Lipidomic analysis identifies long-chain acylcarnitine as a target for ischemic stroke.

INTRODUCTION: Lipid metabolism dysfunction is widely involved in the pathological process of acute ischemic stroke (AIS). The coordination of lipid metabolism between neurons and astrocytes is of great significance. However, the full scope of lipid dynamic changes and the function of key lipids during AIS remain unknown. Hence, identifying lipid alterations and characterizing their key roles in AIS is of great importance. METHODS: Untargeted and targeted lipidomic analyses were applied to profile lipid changes in the ischemic penumbra and peripheral blood of transient middle cerebral artery occlusion (tMCAO) mice as well as the peripheral blood of AIS patients. Infarct volume and neurological deficits were assessed after tMCAO. The cell viability and dendritic complexity of primary neurons were evaluated by CCK8 assay and Sholl analysis. Seahorse, MitoTracker Green, tetramethyl rhodamine methyl ester (TMRM), 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSOX were used as markers of mitochondrial health. Fluorescent and isotopic free fatty acid (FFA) pulse-chase assays were used to track FFA flux in astrocytes. RESULTS: Long-chain acylcarnitines (LCACs) were the lipids with the most dramatic changes in the ischemic penumbra and peripheral blood of tMCAO mice. LCACs were significantly elevated on admission in AIS patients and associated with poor outcomes in AIS patients. Increasing LCACs through a bolus administration of palmitoylcarnitine amplified stroke injury, while decreasing LCACs by overexpressing carnitine palmitoyltransferase 2 (CPT2) ameliorated stroke injury. Palmitoylcarnitine aggravated astrocytic mitochondrial damage after OGD/R, while CPT2 overexpression in astrocytes ameliorated cocultured neuron viability. Further study revealed that astrocytes stimulated by OGD/R liberated FFAs from lipid droplets into mitochondria to form LCACs, resulting in mitochondrial damage and lowered astrocytic metabolic support and thereby aggravated neuronal damage. CONCLUSION: LCACs could accumulate and damage neurons by inducing astrocytic mitochondrial dysfunction in AIS. LCACs play a crucial role in the pathology of AIS and are novel promising diagnostic and prognostic biomarkers for AIS.

Resolvin D1 reprograms energy metabolism to promote microglia to phagocytize neutrophils after ischemic stroke.

Neutrophil aggregation and clearance are important factors affecting neuroinflammatory injury during acute ischemic stroke. Emerging evidence suggests that energy metabolism is essential for microglial functions, especially microglial phagocytosis, which determines the degree of brain injury. Here, we demonstrate that Resolvin D1 (RvD1), a lipid mediator derived from docosahexaenic acid (DHA), promotes the phagocytosis of neutrophils by microglia, thereby reducing neutrophil accumulation in the brain and alleviating neuroinflammation in the ischemic brain. Further studies reveal that RvD1 reprograms energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS), providing sufficient energy for microglial phagocytosis. Moreover, RvD1 enhances microglial glutamine uptake and stimulates glutaminolysis to support OXPHOS to boost ATP production depending on adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation. Overall, our results reveal that RvD1 reprograms energy metabolism to promote the microglial phagocytosis of neutrophils after ischemic stroke. These findings may guide perspectives for stroke therapy from modulating microglial immunometabolism.

Research on Nonlinear Behavior of Local High-Performance Concrete Beam-Column Connections.

The seismic performance index of prefabricated structures is generally obtained via experimental analysis. However, in experimental research, it is impossible that every influencing factor can be taken into account. Therefore, the finite element analysis method can be used as a supplementary method for experimental research to carry out parametric analysis of joints. Based on this test, a hysteretic model of steel bars is developed on the ABAQUS platform; meanwhile, the model is used to simulate the seismic analysis of the proposed local reinforced joints. The hysteresis curve obtained via simulation exhibits a high degree of coincidence with the experimental results. Based on the validated model, a detailed parameter analysis of prefabricated local reinforced concrete frame joints is carried out. The analysis results illustrate that the axial pressure ratio at the top of the column has a minimal impact on the joint's performance. Decreasing the stirrup ratio within the core region, enlarging the diameter of the PC steel bar, and increasing the concrete strength that is poured in the keyway and the core region can raise the cumulative energy consumption of the joints, thereby reducing the damage degree of other units and improving the maximum bearing capability of the joints.

Seismic Performance of Precast Concrete Frame Beam-Column Connections with High-Strength Bars.

As the construction industry is striding towards the industrialization of green buildings, a precast concrete frame beam-column joint with high-strength reinforcement was proposed. Simulate reversed cyclic loading was carried out on two precast connections and one cast-in-place connection to examine the seismic behavior of the proposed new precast connection. The main test variables between the two precast connections were the strength of the reinforcement at the bottom of the beam. The failure shape, hysteresis curve, skeleton curve, strength, deformation ability, stiffness degradation, and energy dissipation were monitored and compared with the cast-in-place connection. The findings of this paper showed that the precast joints had good strength reserve, and the seismic performance in the later stage of loading even exceeds the cast-in-place joints. It was also found that the plastic hinge zone of the beam could be moved away from the column surface via reinforcement method. Additionally, based on the experiment, a detailed nonlinear finite element analysis (FEA) method was developed to reproduce the test response of specific types of bending moment-resistant precast concrete beam-column connections under a reversed loading test, which provided a theoretical reference for further research of the connections.

Activating PPARß/δ Protects against Endoplasmic Reticulum Stress-Induced Astrocytic Apoptosis via UCP2-Dependent Mitophagy in Depressive Model.

As energy metabolism regulation factor, peroxisome proliferator-activated receptor (PPAR) is thought to be a potential target for the treatment of depression. The present study was performed to evaluate the effects of activating PPARß/δ, the most highly expressed subtype in the brain, in depressive in vivo and in vitro models. We observed that PPARß/δ agonist GW0742 significantly alleviated depressive behaviors in mice and promoted the formation of autophagosomes around the damaged mitochondria in hippocampal astrocytes. Our in vitro experiments showed that GW0742 could reduce mitochondrial oxidative stress, and thereby attenuate endoplasmic reticulum (ER) stress-mediated apoptosis pathway via inhibiting IRE1α phosphorylation, subsequently protect against astrocytic apoptosis and loss. Furthermore, we found that PPARß/δ agonist induces astrocytic mitophagy companied with the upregulated UCP2 expressions. Knocking down UCP2 in astrocytes could block the anti-apoptosis and pro-mitophagy effects of GW0742. In conclusion, our findings reveal PPARß/δ activation protects against ER stress-induced astrocytic apoptosis via enhancing UCP2-mediated mitophagy, which contribute to the anti-depressive action. The present study provides a new insight for depression therapy.

[Influence of electroacupuncture of "Daling"(PC 7) on heart rate, duration of arrhythmia and plasma vasoactive intestinal peptide contents in ventricular tachycardia rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on heart rate (HR), arrhythmia duration, and plasma vasoactive intestinal peptide (VIP) level in ventricular tachycardia (VT) rats so as to study its underlying adjustment mechanism. METHODS: A total of 70 SD rats were randomly divided into normal control, model (VT), "Daling" (PC 7, EA-PC 7) and "Taiyuan" (LU 9, EA-LU 9) groups. VT model was duplicated by injection of CsCI (2 mol/L, 1.6 mmoL/kg, femoral vein). EA (2 Hz/15 Hz, 1 mA) was applied to "Daling" (PC 7) and "Taiyuan" (LU 9) for 5 min after inserting acupuncture needles. BL-410 Biofunctional System was used to record the ECG of the standard limb lead II, and plasma VIP content assayed by using radioimmunoassay. RESULTS: Following intravenous injection of CsCI, HR increased significantly in model, EA-PC 7 and EA-LU 9 groups (P < 0.05). Compared to model group, HR at 5 min, 10 min and 15 min after administration of CsCI and the duration of arrhythmia in EA-PC 7 group decreased considerably (P < 0.01). No significant differences were found between EA-LU 9 and model groups in HR and the duration of arrhythmia (P > 0.05). Compared with normal group, the content of plasma VIP in model group decreased apparently (P < 0.05), while in comparison with model group, plasma VIP level in EA-PC 7 group increased considerably (P < 0.01). CONCLUSION: Electroacupuncture of "Daling" (PC7) can effectively suppress CsCI-induced tachycardia which may be closely associated with its effect in reducing plasma VIP level.

(R)-(+)-3-Hydr-oxy-2-methoxy-carbonyl-8-methyl-8-azoniabicyclo-[3.2.1]octane l-bitartrate.

(RS)-(±)-2-Methoxy-carbonyl-3-tropinone is an important inter-mediate for the preparation of cocaine and its derivatives. The molecule in the title compound, C(10)H(16)NO(3) (+)·C(4)H(5)O(6) (-), is present as the enol tautomer. The six-membered ring adopts a half boat conformation, and the five-membered ring a slightly distorted envelope conformation. There are intra- and inter-molecular hydrogen bonds involving the hydroxyl, carboxyl groups and quaternary ammonium groups.