Tangeretin protects human brain microvascular endothelial cells against oxygen-glucose deprivation-induced injury.

Tangeretin, a citrus flavonoid extracted from the peel of citrus fruits, was reported to possess antiasthmatic, antioxidant, anti-inflammatory, and neuroprotective properties. However, the effect of tangeretin on human brain microvascular endothelial cells (HBMECs) has not been examined. This study was designed to investigate the protective effects of tangeretin on oxygen-glucose deprivation (OGD)-induced injury of HBMECs, and explore the underlying mechanisms. Our results showed that tangeretin improved HBMECs viability in response to OGD. In addition, tangeretin was able to increase the activity of superoxide dismutase and decrease the levels of reactive oxygen species and malondialdehyde (MDA), as well as ameliorate cell apoptosis in OGD-stimulated HBMECs. Mechanistic studies showed that tangeretin prevented the activation of JNK signaling pathway in OGD-stimulated HBMECs. Taken together, our current study demonstrated that tangeretin could ameliorate OGD-induced HBMECs injury through the JNK signaling pathway. Thus, tangeretin might be used as a therapeutic strategy for ischemia-reperfusion brain injury and related diseases.

Transcutaneous electrical acupoint stimulation for post-traumatic stress disorder: Assessor-blinded, randomized controlled study.

AIM: Transcutaneous electrical acupoint stimulation (TEAS) has the potential to alleviate post-traumatic stress disorder (PTSD). The purpose of this study was to determine whether adding TEAS to sertraline or cognitive behavioral therapy (CBT) could improve the anti-PTSD efficacy. METHODS: In this randomized controlled trial, 240 PTSD patients (60 in each group) were assigned to receive simulated TEAS combined with sertraline (group A) or with CBT (group B), active TEAS combined with CBT (group C), or active TEAS combined with CBT plus sertraline (group D) for 12 weeks. The outcomes were measured using the Clinician-Administered PTSD Scale, PTSD Check List-Civilian Version, and 17-item Hamilton Rating Scale for Depression. RESULTS: While PTSD symptoms reduced over time in all patients, groups C and D had markedly greater improvement in both PTSD and depressive measures than groups A and B in all post-baseline measurement points, with moderate to very large effect sizes of 0.484-2.244. Groups C and D also had a significantly higher rate than groups A and B on clinical response (85.0% and 95.0% vs 63.3% and 60.0%, P < 0.001) and on remission (15.0% and 25.0% vs 3.3% and 1.7%, P < 0.001). The incidence of adverse events was similar between groups A and D and between groups B and C. CONCLUSIONS: Additional TEAS augments the anti-PTSD and antidepressant efficacy of antidepressants or CBT, without increasing the incidence of adverse effects. TEAS could serve as an effective intervention for PTSD and comorbid depression. This trial was registered with www.chictr.org (no.: ChiCTR1800017255).

Toll-like receptor 3 modulates the behavioral effects of cocaine in mice.

BACKGROUND: The nucleus accumbens in the midbrain dopamine limbic system plays a key role in cocaine addiction. Toll-like receptors (TLRs) are important pattern-recognition receptors (PPRs) in the innate immune system that are also involved in drug dependence; however, the detailed mechanism is largely unknown. METHODS: The present study was designed to investigate the potential role of TLR3 in cocaine addiction. Cocaine-induced conditioned place preference (CPP), locomotor activity, and self-administration were used to determine the effects of TLR3 in the rewarding properties of cocaine. Lentivirus-mediated re-expression of Tlr3 (LV-TLR3) was applied to determine if restoration of TLR3 expression in the NAc is sufficient to restore the cocaine effect in TLR3-/- mice. The protein levels of phospho-NF-κB p65, IKKß, and p-IκBα both in the cytoplasm and nucleus of cocaine-induced CPP mice were detected by Western blot. RESULTS: We showed that both TLR3 deficiency and intra-NAc injection of TLR3 inhibitors significantly attenuated cocaine-induced CPP, locomotor activity, and self-administration in mice. Importantly, the TLR3-/- mice that received intra-NAc injection of LV-TLR3 displayed significant increases in cocaine-induced CPP and locomotor activity. Finally, we found that TLR3 inhibitor reverted cocaine-induced upregulation of phospho-NF-κB p65, IKKß, and p-IκBα. CONCLUSIONS: Taken together, our results describe that TLR3 modulates cocaine-induced behaviors and provide further evidence supporting a role for central pro-inflammatory immune signaling in drug reward. We propose that TLR3 blockade could be a novel approach to treat cocaine addiction.

Arginine Methyltransferase 1 in the Nucleus Accumbens Regulates Behavioral Effects of Cocaine.

Recent evidence suggests that histone modifications play a role in the behavioral effects of cocaine in rodent models. Histone arginine is known to be methylated by protein arginine N-methyltransferases (PRMTs). Evidence shows that PRMT1 contributes to >90% of cellular PRMT activity, which regulates histone H4 arginine 3 asymmetric dimethylation (H4R3me2a). Though histone arginine methylation represents a chemical modification that is relatively stable compared with other histone alterations, it is less well studied in the setting of addiction. Here, we demonstrate that repeated noncontingent cocaine injections increase PRMT1 activity in the nucleus accumbens (NAc) of C57BL/6 mice. We, subsequently, identify a selective inhibitor of PRMT1, SKLB-639, and show that systemic injections of the drug decrease cocaine-induced conditioned place preference to levels observed with genetic knockdown of PRMT1. NAc-specific downregulation of PRMT1 leads to hypomethylation of H4R3me2a, and hypoacetylation of histone H3 lysine 9 and 14. We also found that H4R3me2a is upregulated in NAc after repeated cocaine administration, and that H4R3me2a upregulation in turn controls the expression of Cdk5 and CaMKII. Additionally, the suppression of PRMT1 in NAc with lentiviral-short hairpin PMRT1 decreases levels of CaMKII and Cdk5 in the cocaine-treated group, demonstrating that PRMT1 affects the ability of cocaine to induce CaMKII and Cdk5 in NAc. Notably, increased H4R3me2a by repeated cocaine injections is relatively long-lived, as increased expression was observed for up to 7 d after the last cocaine injection. These results show the role of PRMT1 in the behavioral effects of cocaine. SIGNIFICANCE STATEMENT: This work demonstrated that repeated cocaine injections led to an increase of protein arginine N-methyltransferase (PRMT1) in nucleus accumbens (NAc). We then identified a selective inhibitor of PRMT1 (SKLB-639), which inhibited cocaine-induced conditioned place preference (CPP). Additionally, genetic downregulation of PRMT1 in NAc also attenuated cocaine-caused CPP and locomotion activity, which was associated with decreased expression of histone H4 arginine 3 asymmetric demethylation (H4R3me2a) and hypoacetylation of histone H3 lysine 9 and 14 (acH3K9/K14). This study also showed that H4R3me2a controlled transcriptions of Cdk5 and CaMKII, and that PRMT1 negatively affected the ability of cocaine to induce CaMKII and Cdk5 in NAc. Notably, increased H4R3me2a by repeated cocaine injection was relatively long-lived as increased expression was observed up to 7 d after withdrawal from cocaine. Together, this study suggests that PRMT1 inhibition may serve as a potential therapeutic strategy for cocaine addiction.

Prenatal cocaine exposure impairs cognitive function of progeny via insulin growth factor II epigenetic regulation.

Studies have showed that prenatal cocaine exposure (PCOC) can impair cognitive function and social behavior of the offspring; however, the mechanism underlying such effect is poorly understood. Insulin-like growth factor II (Igf-II), an imprinted gene, has a critical role in memory consolidation and enhancement. We hypothesized that epigenetic regulation of hippocampal Igf-II may attribute to the cognitive deficits of PCOC offspring. We used Morris water maze and open-field task to test the cognitive function in PCOC offspring. The epigenetic alteration involved in hippocampal Igf-II expression deficit in PCOC offspring was studied by determining Igf-II methylation status, DNA methyltransferases (DNMT) expressions and L-methionine level. Moreover, IGF-II rescue experiments were performed and the downstream signalings were investigated in PCOC offspring. In behavioral tests, we observed impaired spatial learning and memory and increased anxiety in PCOC offspring; moreover, hippocampal IGF-II mRNA and protein expressions were significantly decreased. Hippocampal methylation of cytosine-phospho-guanine (CpG) dinucleotides in differentially methylated region (DMR) 2 of Igf-II was elevated in PCOC offspring, which may be driven by the upregulation of L-methionine and DNA methyltransferase (DNMT) 1. Importantly, intra-hippocampal injection of recombinant IGF-II reactivated the repressed calcium calmodulin kinase II α (CaMKIIα) and reversed cognitive deficits in PCOC offspring. Collectively, our findings suggest that cocaine exposure during pregnancy impairs cognitive function of offspring through epigenetic modification of Igf-II gene. Enhancing IGF-II signaling may represent a novel therapeutical strategy for cocaine-induced cognitive impairment.

MCP-1 and CCR2 gene polymorphisms in Parkinson's disease in a Han Chinese cohort.

Monocyte chemoattractant protein-1 (MCP-1) and its receptor CC chemokine receptor-2 (CCR2) play important roles in neuroinflammation and they have been shown to be involved in Parkinson's disease (PD) pathogenesis. In addition, several studies have suggested a role for the MCP-1 and CCR2 genotypes in cognitive impairment and depression, which are common non-motor symptoms in PD patients. In this study, a cohort of 521 PD patients and 556 cases of healthy controls were recruited to investigate the association between the MCP-1 2518A/G (rs1064211) and CCR2 V64I (rs1799864) gene polymorphisms and PD risk in the Chinese population. We also analyze the influence of these genotypes on the cognitive function and depression in PD patients by comparing Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Wechsler Adult Intelligence Scale-Chinese Revision (WAIS-RC), Wechsler Memory Scale-Chinese Revision (WMS-RC) and Hamilton Depression Rating Scale (HAMD) ratings in 217 PD patients. Our results showed no significant differences in the genotype frequency between the PD group and the control group (P > 0.05). In addition, we also failed to find an influence of the MCP-1 and CCR2 genotypes on MMSE scores, MoCA scores, WAIS-RC scores, WMS-RC scores and HAMD scores in PD patients (P > 0.05). The MCP-1 and CCR2 gene polymorphisms may not be genetic risk factors for PD in the Han Chinese population, and they do not appear to influence cognitive function and depression in PD patients.

Cerebrospinal fluid alpha-synuclein as a biomarker for Parkinson's disease diagnosis: a systematic review and meta-analysis.

To date, there are no definitive biomarkers for Parkinson's disease (PD) diagnosis. The detection of cerebrospinal fluid (CSF) alpha (α)-synuclein in PD patients has yielded promising but inconclusive results. To determine the performance of CSF α-synuclein as a diagnostic biomarker of PD and whether CSF α-synuclein can discriminate PD from other neurodegenerative diseases, a systematic search of all relevant studies investigating reproducible CSF α-synuclein quantification methods was conducted in electronic databases. A total of 17 studies that included 3311 patients were included in this systemic review and meta-analysis. The mean CSF α-synuclein concentration was significantly lower in PD patients compared to normal/neurological controls [weighted mean difference (WMD) -0.31; 95% CI, -0.45, -0.16; p < 0.0001] and patients with Alzheimer's disease (AD) [WMD -0.15; 95% CI, -0.26, -0.04; p < 0.0001]. There was no significant difference between PD patients and dementia with Lewy bodies (DLB) patients [WMD -0.03; 95% CI, -0.16, 0.09; p = 0.58] or patients with multiple system atrophy (MSA) [WMD 0.05; 95% CI, -0.04, 0.13; p = 0.25]. Sensitivity and specificity of CSF α-synuclein in the diagnosis of PD was 0.88 (95% CI, 0.84-0.91) and 0.40 (95% CI, 0.35-0.45), respectively. The positive and negative likelihood ratios of CSF α-synuclein in the diagnosis of PD were 1.41 (95% CI, 1.24-1.60), and 0.29 (95% CI, 0.15-0.56), respectively. The corresponding summary receiver operating characteristic (SROC) curve showed an area under the curve (AUC) of 0.73. The concentration of CSF α-synuclein may be a biomarker for the diagnosis of PD. The use of α-synuclein alone however is not sufficient as a single biomarker and it must therefore be used in conjunction with other documented and reliable biomarkers.

1H-Nuclear magnetic resonance-based metabolomic analysis of brain in mice with nicotine treatment.

BACKGROUND: Nicotine is rapidly absorbed from cigarette smoke and therefore induces a number of chronic illnesses with the widespread use of tobacco products. Studies have shown a few cerebral metabolites modified by nicotine; however, endogenous metabolic profiling in brain has not been well explored. RESULTS: H NMR-based on metabonomics was applied to investigate the endogenous metabolic profiling of brain hippocampus, nucleus acumens (NAc), prefrontal cortex (PFC) and striatum. We found that nicotine significantly increased CPP in mice, and some specific cerebral metabolites differentially changed in nicotine-treated mice. These modified metabolites included glutamate, acetylcholine, tryptamine, glucose, lactate, creatine, 3-hydroxybutyrate and nicotinamide-adenine dinucleotide (NAD), which was closely associated with neurotransmitter and energy source. Additionally, glutathione and taurine in hippocampus and striatum, phosphocholine in PFC and glycerol in NAc were significantly modified by nicotine, implying the dysregulation of anti-oxidative stress response and membrane metabolism. CONCLUSIONS: Nicotine induces significant metabonomic alterations in brain, which are involved in neurotransmitter disturbance, energy metabolism dysregulation, anti-oxidation and membrane function disruptions, as well as amino acid metabolism imbalance. These findings provide a new insight into rewarding effects of nicotine and the underlying mechanism.

Major depressive disorder and the risk of irritable bowel syndrome: A Mendelian randomization study.

BACKGROUND: The association between major depressive disorder (MDD) and irritable bowel syndrome (IBS) has been found in observational research; however, the causative relationship between MDD and IBS remains uncertain. Using the two-sample Mendelian randomization (MR) approach, we attempted to examine the causal effect of MDD on IBS. METHODS: Independent genetic variants for MDD identified by Howard et al. based on a genome-wide meta-analysis were selected for this study. Gene-Outcome associations for IBS were gathered from UK Biobank and FinnGen databases. The MR analysis included inverse variance weighted (IVW), MR-Egger regression, weighted median, weighted mode, and MR-PRESSO sensitivity analyses. RESULTS: FinnGen database subjected to inverse variance weighted (IVW) analysis revealed that MDD may be a risk factor for the development of IBS (OR = 1.356, 95% CI: 1.125-1.632, p = 0.0013). The same finding was reached in UK Biobank for IVW (OR = 1.011, 95% CI: 1.006-1.015, p = 3.18 × 10-7 ), MR-Egger progression (OR = 1.030, 95% CI: 1.008-1.051, p = 0.007), and weighted median (OR = 1.011, 95% CI: 1.005-1.016, p = 0.0001). CONCLUSION: Our findings supported a causal relationship between MDD and IBS, which may have implications for the clinical management of IBS in individuals with MDD.

Experimentally validated inverse design of multi-property Fe-Co-Ni alloys.

This study presents a machine learning (ML) framework aimed at accelerating the discovery of multi-property optimized Fe-Ni-Co alloys, addressing the time-consuming, expensive, and inefficient nature of traditional methods of material discovery, development, and deployment. We compiled a detailed heterogeneous database of the magnetic, electrical, and mechanical properties of Fe-Co-Ni alloys, employing a novel ML-based imputation strategy to address gaps in property data. Leveraging this comprehensive database, we developed predictive ML models using tree-based and neural network approaches for optimizing multiple properties simultaneously. An inverse design strategy, utilizing multi-objective Bayesian optimization (MOBO), enabled the identification of promising alloy compositions. This approach was experimentally validated using high-throughput methodology, highlighting alloys such as Fe66.8Co28Ni5.2 and Fe61.9Co22.8Ni15.3, which demonstrated superior properties. The predicted properties data closely matched experimental data within 14% accuracy. Our approach can be extended to a broad range of materials systems to predict novel materials with an optimized set of properties.

Disrupted inter-brain synchronization in the prefrontal cortex between adolescents and young adults with gaming disorders during the real-world cooperating video games.

BACKGROUND: Gaming disorder (GD) and hazardous gaming (HG) have a high incidence among adolescents and young adults and have caused various negative consequences. Interpersonal interaction deficits are closely related to GD and HG, however, the underlying brain mechanisms are still unclear. METHODS: The current study recruited 46 healthy subjects and 32 subjects with GD/HG. Gaming time and frequency, gaming disorder risks, life events, strengths, and difficulties were measured with scales. Subjects were randomly paired into 12 HC-HC dyads, 15 GD/HG-HC dyads, and 7 GD/HG-GD/HG dyads and in pairs completed a real-world cooperating video game - "Tied Together" with functional near-infrared spectroscopy hyperscanning recording in the prefrontal cortex. The inter-brain synchronization in each region of the PFC between dyads was calculated by wavelet to transform coherence to measure brain-to-brain synchronization. RESULTS: We found subjects with GD/HG reported higher risks of gaming. The highest IBS in the left dorsolateral prefrontal cortex significantly decreased in the GD/HG-HC and GD/HG-GD/HG dyads compared with healthy controls. A decreasing highest IBS of the left dlPFC was related to a decreasing level of peer problems. LIMITATIONS: We declare limitations of age gaps of samples, undistinguishing GD from HG, use of sub-samples, and the broad concept of interpersonal interaction. CONCLUSIONS: The current study found a decreased highest IBS in the left dlPFC among adolescents and young adults with gaming diseases. It may provide new prevention and treatment insights into gaming disorders targeting disrupted interpersonal interaction.

Predicting Synthesizability using Machine Learning on Databases of Existing Inorganic Materials.

Defining the metric for synthesizability and predicting new compounds that can be experimentally realized in the realm of data-driven research is a pressing problem in contemporary materials science. The increasing computational power and advancements in machine learning (ML) algorithms provide a new avenue to solve the synthesizability challenge. In this work, using the Inorganic Crystal Structure Database (ICSD) and the Materials Project (MP) database, we represent crystal structures in Fourier-transformed crystal properties (FTCP) representation and use a deep learning model to predict synthesizability in the form of a synthesizability score (SC). Such an SC model, as a synthesizability filter for new materials, enables an efficient and accurate classification to identify promising material candidates. The SC prediction model achieved 82.6/80.6% (precision/recall) overall accuracy in predicting ternary crystal materials. We also trained the SC model by only considering compounds uploaded on the MP before 2015 as the training set and testing on multiple sets of materials uploaded after 2015. In the post-2019 test set, we obtain a high 88.60% true positive rate accuracy, coupled with 9.81% precision, indicating that newly added materials remain unexplored and have high synthesis potential. Further, we provide a list of 100 materials predicted to be synthesizable from this post-2019 dataset (highest SC) for future studies, and our SC model, as a validation filter, is beneficial for future material screening and discovery.

The impact of irrigation modes on agricultural water-energy­carbon nexus.

Despite the tremendous contribution of irrigated agriculture in addressing global food security, there is still confusion for farmers and governments about the choice of irrigation mode owing to the drastic environmental impacts of irrigation, including water shortage, energy crisis, and global warming. Exploring the agricultural water-energy­carbon (WEC) nexus under different irrigation modes helps to accomplish the multi-objective of water & energy saving and carbon emission reduction. In this paper, a conceptual framework was nominated to evaluate the water & energy consumption and carbon emissions for winter wheat irrigation at township level and quantitatively discuss the complex interaction by the coupling coordination degree (CCD) of the WEC system under different irrigation modes in Henan Province, China. We discovered that irrigation modes profoundly affect water and energy consumption and carbon emissions in agriculture, as well as the spatial distribution of CCD from WEC system. Townships under irrigation mode with diversion and irrigation projects as the primary method (WDI) clustered together in the north and east with highest water consumption and carbon emissions, while townships under irrigation mode with rain-fed agriculture as the primary method (PI) accumulated in the west and south with lower water consumption and carbon emissions. Meanwhile, the CCD of the WEC nexus system was in basic coordination (0.40) and showed an unbalanced spatial distribution pattern with high in the southeast and low in the northwest. By comparing four irrigation modes, the coupling level of the WEC nexus system under irrigation mode with groundwater irrigation as the primary method (GI) was better and PI mode was the least ideal. This study helps to further understand agricultural WEC nexus under different irrigation modes and provide references for local governments in selecting appropriate irrigation modes to realize water-energy saving and carbon emission reduction in agricultural activities.

Decreased inter-brain synchronization in the right middle frontal cortex in alcohol use disorder during social interaction: An fNIRS hyperscanning study.

BACKGROUND: Alcohol use disorder (AUD) is a widespread mental disorder and has thrust a heavy burden on the health system all over the world. Social cognition and function are reported to be impaired in AUD, but its neural mechanism is rarely investigated. The current study attempts to fill this gap. METHODS: 28 subjects with AUD and 36 healthy controls (HC) were recruited in this study and were paired into 14 AUD dyads and 18 HC dyads. The drinking problems, depression, anxiety, and impulsivity of subjects were measured. Each dyad completed cooperation and competition tasks with simultaneous frontal functional near-infrared spectroscopy (fNIRS) hyperscanning recording. The inter-brain synchronization (IBS) in the frontal cortex was calculated for each dyad and compared between AUD and HC. The significantly altered IBS in AUD was correlated with clinical measures to explore possible influencing factors. RESULTS: The IBS in the right middle frontal cortex was significantly decreased in AUD under both cooperation (t = -2.257, P = 0.028) and competition (t = -2.488, P = 0.016) task. The IBS during the cooperation task in the right middle frontal cortex in AUD was negatively correlated with non-planning impulsivity (r = -0.673, P = 0.006). LIMITATIONS: This study used cross-sectional data, which limited the causal inference. The synchronization between other brain regions besides the frontal cortex should be further explored in patients with AUD. CONCLUSION: The current study could provide new insights into the neural mechanism of social dysfunction in AUD and facilitate clinical intervention in future practice.

Transcriptome analysis of long non-coding RNAs of the nucleus accumbens in cocaine-conditioned mice.

Cocaine dependence involves in the brain's reward circuit as well as nucleus accumbens (NAc), a key region of the mesolimbic dopamine pathway. Many studies have documented altered expression of genes and identified transcription factor networks and epigenetic processes that are fundamental to cocaine addiction. However, all these investigations have focused on mRNA of encoding genes, which may not always reflect the involvement of long non-coding RNAs (lncRNAs), which has been implied in a broad range of biological processes and complex diseases including brain development and neuropathological process. To explore the potential involvement of lncRNAs in drug addiction, which is viewed as a form of aberrant neuroplasticity, we used a custom-designed microarray to examine the expression profiles of mRNAs and lncRNAs in brain NAc of cocaine-conditioned mice and identified 764 mRNAs, and 603 lncRNAs were differentially expressed. Candidate lncRNAs were identified for further genomic context characterization as sense-overlap, antisense-overlap, intergenic, bidirection, and ultra-conserved region encoding lncRNAs. We found that 410 candidate lncRNAs which have been reported to act in cis or trans to their targeted loci, providing 48 pair mRNA-lncRNAs. These results suggest that the modification of mRNAs expression by cocaine may be associated with the actions of lncRNAs. Taken together, our results show that cocaine can cause the genome-wide alterations of lncRNAs expressed in NAc, and some of these modified RNA transcripts may to play a role in cocaine-induced neural plasticity and addiction.

(1) H-nuclear magnetic resonance-based metabonomic analysis of brain in rhesus monkeys with morphine treatment and withdrawal intervention.

Comprehensive cerebral metabolites involved in morphine dependence have not been well explored. To gain a better understanding of morphine dependence and withdrawal therapy in a model highly related to humans, metabolic changes in brain hippocampus and prefrontal cortex (PFC) of rhesus monkeys were measured by (1) H-nuclear magnetic resonance spectroscopy, coupled with partial least squares and orthogonal signal correction analysis. The results showed that concentrations of myoinositol (M-Ins) and taurine were significantly reduced, whereas lactic acid was increased in hippocampus and PFC of morphine-dependent monkeys. Phosphocholine and creatine increased in PFC but decreased in hippocampus after chronic treatment of morphine. Moreover, N-acetyl aspartate (NAA), γ-aminobutyric acid, glutamate, glutathione, methionine, and homocysteic acid also changed in these brain regions. These results suggest that chronic morphine exposure causes profound disturbances of neurotransmitters, membrane, and energy metabolism in the brain. Notably, morphine-induced dysregulations in NAA, creatine, lactic acid, taurine, M-Ins, and phosphocholine were clearly reversed after intervention with methadone or clonidine. Our study highlights the potential of metabolic profiling to enhance our understanding of metabolite alteration and neurobiological actions associated with morphine addiction and withdrawal therapy in primates.

Taurine protects methamphetamine-induced developmental angiogenesis defect through antioxidant mechanism.

Investigations have characterized addictive drug-induced developmental cardiovascular malformation in human, non-human primate and rodent. However, the underlying mechanism of malformation caused by drugs during pregnancy is still largely unknown, and preventive and therapeutic measures have been lacking. Using 1H NMR spectroscopy, we profiled the metabolites from human embryo endothelial cells exposed to methamphetamine (METH) and quantified a total of 226 peaks. We identified 11 metabolites modified robustly and found that taurine markedly increased. We then validated the hypothesis that this dramatic increase in taurine could attribute to its effect in inhibiting METH-induced developmental angiogenesis defect. Taurine supplement showed a more significant potential than other metabolites in protecting against METH-induced injury in endothelial cells. Taurine strongly attenuated METH-induced inhibition of proliferation and migration in endothelial cells. Furthermore, death rate and vessel abnormality of zebrafish embryos treated with METH were greatly reversed by taurine. In addition, taurine supplement caused a rapid decrease in reactive oxygen species generation and strongly attenuated the excitable arise of antioxidase activities in the beginning of METH exposure prophase. Dysregulations of NF-κB, p-ERK as well as Bax, which reflect apoptosis, cell cycle arrest and oxidative stress in vascular endothelium, were blocked by taurine. Our results provide the first evidence that taurine prevents METH-caused developmental angiogenesis defect through antioxidant mechanism. Taurine could serve as a potential therapeutic or preventive intervention of developmental vascular malformation for the pregnant women with drug use.

Scoparone protects neuronal cells from oxygen glucose deprivation/reoxygenation injury.

Ischemic stroke is one of the leading causes of death and disability in the world. The cerebral ischemia/reperfusion (I/R) injury is considered as the major molecular mechanism in the pathogenesis of ischemic stroke. Scoparone, a major constituent of Artemisia capillaries, has been found to exhibit protective effects against I/R-induced myocardial injury. However, the role of scoparone in cerebral I/R injury has not been elucidated. In the current study, the hippocampal neurons were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) to simulate I/R injury in vitro. The results showed that scoparone improved OGD/R-induced inhibitory effect on cell viability of hippocampal neurons. Scoparone displayed anti-oxidative activity as proved by the decreased levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and increased activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in OGD/R-induced hippocampal neurons. In addition, cell apoptosis was markedly decreased after scoparone treatment in OGD/R-induced hippocampal neurons. The expression of bax was significantly decreased, while bcl-2 expression was increased in the scoparone pretreated hippocampal neurons. Furthermore, the expressions of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were obviously induced by scoparone. Knockdown of Nrf2 by siRNA transfection dramatically attenuated the protective effects of scoparone on OGD/R-induced hippocampal neurons. Collectively, scoparone protected hippocampal neurons from OGD/R-induced injury via activating Nrf2/HO-1 signaling pathway, suggesting that scoparone might be a potential agent for the ischemic stroke therapy.

Hippocampal damage and white matter lesions contribute to cognitive impairment in MPTP-lesioned mice with chronic cerebral hypoperfusion.

OBJECTIVES: Strong evidence has proven that cerebral hypoperfusion is closely related to Parkinson's disease (PD) with cognitive impairment. The aim of this study was to investigate the effect of chronic cerebral hypoperfusion (CCH) on cognitive dysfunction, structural abnormalities of the hippocampus and white matter (WM), and levels of inflammatory cytokines in control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse models. METHODS: In the present study, bilateral common carotid artery stenosis (BCCAS) was performed using microcoils, and the cognitive function and WM lesions (WMLs) after BCCAS were compared between microcoil with 0.18 mm and 0.20 mm diameters. CCH and MPTP-lesioned mice were induced by intraperitoneal injection of MPTP and BCCAS. These mice were further divided into seven groups: a control group, sham-operated group, BCCAS group, PD with normal cognition (PDCN) group, PD with mild cognitive impairment (PDMCI) group, PDCN + BCCAS group, and PDMCI + BCCAS group. After 28 days of BCCAS, the mice were tested through pole-climbing experiments and by TUNEL, Nissl, and Bielschowsky silver staining. Immunohistochemistry was used to evaluate lesions in the dopaminergic (DAergic) nigrostriatal system and the number of activated microglia. Chip-based liquid chromatography was employed to measure the levels of inflammatory cytokines in the plasma. RESULTS: The results indicated that the histological results of the 0.18 mm microcoil were superior to that of the 0.20 mm microcoil. Based on these finding, BCCAS impaired the climbing ability of MPTP-lesioned PD mice. Moreover, immunohistochemistry for tyrosine hydroxylase (TH) revealed a significant reduction in the number of DAergic neurons in the substantia nigra of PD mice following BCCAS, particularly in the PDMCI + BCCAS group. In addition, Nissl, TUNEL and Bielschowsky silver staining confirmed decreased hippocampal neuron numbers, increased neuronal apoptosis and more significant WM fiber damage in the corpus callosum of the PDMCI + BCCAS group. Finally,immunohistochemistry for ionized calcium binding adaptor molecule-1 (Iba-1) and chip-based liquid chromatography revealed significantly increased microglial activation (P < 0.01) and significantly increased levels of interleukin-1ß (IL-1ß) and interferon-γ (IFN-γ) (P < 0.05) in the PDMCI + BCCAS group compared with the corresponding levels in the PDCN + BCCAS group. CONCLUSIONS: Cerebral hypoperfusion can aggravate the cognitive impairment in MPTP-lesioned PD mice. This finding may be related to the hypoperfusion-mediated deterioration of neuroinflammation, aggravation of WM damage, and induction of hippocampal neuron apoptosis in PD mice.

Brain Renin-Angiotensin System Blockade Attenuates Methamphetamine-Induced Hyperlocomotion and Neurotoxicity.

Methamphetamine (METH) abuse has become a major public health concern worldwide without approved pharmacotherapies. The brain renin-angiotensin system (RAS) is involved in the regulation of neuronal function as well as neurological disorders. Angiotensin II (Ang II), which interacts with Ang II type 1 receptor (AT1-R) in the brain, plays an important role as a neuromodulator in dopaminergic transmission. However, the role of brain RAS in METH-induced behavior is largely unknown. Here, we revealed that repeated METH administration significantly upregulated the expression of AT1-R in the striatum of mice, but downregulated dopamine D3 receptor (D3R) expression. A specific AT1-R blocker telmisartan, which can penetrate the brain-blood barrier (BBB), or genetic deletion of AT1-R was sufficient to attenuate METH-triggered hyperlocomotion in mice. However, intraperitoneal injection of AT1-R blocker losartan, which cannot penetrate BBB, failed to attenuate METH-induced behavior. Moreover, intra-striatum re-expression of AT1 with lentiviral virus expressing AT1 reversed the weakened locomotor activity of AT1-/- mice treated with METH. Losartan alleviated METH-induced cytotoxicity in SH-SY5Y cells in vitro, which was accompanied by upregulated expressions of D3R and dopamine transporter. In addition, intraperitoneal injection of perindopril, which is a specific ACE inhibitor and can penetrate BBB, significantly attenuated METH-induced hyperlocomotor activity. Collectively, our results show that blockade of brain RAS attenuates METH-induced hyperlocomotion and neurotoxicity possibly through modulation of D3R expression. Our findings reveal a novel role of Ang II-AT1-R in METH-induced hyperlocomotion.