Chemical Synaptic Transmission Research Articles

Thyroarytenoid Oxidative Metabolism and Synaptic Signaling Dysregulation in the Female Pink1-/- Rat.

Vocal dysfunction, including hypophonia, in Parkinson disease (PD) manifests in the prodromal period and significantly impacts an individual's quality of life. Data from human studies suggest that pathology leading to vocal deficits may be structurally related to the larynx and its function. The Pink1-/- rat is a translational model used to study pathogenesis in the context of early-stage mitochondrial dysfunction. The primary objective of this work was to identify differentially expressed genes in the thyroarytenoid muscle and examine the dysregulated biological pathways in the female rat. RNA sequencing was used to determine thyroarytenoid (TA) muscle gene expression in adult female Pink1-/- rats compared with controls. A bioinformatic approach and the ENRICHR gene analysis tool were used to compare the sequencing dataset with biological pathways and processes, disease relationships, and drug-repurposing compounds. Weighted Gene Co-expression Network Analysis was used to construct biological network modules. The data were compared with a previously published dataset in male rats. Significant upregulated pathways in female Pink1-/- rats included fatty acid oxidation and muscle contraction, synaptic transmission, and neuromuscular processes. Downregulated pathways included anterograde transsynaptic signaling, chemical synaptic transmission, and ion release. Several drug treatment options including cetuximab, fluoxetine, and resveratrol are hypothesized to reverse observed genetic dysregulation. Data presented here are useful for identifying biological pathways that may underlie the mechanisms of peripheral dysfunction including neuromuscular synaptic transmission to the TA muscle. These experimental biomarkers have the potential to be targeted as sites for improving the treatment for hypophonia in early-stage PD. NA Laryngoscope, 133:3412-3421, 2023.

Study on Mechanism of Shenqi Dihuang Decoction in Treating Diabetic Nephropathy Based on Network Pharmacology

Objective: To explore the mechanism of Shenqi Dihuang Decoction in treating diabetic nephropathy based on network pharmacology. Methods: The component targets of Shenqi Dihuang Decoction and diabetic nephropathy (DKD) targets were searched and screened by network database. Using Cytoscape3.7.2 software to construct a network of traditional Chinese medicine components-targets; The protein-protein interaction network (PPI) of Shenqi Dihuang Decoction for CRF treatment was constructed using STRING database, and the core targets were found out through topological analysis. Finally, biological pathway and enrichment analysis were carried out on drug-disease intersection targets. Results: A total of 106 active ingredients of Shenqi Dihuang Decoction were collected. 1532 corresponding targets; DKD disease targets 533; There are 48 common targets for drug components and diseases. Topological analysis was performed with a Degree value 2 times (14.3) higher than the average, and 4 key core targets were finally obtained. Biological process and enrichment analysis show that the prescription mainly involves 13 biological processes, 4 KEGG pathways and 3 typical pathways in treating DKD, mainly involving cell response to hormone stimulation, followed by biological processes such as neuroactive ligand-receptor interaction KEGG pathway, blood circulation, cell response to nitrogen compounds, chemical synaptic transmission, etc. Conclusion: Shenqi Dihuang Decoction mainly acts on PTGS2, NR3C1, NOS3, ESR1 and other targets. Its targets are many and its mechanism is complex. It may play a role mainly through the biological process of regulating the response degree of cells to hormone stimulation.

Novel methylation-related long non-coding RNA clinical outcome prediction method: the clinical phenotype and immune infiltration research in low-grade gliomas.

Recent studies have suggested that long non-coding RNAs (lncRNAs) may play crucial role in low-grade glioma; however, the underlying mechanisms linking them to epigenetic methylation remain unclear. We downloaded expression level data for regulators associated with N1 methyladenosine (m1A), 5-methyladenine (m5C), and N6 methyladenosine (m6A) (M1A/M5C/M6A) methylation from the Cancer Genome Atlas-low-grade glioma (TCGA-LGG) database. We identified the expression patterns of lncRNAs, and selected methylation-related lncRNAs using Pearson correlation coefficient>0.4. Non-negative matrix dimensionality reduction was then used to determine the expression patterns of the methylation-associated lncRNAs. We constructed a weighted gene co-expression network analysis (WGCNA) network to explore the co-expression networks between the two expression patterns. Functional enrichment of the co-expression network was performed to identify biological differences between the expression patterns of different lncRNAs. We also constructed prognostic networks based on the methylation presence in lncRNAs in low-grade gliomas. We identified 44 regulators by literature review. Using a correlation coefficient greater than 0.4, we identified 2330 lncRNAs, among which 108 lncRNAs with independent prognostic values were further screened using univariate Cox regression at P< 0.05. Functional enrichment of the co-expression networks revealed that regulation of trans-synaptic signaling, modulation of chemical synaptic transmission, calmodulin binding, and SNARE binding were mostly enriched in the blue module. The calcium and CA2 signaling pathways were associated with different methylation-related long non-coding chains. Using the Least Absolute Shrinkage Selector Operator (LASSO) regression analysis, we analyzed a prognostic model containing four lncRNAs. The model's risk score was 1.12 *AC012063+0.74 * AC022382+0.32 * AL049712+0.16 * GSEC. Gene set variation analysis (GSVA) revealed significant differences in mismatch repair, cell cycle, WNT signaling pathway, NOTCH signaling pathway, Complement and Cascades, and cancer pathways at different GSEC expression levels. Thus, these results suggest that GSEC may be involved in the proliferation and invasion of low-grade glioma, making it a prognostic risk factor for low-grade glioma. Our analysis identified methylation-related lncRNAs in low-grade gliomas, providing a foundation for further research on lncRNA methylation. We found that GSEC could serve as a candidate methylation marker and a prognostic risk factor for overall survival in low-grade glioma patients. These findings shed light on the underlying mechanisms of low-grade glioma development and may facilitate the development of new treatment strategies.

Integrated UPLC-MS, network pharmacology, and intestinal flora analysis to determine the treatment effect of Qiangzhi decoction on comorbid Tourette syndrome and RRTI.

Tourette syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics. Recurrent respiratory tract infection (RRTI), a commonly occurring disease in childhood, correlates with recurrent and severe course of tic symptoms. Qiangzhi decoction (QZD) is a traditional Chinese medicine that can alleviate TS symptoms while reducing the recurrence of RRTI. However, the mechanism of QZD on TS and RRTI remains unclear. This study aimed to determine the treatment effect of QZD on comorbid TS and RRTI by integrating ultrahigh-performance liquid chromatography mass spectrometry (UPLC-MS), network pharmacology, and intestinal flora analysis. The components of QZD were first identified by UPLC-quadrupole (Q)-orbitrap-MS/MS. The mechanism of QZD on comorbid RRTI and TS was investigated by a series of network pharmacological methods, including target prediction and bioinformatics analysis. Finally, a comorbid TS and RRTI rat model was established by intraperitoneal injection of 3,3-iminodipropionitrile (IDPN), cyclophosphamide (CTX), and lipopolysaccharide (LPS). Alteration of gut microbiota in the alleviation of TS and RRTI by QZD was investigated via intestinal flora analysis. The results of UPLC-Q-orbitrap-MS/MS showed that QZD had 96 types of chemical components. The network pharmacology results demonstrated that targets of QZD involved in the treatment of TS and RRTI involved 1045 biological processes (BPs), 109 cellular components (CCs), and 133 molecular functions (MFs), including synaptic and transsynaptic signaling, chemical synaptic transmission, neurotransmitter receptor activity, G protein-coupled amine receptor activity, and serotonin receptor activity, among others. Firmicutes, Bacteroidetes, Coprococcus, and Lachnospiraceae played crucial roles in gut microbiota of a QZD-treated comorbid TS and RRTI model. Our results revealed QZD provided a multicomponent, multitarget, and multipathway synergistic treatment of comorbid TS and RRTI.

Recordings in an integrating central neuron reveal the mode of action of isoeugenol

Although isoeugenol is one of the most widely used anesthetics in fish, its actual mode of action and thus its applicability for particular interventions is poorly understood. Here we determined effects of isoeugenol on various aspects of sensory and neural function, taking advantage of intracellular in vivo recordings in a uniquely suited identified neuron, the Mauthner neuron in the brain of goldfish. We show that isoeugenol strongly affects hearing and vision, but sensitivity and time course of action differed largely in these two senses. The action potential, chemical and electric synaptic transmission at the central neuron were not affected at low but efficient anesthesia. Effects seen at high concentration thereby do not support current views of how isoeugenol might act on central neurons. We show that isoeugenol is highly useful to anesthetize fish for handling, but that in more severe treatment its application needs to be carefully adapted to task.

Integrating Network Pharmacology, Molecular Docking and Pharmacological Evaluation for Exploring the Polyrhachis vicina Rogers in Ameliorating Depression.

To investigate the mechanisms of antidepressant action of active fraction of Polyrhachis vicina Rogers (AFPR) through network pharmacology, molecular docking and experimental validation. GC-MS was used to predict chemical compounds, corresponding databases were used to predict chemical compound targets and depression targets, Cytoscape software was used to construct and analyze the protein interaction network map, DAVID database was used to analyze gene ontology (GO)and KEGG signaling pathway, and AGFR software was used to perform molecular docking. Subsequently, the underlying action mechanisms of AFPR on depression predicted by network pharmacology analyses were experimentally validated in a CORT-induced depression model in vitro and in vivo. A total of 52 potential targets of AFPR on antidepressant were obtained. GO is mainly related to chemical synaptic transmission, signal transduction and others. KEGG signaling pathways are mainly related to cAMP signaling pathway and C-type lectin receptor signaling pathway. The experiment results showed that AFPR significantly increased the expression of PRKACA, CREB and BDNF in mouse brain tissue and PC12 cells. Furthermore, after interfered of cAMP in PC12 cells, the decreased expression of PRKACA, CREB and BDNF was reversed by AFPR. AFPR may exert antidepressant effects through multiple components, targets and pathways. Furthermore, it could improve neuroplasticity via the cAMP signaling pathway to improve depression-like symptoms.

Identification of Prognostic Markers of DNA Damage and Oxidative Stress in Diagnosing Papillary Renal Cell Carcinoma Based on High-Throughput Bioinformatics Screening.

Papillary renal cell carcinoma (pRCC) is the second most common histological subtype of adult kidney tumors, with a poor prognosis due to limited understanding of the disease mechanism. Herein, we have performed high-throughput bioinformatic screening to explore and identify potential biomarkers of DNA damage and oxidative stress for pRCC. RNA sequencing data related to pRCC were downloaded from the TCGA database, and differentially expressed genes (DEG) were identified by a wide variety of clustering and classification algorithms, including self-organized maps (SOM), artificial neural networks (ANN), support vector machines (SVM), fuzzy logic, and hyphenated techniques such as neuro-fuzzy networks. Then DAVID and STRING online biological information tools were used to analyze functional enrichment of the regulatory networks of DEG and construct a protein-protein interaction (PPI) network, and then the Cytoscape software was used to identify hub genes. The importance of key genes was assessed by the analysis of the Kaplan-Meier survival curves using the R software. Lastly, we have analyzed the expression of hub genes of DNA damage and oxidative stress (BDKRB1, NMUR2, PMCH, and SAA1) in pRCC tissues and adjacent normal tissues, as well as the relationship between the expression of hub genes in pRCC tissues and pathological characteristics and prognosis of pRCC patients. A total of 1,992 DEGs for pRCC were identified, with 1,142 upregulated ones and 850 downregulated ones. The DEGs were significantly enriched in activities including DNA damage and oxidative stress, chemical synaptic transmission, an integral component of the membrane, calcium ion binding, and neuroactive ligand-receptor interaction. cytoHubba in the Cytoscape software was used to determine the top 10 hub genes in the PPI network as BDKRB2, NMUR2, NMU, BDKRB1, LPAR5, KNG1, LPAR3, SAA1, MCHR1, PMCH, and NCAPH. Furthermore, the expression level of hub genes BDKRB1, NMUR2, PMCH, and SAA1 in pRCC tissues was significantly higher than that in the adjacent normal tissues. Meanwhile, the expression level of hub genes BDKRB1, NMUR2, PMCH, and SAA1 in pRCC tissues was significantly positively correlated with tumor stage, lymph node metastasis, and the histopathology grade of pRCC. In addition, high expression levels of hub genes BDKRB1, NMUR2, PMCH, and SAA1 were associated with a poor prognosis for patients with pRCC. Univariate and multivariate analyses showed that the expression of hub genes BDKRB1, NMUR2, PMCH, and SAA1 were independent risk factors for the prognosis of patients with pRCC. The results of this analysis suggested that BDKRB1, NMUR2, PMCH, and SAA1 might be potential prognostic biomarkers and novel therapeutic targets for pRCC.

Mechanism of essential oil from Schizonepeta tenuifolia in treatment of depression based on network pharmacology and experimental verification

This paper aimed to explore the antidepressant effect of the essential oil from Schizonepeta tenuifolia Briq.(EOST) on the treatment of depression and its mechanism by using a combination of network pharmacology and the mouse model of lipopolysaccharide(LPS)-induced depression. The chemical components in EOST were identified using gas chromatography-mass spectrometer(GC-MS), and 12 active components were selected as the study objects. The targets related to EOST were obtained by Traditional Chinese Medicines Systems Pharmacology(TCMSP) and SwissTargetPrediction database. The targets related to depression were screened out through GeneCards, Therapeutic Target Database(TTD), and Online Mendelian Inheritance in Man(OMIM) database. The Venny 2.1 was applied to screen out the common targets of EOST and depression. The targets were imported into Cytoscape 3.7.2 to generate &quot;drug-active component-diease-target&quot; network diagram. The protein-protein interaction(PPI) network was constructed using STRING 11.5 database and Cytoscape 3.7.2, and the core targets were screened out. DAVID 6.8 database was used for Gene Ontology(GO) func-tional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis, and subsequently the enrichment results were visualized through the bioinformatics platform. The mouse model of depression was induced by intraperitoneally injecting with LPS in mice. Before modeling, mice were administrated orally with EOST. The antidepressant effect of EOST was evalua-ted by tail suspension test(TST), forced swimming test(FST), and novelty suppressed feeding test(NSFT) after modeling. The content of interleukin(IL)-1β was determined by enzyme-linked immunosorbent assay(ELISA), and the protein expression levels of IL-1β and pro IL-1β in the hippocampus were determined by Western blot. There were 12 main components and 179 targets in EOAT, of which, 116 targets were related to depression, mainly involved in neuroactive ligand-receptor interaction, calcium signaling pathway, and cyclic adenosine monophosphate(cAMP) signaling pathway. Biological processes such as synaptic signal transduction, G-protein coupled receptor signaling pathway, and chemical synaptic transmission were involved. Molecular functions such as neurotransmitter receptor activity, RNA polymerase Ⅱ transcription factor activity, and heme binding were involved. In mice experiments, the results showed that EOST at 100 mg·kg~(-1) and 50 mg·kg~(-1) significantly shortened the immobility time in TST and FST as well as the feeding latency in NSFT compared with the model group, decreased the levels of serum IL-1β and NO, and reduced the protein expression levels of IL-1β and pro IL-1β in the hippocampus. In conclusion, EOST shows a good antidepressant effect in a multi-component, multi-target, and multi-pathway manner. The mechanism may be attributed to the fact that EOST can down-regulate the protein expression levels of IL-1β and pro IL-1β, decrease the release of inflammatory factors, and reduce neuroinflammation response.

Network pharmacology and LC-MS approachs to explore the active compounds and mechanisms of Yuanjiang decoction for treating bradyarrhythmia

BackgroundYuanjiang decoction (YJD), a traditional Chinese medicinal prescription, has been found to have a significant heart rate-increasing effect and is effective in the treatment of symptomatic bradyarrhythmia in previous studies. However, its specific components and potential mechanisms remain unclear. MethodsIn this study, we detected and identified the main compounds of YJD using liquid chromatography-mass spectrometry (LC-MS). Through the approach of network pharmacology, we predicted the core targets of the active components, bradyarrhythmia targets, and obtained potential anti-bradyarrhythmia targets of YJD. We further performed protein to protein interaction (PPI), gene ontology (GO) enrichment analyses and kyoto encyclopedia of genes and genomes (KEGG) signaling pathway analyses for core targets, and constructed network of key active ingredients-core targets of YJD. Finally, molecular docking and molecular dynamics simulation were performed for key active ingredients and core targets. ResultsThe YJD contains a total of 35 main chemical components. The key active ingredients-core targets network contains 36 nodes and 90 edges, including 20 key active ingredients and 16 core targets. The core targets in the PPI network were TP53, TNF, HRAS, PPARG, IL1B, KCNH2, SCN5A, IDH1, LMNA, ACHE, F2, DRD2, CALM1, KCNQ1, TNNI3, IDH2 and TNNT2. KEGG pathway analysis showed that YJD treatment of bradyarrhythmia mainly involves neuroactive ligand-receptor interaction, adrenergic signaling in cardiomyocytes, cAMP signaling pathway, calcium signaling pathway, cholinergic synaptic and serotonergic synapse signaling pathway. The biological processes mainly include regulation of hormone levels, regulation of cardiac contraction, chemical synaptic transmission, circadian rhythm, positive regulation of heart rate, smooth muscle contraction, response to metal ion, oxidation-reduction process, neurotransmitter transport and import across plasma membrane. Molecular docking and molecular dynamics simulation results showed that hesperidin and tetrahydropalmatine had higher affinity with DRD2 and KCNQ1, respectively. ConclusionThis study reveals the pharmacodynamic material basis of YJD and its potential multicomponent–multitarget–multipathway pharmacological effects, predicted its potential anti-bradyarrhythmia mechanism may be related to the regulation of myocardial autonomic nervous function and related ion channels. Our work demonstrates that YJD has great potential for treating bradyarrhythmias as a complementary medicine, and the results can provide a theoretical basis for the development and clinical application of YJD.

Preliminary exploration of the co-regulation of Alzheimer's disease pathogenic genes by microRNAs and transcription factors.

Alzheimer's disease (AD) is the most common form of age-related neurodegenerative disease. Unfortunately, due to the complexity of pathological types and clinical heterogeneity of AD, there is a lack of satisfactory treatment for AD. Previous studies have shown that microRNAs and transcription factors can modulate genes associated with AD, but the underlying pathophysiology remains unclear. The datasets GSE1297 and GSE5281 were downloaded from the gene expression omnibus (GEO) database and analyzed to obtain the differentially expressed genes (DEGs) through the "R" language "limma" package. The GSE1297 dataset was analyzed by weighted correlation network analysis (WGCNA), and the key gene modules were selected. Next, gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis for the key gene modules were performed. Then, the protein-protein interaction (PPI) network was constructed and the hub genes were identified using the STRING database and Cytoscape software. Finally, for the GSE150693 dataset, the "R" package "survivation" was used to integrate the data of survival time, AD transformation status and 35 characteristics, and the key microRNAs (miRNAs) were selected by Cox method. We also performed regression analysis using least absolute shrinkage and selection operator (Lasso)-Cox to construct and validate prognostic features associated with the four key genes using different databases. We also tried to find drugs targeting key genes through DrugBank database. GO and KEGG enrichment analysis showed that DEGs were mainly enriched in pathways regulating chemical synaptic transmission, glutamatergic synapses and Huntington's disease. In addition, 10 hub genes were selected from the PPI network by using the algorithm Between Centrality. Then, four core genes (TBP, CDK7, GRM5, and GRIA1) were selected by correlation with clinical information, and the established model had very good prognosis in different databases. Finally, hsa-miR-425-5p and hsa-miR-186-5p were determined by COX regression, AD transformation status and aberrant miRNAs. In conclusion, we tried to construct a network in which miRNAs and transcription factors jointly regulate pathogenic genes, and described the process that abnormal miRNAs and abnormal transcription factors TBP and CDK7 jointly regulate the transcription of AD central genes GRM5 and GRIA1. The insights gained from this study offer the potential AD biomarkers, which may be of assistance to the diagnose and therapy of AD.

PGCLCs of human 45,XO reveal pathogenetic pathways of neurocognitive and psychosocial disorders

BackgroundNeurocognitive disorders and psychosocial difficulties are common in patients with Turner syndrome and multiple neurodegenerative diseases, yet there is no effective cure. Human primordial germ cells (hPGCs) are pluripotent germline stem cells in early embryo, which pass genetic information from one generation to the next, whereas all somatic cells will die along with the end of life. However, it is not known whether patient hPGCs with Turner syndrome contain information of neurocognitive and psychosocial illness.ResultsIn this report, we used a high-density of culture system of embryoids derived from iPSCs of a patient with Turner syndrome to ask how pathogenetic pathways are associated with onset of neurocognitive and psychosocial disorders. The hPGC-Like Cells (hPGCLCs) were in vitro specified from iPSCs of 45,XO, 46,XX and 46,XY by the high-density induction of embryoids. Amazingly, we found that the specification process of the hPGCLCs in 45,XO, compared to those in 46,XX and 46,XY, enriched several common pathogenetic pathways regulating neurocognitive and psychosocial disorders, that shared among multiple neurodegenerative diseases and Turner syndrome. The downregulated chemical synaptic transmission pathways, including glutamatergic, GABAergic, and nicotine cholinergic synapses, indicated synaptic dysfunctions, while upregulated pathways that were associated with imbalance of mitochondrial respiratory chain complexes and apoptosis, may contribute to neuronal dysfunctions. Notably, downregulation of three types of ubiquitin ligases E1-E2-E3 and lysosome-associated sulfatases and RAB9A, owing to haploinsufficiency and parental preference of the X chromosome expression, indicated that two pathways of cellular degradation, lysosome and ubiquitin–proteasome, were impaired in the specification process of 45,XO hPGCLCs. This would lead to accumulation of undesired proteins and aggregates, which is a typically pathological hallmark in neurodegenerative diseases.ConclusionsOur data suggest that the specification process of the hPGCLCs in 45,XO, compared to those in 46,XX and 46,XY, enriched pathogenetic pathways that are associated with the onset of neurocognitive and psychosocial disorders.

Intracellular simulated biophoton stimulation and transsynaptic signal transmission

The traditional theory holds that the information transmission between nerve cells includes electrical and chemical transmission; however, these known functional features do face some difficulties to explain the fast and efficient information processing and cognitive processes in the brain due to the existing functional limitations of neuronal networks, such as the dendritic and axonal propagation delays as well as the chemical synaptic transmission time delay that have been debated for a long time. We generated three kinds of ultraweak lasers, called as simulated biophotons, with different spectra and intensities to implement intracellular stimulation in a single nerve cell of the hippocampal areas in mouse brain slices combined with intracellular membrane potential recording and biophoton imaging techniques. We found that the simulated biophoton stimulation can lead to transsynaptic biophotonic activities and transmission in the ipsilateral and contralateral projection circuits in the hippocampus. The activity and transmission characteristics were related to the spectra and intensities of the simulated biophotons but not to the levels of membrane potentials before stimulation. These findings present specific characteristics of neural biophoton signal transmission, which may be involved in the mechanisms of processing, encoding, and storage of neural signals.

Inferring miRNA sponge modules across major neuropsychiatric disorders

The role of non-coding RNAs in neuropsychiatric disorders (NPDs) is an emerging field of study. The long non-coding RNAs (lncRNAs) are shown to sponge the microRNAs (miRNAs) from interacting with their target mRNAs. Investigating the sponge activity of lncRNAs in NPDs will provide further insights into biological mechanisms and help identify disease biomarkers. In this study, a large-scale inference of the lncRNA-related miRNA sponge network of pan-neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia (SCZ), and bipolar disorder (BD), was carried out using brain transcriptomic (RNA-Seq) data. The candidate miRNA sponge modules were identified based on the co-expression pattern of non-coding RNAs, sharing of miRNA binding sites, and sensitivity canonical correlation. miRNA sponge modules are associated with chemical synaptic transmission, nervous system development, metabolism, immune system response, ribosomes, and pathways in cancer. The identified modules showed similar and distinct gene expression patterns depending on the neuropsychiatric condition. The preservation of miRNA sponge modules was shown in the independent brain and blood-transcriptomic datasets of NPDs. We also identified miRNA sponging lncRNAs that may be potential diagnostic biomarkers for NPDs. Our study provides a comprehensive resource on miRNA sponging in NPDs.

Effect of Maternal Body Mass Index on the Transcriptomic Network of Human First-Trimester Chorionic Villi.

The relationship between fertility and maternal body weight is shaped like an inverted "U," meaning that fertility is negatively affected in overweight or underweight women. Timely and appropriate maternal-fetal interaction is a crucial part of successful pregnancy. However, it is not clear how body weight affects maternal-fetal interaction. Placental villi are the bridge for maternal-fetal interaction. Therefore, we collected villi from pregnant women with different body mass indexes (BMI), who voluntarily underwent induced abortion, to construct a molecular network via RNA-seq. Surprisingly, based on global and significant gene network analysis, we found that dysregulation of inflammatory reaction, cell adhesion, and immune response were the most significantly enriched pathways. We also conducted dynamic gene expression analysis with BMI as a variable, and identified several distinct clusters. Among them, cluster 9 showed an inverted "U" shape and genes in it were mainly enriched in chemical synaptic transmission and cell-cell adhesion via plasma-membrane adhesion molecules. Additionally, genes in the "U" shaped cluster (cluster 5) were enriched in regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains and negative regulation of immune response. We thus conclude that maternal body weight can affect maternal-fetal interaction through alterations or aberrant activation of inflammatory reaction and immune response. Regulating inflammatory reaction may be a potential therapeutic strategy to improve fertility of overweight and underweight people.

The Construction and Analysis of a ceRNA Network Related to Salt-Sensitivity Hypertensives.

Background Salt-sensitivity hypertensives (SSH) are an independent risk factor for cardiovascular disease. However, the mechanism of SSH is not clear. This study is aimed at constructing a competing endogenous RNA (ceRNA) network related to SSH. Methods Data sets were collected from the Gene Expression Omnibus database (GEO) to extract data on salt sensitivity RNA of patients with or without hypertensives in GSE135111. Firstly, we analyzed differentially expressed genes (DEGs, log2FC ≥ 0.5 and P < 0.05) and differentially expressed lncRNAs (DELs, log2FC ≥1 and P<0.05) between SSH and salt-sensitive normotension (SSN). Then, the gene ontology (GO), KEGG pathway enrichment analysis, and PPI network construction of DEGs were performed, and the hub genes in the PPI network by cytoHubba (12 methods) were screened out. Finally, a ceRNA network was constructed based on lncRNA-miRNA-mRNA pairs and hub genes. Results 163 DEGs and 65 DELs were screened out. The GO and KEGG pathway analyses of DEGs were mainly enriched in metabolism (e.g., insulin secretion and cellular response to glucagon stimulus and peptidyl-tyrosine dephosphorylation,) and plasma membrane signaling (e.g., cell adhesion and chemical synaptic transmission and integral component of membrane). Additionally, a ceRNA network, including 1 mRNA (EGLN3), 2 miRNAs (hsa-miR-17-5p and hsa-miR-20b-5p), and 1 lncRNA (C1orf143) was successfully constructed. Conclusions In conclusion, the proposed ceRNA network may help elucidate the regulatory mechanism by which lncRNAs function as ceRNAs and contribute to the pathogenesis of SSH. Importantly, candidate lncRNAs, miRNAs, and mRNAs can be further evaluated as a potential therapeutic targets for SSH.

An Integrative Analysis of Identified Schizophrenia-Associated Brain Cell Types and Gene Expression Changes.

Schizophrenia (SCZ) is a severe mental disorder that may result in hallucinations, delusions, and extremely disordered thinking. How each cell type in the brain contributes to SCZ occurrence is still unclear. Here, we leveraged the human dorsolateral prefrontal cortex bulk RNA-seq data, then used the RNA-seq deconvolution algorithm CIBERSORTx to generate SCZ brain single-cell RNA-seq data for a comprehensive analysis to understand SCZ-associated brain cell types and gene expression changes. Firstly, we observed that the proportions of brain cell types in SCZ differed from normal samples. Among these cell types, astrocyte, pericyte, and PAX6 cells were found to have a higher proportion in SCZ patients (astrocyte: SCZ = 0.163, control = 0.145, P.adj = 4.9 × 10−4, effect size = 0.478; pericyte: SCZ = 0.057, control = 0.066, P.adj = 1.1 × 10−4, effect size = 0.519; PAX6: SCZ = 0.014, control = 0.011, P.adj = 0.014, effect size = 0.377), while the L5/6_IT_CAR3 cells and LAMP5 cells are the exact opposite (L5/6_IT_Car3: SCZ = 0.102, control = 0.108, P.adj = 0.016, effect size = 0.369; LAMP5: SCZ = 0.057, control = 0.066, P.adj = 2.2 × 10−6, effect size = 0.617). Next, we investigated gene expression in cell types and functional pathways in SCZ. We observed chemical synaptic transmission dysregulation in two types of GABAergic neurons (PVALB and LAMP5), and immune reaction involvement in GABAergic neurons (SST) and non-neuronal cell types (endothelial and oligodendrocyte). Furthermore, we observed that some differential expression genes from bulk RNA-seq displayed cell-type-specific abnormalities in the expression of molecules in SCZ. Finally, the cell types with the SCZ-related transcriptomic changes could be considered to belong to the same module since we observed two major similar coordinated transcriptomic changes across these cell types. Together, our results offer novel insights into cellular heterogeneity and the molecular mechanisms underlying SCZ.

Hub genes for early diagnosis and therapy of adamantinomatous craniopharyngioma.

Background:Adamantinomatous craniopharyngioma (ACP) is a subtype of craniopharyngioma, a neoplastic disease with a benign pathological phenotype but a poor prognosis in the sellar region. The disease has been considered the most common congenital tumor in the skull. Therefore, this article aims to identify hub genes that might serve as genetic markers of diagnosis, treatment, and prognosis of ACP.Methods:The procedure of this research includes the acquisition of public data, identification and functional annotation of differentially expressed genes (DEGs), construction and analysis of protein-protein interaction network, and the mining and analysis of hub genes by Spearman-rho test, multivariable linear regression, and receiver operator characteristic curve analysis. Quantitative real-time polymerase chain reaction was used to detect the level of mRNA of relative genes.Results:Among 2 datasets, a total of 703 DEGs were identified, mainly enriched in chemical synaptic transmission, cell adhesion, odontogenesis of the dentin-containing tooth, cell junction, extracellular region, extracellular space, structural molecule activity, and structural constituent of cytoskeleton. The protein-protein interaction network was composed of 4379 edges and 589 nodes. Its significant module had 10 hub genes, and SYN1, SYP, and GRIA2 were significantly down-regulated with ACP.Conclusion:In a word, we find out the DEGs between ACP patients and standard samples, which are likely to play an essential role in the development of ACP. At the same time, these DEGs are of great value in tumors’ diagnosis and targeted therapy and could even be mined as biological molecular targets for diagnosing and treating ACP patients.

Network Pharmacology-Based Investigation on Therapeutic Mechanisms of the Angelica dahurica Radix and Ligusticum chuanxiong Rhizoma Herb Pair for Anti-Migraine Effect.

Migraines are a common neurological disorder characterized by desperate throbbing unilateral headaches and are related to phonophobia, photophobia, nausea, and vomiting. The Angelica dahurica Radix and Ligusticum chuanxiong Rhizoma herb pair (ALHP) has been used to treat migraines for centuries in traditional Chinese medicine (TCM). However, the physiological mechanisms of migraine treatment have not yet been elucidated. In this study, a total of 50 hub targets related to the effect of 28 bioactive compounds in ALHP on anti-migraine were obtained through network pharmacology analysis. GO and KEGG analyses of the hub targets demonstrated that ALHP treatment of migraines significantly involved the G-protein-coupled receptor signaling pathway, chemical synaptic transmission, inflammatory response, and other biological processes. According to the degree of gene targets in the network, ACE, SLC3A6, NR3CI, MAPK1, PTGS2, PIK3CA, RELA, GRIN1, GRM5, IL1B, and DRD2 were found to be the core gene targets. The docking results showed a high affinity for docked conformations between compounds and predicted targets. The results of this study suggest that ALHP could treat migraines by regulating immunological functions, diminishing inflammation, and improving immunity through different physiological pathways, which contributes to the scientific base for more in-depth research as well as for a more widespread clinical application of ALHP.

Integrated meta-analysis, data mining, and animal experiments to investigate the efficacy and potential pharmacological mechanism of a TCM tonic prescription, Jianpi Tongmai formula, in depression

BackgroundDepression is a common psychiatric disorder and has become a growing public health issue. Traditional Chinese medicine (TCM) tonic prescriptions have been clinically proven to be an effective treatment for depression. PurposeThis study aimed to identify the core prescription to improve depression among the numerous TCM tonic prescriptions. Methods and resultsFirst, we used meta-analysis to clarify the efficacy and safety of tonic prescriptions in depression among 37 studies and identified 16 effective tonic prescriptions. Second, we conducted data mining to analyze the tonic prescriptions and identified important nourishing herbs. Third, based on the data mining results, we constructed a Delphi experiment to investigate the effects of these important nourishing herbs in depression. Combining the results of Delphi expert questionnaires and weight analysis, a core TCM tonic prescription, Jianpi Tongmai formula (JPTMF) for the treatment of depression, was constructed and was composed of invigorating Spleen qi herbs. Fourth, we verified that JPTMF can improve chronic unpredictable mild stress (CUMS) induced depression-like behaviors in mice. Fifth, we predicted that the mechanism of JPTMF in the treatment of depression was mainly associated with chemical synaptic transmission and neuroinflammation through network pharmacology and determined preliminary confirmation through animal experiments. ConclusionThis study was undertaken to evaluate the efficacy of TCM tonic prescriptions on depression and construct a core TCM tonic prescription, JPTMF, through a progressive analysis. Network pharmacology and animal experiments verified the reliability of JPTMF. The proposal of JPTMF is of innovative significance, and may provide far-reaching implications for improving depression by using nourishing herbs. Furthermore, the integrated methods applied in this study provide an innovative paradigm for the standardization and scientific basis of TCM research.

Identification of a costimulatory molecule-based signature to predict prognostic risk of pancreatic adenocarcinoma

We aimed to investigate the prognostic value of costimulatory molecules in PAAD by generating a CMS. Gene expression data and clinical factors of PAAD patients were obtained from TCGA. The signature was constructed using the survival package progressive Cox risk proportional regression model. Analyses of CMS-related genes, pathways, immune cell infiltration, and somatic mutations were conducted. A five-gene-based CMS was developed, and the risk score for CMS could be an independent risk factor for PAAD patients. Patients were divided into high- and low-risk groups based on the median Y of the CMS model. Differential analysis revealed 341 DEGs between the groups, and KEGG analysis demonstrated that these positively related genes in the high-risk group were mainly involved in chemical synaptic transmission pathway modulation and trans-synaptic signaling pathway regulation. Immune cell infiltration analysis revealed that the high-risk patients had higher proportions of M1 macrophages and T+ CD4 cells, but a lower proportion of M2 macrophages than that of the low-risk group. Mutational analysis revealed that the high-risk group showed a higher proportion of somatic mutations compared with that of the low-risk group. A CMS was developed, and the risk score could be an independent risk factor for PAAD patients.