Anxiety disorder is a major symptom of autism spectrum disorder(ASD)with a comorbidity rate of~40%.However,the neural mechanisms of the emergence of anxiety in ASD remain unclear.In our study,we found that hyperactivi...Anxiety disorder is a major symptom of autism spectrum disorder(ASD)with a comorbidity rate of~40%.However,the neural mechanisms of the emergence of anxiety in ASD remain unclear.In our study,we found that hyperactivity of basolateral amygdala(BLA)pyramidal neurons(PNs)in Shank3 InsG3680 knock-in(InsG3680+/+)mice is involved in the development of anxiety.Electrophysiological results also showed increased excitatory input and decreased inhibitory input in BLA PNs.Chemogenetic inhibition of the excitability of PNs in the BLA rescued the anxiety phenotype of InsG3680+/+mice.Further study found that the diminished control of the BLA by medial prefrontal cortex(mPFC)and optogenetic activation of the mPFC-BLA pathway also had a rescue effect,which increased the feedforward inhibition of the BLA.Taken together,our results suggest that hyperactivity of the BLA and alteration of the mPFC-BLA circuitry are involved in anxiety in InsG3680+/+mice.展开更多
Neuroligins(NLs) are postsynaptic cell-adhesion proteins that play important roles in synapse formation and the excitatory-inhibitory balance. They have been associated with autism in both human genetic and animal mod...Neuroligins(NLs) are postsynaptic cell-adhesion proteins that play important roles in synapse formation and the excitatory-inhibitory balance. They have been associated with autism in both human genetic and animal model studies, and affect synaptic connections and synaptic plasticity in several brain regions. Yet current research mainly focuses on pyramidal neurons, while the function of NLs in interneurons remains to be understood. To explore the functional difference among NLs in the subtypespecific synapse formation of both pyramidal neurons and interneurons, we performed viral-mediated shRNA knockdown of NLs in cultured rat cortical neurons and examined the synapses in the two major types of neurons. Our results showed that in both types of neurons, NL1 and NL3 were involved in excitatory synapse formation, and NL2 in GABAergic synapse formation. Interestingly, NL1 affectedGABAergic synapse formation more specifically than NL3,and NL2 affected excitatory synapse density preferentially in pyramidal neurons. In summary, our results demonstrated that different NLs play distinct roles in regulating the development and balance of excitatory and inhibitory synapses in pyramidal neurons and interneurons.展开更多
The purpose of the present study was to investigate the impact of genetic polymorphism on fluvastatin pharmacokinetics.In addition,we compared the fluvastatin pharmacokinetics differences between extended-release(ER)8...The purpose of the present study was to investigate the impact of genetic polymorphism on fluvastatin pharmacokinetics.In addition,we compared the fluvastatin pharmacokinetics differences between extended-release(ER)80 mg tablet and immediate-release(IR)40 mg capsule in terms of drug metabolism enzyme and transporter genetic polymorphisms.In this open-label,randomized,two-period,two-treatment,crossover study(n=24),effects of ABCG2,SLCO1B1,ABCB1,CYP2C9 and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed.The administration dosage for IR 40 mg and ER 80 mg were twice and once daily,respectively,for total 7 d.Blood samples for pharmacokinetic evaluation were taken on the 1st and 7th d.The lower exposure following ER was observed.For ER tablets,SLCO1B1 T521C genotype correlated with AUC 0-24 of repeat doses(P=0.010).SLCO1B1 T521C genotype had no statistically significant effect on AUC 0-24 of IR capsule of fluvastatin after single or repeated doses.In vitro study demonstrated that when the concentration of fluvastatin was low(<1μmol/l),the uptake of fluvastatin in the HEK293-OATP1B1 with SLCO1B1521TT(K m=0.18μmol/l)was faster than that with SLCO1B1521CC(K m=0.49μmol/l),On the other hand,when concentration reached to higher level(>1μmol/l),transport velocity of fluvastatin by HEK293-OATP1B1 with SLCO1B1521TT(K m=11.4μmol/l)and with SLCO1B1521TCC(K m=15.1μmol/l)tend to be the same.It suggests that the increased effect of SLCO1B1 T521C genotype on ER formulation of fluvastatin was mainly caused by lower blood concentrations.We recommend that formulation should be incorporated into future pharmacogenomics studies.展开更多
Acute liver failure(ALF)is a life-threatening condition associated with macrophagemediated inflammatory responses.Effective therapies and drugs are still lacking to date.Here,we reveal that a derivative of xanthohumol...Acute liver failure(ALF)is a life-threatening condition associated with macrophagemediated inflammatory responses.Effective therapies and drugs are still lacking to date.Here,we reveal that a derivative of xanthohumol,CAM12203,alleviates lipopolysaccharide(LPS)+D-galactosamine(D-GalN)-induced ALF through limiting macrophage-mediated inflammation,with the most significant impact on interleukin-1β(IL-1β)transcription.Through biotin labeling-mediated pull-down and LC-MS/MS analysis,diacylglycerol kinase ζ(DGKζ),a lipid-metabolizing kinase,is identified as the direct target of CAM12203.Mechanistically,DGKζ is induced in macrophages upon inflammatory stimuli and is upregulated observed on clinical liver failure samples.Its product phosphatidic acid(PA)boosts phospholipase C(PLC)-inositol 1,4,5-trisphosphate(IP_(3))-Ca^(2+)signaling and subsequent janus kinase 2(JAK2)-signal transducer and activator of transcription 3(STAT3)cascade,ultimately promoting IL1β production and liver failure.DGKζ knockdown/ablation or inhibition significantly impairs the DGKζ-STAT3-IL-1β pathway along with ALF progression.Finally,CAM12203 is confirmed to be a new DGKζ inhibitor and acts against inflammation in a DGKζ-reliant manner.Taken together,CAM12203 inhibits IL-1β transcription in macrophages by binding to DGKζ and blocking the DGKζ-STAT3 axis,thereby exerting an ameliorative effect on ALF.These results not only highlight CAM12203 as a promising lead compound for ALF treatment,but also define DGKζ as a novel therapeutic target.展开更多
基金supported by grants from the National Natural Science Foundation of China(31970902,U22A20306,and 3192010300)the Municipal Administration of Hospitals Incubating Program(PZ2023009)+1 种基金the Key-Area R&D Program of Guangdong Province(2019B030335001)the Autism Research Special Fund of Zhejiang Foundation for Disabled Persons(2022003).
文摘Anxiety disorder is a major symptom of autism spectrum disorder(ASD)with a comorbidity rate of~40%.However,the neural mechanisms of the emergence of anxiety in ASD remain unclear.In our study,we found that hyperactivity of basolateral amygdala(BLA)pyramidal neurons(PNs)in Shank3 InsG3680 knock-in(InsG3680+/+)mice is involved in the development of anxiety.Electrophysiological results also showed increased excitatory input and decreased inhibitory input in BLA PNs.Chemogenetic inhibition of the excitability of PNs in the BLA rescued the anxiety phenotype of InsG3680+/+mice.Further study found that the diminished control of the BLA by medial prefrontal cortex(mPFC)and optogenetic activation of the mPFC-BLA pathway also had a rescue effect,which increased the feedforward inhibition of the BLA.Taken together,our results suggest that hyperactivity of the BLA and alteration of the mPFC-BLA circuitry are involved in anxiety in InsG3680+/+mice.
基金supported by grants from the National Natural Science Foundation of China(31571049 and81561168022)the National Basic Research Program of China(2015CB910801)+2 种基金Zhejiang Provincial Natural Science Foundation of China(LR19H090001 and LD19H090002)a joint grant from the National Natural Science Foundation of China and the Research Grants Council of Hong Kong,China(8151101104 and N_HKUST625/15)Fundamental Research Funds for the CentralUniversities of China
文摘Neuroligins(NLs) are postsynaptic cell-adhesion proteins that play important roles in synapse formation and the excitatory-inhibitory balance. They have been associated with autism in both human genetic and animal model studies, and affect synaptic connections and synaptic plasticity in several brain regions. Yet current research mainly focuses on pyramidal neurons, while the function of NLs in interneurons remains to be understood. To explore the functional difference among NLs in the subtypespecific synapse formation of both pyramidal neurons and interneurons, we performed viral-mediated shRNA knockdown of NLs in cultured rat cortical neurons and examined the synapses in the two major types of neurons. Our results showed that in both types of neurons, NL1 and NL3 were involved in excitatory synapse formation, and NL2 in GABAergic synapse formation. Interestingly, NL1 affectedGABAergic synapse formation more specifically than NL3,and NL2 affected excitatory synapse density preferentially in pyramidal neurons. In summary, our results demonstrated that different NLs play distinct roles in regulating the development and balance of excitatory and inhibitory synapses in pyramidal neurons and interneurons.
基金This study was supported by grants from the National Key R&D Program of China(No.2016YFC0904900)National Natural Science Foundation(No.81673509 and No.81573504)of China+1 种基金Natural Science Foundation of Beijing Municipality(No.7171012)National Science and Technology Major Projects for“Major New Drugs Innovation and Development”of China(No.2017ZX09304028 and No.2017ZX09101001).
文摘The purpose of the present study was to investigate the impact of genetic polymorphism on fluvastatin pharmacokinetics.In addition,we compared the fluvastatin pharmacokinetics differences between extended-release(ER)80 mg tablet and immediate-release(IR)40 mg capsule in terms of drug metabolism enzyme and transporter genetic polymorphisms.In this open-label,randomized,two-period,two-treatment,crossover study(n=24),effects of ABCG2,SLCO1B1,ABCB1,CYP2C9 and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed.The administration dosage for IR 40 mg and ER 80 mg were twice and once daily,respectively,for total 7 d.Blood samples for pharmacokinetic evaluation were taken on the 1st and 7th d.The lower exposure following ER was observed.For ER tablets,SLCO1B1 T521C genotype correlated with AUC 0-24 of repeat doses(P=0.010).SLCO1B1 T521C genotype had no statistically significant effect on AUC 0-24 of IR capsule of fluvastatin after single or repeated doses.In vitro study demonstrated that when the concentration of fluvastatin was low(<1μmol/l),the uptake of fluvastatin in the HEK293-OATP1B1 with SLCO1B1521TT(K m=0.18μmol/l)was faster than that with SLCO1B1521CC(K m=0.49μmol/l),On the other hand,when concentration reached to higher level(>1μmol/l),transport velocity of fluvastatin by HEK293-OATP1B1 with SLCO1B1521TT(K m=11.4μmol/l)and with SLCO1B1521TCC(K m=15.1μmol/l)tend to be the same.It suggests that the increased effect of SLCO1B1 T521C genotype on ER formulation of fluvastatin was mainly caused by lower blood concentrations.We recommend that formulation should be incorporated into future pharmacogenomics studies.
基金supported by the National Science and Technology Major Project(2024ZD0523103,China)the National Natural Science Foundation of China(92457302,82425058,82304500,and 22494693)+5 种基金the National Key R&D Program of China(2020YFE0205600)the Yangfan Project of Shanghai Science and Technology Commission(23YF1456500,China)the Shanghai“Super Postdoctoral”Incentive Plan(2022692,China)the fellowship of China Postdoctoral Science Foundation(2023M733630)the Tian-Shan Talent Program(2022TSYCLJ0064,China)the Youth Innovation Promotion Association of Chinese Academy of Sciences(E32R4001,China).
文摘Acute liver failure(ALF)is a life-threatening condition associated with macrophagemediated inflammatory responses.Effective therapies and drugs are still lacking to date.Here,we reveal that a derivative of xanthohumol,CAM12203,alleviates lipopolysaccharide(LPS)+D-galactosamine(D-GalN)-induced ALF through limiting macrophage-mediated inflammation,with the most significant impact on interleukin-1β(IL-1β)transcription.Through biotin labeling-mediated pull-down and LC-MS/MS analysis,diacylglycerol kinase ζ(DGKζ),a lipid-metabolizing kinase,is identified as the direct target of CAM12203.Mechanistically,DGKζ is induced in macrophages upon inflammatory stimuli and is upregulated observed on clinical liver failure samples.Its product phosphatidic acid(PA)boosts phospholipase C(PLC)-inositol 1,4,5-trisphosphate(IP_(3))-Ca^(2+)signaling and subsequent janus kinase 2(JAK2)-signal transducer and activator of transcription 3(STAT3)cascade,ultimately promoting IL1β production and liver failure.DGKζ knockdown/ablation or inhibition significantly impairs the DGKζ-STAT3-IL-1β pathway along with ALF progression.Finally,CAM12203 is confirmed to be a new DGKζ inhibitor and acts against inflammation in a DGKζ-reliant manner.Taken together,CAM12203 inhibits IL-1β transcription in macrophages by binding to DGKζ and blocking the DGKζ-STAT3 axis,thereby exerting an ameliorative effect on ALF.These results not only highlight CAM12203 as a promising lead compound for ALF treatment,but also define DGKζ as a novel therapeutic target.
