Role of estrogen in sex differences in memory, emotion and neuropsychiatric disorders.

Estrogen regulates a wide range of neuronal functions in the brain, such as dendritic spine formation, remodeling of synaptic plasticity, cognition, neurotransmission, and neurodevelopment. Estrogen interacts with intracellular estrogen receptors (ERs) and membrane-bound ERs to produce its effect via genomic and non-genomic pathways. Any alterations in these pathways affect the number, size, and shape of dendritic spines in neurons associated with psychiatric diseases. Increasing evidence suggests that estrogen fluctuation causes changes in dendritic spine density, morphology, and synapse numbers of excitatory and inhibitory neurons differently in males and females. In this review, we discuss the role of estrogen hormone in rodents and humans based on sex differences. First, we explain estrogen role in learning and memory and show that a high estrogen level alleviates the deficits in learning and memory. Secondly, we point out that estrogen produces a striking difference in emotional memories in men and women, which leads them to display sex-specific differences in underlying neuronal signaling. Lastly, we discuss that fluctuations in estrogen levels in men and women are related to neuropsychiatric disorders, including schizophrenia, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BPD), major depressive disorder (MDD), substance use disorder (SUD), and anxiety disorders.

Characteristics of amplitude of low-frequency fluctuations in the resting-state functional magnetic resonance imaging of alcohol-dependent patients with depression.

The high comorbidity of alcohol use disorder and depressive disorder is associated with poor patient prognosis. The mechanisms underlying this comorbidity, however, are largely unknown. By applying the amplitude of low-frequency fluctuations parameter in resting-state functional magnetic resonance imaging, this study investigated changes in the brain functioning of alcohol-dependent patients with and without depression. Alcohol-dependent patients (n = 48) and healthy controls (n = 31) were recruited. The alcohol-dependent patients were divided into those with and without depression, according to Patients Health Questionnaire-9 scores. Amplitude of low-frequency fluctuations in resting-state brain images were compared among the alcohol-dependent patients with depression, alcohol-dependent patients without depression, and healthy controls groups. We further examined associations between amplitude of low-frequency fluctuations alterations, alcohol-dependence severity, and depressive levels (assessed with scales). Compared with the healthy controls group, both alcohol groups showed amplitude of low-frequency fluctuations enhancement in the right cerebellum and amplitude of low-frequency fluctuations abatement in the posterior central gyrus. The alcohol-dependent patients with depression group had higher amplitude of low-frequency fluctuations in the right cerebellum than the alcohol-dependent patients without depression group. Additionally, we observed a positive correlation between amplitude of low-frequency fluctuations value and Patients Health Questionnaire-9 score in the right superior temporal gyrus in the alcohol-dependent patients with depression group. Alcohol-dependent subjects showed abnormally increased spontaneous neural activity in the right cerebellum, which was more significant in alcohol-dependent patients with depression. These findings may support a targeted intervention in this brain location for alcohol and depressive disorder comorbidity.

Application of pocket-first technique for implantation of totally implantable venous access ports.

BACKGROUND: While vascular puncture is always performed before making port pocket in the implantation of totally implantable venous access ports (TIVAP), some surgeons preferred to make port pocket first. This study seeks to verify the safety and feasibility for the pocket-first technique. METHODS: The study retrospectively reviewed 447 patients who undergone TIVAP implantation from July 2017 to November 2022. All the patients were divided into two groups based on vascular puncture first or making port pocket first. The general information, operation information and post-operative complications were reviewed and analyzed. RESULTS: All the operations were performed successfully. No difference was observed in the sex, age, height, weight, BMI, port location and total complication rate between the two groups. The operation time of the Puncture Group and the Pocket Group were 46.9 ± 22.4 min and 33.8 ± 13.6 min ( P<0.00001 ). In the patients of SCV approach, the operation time between the two groups were 37.4 ± 14.8 min and 33.5 ± 10.9 min ( P<0.05 ). Multivariate analysis showed the variable BMI and first procedure were independent prognostic factors for operation time. In the cases using SCV/AxV approach the variable first procedure was the only independent prognostic factor for operation time (P = 0.002). CONCLUSIONS: The pocket-first technique can be considered as a safe, feasible and convenient technique for TIVAP implantation. The time consuming is significantly shortened compared with the puncture-first technique and this advantage may be more obvious when using SCV/AxV approach.

Differential regulation of hippocampal transcriptome by circulating estrogen.

Estrogen (E2) modulates the synaptic structure and plasticity in the hippocampus. Previous studies showed that E2 fluctuations during various phases of the menstrual cycle produce subtle neurosynaptic changes that impact women's behavior, emotion, and cognitive functions. In this study, we explored the transcriptome of the hippocampus via RNA-seq (RNA-sequencing) between proestrus (PE) and diestrus (DE) stages in young female rats to determine the effect of E2 of PE and DE stages on hippocampal gene expression. We identified 238 genes (at 1.5-fold-change selection criteria, FDR adjusted p-value < 0.05) as differentially expressed genes (DEGs) that responded to E2 between PE and DE stages. Functional analysis based on Gene Ontology (GO) revealed that a higher E2 level corresponded to an increase in gene transcription among most of the DEGs, suggesting biological mechanisms operating differentially in the hippocampus of female rats between PE and DE stages in the estrus cycle; while analysis with Kyoto Encyclopedia of Genes and Genomes database (KEGG) found that the DEGs involving neuroactive ligand-receptor interaction, antigen processing, cell adhesion molecules, and presentation were upregulated in PE stage, whereas DEGs in pathways relating to bile secretion, coagulation cascades, osteoclast differentiation, cysteine and methionine metabolism were upregulated in DE stage of the estrus cycle. The high-fold expression of DEGs was confirmed by a follow-up quantitative real-time PCR. Our findings in this current study have provided fundamental information for further dissection of neuro-molecular mechanisms in the hippocampus in response to E2 fluctuation and its relationship with disorders.

Brain dysfunction of methamphetamine-associated psychosis in resting state: Approaching schizophrenia and critical role of right superior temporal deficit.

Methamphetamine (MA)-associated psychosis (MAP) is highly debilitating and common among individuals who use the drug, yet the underlying neural mechanism is not clear. This study compared brain functions between patients with MAP and those with schizophrenia during resting state and investigated the effect of brain alteration on the association between MA use and psychosis in patients with MAP. Three groups, including 24 patients with MAP, 17 with schizophrenia in first-episode (SCZ) and 31 healthy controls (HCs), were included after receiving a resting-state functional MRI scan. The severity of psychosis was assessed with Positive and Negative Syndrome Scale (PANSS). Imaging data were analysed using regional homogeneity (ReHo) to measure individual's brain function. Compared with the HC subjects, the MAP and SCZ groups had significantly lower ReHo in the cortical regions including left postcentral cortex, right superior temporal gyrus and right rolandic operculum, while had higher ReHo in the left putamen, with brain dysfunctions being more pronounced in the SCZ group. Among the MAP subjects, a mediating effect of ReHo in the right superior temporal gyrus was found on the association between MA use frequency and PANSS positive score. MAP and schizophrenia had a common trend of brain alteration, with the dysfunction being more pronounced in schizophrenia. This finding implicated that MAP might be a condition with neuropathology approaching schizophrenia. The observed critical role of right superior temporal deficit between MA use and psychosis proposed a potential target for interventions.

MiR-151a is involved in the pathogenesis of atopic dermatitis by regulating interleukin-12 receptor ß2.

MicroRNAs (miRNAs) have been reported to circulate in the blood in a highly stable and cell-free form. Dysregulated expression of miRNAs has been detected in various pathological conditions including atopic dermatitis. In our study, human blood plasma miRNAs were identified by high-throughput sequencing and compared among patients of atopic dermatitis and healthy controls. We found that miR-151a was differentially expressed in the plasma of atopic dermatitis patients. MiR-151a regulates the expression of IL12RB2 by targeting two loci in the 3' untranslated region of the Il12rb2 gene. Moreover, IL12RB2 was remarkably downregulated in Jurkat cells overexpressing miR-151a. Jurkat cells treated with phytohemagglutinin also showed reduced expression of IFN-γ, interleukin-2 (IL-2) and IL-12. Together, these results suggest that miR-151a is involved in the pathogenesis of atopic dermatitis by regulating IL12RB2.

Synthesis and antitumor evaluation of novel 4-anilino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate derivatives as potential EGFR inhibitors.

Novel series of 4-anilino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylates (5a-p, 7, and 8a-e) were synthesized and evaluated for their antiproliferative activity against the A549, HT29, H460, and H1975 cancer cell lines in vitro. Nine compounds (5a-c, 5i, 5j, 7, 8a, 8b, 8i) demonstrated moderate to significant cytotoxic activity with IC50 values below 18 µM on A549 cells, which were comparable to that of the reference gefitinib (IC50 = 18.44 µM). Especially, the further enzymatic analysis on epidermal growth factor receptor (EGFR), HER2, and VEGFR identified compound 5a as a promising hit that exhibited considerable potency both in cellular (IC50 = 5.67, 17.04, 11.29, and 12.65 µM, respectively) and EGFR enzymatic assays (IC50 = 14.8 nM). Compound 5a was capable of down-regulating the expression of EGFR and inhibited EGFR phosphorylation in a dose-dependent manner, representing a potential EGFR candidate for further optimization.

Berbamine Exerts Anti-Inflammatory Effects via Inhibition of NF-κB and MAPK Signaling Pathways.

BACKGROUND/AIMS: This study aimed to investigate the anti-inflammatory activity of Berbamine (BER), a bisbenzylisoquinoline alkaloid extracted from Berberis amurensis (Xiao Bo An), and the underlying mechanisms. METHODS: Macrophages and neutrophils were treated with BER in vitro and stimulated with LPS and fMLP. The effects of BER on the expression of pro-inflammatory mediators in macrophages were evaluated with quantitative RT-PCR and ELISA. The effects of BER on the activation and superoxide release of neutrophils were determined with flow cytometry and WST-1 reduction test. The inhibitory effects of BER on the activation of signaling pathways related to inflammatory response in macrophages were evaluated by western blot analysis. In addition, a mouse peritonitis model was made by peritoneal injection of thioglycollate medium and anti-inflammatory effects of BER were investigated in vivo by quantitative analysis of pro-inflammatory factor production and leukocyte exudation. RESULTS: BER significantly inhibited inflammatory factor expression by LPS-stimulated macrophages and suppressed activation and superoxide release of fMLP-stimulated neutrophils. In the mouse peritonitis model, BER significantly inhibited the activation of macrophages and exudation of neutrophils. According to analysis, BER significantly suppressed phosphorylation of NF-κB and MAPK (JNK and ERK1/2) signaling pathways in LPS-stimulated macrophages. CONCLUSIONS: Collectively, data from this study suggest that BER has anti-inflammatory potential, which is effected via inhibition of NF-κB and MAPK signaling pathways, and thus holds promise for treatment of inflammatory disease.

Surgical treatment of one traumatic carotid artery dissection: A case report and review of the literature.

RATIONALE: Dissection of the cervical arteries is the most commonly identified cause of stroke in young patients. This report helps to investigate the etiology, diagnosis, and treatment of cervical artery dissection (CAD). PATIENT CONCERNS: A 40-year-old female presented with a 3-week history of right carotid artery dissection due to a fall. The patient was admitted to the local hospital 3 weeks ago with a right neck impingement after a fall, and presented with right neck pain. The local hospital CT scan showed a dissection of the middle segment of the right common carotid artery. DIAGNOSES: The patient clinical manifestations and imaging tests confirmed that right carotid artery dissection. INTERVENTIONS: Medical treatment with antiplatelet failed, and the CT scan showed progression of dissection. Carotid endarterectomy (CEA) was performed, and the prognosis is good. OUTCOMES: This patient was followed up at 1 and 6 months after the operation, CT scan showed the original stenotic vessels returned to standard diameter. LESSONS: Diagnosis of CAD mainly depends on clinical manifestations and imaging. we recommend that clinicians can prescribe either anticoagulants or antiplatelet therapy. CAD can be effectively treated by surgical reconstruction, if medical treatment with anticoagulation or antiplatelet fails or if carotid aneurysms and/or high-grade carotid stenosis persisted or have newly developed.

MHC1/LILRB1 axis as an innate immune checkpoint for cancer therapy.

Immune checkpoint blockades (ICBs) have revolutionized cancer therapy through unleashing anti-tumor adaptive immunity. Despite that, they are usually effective only in a small subset of patients and relapse can occur in patients who initially respond to the treatment. Recent breakthroughs in this field have identified innate immune checkpoints harnessed by cancer cells to escape immunosurveillance from innate immunity. MHC1 appears to be such a molecule expressed on cancer cells which can transmit a negative signal to innate immune cells through interaction with leukocyte immunoglobulin like receptor B1 (LILRB1). The review aims to summarize the current understanding of MHC1/LILRB1 axis on mediating cancer immune evasion with an emphasis on the therapeutic potential to block this axis for cancer therapy. Nevertheless, one should note that this field is still in its infancy and more studies are warranted to further verify the effectiveness and safety in clinical as well as the potential to combine with existing immune checkpoints.

Functional Connectivity Differences in the Resting-state of the Amygdala in Alcohol-dependent Patients with Depression.

RATIONALE AND OBJECTIVES: The mechanism of comorbidity between alcohol dependence and depressive disorders are not well understood. This study investigated differences in the brain function of alcohol-dependent patients with and without depression by performing functional connectivity analysis using resting-state functional magnetic resonance imaging. MATERIALS AND METHODS: A total of 29 alcohol-dependent patients with depression, 31 alcohol-dependent patients without depression and 31 healthy control subjects were included in this study. The resting-state functional connectivity between the amygdala and the whole brain was compared among the three groups. Additionally, we examined the correlation between functional connectivity values in significantly different brain regions and levels of alcohol dependence and depression. RESULTS: The resting-state functional connectivity between the left amygdala and the right caudate nucleus was decreased in alcohol-dependent patients. Additionally, the resting-state functional connectivity of the right amygdala with the right caudate nucleus, right transverse temporal gyrus, right temporal pole: superior temporal gyrus were also decreased. In alcohol-dependent patients with depression, not only was functional connectivity between the above brain regions significantly decreased, but so was functional connectivity between the right amygdala and the left middle temporal gyrus. Also, there was no significant correlation between the resting-state functional connectivity values in statistically significant brain regions and the levels of alcohol dependence and depression. CONCLUSION: The impairment of the functional connectivity of the amygdala with caudate nucleus and partial temporal lobe may be involved in the neural mechanism of alcohol dependence comorbidity depressive disorders.

MicroRNA expression profiles of stress susceptibility and resilience in the prelimbic and infralimbic cortex of rats after single prolonged stress.

The experience of traumatic stress can engender lasting memories associated with the trauma, often resulting in post-traumatic stress disorder (PTSD). However, only a minority of individuals develop PTSD symptoms upon exposure. The neurobiological mechanisms underlying the pathology of PTSD are poorly understood. Utilizing a rat model of PTSD, the Single Prolonged Stress (SPS) paradigm, we were able to differentiate between resilient and susceptible individuals. Fourteen days after the SPS exposure, we conducted the behavioral analyses using Elevated Plus Maze (EPM) and Open Field (OF) tests to identify male rats as trauma resilient or susceptible. We focused on the microRNA (miRNA) profiles of the infralimbic (IL) and prelimbic (PL) cortical regions, known to be crucial in regulating the stress response. Our investigation of stressed rats exposed to the SPS procedure yielded divergent response, and differential expression microRNAs (DEmiRs) analysis indicated significant differences in the IL and PL transcriptional response. In the IL cortex, the GO analysis revealed enriched GO terms in the resilient versus control comparison, specifically related to mitogen-activated protein kinase and MAP kinase signaling pathways for their molecular functions as well as cytosol and nucleoplasm for the biological process. In the susceptible versus resilient comparison, the changes in molecular functions were only manifested in the functions of regulation of transcription involved in the G1/S transition of the mitotic cell cycle and skeletal muscle satellite cell activation. However, no enriched GO terms were found in the susceptible versus control comparison. In the PL cortex, results indicated that the DEmiRs were enriched exclusively in the cellular component level of the endoplasmic reticulum lumen in the comparison between resilient and control rats. Overall, our study utilized an animal model of PTSD to investigate the potential correlation between stress-induced behavioral dysfunction and variations in miRNA expression. The aforementioned discoveries have the potential to pave the way for novel therapeutic approaches for PTSD, which could involve the targeted regulation of transcriptome expression.

The neural circuits and molecular mechanisms underlying fear dysregulation in posttraumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a stress-associated complex and debilitating psychiatric disorder due to an imbalance of neurotransmitters in response to traumatic events or fear. PTSD is characterized by re-experiencing, avoidance behavior, hyperarousal, negative emotions, insomnia, personality changes, and memory problems following exposure to severe trauma. However, the biological mechanisms and symptomatology underlying this disorder are still largely unknown or poorly understood. Considerable evidence shows that PTSD results from a dysfunction in highly conserved brain systems involved in regulating stress, anxiety, fear, and reward circuitry. This review provides a contemporary update about PTSD, including new data from the clinical and preclinical literature on stress, PTSD, and fear memory consolidation and extinction processes. First, we present an overview of well-established laboratory models of PTSD and discuss their clinical translational value for finding various treatments for PTSD. We then highlight the research progress on the neural circuits of fear and extinction-related behavior, including the prefrontal cortex, hippocampus, and amygdala. We further describe different molecular mechanisms, including GABAergic, glutamatergic, cholinergic, and neurotropic signaling, responsible for the structural and functional changes during fear acquisition and fear extinction processes in PTSD.

Neural basis of the attention bias during addiction stroop task in methamphetamine-dependent patients with and without a history of psychosis: an ERP study.

Background: Attentional bias plays an important role in sustaining various types of drug addiction. No prior studies examined methamphetamine (MA)-associated psychosis (MAP) relationships between ERP time course and performance on an addiction Stroop task in MA abusers. The aim of the present study was to determine whether MA abusers with (MAP+) or without (MAP-) psychosis exhibit alterations of the ERP during the addiction Stroop task. Methods: Thirty-one healthy controls (CTRL), 14 MAP-, and 24 MAP+ participants were recruited and completed the addiction Stroop task during EEG recording using 32 electrodes. Group variations were compared on measures of behavioral task performance and event-related potentials (ERP) of performance monitoring (N200, P300, N450). The Barratt impulsiveness scores were analyzed to investigate correlations with ERP changes. Results: MA-related word stimulus elicited a more negative N200 amplitude over left-anterior electrodes in MAP- abusers; furthermore, a positive association between the N200 amplitude and Barratt attentional scores and non-planning scores was observed, while no such differences were found in MAP+ abusers. There were no significant differences in reaction time (RT) and error rate between each group. Conclusion: This is the first study to examine psychosis relationships between ERP time course and performance on an addiction Stroop task in MA abusers with or without psychosis. These findings support the association between attentional bias measured by the MA addiction Stroop task and N200 component as well as indicate the possibility of using this cognitive task in combination with ERP technology to detect psychosis factors among abstinent MA abusers.

Substituted benzamides containing azaspiro rings as upregulators of apolipoprotein A-I transcription.

Apolipoprotein A-I (Apo A-I) is the principal protein component of high density lipoprotein (HDL), which is generally considered as a potential therapeutic target against atherosclerosis. The understanding of the Apo A-I regulation mechanism has fuelled the development of novel HDL targeted therapeutic approaches. To identify novel agents that can upregulate Apo A-I expression, we performed a cell-based reporter assay to screen 25,600 small molecules. Based on the dataset obtained from screening, a series of novel analogs of substituted benzamides containing azaspiro rings were assessed for their ability to induce the transcription of the Apo A-I gene, and the structure-activity relationship (SAR) around these analogs was also proposed. The results indicated that the trifluoromethyl substituted benzamide containing an azaspiro ring is a promising backbone for designing Apo A-I transcriptional upregulator and could be viable leads for development of new drugs to prevent and treat atherosclerosis in the future.

Common gray matter loss in the frontal cortex in patients with methamphetamine-associated psychosis and schizophrenia.

BACKGROUND AND HYPOTHESIS: Methamphetamine (MA)-associated psychosis has become a public concern. However, its mechanism is not clear. Investigating similarities and differences between MA-associated psychosis and schizophrenia in brain alterations would be informative for neuropathology. STUDY DESIGN: This study compared gray matter volumes of the brain across four participant groups: healthy controls (HC, n = 53), MA users without psychosis (MA, n = 22), patients with MA-associated psychosis (MAP, n = 34) and patients with schizophrenia (SCZ, n = 33). Clinical predictors of brain alterations, as well as association of brain alterations with psychotic symptoms and attention impairment were further investigated. STUDY RESULTS: Compared with the HC, the MAP and the SCZ showed similar gray matter reductions in the frontal cortex, particularly in prefrontal areas. Moreover, a stepwise extension of gray matter reductions was exhibited across the MA - MAP - SCZ. Duration of abstinence was associated with regional volumetric recovery in the MAP, while this amendment in brain morphometry was not accompanied with symptom's remission. Illness duration of psychosis was among the predictive factors of regional gray matter reductions in both psychotic groups. Volume reductions were found to be associated with attention impairment in the SCZ, while this association was reversed in the MAP in frontal cortex. CONCLUSIONS: This study suggested MA-associated psychosis and schizophrenia had common neuropathology in cognitive-related frontal cortices. A continuum of neuropathology between MA use and schizophrenia was tentatively implicated. Illness progressions and glial repairments could both play roles in neuropathological changes in MA-associated psychosis.

Design, synthesis and biological evaluation of hydroxamic acid derivatives as potential high density lipoprotein (HDL) receptor CLA-1 up-regulating agents.

Trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) were reported in our recent publication as novel human high density lipoprotein (HDL) receptor CD36 and Lysosomal integral membrane protein-II Analogous-1 (CLA-1) up-regulators. As part of a broader effort to more fully explore the structure-activity relationships (SAR) of CLA-1 up-regulators, we synthesized a series of hydroxamic acid derivatives and evaluated their CLA-1 up-regulating activities in HepG2 cells. Some compounds exhibited over 10-fold up-regulation of CLA-1 expression in HepG2 cells at 10 µg/mL concentration. The compound 1g showed the best potency, with a lower EC(50) than TSA (EC(50) = 0.32 µM versus 1.2 µM). These compounds provide early new CLA-1 up-regulators with potential for treating atherosclerosis.

Effect of Gambogic Acid-Loaded Porous-Lipid/PLGA Microbubbles in Combination With Ultrasound-Triggered Microbubble Destruction on Human Glioma.

Gambogic acid (GA) is a highly effective antitumor agent, and it is used for the treatment of a wide range of cancers. It is challenging to deliver drugs to the central nervous system due to the inability of GA to cross the blood-brain barrier (BBB). Studies have shown that ultrasound-targeted microbubble destruction can be used for transient and reversible BBB disruption, significantly facilitating intracerebral drug delivery. We first prepared GA-loaded porous-lipid microbubbles (GA porous-lipid/PLGA MBs), and an in vitro BBB model was established. The cell viability was detected by CCK-8 assay and flow cytometry. The results indicate that U251 human glioma cells were killed by focused ultrasound (FUS) combined with GA/PLGA microbubbles. FUS combined with GA/PLGA microbubbles was capable of locally and transiently enhancing the permeability of BBB under certain conditions. This conformational change allows the release of GA to extracellular space. This study provides novel targets for the treatment of glioma.

Identification of Novel Compounds Enhancing SR-BI mRNA Stability through High-Throughput Screening.

Atherosclerosis is the pathological basis of most cardiovascular diseases. Reverse cholesterol transport (RCT) is a main mechanism of cholesterol homeostasis and involves the direct transport of high-density lipoprotein (HDL) cholesteryl ester by selective cholesterol uptake. Hepatic scavenger receptor class B member 1 (SR-BI) overexpression can effectively promote RCT and reduce atherosclerosis. SR-BI may be an important target for prevention or treatment of atherosclerotic disease. In our study, we inserted human SR-BI mRNA 3' untranslated region (3'UTR) downstream of the luciferase reporter gene, to establish a high-throughput screening model based on stably transfected HepG2 cells and to screen small-molecule compounds that can significantly enhance the mRNA stability of the SR-BI gene. Through multiple screenings of 25 755 compounds, the top five active compounds that have similar structures were obtained, with a positive rate of 0.19%. The five positive compounds could enhance the SR-BI expression and uptake of DiI-HDL in the hepatocyte HepG2. E238B-63 could also effectively extend the half-life of SR-BI mRNA and enhance the SR-BI mRNA and protein level and the uptake of DiI-HDL in hepatocytes in a time-dependent and dose-dependent manner. The structure-activity relationship analysis showed that the structure N-(3-hydroxy-2-pyridyl) carboxamide is possibly the key pharmacophore of the active compound, providing reference for acquiring candidate compounds with better activity. The positive small molecular compounds obtained in this study might become new drug candidates or lead compounds for the treatment of cardiovascular diseases and contribute to the further study of the posttranscriptional regulation mechanism of the SR-BI gene.

MRI-Guided Focused Ultrasound-Induced Blood Brain Barrier Disruption to Deliver Glial Cell Line Derived Neurotropic Factor Proteins into Brain to Treat Rat Depression.

Glial cell line derived neurotropic factor (GDNF) plays a crucial role in the development and maintenance of glial cells, serotonergic and dopaminergic neurons. A positively therapeutic effect has been demonstrated on some animal neurodegenerative diseases. However, the inability to deliver the protein across blood brain barrier (BBB) into damaged brain region limits its clinical application. Here, we developed GDNF-loaded microbubbles (MBs) and achieved a local and precise delivery of GDNF into the brain through MRI-guided focused ultrasound-induced BBB disruption. To demonstrate the therapeutic effect, rat depression model was developed by chronic mild stress treatment. Typical depression behaviors were confirmed. MRI-guided focused ultrasound was used to irradiate the GDNF-loaded MBs. Obvious BBB opening was observed in the treated rat brains and a significant higher GDNF concentration was detected in the ultrasound-treated brain tissues. Behavioral tests demonstrated the increased GDNF could reverse the depressive-like behaviors induced by chronic mild stress, improve the expression of 5-HT 1B receptor and the protein p11, and increase the number of 5-HT or TPH2 immunoreactive neurons. In conclusion, our study provided an effective approach to deliver GDNF proteins into brain to treat rat depression through MRI-guided focused ultrasound-induced destruction of blood-brain barrier.