Septic encephalopathy (SE) is a critical factor determining sepsis mortality. Vascular inflammation is known to be involved in SE, but the molecular events that lead to the development of encephalopathy remain unclear. Using time-lapse in vivo two-photon laser scanning microscopy, we provide the first direct evidence that cecal ligation and puncture in septic mice induces microglial trafficking to sites adjacent to leukocyte adhesion on inflamed cerebral microvessels. Our data further demonstrate that septic injury increased the chemokine CXCL1 level in brain endothelial cells by activating endothelial P2RX7 and eventually enhanced the binding of Mac-1 (CD11b/CD18)-expressing leukocytes to endothelial ICAM-1. In turn, leukocyte adhesion upregulated endothelial CX3CL1, thereby triggering microglia trafficking to the injured site. The sepsis-induced increase in endothelial CX3CL1 was abolished in CD18 hypomorphic mutant mice. Inhibition of the P2RX7 pathway not only decreased endothelial ICAM-1 expression and leukocyte adhesion but also prevented microglia overactivation, reduced brain injury, and consequently doubled the early survival of septic mice. These results demonstrate the role of the P2RX7 pathway in linking neurovascular inflammation to brain damage in vivo and provide a rationale for targeting endothelial P2RX7 for neurovascular protection during SE.

Background This study aimed to investigate the sexspecific prevalence and metabolic risk factors of fatty liver disease (FLD), and to predict the prevalence of steatohepatitis with liver fibrosis in Wuhan, south central China.Methods A cross-sectional study was conducted among 25 032 participants who underwent health checkups from 2010 to 2011 in Zhongnan hospital. ResultsThe prevalence of FLD was higher among men than among women (31.8 vs. 12.9%, P < 0.0001). However, it increased markedly with age among women, and in the agegroups above 60 years, the prevalence was similar between men and women (26.4 vs. 27.6%, P > 0.05). FLD was associated with obesity, increased levels of total cholesterol, triglycerides (TG), low-density lipoproteins, serum uric acid, aspartate aminotransferase, alanine aminotransferase, and fasting blood sugar, an aspartate aminotransferase/alanine aminotransferase ratio of less than 1, and a decreased level of high-density lipoprotein in both sexes. Multiple regression analyses showed that obesity, elevated levels of fasting blood sugar, TG, total cholesterol, and alanine aminotransferase, an aspartate aminotransferase/alanine aminotransferase ratio of less than 1, serum uric acid levels, and decreased high-density lipoprotein levels were related to FLD in men, whereas age played a more prominent role in women.The prevalence of steatohepatitis with advanced fibrosis, estimated using the BMI, age, ALT, and TG index (BAAT index), was 2.5% in men and 1.4% in women; more women with FLD had a BAAT score of 3 or higher compared with men (9.0 vs. 6.6%).Conclusion The prevalence of FLD in China is high among men and elderly women and is mainly related to various metabolic parameters. The prevalence of steatohepatitis with advanced fibrosis is considerably high among individuals with FLD. Eur J Gastroenterol Hepatol

Aims/hypothesis Adenosine is an important regulator of metabolism; however, the role of the A 1 receptor during ageing and obesity is unclear. The aim of this study was to investigate the effects of A 1 signalling in modulating metabolic function during ageing. Methods Age-matched young and aged A 1 (also known as Adora1)-knockout (A 1 −/−) and wild-type (A 1 +/+ ) mice were used. Metabolic regulation was evaluated by body composition, and glucose and insulin tolerance tests. Isolated islets and islet arterioles were used to detect islet endocrine and vascular function. Oxidative stress and inflammation status were measured in metabolic organs and systemically. Results Advanced age was associated with both reduced glucose clearance and insulin sensitivity, as well as increased visceral adipose tissue (VAT)

1. Resistance changes of the afferent and efferent arterioles determine blood flow and filtration rate in the kidney. The tone of both vessels results from the influence of nerves and humoral and paracrine factors, through a balance of constrictor and dilator systems. Angiotensin (Ang) II and nitric oxide (NO) are important factors determining vascular tone. 2. In the present review, we show that, in addition to the basal production of NO, a specific and significant AngII-induced release of NO occurs in glomerular arterioles. Data from investigations of arteriolar contraction, as well as from fluorescence measurements of NO, in the presence of selective angiotensin AT(1) and AT(2) receptor antagonists indicate an AT(1) receptor-stimulated release of NO in afferent arterioles. 3. The AngII-induced liberation of NO could prevent glomerular arterioles from a marked constriction, particularly in situations of high AngII levels in the kidney.

This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

The loss of differences in the maximum constriction and Ang II sensitivity of afferent arterioles between ET-1 tg and WT in the absence of NO suggests pronounced NO effects in afferent arterioles of ET-1 tg. This might contribute to the maintenance of normal renal arteriolar tone in ET-1 tg mice.

Renal interstitial fibrosis (RIF) is a common pathological feature contributing to chronic injury and maladaptive repair following acute kidney injury. Currently, there is no effective therapy for RIF. We have reported that locked nuclear acid (LNA)-anti-miR-150 antagonizes pro-fibrotic pathways in human renal tubular cells by regulating the suppressor of cytokine signal 1 (SOCS1)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. In the present study, we aimed to clarify whether LNA-anti-miR-150 attenuates folic acid-induced RIF mice by regulating this pathway and by reducing pro-inflammatory M1/M2 macrophage polarization. We found that renal miR-150 was upregulated in folic acid-induced RIF mice at day 30 after injection. LNA-anti-miR-150 alleviated the degree of RIF, as shown by periodic acid–Schiff and Masson staining and by the expression of pro-fibrotic proteins, including alpha-smooth muscle actin and fibronectin. In RIF mice, SOCS1 was downregulated, and p-JAK1 and p-STAT1 were upregulated. LNA-anti-miR-150 reversed the changes in renal SOCS1, p-JAK1, and p-STAT1 expression. In addition, renal infiltration of total macrophages, pro-inflammatory M1 and M2 macrophages as well as their secreted cytokines were increased in RIF mice compared to control mice. Importantly, in folic acid-induced RIF mice, LNA-anti-miR-150 attenuated the renal infiltration of total macrophages and pro-inflammatory subsets, including M1 macrophages expressing CD11c and M2 macrophages expressing CD206. We conclude that the anti-renal fibrotic role of LNA-anti-miR-150 in folic acid-induced RIF mice may be mediated by reducing pro-inflammatory M1 and M2 macrophage polarization via the SOCS1/JAK1/STAT1 pathway.

Aims: Acute kidney injury (AKI), a major health burden, lacks effective therapy.Anti-inflammatory actions of a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 (ADAMTS13) may provide a new treatment option for AKI. Along with inflammation, oxidative stress is critical for AKI development, yet the impact of ADAMTS13 on oxidative stress in AKI remains to be fully elucidated. Methods:We assess recombinant human ADAMTS13 (rhADAMTS13) actions on oxidative stress in a murine ischaemia/reperfusion (IR) model. Antioxidant stress-enzyme activities, renal morphology, kidney function markers and vascular function of isolated afferent arterioles are quantified.Results: rhADAMTS13 provided after IR, reduces blood urea nitrogen (BUN) by 33% and serum creatinine (Scr) by 73% in 24 hours post-IR. rhADAMTS13 reduces BUN (40.03 ± 20.34 mmol/L vs 72.35 ± 18.74 mmol/L, P < .01), Scr (75.67 ± 51.19 μmol/L vs 176.17 ± 55.38 μmol/L, P < .01) and proteinuria by 41% in 48 hours post-IR as well. Moreover, rhADAMTS13 administration decreases malondialdehyde (MDA) and increases the activity of antioxidant stress enzymes, and attenuates reactive oxygen species production. rhADAMTS13 also upregulates nuclear factor-erythroid-2-related factor 2/haem oxygenase-1, enhances antioxidant enzymes activity and alleviates endothelial dysfunction. Finally,