Inhibition of the C3a receptor attenuates sepsis-induced acute lung injury by suppressing pyroptosis of the pulmonary vascular endothelial cells.

Acute lung injury (ALI) is the leading cause of bacterial sepsis-related death because of disrupted pulmonary endothelial barrier, resulting in protein-rich pulmonary oedema, an influx of pro-inflammatory cells and refractory hypoxaemia. Several studies have reported that C3a levels are significantly higher in organs with sepsis and their peripheral organs and are closely associated with organ dysfunction and poor prognosis in sepsis. However, the role of the C3a complement in sepsis ALI remains unclear. Therefore, this study aimed to investigate the important role and mechanism of C3a in preventing the occurrence of pyroptosis (a pro-inflammatory form of cell death) to protect the lung endothelial cells (ECs) in sepsis-induced ALI. A septic mouse model was established with cecal ligation and puncture (CLP), which demonstrated that C3a mediated EC pyroptosis through its C3aR receptor. Furthermore, inhibition of the C3a-C3aR axis could block both NLRP3/caspase-1 and caspase-11 pathways, thus preventing pulmonary EC from pyroptosis. These results indicate that inhibition of the C3A-C3AR complement axis can inhibit pulmonary vascular EC pyroptosis, a potential target for the treatment of ALI.

Characteristics of Body Composition and Lifestyle in Chinese University Students with Normal-Weight Obesity: A Cross-Sectional Study.

PURPOSE: Normal weight obesity (NWO), defined as normal body mass index (BMI) and excessive body fat percentage (BF%), has been shown to be associated with a significantly higher risk of developing metabolic syndrome, cardiometabolic dysfunction and with higher mortality. However, there is limited literature regarding the potential associations between NWO and lifestyles. This study aimed to investigate the associations of lifestyles with NWO in Chinese university students. PARTICIPANTS AND METHODS: A total of 279 university students with normal BMI were recruited and divided into NWO and normal weight non-obesity (NWNO) groups by BF%. Body composition and anthropometrics were measured, and participants were asked to finish the Healthy Lifestyle Scale for University Students (HLSUS) questionnaire. RESULTS: A total of 26 male (25.5%) and 71 female (40.1%) students were identified as NWO. Compared to NWNO students, body weight, BMI, body fat mass, visceral fat area, waist circumference and hip circumference of NWO students were all significantly higher both in male and female students (P < 0.05). The body fat mass, BF% and visceral fat area were significantly negatively correlated with the total HLSUS, physical exercise behavior, and dietary nutrition behavior scores in NWNO males, NWO and NWNO females (P < 0.05). The risk of NWO was lower in those students with higher scores in physical exercise behavior in both males (OR = 0.298, 95% CI = 0.121~0.733) and females (OR = 0.653, 95% CI = 0.505~0.843), while dietary nutrition behavior (OR = 0.759, 95% CI = 0.584~0.986) and stress management behavior (OR = 0.503, 95% CI = 0.335~0.755) decreased the risk of NWO only in females. CONCLUSION: The incidence of NWO was high among university students, especially in females, which might be related with unhealthy lifestyles. NWO university students should pay attention to lifestyle adjustments, especially physical exercise, dietary nutrition and stress management, for preventing the health risk in NWO.

Morin exerts protective effects on encephalopathy and sepsis-associated cognitive functions in a murine sepsis model.

Sepsis-associated encephalopathy (SAE) often leads to cognitive impairments in the rest life of septic survivors. The potential pathological changes of SAE are complicated and have not been fully understood. Morin, a flavone compound exhibiting neuroprotective activity and anti-inflammation effect, was employed to treat with CLP-induced septic mice in our study. The data from a novel object recognition test and tail suspension test indicated that morin treatment reversed cognitive dysfunction and relieved depressive-like behaviors in septic mice. Morin down-regulated the expressions of IL-6, MCP-1, TNF-α and IL-10 in serum and diminished microglia activation in septic mice. Additionally, Western blot results showed that morin reduced the phosphokinase GSK3ß activity and elevated the phosphatase PP2A activity, which led to lower tau phosphorylation. Morin reduced Aß deposition and protected the synapse integrity, which might be the possible mechanism of protecting cognitive functions in septic mice. In conclusion, we identified that morin exerted anti-inflammation and anti-neurodegeneration effects in septic mice, and prevented further cognitive impairments.

FK866 attenuates sepsis-induced acute lung injury through c-jun-N-terminal kinase (JNK)-dependent autophagy.

AIMS: Increasing evidence indicates that FK866, a specific noncompetitive nicotinamide phosphoribosyl transferase inhibitor, exhibits a protective effect on acute lung injury (ALI). Autophagy plays a pivotal role in sepsis-induced ALI. However, the contribution of autophagy and the underlying mechanism by which FK866-confered lung protection remains elusive. Herein, we aimed to study whether FK866 could alleviate sepsis-induced ALI via the JNK-dependent autophagy. MAIN METHODS: Male C57BL/6 mice were subjected to cecal ligation and puncture (CLP) to establish the polymicrobial sepsis mice model, and treated with FK866 (10 mg/kg) at 24, 12 and 0.5 h before the CLP procedure. The lung protective effects were measured by lung histopathology, tissue edema, vascular leakage, inflammation infiltration, autophagy-related protein expression and JNK activity. A549 cells were stimulated with LPS (1000 ng/ml) to generate the ALI cell model, and pretreated with FK866 or SP600125 for 30 min to measure the autophagy-related protein expression and JNK activity. KEY FINDINGS: Our results demonstrated that FK866 reduced lung injury score, tissue edema, vascular leakage, and inflammatory infiltration, and upregulated autophagy. The protective effect of autophagy conferred by FK866 on ALI was further clarified by using 3-methyladenine (3MA) and rapamycin. Additionally, the activity of JNK was suppressed by FK866, and inhibition of JNK promoted autophagy and showed a benefit effect. SIGNIFICANCE: Our study indicates that FK866 protects against sepsis-induced ALI by induction of JNK-dependent autophagy. This may provide new insights into the functional mechanism of NAMPT inhibition in sepsis-induced ALI.

Myricetin alleviated hepatic steatosis by acting on microRNA-146b/thyroid hormone receptor b pathway in high-fat diet fed C57BL/6J mice.

Hepatic microRNAs (miRs) regulate local thyroid hormone (TH) action and TH-related lipid metabolism. We previously found that myricetin effectively ameliorated hepatic steatosis by targeting PPAR signaling pathway, in which the differentially expressed genes were TH-responsive. The present study was designed to explore the mechanism by which myricetin regulated miR-dependent TH action and lipid metabolism on high-fat diet (HFD)-induced hepatic steatosis. C57BL/6J mice were fed a HFD with or without 100 mg kg-1 myricetin by oral gavage for 16 weeks (n = 8 for each group). The results showed that myricetin improved HFD-induced hepatic steatosis, increased serum TH levels and hepatic type 1 deiodinase (DIO1) activities, and elevated energy expenditure in relation to the HFD mice. Meanwhile, myricetin inhibited miR-205 and miR-146b up-regulation induced by HFD, and also up-regulated their targets, Dio1 and thyroid hormone receptor b (TRb) expression, at both the transcriptional and translational levels, accompanied by the regulation of TH responsive lipid metabolism genes. Overexpression or knockdown of miR-205 failed to affect Dio1 mRNA and protein levels in primary mouse hepatocytes. Myricetin directly decreased miR-146b expression in miR-146b mimic-treated hepatocytes to elevate TRb levels. However, the beneficial effects of myricetin on hepatic TH action and lipid metabolism were abolished by TRb siRNA in free fatty acid (FFA)-treated hepatocytes. Our results indicated that myricetin attenuated hepatic steatosis via the miR-146b/TRb pathway and should be considered for the management of NAFLD conditions.

Differential effects of quercetin on hippocampus-dependent learning and memory in mice fed with different diets related with oxidative stress.

High fat diets induce oxidative stress which may be involved in neurodegenerative diseases. Quercetin is a kind of antioxidant that has neuroprotective effects and potent7ial pro-oxidant effects as well. In this study, we evaluated cognitive function in mice fed with high fat diets and basic diets with or without quercetin. Male Chinese Kunming (KM) mice were randomly assigned to five groups fed with basic diet (Control), basic diet with 0.005% (w/w) quercetin (CQ1), high fat diet (HFD), HFD with 0.005% (w/w) quercetin (HFDQ1) and 0.01% (w/w) quercetin (HFDQ2) for 13weeks. At the end of the study period, fasting blood glucose (FBG), plasma and hippocampal markers of oxidative stress, plasma lipid status, Morris water maze as well as hippocampal relative mRNA expression of akt, bdnf, camkII, creb, gsk-3ß, nrf2 and pi3k were examined. The results suggested that in comparison to the control group, the escape latency was increased and percent time spent in the target quadrant was decreased, with increased reactive carbonyls, malondialdehyde (MDA) and declined expression of pi3k, akt, nrf2, creb and bdnf in the hippocampus of HFD and CQ1 groups. Conversely, higher quercetin supplemented to HFD improved antioxidant capacity and reversed cognitive decline completely. Significant correlations between the redox status and cognition-related gene expression were observed as well (P<0.05). Thus, in the case of oxidative stress, an appropriate dose of quercetin can attenuate oxidative stress to improve hippocampus dependent cognition. But under a balanced situation, quercetin exerts pro-oxidant effects to impair cognition.

Role of thyroid hormone homeostasis in obesity-prone and obesity-resistant mice fed a high-fat diet.

BACKGROUND: The exact mechanism for different propensities to obesity when consuming a high-fat diet (HFD) is largely unknown. Thyroid hormone (TH) is an important modulator of energy homeostasis and body weight. OBJECTIVE: The present study aimed to find the potential mechanisms of TH in the development of obesity-prone (OP) and obesity-resistant (OR) mice after short-term and long-term HFD feeding. METHODS: C57Bl/6 male mice were randomly divided into two groups: a low-fat diet (LFD) group and an HFD group. In the 7th week, HFD-fed mice were classified as OP or OR according to upper and lower tertiles of body weight. Half of the mice were sacrificed at this time point and the remaining mice were kept on feeding and sacrificed in the 27th week. Indirect calorimetry was performed. At harvest, serum was used for ELISA assays and oxidative stress biomarkers determination. Tissues were dissected for deiodinases activity and relative mRNA expression determination, as well as antioxidant capacity evaluation. RESULTS: In the 7th week, OP mice showed a significant body weight gain, decreased energy expenditure (EE), normal circulating TH levels, and activated HPT axis, whereas OR mice had normal body weight and maintained T(3) levels only through enhancing hepatic D1 activity. In the 27th week, OR mice gained more body weight than LFD mice accompanied by an activation of HPT axis and decreased hepatic deiodination. Genes involved in TH production were down-regulated in OP mice and up-regulated in OR mice. Changes in deiodinases activity and thyroid function were related with redox status in specific tissues. Furthermore, OP mice had more serious hepatic steatosis than OR mice, with up-regulation of T(3) target genes (e.g. Srebp1c, Acc1, Fasn) involved in lipid synthesis and down-regulation of Pgc1α, Cyp7a1 and Cpt1α. CONCLUSIONS: HPT axis function and deiodinases activity might be involved in different propensities to obesity and the ability of OR mice to resist obesity was limited.

[Effects of PASP-KT-NAA on the grain-filling of maize in different accumulated temperature zones of Hilongjiang Province, Norheast China].

Taking the two maize varieties Zhengdan 958 and Fengdan 3 grown on the three accumulated temperature zones (I, II and III) in Heilongjiang Provice as test materials, a field investigation was made in 2010 and 2011 to study the effects of PASP-KT-NAA (PKN), a compound of exogenous plant growth regulators, on the grain filling and yield of the varieties under different environmental temperatures. From zone I to III, the air temperature at the grain filling stage had a decreasing trend, with the average minimum temperature being 12.16, 11.40, and 9.56, respectively. The effective accumulated temperature at the mid-ate amt sae stage of grain filling was too low to be sufficient for grain filling, which severely affected the grain filling process. Applying N, P and K promoted the dry matter accumulation of maize grain and the grain filling rate in the three zones, delayed the peak time (Tmax) of the grain filling rate of Fengdan 3 but advanced that of Zhengdan 958, promoted the growth capacity at peak time of grain filling rate and the maximum grain filling rate of the two varieties, and shortened their active grain filling period. Applying N, P, and K increased the grain yield of the two varieties in the three zones obviously, and, as compared with those in zones I and II , the grain yields of Zhengdan 958 and Fengdan 3 in zone III were increased by 8.2% and 5.1% , and 3.4% and 0.8% , respectively. Therefore, applying N, P and K could help maize utilizing the limited accumulation temperature, improve the grain filling rate, decrease the grain water content, and ultimately, increase the maize yield.