Recombinant Adiponectin Ameliorates Liver Ischemia Reperfusion Injury via Activating the AMPK/eNOS Pathway

Background

It is of importance to minimize ischemia reperfusion (I/R) injury during liver operations. Reducing the inflammatory reaction is an effective way to achieve this goal. Notably, adiponectin (APN) was found to have anti-inflammatory activity in heart and renal I/R injury. Herein, we investigated the role of APN in liver I/R injury.

Methods

Wistar rats were randomized to four groups: (1) sham group; (2) I/R control group; (3) I/R+APN group; and (4) I/R+APN+AMPK inhibitor group. Liver and blood samples were collected 6h and 24h after reperfusion. Liver function and histopathologic changes were assessed. Macrophage and neutrophil infiltration was detected by immunohistochemistry staining, while pro-inflammatory cytokines and chemokines released in the liver were measured using ELISA and RT-PCR, respectively. Apoptosis was analyzed by TUNEL staining and caspase-3 expression in the liver. Downstream molecules of APN were investigated by Western blotting.

Results

Circulatory APN was down-regulated during liver I/R. When exogenous APN treatment was administered during liver I/R, alanine transaminase (ALT) and aspartate aminotransferase (AST) were decreased, and less hepatocyte necrosis was observed. Less inflammatory cell infiltration and pro-inflammatory cytokines/chemokines release were also observed in the I/R+APN group when compared with the I/R control group. APN treatment also reduced hepatocyte apoptosis, evidenced by reduced TUNEL positive cells and less caspase-3 expression in the reperfused liver. Finally, the AMPK/eNOS pathway was found to be activated by APN, and administration of an AMPK inhibitor reversed the beneficial effects of APN.

Conclusion

APN can protect the liver from I/R injury by reducing the inflammatory response and hepatocyte apoptosis, a process that likely involves the AMPK/eNOS pathway. The current study provides a potential pharmacologic target for liver I/R injury.     

二次回归正交旋转组合设计对豆粕氨基酸提取工艺的优化

研究了硫酸水解法提取豆粕中复合氨基酸的工艺条件。在单因素实验的基础上,运用二次回归正交旋转组合设计方法进行了优化,建立回归模型方程并确定最佳工艺条件。结果表明,在液固比25:1、硫酸浓度3.1mol.L-1、提取时间16.0h和提取温度125.0℃的条件下,最佳氨氮得率达59.9mg.g-1。     

Calcineurin-inhibitor minimization in liver transplant patients with calcineurin-inhibitor-related renal dysfunction: a meta-analysis

Background

Introduction of calcineurin-inhibitor (CNI) has made transplantation a miracle in the past century. However, the side effects of long-term use of CNI turn out to be one of the major challenges in the current century. Among these, renal dysfunction attracts more and more attention. Herein, we undertook a meta-analysis to evaluate the efficacy and safety of calcineurin-inhibitor (CNI) minimization protocols in liver transplant recipients with CNI-related renal dysfunction.

Methods

We included randomized trials with no year and language restriction. All data were analyzed using random effect model by Review Manager 5.0. The primary endpoints were glomerular filtration rate (GFR), serum creatinine level (sCr) and creatinine clearance rate (CrCl), and the secondary endpoints were acute rejection episodes, incidence of infection and patient survival at the end of follow-up.

Results

GFR was significantly improved in CNI minimization group than in routine CNI regimen group (Z = 5.45, P<0.00001; I² = 0%). Likely, sCr level was significantly lower in the CNI minimization group (Z = 2.84, P = 0.005; I² = 39%). However, CrCl was not significantly higher in the CNI minimization group (Z = 1.59, P = 0.11; I² = 0%). Both acute rejection episodes and patient survival were comparable between two groups (rejection: Z = 0.01, P = 0.99; I² = 0%; survival: Z = 0.28, P = 0.78; I² = 0%, respectively). However, current CNI minimization protocols may be related to a higher incidence of infections (Z = 3.06, P = 0.002; I² = 0%).

Conclusion

CNI minimization can preserve or even improve renal function in liver transplant patients with renal impairment, while sharing similar short term acute rejection rate and patient survival with routine CNI regimen.     

Enhanced Cyclability of Lithium–Oxygen Batteries with Electrodes Protected by Surface Films Induced via In Situ Electrochemical Process

Although the rechargeable lithium–oxygen (Li–O₂) batteries have extremely high theoretical specific energy, the practical application of these batteries is still limited by the instability of their carbon‐based air‐electrode, Li metal anode, and electrodes, toward reduced oxygen species. Here a simple one‐step in situ electrochemical precharging strategy is demonstrated to generate thin protective films on both carbon nanotubes (CNTs), air‐electrodes and Li metal anodes simultaneously under an inert atmosphere. Li–O₂ cells after such pretreatment demonstrate significantly extended cycle life of 110 and 180 cycles under the capacity‐limited protocol of 1000 mA h g^?1 and 500 mA h g^?1, respectively, which is far more than those without pretreatment. The thin‐films formed from decomposition of electrolyte during in situ electrochemical precharging processes in an inert environment, can protect both CNTs air‐electrode and Li metal anode prior to conventional Li–O₂ discharge/charge cycling, where reactive reduced oxygen species are formed. This work provides a new approach for protection of carbon‐based air‐electrodes and Li metal anodes in practical Li–O₂ batteries, and may also be applied to other battery systems.     

A Novel Complex A/C/G Intergenotypic Recombinant of Hepatitis B Virus Isolated in Southern China

Hepatitis B virus (HBV) genotypes and subgenotypes may vary in geographical distribution and virological features. Previous investigations, including ours, showed that HBV genotypes B and C were respectively predominant in South and North China, while genotypes A and D were infrequently detected and genotype G was not found. In this study, a novel A/C/G intergenotype was identified in patients with chronic HBV infection in Guilin, a city in southern China. Initial phylogenetic analysis based on the S gene suggested the HBV recombinant to be genotype G. However, extended genotyping based on the entire HBV genome indicated it to be an A/C/G intergenotype with a closer relation to genotype C. Breakpoint analysis using the SIMPLOT program revealed that the recombinant had a recombination with a arrangement of genotypes A, G, A and C fragments. Compared with the HBV recombinants harboring one or two genotype G fragments found in Asian countries, this Guilin recombinant was highly similar to the Vietnam (98–99%) and Long An recombinants (96–99%), but had a relatively low similarity to the Thailand one (89%). Unlike those with the typical genotype G of HBV, the patients with the Guilin recombinant were seropositive for HBeAg. Moreover, a relatively high HBV DNA viral load (>2×10⁶ IU/ml) was detected in the patients, and the analysis of viral replication capacity showed that the Guilin recombinant strains had a competent replication capacity similar to genotypes B and C strains. These findings can aid in not only the clarification of the phylogenetic origin of the HBV recombinants with the genotype G fragment found in Asian countries, but also the understanding of the virological properties of these complicated HBV recombinants.     

iRhom2 Mutation Leads to Aberrant Hair Follicle Differentiation in Mice

iRhom1 and iRhom2 are inactive homologues of rhomboid intramembrane serine proteases lacking essential catalytic residues, which are necessary for the maturation of TNFα-converting enzyme (TACE). In addition, iRhoms regulate epidermal growth factor family secretion. The functional significance of iRhom2 during mammalian development is largely unclear. We have identified a spontaneous single gene deletion mutation of iRhom2 in Uncv mice. The iRhom2^Uncv/Uncv mice exhibit hairless phenotype in a BALB/c genetic background. In this study, we observed dysplasia hair follicles in iRhom2^Uncv/Uncv mice from postnatal day 3. Further examination found decreased hair matrix proliferation and aberrant hair shaft and inner root sheath differentiation in iRhom2^Uncv/Uncv mutant hair follicles. iRhom2 is required for the maturation of TACE. Our data demonstrate that iRhom2^Uncv cannot induce the maturation of TACE in vitro and the level of mature TACE is also significantly reduced in the skin of iRhom2^Uncv/Uncv mice. The activation of Notch1, a substrate of TACE, is disturbed, associated with dramatically down-regulation of Lef1 in iRhom2^Uncv/Uncv hair follicle matrix. This study identifies iRhom2 as a novel regulator of hair shaft and inner root sheath differentiation.     

Hilbert-Huang transform for analysis of heart rate variability in cardiac health

This paper introduces a modified technique based on Hilbert-Huang transform (HHT) to improve the spectrum estimates of heart rate variability (HRV). In order to make the beat-to-beat (RR) interval be a function of time and produce an evenly sampled time series, we first adopt a preprocessing method to interpolate and resample the original RR interval. Then, the HHT, which is based on the empirical mode decomposition (EMD) approach to decompose the HRV signal into several monocomponent signals that become analytic signals by means of Hilbert transform, is proposed to extract the features of preprocessed time series and to characterize the dynamic behaviors of parasympathetic and sympathetic nervous system of heart. At last, the frequency behaviors of the Hilbert spectrum and Hilbert marginal spectrum (HMS) are studied to estimate the spectral traits of HRV signals. In this paper, two kinds of experiment data are used to compare our method with the conventional power spectral density (PSD) estimation. The analysis results of the simulated HRV series show that interpolation and resampling are basic requirements for HRV data processing, and HMS is superior to PSD estimation. On the other hand, in order to further prove the superiority of our approach, real HRV signals are collected from seven young health subjects under the condition that autonomic nervous system (ANS) is blocked by certain acute selective blocking drugs: atropine and metoprolol. The high-frequency power/total power ratio and low-frequency power/high-frequency power ratio indicate that compared with the Fourier spectrum based on principal dynamic mode, our method is more sensitive and effective to identify the low-frequency and high-frequency bands of HRV.     

Immunosuppressive treatment for nephrotic idiopathic membranous nephropathy: a meta-analysis based on chinese adults

Background

Idiopathic membranous nephropathy (IMN) is the most common pathological type for nephrotic syndrome in adults in western countries and China. The benefits and harms of immunosuppressive treatment in IMN remain controversial.

Objectives

To assess the efficacy and safety of different immunosuppressive agents in the treatment of nephrotic syndrome caused by IMN.

Methods

PubMed, EMBASE, Cochrane Library and wanfang, weipu, qinghuatongfang, were searched for relevant studies published before December 2011. Reference lists of nephrology textbooks, review articles were checked. A meta-analysis of randomized controlled trials (RCTs) meeting the criteria was performed using Review Manager.

Main Results

17 studies were included, involving 696 patients. Calcineurin inhibitors had a better effect when compared to alkylating agents, on complete remission (RR 1.61, 95% CI 1.13, to 2.30 P = 0.008), partial or complete remission (effective) (CR/PR, RR 1.29, 95% CI 1.09 to 1.52 P = 0.003), and fewer side effects. Among calcineurin inhibitors, tacrolimus (TAC) was shown statistical significance in inducing more remissions. When compared to cyclophosphamide (CTX), leflunomide (LET) showed no beneficial effect, mycophenolate mofetil (MMF) showed significant beneficial on effectiveness (CR/PR, RR: 1.41, 95% CI 1.16 to 1.72 P = 0.0006) but not significant on complete remission (CR, RR: 1.38, 95% CI 0.89 to 2.13 P = 0.15).

Conclusions

This analysis based on Chinese adults and short duration RCTs suggested calcineurin inhibitors, especially TAC, were more effective in proteinuria reduction in IMN with acceptable side effects. Long duration RCTs were needed to confirm the long-term effects of those agents in nephrotic IMN.     

Radiosensitization of Cancer Cells by Inactivation of Cullin-RING E3 Ubiquitin Ligases

Although radiotherapy represents one of the most effective treatment modalities for patients with cancer, inherent and/or acquired resistance of cancer cells to radiotherapy is often an impediment to effective treatment. Diverse strategies have been developed to improve the efficacy of radiotherapy. The ubiquitin-proteasome system (UPS) operates in numerous vital biologic processes by controlling the protein turnover in cells. Ubiquitination is central to the UPS pathway, and it relies on the E3 ubiquitin ligases to catalyze the covalent attachment of ubiquitin to its protein substrates. Cullin-based RING ligases (CRLs) are the largest family of E3 ligases that are responsible for the ubiquitination and destruction of numerous cancer-relevant proteins. Its deregulation has been linked to many human cancers, making it an attractive target for therapeutic intervention. This review discusses how targeting the ubiquitin-proteasome system, particularly CRLs, is an exciting new strategy for radiosensitization in cancer and, specifically, focuses on MLN4924, a recently discovered small-molecule inhibitor of the NEDD8-activating enzyme, which is being characterized as a novel radiosensitizing agent against cancer cells by inactivating CRL E3 ubiquitin ligases.