The role and possible mechanism of the ferroptosis-related SLC7A11/GSH/GPX4 pathway in myocardial ischemia-reperfusion injury.

BACKGROUND: Myocardial ischemia-reperfusion injury (MI/RI) is an unavoidable risk event for acute myocardial infarction, with ferroptosis showing close involvement. We investigated the mechanism of MI/RI inducing myocardial injury by inhibiting the ferroptosis-related SLC7A11/glutathione (GSH)/glutathione peroxidase 4 (GPX4) pathway and activating mitophagy. METHODS: A rat MI/RI model was established, with myocardial infarction area and injury assessed by TTC and H&E staining. Rat cardiomyocytes H9C2 were cultured in vitro, followed by hypoxia/reoxygenation (H/R) modeling and the ferroptosis inhibitor lipoxstatin-1 (Lip-1) treatment, or 3-Methyladenine or rapamycin treatment and overexpression plasmid (oe-SLC7A11) transfection during modeling. Cell viability and death were evaluated by CCK-8 and LDH assays. Mitochondrial morphology was observed by transmission electron microscopy. Mitochondrial membrane potential was detected by fluorescence dye JC-1. Levels of inflammatory factors, reactive oxygen species (ROS), Fe2+, malondialdehyde, lipid peroxidation, GPX4 enzyme activity, glutathione reductase, GSH and glutathione disulfide, and SLC7A11, GPX4, LC3II/I and p62 proteins were determined by ELISA kit, related indicator detection kits and Western blot. RESULTS: The ferroptosis-related SLC7A11/GSH/GPX4 pathway was repressed in MI/RI rat myocardial tissues, inducing myocardial injury. H/R affected GSH synthesis and inhibited GPX4 enzyme activity by down-regulating SLC7A11, thus promoting ferroptosis in cardiomyocytes, which was averted by Lip-1. SLC7A11 overexpression improved H/R-induced cardiomyocyte ferroptosis via the GSH/GPX4 pathway. H/R activated mitophagy in cardiomyocytes. Mitophagy inhibition reversed H/R-induced cellular ferroptosis. Mitophagy activation partially averted SLC7A11 overexpression-improved H/R-induced cardiomyocyte ferroptosis. H/R suppressed the ferroptosis-related SLC7A11/GSH/GPX4 pathway by inducing mitophagy, leading to cardiomyocyte injury. CONCLUSIONS: Increased ROS under H/R conditions triggered cardiomyocyte injury by inducing mitophagy to suppress the ferroptosis-related SLC7A11/GSH/GPX4 signaling pathway activation.

Spatiotemporal dynamics of functional connectivity and association with molecular architecture in schizophrenia.

Schizophrenia is a self-disorder characterized by disrupted brain dynamics and architectures of multiple molecules. This study aims to explore spatiotemporal dynamics and its association with psychiatric symptoms. Resting-state functional magnetic resonance imaging data were collected from 98 patients with schizophrenia. Brain dynamics included the temporal and spatial variations in functional connectivity density and association with symptom scores were evaluated. Moreover, the spatial association between dynamics and receptors/transporters according to prior molecular imaging in healthy subjects was examined. Patients demonstrated decreased temporal variation and increased spatial variation in perceptual and attentional systems. However, increased temporal variation and decreased spatial variation were revealed in higher order networks and subcortical networks in patients. Specifically, spatial variation in perceptual and attentional systems was associated with symptom severity. Moreover, case-control differences were associated with dopamine, serotonin and mu-opioid receptor densities, serotonin reuptake transporter density, dopamine transporter density, and dopamine synthesis capacity. Therefore, this study implicates the abnormal dynamic interactions between the perceptual system and cortical core networks; in addition, the subcortical regions play a role in the dynamic interaction among the cortical regions in schizophrenia. These convergent findings support the importance of brain dynamics and emphasize the contribution of primary information processing to the pathological mechanism underlying schizophrenia.

Progressive trajectories of schizophrenia across symptoms, genes, and the brain.

BACKGROUND: Schizophrenia is characterized by complex psychiatric symptoms and unclear pathological mechanisms. Most previous studies have focused on the morphological changes that occur over the development of the disease; however, the corresponding functional trajectories remain unclear. In the present study, we aimed to explore the progressive trajectories of patterns of dysfunction after diagnosis. METHODS: Eighty-six patients with schizophrenia and 120 healthy controls were recruited as the discovery dataset. Based on multiple functional indicators of resting-state brain functional magnetic resonance imaging, we conducted a duration-sliding dynamic analysis framework to investigate trajectories in association with disease progression. Neuroimaging findings were associated with clinical symptoms and gene expression data from the Allen Human Brain Atlas database. A replication cohort of patients with schizophrenia from the University of California, Los Angeles, was used as the replication dataset for the validation analysis. RESULTS: Five stage-specific phenotypes were identified. A symptom trajectory was characterized by positive-dominated, negative ascendant, negative-dominated, positive ascendant, and negative surpassed stages. Dysfunctional trajectories from primary and subcortical regions to higher-order cortices were recognized; these are associated with abnormal external sensory gating and a disrupted internal excitation-inhibition equilibrium. From stage 1 to stage 5, the importance of neuroimaging features associated with behaviors gradually shifted from primary to higher-order cortices and subcortical regions. Genetic enrichment analysis identified that neurodevelopmental and neurodegenerative factors may be relevant as schizophrenia progresses and highlighted multiple synaptic systems. CONCLUSIONS: Our convergent results indicate that progressive symptoms and functional neuroimaging phenotypes are associated with genetic factors in schizophrenia. Furthermore, the identification of functional trajectories complements previous findings of structural abnormalities and provides potential targets for drug and non-drug interventions in different stages of schizophrenia.

Compressed sensorimotor-to-transmodal hierarchical organization in schizophrenia.

BACKGROUND: Schizophrenia has been primarily conceptualized as a disorder of high-order cognitive functions with deficits in executive brain regions. Yet due to the increasing reports of early sensory processing deficit, recent models focus more on the developmental effects of impaired sensory process on high-order functions. The present study examined whether this pathological interaction relates to an overarching system-level imbalance, specifically a disruption in macroscale hierarchy affecting integration and segregation of unimodal and transmodal networks. METHODS: We applied a novel combination of connectome gradient and stepwise connectivity analysis to resting-state fMRI to characterize the sensorimotor-to-transmodal cortical hierarchy organization (96 patients v. 122 controls). RESULTS: We demonstrated compression of the cortical hierarchy organization in schizophrenia, with a prominent compression from the sensorimotor region and a less prominent compression from the frontal-parietal region, resulting in a diminished separation between sensory and fronto-parietal cognitive systems. Further analyses suggested reduced differentiation related to atypical functional connectome transition from unimodal to transmodal brain areas. Specifically, we found hypo-connectivity within unimodal regions and hyper-connectivity between unimodal regions and fronto-parietal and ventral attention regions along the classical sensation-to-cognition continuum (voxel-level corrected, p < 0.05). CONCLUSIONS: The compression of cortical hierarchy organization represents a novel and integrative system-level substrate underlying the pathological interaction of early sensory and cognitive function in schizophrenia. This abnormal cortical hierarchy organization suggests cascading impairments from the disruption of the somatosensory-motor system and inefficient integration of bottom-up sensory information with attentional demands and executive control processes partially account for high-level cognitive deficits characteristic of schizophrenia.

Characteristics of disrupted topological organization in white matter functional connectome in schizophrenia.

BACKGROUND: Neuroimaging characteristics have demonstrated disrupted functional organization in schizophrenia (SZ), involving large-scale networks within grey matter (GM). However, previous studies have ignored the role of white matter (WM) in supporting brain function. METHODS: Using resting-state functional MRI and graph theoretical approaches, we investigated global topological disruptions of large-scale WM and GM networks in 93 SZ patients and 122 controls. Six global properties [clustering coefficient (Cp), shortest path length (Lp), local efficiency (Eloc), small-worldness (σ), hierarchy (ß) and synchronization (S) and three nodal metrics [nodal degree (Knodal), nodal efficiency (Enodal) and nodal betweenness (Bnodal)] were utilized to quantify the topological organization in both WM and GM networks. RESULTS: At the network level, both WM and GM networks exhibited reductions in Eloc, Cp and S in SZ. The SZ group showed reduced σ and ß only for the WM network. Furthermore, the Cp, Eloc and S of the WM network were negatively correlated with negative symptoms in SZ. At the nodal level, the SZ showed nodal disturbances in the corpus callosum, optic radiation, posterior corona radiata and tempo-occipital WM tracts. For GM, the SZ manifested increased nodal centralities in frontoparietal regions and decreased nodal centralities in temporal regions. CONCLUSIONS: These findings provide the first evidence for abnormal global topological properties in SZ from the perspective of a substantial whole brain, including GM and WM. Nodal centralities enhance GM areas, along with a reduction in adjacent WM, suggest that WM functional alterations may be compensated for adjacent GM impairments in SZ.

Function-structure coupling: White matter functional magnetic resonance imaging hyper-activation associates with structural integrity reductions in schizophrenia.

White matter (WM) microstructure deficit may be an underlying factor in the brain dysconnectivity hypothesis of schizophrenia using diffusion tensor imaging (DTI). However, WM dysfunction is unclear in schizophrenia. This study aimed to investigate the association between structural deficits and functional disturbances in major WM tracts in schizophrenia. Using functional magnetic resonance imaging (fMRI) and DTI, we developed the skeleton-based WM functional analysis, which could achieve voxel-wise function-structure coupling by projecting the fMRI signals onto a skeleton in WM. We measured the fractional anisotropy (FA) and WM low-frequency oscillation (LFO) and their couplings in 93 schizophrenia patients and 122 healthy controls (HCs). An independent open database (62 schizophrenia patients and 71 HCs) was used to test the reproducibility. Finally, associations between WM LFO and five behaviour assessment categories (cognition, emotion, motor, personality and sensory) were examined. This study revealed a reversed pattern of structure and function in frontotemporal tracts, as follows. (a) WM hyper-LFO was associated with reduced FA in schizophrenia. (b) The function-structure association was positive in HCs but negative in schizophrenia patients. Furthermore, function-structure dissociation was exacerbated by long illness duration and severe negative symptoms. (c) WM activations were significantly related to cognition and emotion. This study indicated function-structure dys-coupling, with higher LFO and reduced structural integration in frontotemporal WM, which may reflect a potential mechanism in WM neuropathologic processing of schizophrenia.

Reconfiguration of Dynamic Functional Connectivity in Sensory and Perceptual System in Schizophrenia.

Schizophrenia is thought as a self-disorder with dysfunctional brain connectivity. This self-disorder is often attributed to high-order cognitive impairment. Yet due to the frequent report of sensorial and perceptual deficits, it has been hypothesized that self-disorder in schizophrenia is dysfunctional communication between sensory and cognitive processes. To further verify this assumption, the present study comprehensively examined dynamic reconfigurations of resting-state functional connectivity (rsFC) in schizophrenia at voxel level, region level, and network levels (102 patients vs. 124 controls). We found patients who show consistently increased rsFC variability in sensory and perceptual system, including visual network, sensorimotor network, attention network, and thalamus at all the three levels. However, decreased variability in high-order networks, such as default mode network and frontal-parietal network were only consistently observed at region and network levels. Taken together, these findings highlighted the rudimentary role of elevated instability of information communication in sensory and perceptual system and attenuated whole-brain integration of high-order network in schizophrenia, which provided novel neural evidence to support the hypothesis of disrupted perceptual and cognitive function in schizophrenia. The foci of effects also highlighted that targeting perceptual deficits can be regarded as the key to enhance our understanding of pathophysiology in schizophrenia and promote new treatment intervention.

White-matter functional networks changes in patients with schizophrenia.

Resting-state functional MRI (rsfMRI) is a useful technique for investigating the functional organization of human gray-matter in neuroscience and neuropsychiatry. Nevertheless, most studies have demonstrated the functional connectivity and/or task-related functional activity in the gray-matter. White-matter functional networks have been investigated in healthy subjects. Schizophrenia has been hypothesized to be a brain disorder involving insufficient or ineffective communication associated with white-matter abnormalities. However, previous studies have mainly examined the structural architecture of white-matter using MRI or diffusion tensor imaging and failed to uncover any dysfunctional connectivity within the white-matter on rsfMRI. The current study used rsfMRI to evaluate white-matter functional connectivity in a large cohort of ninety-seven schizophrenia patients and 126 healthy controls. Ten large-scale white-matter networks were identified by a cluster analysis of voxel-based white-matter functional connectivity and classified into superficial, middle and deep layers of networks. Evaluation of the spontaneous oscillation of white-matter networks and the functional connectivity between them showed that patients with schizophrenia had decreased amplitudes of low-frequency oscillation and increased functional connectivity in the superficial perception-motor networks. Additionally, we examined the interactions between white-matter and gray-matter networks. The superficial perception-motor white-matter network had decreased functional connectivity with the cortical perception-motor gray-matter networks. In contrast, the middle and deep white-matter networks had increased functional connectivity with the superficial perception-motor white-matter network and the cortical perception-motor gray-matter network. Thus, we presumed that the disrupted association between the gray-matter and white-matter networks in the perception-motor system may be compensated for through the middle-deep white-matter networks, which may be the foundation of the extensively disrupted connections in schizophrenia.

Reduction in gray matter of cerebellum in schizophrenia and its influence on static and dynamic connectivity.

Pathophysiological and atrophic changes in the cerebellum have been well-documented in schizophrenia. Reduction of gray matter (GM) in the cerebellum was confirmed across cognitive and motor cerebellar modules in schizophrenia. Such abnormalities in the cerebellum could potentially have widespread effects on both sensorimotor and cognitive symptoms. In this study, we investigated how reduction change in the cerebellum affects the static and the dynamic functional connectivity (FC) between the cerebellum and cortical/subcortical networks in schizophrenia. Reduction of GM in the cerebellum was confirmed across the cognitive and motor cerebellar modules in schizophrenic subjects. Results from this study demonstrates that the extent of reduction of GM within cerebellum correlated with increased static FCs between the cerebellum and the cortical/subcortical networks, including frontoparietal network (FPN), and thalamus in patients with schizophrenia. Decreased GM in the cerebellum was also associated with a declined dynamic FC between the cerebellum and the FPN in schizophrenic subjects. The severity of patients' positive symptom was related to these structural-functional coupling score of cerebellum. These findings identified potential cerebellar driven functional changes associated with positive symptom deficits. A post hoc analysis exploring the effect of changed FC within cerebellum, confirmed that a significant positive relationship, between dynamic FCs of cerebellum-thalamus and intracerebellum existed in patients, but not in controls. The reduction of GM within the cerebellum might be associated with modulation of cerebellum-thalamus, and contributes to the dysfunctional cerebellar-cortical communication in schizophrenia. Our results provide a new insight into the role of cerebellum in understanding the pathophysiological of schizophrenia.

Relaxin mitigates microvascular damage and inflammation following cardiac ischemia-reperfusion.

Microvascular obstruction (MVO) and leakage (MVL) forms a pivotal part of microvascular damage following cardiac ischemia-reperfusion (IR). We tested the effect of relaxin therapy on MVO and MVL in mice following cardiac IR injury including severity of MVO and MVL, opening capillaries, infarct size, regional inflammation, cardiac function and remodelling, and permeability of cultured endothelial monolayer. Compared to vehicle group, relaxin treatment (50 µg/kg) reduced no-reflow area by 38% and the content of Evans blue as a permeability tracer by 56% in jeopardized myocardium (both P < 0.05), effects associated with increased opening capillaries. Relaxin also decreased leukocyte density, gene expression of cytokines, and mitigated IR-induced decrease in protein content of VE-cadherin and relaxin receptor. Infarct size was comparable between the two groups. At 2 weeks post-IR, relaxin treatment partially preserved cardiac contractile function and limited chamber dilatation versus untreated controls by echocardiography. Endothelial cell permeability assay demonstrated that relaxin attenuated leakage induced by hypoxia-reoxygenation, H2O2, or cytokines, action that was independent of nitric oxide but associated with the preservation of VE-cadherin. In conclusion, relaxin therapy attenuates IR-induced MVO and MVL and endothelial leakage. This protection was associated with reduced regional inflammatory responses and consequently led to alleviated adverse cardiac remodeling.

Evaluation of functional connectivity in subdivisions of the thalamus in schizophrenia.

BACKGROUND: Previous studies in schizophrenia revealed abnormalities in the cortico-cerebellar-thalamo-cortical circuit (CCTCC) pathway, suggesting the necessity for defining thalamic subdivisions in understanding alterations of brain connectivity.AimsTo parcellate the thalamus into several subdivisions using a data-driven method, and to evaluate the role of each subdivision in the alterations of CCTCC functional connectivity in patients with schizophrenia. METHOD: There were 54 patients with schizophrenia and 42 healthy controls included in this study. First, the thalamic structural and functional connections computed, based on diffusion magnetic resonance imaging (MRI, white matter tractography) and resting-state functional MRI, were clustered to parcellate thalamus. Next, functional connectivity of each thalamus subdivision was investigated, and the alterations in thalamic functional connectivity for patients with schizophrenia were inspected. RESULTS: Based on the data-driven parcellation method, six thalamic subdivisions were defined. Loss of connectivity was observed between several thalamic subdivisions (superior-anterior, ventromedial and dorsolateral part of the thalamus) and the sensorimotor system, anterior cingulate cortex and cerebellum in patients with schizophrenia. A gradual pattern of dysconnectivity was observed across the thalamic subdivisions. Additionally, the altered connectivity negatively correlated with symptom scores and duration of illness in individuals with schizophrenia. CONCLUSIONS: The findings of the study revealed a wide range of thalamic functional dysconnectivity in the CCTCC pathway, increasing our understanding of the relationship between the CCTCC pathway and symptoms associated with schizophrenia, and further indicating a potential alteration pattern in the thalamic nuclei in people with schizophrenia.Declaration of interestNone.

Brain grey-matter volume alteration in adult patients with bipolar disorder under different conditions: a voxel-based meta-analysis

Background: The literature on grey-matter volume alterations in bipolar disorder is heterogeneous in its findings. Methods: Using effect-size differential mapping, we conducted a meta-analysis of grey-matter volume alterations in patients with bipolar disorder compared with healthy controls. Results: We analyzed data from 50 studies that included 1843 patients with bipolar disorder and 2289 controls. Findings revealed lower grey-matter volumes in the bilateral superior frontal gyri, left anterior cingulate cortex and right insula in patients with bipolar disorder and in patients with bipolar disorder type I. Patients with bipolar disorder in the euthymic and depressive phases had spatially distinct regions of altered grey-matter volume. Meta-regression revealed that the proportion of female patients with bipolar disorder or bipolar disorder type I was negatively correlated with regional grey-matter alteration in the right insula; the proportion of patients with bipolar disorder or bipolar disorder type I taking lithium was positively correlated with regional grey-matter alterations in the left anterior cingulate/paracingulate gyri; and the proportion of patients taking antipsychotic medications was negatively correlated with alterations in the anterior cingulate/paracingulate gyri. Limitations: This study was cross-sectional; analysis techniques, patient characteristics and clinical variables in the included studies were heterogeneous. Conclusion: Structural grey-matter abnormalities in patients with bipolar disorder and bipolar disorder type I were mainly in the prefrontal cortex and insula. Patients' mood state might affect grey-matter alterations. Abnormalities in regional grey-matter volume could be correlated with patients' specific demographic and clinical features.

Gray matter bases of psychotic features in adult bipolar disorder: A systematic review and voxel-based meta-analysis of neuroimaging studies.

Psychotic bipolar disorder (P-BD) is a specific subset that presents greater risk of relapse and worse outcomes than nonpsychotic bipolar disorder (NP-BD). To explore the neuroanatomical bases of psychotic dimension in bipolar disorder (BD), a systematic review was carried out based on the gray matter volume (GMV) among P-BD and NP-BD patients and healthy controls (HC). Further, we conducted a meta-analysis of GMV differences between P-BD patients and HC using a whole-brain imaging approach. Our review revealed that P-BD patients exhibited smaller GMVs mainly in the prefronto-temporal and cingulate cortices, the precentral gyrus, and insula relative to HC both qualitatively and quantitatively. Qualitatively the comparison between P-BD and NP-BD patients suggested inconsistent GMV alterations mainly involving the prefrontal cortex, while NP-BD patients showed GMV deficits in local regions compared with HC. The higher proportions of female patients and patients taking psychotropic medication in P-BD and P-BD type I were associated with smaller GMV in the right precentral gyrus, and the right insula, respectively. In conclusions, psychosis in BD might be associated with specific cortical GMV deficits. Gender and psychotropic medication might have effects on the regional GMVs in P-BD patients. It is necessary to distinguish psychotic dimension in neuroimaging studies of BD.

Progressive Reduction in Gray Matter in Patients with Schizophrenia Assessed with MR Imaging by Using Causal Network Analysis.

Purpose To investigate the temporal and causal relationships of structural changes in the brain in patients with schizophrenia. Materials and Methods T1-weighted magnetic resonance (MR) images of 97 patients with schizophrenia (29 women; mean ± standard deviation age, 41 years ± 11.5; range, 16-66 years; illness duration, 16.3 years ± 10.9; range, 0-50 years) and 126 age- and sex-matched (38 years ± 14.9; range, 18-68 years; 42 women) healthy control subjects were evaluated. The causal network of structural covariance was used to assess the causal relationships of structural changes in patients with schizophrenia. This was accomplished by applying Granger causality analysis to the morphometric T1-weighted images ranked according to duration of disease. Results With greater disease duration, reduction in gray matter volume began in the thalamus and progressed to the frontal lobe, and then to the temporal and occipital cortices as well and the cerebellum (P < .00001, false discovery rate corrected). The thalamus was shown to be the primary hub of the directional network and exhibited positive causal effects on the frontal, temporal, and occipital regions as well as on the cerebellum (P < .05, false discovery rate corrected). The frontal regions, which were identified to be transitional points, projected causal effects to the occipital lobe, temporal regions, and the cerebellum and received causal effects from the thalamus (P < .05, false discovery rate corrected). Conclusion Schizophrenia shows progression of gray matter abnormalities over time, with the thalamus as the primary hub and the frontal regions as prominent nodes. © RSNA, 2018 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on March 5, 2018.

The Effects of Music Intervention on Functional Connectivity Strength of the Brain in Schizophrenia.

Schizophrenia is often associated with behavior abnormality in the cognitive and affective domain. Music intervention is used as a complementary treatment for improving symptoms in patients with schizophrenia. However, the neurophysiological correlates of these remissions remain poorly understood. Here, we investigated the effects of music intervention in neural circuits through functional magnetic resonance imaging (fMRI) study in schizophrenic subjects. Under the standard care, patients were randomly assigned to music and non-music interventions (MTSZ, UMTSZ) for 1 month. Resting-state fMRI were acquired over three time points (baseline, 1 month, and 6 months later) in patients and analyzed using functional connectivity strength (FCS) and seed-based functional connection (FC) approaches. At baseline, compared with healthy controls, decreased FCS in the right middle temporal gyrus (MTG) was observed in patients. However, after music intervention, the functional circuitry of the right MTG, which was related with the function of emotion and sensorimotor, was improved in MTSZ. Furthermore, the FC increments were significantly correlated with the improvement of symptoms, while vanishing 6 months later. Together, these findings provided evidence that music intervention might positively modulate the functional connectivity of MTG in patients with schizophrenia; such changes might be associated with the observed therapeutic effects of music intervention on neurocognitive function. This trial is registered with ChiCTR-OPC-14005339.

[Degree centrality of the functional network in schizophrenia patients].

The aim of the present study was to investigate the alternations of brain functional networks at resting state in the schizophrenia (SCH) patients using voxel-wise degree centrality (DC) method. The resting-state functional magnetic resonance imaging (rfMRI) data were collected from 41 SCH patients and 41 matched healthy control subjects and then analyzed by voxel-wise DC method. The DC maps between the patient group and the control group were compared using by two sample t test. The correlation analysis was also performed between DC values and clinical symptom and illness duration in SCH group. Results showed that compared with the control group, SCH patients exhibited significantly decreased DC value in primary sensorimotor network, and increased DC value in executive control network. In addition, DC value of the regions with obvious differences between the two groups significantly correlated to Positive and Negative Syndrome Scale (PANSS) scores and illness duration of SCH patients. The study showed the abnormal functional integration in primary sensorimotor network and executive control network in SCH patients.

Adiponectin improves NF-κB-mediated inflammation and abates atherosclerosis progression in apolipoprotein E-deficient mice.

BACKGROUND: Atherosclerosis is a common pathological basis of cardiovascular disease. Adiponectin (APN) has been shown to have an anti-atherosclerosis effect, and the underlying mechanisms, however, are largely unknown. Nuclear factor κB (NF-κB) has also been regarded as a proatherogenic factor, mainly because of its regulation of a variety of the proinflammatory genes linked to atherosclerosis. It was hypothesized that the inhibitory effects of adiponectin on the atherosclerosis is through the inhibition of NF-κB signaling pathway. METHODS: We injected adenovirus of Ad-eGFP virus (control group) or the same amount of Ad-APN-eGFP virus (APN group) in ApoE(-/-) mice tail-intravenously. Blood samples and aorta were executed at 0 day, 4, and 8 week of high-fat diet feeding. Histopathological changes of aortic arch root were detected. Levels of TC, TG, HDL-C, LDL-C were measured. Adiponectin and Matrix metalloproteinases-9 (MMP-9) concentration were detected by enzyme-linked immunosorbent assay. Gene and protein levels of adiponectin, eNOS, IL-6, MCP-1,VCAM-1, and other inflammatory factors were determined. Adiponectin, NF-κB p65 in aortic arch root were determined by immunofluorescence and western blot. RESULTS: Transduction of Ad-APN inhibited the formation of atherosclerotic plaque in aorta when compared with control group. The lesion formation in aortic arch root was inhibited significantly (P < 0.01). Lesion lumen ratio decreased significantly (P < 0.001). The expression of adiponectin attenuated the increases of serum TC (P < 0.001), TG (P < 0.001), and LDL-C (P < 0.001) induced by the high-fat diet, and the increase in body weight (P < 0.05). As increasing serum adiponectin, the levels of MMP-9 were significantly decreased (P < 0.05). The exogenous adiponectin increased the gene expression of the anti-inflammatory factors eNOS (P < 0.05) and IL-10 (P < 0.001), and reduced the gene expression of inflammatory factors tumor necrosis factor-α (TNF-α) (P < 0.001), IL-6 (P < 0.001), VCAM-1 (P < 0.05), respectively. Adiponectin effectively inhibited the activation of NF-κB pathway and the expression of NF-κB nuclear protein p65. CONCLUSIONS: Adiponectin may protect the aorta from atherosclerotic injury by reducing inflammation. The molecular mechanism may involve inhibited the expression of downstream components of NF-κB and its transcription factors.

Adiponectin abates atherosclerosis by reducing oxidative stress.

BACKGROUND: We investigated whether the anti-atherosclerosis of adiponectin (APN) relates to the reduction of oxidative stress. We observed the overexpression of adiponectin gene with different titers on atherosclerosis (AS) models of high-fat apolipoprotein E-deficient (ApoE-/-) mice. MATERIAL AND METHODS: We divided 48 male ApoE-/- mice into 4 groups: control group, high-fat diet group, low adiponectin group, and high adiponectin group. The low and high adiponectin group mice were treated with recombinant adenovirus expressing mice adiponectin (Ad-APN) with low-dose adiponectin 1.0×108 p.f.u. and high-dose adiponectin 5.0×108 p.f.u. via the tail every 2 weeks and given a high-fat diet for the last 8 weeks. On the 14th day after injection, blood samples were obtained from the vena cava. RESULTS: Along with increased serum adiponectin, serum superoxide dismutase (SOD) activity increased (P<0.05) and concentration of malondialdehyde (MDA) was decreased (P<0.05). Levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) were decreased, especially TC and LDL-C (P<0.05). A real-time fluorescent quantitative polymerase chain reaction test was used to analyze levels of mRNA expression for endothelial nitric oxide synthase (eNOS) and adiponectin in the aorta. Along with increased adiponectin, the mRNA expression of eNOS in the aorta was increased significantly (P<0.05). The lesion formation in the aortic sinus was inhibited by 25% and 31% in the low-APN group and high-APN group, respectively (P<0.05). Along with the increase of adiponectin doses, the damage of atherosclerosis gradually eased. However, the differences between the low-APN group and high-APN group had no statistical significance. CONCLUSIONS: Adiponectin may protect the aorta from atherosclerosis injury by reducing oxidative stress, reducing lesion formation size in the aortic root and reducing TC, TG, and LDL-C in serum. The molecular mechanism may involve preservation of SOD, reducing MDA in serum, and increasing eNOS and adiponectin mRNA expression in the aorta.

Deficient salience and default mode functional integration in high worry-proneness subject: a connectome-wide association study.

Worry has been conceptualized as a relatively uncontrollable chain of thought that increases the risk of mental problems, such as anxiety disorders. Here, we examined the link between individual variation in the functional connectome and worry proneness, which remains unclear. A total of 32 high worry-proneness (HWP) subjects and 25 low worry-proneness (LWP) subjects were recruited. We conducted multivariate distance-based matrix regression to identify phenotypic relationships in high-dimensional brain resting-state functional connectivity data from HWP subjects. Multiple hub regions, including key brain nodes of the salience network (SN) and default mode network (DMN), were identified in HWP subjects. Follow-up analyses revealed that a high worry-proneness score was dominated by functional connectivity between the SN and the DMN. Moreover, HWP subjects showed hypoconnectivity between the cerebellum and the SN and DMN compared with LWP subjects. This cross-sectional study could not fully measure the causal relationships between changes in functional networks and worry proneness in healthy subjects. Functional changes in the cerebellum-cortical region might affect the modulation of external stimuli processing. Together, our results provide new insight into the role of key networks, including the SN, DMN and cerebellum, in understanding the potential mechanism underlying the high worry dimension in healthy subjects.

Relationship Between Excessive Daytime Sleepiness and Caudate Nucleus Volume in Patients with Subjective Cognitive Decline: A Study from the SILCODE Using the Volbrain.

Background: Excessive daytime sleepiness (EDS) and caudate nucleus volume alterations have been linked to Alzheimer's disease (AD), but their relationship remains unclear under the context of subjective cognitive decline (SCD). Objective: This study aimed to investigate the relationship between EDS and caudate nucleus volume in patients with SCD. Methods: The volume of entire brain was measured in 170 patients with SCD, including 37 patients with EDS and 133 non-EDS, from the Sino Longitudinal Study on Cognitive Decline (SILCODE). Participants underwent a comprehensive assessment battery, including neuropsychological and clinical evaluations, blood tests, genetic analysis for APOE ɛ4, and structural MRI scans analyzed using the fully automated segmentation tool, volBrain. Results: Patients with EDS had significantly increased volume in the total and left caudate nucleus compared to non-EDS. The most significant cognitive behavioral factor associated with caudate nucleus volume in the EDS was the Auditory Verbal Learning Test-recognition. Conclusions: These findings suggest that EDS may be associated with alterations in caudate nucleus volume, particularly in the left hemisphere, in the context of SCD. Further research is necessary to understand the underlying mechanisms of this relationship and its implications for clinical management.