RESUMO
Giardiasis is a parasitic disease caused by Giardia lamblia (G. lamblia) that affects people worldwide. Still, few studies report on the immunoregulatory effects of the biomolecules of colostrum during interactions with G. lamblia. This study aimed to assess the concentrations of melatonin and cortisol hormones, the percentage of Treg cells, and the levels of cytokines IL-10 and TGF-ß in colostrum from mothers who tested positive for the parasite. This cross-sectional study analyzed colostrum samples from 25 puerperal. The samples were tested using an ELISA to determine if they were seropositive for G. lamblia and the type of antibody present (IgM and IgG). Based on the results, the samples were divided into three groups: a control group (N = 10) with no reaction to either IgM or IgG, a group seropositive for IgG (IgG+/IgM-; N = 8), and a group seropositive for IgM (IgM+/IgG-; N = 7). The concentrations of melatonin and cortisol were measured using the ELISA method. Additionally, cytokines IL-10 and TGF-ß and immunophenotyping were analyzed using flow cytometry. In the group that tested positive for IgM anti-G. lamblia, the concentration of melatonin was lower. However, in the colostrum from mothers who tested positive for IgG anti-G. lamblia, the level of this hormone had increased. The cortisol levels were similar between the groups, regardless of seropositivity. There was a higher percentage of Treg cells in the colostrum from mothers who tested positive for IgM anti-G. lamblia. TGF-ß levels also increased in the colostrum of mothers who tested positive for IgM anti-G. lamblia. In the seronegative group for G. lamblia, there was a positive correlation between melatonin concentration and the percentage of Treg cells. These data suggest that the increase in regulatory cells and cytokines and the reduction in melatonin in colostrum from mothers with recent giardia infection may contribute to the evolution and manifestation of the disease.
Assuntos
Colostro , Giardia lamblia , Giardíase , Melatonina , Linfócitos T Reguladores , Fator de Crescimento Transformador beta , Melatonina/metabolismo , Melatonina/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Humanos , Feminino , Giardíase/imunologia , Giardíase/parasitologia , Giardia lamblia/imunologia , Adulto , Colostro/imunologia , Colostro/química , Estudos Transversais , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/imunologia , Interleucina-10/metabolismo , Interleucina-10/imunologia , Imunoglobulina M/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Hidrocortisona , Gravidez , Adulto JovemRESUMO
Melatonin is the major product both synthesized and secreted by the pineal gland during the night period and it is the principal chronobiotic hormone that regulates the circadian rhythms and seasonal changes in vertebrate biology. Moreover, melatonin shows both a broad distribution along the phylogenetically distant organisms and a high functional versatility. At the present time, a significant amount of experimental evidence has been reported in scientific literature and has clearly shown a functional relationship between the endocrine, nervous, and immune systems. The biochemistry basis of the functional communication between these systems is the utilization of a common chemicals signals. In this framework, at present melatonin is considered to be a relevant member of the so-called neuro-endocrine-immunological network. Thus, both in vivo and in vitro investigations conducted in both experimental animals and humans, have clearly documented that melatonin has an important immunomodulatory role. However, most of the published results refer to information on T lymphocytes, i.e., cell-mediated immunity. On the contrary, fewer studies have been carried out on B lymphocytes, the cells responsible for the so-called humoral immunity. In this review, we have focused on the biological role of melatonin in the humoral immunity. More precisely, we report the actions of melatonin on B lymphocytes biology and on the production of different types of antibodies.
Assuntos
Linfócitos B , Imunidade Humoral , Melatonina , Melatonina/imunologia , Melatonina/metabolismo , Animais , Humanos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Imunomodulação , Ritmo Circadiano/imunologia , Sistema Imunitário/metabolismo , Sistema Imunitário/imunologia , Glândula Pineal/metabolismo , Glândula Pineal/imunologiaRESUMO
The novel coronavirus pandemic has emerged as one of the significant medical-health challenges of the current century. The World Health Organization has named this new virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the first detection of SARS-CoV-2 in November 2019 in Wuhan, China, physicians, researchers, and others have made it their top priority to find drugs and cures that can effectively treat patients and reduce mortality rates. The symptoms of Coronavirus Disease 2019 (COVID-19) include fever, dry cough, body aches, and anosmia. Various therapeutic compounds have been investigated and applied to mitigate the symptoms in COVID-19 patients and cure the disease. Degenerative virus analyses of the infection incidence and COVID-19 have demonstrated that SARS-CoV-2 penetrates the pulmonary alveoli's endothelial cells through Angiotensin-Converting Enzyme 2 (ACE2) receptors on the membrane, stimulates various signaling pathways and causes excessive secretion of cytokines. The continuous triggering of the innate and acquired immune system, as well as the overproduction of pro-inflammatory factors, cause a severe condition in the COVID-19 patients, which is called "cytokine storm". It can lead to acute respiratory distress syndrome (ARDS) in critical patients. Severe and critical COVID-19 cases demand oxygen therapy and mechanical ventilator support. Various drugs, including immunomodulatory and immunosuppressive agents (e.g., monoclonal antibodies (mAbs) and interleukin antagonists) have been utilized in clinical trials. However, the studies and clinical trials have documented diverging findings, which seem to be due to the differences in these drugs' possible mechanisms of action. These drugs' mechanism of action generally includes suppressing or modulating the immune system, preventing the development of cytokine storm via various signaling pathways, and enhancing the blood vessels' diameter in the lungs. In this review article, multiple medications from different drug families are discussed, and their possible mechanisms of action are also described.
Assuntos
Antivirais/imunologia , Tratamento Farmacológico da COVID-19 , Agentes de Imunomodulação/farmacologia , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Antivirais/farmacologia , Azetidinas/imunologia , Azetidinas/farmacologia , COVID-19/etiologia , Dexametasona/imunologia , Dexametasona/farmacologia , Famotidina/imunologia , Famotidina/farmacologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Infliximab/imunologia , Infliximab/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Melatonina/imunologia , Melatonina/farmacologia , Purinas/imunologia , Purinas/farmacologia , Pirazóis/imunologia , Pirazóis/farmacologia , Sulfonamidas/imunologia , Sulfonamidas/farmacologiaRESUMO
Melatonin is a highly conserved molecule found in prokaryotes and eukaryotes that acts as the darkness hormone, translating environmental lighting to the whole body, and as a moderator of innate and acquired defense, migration, and cell proliferation processes. This review evaluates the importance of pineal activity in monitoring PAMPs and DAMPs and in mounting an inflammatory response or innate immune response. Activation of the immune-pineal axis, which coordinates the pro-and anti-inflammatory phases of an innate immune response, is described. PAMPs and DAMPs promote the immediate suppression of melatonin production by the pineal gland, which allows leukocyte migration. Monocyte-derived macrophages, important phagocytes of microbes, and cellular debris produce melatonin locally and thereby initiate the anti-inflammatory phase of the acute inflammatory response. The role of locally produced melatonin in organs that directly contact the external environment, such as the skin and the gastrointestinal and respiratory tracts, is also discussed. In this context, as resident macrophages are self-renewing cells, we explore evidence indicating that, besides avoiding overreaction of the immune system, extra-pineal melatonin has a fundamental role in the homeostasis of organs and tissues.
Assuntos
Imunidade Inata , Macrófagos/imunologia , Melatonina/imunologia , Glândula Pineal/imunologia , Animais , Humanos , Inflamação/imunologiaRESUMO
Coronavirus (SARS-CoV-2) is spreading rapidly in the world and is still taking a heavy toll. Studies show that cytokine storms and imbalances in T-helper (Th)1/Th2 play a significant role in most acute cases of the disease. A number of medications have been suggested to treat or control the disease but have been discontinued due to their side effects. Melatonin, as an intrinsic molecule, possesses pharmacological anti-inflammatory and antioxidant properties that decreases in concentration with age; as a result, older people are more prone to various diseases. In this study, patients who were hospitalized with a diagnosis of coronavirus disease 2019 (COVID-19) were given a melatonin adjuvant (9 mg daily, orally) for fourteen days. In order to measure markers of Th1 and Th2 inflammatory cytokines (such as interleukin (IL)-2, IL-4, and interferon (IFN)-γ) as well as the expression of Th1 and Th2 regulatory genes (signal transducer and activator of transcription (STAT)4, STAT6, GATA binding protein 3 (GATA3), and T-box expressed in T cell (T-bet)), blood samples were taken from patients at the beginning and end of the treatment. Adjuvant therapy with melatonin controlled and reduced inflammatory cytokines in patients with COVID-19. Melatonin also controlled and modulated the dysregulated genes that regulate the humoral and cellular immune systems mediated by Th1 and Th2. In this study, it was shown for the first time that melatonin can be used as a medicinal adjuvant with anti-inflammatory mechanism to reduce and control inflammatory cytokines by regulating the expression of Th1 and Th2 regulatory genes in patients with COVID-19.
Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19 , Citocinas/sangue , Melatonina , Transdução de Sinais , Células Th1 , Células Th2 , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/imunologia , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/imunologia , Feminino , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/imunologia , Irã (Geográfico)/epidemiologia , Masculino , Melatonina/administração & dosagem , Melatonina/imunologia , Pessoa de Meia-Idade , SARS-CoV-2 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Resultado do TratamentoRESUMO
Myasthenia gravis (MG) is a prototypic organ-specific autoimmune disorder that, in most cases, is mainly mediated by antibodies against the acetylcholine receptor. Evidence implicates CD4+ T helper (Th) cells in the development of MG, whereas regulatory T cells (Tregs) are associated with disease resolution. Melatonin has important immunoregulatory effects in many T cell-mediated autoimmune diseases. However, there are few studies on the role of melatonin in MG. In the present study, we investigated serum melatonin levels and melatonin receptor expression in MG patients and healthy controls (HCs). We also evaluated the impact of melatonin administration on peripheral CD4+ Th cells and related cytokine production. Serum melatonin levels were lower in MG patients than in HCs, and MT1 expression was lower in PBMCs from MG patients than in those from HCs. Administration of melatonin significantly decreased Th1 and Th17 cell responses and proinflammatory cytokine production. Further investigation in vitro revealed that melatonin administration increased FoxP3 and IL-10 expression in CD4+ T cells from MG patients and enhanced the suppressive function of Tregs. These findings indicate that melatonin exerts immunoregulatory activity in MG by balancing effector and regulatory Th cell populations as well as by suppressing proinflammatory cytokine production.
Assuntos
Melatonina/imunologia , Miastenia Gravis/imunologia , Células Th1/imunologia , Células Th17/imunologia , Adulto , Idoso , Feminino , Fatores de Transcrição Forkhead/imunologia , Humanos , Interleucina-10/imunologia , Masculino , Melatonina/sangue , Pessoa de Meia-Idade , Miastenia Gravis/sangue , Receptor MT1 de Melatonina/metabolismoRESUMO
Objectives of the current work were to investigate the role of photoperiod and melatonin in the alteration of immune responses in a reptilian species. Animals were kept on a regimen of short or long days. Blood was obtained and leucocytes were isolated to study various innate immune responses. Lymphocytes were separated from blood by density gradient centrifugation and were used to study proliferation. Respiratory burst activity was measured through nitrobluetetrazolium reduction assay while nitric oxide production by leucocytes was assayed by nitrite assay. Lymphocytes were isolated and used to study proliferation with and without B and T cell mitogens. Photoperiodic manipulation acted differentially on leucocyte counts. Nitrite release was increased while superoxide production was decreased in cultures obtained from the snakes kept on the short day regimen. Significant enhancement of mitogen induced lymphocyte proliferation was observed in cultures from the animals kept in either long or short days compared to cultures from the animals kept in natural ambient day length. Use of in vitro melatonin showed that lymphocytes from the animals, kept in long days, were more reactive. Photoperiod induces changes in immune status which may permit adaptive functional responses in order to maintain seasonal energetic budgets of the animals. Physiological responses (like elevated immune status) are energetically expensive, therefore, animals have evolved a strategy to reduce immune functions at times when energy is invested in reproductive activities. Natrix piscator breeds from September to December and elevated pineal hormone in winter suppresses reproduction while immunity is stimulated.
Assuntos
Ritmo Circadiano/imunologia , Colubridae/imunologia , Imunidade Celular/imunologia , Imunidade Inata/imunologia , Animais , Cruzamento/métodos , Proliferação de Células/fisiologia , Água Doce , Ativação Linfocitária/imunologia , Linfócitos/imunologia , Masculino , Melatonina/imunologia , Fotoperíodo , Reprodução/imunologia , Estações do AnoRESUMO
The reasons for the relative resistance of children to certain infections such as that caused by coronavirus SARS-CoV2 are not yet fully clear. Deciphering these differences can provide important information about the pathogenesis of the disease. Regarding the SARS-CoV2 virus, children are at the same risk of infection as the general population of all ages, with the most serious cases being found in infants. However, it has been reported that the disease is much less frequent than in adults and that most cases are benign or moderate (even with high viral loads), provided there are no other risk factors or underlying diseases. It is not clear why they have lower morbidity and virtually no mortality. A series of findings, relationships and behavioral patterns between the infectious agent and the child host may account for the lower incidence and a greatly attenuated clinical presentation of the disease in children.
Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/patologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/patologia , Adulto , Fatores Etários , Enzima de Conversão de Angiotensina 2 , COVID-19 , Portador Sadio/transmissão , Portador Sadio/virologia , Criança , Coinfecção/epidemiologia , Coinfecção/imunologia , Coinfecção/patologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/transmissão , Humanos , Sistema Imunitário , Estilo de Vida , Melatonina/imunologia , Melatonina/metabolismo , Pandemias , Peptidil Dipeptidase A/imunologia , Peptidil Dipeptidase A/metabolismo , Vacinas Pneumocócicas/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/transmissão , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/patologia , SARS-CoV-2RESUMO
There is a growing appreciation that the regulation of the melatonergic pathways, both pineal and systemic, may be an important aspect in how viruses drive the cellular changes that underpin their control of cellular function. We review the melatonergic pathway role in viral infections, emphasizing influenza and covid-19 infections. Viral, or preexistent, suppression of pineal melatonin disinhibits neutrophil attraction, thereby contributing to an initial "cytokine storm", as well as the regulation of other immune cells. Melatonin induces the circadian gene, Bmal1, which disinhibits the pyruvate dehydrogenase complex (PDC), countering viral inhibition of Bmal1/PDC. PDC drives mitochondrial conversion of pyruvate to acetyl-coenzyme A (acetyl-CoA), thereby increasing the tricarboxylic acid cycle, oxidative phosphorylation, and ATP production. Pineal melatonin suppression attenuates this, preventing the circadian "resetting" of mitochondrial metabolism. This is especially relevant in immune cells, where shifting metabolism from glycolytic to oxidative phosphorylation, switches cells from reactive to quiescent phenotypes. Acetyl-CoA is a necessary cosubstrate for arylalkylamine N-acetyltransferase, providing an acetyl group to serotonin, and thereby initiating the melatonergic pathway. Consequently, pineal melatonin regulates mitochondrial melatonin and immune cell phenotype. Virus- and cytokine-storm-driven control of the pineal and mitochondrial melatonergic pathway therefore regulates immune responses. Virus-and cytokine storm-driven changes also increase gut permeability and dysbiosis, thereby suppressing levels of the short-chain fatty acid, butyrate, and increasing circulating lipopolysaccharide (LPS). The alterations in butyrate and LPS can promote viral replication and host symptom severity via impacts on the melatonergic pathway. Focussing on immune regulators has treatment implications for covid-19 and other viral infections.
Assuntos
Infecções por Coronavirus/fisiopatologia , Influenza Humana/metabolismo , Melatonina/metabolismo , Pneumonia Viral/fisiopatologia , Animais , Betacoronavirus/fisiologia , Vias Biossintéticas , COVID-19 , Ritmo Circadiano , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/imunologia , Humanos , Influenza Humana/imunologia , Melatonina/imunologia , Mitocôndrias/metabolismo , Orthomyxoviridae/fisiologia , Pandemias , Glândula Pineal/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , SARS-CoV-2 , Vírus/classificaçãoRESUMO
BACKGROUND: The aim of the present study is to determine the association of melatonin hormone level on CRP, Total Antioxidant Status, Leukocyte, Procalcitonin, and Malondialdehyde, all acute phase reactants in the dark and light cycle of rats with sepsis model. MATERIALS AND METHODS: In this study, 54 rats were divided into three groups. Whereas the first and third groups had a 12 h dark-light cycle, the second group was exposed to light for 24 h at 21°C-22°C for 10 d without any water and food restrictions. In the second and third groups, sepsis model was formed by cecal ligation and puncture (CLP) method at the end of 10th day, and blood samples were taken at the end of the 10th day. C-reactive protein, Malondialdehyde, Procalcitonin in the blood samples were analyzed by ELISA, and the levels of Total Antioxidant Status and leukocyte were determined by colorimetric method in the subsequent 12 and 24 h. RESULTS: CRP values increased in the second group rats, which were kept continuously under light and had undergone CLP, from 288.8 mg/L to 584.0 mg/L at the end of the 12 h and the end of the 24 h, approximately, two times. In rats, which were kept under 12 h of light, 12 h of darkness, and applied CLP (group 3), these values increased from 416.9 to 619.1; an increase of 1.5 times. When assessed for MDA, it was determined that the differences between Group 2 and Group 3 were more prominent between 0 h and 12 h. While the MDA values in group 2 increased from 16.53 nmol/mL at the 12 h to 17.66 nmol/mL at the 24 h. However, MDA values did not yield statistically significant changes in the third group. Changes in the in PCT values were similar to the MDA values obtained. Increase coefficient of the PCT values between 0 h and 12 h in the second group 2 was 1.26; however, in the third group, it was negligible. CONCLUSIONS: An increase in the oxidative stress was observed in the rats that underwent CLP and melatonin deprivation via continuous 24 h light exposure for 10 d. Accordingly, deprivation of light is considered to be effective in sepsis treatment due to the increase in melatonin levels in intensive care unit patients.
Assuntos
Proteína C-Reativa/análise , Melatonina/sangue , Pró-Calcitonina/sangue , Sepse/imunologia , Animais , Proteína C-Reativa/metabolismo , Modelos Animais de Doenças , Humanos , Unidades de Terapia Intensiva , Luz/efeitos adversos , Masculino , Malondialdeído/imunologia , Malondialdeído/metabolismo , Melatonina/imunologia , Melatonina/metabolismo , Estresse Oxidativo/imunologia , Estresse Oxidativo/efeitos da radiação , Pró-Calcitonina/imunologia , Pró-Calcitonina/metabolismo , Ratos , Sepse/sangue , Sepse/terapia , Transdução de Sinais/imunologia , Transdução de Sinais/efeitos da radiaçãoRESUMO
Recent data highlight the important roles of the gut microbiome, gut permeability, and alterations in mitochondria functioning in the pathophysiology of multiple sclerosis (MS). This article reviews such data, indicating two important aspects of alterations in the gut in the modulation of mitochondria: (1) Gut permeability increases toll-like receptor (TLR) activators, viz circulating lipopolysaccharide (LPS), and exosomal high-mobility group box (HMGB)1. LPS and HMGB1 increase inducible nitric oxide synthase and superoxide, leading to peroxynitrite-driven acidic sphingomyelinase and ceramide. Ceramide is a major driver of MS pathophysiology via its impacts on glia mitochondria functioning; (2) Gut dysbiosis lowers production of the short-chain fatty acid, butyrate. Butyrate is a significant positive regulator of mitochondrial function, as well as suppressing the levels and effects of ceramide. Ceramide acts to suppress the circadian optimizers of mitochondria functioning, viz daytime orexin and night-time melatonin. Orexin, melatonin, and butyrate increase mitochondria oxidative phosphorylation partly via the disinhibition of the pyruvate dehydrogenase complex, leading to an increase in acetyl-coenzyme A (CoA). Acetyl-CoA is a necessary co-substrate for activation of the mitochondria melatonergic pathway, allowing melatonin to optimize mitochondrial function. Data would indicate that gut-driven alterations in ceramide and mitochondrial function, particularly in glia and immune cells, underpin MS pathophysiology. Aryl hydrocarbon receptor (AhR) activators, such as stress-induced kynurenine and air pollutants, may interact with the mitochondrial melatonergic pathway via AhR-induced cytochrome P450 (CYP)1b1, which backward converts melatonin to N-acetylserotonin (NAS). The loss of mitochnodria melatonin coupled with increased NAS has implications for altered mitochondrial function in many cell types that are relevant to MS pathophysiology. NAS is increased in secondary progressive MS, indicating a role for changes in the mitochondria melatonergic pathway in the progression of MS symptomatology. This provides a framework for the integration of diverse bodies of data on MS pathophysiology, with a number of readily applicable treatment interventions, including the utilization of sodium butyrate.
Assuntos
Ceramidas/imunologia , Microbioma Gastrointestinal , Melatonina/imunologia , Esclerose Múltipla/imunologia , Orexinas/imunologia , Ativação Plaquetária , Animais , Butiratos/imunologia , Transtornos Cronobiológicos/imunologia , Transtornos Cronobiológicos/microbiologia , Transtornos Cronobiológicos/patologia , Transtornos Cronobiológicos/fisiopatologia , Humanos , Imunidade Celular , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/patologia , Inflamação/fisiopatologia , Mitocôndrias/imunologia , Mitocôndrias/patologia , Esclerose Múltipla/microbiologia , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Neuroglia/imunologia , Neuroglia/patologiaRESUMO
Autoimmune diseases are a broad spectrum of disorders involved in the imbalance of T-cell subsets, in which interplay or interaction of Th1, Th17 and Tregs are most important, resulting in prolonged inflammation and subsequent tissue damage. Pathogenic Th1 and Th17 cells can secrete signature proinflammatory cytokines, including interferon (IFN)-γ and IL-17, however Tregs can suppress effector cells and dampen a wide spectrum of immune responses. Melatonin (MLT) can regulate the humoral and cellular immune responses, as well as cell proliferation and immune mediators. Treatment with MLT directly interferes with T cell differentiation, controls the balance between pathogenic and regulatory T cells and regulates inflammatory cytokine release. MLT can promote the differentiation of type 1 regulatory T cells via extracellular signal regulated kinase 1/2 (Erk1/2) and retinoic acid-related orphan receptor-α (ROR-α) and suppress the differentiation of Th17 cells via the inhibition of ROR-γt and ROR-α expression through NFIL3. Moreover, MLT inhibits NF-κB signaling pathway to reduce TNF-α and IL-1ß expression, promotes Nrf2 gene and protein expression to reduce oxidative and inflammatory states and regulates Bax and Bcl-2 to reduce apoptosis; all of which alleviate the development of autoimmune diseases. Thus, MLT can serve as a potential new therapeutic target, creating opportunities for the treatment of autoimmune diseases. This review aims to highlight recent advances in the role of MLT in several autoimmune diseases with particular focus given to novel signaling pathways involved in Th17 and Tregs as well as cell proliferation and apoptosis.
Assuntos
Doenças Autoimunes/imunologia , Melatonina/imunologia , Animais , Humanos , Imunomodulação , Receptores de Melatonina/imunologiaRESUMO
Intestinal diseases caused by sleep deprivation (SD) are severe public health threats worldwide. This study focuses on the effect of melatonin on intestinal mucosal injury and microbiota dysbiosis in sleep-deprived mice. Mice subjected to SD had significantly elevated norepinephrine levels and decreased melatonin content in plasma. Consistent with the decrease in melatonin levels, we observed a decrease of antioxidant ability, down-regulation of anti-inflammatory cytokines and up-regulation of pro-inflammatory cytokines in sleep-deprived mice, which resulted in colonic mucosal injury, including a reduced number of goblet cells, proliferating cell nuclear antigen-positive cells, expression of MUC2 and tight junction proteins and elevated expression of ATG5, Beclin1, p-P65 and p-IκB. High-throughput pyrosequencing of 16S rRNA demonstrated that the diversity and richness of the colonic microbiota were decreased in sleep-deprived mice, especially in probiotics, including Akkermansia, Bacteroides and Faecalibacterium. However, the pathogen Aeromonas was markedly increased. By contrast, supplementation with 20 and 40 mg/kg melatonin reversed these SD-induced changes and improved the mucosal injury and dysbiosis of the microbiota in the colon. Our results suggest that the effect of SD on intestinal barrier dysfunction might be an outcome of melatonin suppression rather than a loss of sleep per se. SD-induced intestinal barrier dysfunction involved the suppression of melatonin production and activation of the NF-κB pathway by oxidative stress.
Assuntos
Colo , Microbioma Gastrointestinal/imunologia , Enteropatias , Mucosa Intestinal , Melatonina/imunologia , Privação do Sono , Animais , Colo/imunologia , Colo/microbiologia , Enteropatias/imunologia , Enteropatias/microbiologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Probióticos , Privação do Sono/imunologia , Privação do Sono/microbiologiaRESUMO
The pineal gland is the main organ involved in the transduction process converting environmental light information into a melatonin response. Since light environment was described as an important factor that could affect physiology of teleosts, and because melatonin is a crucial hormone regulating numerous physiological processes, we hypothesized that environmental light may act on both stress and circadian axes which in turn could influence the immune status of pike perch. Therefore, we investigated the effects of two light spectra (red and white) and two light intensities (10 and 100 lx) with a constant photoperiod 12L(8:00-20:00) /12D on pike perch physiological and immune responses. Samples were collected at 04:00 and 16:00 at days 1 and 30 of the experiment. Stress markers, plasma melatonin levels, humoral innate immune markers, and expression of key immune genes in the head kidney were assessed. Light intensity clearly affected pike perch physiology. This included negative growth performances, increase in stress status, decrease in plasma melatonin levels, and immune depression. Light spectrum had only little influences. These results demonstrate that high stress status may have impacted melatonin production and secretion by the pineal organ. The drop in circulating melatonin and the increase in stress status may both be involved in the immune suppression.
Assuntos
Ritmo Circadiano/imunologia , Esocidae/imunologia , Hidrocortisona/imunologia , Luz , Melatonina/imunologia , Glândula Pineal/imunologia , AnimaisRESUMO
BACKGROUND: Down syndrome (DS) is the most common syndromic immunodeficiency with an increased risk of infection, mortality from sepsis, and autoinflammation. Innate immune function is altered in DS and therefore we examined responses in CD11b and Toll like receptor 4 (TLR-4), which are important immune cell surface markers upregulated in response to Lipopolysaccharide (LPS) endotoxin, and the immunomodulator melatonin. Neutrophil and monocyte responses to LPS and melatonin in children with Down syndrome (DS) who were clinically stable were compared to age-matched controls. Whole blood was incubated with LPS and melatonin and the relative expression of CD11b and TLR-4 evaluated by flow cytometry. RESULTS: Children with DS had an increased response to LPS in neutrophils and intermediate monocytes, while also having elevated TLR-4 expression on non-classical monocytes compared to controls at baseline. Melatonin reduced CD11b expression on neutrophils, total monocytes, both classical and intermediate sub-types, in children with DS and controls. CONCLUSION: Melatonin could represent a useful clinical adjunct in the treatment of sepsis as an immunomodulator. Children with DS had increased LPS responses which may contribute to the more adverse outcomes seen in sepsis.
Assuntos
Antígeno CD11b/sangue , Síndrome de Down/imunologia , Lipopolissacarídeos/imunologia , Melatonina/imunologia , Receptor 4 Toll-Like/sangue , Criança , Pré-Escolar , Escherichia coli/imunologia , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Imunomodulação , Masculino , Melatonina/uso terapêutico , Monócitos/imunologia , Neutrófilos/imunologia , Sepse/imunologia , Sepse/mortalidade , Sepse/terapiaRESUMO
The anti-inflammatory activity of melatonin (MT) has been well documented; however, little is known regarding endogenously occurring MT in this respect, especially for large animals. In the current study, we created a MT-enriched animal model (goats) overexpressing the MT synthetase gene Aanat. The responses of these animals to lipopolysaccharide (LPS) stimulation were systematically studied. It was found that LPS treatment exacerbated the inflammatory response in wild-type (WT) goats and increased their temperature to 40 °C. In addition, their granulocyte counts were also significantly elevated. In contrast, these symptoms were not observed in transgenic goats with LPS treatment. The rescue study with MT injection into WT goats who were treated with LPS confirmed that the protective effects in transgenic goats against LPS were attributed to a high level of endogenously produced MT. The proteomic analysis in the peripheral blood mononuclear cells (PBMCs) isolated from the transgenic animals uncovered several potential mechanisms. MT suppressed the lysosome formation as well as its function by downregulation of the lysosome-associated genes Lysosome-associated membrane protein 2 (LAMP2), Insulin-like growth factor 2 receptor (IGF2R), and Arylsulfatase B (ARSB). A high level of MT enhanced the antioxidant capacity of these cells to reduce the cell apoptosis induced by the LPS. In addition, the results also uncovered previously unknown information that showed that MT may have protective effects on some human diseases, including tuberculosis, bladder cancer, and rheumatoid arthritis, by downregulation of these disease-associated genes. All these observations warranted further investigations.
Assuntos
Cabras/imunologia , Leucócitos Mononucleares/imunologia , Lipopolissacarídeos/imunologia , Melatonina/imunologia , Animais , Animais Geneticamente Modificados , Feminino , Cabras/genética , Inflamação/genética , Inflamação/imunologia , Leucócitos Mononucleares/metabolismo , Melatonina/genética , Proteogenômica , Regulação para CimaRESUMO
Melatonin, the 'chemical signal of darkness', is responsible to regulate biological rhythms and different physiological processes. It is mainly produced by the pineal gland as a hormone in a rhythmic daily basis, but it may also be synthesized by other tissues, such as immune cells, under inflammatory conditions. Its abnormal circulating levels have been related to several diseases such as type 2 diabetes, Alzheimer's disease and some types of cancer. Currently, melatonin is exclusively quantified by ELISA or radioimmunoassays, which although are very sensitive techniques and present low detection limits, usually require specialized personal and equipment, restricting the tests to a limited number of patients. To overcome such limitations, we developed a novel easy-to-use electrochemical immunosensor for rapid melatonin quantification. Anti-melatonin antibodies were immobilized into Indium tin oxide (ITO) platforms using (3-Aminopropyl)triethoxysilane (APTES), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysuccinimide (NHS) crosslinkers. The platforms were assayed with synthetic and biologically-present melatonin containing samples. The developed device displayed a linear response in the concentration range from 0.75 to 7.5⯵mol/L and a limit of detection of 0.175⯵mol/L using Electrochemical Impedance Spectroscopy (EIS) (R2â¯=â¯0.989) and 0.513⯵mol/L using Cyclic Voltammetry (CV) (R²â¯=â¯0.953) for synthetic melatonin. Furthermore, the sensors exhibited a good stability and reproducibility (3.45% and 2.87% for EIS and CV, respectively, nâ¯=â¯3), maintaining adequate response even after 30 days of assembly. On biologically-present melatonin-containing samples the device displayed a similar performance when compared to ELISA technique (deviation of 13.31%). We expect that the developed device contributes significantly to the medical area allowing precise and complete diagnosis of the diseases related to abnormal levels of melatonin.
Assuntos
Anticorpos/química , Anticorpos/imunologia , Melatonina/análise , Melatonina/imunologia , Animais , Reações Antígeno-Anticorpo , Técnicas Biossensoriais , Técnicas Eletroquímicas , Eletrodos , Ensaio de Imunoadsorção Enzimática , Masculino , Ratos , Ratos WistarRESUMO
In mammals, a master clock is located within the suprachiasmatic nucleus (SCN) of the hypothalamus, a region that receives input from the retina that is transmitted by the retinohypothalamic tract. The SCN controls the nocturnal synthesis of melatonin by the pineal gland that can influence the activity of the clock's genes and be involved in the inhibition of cancer development. On the other hand, in the literature, some papers highlight that artificial light exposure at night (LAN)-induced circadian disruptions promote cancer. In the present review, we summarize the potential mechanisms by which LAN-evoked disruption of the nocturnal increase in melatonin synthesis counteracts its preventive action on human cancer development and progression. In detail, we discuss: (i) the Warburg effect related to tumor metabolism modification; (ii) genomic instability associated with L1 activity; and (iii) regulation of immunity, including regulatory T cell (Treg) regulation and activity. A better understanding of these processes could significantly contribute to new treatment and prevention strategies against hormone-related cancer types.
Assuntos
Relógios Biológicos/efeitos da radiação , Carcinogênese/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Neoplasias/etiologia , Núcleo Supraquiasmático/efeitos da radiação , Animais , Relógios Biológicos/genética , Relógios Biológicos/imunologia , Proteínas CLOCK/genética , Proteínas CLOCK/imunologia , Proteínas CLOCK/metabolismo , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/metabolismo , Metabolismo Energético/genética , Metabolismo Energético/imunologia , Metabolismo Energético/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Instabilidade Genômica/imunologia , Instabilidade Genômica/efeitos da radiação , Humanos , Imunidade Inata/efeitos da radiação , Luz/efeitos adversos , Melatonina/antagonistas & inibidores , Melatonina/biossíntese , Melatonina/imunologia , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/prevenção & controle , Glândula Pineal/imunologia , Glândula Pineal/metabolismo , Glândula Pineal/efeitos da radiação , Retina/imunologia , Retina/metabolismo , Retina/efeitos da radiação , Núcleo Supraquiasmático/imunologia , Núcleo Supraquiasmático/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/efeitos da radiaçãoRESUMO
We studied the role of endogenous melatonin in the development and functioning of T cells that produce IL-17 (Th17) and regulatory T cells (Treg) during pregnancy. The study was performed ex vivo and in vitro with auto-serum as the source of endogenous melatonin under conditions of blockade of melatonin-dependent signaling. Participation of the hormone in the regulation of differentiation of both CD4+RORγt+ and CD4+FoxP3+T cells and their key products IL-17A and TGF-ß was demonstrated. It is known that the normal gestational process is accompanied by a decrease in Th17/Treg ratio due to hormonal changes. The sensitivity of the studied subpopulations to melatonin during pregnancy can affect its outcome.
Assuntos
Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica/imunologia , Interleucina-17/imunologia , Melatonina/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Diferenciação Celular/efeitos dos fármacos , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Soros Imunes/química , Soros Imunes/farmacologia , Imunofenotipagem , Interleucina-17/genética , Melatonina/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Gravidez , Primeiro Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Receptor MT1 de Melatonina/genética , Receptor MT1 de Melatonina/imunologia , Receptor MT2 de Melatonina/genética , Receptor MT2 de Melatonina/imunologia , Transdução de Sinais , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/citologia , Células Th17/efeitos dos fármacos , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologiaRESUMO
To study the features of secretion of melatonin in the urine in patients with DM type 2 and NAFLD with manifestations of fibrosis and its relationship with some metabolic and immunological parameters, 23 patients with DM type 2 and NAFLD were examined. The degree of fibrosis in patients was diagnosed on the basis of static elastography and the study of indirect fibrosis markers 16 persons (72%) diagnosed with mild fibrosis (F0-F1 on METAVIR), 5 people (18.2%) - with moderate fibrosis (F2-F3 on METAVIR). Only 2 (8.7%) patients did not have any fibrotic disorders, so they were excluded from the further study. All patients underwent determination of melatonin excretion of albumin and in daily urine, as well as the determination of homocysteine in the blood. The level of excretion of melatonin in the urine in patients with DM type 2 and NAFLD did not depend on the degree of fibrosis and on the average was 89.50±16.66 mmol/day, which exceeded the reference values. It has been established that the increase in melatonin level in patients with DM type 2 and NAFLD is associated with the presence of fibrotic changes in the liver and a decrease in the activity of the inflammatory process. In addition, a direct correlation was found between the excretion of melatonin and homocysteine (r=0.43), as well as between melatonin and albumin excretion in the urine (r=0.20). Thus, an increased level of excretion of melatonin in the urine can be not only a marker of liver fibrosis, but also a predictor of cardiovascular disorders in patients with DM type 2 and NAFLD.