Background/Aims: Diabetic subjects are more susceptible to infections, which is partially due to insulin deficiency and hyperglycemia. We hypothesized that insulin influences cytokine release by macrophages from diabetic C57BL/6 mice stimulated with lipopolysaccharides (LPS). Methods: Bone marrow-derived macrophages (BMDM) and tissue-specific macrophages from diabetic (alloxan 60 mg/kg, i.v.) male C57BL/6 mice were stimulated by LPS (100 ng/mL) and/or treated by insulin (1 mU/mL). Results: Using BMDM from diabetic mice, we showed that LPS induced an increase in TNF-α and IL-6 release and p38, SAPK/JNK, ERK 1/2, and Akt (308-Thr and 473-Ser) phosphorylation but not in PKCα/β II and delta. Insulin increased TNF-α and IL-6 secretion in LPS-stimulated macrophages as well as p-p38, p-SAPK/JNK, p-ERK 1/2, p-PI3K (p55) and p-Akt (473-Ser) expression. Furthermore, PI3-kinase inhibition by wortmannin decreased TNF-α release, and inhibition by LY294002 decreased both TNF-α and IL-6 levels after LPS-insulin treatment. PD98059, which inhibits the ERK upstream activators MAPK kinase (MKK) 1 and MKK2, reduced the effect promoted by insulin in BMDM stimulated by LPS In tissue-specific macrophages, insulin reduced LPS-induced TNF-α, IL-6 and IL-1β secretion in alveolar and peritoneal macrophages. Conclusion: These data suggest that insulin through the modulation of PI3-kinase and ERK 1/2 pathways drive different responses in macrophages, thereby enhancing our understanding of the plasticity of these cells.
Macrophages may be a crucial aspect of diabetic complications associated with the inflammatory response. In this study, we examined how hyperglycaemia, a common aspect of diabetes, modulates bone marrow-derived macrophages (BMDMs) under an inflammatory stimulus. To perform this study, BMDMs from non-diabetic and diabetic (60 mg/kg alloxan, i.v.) male C57BL/6 mice (CEUA/FCF/USP-488) were cultured under normal (5.5 mM) and high glucose (HG, 25 or 40 mM) conditions and stimulated or not stimulated with lipopolysaccharide (LPS, 100 ng/mL). Compared to the BMDMs from the normoglycaemic mice, the LPS-stimulated BMDMs from the diabetic mice presented reduced TLR4 expression on the cell surface, lower phagocytic capacity, and reduced secretion of NO and lactate but greater oxygen consumption and greater phosphorylation of p46 SAPK/JNK, p42 ERK MAPK, pAKT and pPKC-δ. When the BMDMs from the non-diabetic mice were cultured under high-glucose conditions and stimulated with LPS, TLR4 expression was reduced on the cell surface and NO and H 2 O 2 levels were reduced. In contrast, the diabetic BMDMs cultured under high glucose conditions presented increased levels of lactate and reduced phosphorylation of AKT, PKC-δ and p46 SAPK/JNK but enhanced phosphorylation of the p46 subunit of SAPK/JNK after LPS stimulation. High glucose levels appear to modify macrophage behaviour, affecting different aspects of diabetic and healthy BMDMs under the same LPS stimulus. Thus, hyperglycaemia leaves a glucose legacy, altering the basal steady state of macrophages.
Background/Aims. The effects of cholecalciferol supplementation on the course of diabetes in humans and animals need to be better understood. Therefore, this study investigated the effect of short-term cholecalciferol supplementation on biochemical and hematological parameters in mice. Methods. Male diabetic (alloxan, 60 mg/kg i.v., 10 days) and nondiabetic mice were supplemented with cholecalciferol for seven days. The following parameters were determined: serum levels of 25-hydroxyvitamin D, phosphorus, calcium, urea, creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, red blood cell count, white blood cell count (WBC), hematocrit, hemoglobin, differential cell counts of peritoneal lavage (PeL), and bronchoalveolar lavage (BAL) fluids and morphological analysis of lung, kidney, and liver tissues. Results. Relative to controls, cholecalciferol supplementation increased serum levels of 25-hydroxyvitamin D, calcium, hemoglobin, hematocrit, and red blood cell counts and decreased leukocyte cell counts of PeL and BAL fluids in diabetic mice. Diabetic mice that were not treated with cholecalciferol had lower serum calcium and albumin levels and hemoglobin, WBC, and mononuclear blood cell counts and higher serum creatinine and urea levels than controls. Conclusion. Our results suggest that cholecalciferol supplementation improves the hematological parameters and reduces leukocyte migration into the PeL and BAL lavage of diabetic mice.
Malaria is an enormous burden on global health that caused 409,000 deaths in 2019. Severe malaria can manifest in the lungs, an illness known as acute respiratory distress syndrome (ARDS). Not much is known about the development of malaria-associated ARDS (MA-ARDS), especially regarding cell death in the lungs. We had previously established a murine model that mimics various human ARDS aspects, such as pulmonary edema, hemorrhages, pleural effusion, and hypoxemia, using DBA/2 mice infected with Plasmodium berghei ANKA. Here, we explored the mechanisms and the involvement of apoptosis in this syndrome. We found that apoptosis contributes to the pathogenesis of MA-ARDS, primarily as facilitators of the alveolar-capillary barrier breakdown. The protection of pulmonary endothelium by inhibiting caspase activation could be a promising therapeutic strategy to prevent the pathogenicity of MA-ARDS. Therefore, intervention in the programmed death cell mechanism could help patients not to develop severe malaria.
ResumoContexto: A população idosa apresenta alta prevalência de hipovitaminose D, sendo provável que, exposta ao uso de anticonvulsivantes, ocorra agravamento dessa condição. Objetivo: Avaliar a interferência do uso crônico de fármacos anticonvulsivantes nos níveis séricos de vitamina D em idosos institucionalizados com idade acima de 65 anos. Métodos: Foram estudados 18 idosos institucionalizados tratados com anticonvulsivantes, por no mínimo 12 meses, comparados a 16 idosos não tratados. Resultados: O estudo demonstrou que os dois grupos cursaram com de ciência de vitamina D, sendo mais pronunciada no grupo tratado com anticonvulsivantes. Embora não houvesse diferença estatisticamente signi cativa nos valores de paratormônio, nos idosos tratados foi observada uma tendência de níveis mais elevados, 53,44 ± 28,92 pg/ml em comparação aos idosos não tratados, 38,5 ± 10,08 pg/ml (P = 0,42). Foi observada diferença estatisticamente signi cativa entre os níveis séricos de 25-hidroxivitamina D nas pacientes do sexo feminino tratadas de 9,22 ± 3,80 ng/ml versus não tratadas, 18,78 ± 7,62 ng/ml (P = 0,03). Conclusão: Nossos achados sugerem que idosos institucionalizados apresentam menores níveis séricos de 25-hidroxivitamina D, con gurando um estado de de ciência, e diferença signi cativa foi detectada nas mulheres tratadas com fármacos anticonvulsivantes. AbstractBackground: Elderly people have a high prevalence of hypovitaminosis D, especially when they are exposed to anticonvulsants. Objective: e present study evaluated the in uence of chronic use of anticonvulsants on serum levels of vitamin D in institutionalized elders aged above 65 years. Methods: Eighteen elderly subjects treated with anticonvulsants were studied for at least 12 months and compared to 16 untreated elders. Results: Vitamin D de ciency was observed in both groups, but the group treated with anticonvulsants showed a more remarkable de ciency. Although there was no statistically signi cant di erence in serum parathyroid hormone levels, elderly patients in treatment had a higher value (53.44 ± 28.92 pg/ml) compared to untreated elders (38.5 ± 10.8 pg/ml: p = 0.42). Statistically signi cant di erence was observed between serum 25-hydroxyvitamin D in treated female patients (9.22 ± 3.80 ng/ml) compared to untreated female patients (18.78 ± 7.62 ng/ml: p = 0.03). Discussion: e observed de ciency in both groups suggests that elderly subjects have lower serum 25-hydroxyvitamin D. Compared to untreated elderly women, elderly women treated with anticonvulsants showed a signi cantly lower serum level of vitamin D.
Ao Deus de Abraão, por estar constantemente me capacitando, fortalecendo-me e me direcionando durante a jornada. À Carolina, meu corpo e minha querida noiva, pelo companheirismo, apoio, dedicação, zelo, paciência, carinho e amor demonstrados e comprovados ao longo de mais de uma década. Meu singelo muito obrigado por me deixar fazer parte da sua vida.Aos meus pais, João e Marina, pelos ensinamentos, carinho, dedicação e apoio indispensáveis.À minha família, principalmente, ao Gustavo, às minhas avós, ao Tio Israel, à Tia Maria de Lourdes, à Tia Marília, à Tia Marta, à Tia Augusta, à Graça, ao Marcos e à Marilene, que, mesmo estando a quilômetros de distância se fazem sempre presentes.Ao Eduardo Lima Nolasco, por ter acreditado no meu trabalho, pela indicação ao professor Dr. Joilson, pela paciência, pelas inúmeras contribuições durante o trabalho e na adaptação ao ritmo paulistano e pelos convites para assistir aos jogos do Botafogo.Ao Dr. Joilson de Oliveira Martins, que me aceitou no seu grupo de pesquisa, acreditou no meu trabalho e tem contribuído para o meu crescimento pessoal e profissional.À Isis Fieri, IC que demonstrou ser uma profissional de alto nível através do desempenho na execução do presente trabalho. À Fernanda Peixoto Barbosa Nunes, pelos ensinamentos sobre São Paulo e pelas diversas ajudas.Ao Fernando Henrique Tessaro Galvão que, juntamente com os demais, auxiliou-me em diversas etapas do trabalho e pela paciência. À Mariana Cristina Ferreira Silva, pela paciência e por todo o suporte técnico e administrativo que foram fundamentais para o trabalho.
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