Neuroactive Ligand-receptor Interaction Research Articles

An integrated strategy of UPLC-Q-TOF-MS analysis, network pharmacology, and molecular docking to explore the chemical constituents and mechanism of Zixue Powder against febrile seizures

Febrile seizures (FS) are the most common type of seizures for children. As a commonly used representative cold formula for resuscitation, Zixue Powder (ZP) has shown great efficacy for the treatment of FS in clinic, while its active ingredients and underlying mechanism remain largely unclear. This study aimed to preliminarily elucidate the material basis of ZP and the potential mechanism for the treatment of FS through ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS), network pharmacology, and molecular docking. UPLC-Q-TOF-MS was firstly applied to characterize the ingredients in ZP, followed by network pharmacology to explore the potential bioactive ingredients and pathways of ZP against FS. Furthermore, molecular docking technique was employed to verify the binding affinity between the screened active ingredients and targets. As a result, 75 ingredients were identified, containing flavonoids, chromogenic ketones, triterpenes and their saponins, organic acids, etc. Through the current study, we focused on 13 potential active ingredients and 14 key potential anti-FS targets of ZP, such as IL6, STAT3, TNF, and MMP9. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that inflammatory response, EGFR tyrosine kinase inhibitor resistance, AGE-RAGE signaling pathway in diabetic complications, and neuroactive ligand-receptor interaction were the main anti-FS signaling pathways. Licochalcones A and B, 26-deoxycimicifugoside, and hederagenin were screened as the main potential active ingredients by molecular docking. In conclusion, this study provides an effective in-depth investigation of the chemical composition, potential bioactive components, and possible anti-FS mechanism of ZP, which lays the foundation for pharmacodynamic studies and clinical applications of ZP.

Postweaning intermittent sleep deprivation enhances defensive attack in adult female mice via the microbiota-gut-brain axis

Sleep is one of the most important physiological activities in life and promotes the growth and development of an individual. In modern society, sleep deprivation (SD), especially among adolescents, has become a common phenomenon. However, long-term SD severely affected adolescents' neurodevelopment leading to abnormal behavioral phenotypes. Clinical studies indicated that sleep problems caused increased aggressive behavior in adolescents. Aggressive behavior was subordinate to social behaviors, in which defensive attack was often the last line for survival. Meanwhile, increasing studies shown that gut microbiota regulated social behaviors by affecting specific brain regions via the gut-brain axis. However, whether postweaning intermittent SD is related to defensive attack in adulthood, and if so, whether it is mediated by the microbiota-gut-brain axis are still elusive. Combined with microbial sequencing and hippocampal metabolomics, the present study mainly investigated the long-term effects of postweaning intermittent SD on defensive attack in adult mice. Our study demonstrated that postweaning intermittent SD enhanced defensive attack and impaired long-term memory formation in adult female mice. Moreover, microbial sequencing and LC-MS analysis showed that postweaning intermittent SD altered the gut microbial composition and the hippocampal metabolic profile in female mice, respectively. Our attention has been drawn to the neuroactive ligand-receptor interaction pathway and related metabolites. In conclusion, our findings provide a new perspective on the relationship of early-life SD and defensive attack in adulthood, and also highlight the importance of sleep in early-life, especially in females.

Long non-coding RNA expression in PBMCs of patients with active pulmonary tuberculosis.

Mycobacterium tuberculosis (Mtb) infection is the primary cause of the chronic infectious illness tuberculosis (TB). Long non-coding RNAs (lncRNAs) are functional RNA molecules that cannot be translated into proteins and play a crucial role in regulating the immune system's innate and adaptive responses. It has been demonstrated that the dysregulation of lncRNA expression is associated with various human diseases. However, the mechanism underlying the involvement of so many lncRNAs in the immune response to TB infection remains unclear. The objective of our current study was to identify a number of significantly differentially expressed lncRNAs in peripheral blood mononuclear cells (PBMCs) from TB patients and to select the most indicative lncRNAs as potential biomarkers for active pulmonary tuberculosis. Microarray analysis was performed to determine the lncRNA and mRNA expression profiles in TB patients using a case-control model. The differentially expressed lncRNAs were subjected to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to investigate potential roles and pathways associated with the pathogenesis of TB infection, and to screen lncRNAs specifically linked to TB infection. Using real-time fluorescence quantitative PCR (QRT-PCR), specific lncRNAs were identified in TB patients and latent infections. Our findings revealed that various signaling pathways were differentially expressed in TB-infected individuals, suggesting a potential role for lncRNAs in the immunological responses driven by TB infection. This study provides crucial guidelines for future functional research. Upregulated lncRNAs were mainly enriched in Neutrophil extracellular trap formation and Chemokine signaling pathways, while downregulated lncRNAs were enriched in Neuroactive ligand-receptor interaction and Cushing syndrome in TB PBMCs. Furthermore, we found that lnc-XPNPEP1-5, lnc-CASKIN2-2, lnc-HSPA13-6, lnc-CLIC5-1, and LINC02502 were significantly downregulated in TB-infected patients, while LINC00528, lnc-SLC45A4-3, and LINC00926 were significantly upregulated in TB patients and latent infections. These eight lncRNAs, identified as novel biological marker candidates for diagnosing TB infection, were validated by real-time fluorescence quantitative PCR (QRT-PCR). The abnormally expressed lncRNAs identified in this research may provide crucial information for understanding the pathophysiological characteristics of TB patients and the dysfunction of PBMCs. Our findings reveal potential targets for early TB diagnosis and therapy, as well as offer new insights into the mechanisms underlying TB infection.

Comparative analysis of the hypothalamus transcriptome of laying ducks with different residual feeding intake

Feed costs account for approximately 60-70% of the cost of poultry farming, and feed utilization is closely related to the profitability of the poultry industry. To understand the causes of the differences in feeding in Shan Partridge ducks, we compared the hypothalamus transcriptome profiles of two groups of ducks using RNA-seq. The two groups were: 1) low residual feed intake (LRFI) group with low feed intake but high feed efficiency, and 2) high residual feed intake (HRFI) group with high feed intake but low feed efficiency. We found 78 DEGs were enriched in nine differential Kyoto Encyclopedia of Genes and Genome (KEGG) pathways, including neuroactive ligand-receptor interaction, GABAergic synapse, nitrogen metabolism, cAMP signaling pathway, calcium signaling pathway, nitrogen metabolism, tyrosine metabolism, ovarian steroidogenesis, and gluconeogenesis. To further identify core genes among the 78 DEGs, we performed protein-protein interaction and co-expression network analyses. After comprehensive analysis and experimental validation, four core genes, namely, glucagon (GCG), cholecystokinin (CCK), gamma-aminobutyric acid type A receptor subunit delta (GABRD), and gamma-aminobutyric acid type A receptor subunit beta1 (GABRB1), were identified as potential core genes responsible for the difference in residual feeding intake between the two breeds. We also investigated the level of cholecystokinin (CCK), neuropeptide Y (NPY), peptide YY(PYY), ghrelin, and glucagon-like peptide1 (GLP-1) hormones in the sera of Shan Partridge ducks at different feeding levels and found that there was a difference between the two groups with respect to GLP-1 and NPY levels. The findings will serve as a reference for future research on the feeding efficiency of Shan Partridge ducks and assist in promoting their genetic breeding.

Retinol Metabolism and Neuroactive Ligand-Receptor Interactions Are Key Pathways Involved in Skeletal Muscle Stem Cells (MuSCs) Aging

Sarcopenia is characterized by the loss of muscle function and mass as one ages. Muscle stem cells (MuSCs) play a central role to this process, as it is responsible for muscle repair and regeneration. The progressive loss of function in aging skeletal muscle stem cells is thought to be highly influential. This study aims to analyze RNASeq data obtained from young and old skeletal muscle stem cells of Mus musculus and uncover differentially expressed genes between the two groups. These differentially expressed genes were then analyzed to uncover key pathways crucial to the process of MuSC aging. This includes retinol metabolism and neuroactive ligand-receptor interactions.

Network pharmacology analysis and experimental validation of Anemarrhenae Rhizoma in treating Alzheimer's disease.

To explore the mechanism of Anemarrhenae Rhizoma in treatment of Alzheimer's Disease (AD). The active ingredients and targets of Anemarrhenae Rhizoma for treatment of AD were screened with network pharmacology methods, the protein-protein interaction (PPI) network was constructed and the core targets were analyzed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriching analysis was performed. The peripheral blood lymphocytes were extracted and lymphoblastoid cell lines (LCL) were constructed and an in vitro cell model of LCL-SKNMC was established. MTT and CCK-8 methods were used to quantify SKNMC/LCL cells, 2 ´, 7 ´-dichlorodihydrofluorescein diacetate (DCFH-DA) probe was used to detect reactive oxygen species (ROS), and immunofluorescence staining was used to detect the generation of Aβ1-42 in a co-cultured model. Western blotting was used to detect protein expression in the co-culture model. The lifespan of N2 nematodes was observed under oxidative stress, normal state, and heat stress; ROS generated by N2 nematodes was detected by DCFH-DA probes. The paralysis time of CL4176 N2 nematodes was evaluated by paralysis assay, and Aβ deposition in the pharynx was detected by Thioflavin S staining. Through network pharmacology, 15 potential active ingredients and 103 drug-disease targets were identified. PPI analysis showed that the Anemarrhenae Rhizoma might play anti-AD roles through albumin, Akt1, tumor necrosis factor, epidermal growth factor receptor (EGFR), vascular endothelial growth factor A (VEGFA), mammalian target of rapamycin (mTOR), amyloid precursor protein (APP) and other related targets. KEGG analysis showed that the pharmacological effects of Anemarrhenae Rhizoma might involve the biological processes of Alzheimer's disease, endocrine resistance, insulin resistance; and neuroactive ligand-receptor interaction, phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway, calcium signaling pathway, AGE-RAGE signaling pathway in diabetes complications, neurotrophic factor signaling pathway and others. The in vitro cell experiments showed that Anemarrhenae Rhizoma was able to reduce the production of ROS and Aβ1-42 (both P<0.01), inhibit the expression of β-secretase 1 (BACE1), APP and Aβ1-42 proteins (all P<0.05), up-regulate the expression of p-PI3K/PI3K, p-AKT/AKT, p-GSK3β/GSK3β in SKNMC cells (all P<0.05). The in vivo studies further confirmed that Anemarrhenae Rhizoma prolonged the lifespan of C. elegans under stress and normal conditions, reduced the accumulation of ROS and the toxicity of Aβ deposition. Anemarrhenae Rhizoma may reduce the production of Aβ in AD and inhibit its induced oxidative stress, which may be achieved by regulating the PI3K/Akt/GSK-3β pathway.

Baimai Ointment relieves chronic pain induced by chronic compression of dorsal root ganglion in rats by regulating neuroactive ligand-receptor interaction and HIF-1 signaling pathway

The Baimai Ointment with the effect of relaxing sinew and activating collaterals demonstrates a definite effect on Baimai disease with pain, spasm, stiffness and other symptoms, while the pharmacodynamic characteristics and mechanism of this agent remain unclear. In this study, a rat model of chronic compression of L4 dorsal root ganglion(CCD) was established by lumbar disc herniation, and the efficacy and mechanism of Baimai Ointment in the treatment of CCD were preliminarily explored by behavioral tests, side effect evaluation, network analysis, antagonist and molecular biology verification. The pharmacodynamic experiment indicated that Baimai Ointment significantly improved the pain thresholds(mechanical pain, thermal pain, and cold pain) and gait behavior of CCD model rats without causing tolerance or obvious toxic and side effects. Baimai Ointment inhibited the second-phase nociceptive response of mice in the formalin test, increased the hot plate threshold of normal mice, and down-regulated the expression of inflammatory cytokines in the spinal cord. Network analysis showed that Baimai Ointment had synergistic effect in the treatment of CCD and was related to descending inhibition/facilitation system and neuroinflammation. Furthermore, behavioral tests, Western blot, and immunofluorescence assay revealed that the pain-relieving effect of Baimai Ointment on CCD may be related to the regulation of the interaction between neuroactive ligand and receptors(neuroligands) such as CHRNA7, ADRA2A, and ADRB2, and the down-regulation of the expression of NOS2/pERK/PI3K, the core regulatory element of HIF-1 signaling pathway in spinal microglia. The findings preliminarily reveal the mechanism of relaxing sinew and activating collaterals of Baimai Ointment in the treatment of Baimai disease, providing a reference for the rational drug use and further research of this agent.

Comparative Transcriptome Analysis Reveals Sexually Dimorphic Gene Expression in the Gonads of Brachymystax tsinlingensis Li

Brachymystax tsinlingensis Li is an endangered cold-water salmonid fish native to China. This study aimed to identify sex-related genes and biological pathways via gonadal transcriptome sequencing of B. tsinlingensis Li. A total of 167,904 unigenes were identified with an average length of 836 bp and an N50 of 1452 bp, of which 84,977 (50.61%) unigenes were successfully annotated in six major databases. Comparative transcriptome analysis identified 22,864 differentially expressed genes (DEGs), of which 17,231 were up-regulated (male-biased genes, mDEGs) and 5633 were down-regulated (female-biased genes, fDEGs). Several DEGs associated with gonadal development were found through Gene Ontology enrichment analysis, such as ccnb1, zp3, bmp15, dmrt1, and psmc3ip. Signaling pathways related to gonadal development were found to be enriched through analysis using the Kyoto Encyclopedia of Genes and Genomes Pathway database, such as genes involves in base excision repair, the notch signaling pathway, neuroactive ligand-receptor interaction, the VEGF signaling pathway, and the estrogen signaling pathway. In addition, mRNA expression levels of 19 DEGs were determined to validate the reliability of the transcriptomic data by quantitative real-time polymerase chain reaction. These results revealed genes and signaling pathways potentially involved in gonadal development in B. tsinlingensis Li and provided basic molecular data for future research on reproductive regulation and breeding of B. tsinlingensis Li.

Potential nervous threat of nanoplastics to Monopterus albus: Implications from a metabolomics study

Nanoplastics, as a new class of environmental pollutants, have been frequently detected in environmental media and organisms. Monopterus albus (M. albus) is an important economic aquatic product with a high dietary consumption. However, the potential biological effects of nanoplastics on M. albus remain unknown. In this study, the effects of polystyrene nanoplastics (PS-NPs) at different concentrations (0, 0.5, 1, 5 and 10 mg/L) on M. albus were investigated using an untargeted metabolomics approach. The results showed that 59, 44, 24, and 31 individual differential metabolites and 16, 9, 6, and 2 significant differential metabolic pathways were significantly changed in 0.5, 1, 5, and 10 mg/L respectively, indicating the greater effect of PS-NPs at the relatively low concentrations. After further analysis, there are four same significant differential metabolic pathways for the 0.5 and 1 mg/L groups, i.e., ABC transporters, cAMP signaling pathway, Neuroactive ligand-receptor interaction, and Synaptic vesicle cycle. In addition, there was one mutual differential metabolic pathway (Neuroactive ligand-receptor interaction) among the four groups, indicative of the probably universal nervous influence of nanoplastics on M. albus. In a word, the current work suggests that PS-NPs might affect the nervous systems of M. albus through disturbing their liver metabolism, and nanoplastics at relatively low concentrations may possess a greater effect, which provides significant information for assessing the toxic effect and exposure risk of nanoplastics to organisms in aquatic environment.

Exploring the potential mechanism of Kaixinsan powder for the same pathogenesis of PTSD and anxiety based on network pharmacology and molecular docking: A review.

Post-traumatic stress disorder (PTSD) and anxiety are common mental illnesses and there are many similar pathogenesis and clinical manifestations between PTSD and anxiety. Kaixinsan powder (KXS), a commonly used prescription in traditional Chinese medicine, has been widely used to treat PTSD and anxiety. This study aims to explore the potential mechanisms of KXS for the same pathogenesis of PTSD and anxiety using a network pharmacology approach. The bioactive components and relevant target genes of KXS were obtained from the database about Traditional Chinese Medicine. The key genes of PTSD and anxiety were derived from disease databases. Subsequently, the network of protein-protein interaction and a network of "drug-components-disease-targets" was constructed. In order to treat PTSD and anxiety, gene ontology enrichment and signaling pathway enrichment were analyzed by using R language and components-core targets associated were validated by molecular docking. One hundred three targets of KXS in treating PTSD and anxiety were identified. The results of protein-protein interaction analysis and molecular docking indicated that AKT1 and IL-6 were crucial targets. Moreover, KEGG analysis has shown that neuroactive ligand-receptor interaction, calcium signaling pathway, and cAMP signaling pathway may play crucial roles in treating PTSD and anxiety. Ten biological process, 10 molecular function, and 10 cellular component were revealed via gene ontology analysis. The network pharmacology study and molecular docking indicated that KXS treated anxiety and PTSD by multiple components, targets, and signaling pathways. These results provide an important reference for subsequent basic research on PTSD and anxiety.

A Network Pharmacology Prediction and Molecular Docking-Based Strategy to Explore the Potential Pharmacological Mechanism of Astragalus membranaceus for Glioma.

Glioma treatment in traditional Chinese medicine has a lengthy history. Astragalus membranaceus, a traditional Chinese herb that is frequently utilized in therapeutic practice, is a component of many Traditional Chinese Medicine formulas that have been documented to have anti-glioma properties. Uncertainty persists regarding the molecular mechanism behind the therapeutic effects. Based on results from network pharmacology and molecular docking, we thoroughly identified the molecular pathways of Astragalus membranaceus' anti-glioma activities in this study. According to the findings of the enrichment analysis, 14 active compounds and 343 targets were eliminated from the screening process. These targets were mainly found in the pathways in cancer, neuroactive ligand-receptor interaction, protein phosphorylation, inflammatory response, positive regulation of phosphorylation, and inflammatory mediator regulation of Transient Receptor Potential (TRP) channels. The results of molecular docking showed that the active substances isoflavanone and 1,7-Dihydroxy-3,9-dimethoxy pterocarpene have strong binding affinities for the respective targets ESR2 and PTGS2. In accordance with the findings of our investigation, Astragalus membranaceus active compounds exhibit a multicomponent and multitarget synergistic therapeutic impact on glioma by actively targeting several targets in various pathways. Additionally, we propose that 1,7-Dihydroxy-3,9-dimethoxy pterocarpene and isoflavanone may be the main active ingredients in the therapy of glioma.

Network pharmacology-based analysis of Jin-Si-Wei on the treatment of Alzheimer's disease

Ethnopharmacological relevanceJin-Si-Wei (JSW), a traditional Chinese medicine (TCM) formula, have cognitive enhancing effect and delay the memory decline in an animal model of AD， which has been reported. However, the therapeutic mechanism of JSW in the treatment of AD remains unclear. Aim of the studyThis study aimed to verify the pharmacodynamics of JSW in the treatment of AD, and to explore its potential mechanism based on network pharmacology, molecular docking and experimental validation both in vitro and in vivo. Materials and methodsIn this study, the underlying mechanism of JSW against AD was investigated by the integration of network pharmacology. Then, the core pathways and biological process of JSW were verified by experiment, including behavioral test and pathological and biochemical assays with 6-month-old APPswe/PS1ΔE9 transgenic (APP/PS1) mice in vivo and verified with Aβ1-42-stimulated SH-SY5Y cells in vitro. At last, molecular docking was used to show the binding activity of each active ingredient to the core genes of JSW treatment in AD. ResultsA Drug-Ingredient-Target network was established, which included 363 ingredients and 116 targets related to the JSW treatment of AD. The main metabolic pathway of JSW treatment for AD is neuroactive ligand-receptor interaction pathway, and biological processes are mainly involved in Aβ metabolic process. In vivo experiments, compared with APP/PS1 mice, the cognitive and memory ability of mice was significantly improved after JSW administration. In brain tissue of APP/PS1 mice, JSW could increase the contents of low-density lipoprotein receptor-related protein 1 (LRP-1), enkephalinase (NEP) and Acetyl choline (ACh), and decrease the contents of Aβ1-42, amyloid precursor protein (APP) and receptor for advanced glycation end products (RAGE), decrease the vitality of cholinesterase (AChE) and choline acetyltransferase (ChAT). Besides, JSW could increase α-secretase expression and decrease β/γ-secretase expression, and improve the number and morphology of synapses in CA1 region of the hippocampus of APP/PS1 mice. In vitro experiments, Drug-Containing Serum (JSW-serum) has a neuroprotective effect by reducing the apoptosis on Aβ1-42-stimulated SH-SY5Y cells. Molecular docking results showed that 2-Isopropyl-8-methylphenanthrene-3,4-dione had strong binding activity with PTGS2, which maybe a potential ingredient for the treatment of AD. ConclusionsJSW improves AD in APP/PS1 mice, and this therapeutic effect may be achieved in part by altering the neuroactive ligand-receptor interaction pathway.

Study on the mechanism of Gastrodiae Rhizoma, Lycii Fructus, and Ziziphi Spinosae Semen in sedation and tranquillising mind.

This study analysed the pharmacological mechanism of Gastrodiae Rhizoma, Lycii Fructus, and Ziziphi Spinosae Semen in sedation and tranquillising mind using network pharmacology methods. The findings of this study aimed to serve as a reference for the development of novel drugs and the clinical expansion and application of traditional Chinese medicine formulas. The chemical constituents and therapeutic targets of Gastrodiae Rhizoma, Lycii Fructus, and Ziziphi Spinosae Semen were acquired from TCMSP, HERB, and ETCM databases. Active components were identified using ADME criteria, while the primary targets associated with sedation and mental tranquillity were obtained from GENECARDS, OMIM, and DRUGBANK databases. A protein-protein interaction (PPI) network analysis was conducted using the STRING platform to investigate potential functional protein modules by the network. The METASCAPE platform was employed for the study of the "component-target" and its associated biological processes and pathways. Subsequently, the "component-target" network was constructed using Cytoscape 3.9.1 software. Finally, the validation of molecular docking was conducted through AUTODOCK. The findings revealed that Quercetin, Atropine, Dauricine, (S)-Coclaurine, and other active ingredients were identified as the core constituents of Gastrodiae Rhizoma, Lycii Fructus, and Ziziphi Spinosae Semen. Additionally, PTGS2, PTGS1, MAOB, GABRA1, SLC6A2, ADRB2, CHRM1, HTR2A, and other targets were identified as the core targets. The results of the molecular docking analysis demonstrated that Quercetin, Atropine, Dauricine, and (S)-Coclaurine exhibited binding solid affinity towards PTGS2 and PTGS1. The predominant biological pathways associated with sedation and tranquilisation primarily involved Neuroactive ligand-receptor interaction and activation of receptors involved in chemical carcinogenesis. This study provided initial findings on the multi-component, multi-target, and multi-pathway mechanism underlying the sedative and tranquillising effects of Gastrodiae Rhizoma, Lycii Fructus, and Ziziphi Spinosae Semen. These findings had the potential to serve as a foundation for the future development and utilisation of Gastrodiae Rhizoma, Lycii Fructus, and Ziziphi Spinosae Semen.

Identification of Immune-Related Genes as Biomarkers for Uremia.

Uremia, which is characterized by immunodeficiency, is associated with the deterioration of kidney function. Immune-related genes (IRGs) are crucial for uremia progression. The co-expression network was constructed to identify key modular genes associated with uremia. IRGs were intersected with differentially expressed genes (DEGs) between uremia and control groups and key modular genes to obtain differentially expressed IRGs (DEIRGs). DEIRGs were subjected to functional enrichment analysis. The protein-protein interaction (PPI) network was constructed. The candidate genes were identified using the cytoHubba tool. The biomarkers were identified using various machine learning algorithms. The diagnostic value of the biomarkers was evaluated using receiver operating characteristic (ROC) analysis. The immune infiltration analysis was implemented. The biological pathways of biomarkers were identified using gene set enrichment analysis and ingenuity pathway analysis. The mRNA expression of biomarkers was validated using blood samples of patients with uremia and healthy subjects with quantitative real-time polymerase chain reaction (qRT-PCR). In total, four biomarkers (PDCD1, NGF, PDGFRB, and ZAP70) were identified by machine learning methods. ROC analysis demonstrated that the area under the curve values of individual biomarkers were > 0.9, indicating good diagnostic power. The nomogram model of biomarkers exhibited good predictive power. The proportions of six immune cells significantly varied between the uremia and control groups. ZAP70 expression was positively correlated with the proportions of resting natural killer (NK) cells, naïve B cells, and regulatory T cells. Functional enrichment analysis revealed that the biomarkers were mainly associated with translational function and neuroactive ligand-receptor interaction. ZAP70 regulated NK cell signaling. The PDCD1 and NGF expression levels determined using qRT-PCR were consistent with those determined using bioinformatics analysis. PDCD1, NGF, PDGFRB, and ZAP70 were identified as biomarkers for uremia, providing a theoretical foundation for uremia diagnosis.

Novel cuproptosis-related lncRNAs can predict the prognosis of patients with multiple myeloma.

Cuproptosis-related long-stranded non-coding RNAs (lncRNAs) have several implications for the prognosis of multiple myeloma (MM). This research aimed to construct a prognostic risk model for MM patients and explore the potential signaling pathways in the risk group. Cuproptosis-related lncRNAs were obtained from the co-expression analysis of cuproptosis-related genes and lncRNAs. Subsequently, twelve cuproptosis-related lncRNAs were selected to construct a prognostic risk model of MM patients by the least absolute shrinkage and selection operator (LASSO) regression. Then, the clinical data of these patients were randomly divided into the training group and the testing group. Next, patients were divided into the low- and high-risk groups according to the median risk score. The Kaplan-Meier survival analysis was performed to clarify the prognostic differences between risk subtypes. Besides, the Cox analysis was conducted to identify whether the risk score can be used as an independent prognostic factor. In addition, the receiver operating characteristic (ROC) curve analysis and the concordance index (C-index) curve analysis were performed to elucidate the value of risk score as a prognostic indicator. Finally, the differential risk analysis and functional enrichment analysis were carried out to identify the potential signaling pathways in the low- and high-risk groups. The results demonstrated that the overall survival (OS) of patients in the high-risk group was shorter than that in the low-risk group. There were significant differences in the expression of genes in MM patients between the high- and low-risk groups. The Gene Ontology (GO) analysis results showed that the differentially expressed risk-related genes (DERGs) were mainly concentrated on the collagen-containing extracellular matrix. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis results, the DERGs may be related to the neuroactive ligand-receptor interaction and mitogen-activated protein kinase (MAPK) signaling pathway, indicating that they may be involved in the progression of tumors. The findings of this study suggest that cuproptosis-related lncRNAs may be effective biomarkers for predicting the prognosis of MM patients, which is anticipated to contribute to the improvement of clinical outcomes.

Screening the components in multi-biological samples and the comparative pharmacokinetic study in healthy and depression model rats of Suan-Zao-Ren decoction combined with a network pharmacology

Ethnopharmacological relevanceSuanzaoren Decoction (SZRD) is a classic traditional Chinese prescription, which has been commonly used for treating insomnia, depression and other nerve system diseases for a long time. Aim of this studyThe present study aimed to explore the metabolic profiles in multi-biological samples and pharmacokinetic mechanism between healthy and depression model rats combined with a network pharmacology approach after administration of SZRD. Materials and methodsIn our study, an ultra-high performance liquid chromatography (UPLC)-Q-Exactive Orbitrap Mass Spectrometry method was firstly used to study the prototype components and metabolites of SZRD in plasma, brain, urine, and feces between healthy and depressed rats. The possible metabolic pathways were also speculated. Then a network pharmacological study was conducted on the components in the plasma of model rats. According to the above components screened by network pharmacology and the other reported representative active components, the comparative pharmacokinetic study was established for the simultaneous determination of mangiferin, spinosin, ferulic acid, liquiritin, formononetin. magnoflorine and isoliquiritin between healthy and depression model rats. Finally, molecular docking was used to validate the binding affinity between key potential targets and active components in pharmacokinetics. ResultsA total of 115 components were identified in healthy rats, and 101 components were identified in model rats. The prototype components and metabolites in plasma, brain, urine, and feces were also distinguished. The main metabolic pathways included phase I and phase II metabolic reactions, such as dehydrogenation, oxidation, hydroxylation, gluconaldehyde conjugation, glutathione conjugation and so on. These results provided a basis for the further study of antidepressive pharmacokinetic and pharmacological action in SZRD. Then, according to the degree value of network pharmacological study, it was predicted that 10 components and 10 core targets, which involved in the critical pathways such as neuroactive ligand-receptor interaction, cyclic adenosine monophosphate (cAMP) signaling pathway, serotonergic synapse, phosphatidylinositol-3 kinase (PI3K)-Akt signaling pathway, etc. Finally, the established pharmacokinetic method was successfully applied to compare the pharmacokinetic behavior of these 7 active components in plasma of healthy and depressed rats after oral administration of SZRD. It showed that except magnoflorine, the pharmacokinetic parameters of each component were different between healthy and depressed rats. Molecular docking analysis also indicated that the active compounds in pharmacokinetics could bind tightly to the key targets of network pharmacological study. ConclusionThis study may provide important information for studying the action mechanism of SZRD in treating depression.

Plasma metabolomic profiling of patients with transient ischemic attack reveals positive role of neutrophils in ischemic tolerance

Transient ischemic attack (TIA) induces ischemic tolerance that can reduce the subsequent ischemic damage and improve prognosis of patients with stroke. However, the underlying mechanisms remain elusive. Recent advances in plasma metabolomics analysis have made it a powerful tool to investigate human pathophysiological phenotypes and mechanisms of diseases. In this study, we aimed to identify the bioactive metabolites from the plasma of patients with TIA for determination of their prophylactic and therapeutic effects on protection against cerebral ischemic stroke, and the mechanism of TIA-induced ischemic tolerance against subsequent stroke. Metabolomic profiling using liquid chromatography-mass spectrometry was performed to identify the TIA-induced differential bioactive metabolites in the plasma samples of 20 patients at day 1 (time for basal metabolites) and day 7 (time for established chronic ischemic tolerance-associated metabolites) after onset of TIA. Mouse middle cerebral artery occlusion (MCAO)-induced stroke model was used to verify their prophylactic and therapeutic potentials. Transcriptomics changes in circulating neutrophils of patients with TIA were determined by RNA-sequencing. Multivariate statistics and integrative analysis of metabolomics and transcriptomics were performed to elucidate the potential mechanism of TIA-induced ischemic tolerance. Plasma metabolomics analysis identified five differentially upregulated metabolites associated with potentially TIA-induced ischemic tolerance, namely all-trans 13,14 dihydroretinol (atDR), 20-carboxyleukotriene B4, prostaglandin B2, cortisol and 9-KODE. They were associated with the metabolic pathways of retinol, arachidonic acid, and neuroactive ligand-receptor interaction. Prophylactic treatment of MCAO mice with these five metabolites significantly improved neurological functions. Additionally, post-stroke treatment with atDR or 9-KODE significantly reduced the cerebral infarct size and enhanced sensorimotor functions, demonstrating the therapeutic potential of these bioactive metabolites. Mechanistically, we found in patients with TIA that these metabolites were positively correlated with circulating neutrophil counts. Integrative analysis of plasma metabolomics and neutrophil transcriptomics further revealed that TIA-induced metabolites are significantly correlated with specific gene expression in circulating neutrophils which showed prominent enrichment in FoxO signaling pathway and upregulation of the anti-inflammatory cytokine IL-10. Finally, we demonstrated that the protective effect of atDR-pretreatment on MCAO mice was abolished when circulating neutrophils were depleted. TIA-induced potential ischemic tolerance is associated with upregulation of plasma bioactive metabolites which can protect against cerebral ischemic damage and improve neurological functions through a positive role of circulating neutrophils. National Natural Science Foundation of China (81974210), Science and Technology Planning Project of Guangdong Province, China (2020A0505100045), Natural Science Foundation of Guangdong Province (2019A1515010671), Science and Technology Program of Guangzhou, China (2023A03J0577), and Natural Science Foundation of Jiangxi, China（20224BAB216043).

Plant-based meat analogues aggravated lipid accumulation by regulating lipid metabolism homeostasis in mice

To determine the effects of plant-based meat analogues on the metabolic health and the possible mechanisms, mice were fed with a real pork diet (AP), a real beef diet (AB), a plant-based pork analogue diet (PP) and plant-based beef analogue diet (PB) for 68 days. Compared with real meat, the plant-based meat analogues increased food and energy intake, body weight, white fat and liver weight and caused adipocyte hypertrophy, hepatic lipid droplet accumulation, and inflammatory responses in mice. Metabolomics revealed that plant-based meat analogues altered the composition of serum metabolites, which regulated lipid metabolism homeostasis. The PB diet upregulated gene expression related to lipid synthesis, lipolysis and adipocyte differentiation while the PP diet upregulated expression of lipolysis-related genes but downregulated expression of adipocyte differentiation-related genes in white adipose tissue. Meanwhile, both PP and PB diets upregulated lipid influx- and synthesis-related genes but downregulated lipid oxidation-related genes in liver. The specific metabolite biomarkers may affect fat accumulation mainly by direct lipid metabolism pathways or indirect amino acid metabolism, protein digestion and absorption, bile secretion, aminoacyl-tRNA biosynthesis, neuroactive ligand-receptor interaction and ABC transporters pathways. These findings provide a new insight into understanding the differences in nutritional functions of meat and plant-based meat analogues.

Influence of Heat Treatment on Tea Polyphenols and Their Impact on Improving Heat Tolerance in Drosophila melanogaster.

This study investigated the potential mechanism of action of tea polyphenols (TPs), one of the major active ingredients in tea, to enhance heat resistance in Drosophila and the attenuating effect of heat treatment of TPs on their efficacy. The results showed that TPs were able to prolong the average survival time of Drosophila under high-temperature stress (p < 0.05), but the effect of TPs in prolonging the survival time of Drosophila melanogaster was significantly reduced (p < 0.05) with increasing TP heat-treatment time until it disappeared. The composition of TPs changed after heat treatment. It was also shown that the weakening of the effect of TPs in improving the heat tolerance of Drosophila was related to the decrease in the content of catechins and phenolic acids in their fractions as well as with the increase in the content of laccase. Transcriptomic analysis showed that the effect of TPs on heat tolerance in Drosophila melanogaster was closely related to the longevity regulation pathway, the neuroactive ligand-receptor interaction signaling pathway, and the drug metabolism-cytochrome P450 pathway. Metabolomics analysis showed that the effect of TP intervention in improving the body's heat tolerance was mainly related to amino acid metabolism and energy metabolism. However, thermal processing weakened the relevance of these transcriptomes and metabolomes. The present study reveals the mechanism of action by which heat-treated TPs affect the body's heat tolerance, which is important for the development and utilization of the heat-protection function of tea.

Decoding the molecular mechanism of stypoldione against breast cancer through network pharmacology and experimental validation

Breast cancer is the primary factor contributing to female mortality worldwide. The incidence has overtaken lung cancer. It is the most difficult illness due to its heterogeneity and is made up of several subtypes, including Luminal A and B, basal-like, Her-2 overexpressed and TNBC. Amongst different breast carcinoma subtypes, TNBC is the most deadly breast cancer subtype. The hostile nature of TNBC is mainly attributed to its lack of three hormonal receptors and hence lack of targeted therapy. Furthermore, the current diagnostic options like radiotherapy, surgery and chemotherapy render unsuccessful due to recurrence, treatment side effects and drug resistance. The majority of anticancer drugs come from natural sources or is developed from them, making nature a significant source of many medicines. Marine-based constituents such as nucleotides, proteins, peptides, and amides are receiving a lot of interest in the field of cancer treatment due to their bioactive properties. The role of stypoldione in this study as a prospective treatment for breast carcinoma was examined, and we sought to comprehend the molecular means/pathways this chemical employs in breast carcinoma. The most promising possibility for an anti-cancer treatment is stypoldione, a marine chemical produced from the brown alga Stypopodium zonale. We investigated stypoldione's mode of action in breast cancer using the network pharmacology method, and we confirmed our research by using a number of computational tools, including UALCAN, cBioportal, TIMER, docking, and simulation. The findings revealed 92 common targets between the chemical and breast cancer target network. Additionally, we found that stypoldione targets a number of unregulated genes in breast cancer, including: ESR1, HSP90AA1, CXCL8, PTGS2, APP, MDM2, JAK2, KDR, LCK, GRM5, MAPK14, KIT, and several signaling pathways such as FOXO signaling pathway, VEGF pathway, calcium signaling pathway, MAPK/ERK pathway and Neuroactive ligand-receptor interaction. The examined medication demonstrated a strong affinity for the major targets, according to a docking analysis. The best hit compound produced a stable protein–ligand pair, as predicted by molecular dynamics simulations. Our results are supported by the fact that when in-vitro assays were done on melanoma using stypoldione compound it was found that its mechanisms of action involved the PI3K/mTOR/Akt and NF-kB pathways. This study was set out to inspect the possible value of stypoldione as a breast cancer cure and to get a deeper understanding of the molecular mechanisms by which this drug acts on breast cancer.