The prognostic values of IRF-1 and Ki-67 for liver transplantation (LT) of hepatocellular carcinoma (HCC) were investigated, as well as the mechanisms of IRF-1 in tumor suppression. Adult orthotropic liver transplantation cases (N = 127) were involved in the analysis. A significant decreased recurrence free survival (RFS) was found in the Ki-67 positive groups. Ki-67, tumor microemboli, the Milan and UCSF criteria were found to be independent risk factors for RFS. In LT for HCC beyond the Milan criteria, a significant decrease in RFS was found in the IRF-1 negative groups. In SK-Hep1 cells, an increase in apoptosis and decrease in autophagy were observed after IFN-γ stimulation, which was accompanied with increasing IRF-1 levels. When IRF-1 siRNA or a caspase inhibitor were used, reductions in LC3-II were diminished or disappeared after IFN-γ stimulation, suggesting that IFN-γ inhibited autophagy via IRF-1 expression and caspase activation. However, after IRF-1 siRNA was introduced, a reduction in LC3-II was found. Thus basic expression of IRF-1 was also necessary for autophagy. IRF-1 may be used as a potential target for HCC treatment based on its capacity to affect apoptosis and autophagy. Ki-67 shows great promise for the prediction of HCC recurrence in LT and can be used as an aid in the selection of LT candidates.
Emerging evidence indicates that the intestinal microbiota could interact with the central nervous system and modulate multiple pathophysiological changes, including the integrity of intestinal barrier and blood-brain barrier, as well as neuroinflammatory response.In the present study, we investigated the potential role of intestinal microbiota in the pathophysiological process of postoperative cognitive dysfunction.Six-monthold APP/PS1 mice were subjected to partial hepatectomy to establish surgery model and exhibited cognitive dysfunction.The expressions of inflammatory mediators increased and tight junction proteins (ZO-1 and Occludin) levels decreased in the intestine and hippocampus.The 16S ribosomal RNA gene sequencing showed altered β diversity and intestinal microbiota richness after surgery, including genus Rodentibacter, Bacteroides, Ruminococcaceae_UCG_014 and Faecalibaculum, as well as family Eggerthellaceae and Muribaculaceae.Furthermore, prebiotics (Xylooligosaccharides, XOS) intervention effectively attenuated surgery-induced cognitive dysfunction and intestinal microbiota alteration, reduced inflammatory responses, and improved the integrity of tight junction barrier in the intestine and hippocampus.In summary, the present study indicates that intestinal microbiota alteration, the related intestinal barrier and blood-brain barrier damage, and inflammatory responses participate the pathophysiological process of postoperative cognitive dysfunction.Prebiotics intervention could be a potential preventative approach.
Objective
To explore the effect of ischemia-reperfusion (IR) on autophagy and interferon regulatory factor 1(IRF-1) expression in mouse liver.
Methods
Hepatic IR injury (IRI) model was established in C57BL/6 mice, and the serum AST and ALT levels were tested in all groups (Sham and IR) at 2 h, 6 h, 12 h and 24 h, respectively. Histopathological feature of IRI was observed, and autophagosomes changes were observed by transmission electron microscope. LC3 expression was detected by immunofluorescence and cell apoptosis was detected by TUNEL assay. IRF-1 mRNA and IRF-1, LC3 and Beclin1 protein were detected by RT-PCR and western blot, respectively.
Results
As the reperfusion progressed, serum AST and ALT levels in the mice were increased and peaked at 12 h. Hepatocyte swelling, hepatic sinusoids narrowing, inflammatory cell infiltration and hepatocyte necrosis were observed in the livers from IR group. Compared with Sham group, there was a significant increase on the number of autophagosomes in IR group. In addition, apoptotic cells were also significantly increased. The expression of IRF-1, Beclin1, and LC3 levels were up-regulated in IR group compared to Sham group.
Conclusion
IR could activate autopha-gy to cause hepatocyte damage, which may be related to the up-regulation of IRF-1.
Key words:
Ischemia-reperfusion; Hepatocytes; Autophagy; Interferon regulatory factor 1
Delayed neurocognitive recovery (dNCR) after surgery is a common postoperative complication in older adult patients. Our previous studies have demonstrated that cognitive impairment after surgery involves an increase in the brain renin-angiotensin system (RAS) activity, including overactivation of the angiotensin 2/angiotensin receptor-1 (Ang II/AT1) axis, which provokes the disruption of the hippocampal blood-brain barrier (BBB). Nevertheless, the potential role of the counter-regulatory RAS axis, the Ang-(1–7)/Mas pathway, in dNCR remains unknown. Using an aged rat model of dNCR, we dynamically investigated the activity of both axes of the RAS following laparotomy. AVE 0991, a nonpeptide analog of Ang-(1–7), was administered intranasally immediately after laparotomy. We found that the elevation of Ang II, induced by surgery was accompanied by a decrease of Ang-(1–7) in the hippocampus, but not in the circulation. Surgery also significantly downregulated hippocampal Mas receptor expression at 24 h postsurgery. Mas activation with intranasal AVE 0991 treatment significantly improved hippocampus-dependent learning and memory deficits induced by surgery. Furthermore, it attenuated hippocampal neuroinflammation, as shown by the decreased level of the microglial activation marker cluster of differentiation 11b (CD11b) and the decreased production of several inflammatory molecules. Along with these beneficial effects, the AVE 0991 treatment also alleviated the imbalance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), modulated the expression of occludin, and alleviated the IgG extravasation, thereby restoring the integrity of the BBB. In conclusion, these data indicate that activation of Mas by AVE 0991 attenuates dNCR after surgery by reducing neuroinflammation and restoring BBB integrity. Our findings suggest that the Ang-(1–7)/Mas pathway may be a novel therapeutic target for treating dNCR after surgery in older adult patients.
Objective
To explore the risk factors of biliary complications of pediatric liver transplantation from donation after cardiac death (DCD).
Methods
The clinical data of 48 cases of pediatric liver transplantation from DCD at First Municipal Central Hospital from March 2013 to March 2015 were retrospectively collected and reviewed.And the risk factors of biliary complications after pediatric liver transplantation from DCD were analyzed.
Results
Eleven (22.9%) pediatric patients developed biliary complications after transplantation.Univariate analysis showed that biliary complications were associated with warm ischemic time (P=0.003), but not with recipient age (P=0.998), recipient gender (P=0.094), MELD score (P=0.159), PELD score (P=0.740), Child-Pugh (P=0.990), cold ischemic time (P=0.990), length of ICU stay (P=0.105), infection or not (P=0.930), other complications (P=0.268) or ABO blood type matching (P=1.106). Multivariate analysis showed that warm ischemic time (P=0.020, OR=10.367, 95% confidence interval 1.451 to 74.089) was an independent prognostic risk factor for biliary complications.
Conclusions
Warm ischemic time is an independent prognostic risk factor for postoperative biliary complications.Thus shorter warm ischemic time of DCD donor may reduce the incidence of biliary complications after pediatric liver transplantation.
Key words:
Biliary complications; Liver transplantation; Tissue and organ procurement; Retrospective studies
Objective
To evaluate the efficacy and safety of sirolimus and tacrolimus after renal transplantation.
Method
PubMed, Web of knowledge, Medline and the Cochrane controlled trials register, Chinese Biomedicaldatabase, and Vip database were searched with the terms and Boolean operators as (kidney transplantation OR renal transplantation) AND (sirolimus OR rapamycin OR rapamune) AND (tacrolimus OR FK506 OR prograf) . Results retrieved were updated on November, 2015. Data were extracted for patient and graft mortality, acute rejection (AR), wound complications, infection, GFR, withdrawl. Professional meta analysis software RevMan 5.3 was employed.
Result
Altogether, 1810 patients from 10 randomized controlled trials (RCTs) were included. Patients in the sirolimus group showed a decreased rate of graft mortality and infection (RR=0.63, 95% CI, 0.45-0.89, P=0.009; RR=4.42, 95% CI, 1.73-11.31, P=0.002). Patients in the sirolimus group showed an increased rate of AR, wound complications , GFR, withdrawl (SMD=-0.52, 95% CI, -0.73-0.31, P<0.000 01; RR=0.54, 95% CI, 0.40-0.73, P<0.000 1; RR=0.17, 95% CI, 0.11-0.25, P<0.000 01; RR=0.44, 95% CI, 0.37-0.51, P<0.000 01). The patient mortality was insignificantly different between two groups.
Conclusion
This meta-analysis concluded that sirolimus showed advantage over tacrolimus about safety when used early after renal transplantation. The options of immunosuppressive regimens after kidney transplantation should be based on the specific condition. To obtain more reliable and accurate clinical data, the RCTs with more rational design, higher methodological quality, larger sample size, including domestic patients, longer follow-up are still needed.
Key words:
Kidney transplantation; Sirolimus; Tacrolimus; Meta-analysis
Stress-induced α-synuclein aggregation, especially the most toxic species (oligomers), may precede synaptic and cognitive dysfunction.Under pathological conditions, α-synuclein is degraded primarily through the autophagic/lysosomal pathway.We assessed the involvement of autophagy in α-synuclein aggregation and cognitive impairment following general anesthesia and surgical stress.Autophagy was found to be suppressed in the aged rat hippocampus after either 4-h propofol anesthesia alone or 2-h propofol anesthesia during a laparotomy surgery.This inhibition of autophagy was accompanied by profound α-synuclein oligomer aggregation and neurotransmitter imbalances in the hippocampus, along with hippocampus-dependent cognitive deficits.These events were not observed 18 weeks after propofol exposure with or without surgical stress.The pharmacological induction of autophagy using rapamycin markedly suppressed α-synuclein oligomerization, restored neurotransmitter equilibrium, and improved cognitive behavior after prolonged anesthesia or anesthesia combined with surgery.Thus, both prolonged propofol anesthesia alone and propofol anesthesia during surgery impaired autophagy, which may have induced abnormal hippocampal α-synuclein aggregation and neurobehavioral deficits in aged rats.These findings suggest that the activation of autophagy and the clearance of pathological α-synuclein oligomers may be novel strategies to ameliorate the common occurrence of postoperative cognitive dysfunction.
The aim of this study is to investigate role of Visfatin, one of the pro-inflammatory adipokines, in sepsis-induced intestinal injury and to clarify the potential mechanism.C57BL/6 mice underwent cecal ligation and puncture (CLP) surgery to establish sepsis model in vivo. Intestinal epithelial cells were stimulated with LPS to mimic sepsis-induced intestinal injury in vitro. FK866 (the inhibitor of Visfatin) with or without XMU-MP-1 (the inhibitor of Hippo signaling) was applied for treatment. The expression levels of Visfatin, NF-κB and Hippo signaling pathways-related proteins were detected by western blot or immunohistochemistry. The intestinal cell apoptosis and intestinal injury were investigated by TUNEL staining and H&E staining, respectively. ELISA was used to determine the production of inflammatory cytokines.The expression of Visfatin increased in CLP mice. FK866 reduced intestinal pathological injury, inflammatory cytokines production, and intestinal cell apoptosis in sepsis mice. Meanwhile, FK866 affected NF-κB and Hippo signaling pathways. Additionally, the effects of FK866 on inflammatory response, apoptosis, Hippo signaling and NF-κB signaling were partly abolished by XMU-MP-1, the inhibitor of Hippo signaling. In vitro experiments also revealed that FK866 exhibited a protective role against LPS-induced inflammatory response and apoptosis in intestinal cells, as well as regulating NF-κB and Hippo signaling, whereas addition of XMU-MP-1 weakened the protective effects of FK866.In short, this study demonstrated that inhibition of Visfatin might alleviate sepsis-induced intestinal injury through Hippo signaling pathway, supporting a further research on Visfatin as a therapeutic target.
// Jin-Dan He 1, * , Zhen Wang 1, * , Shi-Peng Li 1, 4, * , Yan-Jie Xu 1, * , Yao Yu 1 , Yi-Jie Ding 1 , Wen-Li Yu 2 , Rong-Xin Zhang 5 , Hai-Ming Zhang 1, 3 , Hong-Yin Du 2, 1 1 First Central Clinical College, Tianjin Medical University, Tianjin 300192, P.R. China 2 Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, P.R. China 3 Department of Liver Transplantation, Oriental Organ Transplant Center of Tianjin First Central Hospital, Key Laboratory of Organ Transplantation of Tianjin, Tianjin 300192, P.R. China 4 Department of General Surgery, The People's Hospital of Jiaozuo City, Jiaozuo 454002, P.R. China 5 Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Basic Medical College, Tianjin Medical University, Tianjin 300070, P.R. China * These authors have contributed equally to this work Correspondence to: Hong-Yin Du, email: duhongyin2014@yeah.net Hai-Ming Zhang, email: zhanghaiming@medmail.com.cn Keywords: vitexin, hepatocellular carcinoma, autophagy, apoptosis, JNK signaling Received: June 15, 2016 Accepted: August 15, 2016 Published: August 31, 2016 ABSTRACT Vitexin, a flavonoids compound, is known to exhibit broad anti-oxidative, anti-inflammatory, analgesic, and antitumor activity in many cancer xenograft models and cell lines. The purpose of this study was to investigate the antitumor effects and underlying mechanisms of vitexin on hepatocellular carcinoma. In this study, we found that vitexin suppressed the viability of HCC cell lines (SK-Hep1 and Hepa1-6 cells) significantly. Vitexin showed cytotoxic effects against HCC cell lines in vitro by inducing apoptosis and inhibiting autophagy. Vitexin induced apoptosis in a concentration-dependent manner, and caused up-regulations of Caspase-3, Cleave Caspase-3, and a down-regulation of Bcl-2. The expression of autophagy-related protein LC3 II was significantly decreased after vitexin treatment. Moreover, western blot analysis presented that vitexin markedly up-regulated the levels of p-JNK and down-regulated the levels of p-Erk1/2 in SK-Hep1 cells and Hepa1-6 cells. Cotreatment with JNK inhibitor SP600125, we demonstrated that apoptosis induced by vitexin was suppressed, while the inhibition of autophagy by vitexin was reversed. The results of colony formation assay and mouse model confirmed the growth inhibition role of vitexin on HCC in vitro and in vivo . In conclusion, vitexin inhibits HCC growth by way of apoptosis induction and autophagy suppression, both of which are through JNK MAPK pathway. Therefore, vitexin could be regarded as a potent therapeutic agent for the treatment of HCC.
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