Selective vulnerability of hippocampal sub-regions in patients with subcortical vascular mild cognitive impairment.

Early diagnosis of subcortical vascular mild cognitive impairment (svMCI) is clinically essential because it is the most reversible subtype of all cognitive impairments. Since structural alterations of hippocampal sub-regions have been well studied in neurodegenerative diseases with pathophysiological cognitive impairments, we were eager to determine whether there is a selective vulnerability of hippocampal sub-fields in patients with svMCI. Our study included 34 svMCI patients and 34 normal controls (NCs), with analysis of T1 images and Montreal Cognitive Assessment (MoCA) scores. Gray matter volume (GMV) of hippocampal sub-regions was quantified and compared between the groups, adjusting for age, sex, and education. Additionally, we explored correlations between altered GMV in hippocampal sub-fields and MoCA scores in svMCI patients. Patients with svMCI exhibited selectively reduced GMV in several left hippocampal sub-regions, such as the hippocampal tail, hippocampal fissure, CA1 head, ML-HP head, CA4 head, and CA3 head, as well as decreased GMV in the right hippocampal tail. Specifically, GMV in the left CA3 head was inversely correlated with MoCA scores in svMCI patients. Our findings indicate that the atrophy pattern of patients with svMCI was predominantly located in the left hippocampal sub-regions. The left CA3 might be a crucial area underlying the distinct pathophysiological mechanisms of cognitive impairments with subcortical vascular origins.

Adjunctive continuous theta burst stimulation for major depressive disorder or bipolar depression: A meta-analysis of randomized controlled studies.

OBJECTIVES: As a novel type of theta burst stimulation (TBS), continuous TBS (cTBS) has been shown to have mixed therapeutic effects for major depressive disorder (MDD) or bipolar depression (BD). Thus, we performed a meta-analysis of randomized controlled trials (RCTs) of cTBS for treating major depressive episodes in patients with MDD or BD. METHODS: A systematic search of four major bibliographic databases (PubMed, EMBASE, Cochrane Library, and PsycINFO) was conducted from inception dates to February 3, 2023 to identify eligible studies. The data were analyzed using a random-effects model. RESULTS: Three RCTs (n = 78, active cTBS = 37 and sham cTBS = 41) were included the meta-analysis. No significant differences were found in terms of change in Hamilton Depression Rating Scale (HAMD) scores (3 RCTs, n = 78, SMD = -0.09, 95 % CI: -0.53 to 0.36; I2 = 0 %; P = 0.71) and study-defined response (2 RCTs, n = 58, 26.7 % versus 21.4 %, RR = 1.20, 95 % CI: 0.48 to 2.96; I2 = 0 %; P = 0.70) between active and sham cTBS groups. Similarly, no group differences were found in the rates of adverse events and discontinuation due to any reason (P > 0.05). LIMITATIONS: Meta-analysis had small sample sizes and low number of included studies. CONCLUSIONS: Although cTBS appeared to be a safe and well-tolerated option for treating major depressive episodes in MDD or BD patients, no advantage in treatment effects was found in this meta-analysis. Future large-scale studies are warranted to assess the efficacy of cTBS for MDD or BD patients with a major depressive episode.

Blocking Pannexin-1 Channels Alleviates Thalamic Hemorrhage-Induced Pain and Inflammatory Depolarization of Microglia in Mice.

Central post-stroke pain (CPSP) is a neuropathic pain syndrome that frequently occurs following cerebral stroke. The pathogenesis of CPSP is mainly due to thalamic injury caused by ischemia and hemorrhage. However, its underlying mechanism is far from clear. In the present study, a thalamic hemorrhage (TH) model was established in young male mice by microinjection of 0.075 U of type IV collagenase into the unilateral ventral posterior lateral nucleus and ventral posterior medial nucleus of the thalamus. We found that TH led to microglial pannexin (Panx)-1, a large-pore ion channel, opening within the thalamus accompanied with thalamic tissue injury, pain sensitivities, and neurological deficit, which were significantly prevented by either intraperitoneal injection of the Panx1 blocker carbenoxolone or intracerebroventricular perfusion of the inhibitory mimetic peptide 10Panx. However, inhibition of Panx1 has no additive effect on pain sensitivities upon pharmacological depletion of microglia. Mechanistically, we found that carbenoxolone alleviated TH-induced proinflammatory factors transcription, neuronal apoptosis, and neurite disassembly within the thalamus. In summary, we conclude that blocking of microglial Panx1 channels alleviates CPSP and neurological deficit through, at least in part, reducing neural damage mediated by the inflammatory response of thalamic microglia after TH. Targeting Panx1 might be a potential strategy in the treatment of CPSP.

Accelerated intermittent theta burst stimulation for major depressive disorder or bipolar depression: A systematic review and meta-analysis.

We aimed to systematically evaluate the clinical efficacy and safety of accelerated intermittent theta burst stimulation (aiTBS) for patients with major depressive disorder (MDD) or bipolar depression (BD). A random-effects model was adopted to analyze the primary and secondary outcomes using the Review Manager, Version 5.3 software. This meta-analysis (MA) identified five double-blind randomized controlled trials (RCTs) comprising 239 MDD or BD patients with a major depressive episode. Active aiTBS overperformed sham stimulation in the study-defined response. This MA found preliminary evidence that active aiTBS resulted in a greater response in treating major depressive episodes in MDD or BD patients than sham stimulation.

Comparison of Efficacy and Safety of Magnetic Seizure Therapy and Electroconvulsive Therapy for Depression: A Systematic Review.

OBJECTIVES: As a new physical therapeutic technique, magnetic seizure therapy (MST) has established efficacy in the treatment of depression with few cognitive side effects, and thus appears to be a potential alternative to electroconvulsive therapy (ECT). The findings of randomized controlled trials (RCTs) examining the efficacy and safety of MST versus ECT for depression are inconsistent. This systematic review of RCTs was designed with the aim of assessing the safety and efficacy of MST versus ECT for patients with depression. METHODS: The WanFang, Chinese Journal Net (CNKI), EMBASE, PubMed, Cochrane Library, and PsycINFO databases were systematically searched by three independent investigators, from their inceptions to July 24, 2021. RESULTS: In total, four RCTs (n = 86) were included and analyzed. Meta-analyses of study-defined response (risk ratio (RR) = 1.36; 95% CI = 0.78 to 2.36; p = 0.28; I2 = 0%), study-defined remission (RR = 1.17; 95% CI = 0.61 to 2.23; p = 0.64; I2 = 0%), and the improvement in depressive symptoms (standardized mean difference (SMD) = 0.21; 95% CI = -0.29 to 0.71; p = 0.42; I2 = 0%) did not present significant differences between MST and ECT. Three RCTs evaluated the cognitive effects of MST compared with ECT using different cognitive measuring tools, but with mixed findings. Only two RCTs reported adverse drug reactions (ADRs), but these lacked specific data. Only one RCT reported discontinuation due to any reason. CONCLUSIONS: This preliminary study suggests that MST appears to have a similar antidepressant effect as ECT for depression, but mixed findings on adverse cognitive effects were reported.

Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke.

Ischemic stroke can cause blood-brain barrier (BBB) injury, which worsens brain damage induced by stroke. Abnormal expression of tight junction proteins in endothelial cells (ECs) can increase intracellular space and BBB leakage. Selective inhibition of mitogen-activated protein kinase, the negative regulatory substrate of mitogen-activated protein kinase phosphatase (MKP)-1, improves tight junction protein function in ECs, and genetic deletion of MKP-1 aggravates ischemic brain injury. However, whether the latter affects BBB integrity, and the cell type-specific mechanism underlying this process, remain unclear. In this study, we established an adult male mouse model of ischemic stroke by occluding the middle cerebral artery for 60 minutes and overexpressed MKP-1 in ECs on the injured side via lentiviral transfection before stroke. We found that overexpression of MKP-1 in ECs reduced infarct volume, reduced the level of inflammatory factors interleukin-1ß, interleukin-6, and chemokine C-C motif ligand-2, inhibited vascular injury, and promoted the recovery of sensorimotor and memory/cognitive function. Overexpression of MKP-1 in ECs also inhibited the activation of cerebral ischemia-induced extracellular signal-regulated kinase (ERK) 1/2 and the downregulation of occludin expression. Finally, to investigate the mechanism by which MKP-1 exerted these functions in ECs, we established an ischemic stroke model in vitro by depriving the primary endothelial cell of oxygen and glucose, and pharmacologically inhibited the activity of MKP-1 and ERK1/2. Our findings suggest that MKP-1 inhibition aggravates oxygen and glucose deprivation-induced cell death, cell monolayer leakage, and downregulation of occludin expression, and that inhibiting ERK1/2 can reverse these effects. In addition, co-inhibition of MKP-1 and ERK1/2 exhibited similar effects to inhibition of ERK1/2. These findings suggest that overexpression of MKP-1 in ECs can prevent ischemia-induced occludin downregulation and cell death via deactivating ERK1/2, thereby protecting the integrity of BBB, alleviating brain injury, and improving post-stroke prognosis.

Have one's view of the important overshadowed by the trivial: chronic progressive external ophthalmoplegia combined with unilateral facial nerve injury: a case report and literature review.

Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial encephalomyopathy that is characterized by progressive ptosis and impaired ocular motility. Owing to its nonspecific clinical manifestations, CPEO is often misdiagnosed as other conditions. Herein, we present the case of a 34-year-old woman who primarily presented with incomplete left eyelid closure and limited bilateral eye movements. During the 6-year disease course, she was diagnosed with myasthenia gravis and cranial polyneuritis. Finally, skeletal muscle tissue biopsy confirmed the diagnosis. Biopsy revealed pathological changes in mitochondrial myopathy. Furthermore, mitochondrial gene testing of the skeletal muscle revealed a single chrmM:8469-13447 deletion. In addition, we summarized the findings of 26 patients with CPEO/Kearns-Sayre syndrome who were misdiagnosed with other diseases owing to ocular symptoms. In conclusion, we reported a rare clinical case and emphasized the symptomatic diversity of CPEO. Furthermore, we provided a brief review of the diagnosis and differential diagnosis of the disease.

Constructing a competitive endogenous RNA network of EndMT-related atherosclerosis through weighted gene co-expression network analysis.

Atherosclerosis is a chronic inflammatory disease characterized by endothelial dysfunction and plaque formation. Under pro-inflammatory conditions, endothelial cells can undergo endothelial-to-mesenchymal transition (EndMT), contributing to atherosclerosis development. However, the specific regulatory mechanisms by which EndMT contributes to atherosclerosis remain unclear and require further investigation. Dan-Shen-Yin (DSY), a traditional Chinese herbal formula, is commonly used for cardiovascular diseases, but its molecular mechanisms remain elusive. Emerging evidence indicates that competing endogenous RNA (ceRNA) networks play critical roles in atherosclerosis pathogenesis. In this study, we constructed an EndMT-associated ceRNA network during atherosclerosis progression by integrating gene expression profiles from the Gene Expression Omnibus (GEO) database and weighted gene co-expression network analysis. Functional enrichment analysis revealed this EndMT-related ceRNA network is predominantly involved in inflammatory responses. ROC curve analysis showed the identified hub genes can effectively distinguish between normal vasculature and atherosclerotic lesions. Furthermore, Kaplan-Meier analysis demonstrated that high expression of IL1B significantly predicts ischemic events in atherosclerosis. Molecular docking revealed most DSY bioactive components can bind key EndMT-related lncRNAs, including AC003092.1, MIR181A1HG, MIR155HG, WEE2-AS1, and MIR137HG, suggesting DSY may mitigate EndMT in atherosclerosis by modulating the ceRNA network.

Autoimmune antibodies in first-episode psychosis with red flags: A hospital-based case-control study protocol.

Background: Research is increasingly identifying an overlap between psychosis and immunological dysregulation. Certain autoantibodies are being identified in a small but probably relevant subgroup of patients with psychosis. The term "autoimmune psychosis" (AIP) and its corresponding red-flag signs present the opportunity for a new field in psychiatry to promote diagnostic workup and immunomodulating therapy in individual cases. Objectives: The present protocol aims to determine the seroprevalence of autoantibodies in first-episode psychosis (FEPs) using AIP red flag signs, and to explore the frequency of autoantibody subtypes and potential mediating confounders. Methods/design: This is a hospital-based case-control study. All participants will be consecutively selected from the main tertiary psychiatric hospital in Shenzhen City, China. Individuals admitted to the psychiatric ward and diagnosed with FEPs will be enrolled. Based on recent consensus, participants with red flags of AIPs will be defined as cases, while the remainder will be matched as controls. Seropositive antibodies will be detected and verified in cerebrospinal fluid (CSF) samples based on the fixed cell-based assay (CBA) method. The propensity score-adjusted odds ratios will be determined to investigate the key mediating confounders regarding autoantibody subtypes and red flag subsets. Discussion: The results of this study will facilitate the early identification of AIPs in FEP patients using the red flag sign and help identify key mediators that improve the accuracy of diagnostic algorithms. It will have clinical significance to focus on serum antibodies that have been verified in CSF samples, due to its consistency with clinical practices in current psychiatry.

Lateralized brain activities in subcortical vascular mild cognitive impairment with differential Chinese medicine patterns: A resting-state functional magnetic resonance imaging study.

Background: Subcortical vascular mild cognitive impairment (svMCI) is one of the most treatable cognitive impairments, but could be hampered by the high clinical heterogeneities. Further classification by Chinese Medicine (CM) patterns has been proved to stratify its clinical heterogeneities. It remains largely unknown of the spontaneous brain activities regarding deficiency patterns (DPs) and excess patterns (EPs) of svMCI patients based on fMRI data. Objective: We aim to provide neuroimaging evidence of altered resting-state brain activities associated with DPs and EPs in svMCI patients. Methods: Thirty-seven svMCI patients (PAs) and 23 healthy controls (CNs) were consecutively enrolled. All patients were categorized into either the EP group (n = 16) and the DP group (n = 21) based on a quantitative CM scale. The fractional amplitude of low-frequency fluctuation (fALFF) value was used to make comparisons between different subgroups. Results: The DP group showed significant differences of fALFF values in the right middle frontal gyrus and the right cerebellum, while the EP group showed significant differences in the left orbitofrontal gyrus and the left cerebellum, when compared with the CN group. When compared with the EP group, the DP group had markedly increased fALFF values in the left superior temporal gyrus, right middle temporal gyrus and brainstem. The decreased fALFF values was shown in the right anterior cingulate and paracingulate gyri. Among the extensive areas of frontotemporal lobe, the Montreal Cognitive Assessment (MoCA) scores were significantly correlated with the reduced fALFF value of the right middle frontal gyrus and the left orbitofrontal gyrus. Conclusion: Our results indicated that the DPs and EPs presented the lateralization pattern in the bilateral frontal gyrus, which will probably benefit the future investigation of the pathogenesis of svMCI patients.

Network pharmacology and experimental analysis to reveal the mechanism of Dan-Shen-Yin against endothelial to mesenchymal transition in atherosclerosis.

Atherosclerosis is a chronic inflammatory disease characterized by the formation of plaque and endothelial dysfunction. Under pro-inflammatory conditions, endothelial cells adopt a mesenchymal phenotype by a process called endothelial-to-mesenchymal transition (EndMT) which plays an important role in the pathogenesis of atherosclerosis. Dan-Shen-Yin (DSY) is a well-known traditional Chinese medicine used in the treatment of cardiovascular disease. However, the molecular mechanism whereby DSY mitigates atherosclerosis remains unknown. Therefore, we employed a network pharmacology-based strategy in this study to determine the therapeutic targets of DSY, and in vitro experiments to understand the molecular pharmacology mechanism. The targets of the active ingredients of DSY related to EndMT and atherosclerosis were obtained and used to construct a protein-protein interaction (PPI) network followed by network topology and functional enrichment analysis. Network pharmacology analysis revealed that the PI3K/AKT pathway was the principal signaling pathway of DSY against EndMT in atherosclerosis. Molecular docking simulations indicated strong binding capabilities of DSY's bioactive ingredients toward PI3K/AKT pathway molecules. Experimentally, DSY could efficiently modify expression of signature EndMT genes and decrease expression of PI3K/AKT pathway signals including integrin αV, integrin ß1, PI3K, and AKT1 in TGF-ß2-treated HUVECs. LASP1, which is upstream of the PI3K/AKT pathway, had strong binding affinity to the majority of DSY's bioactive ingredients, was induced by EndMT-promoting stimuli involving IL-1ß, TGF-ß2, and hypoxia, and was downregulated by DSY. Knock-down of LASP1 attenuated the expression of integrin αV, integrin ß1, PI3K, AKT1 and EndMT-related genes induced by TGF-ß2, and minimized the effect of DSY. Thus, our study showed that DSY potentially exerted anti-EndMT activity through the LASP1/PI3K/AKT pathway, providing a possible new therapeutic intervention for atherosclerosis.

Hydroxysafflor Yellow A Alleviates Ischemic Stroke in Rats via HIF-1[Formula: see text], BNIP3, and Notch1-Mediated Inhibition of Autophagy.

Stroke has become a major cause of death and disability worldwide. The cellular recycling pathway autophagy has been implicated in ischemia-induced neuronal changes, but whether autophagy plays a beneficial or detrimental role is controversial. Hydroxysafflor Yellow A (HSYA), a popular herbal medicine, is an extract of Carthamus tinctorius and is used to treat ischemic stroke (IS) in China. HSYA has been shown to prevent cardiovascular and cerebral ischemia/reperfusion injury in animal models. However, the specific active ingredients and molecular mechanisms of HSYA in IS remain unclear. Here, we investigated the effect of HSYA treatment on autophagy in a rat model of IS. IS was induced in rats by middle cerebral artery occlusion. Rats were treated once daily for 3 days with saline, HYSA, or the neuroprotective agent Edaravone. Neurobehavioral testing was performed on days 1, 2, and 3 post-surgery. Brains were removed on day 3 post-surgery for histological evaluation of infarct area, morphology, and for qRT-PCR and western blot analysis of the expression of the autophagy factor LC3 and the signaling molecules HIF-1[Formula: see text], BNIP3, and Notch1. Molecular docking studies were performed in silico to predict potential interactions between HSYA and LC3, HIF-1[Formula: see text], BNIP3, and Notch1 proteins. The result showed that HSYA treatment markedly alleviated IS-induced neurobehavioral deficits and reduced brain infarct area and tissue damage. HSYA also significantly reduced hippocampal expression levels of LC3, HIF-1[Formula: see text], BNIP3, and Notch1. The beneficial effect of HSYA was generally superior to that of Edaravone. Molecular modeling suggested that HSYA may bind strongly to HIF-1[Formula: see text], BNIP3, and Notch1 but weakly to LC3. In conclusion, HSYA inhibits post-IS autophagy induction in the brain, possibly by suppressing HIF-1[Formula: see text], BNIP3 and Notch1. HSYA may have utility as a post-IS neuroprotective agent.

Systematic analysis of the mechanism of hydroxysafflor yellow A for treating ischemic stroke based on network pharmacology technology.

In this study, we analyzed the mechanism of hydroxysafflor yellow A (HSYA) for treating ischemic stroke (IS) based on network pharmacology tools, and verified the kernel targets via animal experiments. The targets of HSYA were collected via PharmMapper server and the IS-related targets were searched using Genecards, Online Mendelian Inheritance in Man, Therapeutic Target, and Disgenet databases. The targets identified from the above two steps were overlapped to acquire candidate targets involved in the effects of HSYA for treating IS. Subsequently, the Database for Annotation, Visualization, and Integrated Discovery was used for gene ontology analysis and the Kyoto encyclopedia of genes and genomes pathway analysis. Cytoscape 3.7.1 was applied to establish the component-target-pathway network. Potential core targets were obtained by protein-protein interaction analysis. Furthermore, Autodock Vina was used to identify core genes, and animal experiments was used to verify the expression level of core genes. On the basis of the modified neurologic severity score and the results of 2,3,5-Triphenyltetrazolium chloride and Hematoxylin-eosin staining, we confirmed that HSYA reduced the infarct volume in rats and protected neuronal cells in the hippocampal region after IS. Western blot and immunohistochemical staining showed that HSYA increased the expression of epidermal growth factor receptor, hypoxia inducible factor 1 alpha, and endothelial nitric oxide synthase (P < 0.05). The effects of HSYA on IS are mediated through several targets and pathways related to the regulation of oxidative stress and the renewal of cell and blood vessels while improving post-ischemic brain impairment.

Anti-apoptotic efficacy of Qingnao Yizhi formula in hypoxia/reoxygenation primary cortical neurons through the promotion of synaptic plasticity by modulating the NogoA-Nogo receptor/Rho-Rho kinase signaling pathway.

OBJECTIVE: To evaluate the anti-apoptotic efficacy of Qingnao Yizhi formula (，QNYZ) in cultured cerebral cortical neuronal cells (CNCs) and the regulation of the NogoA-Nogo receptor (NgR)/Rho-Rho kinase (ROCK) signaling pathway. METHODS: Primary cultured CNCs were randomly divided into the following groups: normal control group (N-C), hypoxia-reoxygenation group (H/R), high-dose QNYZ group (Q-H), low-dose QNYZ group (Q-L) butylphthalide (NBP) group, and Y-27632 (a selective ROCK transduction pathway inhibiter) group. Except those in the N-C group, CNCs were placed in hypoxic conditions for 24 h and then in reoxygenation conditions for 24 h. Cell media was changed every 48 h, and various assays were performed on the 7th day. Cell viability was evaluated by measuring mitochondrial dehydrogenase activity, using a CCK-8 assay, in triplicate. Synapsin (SYN) protein concentrations were evaluated by enzyme-linked immunosorbent assay. NogoA and RhoA protein expression were evaluated through Western blotting. The gene expression of NogoA, NgR, RhoA, and ROCK was evaluated by reverse transcription-polymerase chain reaction. Cell apoptosis was measured using a terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling assay. RESULTS: Compared with the N-C group, the cell viability of the H/R group decreased significantly (P < 0.05). The cell viability values for the Q-H and Q-L groups increased compared with that for the H/R group, and the difference was significant for the Q-H group (P < 0.05). The NogoA and RhoA protein levels and the NogoA, NgR, RhoA, and ROCK mRNA expression levels increased in the H/R group, compared with the N-C group, and decreased significantly in the Q-H and Q-L groups (P < 0.05) and in the Y-27632 group (P < 0.05) compared with the H/R group. The SYN levels in the Q-H, Q-L, and NBP groups significantly increased compared with that in the H/R group (P < 0.05). Compared with the H/R group, the numbers of apoptotic cells in the Q-H, Q-L, and NBP groups significantly decreased (P < 0.05). CONCLUSION: The presented study demonstrated that QNYZ exerted anti-apoptotic effects on H/R-induced CNCs, possibly through the modulation of the NogoA-NgR/Rho-ROCK signaling pathway and the promotion of synaptic plasticity in H/R CNCs.

Hydroxysafflor Yellow A Exerts Anti-Inflammatory Effects Mediated by SIRT1 in Lipopolysaccharide-Induced Microglia Activation.

Abnormal microglia activation causes sever neuroinflammation, contributing to the development of many diseases, yet the mechanism remains incompletely unknown. In current study, we identified that Hydroxysafflor yellow A (HYA), a chalcone glycoside derived from Carthamus tinctorius L effectively attenuates LPS-induced inflammation response in primary microglia via regulating the expression of inflammatory genes and remodeling the polarization of microglia. We also reported the effects of HYA on improving lipopolysaccharide (LPS)-stimulated mitochondrial dysfunction and oxidative stress for the first time. Interestingly, we found that HYA could serves as an effective SIRT1 activator. Deficiency of SIRT1 abrogates the protective effects of HYA against LPS-induced response. Overall, our data suggest HYA, a novel SIRT1 activator, could serve as an effective approach to treat LPS-induced neurodegenerative diseases.

Astragalus polysaccharide alleviates cognitive impairment and ß-amyloid accumulation in APP/PS1 mice via Nrf2 pathway.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, and its etiology and pathogenesis are not fully understood. Astragalus polysaccharide (APS) has many pharmacological activities, but there are few reports about its role in AD. Using the common AD model APP/PS1 mice, it was found that the expression of Keap1 (a negative regulatory factor of Nrf2), the protein level of cytoplasmic Nrf2 and the content of MDA were increased significantly, while the mRNA level of Nrf2, the expression of Nrf2 in nucleus and the contents of SOD and GSH-Px were decreased significantly. APS treatment significantly increased the expression of Nrf2 in the nucleus but decreased its expression in the cytoplasm, and restored the expression levels of Keap1, SOD, GSH-Px and MDA. When APP/PS1 mice were treated with APS and injected with Nrf2 siRNA, the down-regulation of Nrf2 expression significantly blocked the regulation of APS on oxidative stress. Continuing to test the physiological function of AD mice showed that the spatial learning and memory abilities of APP/PS1 mice were impaired, the apoptosis of brain cells and the content of ß-amyloid (Aß) were significantly increased. APS treatment significantly improved the cognitive ability of APP/PS1 mice, reduced apoptosis and the accumulation of Aß, but the above effects of APS were blocked by Nrf2 siRNA injection. Therefore, APS can activate Nrf2 pathway to improve the physiological function of AD mice, which may have important clinical application value.

Neuroprotective Effects of Dexmedetomidine Preconditioning on Oxygen-glucose Deprivation-reoxygenation Injury in PC12 Cells via Regulation of Ca2+-STIM1/Orai1 Signaling.

Dexmedetomidine (DEX), a potent and highly selective agonist for α2-adrenergic receptors (α2AR), exerts neuroprotective effects by reducing apoptosis through decreased neuronal Ca2+ influx. However, the exact action mechanism of DEX and its effects on oxygen-glucose deprivation-reoxygenation (OGD/R) injury in vitro are unknown. We demonstrate that DEX pretreatment reduced OGD/R injury in PC12 cells, as evidenced by decreased oxidative stress, autophagy, and neuronal apoptosis. Specifically, DEX pretreatment decreased the expression levels of stromal interaction molecule 1 (STIM1) and calcium release-activated calcium channel protein 1 (Orai1), and reduced the concentration of intracellular calcium pools. In addition, variations in cytosolic calcium concentration altered apoptosis rate of PC12 cells after exposure to hypoxic conditions, which were modulated through STIM1/Orai1 signaling. Moreover, DEX pretreatment decreased the expression levels of Beclin-1 and microtubule-associated protein 1A/1B-light chain 3 (LC3), hallmark markers of autophagy, and the formation of autophagosomes. In conclusion, these results suggested that DEX exerts neuroprotective effects against oxidative stress, autophagy, and neuronal apoptosis after OGD/R injury via modulation of Ca2+-STIM1/Orai1 signaling. Our results offer insights into the molecular mechanisms of DEX in protecting against neuronal ischemia-reperfusion injury.

Neuroprotective effects of 1-O-hexyl-2,3,5-trimethylhydroquinone on ischaemia/reperfusion-induced neuronal injury by activating the Nrf2/HO-1 pathway.

1-O-Hexyl-2,3,5-trimethylhydroquinone (HTHQ), a lipophilic phenolic agent, has an antioxidant activity and reactive oxygen species (ROS) scavenging property. However, the role of HTHQ on cerebral ischaemic/reperfusion (I/R) injury and the underlying mechanisms remain poorly understood. In the present study, we demonstrated that HTHQ treatment ameliorated cerebral I/R injury in vivo, as demonstrated by the decreased infarct volume ration, neurological deficits, oxidative stress and neuronal apoptosis. HTHQ treatment increased the levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant protein, haeme oxygenase-1 (HO-1). In addition, HTHQ treatment decreases oxidative stress and neuronal apoptosis of PC12 cells following hypoxia and reperfusion (H/R) in vitro. Moreover, we provided evidence that PC12 cells were more vulnerable to H/R-induced oxidative stress after si-Nrf2 transfection, and the HTHQ-mediated protection was lost in PC12 cells transfected with siNrf2. In conclusion, these results suggested that HTHQ possesses neuroprotective effects against oxidative stress and apoptosis after cerebral I/R injury via activation of the Nrf2/HO-1 pathway.

A network pharmacology approach to investigate the mechanism of Shuxuening injection in the treatment of ischemic stroke.

ETHNOPHARMACOLOGICAL RELEVANCE: Shuxuening injection (SXNI), a popular herbal medicine, is an extract of Ginkgo biloba leaves (GBE), and is used to treat ischemic stroke (IS) in China. However, its specific active ingredients and molecular mechanisms in IS remain unclear. AIM OF THE STUDY: The purpose of the research is to identify the main active ingredients in GBE and explore its molecular mechanisms in the treatment of IS. MATERIALS AND METHODS: The main active components of GBE were discerned through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis (TCMSP), Traditional Chinese Medicine Integrated Database (TCMID), Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM) database, and absorption, distribution, metabolism and excretion (ADME) analysis. The targets related to IS were obtained using Genecards, Online Mendelian Inheritance in Man (OMIM), Therapeutic Target Database (TTD), and Disgenet. We discovered an intersection of genes. Subsequently, protein-protein interaction (PPI) networks were constructed with Cytoscape 3.7.1 and the String database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to analyze the intersection of targets via the Database for Annotation, Visualization, and Integrated Discovery (DAVID) 6.8. Built on the above analysis, we made a Compound-Target-Pathway (C-T-P) network. Autodock Vina was used for molecular docking analysis. Maestro 11.9 was used to calculate the root-mean-square deviation (RMSD). Animal experiments were performed to verify the core targets. Triphenyl tetrazolium chloride (TTC) staining was used to calculate the infarct volume in rats. Hematoxylin-eosin (HE) staining was employed to observe the morphology of hippocampal neuron cells. RT-qPCR was applied to detect relative mRNA levels, and protein expression was determined using Western blotting. RESULTS: Molecular docking showed that PTGS2, NOS3 and CASP3 docked with small molecule compounds. According to RT-qPCR and Western blotting, mRNA and protein expression of PTGS2 and CASP3 were up-regulated (P < 0.05), and mRNA and protein levels of NOS3 were down-regulated (P < 0.05). CONCLUSIONS: SXNI can treat IS through multiple targets and routes, and reduce the apoptosis of neuron cells in brain tissue by inhibiting inflammation and regulating the level of oxidative stress, thereby protecting rats brain tissue.

[Effect of "Yinqi Guiyuan" needling on primary insomnia].

OBJECTIVE: To observe the clinical effect of "Yinqi Guiyuan" needling in the treatment of primary insomnia. METHODS: A total of 79 primary insomnia outpatients were randomly divided into treatment group (n=40) and control group (n=39). The patients in the control group were given oral Estazolam tablets once a day, for successive 4 weeks. For patients of the treatment group, Zhongwan (CV12), Xiawan (CV10), Qihai (CV6), Guanyuan (CV4), Baihui (GV20), etc., were punctured with filiform needles for 30 min. The treatment was conducted three times per week for 4 successive weeks. The sleep quality (sleeping quality, falling asleep time, sleep duration, sleep efficiency, sleep disorders, hypnotic and daytime dysfunction, 0 to 21 points) was evaluated by using Pittsburgh Sleep Quality Index (PSQI). The severity of insomnia (self-perception, sleep satisfaction, daytime function damage, sensibility change, and concern for sleep problems, 0 to 28 points) was assessed using insomnia severity index (ISI) score. The therapeutic effect was evaluated according to the PSQI score reduction rate = (pre-treatment PSQI score-post-treatment PSQI score)/pre-treatment PSQI score ×100%. RESULTS: After treatment, the total score of PSQI, ISI and the score of each item were all significantly reduced in the two groups relevant to their own pre-treatment (P<0.05). The total score, and scores of hypnotic and daytime dysfunction were significantly lower in the treatment group than in the control group (P<0.05). Of the 40 and 39 cases in the treatment and control groups, 5 (12.50%) and 4 (10.25%) were cured, 20 (50.00%) and 18 (46.15%) experienced marked improvement, 12 (30.00%) and 13 (33.33%) were effective, and 3 (7.50%) and 4 (10.25%) ineffective, with the total effective rate being 92.50% and 89.74%, respectively. No significant difference was found between the two groups in the effective rate (P>0.05). CONCLUSION: "Yinqi Guiyuan" needling and Estazolam are comparable in treatment primary insomnia, and the former is superior to the latter in avoiding hypnotic drug use and in improving daytime function.