FK506 contributes to peripheral nerve regeneration by inhibiting neuroinflammatory responses and promoting neuron survival

FK506(Tacrolimus)is a systemic immunosuppressant approved by the U.S.Food and Drug Administration.FK506 has been shown to promote peripheral nerve regeneration,however,its precise mechanism of action and its pathways remain unclear.In this study,we established a rat model of sciatic nerve injury and found that FK506 improved the morphology of the injured sciatic nerve,increased the numbers of motor and sensory neurons,reduced inflammatory responses,markedly improved the conduction function of the injured nerve,and promoted motor function recovery.These findings suggest that FK506 promotes peripheral nerve structure recovery and functional regeneration by reducing the intensity of inflammation after neuronal injury and increasing the number of surviving neurons.

Neutrophil peptide 1 accelerates the clearance of degenerative axons during Wallerian degeneration by activating macrophages after peripheral nerve crush injury

Macrophages play an important role in peripheral nerve regeneration,but the specific mechanism of regeneration is still unclear.Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide closely involved in peripheral nerve regeneration.However,the mechanism by which neutrophil peptide 1 enhances nerve regeneration remains unclear.This study was designed to investigate the relationship between neutrophil peptide 1 and macrophages in vivo and in vitro in peripheral nerve crush injury.The functions of RAW 264.7 cells we re elucidated by Cell Counting Kit-8 assay,flow cytometry,migration assays,phagocytosis assays,immunohistochemistry and enzyme-linked immunosorbent assay.Axonal debris phagocytosis was observed using the CUBIC(Clear,Unobstructed Brain/Body Imaging Cocktails and Computational analysis)optical clearing technique during Wallerian degeneration.Macrophage inflammatory factor expression in different polarization states was detected using a protein chip.The results showed that neutrophil peptide 1 promoted the prolife ration,migration and phagocytosis of macrophages,and CD206 expression on the surfa ce of macrophages,indicating M2 polarization.The axonal debris clearance rate during Wallerian degeneration was enhanced after neutrophil peptide 1 intervention.Neutrophil peptide 1 also downregulated inflammatory factors interleukin-1α,-6,-12,and tumor necrosis factor-αin invo and in vitro.Thus,the results suggest that neutrophil peptide 1 activates macrophages and accelerates Wallerian degeneration,which may be one mechanism by which neutrophil peptide 1 enhances peripheral nerve regeneration.

Postoperative Complications and Survival Analysis of Surgical Resection for Hilar Cholangiocarcinoma:A Retrospective Study of Fifty-Nine Consecutive Patients

Objective Hilar cholangiocarcinoma(HC)is invariably fatal without surgical resection.The primary aim of the current study was to determine the safety of variable surgical resections for patient with HC and their survival after surgical resection.In addition,prognostic factor for the overall survival was also evaluated.Methods The study included 59 consecutive patients who were newly diagnosed with HC and underwent surgical resections with curative intend between February 2009 and February 2017.Patients were followed up at 3-6 months intervals after hospital discharge.Postoperative complications and overall survival were determined.Associations of clinicopathologic and surgeon-related factors with overall survival were evaluated through univariate analysis and Cox regression analysis.Results Of patients with Bismuth and Corlette(B&C)type HI(n=19)and IV(n=25)HC lesions,33(55.9%)were treated with hilar resection combined with major liver resection(MLR),while the other 11 patients with type HI and IV,and those with type I(n=8)and II(n=7)HC lesions were treated with hilar resection.The overall surgical mortality was 5.1%and surgical morbidity was 35.6%.There was no statistical difference in the mortality between MLR group and hilar resection group(6.1%vs.3.8%;X2=0.703,P=0.145).The median follow-up period was 18 months(range,1-94 months).The 1-,3-,5-year survival rate was 59.3%,36.5%,and 17.7%,respectively.The overall survival after resections was 18 months.In HC patients with B&C type III and IV lesions,the median survival was 23 months for hilar resection with MLR and 8 months for hilar resection alone;the 1-,3-,5-year cumulative survival rate was 63.9%,23.3%,and 15.5%,respectively for hilar resection with MLR,and 11.1%,0,and 0,respectively for hilar resection alone,with significant diflerene observed(HR,9.902;95%CI,2.636-19.571,P=0.001).Four factors were independently associated with overall survival:preoperative serum Cal9-9(HR,7.039;95%CI,2.803-17.678,P<0.001),histopathologic grade(HR,4.964;95%CI,1.046-23.552,?=0.044),surgical margins(P=0.031),andAJCC staging(P=0.015).Conclusions R0 resection is efficacious in surgical treatment of HC.MLR in combination with caudate lobe resection may increase the chance of R0 resection and improve survival of HC patients with B&C type IK and IV lesions.Preoperatively prepared for biliary drainage may ensure the safety of MLR in most HC patients.Novel adjuvant therapies are needed to improve the survival of HC patients with poor prognostic factors.