Physalin B reduces Aβ secretion through down-regulation of BACE1 expression by activating FoxO1 and inhibiting STAT3 phosphorylation / 中国天然药物

Physalin B (PB), one of the major active steroidal constituents of Solanaceae Physalis plants, has a wide variety of biological activities. We found that PB significantly down-regulated β-amyloid (Aβ) secretion in N2a/APPsw cells. However, the underlying mechanisms are not well understood. In the current study, we investigated the changes in key enzymes involved in β-amyloid precursor protein (APP) metabolism and other APP metabolites by treating N2a/APPsw cells with PB at different concentrations. The results indicated that PB reduced Aβ secretion, which was caused by down-regulation of β-secretase (BACE1) expression, as indicated at both the protein and mRNA levels. Further research revealed that PB regulated BACE1 expression by inducing the activation of forkhead box O1 (FoxO1) and inhibiting the phosphorylation of signal transducer and activator of transcription 3 (STAT3). In addition, the effect of PB on BACE1 expression and Aβ secretion was reversed by treatment with FoxO1 siRNA and STAT3 antagonist S3I-201. In conclusion, these data demonstrated that PB can effectively down-regulate the expression of BACE1 to reduce Aβsecretion by activating the expression of FoxO1 and inhibiting the phosphorylation of STAT3.

Effect of progesterone on expression of brain tissue damage factors and anti damage factors in neonatal rats with hypoxic-ischemic brain damage / 中华实用儿科临床杂志

Objective To study the effect of progesterone on tumor necrosis factor (TNF-α),interleukin-1β (IL-1β),nerve growth factor(NGF) and brain derived neurotrophic factor(BDNF) expression in the cortex and hippocampus tissue in newborn rats with hypoxic-ischemic brain damage (HIBD),and to discuss the protective molecular mechanism of progesterone on HIBD in neonatal rats.Methods Forty-eight 7-day-old neonatal rats were randomly divided into 3 groups:sham-operated group,hypoxic-ischemic group and pretreatment group.Rats in hypoxic-ischemic group and pretreatment group were subjected to left common carotid artery ligation,then they were exposed to 80 mL/L oxygen and 920 mL/L nitrogen gas in the closed container at 37 ℃ for up to 2.5 h to establish HIBD models.Progesterone was injected intraperitoneally into the rats in the pretreatment group 30 min before hypoxia,and solution was injected into the first 2 groups.All the rats were killed at the 24 h after operation.The levels of TNF-α,IL-1β,NGF,BDNF were measured by enzyme linked immunosorbent assay and the expressions of TNF-α,IL-13,NGF,BDNF mRNA were analyzed by reverse transcription-polymerase chain reaction.Results The contents of TNF-α,IL-1β,NGF,BDNF and their mRNA expressions in hypoxic-ischemic group were significantly higher than those in the sham-operated group.In pretreatment groups,the levels of TNF-α,IL-1β and their mRNA expressions were significantly lower than those in hypoxic-ischemic group.The levels of NGF,BDNF and their mRNA expressions in pretreatment group were significantly higher than those in hypoxic-ischemic group (all P ＜ 0.05).Conclusions Progesterone exerts neuroprotective effect on hypoxic-ischemic encephalopathy-induced brain damage,and the action mechanism is related to down-regulate the expression of damage factor and up-regulate the expression of anti damage factor.

Mechanism of MBL inhibiting the LPS-induced DC maturation / 中国实验血液学杂志

The study was aimed to investigate the mechanism of mannan-binding lectin (MBL) on bacterial lipopolysaccharide (LPS)-induced human peripheral blood monocyte-derived dendritic cell (DC) maturation. The monocytes were prepared from the peripheral blood of healthy adult volunteers. The immature dendritic cells (imDC) were induced by 5-day-culture in medium supplemented with rhGM-CSF and rhIL-4. FACS was used to investigate the interaction of MBL with imDC and the impact of MBL on LPS binding to imDC. ELISA and Western blot was used to analyze the interaction of MBL with soluble TLR4 ectodomain protein (sTLR4); Western blot was used to detect LPS-induced NF-κB translocation in imDC. The results showed that MBL could directly bind to imDC in the presence of calcium. sTLR4 protein or LPS could competitively inhibit the binding of MBL to imDC. ELISA and Western blot showed that MBL could evidently bind to sTLR4 protein in a concentration-dependent manner. FACS showed that MBL could competitively inhibit the binding of LPS to imDC by binding to imDC directly. Western blot showed that MBL decreased LPS-induced NF-κB translocation in imDC. It is concluded that MBL may competitively inhibit the binding of LPS to imDC by binding to TLR4 expressed on imDC, resulted in inhibition of LPS-induced DC maturation, suggesting that MBL can regulate DC maturation through ligand-binding. This study provides the good foundation to clarify the mechanism of MBL inhibiting the LPS-induced DC maturation.

Effects of activation of liver X receptor and peroxisome proliferator-activated receptor alpha on bile acid synthesis in rats / 中国医学科学院学报

<p><b>OBJECTIVE</b>To explore the effects of the simultaneous activation of liver X receptor (LXR) and peroxisome proliferator-activated receptor alpha (PPARalpha) on bile acid biosynthesis in rats.</p><p><b>METHODS</b>Totally 36 male SD rats were divided into three groups with 12 rats in each group: control group, high cholesterol (HC) group, and high cholesterol + fenofibrate (HC + FENO) group. Total bile acids (serum bile acids plus fecal bile acids) level was assayed. The levels of mRNA for peroxisomal palmitoyl-CoA oxidase (Acox1), LXR, cholesterol 7alpha-hydroxylase (CYP7A1), D-bifunctional protein (DBP), trihydroxycoprostanoyl-CoA oxidase (Acox2), sterol 12alpha-hydroxylase (CYP8B1), and sterol 27-hydroxylase (CYP27A1) in liver were detected by RT-PCR.</p><p><b>RESULTS</b>Total bile acid level was significantly higher in HC + FENO group than in HC group (P < 0.01), and both were significantly higher than that in control group (P < 0.01). Compared with HC group, the mRNA expression of Acox1 and DBP was significantly higher in HC + FENO group (P < 0.01), but no statistical differences was found between HC group and control group. The mRNA levels of LXR and CYP7A1 in HC + FENO group and HC group were not significantly different but were both significantly higher than that in control group (P < 0.01, P < 0.05). No changes were observed in Acox2, CYPSB1, and CYP27A1 mRNA levels among these three groups.</p><p><b>CONCLUSION</b>Simultaneous activation of LXR and PPARalpha can increase of CYP7A1 and DBP mRNA exDression and thus accelerates the biosynthesis of bile acid.</p>

Relationship between the increase of hepatic D-bifunctional protein activity and bile acid biosynthesis in rats / 中国医学科学院学报

<p><b>OBJECTIVE</b>To determine the physiological role of D-bifunctional protein (DBP) in bile acid biosynthesis through investigating the effect of increasing activity of DBP on bile acid biosynthesis.</p><p><b>METHODS</b>Twenty male Wistar rats were divided into two groups: diethylhexyl phthalate (DEHP) group (n = 10) and control group (n = 10). Serum triglyceride, total cholesterol, hepatic DBP activity, and fecal bile acids were assayed. The mRNA levels of hepatic peroxisome proliferator-activated receptor alpha (PPARalpha), DBP, and cholesterol 7alpha-hydroxylase (CYP7A1) were detected by RT-PCR.</p><p><b>RESULTS</b>Compared with control group, serum triglyceride level was decreased significantly and PPARalphamRNA level was increased significantly in DEHP group (P < 0.01). Together with a sharp induction of DBP mRNA expression and DBP activity in DEHP group (P < 0.01), the levels of CYP7A1 mRNA and fecal bile acids were significantly increased by 1.9 times and 1.6 times respectively compared to control group (P < 0.01). There was a significantly positive correlation between DBP mRNA level or DBP activity and CYP7A1 mRNA level (r = 0.89, P < 0.01; r = 0.95, P < 0.01).</p><p><b>CONCLUSION</b>The up-regulation of DBP mRNA and activity in liver can result in the increase in CYP7A1 mRNA expression and bile acid biosynthesis, suggesting that DBP may be involved in bile acid biosynthesis together with CYP7A1.</p>