Acute sleep deprivation leads to depression-like behavior by modulating AMPK-autophagy signaling / 安徽医科大学学报

Objective @# This work mainly studied the effects of acute sleep deprivation (SD) on anxiety and depres- sion behavior in mice，and explored possible molecular mechanisms．@*Methods @#33 male 8-week-old C57BL /6 mice were randomly divided into environment control (EC) group and a SD group．The open field test and elevated plus maze test were used to evaluate their spontaneous and anxiety behavior，while the forced swimming test and tail suspension test were used to detect depression behavior in mice．The expression of neuroinflammatory proteins and the levels of autophagy-related proteins were detected by Western blot method. @*Results @#Behavioral results showed that comparing to the EC group，the total distance traveled by mice in the SD group significantly increased in the open field test(P ＜0. 01 ) ，while the number of crossings and time spent in the central area did not show significant differences. Results from the forced swimming test showed that immobility time significantly increased in the SD group mice(P ＜0. 01 ) ，but there were no significant differences in tail suspension and elevated plus maze test. Western blot results showed that comparing to the EC group，the levels of NLRP1，TNF-α, IL-1 β, IL-18，and autophagy protein p62 in the hippocampus of the SD group mice significantly increased，while the levels of Atg5，Atg7 decreased significantly，and the phosphorylation level of AMPK also decreased significantly．@*Conclusion @#SD may induce depression-like behavior in mice by inhibiting the AMPK-autophagy signaling pathway in the hippocampus and upregulating neuroinflammatory levels.

corilagin protects non-alcoholic fatty liver disease in mice induced by high fat and high sugar diet via regulating AMPK-autophagy signaling / 中国药理学通报

Aim To explore the effects of corilagin on non-alcoholic fatty liver disease induced by high-fat and high-sugar diet in mice via regulating AMPK-autophagy signaling. Methods Healthy 8-week-old male C57BL/6J mice were randomly divided into control group, model group and corilagin group. The mice of model group and corilagin group were fed with a high-fat and high-sugar diet for four weeks at the age of eight weeks. The corilagin group mice were also intraperitoneally injected with corilagin (20 mg • k g

Effects of orientin on insulin resistance in 3T3-L1 adipocytes and its mechanism / 中国药理学通报

Aim To investigate the effect of orientin on proliferation and differentiation of 3T3-L1 pre-adipocytes and on insulin resistance(IR) in 3T3-L1 adipocytes and the possible mechanisms.Methods MTT assay and oil red O staining were applied to investigate the proliferation and the differentiation of 3T3-L1 pre-adipocytes, respectively.The intracellular triglyceride(TG) contents were detected by enzymatic analysis.IR model was induced with dexamethasone.A fluorescent glucose analogue, 2-NBDG, was used to measure the rate of glucose uptake.Western blot was used to detect the protein level of GLUT4 and phosphorylation of AMPK and ACC.The GLUT4 translocation was measured by fluorescent-immunohistochemistry.Results Orientin decreased the formation of lipid droplets and intracellular TG contents(P<0.01) in a concentration-dependent manner(P<0.05), but it had no obvious effects on the cell vitality.Under the IR state, orientin significantly increased 3T3-L1 adipocytes glucose uptake(P<0.05).Meanwhile, orientin up-regulated the protein expression of p-AMPK, p-ACC, and enhanced GLUT4 translocation and its expression.Conclusion Orientin can effectively inhibit the differentiation of 3T3-L1 pre-adipocytes and increase insulin sensitivity due to the activation of AMPK/GLUT4 signal pathway.

A memória hiperglicêmica no rim diabético: marcas metabólicas, moleculares e epigenéticas / The hyperglycemic memory in diabetic kidney: metabolic, molecular, and epigenetic marks

A nefropatia diabética (ND) é uma das complicações microvasculares do diabetes e consiste no dano ao parênquima renal por consequência de uma série de fatores hemodinâmicos e moleculares. A ocorrência de ND e de outras complicações mesmo em indivíduos sob adequado controle glicêmico tem sido associada a um fenômeno conhecido como memória metabólica. Neste trabalho foram investigadas vias bioquímicas e moleculares persistentemente alteradas no rim de animais diabéticos tratados após um período inicial de hiperglicemia, com o propósito de entender os mecanismos envolvidos na memória metabólica. Para tanto, ratos com diabetes induzida por estreptozotocina foram mantidos hiperglicêmicos durante 4 semanas (período curto) ou 12 semanas (período longo) e posteriormente tratados com insulina isoladamente ou combinada com metformina (100mg/kg/dia) durante as 4 (período curto) ou 12 (período longo) semanas seguintes. Todos os animais tratados tiveram os seus níveis glicêmicos e função renal normalizados. Os tratamentos também foram capazes de normalizar os níveis elevados de malonaldeído no rim, bem como a excreção aumentada dos adutos de DNA 8-oxo-2'-desoxiguanosina (8-oxodG) e N2-carboxietil-2'- desoxiguanosina (CEdG) na urina observados nos animais diabéticos. Níveis aumentados de 8-oxodG foram detectados em DNA mitocondrial (mtDNA), mas não em DNA nuclear, de animais diabéticos apenas no período curto de estudo e também foram normalizados após o controle glicêmico. Nós identificamos uma via gradualmente alterada durante o curso do diabetes que permanece persistentemente alterada após o controle glicêmico tardio. Essa via compreende um declínio precoce do clearance de ácido úrico e expressão da pAMPK, seguida pelo acúmulo de fumarato, expressão aumentada de TGF-ß, expressão reduzida de PGC-1α e redução da metilação e hidroximetilação do mtDNA. A redução persistente do clearance de ácido úrico em animais diabéticos tratados pode sustentar as alterações bioquímicas renais prolongadas observadas após o controle glicêmico, e essa regulação é provavelmente mediada pela redução sustentada da expressão de pAMPK e pela indução de inflamação. Este trabalho propõe a primeira consideração do possível papel da hiperuricemia e das alterações bioquímicas subjacentes como parte da memória metabólica na nefropatia diabética

Diabetic nephropathy is one of the diabetes microvascular complications, and it consists on the damage to the renal parenchyma due to several hemodynamic and molecular factors. The occurrence of diabetic nephropathy and other complications even in those individuals under tight glycemic control has been associated to a phenomenon known as metabolic memory. Here we investigated biochemical and molecular pathways persistently altered in the kidney of diabetic animals treated after a previous period of hyperglycemia, aiming to understand underlying mechanisms in metabolic memory. Streptozotocin-induced diabetic rats were maintained hyperglycemic during 4 (short period) or 12 weeks (long period), and then they were treated with insulin alone or combined with metformin (100 mg/kg/day) for the following 4 or 12 weeks, respectively. All the treated animals had them glycemic levels and renal function normalized. The treatments were also able to control enhanced kidney malondialdehyde levels, as well as the increased urine excretion of the DNA adducts 8-oxo-2'- deoxyguanosine (8-oxodG) and N2-carboxyethyl-2'-deoxyguanosine seen in diabetic animals. Increased levels of 8-oxodG were detected in mitochondrial DNA, but not in nuclear DNA of diabetic animals in the short period, and were also recovered after glycemic control. We have identified a kidney pathway that is gradually altered during the course of diabetes and remains persistently changed after late glycemic control. This pathway comprises an early decline of uric acid clearance and pAMPK expression followed by fumarate accumulation, increased TGF-ß expression, reduced PGC-1α expression, and downregulation of methylation and hydroxymethylation of mitochondrial DNA. The sustained decrease of uric acid clearance in treated diabetes may support the prolonged kidney biochemical alterations observed after tight glycemic control, and this regulation is likely mediated by the sustained decrease of AMPK activity and the induction of inflammation. This work proposes the first consideration of the possible role of hyperuricemia and the underlying biochemical changes as part of metabolic memory in diabetic nephropathy