Extracellular Matrix Remodeling Alleviates Memory Deficits in Alzheimer's Disease by Enhancing the Astrocytic Autophagy-Lysosome Pathway.

Extracellular matrix (ECM) remodeling is strongly linked to Alzheimer's disease (AD) risk; however, the underlying mechanisms are not fully understood. Here, it is found that the injection of chondroitinase ABC (ChABC), mimicking ECM remodeling, into the medial prefrontal cortex (mPFC) reversed short-term memory loss and reduced amyloid-beta (Aß) deposition in 5xFAD mice. ECM remodeling also reactivated astrocytes, reduced the levels of aggrecan in Aß plaques, and enhanced astrocyte recruitment to surrounding plaques. Importantly, ECM remodeling enhanced the autophagy-lysosome pathway in astrocytes, thereby mediating Aß clearance and alleviating AD pathology. ECM remodeling also promoted Aß plaque phagocytosis by astrocytes by activating the astrocytic phagocytosis receptor MERTK and promoting astrocytic vesicle circulation. The study identified a cellular mechanism in which ECM remodeling activates the astrocytic autophagy-lysosomal pathway and alleviates AD pathology. Targeting ECM remodeling may represent a potential therapeutic strategy for AD and serve as a reference for the treatment of this disease.

Oxidative insertion of amines into conjugated macrocycles: transformation of antiaromatic norcorrole into aromatic azacorrole.

A new group of aromatic porphyrinoids was obtained by an oxidative insertion of primary amines into the antiaromatic ring of 5,14-dimesityl-norcorrolatonickel(II) activated by iodosobenzene. The substituted 10-azacorroles thus formed were characterized by spectroscopic and electrochemical methods, and XRD analysis. Protonated forms of azacorroles were shown to remain aromatic despite disconnection of the original π-electron delocalization path.

Mirror image pain mediated by D2 receptor regulation of astrocytic Cx43 phosphorylation and channel opening.

Mirror image pain (MIP), a clinical syndrome of contralateral pain hypersensitivity caused by unilateral injury, has been identified in various neuropathological conditions. Gap junctional protein Connexin 43 (Cx43), its phosphorylation levels and dopamine D2 receptor (DRD2) play key integrating roles in pain processing. We presume D2DR activity may affect Cx43 hemichannel opening via Cx43 phosphorylation levels to regulate MIP. This study shows that spinal astrocytic Cx43 directly interacts with DRD2 to mediate MIP. DRD2 and Cx43 expression levels were asymmetrically elevated in bilateral spinal during MIP, and DRD2 modulated the opening of primary astrocytic Cx43 hemichannels. Furthermore, Cx43 phosphorylation at Ser373 was increased during MIP, but decreased in DRD2 knockout (KO) mice. Finally, activation of spinal protein kinase A (PKA) altered the expression of Cx43 and its phosphorylation bilaterally, thus reversing the analgesic effect in DRD2 KO mice. Together, these data reveal that spinal Cx43 phosphorylation and channel opening are regulated by DRD2 via PKA activation, and that spinal Cx43 and DRD2 are key molecular sensors mediating mirror image pain.

1,3-Dipolar cycloaddition of polycyclic azomethine ylide to norcorroles: towards dibenzoullazine-fused derivatives.

A 1,3-cycloaddition reaction of 2-(tert-butyl)-8H-isoquinolino[4,3,2-de]phenanthridin-9-ium chloride to NiII norcorrole in the presence of base is shown to produce a family of chiral derivatives of polycyclic system(s) fused with pyrrole subunit(s) of the macrocycle. Dehydrogenation of the cycloaddition products gave rise to dibenzoullazine ortho-fused antiaromatic porphyrinoids.

Neural Circuits for Social Interactions: From Microcircuits to Input-Output Circuits.

Social behaviors entail responses to social information and requires the perception and integration of social cues through a complex cognition process that involves attention, memory, motivation, and emotion. Neurobiological and molecular mechanisms underlying social behavior are highly conserved across species, and inter- and intra-specific variability observed in social behavior can be explained to large extent by differential activity of a conserved neural network. However, neural microcircuits and precise networks involved in social behavior remain mysterious. In this review, we summarize the microcircuits and input-output circuits on the molecular, cellular, and network levels of different social interactions, such as social exploration, social hierarchy, social memory, and social preference. This review provides a broad view of how multiple microcircuits and input-output circuits converge on the medial prefrontal cortex, hippocampus, and amygdala to regulate complex social behaviors, as well as a potential novel view for better control over pathological development.

Role of the Extracellular Matrix in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease with complex pathological characteristics, whose etiology and pathogenesis are still unclear. Over the past few decades, the role of the extracellular matrix (ECM) has gained importance in neurodegenerative disease. In this review, we describe the role of the ECM in AD, focusing on the aspects of synaptic transmission, amyloid-ß-plaque generation and degradation, Tau-protein production, oxidative-stress response, and inflammatory response. The function of ECM in the pathological process of AD will inform future research on the etiology and pathogenesis of AD.

The Effects of Different Fluorescent Indicators in Observing the Changes of the Mitochondrial Membrane Potential during Oxidative Stress-Induced Mitochondrial Injury of Cardiac H9c2 Cells.

We evaluated the ability of different fluorescent indicators by various analytical instruments, including a laser scanning confocal microscope (LSCM), fluorescence plate reader, and flow cytometer (FCM), to measure the mitochondrial membrane potential (ΔΨm) of cardiac H9c2 cells during oxidative stress-induced mitochondrial injury. The mitochondrial oxygen consumption rate and a transmission electron microscope were used to detect changes in mitochondrial functions and morphology, respectively. Cardiac H9c2 cells were exposed to H2O2 (500, 750, 1000, and 1250 µM) to induce mitochondrial oxidative stress injury, and fluorescent indicators including tetramethyl rhodamine ethyl ester (TMRE), 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine iodide (JC-1), and rhodamine 123 (R123) were used to detect changes in ΔΨm using an LSCM, fluorescence plate reader, and FCM. The decrease in ΔΨm caused by H2O2 was determined by endpoint and dynamic analyses after staining with JC-1 or TMRE. With the R123 probe, the LSCM could only detect the change in ΔΨm caused by 1000 µM H2O2. Moreover, R123 was less effective than JC-1 and TMRE for measurement of ΔΨm by the LSCM. Our data indicated that an LSCM is the most suitable instrument to detect dynamic changes in ΔΨm, whereas all three instruments can detect ΔΨm at the endpoint.

[Role of mitochondrial permeability transition pore in mediating the inhibitory effect of gastrodin on oxidative stress in cardiac myocytes in vitro].

OBJECTIVE: To explore the role of mitochondrial permeability transition pore (mPTP) in mediating the protective effect of gastrodin against oxidative stress damage in H9c2 cardiac myocytes. METHODS: H9c2 cardiac myocytes were treated with H2O2, gastrodin, gastrodin+H2O2, cyclosporin A (CsA), or CsA+gas+H2O2 group. MTT assay was used to detect the survival ratio of H9c2 cells, and flow cytometry with Annexin V-FITC/PI double staining was used to analyze the early apoptosis rate after the treatments. The concentration of ATP and level of reactive oxygen species (ROS) in the cells were detected using commercial kits. The mitochondrial membrane potential of the cells was detected with laser confocal microscopy. The expression of cytochrome C was detected with Western blotting, and the activity of caspase-3 was also assessed in the cells. RESULTS: Gastrodin pretreatment could prevent oxidative stress-induced reduction of mitochondrial membrane potential, and this effect was inhibited by the application of CsA. Gastrodin significantly lowered the levels of ROS and apoptosis-related factors in H2O2-exposed cells, and such effects were reversed by CsA. CsA significantly antagonized the protective effect of gastrodin against apoptosis in H2O2-exposed cells. CONCLUSIONS: Gastrodin prevents oxidative stress-induced injury in H9c2 cells by inhibiting mPTP opening to reduce the cell apoptosis.