Corynoxine B targets at HMGB1/2 to enhance autophagy forα-synuclein clearance in fly and rodent models of Parkinson's disease

Parkinson's disease(PD)is the most common neurodegenerative movement disease.It is featured by abnormal alphα-synuclein(α-syn)aggregation in dopaminergic neurons in the substantia nigra.Macroautophagy(autophagy)is an evolutionarily conserved cellular process for degradation of cellular contents,including protein aggregates,to maintain cellular homeostasis.Corynoxine B(Cory B),a natural alkaloid isolated from Uncaria rhynchophylla(Miq.)Jacks.,has been reported to promote the clearance ofα-syn in cell models by inducing autophagy.However,the molecular mechanism by which Cory B induces autophagy is not known,and theα-syn-lowering activity of Cory B has not been verified in animal models.Here,we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2.Depletion of HMGB1/2 impaired Cory B-induced autophagy.We showed for the first time that,similar to HMGB1,HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinaseⅢactivity both under basal and stimulated conditions.By applying cellular thermal shift assay,surface plasmon resonance,and molecular docking,we confirmed that Cory B directly binds to HMGB1/2 near the C106 site.Furthermore,in vivo studies with a wild-typeα-syn transgenic drosophila model of PD and an A53Tα-syn transgenic mouse model of PD,Cory B enhanced autophagy,promotedα-syn clearance and improved behavioral abnormalities.Taken together,the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinaseⅢactivity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.

Efficacy of acupuncture on repair of glial scars in rats with traumatic brain injury

OBJECTIVE:To explore the underlying mechanism of acupuncture on nerve repair by investigating its effect on the differentiation of glial cells and the repair of glial scars.METHODS:Sprague-Dawley rats were randomly allocated to three groups:normal group,model group,and acupuncture group.Acupuncture was applied at Renzhong(GV26),Baihui(GV20),Fengfu(GV16),Yamen(GV15)and Hegu(LI4)within 12 h after TBI modeling with a frequency of one session per day for 4 weeks.Neurobehavioral assessment,hematoxylin and eosin staining,immunofluorescence detection,and magnetic resonance imaging scanning were performed on days 3,7,14,and 28 after modeling of traumatic brain injury(TBI).RESULTS:Acupuncture promoted the proliferation of glial cells and glial scars at an early stage but inhibited the proliferation of glial cells and glial scars at a late stage.Morphological observations and immunofluorescence histochemistry showed that the morphology of the perilesional cortex in the acupuncture group was improved and the number of neurons was increased when compared with the model group.The lesion size of ipsilateral brain parenchyma in the acupuncture group was smaller than in the model group on days 7,14,and 28(P<0.05)after TBI modeling.CONCLUSIONS:Acupuncture might have a bidirectional regulatory effect on glial scar repair after TBI by promoting the proliferation of glial cells and glial scars to limit the injured area and relieve nerve injury during the early stages,and by inhibiting glial scar hyperplasia to benefit the regeneration and repair of neurons and axons and promote neurological function recovery during the later stages.

Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology:Implications for Alzheimer's disease therapy

Alzheimer's disease(AD),characterized by the accumulation of protein aggregates including phosphorylated Tau aggregates,is the most common neurodegenerative disorder with limited therapeutic agents.Autophagy plays a critical role in the degradation of phosphorylated Tau aggregates,and transcription factor EB(TFEB)is a master regulator of autophagy and lysosomal biogenesis.Thus,small-molecule autophagy enhancers targeting TFEB hold promise for AD therapy.Here,we found that celastrol,an active ingredient isolated from the root extracts of Tripterygium wilfordii(Lei Gong Teng in Chinese)enhanced TFEB-mediated autophagy and lysosomal biogenesis in vitro and in mouse brains.Importantly,celastrol reduced phosphorylated Tau aggregates and attenuated memory dysfunction and cognitive deficits in P301S Tau and 3xTg mice,two commonly used AD animal models.Mechanistical studies suggest that TFEB-mediated autophagy-lysosomal pathway is responsible for phosphorylated Tau degradation in response to celastrol.Overall,our findings indicate that Celastrol is a novel TFEB activator that promotes the degradation of phosphorylated Tau aggregates and improves memory in AD animal models.Therefore,Celastrol shows potential as a novel agent for the treatment and/or prevention of AD and other tauopathies.

Acupoint Injection Decreases Anesthetic Cosumption during Combined Spinal-Epidural and Patient-Controlled Epidural Labor Analgesia

Objective:To explore if acupoint injection can improve analgesic effects or delivery outcomes in parturients who received combined spinal-epidural analgesia(CSEA)and patient-controlled epidural analgesia(PCEA)for labor analgesia.Methods:A total of 307 participants were prospectively collected from July 2017 to December 2019.The participants were randomized into the combined acupoint injection with CSEA plus PCEA group(AICP group,n=168)and CSEA plus PCEA group(CP group,n=139)for labor analgesia using a random number table.Both groups received CSEA plus PCEA at cervical dilation 3 cm during labor process,and parturients of the AICP group were implemented acupoint injection for which bilateral acupoint of Zusanli(ST 36)and Sanyinjiao(SP 6)were selected in addition.The primary outcome was Visual Analogue Scale(VAS)score,and the secondary outcomes were obstetric outcomes and requirement of anesthetics doses.Safety evaluations were performed after intervention.Results:The VAS scores were significantly lower in the AICP group than in the CP group at 10,30,60,and 120 min after labor analgesia(all P<0.05).The latent phase of the AICP group was shorter than that of the CP group(P<0.05).There were less additional anesthetics consumption,lower incidences of uterine atony,fever,pruritus and urinary retention in the AICP group than those in the CP group(all P<0.05).Conclusion:Acupoint injection combined CSEA plus PCEA for labor analgesia can decrease the anesthetic consumption,improve analgesic quality,and reduce adverse reactions in the parturients.(Registration No.ChiMCTR-2000003120)