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.

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.

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.

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.

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.

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.

Antennal transcriptome and differential expression of olfactory genes in the yellow peach moth, Conogethes punctiferalis (Lepidoptera: Crambidae).

The yellow peach moth (YPM), Conogethes punctiferalis (Guenée), is a multivoltine insect pest of crops and fruits. Antennal-expressed receptors are important for insects to detect olfactory cues for host finding, mate attraction and oviposition site selection. However, few olfactory related genes were reported in YPM until now. In the present study, we sequenced and characterized the antennal transcriptomes of male and female YPM. In total, 15 putative odorant binding proteins (OBPs), 46 putative odorant receptors (ORs) and 7 putative ionotropic receptors (IRs) were annotated and identified as olfactory-related genes of C. punctiferalis. Further analysis of RT-qPCR revealed that all these olfactory genes are primarily or uniquely expressed in male and female antennae. Among which, 3 OBPs (OBP4, OBP8 and PBP2) and 4 ORs (OR22, OR26, OR44 and OR46) were specially expressed in male antennae, whereas 4 ORs (OR5, OR16, OR25 and OR42) were primarily expressed in female antennae. The predicted protein sequences were compared with homologs in other lepidopteran species and model insects, which showed high sequence homologies between C. punctiferalis and O. furnacalis. Our work allows for further functional studies of pheromone and general odorant detection genes, which might be meaningful targets for pest management.

MicroRNAs 185, 96, and 223 repress selective high-density lipoprotein cholesterol uptake through posttranscriptional inhibition.

Hepatic scavenger receptor class B type I (SR-BI) plays an important role in selective high-density lipoprotein cholesterol (HDL-C) uptake, which is a pivotal step of reverse cholesterol transport. In this study, the potential involvement of microRNAs (miRNAs) in posttranscriptional regulation of hepatic SR-BI and selective HDL-C uptake was investigated. The level of SR-BI expression was repressed by miRNA 185 (miR-185), miR-96, and miR-223, while the uptake of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-HDL was decreased by 31.9% (P < 0.001), 23.9% (P < 0.05), and 15.4% (P < 0.05), respectively, in HepG2 cells. The inhibition of these miRNAs by their anti-miRNAs had opposite effects in these hepatic cells. The critical effect of miR-185 was further validated by the loss of regulation in constructs with mutated miR-185 target sites. In addition, these miRNAs directly targeted the 3' untranslated region (UTR) of SR-BI with a coordinated effect. Interestingly, the decrease of miR-96 and miR-185 coincided with the increase of SR-BI in the livers of ApoE KO mice on a high-fat diet. These data suggest that miR-185, miR-96, and miR-223 may repress selective HDL-C uptake through the inhibition of SR-BI in human hepatic cells, implying a novel mode of regulation of hepatic SR-BI and an important role of miRNAs in modulating cholesterol metabolism.

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.