Anandamide reduces the migration of lymphocytes to the intestine by CB2 activation and reduces TNF-α in the target organs, protecting mice from graft-versus-host disease.

Graft-versus-host disease (GVHD) is a serious inflammatory illness that often occurs as a secondary complication of bone marrow transplantation. Current therapies have limited effectiveness and fail to achieve a balance between inflammation and the graft-versus-tumor effect. In this study, we investigate the effects of the endocannabinoid anandamide on the complex pathology of GVHD. We assess the effects of an irreversible inhibitor of fatty acid amine hydrolase or exogenous anandamide and find that they increase survival and reduce clinical signs in GVHD mice. In the intestine of GVHD mice, treatment with exogenous anandamide also leads to a reduction in the number of CD3+, CD3+CD4+, and CD3+CD8+ cells, which reduces the activation of CD3+CD4+ and CD3+CD8+ cells, as assessed by enhanced CD28 expression, a T cell co-stimulatory molecule. Exogenous AEA was also able to reduce TNF-α and increase IL-10 in the intestine of GVHD mice. In the liver, exogenous AEA reduces injury, TNF-α levels, and the number of CD3+CD8+ cells. Interestingly, anandamide reduces Mac-1α, which lowers the adhesion of transplanted cells in mesenteric veins. These effects are mimicked by JWH133-a CB2 selective agonist-and abolished by treatment with a CB2 antagonist. Furthermore, the effects caused by anandamide treatment on survival were related to the CB2 receptor, as the CB2 antagonist abolished it. This study shows the critical role of the CB2 receptor in the modulation of the inflammatory response of GVHD by treatment with anandamide, the most prominent endocannabinoid.

COX/iNOS dependence for angiotensin-II-induced endothelial dysfunction.

Vascular dysfunction induced by angiotensin-II can result from direct effects on vascular and inflammatory cells and indirect hemodynamic effects. Using isolated and functional cultured aortas, we aimed to identify the effects of angiotensin-II on cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS) and evaluate their impact on vascular reactivity. Aortic rings from mice were incubated overnight in culture medium containing angiotensin-II (100 nmol/L) or vehicle to induce vascular disfunction. Vascular reactivity of cultured arteries was evaluated in a bath chamber. Immunofluorescence staining for COX-1 and COX-2 was performed. Nitric oxide (NO) formation was approached by the levels of nitrite, a NO end product, and using a fluorescent probe (DAF). Oxidative and nitrosative stress were determined by DHE fluorescence and nitrotyrosine staining, respectively. Arteries cultured with angiotensin-II showed impairment of endothelium-dependent relaxation, which was reversed by the AT1 receptor antagonist. Inhibition of COX and iNOS restored vascular relaxation, suggesting a common pathway in which angiotensin-II triggers COX and iNOS, leading to vasoconstrictor receptors activation. Moreover, using selective antagonists, TP and EP were identified as the receptors involved in this response. Endothelium-dependent contractions of angiotensin-II-cultured aortas were blunted by ibuprofen, and increased COX-2 immunostaining was found in the arteries, indicating endothelium release of vasoconstrictor prostanoids. Angiotensin-II induced increased reactive oxygen species and NO production. An iNOS inhibitor prevented NO enhancement and nitrotyrosine accumulation in arteries stimulated with angiotensin-II. These results confirm that angiotensin-II causes vascular inflammation that culminates in endothelial dysfunction in an iNOS and COX codependent manner.

Cannabidiol Enhances Intestinal Cannabinoid Receptor Type 2 Receptor Expression and Activation Increasing Regulatory T Cells and Reduces Murine Acute Graft-versus-Host Disease without Interfering with the Graft-versus-Leukemia Response.

Cannabidiol (CBD) is a highly lipidic phytocannabinoid with remarkable anti-inflammatory effects. The aim of this study was to evaluate CBD's effects and mechanisms of action in the treatment of mice subjected to acute graft-versus-host disease (aGVHD). aGVHD was induced by the transplantation of bone marrow cells and splenocytes from C57BL-6j to Balb-c mice. The recipient mice were treated daily with CBD, and the treatment reduced mouse mortality by decreasing inflammation and injury and promoting immune regulation in the jejunum, ileum, and liver. Analysis of the jejunum and ileum showed that CBD treatment reduced the levels of C-C motif chemokine ligand (CCL) 2, CCL3, CCL5, tumor necrosis factor α, and interferon γ (IFNγ). CCL3 and IFNγ levels were also decreased in the liver. Mechanistically, CBD also increased the number of cannabinoid receptor type 2 (CB2) receptors on CD4+ and forkhead box P3+ cells in the intestine, which may explain the reduction in proinflammatory cytokines and chemokines. Antagonists of the CB2 receptor reduced the survival rates of CBD-treated mice, suggesting the participation of this receptor in the effects of CBD. Furthermore, treatment with CBD did not interfere with the graft-versus-leukemia response. CBD treatment appears to protect aGVHD mice by anti-inflammatory and immunomodulatory effects partially mediated by CB2 receptor interaction. Altogether, our study suggests that CBD represents an interesting approach in the treatment of aGVHD, with potential therapeutic applications in patients undergoing bone marrow transplantation. SIGNIFICANCE STATEMENT: This study provides for the first time a mechanism by which cannabidiol, a phytocannabinoid with no psychoactive effect, induces immunomodulation in the graft-versus-host disease. Enhancing intestinal cannabinoid receptor type 2 (CB2) receptor expression on CD4+ and forkhead box P3+ cells and increasing the number of these regulatory cells, cannabidiol decreases proinflammatory cytokines and increases graft-versus-host disease mice survival. This effect is dependent of CB2 receptor activation. Besides, cannabidiol did not interfere with graft-versus-leukemia response, a central response to avoid primary disease relapse.

Atenção preventiva e educativa em saúde do idoso: uma proposta de integração de saberes e práticas / Preventive care and education in elderly health: a proposal for the integration of knowledges and practices

O envelhecimento da população brasileira trouxe mudanças em seu perfil epidemiológico, como o aumento da ocorrência de doenças crônicas e incapacidades funcionais, além de maior demanda por serviços de saúde, representando um desafio para a Saúde Coletiva no conhecimento das suas especificidades. Nesse sentido, idosos do Programa de Assistência ao Idoso do SESC Minas, na cidade de Governador Valadares (MG), responderam a um questionário semi estruturado para variáveis socioeconômicas, condições de saúde e hábitos de vida a fim de se traçar um diagnóstico desta população e direcionar ações interdisciplinares educativas e preventivas como incentivo ao envelhecimento ativo. Os dados revelaram as principais doenças: hipertensão arterial (63,8%), osteoartrite (25,5%), cardiopatias (17%) e diabetes (10,6%). A poli farmácia foi identificada em 29,8% dos idosos, incluindo o uso de medicamentos alopáticos, fitoterápicos e plantas medicinais. Doze idosos (25,5%) relataram possuir lesões de pele, 72,3% informaram uso de próteses dentárias e 2,1% próteses ortopédicas. A maioria dos idosos classificou sua alimentação como saudável (85,1%), mas todos relataram algum tipo de perda funcional. Os resultados demonstram que o Programa Assistencial conta com idosos com o perfil de saúde semelhante ao da população idosa brasileira, com ampla ocorrência de doenças crônicas, edentulismo, incapacidades funcionais e elevado consumo de medicamentos. O presente estudo reforça a importância do trabalho interdisciplinar como subsídio para o desenvolvimento de intervenções mais sensíveis e eficazes, considerando a perspectiva do próprio indivíduo e suas necessidades.

The aging of the Brazilian population brought changes in their epidemiological profile: increased occurrence of chronic illnesses and functional disabilities; increased demand for health services. The knowledge of the characteristics and elements of such changes have represented a challenge to public health researchers. A preliminary attempt to meet such challenge comes from a program of assistance to the elderly in the city of Governador Valadares, Minas Gerais, Brazil, with the support of an independent agency backed by the commercial sector (SESC-Minas). A sample of individuals aged 60 and above responded to a semi-structured questionnaire to socioeconomic variables, health conditions and life styles. The survey was a research instrument for the proposal of preventive action and active ageing. The data revealed the main diseases: arterial hypertension (63.8 percent); osteoarthritis (25.5 percent); heart diseases (17%) and diabetes (10.6 percent). “`Polipharmacy” was identified in 29.8% of seniors, including the use of allopathic drugs, phytotherapy and medicinal plants. 25.5 percent reported skin lesions, 72.3% wore dentures and 2.1% orthopedic prostheses. Most elderly people claimed to follow a healthy diet (85.1%), but all reported some form of functional loss. The results suggest that the Program relies on the participation of seniors with health profile similar to the general population of Brazilian elderly, with wide occurrence of chronic diseases, edentulism and high consumption of medicines. This study reinforces the importance of interdisciplinary work as subsidy for the development of more effective interventions, taking into account the perspectives of the elderly and their needs.

Atenção preventiva e educativa em saúde do idoso: uma proposta de integração de saberes e práticas / Preventive care and education in elderly health: a proposal for the integration of knowledges and practices

O envelhecimento da população brasileira trouxe mudanças em seu perfil epidemiológico, como o aumento da ocorrência de doenças crônicas e incapacidades funcionais, além de maior demanda por serviços de saúde, representando um desafio para a Saúde Coletiva no conhecimento das suas especificidades. Nesse sentido, idosos do Programa de Assistência ao Idoso do SESC Minas, na cidade de Governador Valadares (MG), responderam a um questionário semiestruturado para variáveis socioeconômicas, condições de saúde e hábitos de vida a fim de se traçar um diagnóstico desta população e direcionar ações interdisciplinares educativas e preventivas como incentivo ao envelhecimento ativo. Os dados revelaram as principais doenças: hipertensão arterial (63,8%), osteoartrite (25,5%), cardiopatias (17%) e diabetes (10,6%). A polifarmácia foi identificada em 29,8% dos idosos, incluindo o uso de medicamentos alopáticos, fitoterápicos e plantas medicinais. Doze idosos (25,5%) relataram possuir lesões de pele, 72,3% informaram uso de próteses dentárias e 2,1% próteses ortopédicas. A maioria dos idosos classificou sua alimentação como saudável (85,1%), mas todos relataram algum tipo de perda funcional. Os resultados demonstram que o Programa Assistencial conta com idosos com o perfil de saúde semelhante ao da população idosa brasileira, com ampla ocorrência de doenças crônicas, edentulismo, incapacidades funcionais e elevado consumo de medicamentos. O presente estudo reforça a importância do trabalho interdisciplinar como subsídio para o desenvolvimento de intervenções mais sensíveis e eficazes, considerando a perspectiva do próprio indivíduo e suas necessidades. (AU)

The aging of the Brazilian population brought changes in their epidemiological profile: increased occurrence of chronic illnesses and functional disabilities; increased demand for health services. The knowledge of the characteristics and elements of such changes have represented a challenge to public health researchers. A preliminary attempt to meet such challenge comes from a program of assistance to the elderly in the city of Governador Valadares, Minas Gerais, Brazil, with the support of an independent agency backed by the commercial sector (SESC-Minas). A sample of individuals aged 60 and above responded to a semi-structured questionnaire to socioeconomic variables, health conditions and life styles. The survey was a research instrument for the proposal of preventive action and active ageing. The data revealed the main diseases: arterial hypertension (63.8 percent); osteoarthritis (25.5 percent); heart diseases (17%) and diabetes (10.6 percent). “`Polipharmacy” was identified in 29.8% of seniors, including the use of allopathic drugs, phytotherapy and medicinal plants. 25.5 percent reported skin lesions, 72.3% wore dentures and 2.1% orthopedic prostheses. Most elderly people claimed to follow a healthy diet (85.1%), but all reported some form of functional loss. The results suggest that the Program relies on the participation of seniors with health profile similar to the general population of Brazilian elderly, with wide occurrence of chronic diseases, edentulism and high consumption of medicines. This study reinforces the importance of interdisciplinary work as subsidy for the development of more effective interventions, taking into account the perspectives of the elderly and their needs. (AU)

[Role of nitric oxide in the control of the pulmonary circulation: physiological, pathophysiological, and therapeutic implications]. / Papel do óxido nítrico na regulação da circulação pulmonar: implicações fisiológicas, fisiopatológicas e terapêuticas.

Nitric oxide (NO) is an endogenous vasoactive compound that contributes to pulmonary vascular homeostasis and is produced by three nitric oxide synthase (NOS) isoforms-neuronal NOS (nNOS); inducible NOS (iNOS); and endothelial NOS (eNOS)-all three of which are present in the lung. Studies using pharmacological inhibitors or knockout mice have shown that eNOS-derived NO plays an important role in modulating pulmonary vascular tone and attenuating pulmonary hypertension. However, studies focusing on the role of iNOS have shown that this isoform contributes to the pathophysiology of acute lung injury and acute respiratory distress syndrome. This review aimed at outlining the role played by NO in the control of pulmonary circulation, both under physiological and pathophysiological conditions. In addition, we review the evidence that the L-arginine-NO-cyclic guanosine monophosphate pathway is a major pharmacological target in the treatment of pulmonary vascular diseases.

Papel do óxido nítrico na regulação da circulação pulmonar: implicações fisiológicas, fisiopatológicas e terapêuticas / Role of nitric oxide in the control of the pulmonary circulation: physiological, pathophysiological, and therapeutic implications

O nitric oxide (NO, óxido nítrico) é um mediador endógeno vasoativo que contribui para a homeostase vascular pulmonar. O NO é produzido por três isoformas das nitric oxide synthases (NOS, óxido nítrico sintases)-NOS neuronial (nNOS); NOS induzida (iNOS); e NOS endotelial (eNOS)-estando as três presentes no pulmão. Estudos que utilizaram inibidores farmacológicos ou camundongos knockout têm demonstrado que o NO derivado da eNOS desempenha importantes papéis ao modular o tônus vascular pulmonar e atenuar a hipertensão pulmonar. Por outro lado, estudos focados no papel da iNOS têm mostrado que essa isoforma contribui para a fisiopatologia da lesão pulmonar aguda e da síndrome do desconforto respiratório agudo. Esta revisão objetivou delinear o papel desempenhado pelo NO no controle da circulação pulmonar, tanto em condições fisiológicas como fisiopatológicas. Além disso, revisamos as evidências de que a via L-arginina-NO-guanosina monofosfato cíclico seja um importante alvo farmacológico para a terapia de doenças vasculares pulmonares.

Nitric oxide (NO) is an endogenous vasoactive compound that contributes to pulmonary vascular homeostasis and is produced by three nitric oxide synthase (NOS) isoforms-neuronal NOS (nNOS); inducible NOS (iNOS); and endothelial NOS (eNOS)-all three of which are present in the lung. Studies using pharmacological inhibitors or knockout mice have shown that eNOS-derived NO plays an important role in modulating pulmonary vascular tone and attenuating pulmonary hypertension. However, studies focusing on the role of iNOS have shown that this isoform contributes to the pathophysiology of acute lung injury and acute respiratory distress syndrome. This review aimed at outlining the role played by NO in the control of pulmonary circulation, both under physiological and pathophysiological conditions. In addition, we review the evidence that the L-arginine-NO-cyclic guanosine monophosphate pathway is a major pharmacological target in the treatment of pulmonary vascular diseases.