RESUMO
Fluorides are contaminants that occur frequently and, generally, naturally in groundwater, affecting countries that depend on these waters for irrigation and human consumption. Chronic exposure to fluorides generates various health effects; therefore, this research was based on education and risk communication to contribute to the resolution of the problem of fluoride exposure in the population. The objective was to develop the capacity to design risk communication programs for personnel involved in the response and management of environmental health risks, with emphasis on fluoride exposure. An online pilot training course on risk communication and fluoride exposure was designed and implemented. For the analysis of the risk perception and knowledge of the participants, before and after the course, a questionnaire was applied and a focus group was conducted. In addition, the participants carried out a series of activities and designed a risk communication program to assess the degree to which the capacity to develop risk communication programs was achieved. To improve the pilot course, two satisfaction surveys were designed and implemented, and a SWOT (Strengths, Weaknesses, Opportunities, and Threats) analysis was conducted. The results showed an increase in the level of knowledge and changes in the participants' perception; regarding the ability to design risk communication programs, two participants were able to design them excellently. Previous experience, motivation, commitment to learn and the feedback provided during the course influenced the development of this ability.
Los fluoruros son contaminantes presentes con frecuencia y generalmente de forma natural en aguas subterráneas, y afectan a países que dependen de estas aguas para el riego y el consumo humano. La exposición crónica a fluoruros genera diversos efectos a la salud; por lo anterior, esta investigación se basó en la educación y la comunicación de riesgos para contribuir a la resolución del problema de exposición a fluoruros en la población. El objetivo fue desarrollar la capacidad de diseñar programas de comunicación de riesgos del personal involucrado en la respuesta y manejo de los riesgos ambientales para la salud, con énfasis en la exposición a fluoruros. Se diseñó e implementó un curso piloto de formación en línea sobre comunicación de riesgos y exposición a fluoruros. Para el análisis de la percepción de riesgos y conocimientos de los participantes, antes y después del curso, se aplicó un cuestionario y se llevó a cabo un grupo focal. Además, los asistentes realizaron una serie de actividades y diseñaron un programa de comunicación de riesgos con el que se valoró el grado en que se alcanzó la capacidad de desarrollar programas de comunicación de riesgos. Para mejorar el curso piloto se diseñaron y aplicaron dos encuestas de satisfacción y se realizó un análisis FODA (Fortalezas, Oportunidades, Debilidades, Amenazas). Los resultados mostraron un incremento en el nivel de conocimientos y cambios en la percepción de los participantes; en cuanto a la capacidad de diseñar programas de comunicación de riesgos, dos participantes lograron diseñarlo de manera excelente. La experiencia previa, la motivación, el compromiso para aprender y la retroalimentación brindada durante el curso, influyeron en el desarrollo de esta capacidad.
Os fluoretos são contaminantes que ocorrem com frequência e, geralmente, de forma natural nas águas subterrâneas, afetando os países que dependem dessas águas para irrigação e consumo humano. A exposição crônica aos fluoretos gera vários efeitos à saúde; portanto, esta pesquisa baseou-se na educação e na comunicação de riscos para contribuir com a solução do problema da exposição ao fluoreto na população. O objetivo foi desenvolver a capacidade de elaborar programas de comunicação de risco para o pessoal envolvido na resposta e no gerenciamento de riscos ambientais à saúde, com ênfase na exposição à fluoretos. Foi elaborado e implementado um curso piloto de treinamento online sobre comunicação de riscos e exposição. Para a análise da percepção de risco e do conhecimento dos participantes antes e depois do curso, foi aplicado um questionário e aplicado um grupo de foco. Além disso, os participantes realizaram uma série de atividades e elaboraram um programa de comunicação de riscos para avaliar até que ponto a capacidade de desenvolver programas de comunicação de riscos foi alcançada. Para aprimorar o curso piloto, foram duas pesquisas de satisfação foram desenvolvidas e implementadas e uma análise FOFA (Forças, Oportunidades, Fraquezas e Ameaças) foi aplicada. Os resultados mostraram um aumento no nível de conhecimento e mudanças nas percepções dos participantes; em termos da capacidade de elaborar programas de comunicação de riscos, dois participantes conseguiram elaborar excelentes programas de comunicação de riscos. A experiência prévia, a motivação, o compromisso com o aprendizado e o feedback fornecido durante o curso influenciaram o desenvolvimento dessa capacidade.
Assuntos
Comunicação , Educação a Distância , Exposição Ambiental , Saúde Ambiental , Fluoretos , Educação em Saúde , Educadores em Saúde , Fatores de Risco , Humanos , Educação Baseada em Competências , Educação a Distância/métodos , Exposição Ambiental/efeitos adversos , Saúde Ambiental/educação , Saúde Ambiental/métodos , Fluoretos/administração & dosagem , Fluoretos/efeitos adversos , Grupos Focais , Feedback Formativo , Água Subterrânea/química , Educação em Saúde/métodos , Internet , Motivação , Projetos Piloto , Avaliação de Programas e Projetos de Saúde , CriançaRESUMO
Human papillomavirus (HPV)-positive Head and Neck Squamous Cell Carcinomas (HNSCC) comprise a particular cancer entity traditionally associated with better clinical outcomes. Around 25% of HNSCC are HPV positive, HPV16 being the most prevalent type. Nevertheless, close to 30% of the HPV-positive patients have an unfavorable prognosis, revealing that this type of tumor exhibits great heterogeneity leading to different clinical behaviors. Efforts have been made to identify RNA molecules with prognostic value associated with the clinical outcome of patients with HPV-positive HNSCC, with the aim of identifying patients at high risk of metastasis, disease recurrence, and poor survival, who would require closer clinical follow-up and timely intervention. Moreover, the molecular identification of those HPV-positive HNSCC patients with good prognosis will allow the implementation of de-escalating therapeutic strategies, aiming to reduce side effects, resulting in a better quality of life. This review compiles a series of recent studies addressing different methodological and conceptual approaches aimed at searching for potential gene expression-based biomarkers associated with the prognosis of patients with HPV-positive HNSCC.
Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Prognóstico , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Neoplasias de Cabeça e Pescoço/virologia , Neoplasias de Cabeça e Pescoço/genética , Papillomaviridae/genética , Regulação Neoplásica da Expressão GênicaRESUMO
This work aimed to show which treatments showed efficacy against coronavirus disease 2019 (COVID-19); therefore, the results of 37 clinical trials started in 2020 and completed in 2021 are reviewed and discussed here. These were selected from databases, excluding vaccines, computational studies, in silico, in vitro, and those with hyperimmune sera from recovered patients. We found 34 drugs, one vitamin, and one herbal remedy with pharmacological activity against symptomatic COVID-19. They reduced mortality, disease progression, or recovery time. For each treatment, the identifier and type of trial, the severity of the disease, the sponsor, the country where the trial was conducted, and the trial results are presented. The drugs were classified according to their mechanism of action. Several drugs that reduced mortality also reduced inflammation in the most severe cases. These include some that are not considered anti-inflammatory, such as Aviptadil, pyridostigmine bromide, anakinra, imatinib, baricitinib, and bevacizumab, as well as the combination of ivermectin, aspirin, dexamethasone, and enoxaparin. Nigella sativa seeds with honey have also been reported to have therapeutic activity. On the other hand, tofacitinib, novaferon with ritonavir, and lopinavir were also effective, as well as in combination with antiviral therapies such as danoprevir with ritonavir. The natural products colchicine and Vitamin D3 were only effective in patients with mild-to-moderate COVID-19, as was hydroxychloroquine. Drug repositioning has been the main tool in the search for effective therapies by expanding the pharmacological options available to patients.
El objetivo del presente trabajo fue conocer qué tratamientos mostraron efectividad contra COVID-19, para lo cual se revisan y discuten los resultados de 37 estudios clínicos iniciados durante 2020 y concluidos en 2021. Estos fueron seleccionados de bases de datos, excluyendo vacunas, estudios computacionales, in silico, in vitro y con sueros hiperinmunes de pacientes recuperados. Se documentaron 34 fármacos, una vitamina y un remedio herbolario, con actividad farmacológica ante COVID-19 sintomático. Estos redujeron la mortalidad, el progreso de la enfermedad, o el tiempo de recuperación. Para cada tratamiento se presenta identificador y tipo de estudio, la gravedad de la enfermedad, patrocinador, país donde se realizó, así como sus resultados. Los fármacos se clasificaron de acuerdo con su mecanismo de acción. Varios fármacos que redujeron la mortalidad también disminuyeron la inflamación en los casos más graves. Esto incluyendo algunos no considerados antiinflamatorios, como el aviptadil, el bromuro de piridostigmina, el anakinra, el imatinib, el baricitinib y el bevacizumab, así como la combinación de ivermectina, aspirina, dexametasona y enoxaparina. También se reportaron con actividad terapéutica las semillas de Nigella sativa con miel. Además, resultaron efectivos el tofacitinib, el novaferón con ritonavir y lopinavir, así como los antivirales en terapias combinadas como el danoprevir con ritonavir. Los productos naturales colchicina y vitamina D3, solo tuvieron actividad en los pacientes en estado leve a moderado de la COVID-19, así como la hidroxicloroquina. El reposicionamiento de fármacos fue la principal herramienta para buscar terapias efectivas ampliando las opciones farmacológicas accesibles a los pacientes.
Assuntos
Produtos Biológicos , COVID-19 , Humanos , Ritonavir/uso terapêutico , Antivirais/uso terapêutico , Antivirais/farmacologia , SARS-CoV-2 , PandemiasRESUMO
Abstract This work aimed to show which treatments showed efficacy against coronavirus disease 2019 (COVID-19); therefore, the results of 37 clinical trials started in 2020 and completed in 2021 are reviewed and discussed here. These were selected from databases, excluding vaccines, computational studies, in silico, in vitro, and those with hyperimmune sera from recovered patients. We found 34 drugs, one vitamin, and one herbal remedy with pharmacological activity against symptomatic COVID-19. They reduced mortality, disease progression, or recovery time. For each treatment, the identifier and type of trial, the severity of the disease, the sponsor, the country where the trial was conducted, and the trial results are presented. The drugs were classified according to their mechanism of action. Several drugs that reduced mortality also reduced inflammation in the most severe cases. These include some that are not considered anti-inflammatory, such as Aviptadil, pyridostigmine bromide, anakinra, imatinib, baricitinib, and bevacizumab, as well as the combination of ivermectin, aspirin, dexamethasone, and enoxaparin. Nigella sativa seeds with honey have also been reported to have therapeutic activity. On the other hand, tofacitinib, novaferon with ritonavir, and lopinavir were also effective, as well as in combination with antiviral therapies such as danoprevir with ritonavir. The natural products colchicine and Vitamin D3 were only effective in patients with mild-to-moderate COVID-19, as was hydroxychloroquine. Drug repositioning has been the main tool in the search for effective therapies by expanding the pharmacological options available to patients.
Resumen El objetivo del presente trabajo fue conocer qué tratamientos mostraron efectividad contra COVID-19, para lo cual se revisan y discuten los resultados de 37 estudios clínicos iniciados durante 2020 y concluidos en 2021. Estos fueron seleccionados de bases de datos, excluyendo vacunas, estudios computacionales, in silico, in vitro y con sueros hiperinmunes de pacientes recuperados. Se documentaron 34 fármacos, una vitamina y un remedio herbolario, con actividad farmacológica ante COVID-19 sintomático. Estos redujeron la mortalidad, el progreso de la enfermedad, o el tiempo de recuperación. Para cada tratamiento se presenta identificador y tipo de estudio, la gravedad de la enfermedad, patrocinador, país donde se realizó, así como sus resultados. Los fármacos se clasificaron de acuerdo con su mecanismo de acción. Varios fármacos que redujeron la mortalidad también disminuyeron la inflamación en los casos más graves. Esto incluyendo algunos no considerados antiinflamatorios, como el aviptadil, el bromuro de piridostigmina, el anakinra, el imatinib, el baricitinib y el bevacizumab, así como la combinación de ivermectina, aspirina, dexametasona y enoxaparina. También se reportaron con actividad terapéutica las semillas de Nigella sativa con miel. Además, resultaron efectivos el tofacitinib, el novaferón con ritonavir y lopinavir, así como los antivirales en terapias combinadas como el danoprevir con ritonavir. Los productos naturales colchicina y vitamina D3, solo tuvieron actividad en los pacientes en estado leve a moderado de la COVID-19, así como la hidroxicloroquina. El reposicionamiento de fármacos fue la principal herramienta para buscar terapias efectivas ampliando las opciones farmacológicas accesibles a los pacientes.
RESUMO
Methadone is an effective and long-lasting analgesic drug that is also used in medication-assisted treatment for people with opioid use disorders. Although there is evidence that methadone activates µ-opioid and Toll-like-4 receptors (TLR-4s), its effects on distinct immune cells, including mast cells (MCs), are not well characterized. MCs express µ-opioid and Toll-like receptors (TLRs) and constitute an important cell lineage involved in allergy and effective innate immunity responses. In the present study, murine bone-marrow-derived mast cells (BMMCs) were treated with methadone to evaluate cell viability by flow cytometry, cell morphology with immunofluorescence and scanning electron microscopy, reactive oxygen species (ROS) production, and intracellular calcium concentration ([Ca2+]i) increase. We found that exposure of BMMCs to 0.5 mM or 1 mM methadone rapidly induced cell death by forming extracellular DNA traps (ETosis). Methadone-induced cell death depended on ROS formation and [Ca2+]i. Using pharmacological approaches and TLR4-defective BMMC cultures, we found that µ-opioid receptors were necessary for both methadone-induced ROS production and intracellular calcium increase. Remarkably, TLR4 receptors were also involved in methadone-induced ROS production as it did not occur in BMMCs obtained from TLR4-deficient mice. Finally, confocal microscopy images showed a significant co-localization of µ-opioid and TLR4 receptors that increased after methadone treatment. Our results suggest that methadone produces MCETosis by a mechanism requiring a novel crosstalk pathway between µ-opioid and TLR4 receptors.
Assuntos
Analgésicos Opioides , Armadilhas Extracelulares , Humanos , Animais , Camundongos , Analgésicos Opioides/farmacologia , Receptor 4 Toll-Like/metabolismo , Metadona/farmacologia , Mastócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Medula Óssea/metabolismo , Cálcio/metabolismo , Armadilhas Extracelulares/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptores Toll-Like/metabolismoRESUMO
Resumen: Los fluoruros son contaminantes presentes con frecuencia y generalmente de forma natural en aguas subterráneas, y afectan a países que dependen de estas aguas para el riego y el consumo humano. La exposición crónica a fluoruros genera diversos efectos a la salud; por lo anterior, esta investigación se basó en la educación y la comunicación de riesgos para contribuir a la resolución del problema de exposición a fluoruros en la población. El objetivo fue desarrollar la capacidad de diseñar programas de comunicación de riesgos del personal involucrado en la respuesta y manejo de los riesgos ambientales para la salud, con énfasis en la exposición a fluoruros. Se diseñó e implementó un curso piloto de formación en línea sobre comunicación de riesgos y exposición a fluoruros. Para el análisis de la percepción de riesgos y conocimientos de los participantes, antes y después del curso, se aplicó un cuestionario y se llevó a cabo un grupo focal. Además, los asistentes realizaron una serie de actividades y diseñaron un programa de comunicación de riesgos con el que se valoró el grado en que se alcanzó la capacidad de desarrollar programas de comunicación de riesgos. Para mejorar el curso piloto se diseñaron y aplicaron dos encuestas de satisfacción y se realizó un análisis FODA (Fortalezas, Oportunidades, Debilidades, Amenazas). Los resultados mostraron un incremento en el nivel de conocimientos y cambios en la percepción de los participantes; en cuanto a la capacidad de diseñar programas de comunicación de riesgos, dos participantes lograron diseñarlo de manera excelente. La experiencia previa, la motivación, el compromiso para aprender y la retroalimentación brindada durante el curso, influyeron en el desarrollo de esta capacidad.
Abstract: Fluorides are contaminants that occur frequently and, generally, naturally in groundwater, affecting countries that depend on these waters for irrigation and human consumption. Chronic exposure to fluorides generates various health effects; therefore, this research was based on education and risk communication to contribute to the resolution of the problem of fluoride exposure in the population. The objective was to develop the capacity to design risk communication programs for personnel involved in the response and management of environmental health risks, with emphasis on fluoride exposure. An online pilot training course on risk communication and fluoride exposure was designed and implemented. For the analysis of the risk perception and knowledge of the participants, before and after the course, a questionnaire was applied and a focus group was conducted. In addition, the participants carried out a series of activities and designed a risk communication program to assess the degree to which the capacity to develop risk communication programs was achieved. To improve the pilot course, two satisfaction surveys were designed and implemented, and a SWOT (Strengths, Weaknesses, Opportunities, and Threats) analysis was conducted. The results showed an increase in the level of knowledge and changes in the participants' perception; regarding the ability to design risk communication programs, two participants were able to design them excellently. Previous experience, motivation, commitment to learn and the feedback provided during the course influenced the development of this ability.
Resumo: Os fluoretos são contaminantes que ocorrem com frequência e, geralmente, de forma natural nas águas subterrâneas, afetando os países que dependem dessas águas para irrigação e consumo humano. A exposição crônica aos fluoretos gera vários efeitos à saúde; portanto, esta pesquisa baseou-se na educação e na comunicação de riscos para contribuir com a solução do problema da exposição ao fluoreto na população. O objetivo foi desenvolver a capacidade de elaborar programas de comunicação de risco para o pessoal envolvido na resposta e no gerenciamento de riscos ambientais à saúde, com ênfase na exposição à fluoretos. Foi elaborado e implementado um curso piloto de treinamento online sobre comunicação de riscos e exposição. Para a análise da percepção de risco e do conhecimento dos participantes antes e depois do curso, foi aplicado um questionário e aplicado um grupo de foco. Além disso, os participantes realizaram uma série de atividades e elaboraram um programa de comunicação de riscos para avaliar até que ponto a capacidade de desenvolver programas de comunicação de riscos foi alcançada. Para aprimorar o curso piloto, foram duas pesquisas de satisfação foram desenvolvidas e implementadas e uma análise FOFA (Forças, Oportunidades, Fraquezas e Ameaças) foi aplicada. Os resultados mostraram um aumento no nível de conhecimento e mudanças nas percepções dos participantes; em termos da capacidade de elaborar programas de comunicação de riscos, dois participantes conseguiram elaborar excelentes programas de comunicação de riscos. A experiência prévia, a motivação, o compromisso com o aprendizado e o feedback fornecido durante o curso influenciaram o desenvolvimento dessa capacidade.
RESUMO
Alcohol consumption has been linked to numerous pathologic conditions, including infectious diseases and several types of cancer. Alcohol exerts its modulatory effects on the immune system (IS) in a dose- and time-dependent manner. Numerous studies indicate that these alterations affect responses such as peripheral inflammation or decreased antibody production and promote chronic inflammation, leading to cell death. The molecular mechanisms underlying these effects involve generating an oxidative tissue environment, producing cell damage-associated molecular patterns (DAMPs), and activating pattern recognition receptors. In particular, toll-like receptors and their signaling system emerge as central elements whose activity is altered by alcohol intake. There is also some epidemiological evidence demonstrating the causal role of alcohol in the development of various types of cancer, such as head-and-neck cancer, esophageal cancer, colorectal cancer, liver cancer, and breast cancer. Most recent evidence suggests that factors related to alcohol consumption and cancer include increased levels of acetaldehyde, production of reactive oxygen species, alteration in DNA methylation, and modifications in retinoid metabolism. In addition, changes associated with alcohol use on the IS and intestinal microbiota may favor the growth of some types of tumors.
Assuntos
Neoplasias da Mama , Etanol , Humanos , Feminino , Etanol/metabolismo , Acetaldeído/metabolismo , Consumo de Bebidas Alcoólicas/efeitos adversos , InflamaçãoRESUMO
ABSTRACT Alcohol consumption has been linked to numerous pathologic conditions, including infectious diseases and several types of cancer. Alcohol exerts its modulatory effects on the immune system (IS) in a dose- and time-dependent manner. Numerous studies indicate that these alterations affect responses such as peripheral inflammation or decreased antibody production and promote chronic inflammation, leading to cell death. The molecular mechanisms underlying these effects involve generating an oxidative tissue environment, producing cell damage-associated molecular patterns (DAMPs), and activating pattern recognition receptors. In particular, toll-like receptors and their signaling system emerge as central elements whose activity is altered by alcohol intake. There is also some epidemiological evidence demonstrating the causal role of alcohol in the development of various types of cancer, such as head-and-neck cancer, esophageal cancer, colorectal cancer, liver cancer, and breast cancer. Most recent evidence suggests that factors related to alcohol consumption and cancer include increased levels of acetaldehyde, production of reactive oxygen species, alteration in DNA methylation, and modifications in retinoid metabolism. In addition, changes associated with alcohol use on the IS and intestinal microbiota may favor the growth of some types of tumors.
RESUMO
Allergic reactions are highly prevalent pathologies initiated by the production of IgE antibodies against harmless antigens (allergens) and the activation of the high-affinity IgE receptor (FcεRI) expressed in the surface of basophils and mast cells (MCs). Research on the mechanisms of negative control of those exacerbated inflammatory reactions has been intense in recent years. Endocannabinoids (eCBs) show important regulatory effects on MC-mediated immune responses, mainly inhibiting the production of pro-inflammatory mediators. However, the description of the molecular mechanisms involved in eCB control of MC activation is far from complete. In this review, we aim to summarize the available information regarding the role of eCBs in the modulation of FcεRI-dependent activation of that cell type, emphasizing the description of the eCB system and the existence of some of its elements in MCs. Unique characteristics of the eCB system and cannabinoid receptors (CBRs) localization and signaling in MCs are mentioned. The described and putative points of cross-talk between CBRs and FcεRI signaling cascades are also presented. Finally, we discuss some important considerations in the study of the effects of eCBs in MCs and the perspectives in the field.
Assuntos
Hipersensibilidade , Receptores de IgE , Humanos , Receptores de IgE/metabolismo , Imunoglobulina E/metabolismo , Imunoglobulina E/farmacologia , Endocanabinoides/metabolismo , Endocanabinoides/farmacologia , Mastócitos/metabolismo , Hipersensibilidade/metabolismoRESUMO
Mast cells (MCs) are the main participants in the control of immune reactions associated with inflammation, allergies, defense against pathogens, and tumor growth. Bioactive lipids are lipophilic compounds able to modulate MC activation. Here, we explored some of the effects of the bioactive lipid lysophosphatidylinositol (LPI) on MCs. Utilizing murine bone marrow-derived mast cells (BMMCs), we found that LPI did not cause degranulation, but slightly increased FcεRI-dependent ß-hexosaminidase release. However, LPI induced strong chemotaxis together with changes in LIM kinase (LIMK) and cofilin phosphorylation. LPI also promoted modifications to actin cytoskeleton dynamics that were detected by an increase in cell size and interruptions in the continuity of the cortical actin ring. The chemotaxis and cortical actin ring changes were dependent on GPR55 receptor activation, since the specific agonist O1602 mimicked the effects of LPI and the selective antagonist ML193 prevented them. The LPI and O1602-dependent stimulation of BMMC also led to VEGF, TNF, IL-1α, and IL-1ß mRNA accumulation, but, in contrast with chemotaxis-related processes, the effects on cytokine transcription were dependent on GPR55 and cannabinoid (CB) 2 receptors, since they were sensitive to ML193 and to the specific CB2 receptor antagonist AM630. Remarkably, GPR55-dependent BMMC chemotaxis was observed towards conditioned media from distinct mouse and human cancer cells. Our data suggest that LPI induces the chemotaxis of MCs and leads to cytokine production in MC in vitro with the differential participation of GPR55 and CB2 receptors. These effects could play a significant role in the recruitment of MCs to tumors and the production of MC-derived pro-angiogenic factors in the tumor microenvironment.
Assuntos
Receptor CB2 de Canabinoide , Receptores Acoplados a Proteínas G , Camundongos , Humanos , Animais , Receptores Acoplados a Proteínas G/genética , Receptor CB2 de Canabinoide/genética , Quimiotaxia , Mastócitos , Citocinas , Actinas , Receptores de Canabinoides/genética , Lisofosfolipídeos/farmacologia , Lisofosfolipídeos/fisiologiaRESUMO
Toll-like receptors (TLRs) are central players in innate immunity responses. They are expressed in glial cells and neurons, and their overactivation leads to the production of proinflammatory molecules, neuroinflammation, and neural damage associated with many neurodegenerative pathologies, such as Huntington's disease (HD). HD is an inherited disorder caused by a mutation in the gene coding for the protein Huntingtin (Htt). Expression of mutated Htt (mHtt) causes progressive neuronal degeneration characterized by striatal loss of GABAergic neurons, oxidative damage, neuroinflammatory processes, and impaired motor behavior. The main animal models to study HD are the intrastriatal injection of quinolinic acid (QA) and the transgenic B6CBA-Tg (HDexon1)61Gpb/1 J mice (R6/1). Those models mimic neuronal damage and systemic manifestations of HD. The objective of this work was to study the participation of TLR4 in the manifestations of neuronal damage and HD symptoms in the two mentioned models. For this purpose, C57BL6/J and TLR4-KO mice were administered with QA, and after that motor activity, and neuronal and oxidative damages were measured. R6/1 and TLR4-KO were mated to study the effect of low expression of TLR4 on the phenotype manifestation in R6/1 mice. We found that TLR4 is involved in motor activity, and neurological and oxidative damage induced by intrastriatal injection of QA, and the low expression of TLR4 causes a delay in the onset of phenotypic manifestations by the mHtt expression in R6/1 mice. Our results show that TLR4 is involved in both models of HD and focuses then as a therapeutic target for some deleterious reactions in HD.
Assuntos
Doença de Huntington , Camundongos , Animais , Doença de Huntington/genética , Camundongos Transgênicos , Receptor 4 Toll-Like/metabolismo , Neurônios/metabolismo , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Proteína Huntingtina/metabolismoRESUMO
High-risk human papillomavirus (HPV) infection is the main risk factor for cervical cancer (CC) development, where the continuous expression of E6 and E7 oncoproteins maintain the malignant phenotype. In Mexico, around 70% of CC cases are diagnosed in advanced stages, impacting the survival of patients. The aim of this work was to identify biomarkers affected by HPV-16 E6 and E7 oncoproteins that impact the prognosis of CC patients. Expression profiles dependent on E6 and E7 oncoproteins, as well as their relationship with biological processes and cellular signaling pathways, were analyzed in CC cells. A comparison among expression profiles of E6- and E7-expressing cells and that from a CC cohort obtained from The Cancer Genome Atlas (TCGA) demonstrated that the expression of 13 genes impacts the overall survival (OS). A multivariate analysis revealed that the downregulated expression of RIPOR2 was strongly associated with a worse OS. RIPOR2, including its transcriptional variants, were overwhelmingly depleted in E6- and E7-expressing cells. Finally, in a Mexican cohort, it was found that in premalignant cervical lesions, RIPOR2 expression decreases as the lesions progress; meanwhile, decreased RIPOR2 expression was also associated with a worse OS in CC patients.
Assuntos
Moléculas de Adesão Celular , Proteínas Oncogênicas Virais , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Papillomavirus Humano 16 , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/genética , Prognóstico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Moléculas de Adesão Celular/genética , Infecções por Papillomavirus/genéticaRESUMO
Mast cells (MC) play a central role in the early containment of bacterial infections, such as that caused by Listeria monocytogenes (L.m). The mechanisms of MC activation induced by L.m infection are well known, so it is possible to evaluate whether they are susceptible to targeting and modulation by different drugs. Recent evidence indicates that valproic acid (VPA) inhibits the immune response which favors L.m pathogenesis in vivo. Herein, we examined the immunomodulatory effect of VPA on L.m-mediated MC activation. To this end, bone marrow-derived mast cells (BMMC) were pre-incubated with VPA and then stimulated with L.m. We found that VPA reduced MC degranulation and cytokine release induced by L.m. MC activation during L.m infection relies on Toll-Like Receptor 2 (TLR2) engagement, however VPA treatment did not affect MC TLR2 cell surface expression. Moreover, VPA was able to decrease MC activation by the classic TLR2 ligands, peptidoglycan and lipopeptide Pam3CSK4. VPA also reduced cytokine production in response to Listeriolysin O (LLO), which activates MC by a TLR2-independent mechanism. In addition, VPA decreased the activation of critical events on MC signaling cascades, such as the increase on intracellular Ca2+ and phosphorylation of p38, ERK1/2 and -p65 subunit of NF-κB. Altogether, our data demonstrate that VPA affects key cell signaling events that regulate MC activation following L.m infection. These results indicate that VPA can modulate the functional activity of different immune cells that participate in the control of L.m infection.
Assuntos
Listeria monocytogenes , Listeriose , Citocinas/metabolismo , Humanos , Lipopeptídeos/metabolismo , Listeriose/tratamento farmacológico , Listeriose/metabolismo , Mastócitos/metabolismo , NF-kappa B/metabolismo , Peptidoglicano/metabolismo , Receptor 2 Toll-Like/metabolismo , Ácido Valproico/metabolismo , Ácido Valproico/farmacologiaRESUMO
BACKGROUND: COVID-19, the disease caused by SARS-CoV-2 virus infection, has been a major public health problem worldwide in the last 2 years. SARS-CoV-2-dependent activation of innate immune receptors contributes to the strong local and systemic inflammatory reaction associated with rapid disease evolution. The receptor-binding domain (RBD) of Spike (S) viral protein (S-RBD) is essential for virus infection and its interacting molecules in target cells are still under identification. On the other hand, the search for accessible natural molecules with potential therapeutic use has been intense and remains an active field of investigation. METHODS: C57BL6/J (control) and Toll-like receptor (TLR) 4-deficient (Lps del) mice were nebulized with recombinant S-RBD. Tumor Necrosis Factor-alpha (TNF-α) and Interleukin (IL)-6 production in bronchoalveolar lavages (BALs) was determined by enzyme-linked immunosorbent assay (ELISA). Lung-infiltrating cells recovered in BALs were quantified by hematoxylin-eosin (H&E) stain. In selected groups of animals, the natural compound Jacareubin or dexamethasone were intraperitoneally (ip) administered 2 hours before nebulization. RESULTS: A rapid lung production of TNF-α and IL-6 and cell infiltration was induced by S-RBD nebulization in control but not in Lps del mice. Pre-treatment with Jacareubin or dexamethasone prevented S-RBD-induced TNF-α and IL-6 secretion in BALs from control animals. CONCLUSIONS: S-RBD domain promotes lung TNF-α and IL-6 production in a TLR4-dependent fashion in C57BL6/J mice. Xanthone Jacareubin possesses potential anti-COVID-19 properties that, together with the previously tested anti-inflammatory activity, safety, and tolerance, make it a valuable drug to be further investigated for the treatment of cytokine production caused by SARS-CoV-2 infection.
Assuntos
Tratamento Farmacológico da COVID-19 , Glicoproteína da Espícula de Coronavírus , Animais , Camundongos , Dexametasona , Interleucina-6 , Pulmão , SARS-CoV-2 , Receptor 4 Toll-Like , Fator de Necrose Tumoral alfa , Xantonas/farmacologia , Inflamação/tratamento farmacológicoRESUMO
Mast cells (MCs) play important roles in tumor development, executing pro- or antitumoral functions depending on tumor type and tumor microenvironment (TME) conditions. Cyclic hypoxia (cyH) is a common feature of TME since tumor blood vessels fail to provide a continuous supply of oxygen to the tumor mass. Here, we hypothesized that the localization of MCs in cyH regions within solid tumors could modify their transcriptional profile and activation parameters. Using confocal microscopy, we found an important number of MCs in cyH zones of murine melanoma B16-F1 tumors. Applying microarray analysis to examine the transcriptome of murine bone-marrow-derived MCs (BMMCs) exposed to interleaved cycles of hypoxia and re-oxygenation, we identified altered expression of 2512 genes. Functional enrichment analysis revealed that the transcriptional signature of MCs exposed to cyH is associated with oxidative phosphorylation and the FcεRI signaling pathway. Interestingly, FcεRI-dependent degranulation, calcium mobilization, and PLC-γ activity, as well as Tnf-α, Il-4, and Il-2 gene expression after IgE/antigen challenge were increased in BMMCs exposed to cyH compared with those maintained in normoxia. Taken together, our findings indicate that cyH causes an important phenotypic change in MCs that should be considered in the design of inflammation-targeted therapies to control tumor growth.
Assuntos
Mastócitos , Receptores de IgE , Animais , Hipóxia/genética , Hipóxia/metabolismo , Mastócitos/metabolismo , Camundongos , Fenótipo , Receptores de IgE/genética , Receptores de IgE/metabolismo , Transcriptoma/genéticaRESUMO
Mast cells (MCs) are tissue-resident immune cells that are important players in diseases associated with chronic inflammation such as cancer. Since MCs can infiltrate solid tumors and promote or limit tumor growth, a possible polarization of MCs to pro-tumoral or anti-tumoral phenotypes has been proposed and remains as a challenging research field. Here, we review the recent evidence regarding the complex relationship between MCs and tumor cells. In particular, we consider: (1) the multifaceted role of MCs on tumor growth suggested by histological analysis of tumor biopsies and studies performed in MC-deficient animal models; (2) the signaling pathways triggered by tumor-derived chemotactic mediators and bioactive lipids that promote MC migration and modulate their function inside tumors; (3) the possible phenotypic changes on MCs triggered by prevalent conditions in the tumor microenvironment (TME) such as hypoxia; (4) the signaling pathways that specifically lead to the production of angiogenic factors, mainly VEGF; and (5) the possible role of MCs on tumor fibrosis and metastasis. Finally, we discuss the novel literature on the molecular mechanisms potentially related to phenotypic changes that MCs undergo into the TME and some therapeutic strategies targeting MC activation to limit tumor growth.
Assuntos
Transtornos Mieloproliferativos , Neoplasias , Animais , Mastócitos/metabolismo , Transtornos Mieloproliferativos/metabolismo , Neoplasias/metabolismo , Transdução de Sinais , Microambiente TumoralRESUMO
Huntington´s disease (HD) is a pathological condition that can be studied in mice by the administration of quinolinic acid (QUIN), an agonist of the N-methyl-d-aspartate receptor (NMDAR) that induces NMDAR-mediated cytotoxicity and neuroinflammation. Mast cells (MCs) participate in numerous inflammatory processes through the release of important amounts of histamine (HA). In this study, we aimed to characterize the participation of MCs and HA in the establishment of neural and oxidative damage in the QUIN-induced model of HD. C57BL6/J mice (WT), MC-deficient c-KitW-sh/W-sh (Wsh) mice and Wsh mice reconstituted by intracerebroventricular (i.c.v.) injection of 5 × 105 bone marrow-derived mast cells (BMMCs), or i.c.v. administered with HA (5 µg) were used. All groups of animals were intrastriatally injected with 1 µL QUIN (30 nmol/µL) and 3 days later, apomorphine-induced circling behavior, striatal GABA levels and the number of Fluoro-Jade positive cells, as indicators of neuronal damage, were determined. Also, lipid peroxidation (LP) and reactive oxygen species production (ROS), as markers of oxidative damage, were analyzed. Wsh mice showed less QUIN-induced neuronal and oxidative damage than WT and Wsh-MC reconstituted animals. Histamine administration restored the QUIN-induced neuronal and oxidative damage in the non-reconstituted Wsh mice to levels equivalent or superior to those observed in WT mice. Our results demonstrate that MCs and HA participate in the neuronal and oxidative damages observed in mice subjected to the QUIN -induced model of Huntington's disease.
Assuntos
Histamina/imunologia , Doença de Huntington/imunologia , Doença de Huntington/patologia , Mastócitos/imunologia , Neurônios/patologia , Animais , Modelos Animais de Doenças , Feminino , Histamina/metabolismo , Doença de Huntington/induzido quimicamente , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ácido Quinolínico/toxicidadeRESUMO
Morphine promotes neuroinflammation after NOD-like receptor protein 3 (NLRP3) oligomerization in glial cells, but the capacity of other opioids to induce neuroinflammation and its relationship to the development of analgesic tolerance is unknown. We studied the effects of morphine and fentanyl on NLRP3 inflammasome activation in glial and neuronal cells in the dorsal raphe nucleus (DRN), a region involved in pain regulation. Male Wistar rats received i.p. injections of morphine (10 mg/kg) or fentanyl (0.1 mg/kg) 3 × daily for 7 days and were tested for nociception. Two hours after the last (19th) administration, we analyzed NLRP3 oligomerization, caspase-1 activation and gasdermin D-N (GSDMD-N) expression in microglia (CD11b positive cells), astrocytes (GFAP-positive cells) and neurons (NeuN-positive cells). Tolerance developed to both opioids, but only fentanyl produced hyperalgesia. Morphine and fentanyl activated NLRP3 inflammasome in astrocytes and serotonergic (TPH-2-positive) neurons, but fentanyl effects were more pronounced. Both opioids increased GFAP and CD11b immunoreactivity, caspase-1 and GSDMD activation, indicating pyroptotic cell death. The opioid receptor antagonist (-)-naloxone, but not the TLR4 receptor antagonist (+)-naloxone, prevented microglia activation and NLRP3 oligomerization. Only (+)-naloxone prevented astrocytes' activation. The anti-inflammatory agent minocycline and the NLRP3 inhibitor MCC950 delayed tolerance to morphine and fentanyl antinociception and prevented fentanyl-induced hyperalgesia. MCC950 also prevented opioid-induced NLRP3 oligomerization. In conclusion, morphine and fentanyl differentially induce cell-specific activation of NLRP3 inflammasome and pyroptosis in the DRN through TLR4 receptors in astrocytes and through opioid receptors in neurons, indicating that neuroinflammation is involved in opioid-induced analgesia and fentanyl-induced hyperalgesia after repeated administrations.
Assuntos
Fentanila , Morfina , Analgésicos Opioides/farmacologia , Animais , Núcleo Dorsal da Rafe/metabolismo , Fentanila/farmacologia , Masculino , Morfina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR , Piroptose , Ratos , Ratos Wistar , Receptores Opioides/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
Mast cells (MCs) are strategically located in tissues close to the external environment, being one of the first immune cells to interact with invading pathogens. They are long living effector cells equipped with different receptors that allow microbial recognition. Once activated, MCs release numerous biologically active mediators in the site of pathogen contact, which induce vascular endothelium modification, inflammation development and extracellular matrix remodeling. Efficient and direct antimicrobial mechanisms of MCs involve phagocytosis with oxidative and non-oxidative microbial destruction, extracellular trap formation, and the release of antimicrobial substances. MCs also contribute to host defense through the attraction and activation of phagocytic and inflammatory cells, shaping the innate and adaptive immune responses. However, as part of their response to pathogens and under an impaired, sustained, or systemic activation, MCs may contribute to tissue damage. This review will focus on the current knowledge about direct and indirect contribution of MCs to pathogen clearance. Antimicrobial mechanisms of MCs are addressed with special attention to signaling pathways involved and molecular weapons implicated. The role of MCs in a dysregulated host response that can increase morbidity and mortality is also reviewed and discussed, highlighting the complexity of MCs biology in the context of host-pathogen interactions.