ABSTRACT
Epidemiological and animal studies indicate that pre-existing diabetes increases the risk of Parkinson's disease(PD).However,the mechanisms underlying this association remain unclear.In the present study,we found that high glucose(HG)levels in the cerebrospinal fluid(CSF)of diabetic rats might enhance the effect of a subthreshold dose of the neurotoxin 6-hydroxydopamine(6-OHDA)on the development of motor disorders,and the damage to the nigrostriatal dopaminergic neuronal pathway.In vitro,HG promoted the 6-OHDA-induced apoptosis in PC12 cells differentiated to neurons with nerve growth factor(NGF)(NGF-PC12).Metabolomics showed that HG promoted hyperglycolysis in neurons and impaired tricarboxylic acid cycle(TCA cycle)activity,which was closely related to abnormal mito-chondrial fusion,thus resulting in mitochondrial loss.Interestingly,HG-induced upregulation of pyruvate kinase M2(PKM2)combined with 6-OHDA exposure not only mediated glycolysis but also promoted abnormal mitochondrial fusion by upregulating the expression of MFN2 in NGF-PC12 cells.In addition,we found that PKM2 knockdown rescued the abnormal mitochondrial fusion and cell apoptosis induced by HG+6-OHDA.Furthermore,we found that shikonin(SK),an inhibitor of PKM2,restored the mito-chondrial number,promoted TCA cycle activity,reversed hyperglycolysis,enhanced the tolerance of cultured neurons to 6-OHDA,and reduced the risk of PD in diabetic rats.Overall,our results indicate that diabetes promotes hyperglycolysis and abnormal mitochondrial fusion in neurons through the upre-gulation of PKM2,leading to an increase in the vulnerability of dopaminergic neurons to 6-OHDA.Thus,the inhibition of PKM2 and restoration of mitochondrial metabolic homeostasis/pathways may prevent the occurrence and development of diabetic PD.
ABSTRACT
Objective To investigate the clinical effect of distal radioulnar ligament reconstruction by autologous tendon pal‐maris longus transplantation under arthroscopic assistance in treating chronic instability of the distal radioulnar joint .Methods Seven patients with chronic instability of the distal radioulnar joint after failure of conservation therapy were definitely diagnosed by the wrist joint exploration .Then the autologous tendon palmaris longus was taken for conducting the anatomical reconstruction of distal radioulnar ligament ;the average follow up was 12 months .The preoperative and postoperative grip strength and the motion of wrist joint were recorded ;the pain status of the wrist joint was evaluated by using the visual analogue scale (VAS) ,and the wrist function status was evaluated by using the Disabilities of the Arm ,Shoulder and Hand(DASH) and the Modified Mayo Wrist Score (MMWS) .Results The average VAS score of the rist joint motion was recovered from (7 ± 2) points before operation to (3 ± 3) points after operation ,the MMWS score was improved from preoperative (50 ± 9) points to postoperative (83 ± 11) points ,the DASH score was decreased significantly from preoperative (37 ± 15) points to postoperative (16 ± 10) points ,the grip strength was improved from preoperative 84 .5 ± 16 .0 to postoperative 93 .4 ± 11 .0 ,the differences were statistically significant .The mean range of motion(ROM ) in flexion/extension of the wrist was increased from preoperative 93 .5% ± 6 .0% to postoperative 96 .4% ± 3 .0% ,the ROM in pronation/supination of the forearm was increased from preoperative 92 .6% ± 7 .0% to postoperative 97 .2% ± 5 .0% ,but the differences were not statistically significant .Conclusion Under arthroscopic assistance ,the anatomical reconstruc‐tion of the distal radioulnar ligaments is an effective treatment method for treating chronic distal radioulnar joint instability ,its short term follow up has satisfactory effect .