especially the release of a storm of pro-inflammatory cytokines. This coronavirus infects by first binding to the ectoenzyme Angiotensin Converting Enzyme 2 (ACE2), a serine protease acting as the receptor, while another serine protease is necessary for priming the viral spike "S" protein required for entering the cells. Repurposing existing drugs for potential anti-coronavirus activity have failed. As a result, there were intense efforts to rapidly produce ways of providing prophylactic active immunization (vaccines) or abortive passive (convalescent plasma or monoclonal antibodies) neutralizing antibodies. The availability of vaccines for COVID-19 have been largely successful, but many questions still remain unanswered. In spite of the original enthusiasm, clinical studies using convalescent serum or monoclonal antibodies have shown limited benefit. Moreover, the emergence of Long-COVID syndrome in most infected patients necessitates the development of treatment approaches that may prevent viral entry by blocking both serine proteases involved, as with a liposomal blend of the natural flavonoids luteolin and quercetin.
Assuntos
COVID-19 , Glicoproteína da Espícula de Coronavírus , Anticorpos Antivirais , COVID-19/terapia , Vacinas contra COVID-19 , Humanos , Imunização Passiva , Peptidil Dipeptidase A , RNA Viral , SARS-CoV-2 , Soroterapia para COVID-19RESUMO
COVID-19 derives from infection with Coronavirus [severe acute respiratory syndrome (SARS)-CoV-2] and is associated with high morbidity and mortality due to release of a storm of pro-inflammatory cytokines and thrombogenic agents resulting in destruction of the lungs. Many reports indicate that a considerable number of patients who are positive for SARS-CoV-2 are asymptomatic or have mild symptoms. However, increasing evidence suggests that many such patients who either recovered from or had mild symptoms after COVID-19 exhibit diffuse, multiorgan, symptoms months after the infection. These symptoms include malaise, myalgias, chest tightness, brain fog and other neuropsychiatric symptoms that were originally reported in children and named Multisystem Inflammatory Syndrome (MIS-C). Now the US Center for Disease Control (CDC) announced the recognition of a similar condition in adults, named Multisystem Inflammatory Syndrome (MIS-A). The symptoms characterizing these conditions are very similar to those associated with Mast Cell Activation Syndrome (MCAS, US ICD-110 code D89.42-idiopathic mast cell activation syndrome). Hence, the possibility of MCAS should be evaluated in any patient with MIS and/or multisystem inflammatory symptoms. In either case, these syndromes should be addressed with liposomal formulation (in olive pomace oil) of the flavone luteolin (e.g. PureLut® or FibroProtek®) together with the antihistamine rupatadine, which also has anti-platelet activating factor (PAF) activity and inhibits mast cells that have been implicated in the pathogenesis of cytokine storms in COVID-19.
Assuntos
Infecções por Coronavirus/patologia , Mastocitose/virologia , Pneumonia Viral/patologia , Síndrome de Resposta Inflamatória Sistêmica , Adulto , Betacoronavirus , COVID-19 , Criança , Ciproeptadina/administração & dosagem , Ciproeptadina/análogos & derivados , Humanos , Luteolina/administração & dosagem , Mastocitose/tratamento farmacológico , Pandemias , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológicoRESUMO
Periodontitis is a complex, multifactorial chronic disease involving continuous interactions among bacteria, host immune/inflammatory responses, and modifying genetic and environmental factors. More than any other cytokine family, the interleukin (IL)-1 family includes key signaling molecules that trigger and perpetuate periodontal inflammation. Over the years, the IL-1 family expanded to include 11 members of cytokines, some with agonist activity (IL-1α, IL-1ß, IL-18, IL-33, IL-36α, IL-36ß, and IL-36γ), receptor antagonists (IL-1Ra, IL-36Ra), and 2 anti-inflammatory cytokines (IL-37, IL-38). The IL-1 receptor antagonist (IL-1Ra) has emerged as a pivotal player in the defense against periodontitis. IL-33 primarily induces the production of Th2-associated cytokines but acts as an "alarmin" via stimulation of mast cells. The IL-36 subclass of cytokines may be important in regulating mucosal inflammation and homeostasis. IL-37 suppresses innate and acquired immune responses. IL-38 is the most recent member of the IL-1 superfamily and has anti-inflammatory properties similar to those of IL-37 but through different receptors. However, limited evidence exists regarding the role of IL-37 and IL-38 in periodontitis. Despite the development of IL-1 blocking agents, therapeutic blockade of select IL-1 family members for periodontitis has only been partially investigated in preclinical and clinical research, while the development of IL-37 and IL-38 as novel anti-inflammatory drugs has not been considered adequately. Here, we review the key properties of the IL-1 family members and provide insights into targeting or promoting select cytokines as new therapeutic agents.
Assuntos
Citocinas , Inflamação , Imunidade Adaptativa , Humanos , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-18 , InterleucinasRESUMO
Recent announcements indicated, without sharing any distinct published set of results, that the corticosteroid dexamethasone may reduce mortality of severe COVID-19 patients only. The recent Coronavirus [severe acute respiratory syndrome (SARS)-CoV-2]-associated multiorgan disease, called COVID-19, has high morbidity and mortality due to autoimmune destruction of the lungs stemming from the release of a storm of pro-inflammatory cytokines. Defense against this Corona virus requires activated T cells and specific antibodies. Instead, cytokines are responsible for the serious sequelae of COVID-19 that damage the lungs. Dexamethasone is a synthetic corticosteroid approved by the FDA 1958 as a broad-spectrum immunosuppressor and it is about 30 times as active and with longer duration of action (2-3 days) than cortisone. Dexamethasone would limit the production of and damaging effect of the cytokines, but will also inhibit the protective function of T cells and block B cells from making antibodies, potentially leading to increased plasma viral load that will persist after a patient survives SARS. Moreover, dexamethasone would block macrophages from clearing secondary, nosocomial, infections. Hence, dexamethasone may be useful for the short-term in severe, intubated, COVID-19 patients, but could be outright dangerous during recovery since the virus will not only persist, but the body will be prevented from generating protective antibodies. Instead, a pulse of intravenous dexamethasone may be followed by administration of nebulized triamcinolone (6 times as active as cortisone) to concentrate in the lungs only. These corticosteroids could be given together with the natural flavonoid luteolin because of its antiviral and anti-inflammatory properties, especially its ability to inhibit mast cells, which are the main source of cytokines in the lungs. At the end, we should remember that "The good physician treats the disease; the great physician treats the patient who has the disease" [Sir William Osler's (1849-1919)].
Assuntos
Infecções por Coronavirus/tratamento farmacológico , Dexametasona/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Betacoronavirus , COVID-19 , Humanos , Pandemias , SARS-CoV-2 , Tratamento Farmacológico da COVID-19RESUMO
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder affecting 1/3000 individuals worldwide. It results from germline mutations of the neurofibromin gene and it is fully penetrant by the age of 5. Neurofibromin is a 2818 amino acid protein that is produced in many cell types, but its levels are especially high in the nervous system.
Assuntos
Mastócitos/citologia , Neurofibromatose 1/patologia , Genes da Neurofibromatose 1 , HumanosRESUMO
Neurodevelopment has been studied extensively, especially in respect to abuse, anoxia, nutritional status and prematurity/low birth weight. However, less attention has been paid to innate and environmental factors, as well as to inflammatory conditions that may adversely affect neurodevelopment and learning in children. These include heavy metals, herbicides and polyvinyl chlorides (PVCs), mycotoxins, viral infections and Lyme disease-associated pathogens, as well as number of conditions such as chronic inflammatory response syndrome (CIRS) and Mast cell activation syndrome (MCAS). Early recognition of factors/conditions that could interfere with neurodevelopment is critical. Corrective actions, including the use of some unique natural flavonoids, could have lasting beneficial results.
Assuntos
Sistema Nervoso Central/fisiopatologia , Desenvolvimento Infantil , Sistema Nervoso Central/efeitos dos fármacos , Criança , Flavonoides/uso terapêutico , Herbicidas/efeitos adversos , Humanos , Inflamação/complicações , Aprendizagem , Doença de Lyme/complicações , Mastocitose/complicações , Metais Pesados/efeitos adversos , Micotoxinas/efeitos adversos , Cloreto de Polivinila/efeitos adversos , Viroses/complicaçõesRESUMO
Stress and inflammation have become the curses of our times and are the main pathogenetic factors in multiple diseases that are often comorbid and include allergies and asthma, eczema and psoriasis, fibromyalgia syndrome, mast cell activation syndrome, irritable bowel syndrome, myalgic encephalomyelitis/chronic fatigue syndrome and autism spectrum disorder (ASD). Unfortunately, there are no effective drugs. Cross-talk between mast cells and microglia in the hypothalamus and amygdala could explain stress-induced inflammation. We recently showed that the "alarmin" IL-33 could play a major role through its synergistic action with the neuropeptide substance P to stimulate human mast cell secretion of the pro-inflammatory molecules IL-1ß, TNF and VEGF. A new formulation using pure luteolin with Ashwagandha has now been developed and could be of significant benefit to patients suffering from these diseases.
Assuntos
Inflamação/fisiopatologia , Inflamação/terapia , Luteolina/uso terapêutico , Estresse Psicológico/fisiopatologia , Estresse Psicológico/terapia , Tonsila do Cerebelo , Humanos , Hipotálamo , Interleucina-1beta , Interleucina-33 , Mastócitos , Microglia , Extratos Vegetais , Fator de Necrose Tumoral alfa , Fator A de Crescimento do Endotélio VascularRESUMO
BACKGROUND: Fibrosis involves the activation of inflammatory cells, leading to a decrease in physiological function of the affected organ or tissue. AIMS: To update and synthesize relevant information concerning fibrosis into a new hypothesis to explain the pathogenesis of fibrosis and propose potential novel therapeutic approaches. MATERIALS AND METHODS: Literature was reviewed and relevant information is discussed in the context of the pathogenesis of fibrosis. RESULTS: A number of cytokines and their mRNA are involved in the circulatory system and in organs of patients with fibrotic tissues. The profibrotic cytokines are generated by several activated immune cells, including fibroblasts and mast cells (MCs), which are important for tissue inflammatory responses to different types of injury. MC-derived TNF, IL-1, and IL-33 contribute crucially to the initiation of a cascade of the host defence mechanism(s), leading to the fibrosis process. Inhibition of TNF and inflammatory cytokines may slow the progression of fibrosis and improve the pathological status of the affected subject. IL-37 is generated by various types of immune cells and is an IL-1 family member protein. IL-37 is not a receptor antagonist; it binds IL-18 receptor alpha (IL-18Rα) and delivers the inhibitory signal by using TIR8. It has been shown that IL-37 can be protective in inflammation and injury, and inhibits both innate and adaptive immunity. DISCUSSION: IL-37 may be useful for suppression of inflammatory diseases induced by inhibiting MyD88-dependent TLR signalling. In addition, IL-37 downregulates NF-κB induced by TLR2 or TLR4 through a mechanism dependent on IL-18Rα. CONCLUSION: This review summarizes current knowledge on the role of MC in inflammation and tissue/organ fibrosis, with a focus on the therapeutic potential of IL-37-targeting cytokines.
Assuntos
Fibrose/metabolismo , Fibrose/patologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1/metabolismo , Mastócitos/metabolismo , Mastócitos/patologia , Animais , Fibroblastos/metabolismo , Fibroblastos/patologia , HumanosRESUMO
Cachexia is a wasting condition associated with late stages of many chronic illnesses and may be present in up to 80% of patients with advanced cancers. Cachexia is a metabolic derangement resulting in a disturbance to the homeostasis of muscle breakdown and synthesis, favoring catabolism and muscle loss. Despite making strides in treating cancer itself, there have been no major advances in the treatment of cachexia pharmacologically or nutritionally. Clinical trials using anti-TNF biologics and thalidomide have largely failed. A new approach may be to focus on other possible waste-inducing mediators, possibly derived from mast cells, and the beneficial action of select natural flavonoids.
Assuntos
Caquexia , Flavonoides/uso terapêutico , Mastócitos , Neoplasias , Talidomida/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Caquexia/tratamento farmacológico , Caquexia/metabolismo , Caquexia/patologia , Humanos , Mastócitos/metabolismo , Mastócitos/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologiaRESUMO
IL-1 family members include inflammatory and anti-inflammatory cytokines. They can be beneficial or detrimental, not only in cancer, but also in inflammatory conditions. Mast cells (MCs) originate from CD34+/CD117+/CD13+ pluripotent hematopoietic stem cells, express c-Kit receptor (c-Kit-R), which regulates the proliferation and sustain the survival, differentiation and maturation of MCs. They are immune cells involved in innate and adaptive immunity, allergy, autoimmunity, cancer and inflammation. MCs along with T cells and macrophages release interleukin (IL)-10, which is a pleiotropic immunoregulatory cytokine with multiple biological effects. IL-10 inhibits Th1 inflammatory cells, in particular TNF mostly generated by macrophages and MCs, and down-regulates IFN-γ, IL-1 and IL-6. IL-37 is a family member cytokine which binds IL-18 receptor α chain and inhibits inflammatory mediators including TNF, IL-1, IL-6, IL-33 and nitric oxide (NO). IL-37 similar to IL-10 inhibits MC inflammatory cytokines in several disorders, including asthma, allergy, arthrtitis and cancer. Here we report a study comparing IL-10 with IL-37, two anti-inflammatory cytokines.
Assuntos
Imunidade Adaptativa , Imunidade Inata , Mastócitos/imunologia , Transdução de Sinais/imunologia , Animais , Antígenos CD/imunologia , Artrite/imunologia , Artrite/patologia , Asma/imunologia , Asma/patologia , Citocinas/imunologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Mastócitos/patologia , Neoplasias/imunologia , Neoplasias/patologia , Óxido Nítrico/imunologia , Células Th1/imunologia , Células Th1/patologiaRESUMO
Mast cells (MCs) are tissue-resident immune cells that participate in a variety of allergic and inflammatory conditions, including periodontal disease, through the release of cytokines, chemokines and proteolytic enzymes. Porhyromonas gingivalis (P. g) is widely recognized as a major pathogen in the development and progression of periodontitis. Here we compared the differential effects of lipopolysaccharides (LPS) from P. g and E. coli on the expression and production of tumor necrosis factor (TNF), vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein (MCP-1) by human MCs. Human LAD2 MCs were stimulated with LPS from either P. g or E. coli (1-1000 ng/ml). MCs were also stimulated with SP (2µM) serving as the positive control or media alone as the negative control. After 24 h, the cells and supernatant fluids were collected and analyzed for ß-Hexosaminidase (ß-hex) spectrophotometrically, TNF, VEGF and MCP-1 release by ELISA and real-time polymerase chain reaction (PCR) for mediator gene expression, respectively. To assess the functional role of tolllike receptors (TRL) in mediator release, MCs were pre-incubated with either anti-TLR2 or anti- TLR4 (2 µg/ml) polyclonal antibody for 1 h before stimulation with LPS. When MCs were stimulated with SP (2 µM), there was a statistically significant ß-hex release as well as release of TNF, VEGF and MCP-1. Stimulation of MCs with either type of LPS did not induce degranulation based on the lack of ß-hex release. However, both types of LPS stimulated expression and release of TNF, VEGF and MCP-1. Although, P. g LPS induced significant release of TNF, VEGF and MCP-1, the effect was not concentration-dependent. There was no statistically significant difference between the effects of P. g and E. coli LPS. P. g LPS stimulated TNF through TLR-2 while E. coli utilized TRL-4 instead. In contrast, VEGF release by P. g LPS required both TRL-2 and TRL-4 while E. coli LPS required TLR-4. Release of MCP-1 was independent of TLR-2 or TLR-4. P. g LPS activates human MCs to generate and release TNF, VEGF and MCP-1 through different TLRs than E. coli LPS. MCs may, therefore, be involved in the inflammatory processes responsible for periodontal disease.
Assuntos
Endotoxinas/farmacologia , Escherichia coli/fisiologia , Mediadores da Inflamação/fisiologia , Lipopolissacarídeos/farmacologia , Mastócitos/efeitos dos fármacos , Periodontite/imunologia , Porphyromonas gingivalis/fisiologia , Degranulação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quimiocina CCL2/biossíntese , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Escherichia coli/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia de Mastócitos/patologia , Mastócitos/fisiologia , Periodontite/microbiologia , Porphyromonas gingivalis/química , RNA Mensageiro/biossíntese , Substância P/farmacologia , Receptor 2 Toll-Like/antagonistas & inibidores , Receptor 2 Toll-Like/fisiologia , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/fisiologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Endocrinology systems exert an important effect on vascular function and have direct actions on blood vessels. Estrogens provoke an increase in skin elasticity, epidermal hydration, skin thickness, reduce skin wrinkles and augment the content of collagen and the level of vascularisation. Therefore, there is an intricate cross-talk between skin conditions and stress. In stress, ß2--adrenoreceptor (ß2AR) pathway, cortisol, epinephrine and norepinephrine increase DNA damage and interfere with the regulation of the cell cycle, contributing to aging and skin diseases. Substance P is a neuropeptide released in the skin from the peripheral nerve and is related to stress and inflammation. SP provokes infiltration of inflammatory cells in the skin and induces a variety of cytokines/chemokines. Corticotropin-releasing hormone (CRH), produced by mast cells, is a neuropeptide also expressed in skin and responds to stress. CRH initiates diverse intracellular signaling pathways, including cAMP, protein kinase C, and mitogen-activated protein kinases (MAPK). Under stress, CRH, glucocorticoids, epinephrine and cytokines are generated. Moreover, the release of ACTH binds the receptor MC2-R and stimulates the generation of glucocorticoids such as corticosterone and cortisol, which interact with the transcription factors AP-1 and NF-kB. In skin keratinocytes, ACTH promotes the generation of pro-inflammatory cytokines, which enhances T-cell activity. Cortisol is immunosuppressive by inhibiting Th1 and Th2 cell response, antigen presentation, antibody and cytokine/chemokine production. However, glucocorticoids are certainly helpful in Th1-mediated autoimmune disorders. On the other hand, cytokines, such as TNF, IL-1 and IL-6, stimulate the generation of CRH and activate HPA axis in inflammatory states. Here, we describe for the first time a cross-talk between endocrinology and skin, including pro-inflammatory cytokines and neurogenic inflammatory pathways.
Assuntos
Sistema Endócrino/fisiologia , Pele/imunologia , Hormônio Adrenocorticotrópico/fisiologia , Animais , Hormônio Liberador da Corticotropina/fisiologia , Citocinas/fisiologia , Humanos , Transdução de Sinais/fisiologia , Estresse Psicológico/fisiopatologia , Substância P/fisiologiaRESUMO
Autism spectrum disorders (ASDs) affect as many as 1 in 45 children and are characterized by deficits in sociability and communication, as well as stereotypic movements. Many children also show severe anxiety. The lack of distinct pathogenesis and reliable biomarkers hampers the development of effective treatments. As a result, most children with ASD are prescribed psychopharmacologic agents that do not address the core symptoms of ASD. Autoantibodies against brain epitopes in mothers of children with ASD and many such children strongly correlate with allergic symptoms and indicate an aberrant immune response, as well as disruption of the blood-brain barrier (BBB). Recent epidemiological studies have shown a strong statistical correlation between risk for ASD and either maternal or infantile atopic diseases, such as asthma, eczema, food allergies and food intolerance, all of which involve activation of mast cells (MCs). These unique tissue immune cells are located perivascularly in all tissues, including the thalamus and hypothalamus, which regulate emotions. MC-derived inflammatory and vasoactive mediators increase BBB permeability. Expression of the inflammatory molecules interleukin (IL-1ß), IL-6, 1 L-17 and tumor necrosis factor (TNF) is increased in the brain, cerebrospinal fluid and serum of some patients with ASD, while NF-kB is activated in brain samples and stimulated peripheral blood immune cells of other patients; however, these molecules are not specific. Instead the peptide neurotensin is uniquely elevated in the serum of children with ASD, as is corticotropin-releasing hormone, secreted from the hypothalamus under stress. Both peptides trigger MC to release IL-6 and TNF, which in turn, stimulate microglia proliferation and activation, leading to disruption of neuronal connectivity. MC-derived IL-6 and TGFß induce maturation of Th17 cells and MCs also secrete IL-17, which is increased in ASD. Serum IL-6 and TNF may define an ASD subgroup that benefits most from treatment with the natural flavonoid luteolin. Atopic diseases may create a phenotype susceptible to ASD and formulations targeting focal inflammation of the brain could have great promise in the treatment of ASD.
Assuntos
Transtorno do Espectro Autista/imunologia , Encéfalo/imunologia , Hipersensibilidade/imunologia , Inflamação/imunologia , Transtorno do Espectro Autista/dietoterapia , Autoanticorpos/sangue , Criança , Humanos , Mediadores da Inflamação/sangue , Luteolina/uso terapêutico , Neurotensina/sangueRESUMO
Autism spectrum disorders (ASDs) have been associated with brain inflammation as indicated by microglia activation, as well as brain expression and increased plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF). Here we report that serum levels of IL-6 and TNF were elevated (61.95 ± 94.76 pg ml(-1) and 313.8 ± 444.3 pg ml(-1), respectively) in the same cohort of patients with elevated serum levels of corticotropin-releasing hormone (CRH) and neurotensin (NT), while IL-9, IL-31 and IL-33 were not different from controls. The elevated CRH and NT levels did not change after treatment with a luteolin-containing dietary formulation. However, the mean serum IL-6 and TNF levels decreased significantly (P=0.036 and P=0.015, respectively) at the end of the treatment period (26 weeks) as compared with levels at the beginning; these decreases were strongly associated with children whose behavior improved the most after luteolin formulation treatment. Our results indicate that there are distinct subgroups of children within the ASDs that may be identifiable through serum levels of IL-6 and TNF and that these cytokines may constitute distinct prognostic markers for at least the beneficial effect of luteolin formulation.
Assuntos
Transtorno do Espectro Autista , Sintomas Comportamentais , Dietoterapia/métodos , Interleucina-6/sangue , Luteolina/farmacologia , Fator de Necrose Tumoral alfa/sangue , Transtorno do Espectro Autista/sangue , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/dietoterapia , Transtorno do Espectro Autista/psicologia , Sintomas Comportamentais/diagnóstico , Sintomas Comportamentais/dietoterapia , Criança , Pré-Escolar , Hormônio Liberador da Corticotropina/sangue , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Alimentos Formulados , Humanos , Inflamação/metabolismo , Masculino , Neurotensina/sangue , Prognóstico , Reprodutibilidade dos Testes , Resultado do TratamentoRESUMO
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by defects in communication and social interactions, as well as stereotypic behaviors. Symptoms typically worsen with anxiety and stress. ASD occur in early childhood, often present with regression and have a prevalence of 1 out of 68 children. The lack of distinct pathogenesis or any objective biomarkers or reliable animal models hampers our understanding and treatment of ASD. Neurotensin (NT) and corticotropin-releasing hormone (CRH) are secreted under stress in various tissues, and have proinflammatory actions. We had previously shown that NT augments the ability of CRH to increase mast cell (MC)-dependent skin vascular permeability in rodents. CRH also induced NT receptor gene and protein expression in MCs, which have been implicated in ASD. Here we report that serum of ASD children (4-10 years old) has significantly higher NT and CRH levels as compared with normotypic controls. Moreover, there is a statistically significant correlation between the number of children with gastrointestinal symptoms and high serum NT levels. In Bull Terriers that exhibit a behavioral phenotype similar to the clinical presentation of ASD, NT and CRH levels are also significantly elevated, as compared with unaffected dogs of the same breed. Further investigation of serum NT and CRH, as well as characterization of this putative canine breed could provide useful insights into the pathogenesis, diagnosis and treatment of ASD.
Assuntos
Comportamento Animal , Transtornos Globais do Desenvolvimento Infantil/sangue , Hormônio Liberador da Corticotropina/sangue , Neurotensina/sangue , Fenótipo , Animais , Criança , Pré-Escolar , Modelos Animais de Doenças , Cães , Feminino , Humanos , Masculino , Comportamento EstereotipadoRESUMO
Increasing evidence indicates that tumor microenvironment (TME) is crucial in tumor survival and metastases. Inflammatory cells accumulate around tumors and strangely appear to be permissive to their growth. One key stroma cell is the mast cell (MC), which can secrete numerous pro- and antitumor molecules. We investigated the presence and degranulation state of MC in pancreatic ductal adenocarcinoma (PDAC) as compared to acute ancreatitis (AP). Three different detection methods: (a) toluidine blue staining, as well as immunohistochemistry for (b) tryptase and (c) c-kit, were utilized to assess the number and extent of degranulation of MC in PDAC tissue (n=7), uninvolved pancreatic tissue derived from tumor-free margins (n=7) and tissue form AP (n=4). The number of MC detected with all three methods was significantly increased in PDAC, as compared to normal pancreatic tissue derived from tumor-free margins (p<0.05). The highest number of MC was identified by c-kit, 22.2∓7.5 per high power field (HPF) in PDAC vs 9.7∓5.1 per HPF in normal tissue. Contrary to MC in AP, where most of the detected MC were found degranulated, MC in PDAC appeared intact. In conclusion, MC are increased in number, but not degranulated in PDAC, suggesting that they may contribute to cancer growth by permitting selective release of pro-tumorogenic molecules.
Assuntos
Carcinoma Ductal Pancreático/imunologia , Mastócitos/imunologia , Neoplasias Pancreáticas/imunologia , Pancreatite/imunologia , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Carcinoma Ductal Pancreático/enzimologia , Carcinoma Ductal Pancreático/patologia , Contagem de Células , Degranulação Celular , Feminino , Humanos , Imuno-Histoquímica , Masculino , Mastócitos/enzimologia , Mastócitos/patologia , Pessoa de Meia-Idade , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/patologia , Pancreatite/enzimologia , Pancreatite/patologia , Proteínas Proto-Oncogênicas c-kit/análise , Coloração e Rotulagem , Triptases/análise , Microambiente TumoralRESUMO
Vitiligo is a disorder of depigmentation, for which the pathogenesis is as yet unclear. Interleukin (IL)-8 (CXCL8) is a key inflammatory chemokine. We investigated the regulation of IL-8 production in human melanocytes, and the IL-8 serum levels and skin gene expression in patients with vitiligo and in controls. Cultured melanocytes were stimulated for 24 h with tumour necrosis factor (TNF) 100 ng/mL and IL-1ß 10 ng/mL, with or without pretreatment with luteolin 50 µmol/L for 30 min, and IL-8 release was measured by ELISA. Serum cytokines were measured by a microbead array. Skin biopsies were taken from healthy subjects (n = 14) as well as from marginal lesional and nonlesional skin from patients with vitiligo (n = 15). IL-8 gene expression was evaluated by quantitative real time PCR. Both TNF and IL-1ß stimulated significant IL-8 release (P < 0.01) from melanocytes, whereas pretreatment with luteolin significantly inhibited this effect (P < 0.01). IL-8 gene expression was significantly increased in vitiligo compared with control skin (P < 0.05). IL-8 may be involved in vitiligo inflammation. Inhibition by luteolin of IL-8 release could be useful for vitiligo therapy.
Assuntos
Interleucina-8/metabolismo , Luteolina/farmacologia , Melanócitos/efeitos dos fármacos , Vitiligo/metabolismo , Adulto , Estudos de Casos e Controles , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Feminino , Perfilação da Expressão Gênica , Humanos , Interleucina-1beta/farmacologia , Interleucina-6/metabolismo , Masculino , Melanócitos/metabolismo , Pessoa de Meia-Idade , Pele/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Vitiligo/tratamento farmacológicoRESUMO
OBJECTIVE: To investigate the hypothesis that levels of interferon (IFN)-γ and interleukin (IL)-4, as well as the newer cytokines IL-33 and thymic stromal lymphopoietin (TSLP), in gingival crevicular fluid (GCF) samples differ from sites of patients at various clinical stages of periodontal disease and controls. BACKGROUND: Periodontal diseases result from the complex interplay between pathogenic bacteria and the host's immune responses. Several inflammatory mediators, such as IFN-γ and IL-4, have been detected in GCF samples in patients with periodontitis, but the results are mostly contradicting due to the lack of uniformity and collection of sites and methods of analysis. MATERIAL AND METHODS: GCF samples were collected from sites with different clinical characteristics (healthy, gingivitis and periodontitis sites) from periodontally healthy ( n = 14), plaque-induced gingivitis (n = 17) and chronic periodontitis (n = 11) subjects. The GCF samples were analyzed for the frequency of detection and levels of IFN-γ, IL-4, IL-33 and TSLP using a multiplex bead immunoassay. RESULTS: Inflamed sites in both patients with plaque-induced gingivitis and chronic periodontitis showed statistically significantly higher volume of GCF compared to non-inflamed sites in all patients. IFN-γ could be detected in about 50-70% of the samples analyzed and at significantly higher levels in sites with periodontitis compared to healthy sites in patients with chronic periodontitis (p = 0.035). We also show a statistically significant decrease of IFN-? in healthy sites of patients with chronic periodontitis as compared to gingivitis sites in patients with plaque-induced gingivitis (p = 0.047). Only some of the GCF samples showed detectable levels for IL-4 and TSLP, while IL-33 was below the detection level in all samples collected. CONCLUSIONS: These results suggest that IFN-γ levels in GCF depend on the clinical stage of the site and not on the disease stage of the patient, but need to be expanded to a greater number of subjects and additional analysis of corresponding gingival tissue biopsies for cytokine gene expression.