Dietary protein modulates intestinal dendritic cells to establish mucosal homeostasis.

Dietary proteins are taken up by intestinal dendritic cells (DCs), cleaved into peptides, loaded to major histocompatibility complexes, and presented to T cells to generate an immune response. Amino acid (AA)-diets do not have the same effects because AAs cannot bind to major histocompatibility complex to activate T cells. Here, we show that impairment in regulatory T cell generation and loss of tolerance in mice fed a diet lacking whole protein is associated with major transcriptional changes in intestinal DCs including downregulation of genes related to DC maturation, activation and decreased gene expression of immune checkpoint molecules. Moreover, the AA-diet had a profound effect on microbiome composition, including an increase in Akkermansia muciniphilia and Oscillibacter and a decrease in Lactococcus lactis and Bifidobacterium. Although microbiome transfer experiments showed that AA-driven microbiome modulates intestinal DC gene expression, most of the unique transcriptional change in DC was linked to the absence of whole protein in the diet. Our findings highlight the importance of dietary proteins for intestinal DC function and mucosal tolerance.

Prevention of lipid droplet accumulation by DGAT1 inhibition ameliorates sepsis-induced liver injury and inflammation.

Background & Aims: Lipid droplet (LD) accumulation in cells and tissues is understood to be an evolutionarily conserved tissue tolerance mechanism to prevent lipotoxicity caused by excess lipids; however, the presence of excess LDs has been associated with numerous diseases. Sepsis triggers the reprogramming of lipid metabolism and LD accumulation in cells and tissues, including the liver. The functions and consequences of sepsis-triggered liver LD accumulation are not well known. Methods: Experimental sepsis was induced by CLP (caecal ligation and puncture) in mice. Markers of hepatic steatosis, liver injury, hepatic oxidative stress, and inflammation were analysed using a combination of functional, imaging, lipidomic, protein expression and immune-enzymatic assays. To prevent LD formation, mice were treated orally with A922500, a pharmacological inhibitor of DGAT1. Results: We identified that liver LD overload correlates with liver injury and sepsis severity. Moreover, the progression of steatosis from 24 h to 48 h post-CLP occurs in parallel with increased cytokine expression, inflammatory cell recruitment and oxidative stress. Lipidomic analysis of purified LDs demonstrated that sepsis leads LDs to harbour increased amounts of unsaturated fatty acids, mostly 18:1 and 18:2. An increased content of lipoperoxides within LDs was also observed. Conversely, the impairment of LD formation by inhibition of the DGAT1 enzyme reduces levels of hepatic inflammation and lipid peroxidation markers and ameliorates sepsis-induced liver injury. Conclusions: Our results indicate that sepsis triggers lipid metabolism alterations that culminate in increased liver LD accumulation. Increased LDs are associated with disease severity and liver injury. Moreover, inhibition of LD accumulation decreased the production of inflammatory mediators and lipid peroxidation while improving tissue function, suggesting that LDs contribute to the pathogenesis of liver injury triggered by sepsis. Impact and Implications: Sepsis is a complex life-threatening syndrome caused by dysregulated inflammatory and metabolic host responses to infection. The observation that lipid droplets may contribute to sepsis-associated organ injury by amplifying lipid peroxidation and inflammation provides a rationale for therapeutically targeting lipid droplets and lipid metabolism in sepsis.

Efeitos anti-hipertensivos do aceturato de diminazeno: um ativador da enzima conversora de angiotensina 2 em ratos / Antihypertensive effects of diminazene aceturate: an activator of angiotensin-2 converting enzyme in rats

INTRODUÇÃO: O sistema renina-angiotensina-aldosterona desempenha importante papel cardiovascular. A enzima conversora de angiotensina 2 (ECA2) degrada a Angiotensina II em Angiotensina-(1-7), que se liga ao receptor Mas e há liberação de óxido nítrico (NO). Recentemente, foi descrito o aceturato de diminazeno (DIZE), ativador da ECA2. OBJETIVOS: Avaliar a ação do DIZE na pressão arterial (PA) e frequência cardíaca (FC) de ratos normotensos e hipertensos, além de explorar seu mecanismo de ação em vasos isolados. Métodos: Estudo de intervenção em ratos submetidos a implante de cânulas na artéria femoral para registrar PA e FC e na veia femoral para injeção de DIZE e salina (controle). O efeito no fluxo sanguíneo de arteríolas mesentéricas foi avaliado por microscopia intravital. Para induzir hipertensão arterial foi usado o modelo de hipertensão renovascular (2-kidney1clip; 2K1C). Após o procedimento, os animais foram tratados com DIZE, captopril ou salina e posteriormente feita análise histológica dos corações. No estudo in vitro de vasos isolados, o mecanismo de ação do DIZE foi avaliado usando o A-779, bloqueador do Mas, e o L-NAME, inibidor da NO sintase. RESULTADOS e CONCLUSÕES: O DIZE causou redução na PA com aumento compensatório da FC de maneira dose-dependente em ratos normotensos (Fig.1). O efeito hipotensor do DIZE foi semelhante ao do captopril em ratos hipertensos e não houve alteração na FC (Fig.1). Houve diminuição na velocidade do fluxo nas arteríolas no leito vascular mesentérico em ratos normotensos. A vasodilatação foi dependente do Mas e da liberação de NO. O DIZE preveniu o desenvolvimento de hipertrofia cardíaca em ratos hipertensos. Conclui-se que o DIZE tem efeito hipotensor em ratos normotensos e hipertensos devido a liberação de NO após ativação do Mas. (AU)

Anti-inflammatory drugs: basic knowledge to a safe prescription: [review] / Drogas antiinflamatórias: conhecimentos básicos para uma prescrição segura: [revisão]

Nearly six million new people suffer from back pain and another 45 million Americans suffer from chronic headaches. It is obvious that the most prescribed compounds on the Earth are the analgesic and anti-inflammatory drugs. However, much is sold, but there is still much to learn about them, In this brief review, basic pharmacology and physiology of the inflammatory process will be discussed, proving elementary basis to a rational prescription of anti-inflammatory drugs. In a addition, a historical approach about how this multibillion dollar market has grown and the most studied alternatives in the treatment of pain will be addressed. Finally, future perspectives about the prescription of anti-inflammatory drugs pointed to the necessity of constant update by the health professional and the adjustment of the type and the dose of the drug.

Quase seis milhões povos novos sofrem da dor traseira e uns outros 45 milhões americanos sofrem das dores de cabeça crônicas. É óbvio que os compostos os mais prescritos na terra são as drogas analgésicas e anti-inflmatórias. Entretanto, muito é vendido, mas há ainda muito a aprender sobre elas. Nesta breve revisão, a farmacologia e a fisiologia básicas do processo inflamatório serão discutidas, provando a base elementar a uma prescrição racional de drogas anti-inflammatórias. Além, uma aproximação histórica sobre como este mercado de vários bilhões de dollares creceu e as alternativas as mais estudadas no tratamento da dor serão endereçadas. Finalmente, perspectivas futuras sobre a prescrição das drogas anti-inflammatórias aguçado à necessidade da actualização constante pelo profissional de saúde e do ajuste do tipo e à dose da droga.