Neuroactive Ligand-receptor Interaction Pathway Research Articles

High-gamma frequency flash stimulation as a possible cognitive facilitator in rat pups

High-gamma frequency flashes can enhance cognition by synchronizing neural oscillations in mammals. Early flash treatment promotes the development of improved cognitive functions in young children. However, it is unclear whether exposure to high-gamma frequency flashes in preschool-aged individuals affects cognition in preadolescents by regulating neural oscillations in the brain. Here, we aimed to investigate the effects of gamma-frequency flashes on cognitive ability. In this study, the effect of high-frequency flicker on cognitive performance was verified by behavioural experiments such as the open-field test and the water maze, but also proteomics. We found that external 40 Hz and 70 Hz frequency flashes synchronized neural oscillations at the corresponding frequencies in the primary visual cortex (V1) of rats. Rats that underwent 70 Hz flash intervention had better cognitive behavioural performance in the early stages of training. The 70 Hz flash frequency upregulated proteins associated with neuronal growth and differentiation, such as Snapin, FoxO3, Hspa12a, and Penk, and activated the MAPK signalling pathway, signalling pathway regulating stem cell pluripotency, and the neuroactive ligand-receptor interaction pathway. These proteins and pathways play important roles in cognitive functions. Our study revealed that 70 Hz flashes received by young children early in their development substantially promote the growth of cognitive capabilities in the brain. Exposure to 70 Hz flashes may be a new intervention method and a new strategy for improving cognition.

Exploring the potential pharmacological mechanism of aripiprazole against hyperprolactinemia based on network pharmacology and molecular docking

The current primary therapeutic approach for schizophrenia is antipsychotic medication, and antipsychotic-induced hyperprolactinemia occurs in 40–80% of patients with schizophrenia. Aripiprazole, an atypical antipsychotic belonging to the quinolinone derivative class, can reduce the likelihood of developing hyperprolactinemia, but the pharmacological mechanisms of this reduction are unknown. This study aimed to explore the molecular mechanism of action of aripiprazole in treating hyperprolactinemia based on network pharmacology and molecular docking techniques. This study identified a total of 151 potential targets for aripiprazole from the DrugBank, TCMSP, BATMAN-TCM, TargetNet, and SwissTargetPrediction databases. Additionally, 71 hyperprolactinemia targets were obtained from the PharmGKB, DrugBank, TTD, GeneCards, OMIM, and DisGENET databases. Utilizing Venny 2.1.0 software, an intersection of 27 genes was identified between aripiprazole and hyperprolactinemia. To construct a common target protein–protein interaction (PPI) network, the common targets obtained from both sources were input into the STRING database. The resulting PPI network was then imported into Cytoscape 3.7.2 software, which identified eight core targets associated with aripiprazole’s treatment of hyperprolactinemia. Subsequently, a PPI network was established for these targets. Enrichment analysis of the key targets was conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes in the DAVID database. Additionally, molecular docking verification of the interaction between aripiprazole and the core targets was performed using AutoDock Vina software. Aripiprazole’s intervention in hyperprolactinemia primarily targets the following core proteins: Solute Carrier Family 6 Member 3 (SLC6A3), monoamine oxidase (MAO-B), Dopamine D2 receptor (DRD2), 5-hydroxytryptamine (serotonin) receptor 2A (HTR2A), 5-hydroxytryptamine (serotonin) receptor 2C (HTR2C), cytochrome P450 2D6 (CYP2D6), Dopamine D1 receptor (DRD1), Dopamine D4 receptor (DRD4). These targets are predominantly involved in biological processes such as the adenylate cyclase-activating adrenergic receptor signaling pathway, G-protein coupled receptor signaling pathway coupled to cyclic nucleotide second messenger, phospholipase C-activating G-protein coupled receptor signaling pathway, chemical synaptic transmission, and response to xenobiotic stimulus. Primary enrichment occurs in signaling pathways such as the neuroactive ligand-receptor interaction and serotonergic synapse pathways. Molecular docking results demonstrate a favorable affinity between aripiprazole and the core target proteins MAO-B, DRD2, SLC6A3, HTR2C, HTR2A, CYP2D6, DRD4, and DRD1. Network pharmacology predicted potential targets and signaling pathways for aripiprazole’s intervention in hyperprolactinemia, offering theoretical support and a reference basis for optimizing clinical strategies and drug development involving aripiprazole.

Effect of high mobility group box 1 pathway inhibition on gene expression in the prefrontal cortex of mice exposed to alcohol

The high mobility group box 1 (HMGB1) pathway plays a pivotal role in the development of alcohol-induced brain injury. Glycyrrhizinic acid (GlyA) is widely regarded as an inhibitor of HMGB1. The objective is to investigate the impact on gene expression in the prefrontal cortex,we sequenced the transcriptome in control, alcohol-exposed, and HMGB1-inhibited groups of mice. We verified our findings by real-time quantitative PCR (qRT-PCR). An alcohol exposure model was established in mice by intraperitoneal injection of alcohol. Transcriptome sequencing and bioinformatics analyses were performed on prefrontal cortex tissue. Kyoto Encyclopedia of Genes and Genomes analysis was performed to identify pivotal pathways of differentially expressed genes. The role of relevant genes was verified by qRT-PCR. Expression of genes involved in the neuroactive ligand-receptor interaction pathway exhibited an increase in mice from the alcohol-exposed group.However, there were no significant differences observed in the expression of these genes between control and those receiving an intraperitoneal injection of alcohol along with a HMGB1 inhibitor. Mice in the alcohol-exposed group showed increased gene expression of Cysltr2, Chrna6, Chrna3, Chrnb4, and Pmch. Expression of these genes was decreased in mice injected with HMGB1 inhibitor. Our study demonstrates that alcohol primarily influences gene expression in the prefrontal cortex of mice through the neuroactive ligand-receptor interaction pathway. HMGB1 inhibitor effectively inhibited the expression of this pathway. This study provides a novel route for drug development in alcohol-induced brain injury.

LDH nanoparticles-doped cellulose nanofiber scaffolds with aligned microchannels direct high-efficiency neural regeneration and organized neural circuit remodeling through RhoA/Rock/Myosin II pathway

Spinal cord injury (SCI) triggers interconnected malignant pathological cascades culminating in structural abnormalities and composition changes of neural tissues and impairs spinal cord tissue function. Cellulose nanofibers (CNF) have considerable potential in mimicking tissue microstructure for nerve regeneration, but the effectiveness of CNF in repairing SCI remains poorly understood. In this study, we designed a Mg–Fe layered double hydroxide (LDH)-doped cellulose nanofiber (CNF) scaffold with aligned intact microchannels and homogeneously distributed pores (CNF-LDH), loaded with retinoic acid and sonic hedgehog (CNF-LDH-RS) for neuroregeneration. The aligned microchannel structure and chemical cues in the scaffold were designed further to enhance the differentiation of neural stem cells towards neurons and promote axon growth while inhibiting differentiation to astrocytes. Transplanting the scaffolds into a completely transected SCI mice model dramatically improved behavioral and electrophysiological outcomes underpinned by robust neuronal regeneration, significant axonal growth and orderly neural circuit remodeling. RNA-seq analysis revealed the pivotal roles of the RhoA/Rock/Myosin II pathway and neuroactive ligand-receptor interaction pathway in SCI repair by CNF-LDH-RS. Particularly, Myosin II emerged as a key gene for functional recovery, and its effect on negative regulation of axon growth was suppressed by the scaffolds, resulting in a distinctly oriented growth of the axons along the microchannel structure. The results indicate that CNF-LDH scaffolds rationally combined with physical and biochemical cues create promising tissue-engineered substrates to facilitate the repair of spinal cord injury.

Prefrontal cortex astrocytes in major depressive disorder: exploring pathogenic mechanisms and potential therapeutic targets.

Major depressive disorder (MDD) is a prevalent mental health condition characterized by persistent feelings of sadness and hopelessness, affecting millions globally. The precise molecular mechanisms underlying MDD remain elusive, necessitating comprehensive investigations. Our study integrates transcriptomic analysis, functional assays, and computational modeling to explore the molecular landscape of MDD, focusing on the DLPFC. We identify key genomic alterations and co-expression modules associated with MDD, highlighting potential therapeutic targets. Functional enrichment and protein-protein interaction analyses emphasize the role of astrocytes in MDD progression. Machine learning is employed to develop a predictive model for MDD risk assessment. Single-cell and spatial transcriptomic analyses provide insights into cell type-specific expression patterns, particularly regarding astrocytes. We have identified significant genomic alterations and co-expression modules associated with MDD in the DLPFC. Key genes involved in neuroactive ligand-receptor interaction pathways, notably in astrocytes, have been highlighted. Additionally, we developed a predictive model for MDD risk assessment based on selected key genes. Single-cell and spatial transcriptomic analyses underscored the role of astrocytes in MDD. Virtual screening of compounds targeting GPR37L1, KCNJ10, and PPP1R3C proteins has identified potential therapeutic candidates. In summary, our comprehensive approach enhances the understanding of MDD's molecular underpinnings and offers promising opportunities for advancing therapeutic interventions, ultimately aiming to alleviate the burden of this debilitating mental health condition. KEY MESSAGES: Our investigation furnishes insightful revelations concerning the dysregulation of astrocyte-associated processes in MDD. We have pinpointed specific genes, namely KCNJ10, PPP1R3C, and GPR37L1, as potential candidates warranting further exploration and therapeutic intervention. We incorporate a virtual screening of small molecule compounds targeting KCNJ10, PPP1R3C, and GPR37L1, presenting a promising trajectory for drug discovery in MDD.

Characterization of natural compounds derived from diatom C. gracilis as potential therapeutic agents: An in-silico networking and docking study

Marine diatom Chaetoceros gracilis have been known as the key player regulating the nutritional content of aquaculture species. Being able to synthesize an array of high value bioactive compounds like amino acids, lipids, terpenoids and polysaccharides, it also serves as potential therapeutic and nutraceutical agent. This in silico-based study elucidates the interactive association of different compounds, proteins and pathways of the diatom C. gracilis through an integrated network pharmacology and molecular docking approach. According to the Network analysis of the 41 compounds detected, saturated hydrocarbons, diterpenoids and phenolic compounds scored the highest degree (score > 140). These compounds were further coded for approximately 349 protein targets and almost 490 different pathways. HSP90AA1, STAT3, HIF1A, MTOR, ESR1, PIK3CA, MAPK1 and PTGS2 secured highest degree of protein-protein interaction according to STRING database. The gene enrichment analysis further revealed that these proteins were closely associated with metabolic pathways like Pathways in cancer, neuroactive ligand-receptor interaction, calcium and cAMP signaling pathway, PI3K-Akt signaling pathway, Alzheimer's disease and pathways of neurodegeneration which played an instrumental role in the metabolism of diseases and disorders like cancers of breast, prostrate, and liver, schizophrenia and other mental and hypertensive disorders. Furthermore, the molecular docking and toxicity assessment of a few novel compounds was done with mTOR and HSP90AA1 which revealed promising and stable interactions. Thus, this study provides the first in silico insight outlining the anti-cancerous and neuroprotective potential of novel bioactive compounds derived from marine diatom C.gracilis.

SRF Facilitates Transcriptional Inhibition of Gem Expression by m6A Methyltransferase METTL3 to Suppress Neuronal Damage in Epilepsy.

A bioinformatics analysis was conducted to screen for relevant expression datasets of the transcription factor SRF knockout mice. The aim was to investigate the relationship between SRF and m6A-related genes, predict how SRF regulates the m6A modification of GEM genes mediated by METTL3, and explore potential molecular mechanisms associated with neurotrauma. Disease gene databases such as GeneCards, DisGeNET, and Phenolyzer, and transcription factor databases TFDB and TRRUST, were used to obtain epilepsy-related genes and transcription factors. The intersection was then selected. Expression data of SRF knockout epilepsy mice were obtained from the GEO database and used to filter differentially expressed genes. Important module genes related to the disease were selected through WGCNA co-expression analysis. The intersection between these genes and the differentially expressed genes was performed, followed by PPI network analysis and GO/KEGG enrichment analysis. Furthermore, the core genes were selected using the cytoHubba plugin of the Cytoscape software. Differential expression analysis was performed on m6A-related factors in the GEO dataset, and the relationship between SRF and m6A-related factors and core genes was analyzed. The m6A binding sites of SRF with the METTL3 promoter and target gene Gem were predicted using the AnimalTFDB and SRAMP websites, respectively. We found that the transcription factor SRF may be a key gene in epilepsy during neuronal development. Further WGCNA analysis showed that 129 module genes were associated with SRF knockout epilepsy, and these differentially expressed genes were mainly enriched in the neuroactive ligand-receptor interaction pathway. The final results indicate that knocking out SRF may inhibit the transcription of METTL3, thereby inhibiting the m6A modification of Gem and leading to upregulation of Gem expression, thereby playing an important role in neuronal damage. Knocking out the SRF gene may inhibit the transcription of m6A methyltransferase METTL3, thereby inhibiting the m6A modification of GEM genes mediated by METTL3, promoting GEM gene expression, and leading to the occurrence of epilepsy-related neuron injury. Further investigation revealed that SRF overexpression can potentially enhance the transcription of METTL3, thus promoting m6A modification of GEM, resulting in downregulation of GEM expression. This process regulates oxidative stress in epileptic mouse neurons, suppresses inflammatory responses, and mitigates associated damage. Additionally, an in vitro neuronal epileptic model was established, and experimental techniques such as qRT-PCR and WB were employed to assess the expression of SRF, METTL3, and GEM in hippocampal tissues and neurons. The experimental results were consistent with our predictions, demonstrating that overexpression of SRF can inhibit the development of epilepsy-related neuronal damage. This study reveals that knockout of the SRF gene may suppress the transcription of m6A methyltransferase METTL3, thereby inhibiting m6A modification of the GEM gene mediated by METTL3 and subsequently promoting the expression of the GEM gene, leading to the occurrence of epilepsy-related neuronal damage.

Hydrolyzed Chicken Meat Extract and Its Bioactive Cyclopeptides Protect Neural Function by Attenuating Inflammation and Apoptosis via PI3K/AKT and AMPK Pathways.

Cognitive decline is inevitable with age, and due to the lack of well-established pharmacotherapies for neurodegenerative disorders, dietary supplements have become important alternatives to ameliorate brain deterioration. Hydrolyzed chicken meat extract (HCE) and its bioactive components were previously found to improve neuroinflammation and cognitive decline by regulating microglia polarization. However, the effects and mechanisms of these bioactives on neurons remain unclear. Here, the most potent bioactive component on neural function in HCE was screened out, and the detailed mechanism was clarified through in vivo and in vitro experiments. We found that HCE, cyclo(Val-Pro), cyclo(Phe-Phe), cyclo(His-Pro), cyclo(Leu-Lys), and arginine exerted stronger anti-inflammatory and antioxidant effects among the 12 bioactives in amyloid β (Aβ)-treated HT-22 cells. Further transcriptome sequencing and polymerase chain reaction (PCR) array analysis showed that these bioactives participated in different signaling pathways, and cyclo(Val-Pro) was identified as the most potent cyclic dipeptide. In addition, the antiapoptotic and neuroprotective effect of cyclo(Val-Pro) was partly regulated by the activation of PI3K/AKT and AMPK pathways, and the inhibition of these pathways abolished the effect of cyclo(Val-Pro). Moreover, cyclo(Val-Pro) enhanced cognitive function and neurogenesis and alleviated neuroinflammation and oxidative stress in middle-aged mice, with an effect similar to HCE. Hippocampal transcriptome analysis further revealed that HCE and cyclo(Val-Pro) significantly enriched the neuroactive ligand-receptor interaction pathway, verified by enhanced neurotransmitter levels and upregulated neurotransmitter receptor-related gene expression. Therefore, the mechanism of cyclo(Val-Pro) on neural function might be associated with PI3K/AKT and AMPK pathway-mediated antiapoptotic effect and neurogenesis and the activation of the neurotransmitter-receptor pathway.

Enantioselective toxicity of the neonicotinoid dinotefuran on honeybee (Apis mellifera) larvae

The threat of neonicotinoids to insect pollinators, particularly honeybees (Apis mellifera), is a global concern, but the risk of chiral neonicotinoids to insect larvae remains poorly understood. In the current study, we evaluated the acute and chronic toxicity of dinotefuran enantiomers to honeybee larvae in vitro and explored the mechanism of toxicity. The results showed that the acute median lethal dose (LD50) of S-dinotefuran to honeybee larvae was 30.0 μg/larva after oral exposure for 72 h, which was more toxic than rac-dinotefuran (92.7 μg/larva) and R-dinotefuran (183.6 μg/larva). Although the acute toxicity of the three forms of dinotefuran to larvae was lower than that to adults, chronic exposure significantly reduced larval survival, larval weight, and weight of newly emerged adults. Analysis of gene expression and hormone titer indicated that dinotefuran affects larval growth and development by interfering with nutrient digestion and absorption and the molting system. Analysis of hemolymph metabolome further revealed that disturbances in the neuroactive ligand-receptor interaction pathway and energy metabolism are the key mechanisms of dinotefuran toxicity to bee larvae. In addition, melatonin and vitellogenin are used by larvae to cope with dinotefuran-induced oxidative stress. Our results contribute to a comprehensive understanding of dinotefuran damage to bees and provide new insights into the mechanism of enantioselective toxicity of insecticides to insect larvae.

Comparison of Brain Gene Expression Profiles Associated with Auto-Grooming Behavior between Apis cerana and Apis mellifera Infested by Varroa destructor.

The grooming behavior of honeybees serves as a crucial auto-protective mechanism against Varroa mite infestations. Compared to Apis mellifera, Apis cerana demonstrates more effective grooming behavior in removing Varroa mites from the bodies of infested bees. However, the underlying mechanisms regulating grooming behavior remain elusive. In this study, we evaluated the efficacy of the auto-grooming behavior between A. cerana and A. mellifera and employed RNA-sequencing technology to identify differentially expressed genes (DEGs) in bee brains with varying degrees of grooming behavior intensity. We observed that A. cerana exhibited a higher frequency of mite removal between day 5 and day 15 compared to A. mellifera, with day-9 bees showing the highest frequency of mite removal in A. cerana. RNA-sequencing results revealed the differential expression of the HTR2A and SLC17A8 genes in A. cerana and the CCKAR and TpnC47D genes in A. mellifera. Subsequent homology analysis identified the HTR2A gene and SLC17A8 gene of A. cerana as homologous to the HTR2A gene and SLC17A7 gene of A. mellifera. These DEGs are annotated in the neuroactive ligand-receptor interaction pathway, the glutamatergic synaptic pathway, and the calcium signaling pathway. Moreover, CCKAR, TpnC47D, HTR2A, and SLC17A7 may be closely related to the auto-grooming behavior of A. mellifera, conferring resistance against Varroa infestation. Our results further explain the relationship between honeybee grooming behavior and brain function at the molecular level and provide a reference basis for further studies of the mechanism of honeybee grooming behavior.

Transcriptomics of pectoralis major muscles uncovers a footprint of enriched pathways in five diverse backyard chicken breeds of India

Genetic diversity existing between the chicken breeds can be used as a means to unravel the biological mechanisms affecting traits of commercial prominence. The present study attempted to compare the biological pathways enriched in pectoralis major muscles in five diverse chicken breeds. RNA sequencing data was generated from four biological replicates of pectoralis major muscles from Ankleshwar, Aseel, Kadaknath, Punjab Brown and Nicobari chicken. A total of 40 genes each for Nicobari and Aseel, 46 for Punjab Brown, 65 for Kadaknath and 86 for Ankaleshwar were found to be unique. The Neuroactive ligand-receptor interaction pathway was enriched in Ankaleshwar, Aseel and Kadaknath. However, the set of genes identified in this pathway were associated with different ligand receptors in each of the three breeds. The Wnt signaling pathway showed significant enrichment in Nicobari chicken while the Steroid biosynthesis pathway showed prominent expression in Punjab Brown chicken. The significant pathways pinpoint to genetic characteristics associated with each breed suggesting a transcriptome footprint. Our study is a first step toward determining the genetic basis of phenotypic diversity in chicken.

Identification of genes associated with sperm storage capacity in hens at different times after insemination by RNA-seq and Ribo-seq

BackgroundSperm storage capacity (SSC) determines the duration of fertility in hens and is an important reproduction trait that cannot be ignored in production. Currently, the genetic mechanism of SSC is still unclear in hens. Therefore, to explore the genetic basis of SSC, we analyzed the uterus-vagina junction (UVJ) of hens with different SSC at different times after insemination by RNA-seq and Ribo-seq.ResultsOur results showed that 589, 596, and 527 differentially expressed genes (DEGs), 730, 783, and 324 differentially translated genes (DTGs), and 804, 625, and 467 differential translation efficiency genes (DTEGs) were detected on the 5th, 10th, and 15th days after insemination, respectively. In transcription levels, we found that the differences of SSC at different times after insemination were mainly reflected in the transmission of information between cells, the composition of intercellular adhesion complexes, the regulation of ion channels, the regulation of cellular physiological activities, the composition of cells, and the composition of cell membranes. In translation efficiency (TE) levels, the differences of SSC were mainly related to the physiological and metabolic activities in the cell, the composition of the organelle membrane, the physiological activities of oxidation, cell components, and cell growth processes. According to pathway analysis, SSC was related to neuroactive ligand-receptor interaction, histidine metabolism, and PPAR signaling pathway at the transcriptional level and glutathione metabolism, oxidative phosphorylation, calcium signaling pathway, cell adhesion molecules, galactose metabolism, and Wnt signaling pathway at the TE level. We screened candidate genes affecting SSC at transcriptional levels (COL4A4, MUC6, MCHR2, TACR1, AVPR1A, COL1A1, HK2, RB1, VIPR2, HMGCS2) and TE levels(COL4A4, MUC6, CYCS, NDUFA13, CYTB, RRM2, CAMK4, HRH2, LCT, GCK, GALT). Among them, COL4A4 and MUC6 were the key candidate genes differing in transcription, translation, and translation efficiency.ConclusionsOur study used the combined analysis of RNA-seq and Ribo-seq for the first time to investigate the SSC and reveal the physiological processes associated with SSC. The key candidate genes affecting SSC were screened, and the theoretical basis was provided for the analysis of the molecular regulation mechanism of SSC.

Ionizing radiation induces neurotoxicity in Xenopus laevis embryos through neuroactive ligand-receptor interaction pathway

Ionizing radiation (IR) poses a significant threat to both the natural environment and biological health. Exposure to specific doses of ionizing radiation early in an organism's development can lead to developmental toxicity, particularly neurotoxicity. Through experimentation with Xenopus laevis (X. laevis), we examined the effects of radiation on early developmental stage. Our findings revealed that radiation led to developmental abnormalities and mortality in X. laevis embryos in a dose-dependent manner, disrupting redox homeostasis and inducing cell apoptosis. Additionally, radiation caused neurotoxic effects, resulting in abnormal behavior and neuron damage in the embryos. Further investigation into the underlying mechanisms of radiation-induced neurotoxicity indicated the potential involvement of the neuroactive ligand-receptor interaction pathway, which was supported by RNA-Seq analysis. Validation of gene expression associated with this pathway and analysis of neurotransmitter levels confirmed our hypothesis. In addition, we further validated the important role of this signaling pathway in radiation-induced neurotoxicity through edaravone rescue experiments. This research establishes a valuable model for radiation damage studying and provides some insight into radiation-induced neurotoxicity mechanisms.

The Potential Antinociceptive Effect and Mechanism of Cannabis sativa L. Extract on Paclitaxel-Induced Neuropathic Pain in Rats Uncovered by Multi-Omics Analysis.

Cannabis sativa L. (hemp) is a herbaceous plant rich in cannabinoids with a long history of use in pain treatment. The most well-characterized cannabinoids, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC), garnered much attention in chemotherapy-induced peripheral neuropathy (CIPN) treatment. However, few studies have investigated the biological benefits and mechanism of hemp extract on CIPN. In the present study, hemp extract (JG) rich in cannabinoids was extracted by supercritical fluid carbon dioxide extraction (SFCE). The antinociceptive efficacy was evaluated using a paclitaxel-induced peripheral neuropathy (PIPN) rat model based on behavioral tests. Further omics-based approaches were applied to explore the potential mechanisms. The results showed that JG decreased mechanical allodynia, thermal hyperalgesia, and inflammatory cytokines in PIPN rats significantly. Transcriptome analysis identified seven key genes significantly regulated by JG in PIPN model rats, mainly related to the neuroactive ligand-receptor interaction pathway, PPAR signaling pathway, and cAMP signaling pathway. In metabolomic analysis, a total of 39 significantly altered metabolites were identified, mainly correlated with pentose and glucuronate interconversions and the glycerophospholipid metabolism pathway. Gut microbiota analysis suggested that increased community Lachnoclostridium and Lachnospiraceae_UCG-006 in PIPN rats can be reversed significantly by JG. In conclusion, hemp extract exhibited antinociceptive effects on PIPN. The analgesic mechanism was probably related to the regulation of inflammation, neuroactive ligand-receptor interaction pathway, sphingolipid metabolism, etc. This study provides novel insights into the functional interactions of Cannabis sativa L. extract on PIPN.

Deciphering the therapeutic potential of SheXiangXinTongNing: Interplay between gut microbiota and brain metabolomics in a CUMS mice model, with a focus on tryptophan metabolism

Depression, a prevalent and multifaceted mental disorder, has emerged as a significant public health concern due to its escalating prevalence and heightened risk of severe suicidality. Given its profound impact, the imperative for preventing and intervening in depression is paramount. Substantial evidence underscores intricate connections between depression and cardiovascular health. SheXiangXinTongNing (XTN), a recognized traditional Chinese medicine for treating Coronary Heart Disease (CHD), prompted our exploration into its antidepressant effects and underlying mechanisms. In this investigation, we assessed XTN's antidepressant potential using the chronic unpredictable mild stress (CUMS) mice model and behavioral tests. Employing network pharmacology, we delved into the intricate mechanisms at play. We characterized the microbial composition and function in CUMS mice, both with and without XTN treatment, utilizing 16S rRNA sequencing and metabolomics analysis. The joint analysis of these results via Cytoscape identified pivotal metabolic pathways. In the realm of network pharmacology, XTN administration exhibited antidepressant effects by modulating pathways such as IL-17, neuroactive ligand-receptor interaction, PI3K-Akt, cAMP, calcium, and dopamine synapse signaling pathways. Our findings revealed that XTN significantly mitigated depression-like symptoms and cognitive deficits in CUMS mice by inhibiting neuroinflammation and pyroptosis. Furthermore, 16S rRNA sequencing unveiled that XTN increased the alpha-diversity and beta-diversity of the gut microbiome in CUMS mice. Metabolomics analysis identified brain metabolites crucial for distinguishing between the CUMS and CUMS+XTN groups, with a focus on pathways like Tryptophan metabolism and Linoleic acid metabolism. Notably, specific bacterial families, including Alloprevotella, Helicobacter, Allobaculum, and Clostridia, exhibited robust co-occurring relationships with brain tryptophan metabolomics, hinting at the potential mediating role of gut microbiome alterations and metabolites in the efficacy of XTN treatment. In conclusion, our study unveils modifications in microbial compositions and metabolic functions may be pivotal in understanding the response to XTN treatment, offering novel insights into the mechanisms underpinning the efficacy of antidepressants.

Hypoglycemic Activity of Rice Resistant-Starch Metabolites: A Mechanistic Network Pharmacology and In Vitro Approach.

Rice (Oryza sativa L.) is one of the primary sources of energy and nutrients needed by the body, and rice resistant starch (RRS) has been found to have hypoglycemic effects. However, its biological activity and specific mechanisms still need to be further elucidated. In the present study, 52 RRS differential metabolites were obtained from mouse liver, rat serum, canine feces, and human urine, and 246 potential targets were identified through a literature review and database analysis. A total of 151 common targets were identified by intersecting them with the targets of type 2 diabetes mellitus (T2DM). After network pharmacology analysis, 11 core metabolites were identified, including linolenic acid, chenodeoxycholic acid, ursodeoxycholic acid, deoxycholic acid, lithocholic acid, lithocholylglycine, glycoursodeoxycholic acid, phenylalanine, norepinephrine, cholic acid, and L-glutamic acid, and 16 core targets were identified, including MAPK3, MAPK1, EGFR, ESR1, PRKCA, FYN, LCK, DLG4, ITGB1, IL6, PTPN11, RARA, NR3C1, PTPN6, PPARA, and ITGAV. The core pathways included the neuroactive ligand-receptor interaction, cancer, and arachidonic acid metabolism pathways. The molecular docking results showed that bile acids such as glycoursodeoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, lithocholic acid, deoxycholic acid, and cholic acid exhibited strong docking effects with EGFR, ITGAV, ITGB1, MAPK3, NR3C1, α-glucosidase, and α-amylase. In vitro hypoglycemic experiments further suggested that bile acids showed significant inhibitory effects on α-glucosidase and α-amylase, with CDCA and UDCA having the most prominent inhibitory effect. In summary, this study reveals a possible hypoglycemic pathway of RRS metabolites and provides new research perspectives to further explore the therapeutic mechanism of bile acids in T2DM.

Integration of Whole-Genome Resequencing and Transcriptome Sequencing Reveals Candidate Genes in High Glossiness of Eggshell.

Eggshell gloss is an important characteristic for the manifestation of eggshell appearance. However, no study has yet identified potential candidate genes for eggshell gloss between high-gloss (HG) and low-gloss (LG) chickens. The aim of this study was to perform a preliminary investigation into the formation mechanism of eggshell gloss and to identify potential genes. The eggshell gloss of 300-day-old Rhode Island Red hens was measured from three aspects. Uterine tissues of the selected HG and LG (n = 5) hens were collected for RNA-seq. Blood samples were also collected for whole-genome resequencing (WGRS). RNA-seq analysis showed that 150 differentially expressed genes (DEGs) were identified in the uterine tissues of HG and LG hens. These DEGs were mainly enriched in the calcium signaling pathway and the neuroactive ligand-receptor interaction pathway. Importantly, these two pathways were also significantly enriched in the WGRS analysis results. Further joint analysis of WGRS and RNA-seq data revealed that 5-hydroxytryptamine receptor 1F (HTR1F), zinc finger protein 536 (ZNF536), NEDD8 ubiquitin-like modifier (NEDD8), nerve growth factor (NGF) and calmodulin 1 (CALM1) are potential candidate genes for eggshell gloss. In summary, our research provides a reference for the study of eggshell gloss and lays a foundation for improving egg glossiness in layer breeding.

Antidepressant and anxiolytic potential of Citrus reticulata Blanco essential oil: a network pharmacology and animal model study.

Citrus reticulata Blanco essential oil (CBEO) has attracted increasing attention as a potential treatment for depression and anxiety in recent years. However, there is limited evidence regarding the active compounds responsible for its therapeutic effects. In addition, substantial amounts of CBEO and prolonged therapy are often required. This study aims to investigate the rapid acting antidepressant and anxiolytic effects of CBEO, identify the underlying composition as well as optimize its dosage and duration. CBEO composition was determined using gas chromatography-mass spectrometry (GC-MS), and the corresponding targets were obtained from the SwissTargetPrediction database. Depression-related targets were collected from DisGeNET, GeneCards, Therapeutic Target Database, and Online Mendelian Inheritance in Man. Subsequently, the overlap between CBEO and depression targets was utilized to build a network diagram depicting the relationship between the active ingredients and targets using Cytoscape software. The STRING database facilitated the construction of a protein-protein interaction network, and the Ma'ayan Laboratory Enrichment tool was employed for Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Wiki pathway analyses. Molecular docking was conducted using AutoDock Vina and Discovery Studio Visualizer. Topological analysis predicted the main antidepressant active ingredients in CBEO. A mixture of these compounds was prepared based on their relative GC-MS ratios. Tail suspension test, elevated plus maze, corticosterone-induced PC12 cells, and lipopolysaccharide (LPS)-induced BV2 cells were used to validate the antidepressant and anxiolytic potential of CBEO and CBEO's main bioactive constituents. CBEO contains 18 components that target 121 proteins. We identified 595 targets associated with depression; among them, 29 targets were located between essential oils and depression. Topological results revealed that linalool, p-cymene, α-terpinene, terpinen-4-ol, and α-terpineol were the major active compounds of CBEO in the management of depression. GO analysis identified G protein-coupled opioid receptor activity, phospholipase C-activating G protein-coupled receptor, and neuron projections that were mostly related to molecular functions, cellular components, and biological processes. Neuroactive ligand-receptor interactions, chemical carcinogenesis, and calcium signaling pathways were the major pathways identified in KEGG analysis. Molecular docking showed that the main bioactive ingredients of CBEO had favorable binding affinities for Protein-Protein Interaction's hub proteins, including OPRM1, PTGS2, ESR1, SLC6A4, DRD2, and NR3C1. These five compounds were then mixed at 0.8:5:0.6:2:1 (w/w) ratio to form a CBEO antidepressant active compound mixture. An acute intranasal treatment of CBEO (25mg/kg) only demonstrated an antidepressant effect, whereas the main bioactive compounds combination (12.5mg/kg) illustrated both antidepressant and anxiolytic effects in mice. Linalool, p-cymene, and terpinene-4-ol exhibited neuroprotective and anti-neuroinflammation in the in vitro study, while these effects were not observed for α-terpinene and α-terpineol. Linalool, p-cymene, α-terpinene, terpinen-4-ol, and α-terpineol cymene might be mainly contributing to CBEO's antidepressant effect by regulating neuroactive ligand-receptor interaction, neuron projection, and receptor signaling pathway. A mixture of these compounds showed rapid antidepressant potential via intranasal administration, which was comparable to that of CBEO. The mixture also exhibited an anxiolytic effect while not seen in CBEO.

Cerebral Artery Overexpression of the NMUR1 Gene Is Associated with Moyamoya Disease: A Weighted Gene Co-Expression Network Analysis

Introduction: This study aimed to elucidate mechanisms underlying moyamoya disease (MMD) pathogenesis and to identify potential novel biomarkers. We utilized gene co-expression networks to identify hub genes associated with the disease. Methods: Twenty-one middle cerebral artery (MCA) samples from MMD patients and 11 MCA control samples were obtained from the Gene Expression Omnibus (GEO) dataset, GSE189993. To discover functional pathways and potential biomarkers, weighted gene co-expression network analysis (WGCNA) was employed. The hub genes identified were re-assessed through differential gene expression analysis (DGEA) via DESeq2 for further reliability verification. Additional 4 samples from the superficial temporal arteries (STAs) from MMD patients were obtained from GSE141025, and a subgroup analysis stratified by arterial type (MCA vs. STA) DGEA was performed to assess if the hub genes associated with MMD are expressed significantly greater on the affected arteries compared to healthy ones in MMD. Results: WGCNA revealed a predominant module encompassing 139 hub genes, predominantly associated with the neuroactive ligand-receptor interaction (NLRI) pathway. Of those, 17 genes were validated as significantly differentially expressed. Neuromedin U receptor 1 (NMUR1) and thyrotropin-releasing hormone were 2 out of the 17 hub genes involved in the NLRI pathway (log fold change [logFC]: 1.150, p = 0.00028; logFC: 1.146, p = 0.00115, respectively). MMD-only subgroup analysis stratified by location showed that NMUR1 is significantly overexpressed in the MCA compared to the STA (logFC: 1.962; p = 0.00053) which further suggests its possible localized involvement in the progressive stenosis seen in the cerebral arteries in MMD. Conclusion: This is the first study to have performed WGCNA on samples directly affected by MMD. NMUR1 expression is well known to induce localized arterial smooth muscle constriction and, recently, type 2 inflammation which can predispose to arterial stenosis potentially advancing the symptoms and progression of MMD. Further validation and functional studies are necessary to understand the precise role of NMUR1 upregulation in MMD and its potential implications.

Elucidating shared biomarkers in gastroesophageal reflux disease and idiopathic pulmonary fibrosis: insights into novel therapeutic targets and the role of angelicae sinensis radix.

Background: The etiological underpinnings of gastroesophageal reflux disease (GERD) and idiopathic pulmonary fibrosis (IPF) remain elusive, coupled with a scarcity of effective therapeutic interventions for IPF. Angelicae sinensis radix (ASR, also named Danggui) is a Chinese herb with potential anti-fibrotic properties, that holds promise as a therapeutic agent for IPF. Objective: This study seeks to elucidate the causal interplay and potential mechanisms underlying the coexistence of GERD and IPF. Furthermore, it aims to investigate the regulatory effect of ASR on this complex relationship. Methods: A two-sample Mendelian randomization (TSMR) approach was employed to delineate the causal connection between gastroesophageal reflux disease and IPF, with Phennoscanner V2 employed to mitigate confounding factors. Utilizing single nucleotide polymorphism (SNPs) and publicly available microarray data, we analyzed potential targets and mechanisms related to IPF in GERD. Network pharmacology and molecular docking were employed to explore the targets and efficacy of ASR in treating GERD-related IPF. External datasets were subsequently utilized to identify potential diagnostic biomarkers for GERD-related IPF. Results: The IVW analysis demonstrated a positive causal relationship between GERD and IPF (IVW: OR = 1.002, 95%CI: 1.001, 1.003; p < 0.001). Twenty-five shared differentially expressed genes (DEGs) were identified. GO functional analysis revealed enrichment in neural, cellular, and brain development processes, concentrated in chromosomes and plasma membranes, with protein binding and activation involvement. KEGG analysis unveiled enrichment in proteoglycan, ERBB, and neuroactive ligand-receptor interaction pathways in cancer. Protein-protein interaction (PPI) analysis identified seven hub genes. Network pharmacology analysis demonstrated that 104 components of ASR targeted five hub genes (PDE4B, DRD2, ERBB4, ESR1, GRM8), with molecular docking confirming their excellent binding efficiency. GRM8 and ESR1 emerged as potential diagnostic biomarkers for GERD-related IPF (ESR1: AUCGERD = 0.762, AUCIPF = 0.725; GRM8: AUCGERD = 0.717, AUCIPF = 0.908). GRM8 and ESR1 emerged as potential diagnostic biomarkers for GERD-related IPF, validated in external datasets. Conclusion: This study establishes a causal link between GERD and IPF, identifying five key targets and two potential diagnostic biomarkers for GERD-related IPF. ASR exhibits intervention efficacy and favorable binding characteristics, positioning it as a promising candidate for treating GERD-related IPF. The potential regulatory mechanisms may involve cell responses to fibroblast growth factor stimulation and steroidal hormone-mediated signaling pathways.