Ligand-receptor Interactions Research Articles

DNA methylation profiling of CpG islands in trigeminal ganglion of rats with orofacial pain induced by experimental tooth movement

BackgroundTooth movement induced orofacial pain is the most cited negative effect during orthodontic treatment, while treatment options without side effects are limited. The differential expression of pain-related genes due to DNA methylation and demethylation is instrumental in pain. The purpose of the study was to evaluate the DNA methylation profiling of CpG islands (CGI) and CGI shores in promoter regions in trigeminal ganglions (TG) of tooth movement induced orofacial pain rats, thus to further insight the DNA methylation regulation in orofacial pain.Materials and methodsAn orofacial pain rat model was constructed by ligating coil springs between the incisor and first maxillary molar with 40 g of force. The Rat Grimace Score (RGS) was used for pain evaluation. The genome methylation status was analyzed by the reduced representation bisulfite sequencing (RRBS) technique. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analyses were conducted in the differentially methylated regions (DMRs). Moreover, a protein-protein interaction (PPI) network was established to detect annotated genes associated with pain.ResultsRGS was significantly higher in orofacial pain rats than in sham rats. RRBS showed widespread methylation changes in CGI and CGI shores in TG promoter regions. Both 902 hypermethylated DMRs and 862 hypomethylated DMRs were found in the CGIs of promoter regions. KEGG analysis revealed that annotated genes are participated in endocrine, nervous, immune, and sensory systems. Moreover, the “Calcium signaling pathway”, “Wnt signaling pathway” and “Neuroactive ligand-receptor interaction” were significantly enriched pathways. Furthermore, PPI network showed several genes (Ctnnb1, Dlg4, Creb1, Camk2g, Bmp2, etc.) with different methylation statuses were reported to be associated with pain.ConclusionsThis study demonstrated methylation changes were existed in CGI and CGI shores in TG promoter regions when pain occurs, thus providing a basis for further study on the mechanism of DNA methylation in orofacial pain.

Nanoparticle targeting strategies for traumatic brain injury.

Nanoparticle (NP)-based drug delivery systems hold immense potential for targeted therapy and diagnosis of neurological disorders, overcoming the limitations of conventional treatment modalities. This review explores the design considerations and functionalization strategies of NPs for precise targeting of the brain and central nervous system. This review discusses the challenges associated with drug delivery to the brain, including the blood-brain barrier and the complex heterogeneity of traumatic brain injury. We also examine the physicochemical properties of NPs, emphasizing the role of size, shape, and surface characteristics in their interactions with biological barriers and cellular uptake mechanisms. The review concludes by exploring the options of targeting ligands designed to augment NP affinity and retention to specific brain regions or cell types. Various targeting ligands are discussed for their ability to mimic receptor-ligand interaction, and brain-specific extracellular matrix components. Strategies to mimic viral mechanisms to increase uptake are discussed. Finally, the emergence of antibody, antibody fragments, and antibody mimicking peptides are discussed as promising targeting strategies. By integrating insights from these scientific fields, this review provides an understanding of NP-based targeting strategies for personalized medicine approaches to neurological disorders. The design considerations discussed here pave the way for the development of NP platforms with enhanced therapeutic efficacy and minimized off-target effects, ultimately advancing the field of neural engineering.

Molecular docking and transcriptomic analysis reveal the mechanism of myosin-derived peptides activating bitter receptor of hT2R1

To better understand the bitterness effect and molecule mechanism of myosin-derived peptides activating bitter receptors, the interaction between myosin-derived peptides of dry-cured ham and bitter receptors was investigated by molecular docking and molecular dynamics simulation; the signal transduction mechanism of myosin-derived peptides was explored by HEK-293T cells using calcium imaging and transcriptomics analysis. Lower CDOCKER energy was observed during the interaction between myosin-derived peptides and hT2R1 by molecular docking compared with hT2R4, hT2R5, hT2R8, hT2R14 and hT2R16. Hydrogen bonds and hydrophobic interaction were the most important interaction forces which stabilized the interaction of hT2R1 and myosin-derived peptides. Compared with LEKEKSELK and TEELEEAKK, the RMSF values and EC50 values of HVLATLGEK were lower, indicating that hT2R1 was more sensitive to HVLATLGEK stimulation. Transcriptomics and KEGG analyses showed that 767 differentially expressed genes were found and mainly involved in cAMP signaling pathway, neuroactive ligand-receptor interaction, calcium signaling pathway and MAPK signaling pathway after stimulating of HVLATLGEK. Protein-protein interaction network further demonstrated that DDIT3, FOS, FOSB, MYC, EGR1 and CCN2 were the key genes to connect the six functional clusters including ligand-receptor interaction and signal transduction.

PANoptosis Signaling Enables Broad Immune Response in Psoriasis: From Pathogenesis to New Therapeutic Strategies

BackgroundAccumulating evidence suggests that regulated cell death, such as pyroptosis, apoptosis, and necroptosis, is deeply involved in the pathogenesis of psoriasis. As a newly recognized form of systematic cell death, PANoptosis is involved in a variety of inflammatory disorders through amplifying inflammatory and immune cascades, but its role in psoriasis remains elusive. ObjectivesTo reveal the role of PANoptosis in psoriasis for a potential therapeutic strategy. MethodsMultitranscriptomic analysis and experimental validation were used to identify PANoptosis signaling in psoriasis. RNA-seq and scRNA-seq analyses were performed to establish a PANoptosis-mediated immune response in psoriasis, which revealed hub genes through WGCNA and predicted disulfiram as a potential drug. The effect and mechanism of disulfiram were verified in imiquimod (IMQ)-induced psoriasis. ResultsHere, we found a highlighted PANoptosis signature in psoriasis patients through multitranscriptomic analysis and experimental validation. Based on this, two distinct PANoptosis patterns (non/high) were identified, which were the options for clinical classification. The high-PANoptosis-related group had a higher response rate to immune cell infiltration (such as M1 macrophages and keratinocytes). Subsequently, WGCNA showed the hub genes (e.g., S100A12, CYCS, NOD2, STAT1, HSPA4, AIM2, MAPK7), which were significantly associated with clinical phenotype, PANoptosis signature, and identified immune response in psoriasis. Finally, we explored disulfiram (DSF) as a candidate drug for psoriasis through network pharmacology, which ameliorated IMQ-mediated psoriatic symptoms through antipyroptosis-mediated inflammation and enhanced apoptotic progression. By analyzing the specific ligandreceptor interaction pairs within and between cell lineages, we speculated that DSF might exert its effects by targeting keratinocytes directly or targeting M1 macrophages to downregulate the proliferation of keratinocytes. ConclusionsPANoptosis with its mediated immune cell infiltration provides a roadmap for research on the pathogenesis and therapeutic strategies of psoriasis.

Molecular Dynamics and Spatial Response of Proliferation and Apoptosis in Wound Healing and Early Intestinal Regeneration of sea cucumber Apostichopus japonicus

The sea cucumber, Apostichopus japonicus, exhibits significant regenerative capabilities. To ensure survival and reduce metabolic costs under adverse conditions, A. japonicus can expel intestine, respiratory trees and other internal organs. It takes only 14 days to regenerate a fully connected, lumen-containing intestine. Despite numerous reports characterizing the cellular events in intestinal regeneration, limited investigation has been conducted on the molecular events that occur during wound healing and the initial stages of regeneration after evisceration. Here, we identified differentially expressed genes (DEGs) during wound healing (6 hours post-evisceration, Aj6hpe) and early intestinal regeneration (Aj1dpe, Aj3dpe, Aj7dpe). Cell proliferation and apoptosis were detected by EdU and TUNEL assays, respectively. Results demonstrated that calcium ion and neuroactive ligand-receptor interaction were involved in the transmission of injury signals from evisceration to Aj1dpe. The main events occurring in the wound healing and early regeneration process were autophagy, apoptosis, dedifferentiation, migration and shutdown of feeding. Cell proliferation was primarily observed during the lumen formation stage. Maximal number of apoptotic cells were found during wound healing stage (6 hpe - 1 dpe). Consequently, the immune response is mainly mobilized by neural regulation after evisceration. Our findings bridge the gap between evisceration and regeneration, illuminating the molecular events that mediate damage response and initiate regeneration. This study significantly advances our understanding of the mechanisms underlying intestinal regeneration.

Computational Studies and Antimicrobial Activity of 1-(benzo[d]oxazol-2- yl)-3,5-diphenylformazan Derivatives.

Due to the biological importance of the benzoxazole derivatives, some 1- (benzo[d]oxazol-2-yl)-3,5-diphenyl-formazans 4a-f were synthesized and screened for in-silico studies and in-vitro antibacterial activity. The benzo[d]oxazole-2-thiol (1) was prepared by reacting with 2-aminophenol and carbon disulfide in the presence of alcoholic potassium hydroxide. Then 2-hydrazinylbenzo[d] oxazole (2) was synthesized from the reaction of compound 1 with hydrazine hydrate in the presence of alcohol. Compound 2 was reacted with aromatic aldehydes to give Schiff base, 2-(2- benzylidene-hydrazinyl)benzo[d]oxazole derivatives 3a-f. The title compounds, formazan derivatives 4a-f, were prepared by a reaction of benzene diazonium chloride. All compounds were confirmed by their physical data, FTIR, 1H-NMR, and 13CNMR spectral data. All the prepared title compounds were screened for in-silico studies and in-vitro antibacterial activity on various microbial strains. Molecular docking against the 4URO receptor demonstrated that molecule 4c showed a maximum dock score of (-) 8.0 kcal/mol. MD simulation data reflected the stable ligand-receptor interaction. As per MM/PBSA analysis, the maximum free binding energy of (-) 58.831 kJ/mol was exhibited by 4c. DFT calculation data confirmed that most of the molecules were soft molecules with electrophilic nature. The synthesized molecules were validated using molecular docking, MD simulation, MMPBSA analysis, and DFT calculation. Among all the molecules, 4c showed maximum activity. The activity profile of the synthesized molecules against tested micro-organisms was found to be 4c>4b>4a>4e>4f>4d.

A Comprehensive Review on Prospects of Polymeric Nanoparticles for Treatment of Diabetes Mellitus: Receptors-Ligands, In vitro & In vivo Studies.

As per International Diabetes Federation Report 2022, worldwide diabetes mellitus (DM) caused 6.7M moralities and ~537M adults suffering from diabetes mellitus. It is a chronic condition due to β-cell destruction or insulin resistance that leads to insulin deficiency. This review discusses Type-1 DM and Type-2 DM pathophysiology in detail, with challenges in management and treatment. The toxicity issues of conventional drugs and insulin injections are complex to manage. Thus, there is a need for technological intervention. In recent years, nanotechnology has found a fruitful advancement of novel drug delivery systems that might potentially increase the efficacy of anti-diabetic drugs. Amongst nano-formulations, polymeric nanoparticles have been studied to enhance the bioavailability and efficacy of anti-diabetic drugs and insulin. In the present review, we summarized polymeric nanoparticles with different polymers utilized to deliver anti-diabetic drugs with in vitro and in vivo studies. Furthermore, this review also includes the role of receptors and ligands in diabetes mellitus and the utilization of receptor-ligand interaction to develop targeted nanoparticles. Additionally, we discussed the utility of nanoparticles for the delivery of phytoconstituents which aids in protecting the oxidative stress generated during diabetes mellitus. Atlast, this article also comprises of numerous patents that have been filed or granted for the delivery of antidiabetic and anticancer molecules for the treatment of diabetes mellitus and pancreatic cancer.

Single-cell transcriptomics reveals over-activated reactive oxygen species pathway in hepatocytes in the development of hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor and a primary cause of cancer-relevant deaths worldwide. The role of reactive oxygen species (ROS) in HCC development is less studied. Methods: Seurat package and CellMarker database were employed for single-cell RNA sequencing (scRNA-seq) analysis based on the GSE189175 dataset from Gene Expression Omnibus (GEO). DAVID and MsigDB database were utilized for pathway analysis. SCENIC analysis was performed to map a transcription factors (TFs) regulatory network. CellChat was used for cellular communication analysis. Results: Six major cell subpopulations were identified, among which hepatocytes accounted for the highest proportion in both cancer and adjacent tissues. The enrichment scores of the 50 hallmark gene sets showed that the ROS pathway was abnormally activated in HCC hepatocytes and positively correlated with energy metabolism-related pathways (glucose metabolism, lipid metabolism, amino acid metabolism, etc.). Then, the hepatocytes were divided into four subgroups. Noticeably, GPX4+ hepatocytes with the highest activity of the ROS pathway was related to a worse prognosis of HCC. Mechanism analysis revealed that JUND was involved in the positive regulation of the ROS pathway in GPX4+ hepatocytes. It was found that the interdependent ligand-receptor interaction between GPX4+ liver cells and immune cells facilitated the malignant development of HCC. Conclusion: ROS pathway was over-activated in the hepatocytes of HCC tissues. GPX4+ hepatocytes having the highest activity of the ROS pathway closely interacted with T cells and M2 macrophage cells. Molecular subtypes and risk score signature based on the ROS pathway and its potential target gene JUND are encouraged to be developed for improving the precision treatment of HCC.

THGB: predicting ligand-receptor interactions by combining tree boosting and histogram-based gradient boosting

Ligand-receptor interaction (LRI) prediction has great significance in biological and medical research and facilitates to infer and analyze cell-to-cell communication. However, wet experiments for new LRI discovery are costly and time-consuming. Here, we propose a computational model called THGB to uncover new LRIs. THGB first extracts feature information of Ligand-Receptor (LR) pairs using iFeature. Next, it adopts a tree boosting model to obtain representative LR features. Finally, it devises the histogram-based gradient boosting model to capture high-quality LRIs. To assess the THGB performance, we compared it with three new LRI prediction models (i.e., CellEnBoost, CellGiQ, and CellComNet) and one classical protein-protein interaction inference model PIPR. The results demonstrated that THGB achieved the best overall predictions in terms of six evaluation indictors (i.e., precision, recall, accuracy, F1-score, AUC, and AUPR). To measure the effect of LR feature selection on the prediction, THGB was compared with four feature selection methods (i.e., PCA, NMF, LLE, and TSVD). The results showed that the tree boosting model was more appropriate to select representative LR features and improve LRI prediction. We also conducted ablation study and found that THGB with feature selection outperformed THGB without feature selection. We hope that THGB is a useful tool to find new LRIs and further infer cell-to-cell communication.

Spatial differences in gene expression across the dorsal raphe nucleus in a model of early Alzheimer's disease.

Persons with Alzheimer's disease (AD) present with changes in mood, sleep, and arousal that may precede the clinical manifestation of cognitive decline. These early symptoms can be driven by changes in the serotonergic (5-HT) nuclei of the brainstem, particularly the dorsal raphe nucleus (DRN). It is unclear why all 5-HT neurons do not simultaneously develop AD pathology that progresses at the same rate. We sought to identify any underlying genetic components associated with susceptibility or resistance of 5-HT neurons to AD pathology. The Visium Spatial Gene Expression platform was used to identify transcriptomic changes across the DRN in a preclinical model of early AD, human tau-overexpressing mice (htau mice). We further used RNAscope and immunohistochemical assessment to validate findings of primary interest. We find that the DRN of htau mice differentially expresses AD-related genes, including those related to kinase binding, ion channel activity, ligand-receptor interactions, and regulation of serine/threonine kinases. We further find that computational sub-clustering of the DRN is consistent with previous circuitry-driven characterizations, allowing for spatial bounding of distinct subregions within the DRN. Of these, we find the dorsolateral DRN is preferentially impacted by 5-HT neuron loss and development of tau pathology, which coincides with increased expression of the long noncoding RNA Map2k3os. Map2k3os may serve regulatory roles relevant for tau phosphorylation and warrants further investigation to characterize its interactions. Overall, this report demonstrates the power of large-scale spatial transcriptomics technologies, while underscoring the need for convergent-data validation to overcome their limitations.

Molecular Docking: Study of Chalcone Derivatives from Boesenbergia pandurata Targeting Estrogen Receptor Alpha (ER–a) for Breast Cancer

The increasing number of cancer patients and the challenge of multidrug resistance (MDR) demand more effective drugs, which can be developed by modifying compounds derived from natural resources, such as the flavonoid-rich temu kunci rhizome (Boesenbergia pandurata (Roxb.) Schlecht.). This study aims to predict the cytotoxicity and toxicity of 20 Pinostrobin derivatives and 19 Chalcone derivatives as potential anticancer candidates. Estrogen receptor alpha (ER-α), a validated cancer therapy target, was used for molecular docking in in silico tests using Molecular Graphics Laboratory (MGL) Tools (including, AutoDock Vina, AutoDock Tools 4.1, and Python 2.5.2) and PyRx Program. Toxicity was predicted using the pkCSM program and Protox online tool. The docking process involved binding the compounds to ER-α (PDB IDs 6CHZ and 3ERT), with the binding energy indicating activity; lower binding energy values suggest greater cytotoxic potential and stronger ligand-receptor interactions. The results showed that Chalcone derivatives from temu kunci exhibited lower toxicity and higher cytotoxic activity compared to Pinostrobin derivatives and the reference compound, Tamoxifen (TAM). Notably, Bis-3-chlorobenzyloxychalcone and Bis-2-chlorobenzyloxychalcone demonstrated the highest predicted cytotoxic activity. In conclusion, Chalcone derivatives are promising candidates for further development as more effective anticancer drugs, especially those that outperform Tamoxifen. These findings highlight the potential of natural compounds, particularly Chalcone derivatives, in combating cancer while addressing the growing challenge of MDR in clinical treatments.

Vibrational spectroscopic characterization, quantum chemical, molecular docking and molecular dynamics investigations of cyclo(L-phenylalanyl-L-proline), an anticancer agent

The molecular structure and spectral properties of cyclo(L-Phenylalanyl-L-Proline) dipeptide, which has several biological activities, were investigated. Firstly, conformational preference of the cyclo(L-Phenylalanyl-L-Proline) was searched and obtained lowest energy conformer of the cyclic dipeptide was then optimized using Density Functional Theory with wb97xd/6-311++G(d,p) level of theory. A detailed vibrational spectral analysis has been carried out and assignments of the fundamental modes have been proposed. The experimental vibrational wavenumbers of the investigated compound display good agreement with the computed values. The Frontier Molecular Orbitals, Molecular Electrostatic Potential and electronic transitions of the investigated compound were discussed. In addition, the 1H and 13C NMR chemical shifts of the cyclic dipeptide were calculated and the results were compared with the experimental values. Also, to evaluate the anticancer potential, molecular docking studies of cyclo(L-Phenylalanyl-L-Proline) within the ATP-binding sites of both wild type (EGFRWT; ID: 4HJO) and mutant (EGFRT790M; ID: 3W2O) Epidermal Growth Factor Receptor were performed. The results indicated that cyclo(Phe-Pro) has high binding affinities toward both EGFRWT (−6.6 kcal/mol) and EGFRT790M (−7.7 kcal/mol) receptors, thus, has good anticancer activity and also has potential to overcome drug resistance in therapy. Molecular dynamics simulations on cyclo(L-Phenylalanyl-L-Proline)-wild type complex were conducted through a 50-nanosecond timed to investigate the ligand-receptor interactions in more detail, and to determine the binding free energy accurately. The binding free energy of the cyclo(L-Phenylalanyl-L-Proline)-wild type complex was calculated to be −27.18 kcal/mol.

Liu-Shen-Wan inhibits PI3K/Akt and TRPV1 signaling alleviating bone cancer pain in rats

ABSTRACT Patients with advanced-stage cancers often suffer from severe pain caused by bone metastasis and destruction, for which effective treatment options are limited. Liu-Shen-Wan (LSW) is a widely recognized herbal formula utilized for pain relief. This study aims to elucidate the effects of LSW on bone cancer pain (BCP). In this study, the pharmacology of LSW on BCP was screened by network pharmacology. A BCP model was conducted using Walker 256 cells. Paw withdrawal threshold and paw withdrawal latency were employed as measures to assess the pain threshold in rats. The pathways and cell types of LSW against BCP were explored. Next, the impact of LSW on Walker 256 cells was evaluated, and UPLC-MS was utilized to identify the active ingredients of LSW. Furthermore, the effects of the key active ingredient, Bufalin, on the BCP rats were evaluated. There were 275 shared targets between LSW and BCP, which were enriched in neural tissue ligand-receptor interaction pathway. LSW increased pain threshold and decreased inflammatory cytokines levels in BCP rats by inhibiting PI3K/Akt and transient receptor potential vanilloid 1 (TRPV1) signaling through astrocytes and microglia. LY294002 further alleviated BCP in rats, while the effects were reversed after treatment with insulin-like growth factor 1 (IGF-1). Both LSW and its active ingredient Bufalin were shown to inhibit the viability and migration of Walker 256 cells and induce apoptosis. Bufalin appears to be the key active ingredient of LSW and exerts its pain-relieving effects by suppressing PI3K/Akt and TRPV1 signaling in BCP.

Identification of a novel prognostic signature for breast cancer derived from post-translational ubiquitin and ubiquitin-like modification-related genes.

Ubiquitin and ubiquitin-like (UUL) modifications play pleiotropic functions and are subject to fine regulatory mechanisms frequently altered in cancer. However, the comprehensive impact of UUL modification on breast cancer remains unclear. Transcriptomic and clinical data of breast cancer were downloaded from TCGA and GEO databases. Molecular subtyping of breast cancer was conducted using the NMF and CIBERSORT algorithms. Prognostic genes were identified via univariate, lasso and multivariate Cox regression analyses. Clinical pathological features, immune cell infiltration, immune therapeutic response and chemotherapy drug sensitivity were compared between groups using the Wilcoxon test. Survival analysis was performed using the Kaplan-Meier method and log-rank test. A total of 63 UUL modification-related genes were differentially expressed, with 29 up-regulated and 34 down-regulated genes. These genes were used to generate two UUL modification patterns that exhibited significant differences in prognostic features and immune cell infiltration. The UUL modification patterns were associated with 2038 differentially expressed genes that were significantly enriched in nuclear division, chromosome segregation, neuroactive ligand-receptor interaction, cell cycle, and other biological processes. Of these genes, 425 were associated with breast cancer prognosis, which enabled the classification of breast cancer into two clusters with significantly distinct prognoses. We developed a prognostic model, UULscore, which comprised nine genes and showed a significant correlation with partial immune cell infiltration. Furthermore, UULscore demonstrated potential predictive value in breast cancer overall survival prediction, immune therapeutic response, and chemotherapy drug sensitivity. UULscore, stage, radiotherapy, and chemotherapy were identified as independent prognostic factors for breast cancer. Based on these factors, a nomogram model was constructed, which demonstrated exceptional prognostic predictive performance. The present study identified two UUL modification-derived molecular subtypes in breast cancer, and have successfully constructed a risk-scoring model that holds potential value in prognosis, immune infiltration, immune therapeutic response, and chemotherapy sensitivity.

The Mechanism of Propofol in Treating Depression-like Behaviors Based on Network Pharmacology and Experimental Validation

Objective: To explore the potential mechanism of propofol in improving antidepressant-like behavior through network pharmacology and animal experimental validation, providing theoretical and experimental support for the development of novel antidepressant drugs based on propofol. Methods: 1. The targets of propofol and the disease targets of depression were screened through Swiss Target prediction, Super-pred, SEA, Drugbank, CTD, GeneCards, OMIM, and TTD databases. A protein-protein interaction (PPI) network was constructed, and the core targets were screened and visualized using CytoScape 3.10.2 software. Additionally, GO and KEGG enrichment analyses of the intersection targets were performed using the Metascape database. 2. Thirty male C57BL/6 mice were randomly divided into the CON group, LH model group, and PRO treatment group, with 10 mice in each group. The sucrose preference test, forced swim test, and tail suspension test were conducted to determine whether the depression model was successfully established and to assess the improvement effect of propofol on antidepressant-like behavior. 3. The pathological morphological changes of hippocampal neurons in the three groups of mice were observed through HE staining experiments. The expression of mGluR5 protein in the hippocampus was analyzed by Western blot. Results: 1. Network pharmacology analysis indicated that propofol may exert antidepressant effects by acting on core genes such as ALB, ESR1, NFKB1, HSP90AB1, and EGFR. These core target genes were mainly enriched in biological processes such as synaptic transmission and membrane potential regulation; they involved cellular components such as GABA receptor complexes and synaptic membranes; and they included molecular functions such as neurotransmitter receptor activity. Additionally, propofol may exert antidepressant effects through signaling pathways such as neuroactive ligand-receptor interaction, morphine addiction, and GABAergic synapse. 2. Compared with the CON group, the sucrose preference rate of mice in the LH model group significantly decreased, while the immobility time in the forced swim test and tail suspension test significantly increased. Compared with the LH model group, the sucrose preference rate of mice in the PRO treatment group significantly increased, and the immobility time significantly decreased. 3. The HE results showed that compared with the CON group, the number of neurons in the LH group decreased, with loose arrangement, pycnotic and deeply stained nuclei with blurred boundaries. However, the number of necrotic neurons in the PRO group significantly decreased. The Western blot results showed that compared with the CON group, the expression level of mGluR5 protein in the LH model group significantly increased, while it significantly decreased in the PRO treatment group compared with the LH model group. Conclusion: Propofol may exert antidepressant effects by regulating the expression of mGluR5, improving antidepressant-like behavior, and reducing hippocampal neuronal necrosis.

Identification and computational chemistry analysis of anti-prostatic hyperplasia peptides from Syngnathus schlegeli.

Pipefish is traditionally used in Chinese folklore as a male tonic.Recent studies show that Syngnathus schlegeliextracts effectively combat benign prostatic hyperplasia (BPH). However, the specificactive compounds involved and their mechanisms of action are not fully understood. This study aimed to investigate how pipefish peptides alleviate BPH using network pharmacology, molecular docking, and quantum chemical techniques. SN4, a gel-separated fraction from the neutral enzymatic hydrolysates of S. schlegeli, reveal 3470 peptide sequences, predominantly tetrapeptides enriched in Phe, Trp, Leu, and Ile.Network pharmacology identified SRC, AKT, and ITGB3 as primary targets. Molecular docking and in vitro tests on TP-induced RWPE-1 cell proliferation showed that peptides (FVDW, FIFE) were potentially active.In silico docking and quantum chemistry analysis showed that the N-terminal Phe linked to Ile/Val in FVDW and FIFE interacted with AKT1, ITGB3, and SRC proteins, enhancing ligand-receptor interactions and affinity, also highlighting their potential for improving BPH.

A Mechanistic Approach on Perception Mode of ABA Receptors (PYLs) to Novel Opabactin Analogues.

This study explored the structural mechanisms governing the binding of opabactin (OP) analogues 2-6 to abscisic acid (ABA) receptors by employing a combination of micro-scale thermophoresis (MST), phosphatase activity inhibition assays, and molecular dynamics simulations. The compounds 3-6 selectively activated PYR1, PYL2, and PYL6, while exhibiting minimal activity against PYL10, thus identifying them as selective ABA receptor agonists. Additionally, these analogues exerted a significant inhibitory effect on the phosphatase HAB1 upon binding to the receptors. The molecular dynamics simulations further elucidated the detailed binding interactions between various OP analogues and the ABA receptor PYR1, highlighting their role in inducing conformational changes within the receptor. Specifically, the study focused on the facilitation of the closure of the Gate and CL1 loops and the fine-tuning of the Latch loop to enhance the plasticity of the binding pocket, thereby influencing receptor-ligand interactions. The investigation emphasized the critical role of conserved water molecules in stabilizing the ligand-PYLs-PP2Cs complexes. Furthermore, free energy decomposition calculations demonstrated that the ligand's affinity was significantly affected by its ability to establish polar contacts between the polar groups within the ligand tail and the residues at the base of the binding pocket. This research lays a robust foundation for the development of novel ABA functional analogues with improved activity.

Impacts of nanopolystyrene and/or phoxim exposure at environmentally relevant concentrations on the intestinal histopathology, intestinal microbiota, and metabolome in Eriocheir sinensis

Nanopolystyrene (NP) pollution in aquatic environments has become an increasing concern. Phoxim (PHO), one of the major organophosphorus pesticides, has also been detected in aquatic environments, posing serious health risks to crustaceans. This study aimed to assess the detrimental effects of NP and/or PHO exposure at environmentally relevant concentrations on the intestinal histopathology, intestinal microbiota, and metabolome of adult crabs (Eriocheir sinensis) for 21 days. Our study revealed significant histopathological abnormalities in the intestines. In all the exposure groups, there was a discovery of vacuolar degeneration occurring in epithelial cells. Additionally, the peritrophic membrane exhibited thinning after NP or PHO single exposure, while thickening was observed after co-exposure. Exposure to NP and/or PHO disrupted the intestinal microbiota homeostasis, as evidenced by the proliferation of pathogenic bacteria and suppression of beneficial bacteria. Notably, PHO exposure resulted in increased abundance of pathogenic bacteria (Spiroplasma and Arcobacter) and decreased abundance of beneficial bacteria (Bacteroides). Analysis of the metabolome revealed that exposure to NP and/or PHO led to alterations in the metabolic profile as well as several critical pathways. Among these, the upregulation of arachidonic acid metabolism, ABC transporters, and biosynthesis of amino acids was observed in both NP single exposure and co-exposure, while PHO single exposure downregulated these pathways. Additionally, NP and/or PHO exposure downregulated neuroactive ligand-receptor interaction. Spearman correlation analysis revealed that the significant reduction of some differentially expressed metabolites (DEMs) was potentially regulated by the low-abundance bacterial genera following exposure to NP and/or PHO. And these DEMs have a role in anti-inflammatory or antioxidant properties. Collectively, our results offer novel perspectives on the intestinal toxicity of crustaceans by NP and/or PHO at environmentally relevant concentrations.

Molecular Characterization of miRNAs in Myzus persicae Carrying Brassica Yellows Virus.

microRNAs (miRNAs) influence many biological processes at the post-transcriptional level. However, the molecular characterization of miRNAs in the Myzus persicae response to Brassica yellows virus (BrYV) stress remains unclear. In this study, we present the results of miRNA profiling in Myzus persicae under two different treatments: treatment one (raised on turnip plants), and treatment two (raised on Arabidopsis thaliana). A total of 72 known and 113 novel mature miRNAs were identified in both non-viruliferous and viruliferous aphids, under treatment one. In treatment two, 72 known and 112 novel mature miRNAs were identified in BrYV-free aphids; meanwhile, 71 known and 115 novel miRNAs were identified in BrYV-carrying aphids. Moreover, eight upregulated and four downregulated miRNAs were identified in viruliferous aphids under treatment two, whereas only two miRNAs were differentially expressed under treatment one. These results indicated the relative BrYV level could influence miRNA expression in aphids. KEGG enrichment analysis showed the predicted genes targeted by differentially expressed miRNAs were primarily involved in Peroxisome, neuroactive ligand-receptor interaction, and metabolism of xenobiotics by cytochrome P450 pathways. Taken together, these findings reveal the effect of BrYV on miRNAs in Myzus persicae and provide key clues for further studies on the molecular mechanisms of BrYV transmission via aphids.

Abstract B022: Investigating how monocytes impair NK cell cytotoxicity in lung metastasis of triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) accounts for 20% of breast cancer (BC) cases worldwide, yet due to its aggressive phenotype and lack of targeted therapies it has the worst prognosis amongst BC subtypes. Up to 40% of TNBC patients will relapse after treatment and develop distant metastasis. Metastasis is the complex process by which disseminated tumor cells (DTCs) leave the primary tumor and grow at distal sites. Since most metastases occur within 3 years of diagnosis, the rapid onset and lack of effective treatments in metastatic TNBC (mTNBC) means less than 20% of patients survive after 4 years. Even though it is the most “immune-activated” BC subtype, and immune checkpoint blockade (ICB) has shown clinical benefits in early TNBC, there is a clear need for novel immunotherapeutic approaches for patients with mTNBC. Natural killer (NK) cells are innate lymphocytes that function as the body’s first line defense against metastatic cancer cells. NK cells eliminate DTCs in the blood or at distal sites via NK cell cytotoxicity (NKCC) and this process is known to be impaired in successful metastasis. We hypothesized that other cells within the tumor microenvironment (TME) can inhibit NKCC at the earliest stages of metastatic outgrowth. We have used Cherry-niche, an in vivo labelling tool, to characterize how TME cells change in early and established lung micro-metastases by single-cell RNA sequencing (scRNA-seq) and flow cytometry. Our initial analyses showed that monocytes are highly enriched, not only in the entire metastatic lung, but specifically in the established niche surrounding DTCs. Although we detected a slight increase in total NK cells, there was a shift in maturation status with fewer mature NK cells (CD27-CD11b+) and more immature NK cells (CD27+/-CD11b-) in the metastatic lung. Furthermore, NK cells were largely absent from the metastatic niche and those that were present displayed a dysfunctional phenotype. CellChat and NicheNet analyses of our scRNA-seq data predicted that several receptor-ligand interactions, including the cytokine macrophage migration inhibitory factor (MIF), can mediate the crosstalk between NK cells and monocytes. Next, we developed an in vitro 3D co-culture system to study the effect of blood-derived monocytes on human NKCC against mTNBC cells. We found that monocytes can suppress NKCC against MDA-MB-231 cells and decrease the viability of mature NK cells. Furthermore, recombinant MIF was able to directly inhibit NKCC, whilst a selective MIF antagonist was able to rescue monocyte-induced impairment of NKCC. These data implicate MIF as a critical monocyte-derived factor in the suppression of NK cell function against mTNBC cells. Future work will aim to identify the exact mechanism by which MIF inhibits NKCC, whilst also evaluate the effect of monocyte depletion and MIF inhibition on metastatic outgrowth and NK cell activation/maturation in vivo. This study will reveal novel inter-cellular dynamics occurring in the metastatic lung, as well as immunotherapeutic targets that may restore NKCC in mTNBC. Citation Format: Christos Ermogenous, Luigi Ombrato, Gordon Beattie. Investigating how monocytes impair NK cell cytotoxicity in lung metastasis of triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B022.