Abstract Background Neuronal hyperactivity related to β-amyloid (Aβ) is considered an early warning sign of Alzheimer disease (AD). Although increasing evidence supports this opinion, the underlying mechanisms are still unknown. Methods Here, we recorded whole-cell synaptic currents and membrane potentials using patch clamping of acute hippocampal slices from human amyloid precursor protein (APP)/presenilin-1 transgenic (5XFAD) mice and their wild-type littermates. Biochemical methods, electron microscopic imaging, behavioral tests, and intraventricular drug delivery applied with osmotic pumps were used in this study. Results We confirmed hyperactivity of hippocampal CA1 pyramidal neurons in 5XFAD mice using whole-cell electrophysiological recording at 2.5 months old, when local Aβ-positive plaques had not developed and only mild cognitive dysfunction occurred. We further discovered attenuated inhibitory postsynaptic currents and unchanged excitatory postsynaptic currents in CA1 pyramidal neurons, in which the intrinsic excitability was unchanged. Moreover, the density of both γ-aminobutyric acid A (GABA A ) receptor subunits, α1 and γ2, was reduced in synapses of the hippocampus in transgenic mice. Intriguingly, early intervention with the GABA A receptor agonist gaboxadol reversed the hippocampal hyperactivity and modestly ameliorated cognitive performance in 5XFAD mice under our experimental conditions. Conclusions Inhibitory postsynaptic disruption critically contributes to abnormalities in the hippocampal network and cognition in 5XFAD mice and possibly in AD. Therefore, strengthening the GABAergic system could be a promising therapy for AD in the early stages.
Review question / Objective: P: Patients with tricuspid regurgitation requiring tricuspid annuloplasty.I/C: Comparison of 3D rigid ring and suture, flexible band, flat rigid ring and other shaping techniques in the treatment of TR.O: aortic cross-clamp (ACC) time, cardiopulmonary bypass (CPB) time, postoperative TR grade (defined as TR grade within one week after surgery), perioperative mortality (defined as hospital mortality or 30-day death rate), late mortality rate (defined as the total mortality rate during follow-up), early complication rate (defined as the rate of complication within 30 days after surgery) and recurrent TR (defined as postoperative moderate and above TR (grade 2-4)).S: Controlled Trial (RCT) or cohort study.Objective: we conducted this systematic review and meta-analysis to compare the effects of 3D rigid annulus and other methods in TAP, and provide a reference for selecting the appropriate annulus type during tricuspid annuloplasty.
Objective:To investigate the expression of heme oxygenase-1(HO-1) in hippocampus of neonatal rats with hypoxic-ischemic brain damage(HIBD),and expore the possible neuroprotective mechanism of naloxone on HIBD.Methods:Neonatal 7-day SD rats were randomly divided into three equal groups:Group S(sham operation group),Group C(HIBD+nomal saline treatment),Group N(HIBD + naloxone treatment).HIBD models were established by Rice method.All of the groups were further divided into six subgroups(n = 8 in each subgroup) according to the time points 3 h,6 h,12 h,24 h,3 d,7 d,after H/I.Western blot was used to detect the protein level of HO-1.Variation of HO-1 activity in hippocampus was detected by biochemical test.The apoptosis cells in hippocampus were detected by TUNEL.Results:① Expression of HO-1 protein:Western blot showed that the expression of HO-1 in hippocampus in Group S was very low and the same at different time points,but the expressions of HO-1 in hippocampus in Group N,Group C increased markedly from 3 h and reached peak at 24 h post-H/I,then gradually decreased,and almost returned to the original levels 7 d after H/I,but still higher than Group S(P 0.01).The expressions of HO-1 12 h,24 h,3 d,7 d after H/I in Group N were significantly higher than those of Group C(P 0.01).② Variation of HO-1 activity:The variation of HO-1 activity in Group C was increased from 3 h and reached peak at 24 h post-H/I,returned to the original level 7 d after H/I.HO-1 activities 12 h,24 h,3 d after H/I in Group N were significantly higher than those of Group C(P 0.01).③ Apoptotic cells detection:TUNEL staining showed that the numbers of apoptotic cells in Group N,Group C in hippocampus of ipsilateral hemisphere gradually increased at 3 h,peaked at 24 h and decreased at 3 d after H/I,the numbers of apoptotic cells in Group N 24 h,3 d,7 d after H/I were significantly lower than Group C(P 0.01).Conclusion:①The expression of HO-1 in hippocampus increased after H/I injury,HO-1 is involved in the regulation of neuronal apoptosis and implicated in pathophysiological mechanisms of neuronal damage after H/I.②Naloxone has a protective effect on H/I-induced neuronal injure,may exert its neuroprotective mechanisms by increasing HO-1 expression.
To investigate the influence of edaravone on the expression of growth arrest and DNA damage-inducible protein 34 (GADD34). A total of 108 healthy male Sprague-Dawley rats were randomly divided into sham operation group, model group and edaravone group (36 cases for each group). Transient focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 h followed by reperfusion in Sprague-Dawley rats. Then, GADD34 expression was measured with immunohistochemistry at different time-points after reperfusion in the peri-infarct regions of all rats. The GADD34 expression was detected in the peri-infarct regions of rats 1 h after reperfusion, which reached its peak 24 h after reperfusion. And edaravone could significantly down-regulate the GADD34 expression. Edaravon could down-regulate GADD34 expression, which suggests that edaravone may exert an important function in inhibiting endoplasmic reticulum stress reaction by scavenging free radicals in the upper stream.
To study the expression of fatty acid binding protein 4 (FABP4) in lungs and bronchoalveolar lavage fluid (BALF) of preterm rats exposed to 60% O2 and to elucidate the relationship between the changes of FABP4 expression and the pathogenesis of bronchopulmonary dysplasia (BPD).Hyperoxic lung injury was induced by exposing to 60% O2 in Spraque-Dawley rats within 6 hours after birth. Rats exposed to air were used as the control group. The lungs from groups aged postnatal days 3, 7 and 14 were removed and dissected from the main bronchi for analysis. Eight rats of each group were used to assess expression of FABP4 in lungs by immunohistochemistry and ELISA. Lung FABP4 mRNA levels were measured by semi-quantitative reverse transcription polymerase chain reaction. The levels of FABP4 in BALF were measured using ELISA.FABP4 immunoreactivity was detected in the majority of alveolar macrophages, bronchial epithelial cells and endothelial cells. FABP4 protein levels in lung tissues in the hyperoxic exposure group increased significantly compared with the control group on days 3, 7 and 14 after birth (P<0.05), and FABP4 mRNA levels in lung tissues also increased significantly in the hyperoxic exposure group compared with the control group on days 7 and 14 after birth (P<0.05). The hyperoxic exposure group demonstrated increased FABP4 levels in BALF compared with the control group on days 7 and 14 after birth (P<0.05).FABP4 levels increase in preterm rat lungs after hyperoxic lung injury, which may contribute to the pathogenesis of BPD.
The double-arrow hollow cylinder (DAHC) has excellent mechanical properties under axial compression loads due to its negative Poisson ratio structure. To improve finite element simulation efficiency for parameter optimization analysis, an automatic modeling program for DAHC negative Poisson ratio structures was developed on the ABAQUS platform using Python. The sample was manufactured using selective laser melting additive manufacturing based on the solid model and then simulated using the finite element method. The accuracy of the automatic modeling method was confirmed by comparing load–displacement curves and deformation cloud images with static compression test results. The DAHC automatic modeling program based on Python can reduce workload during parameter optimization analysis and improve finite element analysis efficiency.
Objective To find the differential proteins of blood stasis syndrome of coronary heart disease(CHD),and explore the possible internal pathogenesis of blood stasis syndrome.Methods The model of blood stasis syndrome of chronic myocardial ischemia was established by applying the method of placing Ameroid ring in the left anterior descending coronary artery in Chinese miniswines.All miniswines were randomly divided into the sham-operation group and model group.The status of myocardial ischemia(0-8 weeks) was observed dynastically in the model.The stenosis of coronary artery was observed by using coronary angiography(CAG).The study of comparative proteomics was conducted by applying two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry(MALDI-TOF-MS) in 10 miniswines of the sham-operation group and 9 ones of the model group.The relevant differential proteins were verified initially by using Western blot method at later stage of the test for determining further the differential proteins of CHD myocardial ischemia.Results The initial study found out that there were 5 distinct down-regulated protein spots and 8 distinct up-regulated protein spots in the model group compared with the sham-operation group.The identification of MALDI-TOF-MS was used in some differential protein spots and the result was determined by second-order mass spectrum at the same time.The differential proteins were mainly oxidative stress proteins and relevant myocardial structural proteins,including heat shock 27 kDa protein(HSP27),peroxiredoxin 3 isoform 1,cardiac troponin T(cTnT) and myosin light polypeptide.Conclusion The myocardial manifestations were observed as oxidative stress lesion and changes of myocardial structural proteins in blood stasis syndrome of CHD chronic myocardial ischemia.The relevant differential proteins can be taken as the target of medicinal treatment.
The reactive oxygen species and Ca2+ overload play a critical role in ischemia/reperfusion (I/R) injury. MCI-186 has potent effects in the brain as a free radical scavenger in ischemia-reperfusion. Acute glucose-oxygen deprivation and subsequent reoxygenation were used to model ischemia/reperfusion injury in cultured hippocampal cells. MCI-186 reduced malondialdehyde level and raised the SOD activity when applied upon reoxygenation in a dose-dependent manner compared with the untreated group. The peak neuroprotective effects occurred at 100 and 300 microM. Intracellular free calcium concentration ([Ca2+]i) was significantly reduced in the 100 microM MCI-186-treated group compared to the untreated group (32.5+/-4.0 versus 50.2+/-3.6, p<0.01). Treatment with 100 microM MCI-186 significantly inhibited the decrease of mitochondria membrane potential after simulated ischemia/reperfusion (204+/-11.6% compared with the untreated group, p<0.01). Cell apoptotic rate was significantly decreased following MCI-186 treatment from 33.7+/-2.3% (untreated group) to 16.6+/-1.4% (100 microM MCI-186 treated group). There was no significantly protective difference between 100 and 300 microM MCI-186. MCI-186 effectively protects neuron injury after simulated ischemia/reperfusion by inhibiting lipid peroxidation, reducing Ca2+ overload, elevating mitochondria membrane potential, and decreasing apoptosis.
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