LDHA Desuccinylase Sirtuin 5 as A Novel Cancer Metastatic Stimulator in Aggressive Prostate Cancer

Prostate cancer(PCa)is the most commonly diagnosed genital cancer in men worldwide.Around 80%of the patients who developed advanced PCa suffered from bone metastasis,with a sharp drop in the survival rate.Despite great efforts,the detailed mechanisms underlying castration-resistant PCa(CRPC)remain unclear.Sirtuin 5(SIRT5),an NAD+-dependent desuccinylase,is hypothesized to be a key regulator of various cancers.However,compared to other SIRTs,the role of SIRT5 in cancer has not been extensively studied.Here,we revealed significantly decreased SIRT5 levels in aggressive PCa cells relative to the PCa stages.The correlation between the decrease in the SIRT5 level and the patient’s reduced survival rate was also confirmed.Using quantitative global succinylome analysis,we characterized a significant increase in the succinylation at lysine 118(K118su)of lactate dehydrogenase A(LDHA),which plays a role in increasing LDH activity.As a substrate of SIRT5,LDHA-K118su significantly increased the migration and invasion of PCa cells and LDH activity in PCa patients.This study reveals the reduction of SIRT5 protein expression and LDHA-K118su as a novel mechanism involved in PCa progression,which could serve as a new target to prevent CPRC progression for PCa treatment.

Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aβplaques and brain rhythms in 5×FAD mice

Background:Alzheimer's disease(AD)is the most common cause of dementia,and is characterized by amyloid-β(Aβ)plaques and tauopathy.Reducing Aβhas been considered a major AD treatment strategy in pharmacological and non-pharmacological approaches.Impairment of gamma oscillations,which play an important role in perception and cognitive function,has been shown in mouse AD models and human patients.Recently,the therapeutic effect of gamma entrainment in AD mouse models has been reported.Given that ultrasound is an emerging neuromodulation modality,we investigated the effect of ultrasound stimulation pulsed at gamma frequency(40 Hz)in an AD mouse model.Methods:We implanted electroencephalogram(EEG)electrodes and a piezo-ceramic disc ultrasound transducer on the skull surface of 6-month-old 5×FAD and wild-type control mice(n=12 and 6,respectively).Six 5×FAD mice were treated with two-hour ultrasound stimulation at 40 Hz daily for two weeks,and the other six mice received sham treatment.Soluble and insoluble Aβlevels in the brain were measured by enzyme-linked immunosorbent assay.Spontaneous EEG gamma power was computed by wavelet analysis,and the brain connectivity was examined with phase-locking value and cross-frequency phase-amplitude coupling.Results:We found that the total Aβ42 levels,especially insoluble Aβ42;in the treatment group decreased in pre-and infra-limbic cortex(PIL)compared to that of the sham treatment group.A reduction in the number of Aβplaques was also observed in the hippocampus.There was no increase in microbleeding in the transcranial ultrasound stimulation(tUS)group.In addition,the length and number of microglial processes decreased in PIL and hippocampus.Encel-phalographic spontaneous gamma power was increased,and cross-frequency coupling was normalized,implying functional improvement after tUS stimulation.Conclusion:These results suggest that the transcranial ultrasound-based gamma-band entrainment technique can be an effective therapy for AD by reducing the Aβload and improving brain connectivity.