Electroacupuncture improves cognitive function in a rat model of mild traumatic brain injury by regulating the SIRT-1/PGC-1α/mitochondrial pathway

Background:Mild traumatic brain injury(mTBI)is a common neurological trauma that can lead to cognitive impairment.The sirtuin-1(SIRT-1)/peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α)pathway has been reported to have neuroprotective effects in rats with craniocerebral injury.We evaluated potential mechanisms underlying electroacupuncture-mediated recovery of cognitive function after mTBI,focusing on the SIRT-1/PGC-1α/mitochondrial pathway.Methods:We included forty 6-week-old male Sprague-Dawley rats in this study.Rats were randomly divided into four groups:controlled cortical impactor(CCI,n=10),sham operation(sham,n=10),electroacupuncture-treated CCI(CCI+EA,n=10),and electroacupuncture-treated sham(sham+EA,n=10)group.Randomization was performed by assigning a random number to each rat and using a random number table.The mTBI rat model was established using a controllable cortical impactor.Electroacupuncture therapy was performed on the back of rats,by inserting acupuncture needles to the specific acupoints and setting appropriate parameters for treatment.We evaluated spatial learning and memory functions with the Morris water maze test.We performed quantitative real-time polymerase chain reaction(qRT-PCR),western blotting,adenosine triphosphate(ATP)determination,and mitochondrial respiratory chain complex I(MRCC I)determination on rat hippocampal tissue.We analyzed SIRT-1/PGC-1α expression levels and the results of mitochondrial function assays,and compared differences between groups using bilateral Student’s t-tests.Results:Compared with the sham group,SIRT-1/PGC-1α expression was downregulated in the hippocampus of CCI group(P<0.01).Although this expression was upregulated following electroacupuncture,it did not reach the levels observed in the sham group(P<0.05).Compared with the sham group,MRCC I and ATP levels in the CCI group were significantly reduced,and increased after electroacupuncture(P<0.01).In the Morris water maze,electroacupuncture reduced the incubation period of rats and increased average speed and number of crossing platforms(P<0.05).Conclusion:Electroacupuncture may improve cognitive function in the mTBI rat model by regulating the SIRT-1/PGC-1α/mitochondrial pathway.

NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion

Nicotinamide phosphoribosyl transferase(NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and inflammation.However,therapeutic benefit of NAMPT enzymatic inhibitors appears very limited,likely due to the failure to intervene nonenzymatic functions of NAMPT.Herein,we show that NAMPT dampens antitumor immunity by promoting the expansion of tumor infiltrating myeloid derived suppressive cells(MDSCs) via a mechanism independent of its enzymatic activity.Using proteolysis-targeting chimera(PROTAC) technology,PROTAC A7 is identified as a potent and selective degrader of NAMPT,which degrades intracellular NAMPT(iNAMPT) via the ubiquitin-proteasome system,and in turn decreases the secretion of extracellular NAMPT(eNAMPT),the major player of the non-enzymatic activity of NAMPT.In vivo,PROTAC A7 efficiently degrades NAMPT,inhibits tumor infiltrating MDSCs,and boosts antitumor efficacy.Of note,the anticancer activity of PROTAC A7 is superior to NAMPT enzymatic inhibitors that fail to achieve the same impact on MDSCs.Together,our findings uncover the new role of enzymatically-independent function of NAMPT in remodeling the immunosuppressive tumor microenvironment,and reports the first NAMPT PROTAC A7 that is able to block the pro-tumor function of both iNAMPT and eNAMPT,pointing out a new direction for the development of NAMPT-targeted therapies.