Inflammation plays a crucial role in the initiation and progression of sepsis and induces alterations in brain neurotransmission, thereby contributing to the development of sepsis-associated encephalopathy(SAE).Parval...Inflammation plays a crucial role in the initiation and progression of sepsis and induces alterations in brain neurotransmission, thereby contributing to the development of sepsis-associated encephalopathy(SAE).Parvalbumin(PV) interneurons are pivotal contributors to cognitive processes and have been implicated in various central nervous system dysfunctions, including SAE. Oxytocin, known for its ability to augment the firing rate of gamma-aminobutyric acid(GABA)-ergic interneurons and directly stimulate inhibitory interneurons to enhance the tonic inhibition of pyramidal neurons, has prompted an investigation into its potential therapeutic effects on cognitive dysfunction in SAE. In the current study, we administered intranasal oxytocin to SAE mice induced by lipopolysaccharide. Behavioral assessments, including open field, Y-maze, and fear conditioning, were used to evaluate cognitive performance. Golgi staining revealed hippocampal synaptic deterioration, local field potential recordings showed weakened gamma oscillations, and immunofluorescence staining demonstrated decreased PV expression in the cornu ammonis 1(CA1) region of the hippocampus following lipopolysaccharide treatment, all of which were alleviated by oxytocin administration. Furthermore, immunofluorescence staining of PV co-localization with vesicular glutamate transporter 1 or vesicular GABA transporter indicated a balanced excitation/inhibition effect of neurotransmitters on PV interneurons after oxytocin administration in the SAE mice, leading to an improved cognitive function. In conclusion, oxytocin treatment improved cognitive function by increasing the number of PV^(+) neurons in the hippocampal CA1 region, restoring the balance of excitatory/inhibitory synaptic transmission on PV interneurons, and enhancing hippocampal CA1 local field potential gamma oscillations. These findings suggest a potential mechanism underlying the beneficial effects of oxytocin in SAE.展开更多
Methamphetamine addiction is a brain disorder characterized by persistent drug-seeking behavior, which has been linked with aberrant synaptic plasticity. An increasing body of evidence suggests that aberrant synaptic ...Methamphetamine addiction is a brain disorder characterized by persistent drug-seeking behavior, which has been linked with aberrant synaptic plasticity. An increasing body of evidence suggests that aberrant synaptic plasticity is associated with the activation of the NOD-like receptor family pyrin domain containing-3(NLRP3) inflammasome. 3′-Deoxyadenosin, an active component of the Chinese fungus Cordyceps militaris, has strong anti-inflammatory effects. However, whether 3′-deoxyadenosin attenuates methamphetamine-induced aberrant synaptic plasticity via an NLRP3-mediated inflammatory mechanism remains unclear. We first observed that 3′-deoxyadenosin attenuated conditioned place preference scores in methamphetamine-treated mice and decreased the expression of c-fos in hippocampal neurons. Furthermore, we found that 3′-deoxyadenosin reduced the aberrant potentiation of glutamatergic transmission and restored the methamphetamine-induced impairment of synaptic plasticity. We also found that 3′-deoxyadenosin decreased the expression of NLRP3 and neuronal injury. Importantly, a direct NLRP3 deficiency reduced methamphetamine-induced seeking behavior, attenuated the impaired synaptic plasticity, and prevented neuronal damage. Finally, NLRP3 activation reversed the effect of 3′-deoxyadenosin on behavior and synaptic plasticity, suggesting that the anti-neuroinflammatory mechanism of 3′-deoxyadenosin on aberrant synaptic plasticity reduces methamphetamine-induced seeking behavior. Taken together, 3′-deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome.展开更多
The benefits and harms of corticosteroids for patients with severe coronavirus disease 2019(COVID-19)remain unclear.We systematically searched PubMed,Embase,and Cochrane Central Register of Controlled Trials from Dece...The benefits and harms of corticosteroids for patients with severe coronavirus disease 2019(COVID-19)remain unclear.We systematically searched PubMed,Embase,and Cochrane Central Register of Controlled Trials from December 31,2019 to October 1,2020 to identify randomized controlled trials(RCTs)that evaluated corticosteroids in severe COVID-19 patients.The primary outcome was all-cause mortality at the longest follow-up.Secondary outcomes included a composite disease progression(progression to intubation,ventilation,extracorporeal membrane oxygenation,ICU transfer,or death among those not ventilated at enrollment)and incidence of serious adverse events.A random-effects model was applied to calculate risk ratio(RR)with 95%confidence intervals(Cis).We used the Grading of Recommendations Assessment,Development,and Evaluation approach to evaluate the certainty of the evidence.Seven RCTs involving 6250 patients were included,of which the Randomized Evaluation of COVID-19 Therapy(RECOVERY)trial comprised nearly 78%of all included subjects.Results showed that corticosteroids were associated with a decreased all-cause mortality(27.3 vs.31.1%;RR:0.85;95%CI:0.73-0.99;P=0.04;low-certainty evidence).Trial sequential analysis suggested that more trials were still required to confirm the results.However,such survival benefit was absent if RECOVERY trial was excluded(RR:0.83;95%CI:0.65-1.06;P=0.13).Furthermore,corticosteroids decreased the occurrence of composite disease progression(30.6 vs.33.3%;RR:0.77;95%CI:0.64-0.92;P=0.005),but not increased the incidence of serious'adverse events(3.5 vs.3.4%;RR:1.16;95%CI:0.39-3.43;P=0.79).展开更多
基金supported by grants from the general project of Nanjing Medical University Science and Technology Development Foundation (Grant No.NMUB20210112)。
文摘Inflammation plays a crucial role in the initiation and progression of sepsis and induces alterations in brain neurotransmission, thereby contributing to the development of sepsis-associated encephalopathy(SAE).Parvalbumin(PV) interneurons are pivotal contributors to cognitive processes and have been implicated in various central nervous system dysfunctions, including SAE. Oxytocin, known for its ability to augment the firing rate of gamma-aminobutyric acid(GABA)-ergic interneurons and directly stimulate inhibitory interneurons to enhance the tonic inhibition of pyramidal neurons, has prompted an investigation into its potential therapeutic effects on cognitive dysfunction in SAE. In the current study, we administered intranasal oxytocin to SAE mice induced by lipopolysaccharide. Behavioral assessments, including open field, Y-maze, and fear conditioning, were used to evaluate cognitive performance. Golgi staining revealed hippocampal synaptic deterioration, local field potential recordings showed weakened gamma oscillations, and immunofluorescence staining demonstrated decreased PV expression in the cornu ammonis 1(CA1) region of the hippocampus following lipopolysaccharide treatment, all of which were alleviated by oxytocin administration. Furthermore, immunofluorescence staining of PV co-localization with vesicular glutamate transporter 1 or vesicular GABA transporter indicated a balanced excitation/inhibition effect of neurotransmitters on PV interneurons after oxytocin administration in the SAE mice, leading to an improved cognitive function. In conclusion, oxytocin treatment improved cognitive function by increasing the number of PV^(+) neurons in the hippocampal CA1 region, restoring the balance of excitatory/inhibitory synaptic transmission on PV interneurons, and enhancing hippocampal CA1 local field potential gamma oscillations. These findings suggest a potential mechanism underlying the beneficial effects of oxytocin in SAE.
基金supported by the National Natural Science Foundation of China,No.81971246 (to TM)Opening Foundation of Jiangsu Key Laboratory of Neurodegeneration,Nanjing Medical University,No.KF202204 (to LZ and SF)。
文摘Methamphetamine addiction is a brain disorder characterized by persistent drug-seeking behavior, which has been linked with aberrant synaptic plasticity. An increasing body of evidence suggests that aberrant synaptic plasticity is associated with the activation of the NOD-like receptor family pyrin domain containing-3(NLRP3) inflammasome. 3′-Deoxyadenosin, an active component of the Chinese fungus Cordyceps militaris, has strong anti-inflammatory effects. However, whether 3′-deoxyadenosin attenuates methamphetamine-induced aberrant synaptic plasticity via an NLRP3-mediated inflammatory mechanism remains unclear. We first observed that 3′-deoxyadenosin attenuated conditioned place preference scores in methamphetamine-treated mice and decreased the expression of c-fos in hippocampal neurons. Furthermore, we found that 3′-deoxyadenosin reduced the aberrant potentiation of glutamatergic transmission and restored the methamphetamine-induced impairment of synaptic plasticity. We also found that 3′-deoxyadenosin decreased the expression of NLRP3 and neuronal injury. Importantly, a direct NLRP3 deficiency reduced methamphetamine-induced seeking behavior, attenuated the impaired synaptic plasticity, and prevented neuronal damage. Finally, NLRP3 activation reversed the effect of 3′-deoxyadenosin on behavior and synaptic plasticity, suggesting that the anti-neuroinflammatory mechanism of 3′-deoxyadenosin on aberrant synaptic plasticity reduces methamphetamine-induced seeking behavior. Taken together, 3′-deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome.
基金supported by grants from the National Natural Science Foundation of China(81600960 and 81971045).
文摘The benefits and harms of corticosteroids for patients with severe coronavirus disease 2019(COVID-19)remain unclear.We systematically searched PubMed,Embase,and Cochrane Central Register of Controlled Trials from December 31,2019 to October 1,2020 to identify randomized controlled trials(RCTs)that evaluated corticosteroids in severe COVID-19 patients.The primary outcome was all-cause mortality at the longest follow-up.Secondary outcomes included a composite disease progression(progression to intubation,ventilation,extracorporeal membrane oxygenation,ICU transfer,or death among those not ventilated at enrollment)and incidence of serious adverse events.A random-effects model was applied to calculate risk ratio(RR)with 95%confidence intervals(Cis).We used the Grading of Recommendations Assessment,Development,and Evaluation approach to evaluate the certainty of the evidence.Seven RCTs involving 6250 patients were included,of which the Randomized Evaluation of COVID-19 Therapy(RECOVERY)trial comprised nearly 78%of all included subjects.Results showed that corticosteroids were associated with a decreased all-cause mortality(27.3 vs.31.1%;RR:0.85;95%CI:0.73-0.99;P=0.04;low-certainty evidence).Trial sequential analysis suggested that more trials were still required to confirm the results.However,such survival benefit was absent if RECOVERY trial was excluded(RR:0.83;95%CI:0.65-1.06;P=0.13).Furthermore,corticosteroids decreased the occurrence of composite disease progression(30.6 vs.33.3%;RR:0.77;95%CI:0.64-0.92;P=0.005),but not increased the incidence of serious'adverse events(3.5 vs.3.4%;RR:1.16;95%CI:0.39-3.43;P=0.79).
