Том 30, № 25 (2024)
- Год: 2024
- Статей: 6
- URL: https://vestnikugrasu.org/1381-6128/issue/view/10172
Immunology, Inflammation & Allergy
The Hidden Dangers of Meftal: A Drug Safety Alert for a Frequently Used NSAID



Construction, Features and Regulatory Aspects of Organ-chip for Drug Delivery Applications: Advances and Prospective
Аннотация
:Organ-on-chip is an innovative technique that emerged from tissue engineering and microfluidic technologies. Organ-on-chip devices (OoCs) are anticipated to provide efficient explanations for dealing with challenges in pharmaceutical advancement and individualized illness therapies. Organ-on-chip is an advanced method that can replicate human organs' physiological conditions and functions on a small chip. It possesses the capacity to greatly transform the drug development process by enabling the simulation of diseases and the testing of drugs. Effective integration of this advanced technical platform with common pharmaceutical and medical contexts is still a challenge. Microfluidic technology, a micro-level technique, has become a potent tool for biomedical engineering research. As a result, it has revolutionized disciplines, including physiological material interpreting, compound detection, cell-based assay, tissue engineering, biological diagnostics, and pharmaceutical identification. This article aims to offer an overview of newly developed organ-on-a-chip systems. It includes single-organ platforms, emphasizing the most researched organs, including the heart, liver, blood arteries, and lungs. Subsequently, it provides a concise overview of tumor-on-a-chip systems and emphasizes their use in evaluating anti-cancer medications.



Exploration of the Shared Gene Signatures and Molecular Mechanisms between Chronic Bronchitis and Antineutrophil Cytoplasmic Antibody-associated Glomerulonephritis: Evidence from Transcriptome Data
Аннотация
Background:Chronic Bronchitis (CB) is a recurrent and persistent pulmonary inflammation disease. Growing evidence suggests an association between CB and Anti-neutrophil Cytoplasmic Antibody-associated Glomerulonephritis (ANCA-GN). However, the precise mechanisms underlying their association remain unclear.
Aims:The purpose of this study was to further explore the molecular mechanism of the occurrence of chronic bronchitis (CB) associated with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA- GN).
Objective:Our study aimed to investigate the potential shared pathogenesis of CB-associated ANCA-GN.
Methods:Datasets of ANCA (GSE108113 and GSE104948) and CB (GSE151052 and GSE162635) were obtained from the Gene Expression Omnibus (GEO) datasets. Firstly, GSE108113 and GSE151052 were analyzed to identify common differentially expressed genes (DEGs) by Limma package. Based on common DEGs, protein-protein interaction (PPI) network and functional enrichment analyses, including GO, KEGG, and GSEA, were performed. Then, hub genes were identified by degree algorithm and validated in GSE104948 and GSE162635. Further PPI network and functional enrichment analyses were performed on hub genes. Additionally, a competitive ceRNA network was constructed through miRanda and spongeScan. Transcription factors (TFs) were predicted and verified using the TRRUST database. Furthermore, the CIBERSORT algorithm was employed to explore immune cell infiltration. The Drug Gene Interaction Database (DGIDB) was utilized to predict small-molecular compounds of CB and ANCA-GN.
Result:A total of 963 DEGs were identified in the integrated CB dataset, and 610 DEGs were identified in the integrated ANCA-GN dataset. Totally, we identified 22 common DEGs, of which 10 hub genes (LYZ, IRF1, PIK3CG, IL2RG, NT5E, ARG2, HBEGF, NFATC2, ALPL, and FKBP5) were primarily involved in inflammation and immune responses. Focusing on hub genes, we constructed a ceRNA network composed of 323 miRNAs and 348 lncRNAs. Additionally, five TFs (SP1, RELA, NFKB1, HIF1A, and SP3) were identified to regulate the hub genes. Furthermore, immune cell infiltration results revealed immunoregulation in CB and ANCA-GN. Finally, some small-molecular compounds (Daclizumab, Aldesleukin, and NT5E) were predicted to predominantly regulate inflammation and immunity, especially IL-2.
Conclusion:Our study explores the inflammatory-immune pathways underlying CB-associated ANCA-GN and emphasizes the importance of NETs and lymphocyte differentiation, providing novel insights into the shared pathogenesis and therapeutic targets.



Discovery of an EP300 Inhibitor using Structure-based Virtual Screening and Bioactivity Evaluation
Аннотация
Background:EP300 (E1A binding protein p300) played a significant role in serial diseases such as cancer, neurodegenerative disease. Therefore, it became a significant target.
Methods:Targeting EP300 discovery of a novel drug to alleviate these diseases. In this paper, 17 candidate compounds were obtained using a structure-based virtual screening approach, 4449-0460, with an IC50 of 5.89 ± 2.08 uM, which was identified by the EP300 bioactivity test. 4449-0460 consisted of three rings. The middle benzene ring connected the 5-ethylideneimidazolidine-2,4-dione group and the 3-F-Phenylmethoxy group.
Results:Furthermore, the interaction mechanism between 4449-0460 and EP300 was explored by combining molecular dynamics (MD) simulations and binding free energy calculation methods.
Conclusion:The binding free energy of EP300 with 4449-0460 was -10.93 kcal/mol, and mainly came from the nonpolar energy term (ΔGnonpolar). Pro1074, Phe1075, Val1079, Leu1084, and Val1138 were the key residues in EP300/4449-0460 binding with more -1 kcal/mol energy contribution. 4449-0460 was a promising inhibitor targeting EP300, which had implications for the development of drugs for EP300-related diseases.



Nicotine-induced Genetic and Epigenetic Modifications in Primary Human Amniotic Fluid Stem Cells
Аннотация
Background:Smoking during pregnancy has been linked to adverse health outcomes in offspring, but the underlying mechanisms are not fully understood. To date, the effect of maternal smoking has been tested in primary tissues and animal models, but the scarcity of human tissues limits experimental studies. Evidence regarding smoking-related molecular alteration and gene expression profiles in stem cells is still lacking.
Methods:We developed a cell culture model of human amniotic fluid stem cells (hAFSCs) of nicotine (NIC) exposure to examine the impact of maternal smoking on epigenetic alterations of the fetus.
Results:NIC 0.1 µM(equivalent to "light" smoking, i.e., 5 cigarettes/day) did not significantly affect cell viability; however, significant alterations in DNA methylation and N6-methyladenosine (m6A) RNA methylation in hAFSCs occurred. These epigenetic changes may influence the gene expression and function of hAFSCs. Furthermore, NIC exposure caused time-dependent alterations of the expression of pluripotency genes and cell surface markers, suggesting enhanced cell stemness and impaired differentiation potential. Furthermore, NICtreated cells showed reduced mRNA levels of key adipogenic markers and hypomethylation of the promoter region of the imprinted gene H19 during adipogenic differentiation, potentially suppressing adipo/lipogenesis. Differential expression of 16 miRNAs, with predicted target genes involved in various metabolic pathways and linked to pathological conditions, including cognitive delay and fetal growth retardation, has been detected.
Conclusions:Our findings highlight multi-level effects of NIC on hAFSCs, including epigenetic modifications, altered gene expression, and impaired cellular differentiation, which may contribute to long-term consequences of smoking in pregnancy and its potential impact on offspring health and development.



Mechanism of Preventing Recurrence of Stage II-III Colorectal Cancer Metastasis with Immuno-inflammatory and Hypoxic Microenvironment by a Four Ingredients Chinese Herbal Formula: A Bioinformatics and Network Pharmacology Analysis
Аннотация
Background:Colorectal Cancer (CRC) is one of the top three malignancies with the highest incidence and mortality.
Objective:The study aimed to identify the effect of Traditional Chinese Medicine (TCM) on postoperative patients with stage II-III CRC and explore the core herb combination and its mechanism.
Methods:An observational cohort study was conducted on patients diagnosed with stage II-III CRC from January 2016 to January 2021. The primary outcome was disease-free survival, which was compared between the patients who received TCM or not, and the secondary outcome was the hazard ratio. The relevance principle was used to obtain the candidate herb combinations, and the core combination was evaluated through an assessment of efficacy and representativeness. Then, biological processes and signaling pathways associated with CRC were obtained by Gene Ontology function, Kyoto Encyclopedia of Gene and Genomes pathway, and Wikipathway. Furthermore, hub genes were screened by the Kaplan-Meier estimator, and molecular docking was employed to predict the binding sites of key ingredients to hub genes. The correlation analysis was employed for the correlations between the hub genes and tumor-infiltrating immune cells and hypoxiarelated genes. Ultimately, a quantitative polymerase chain reaction was performed to verify the regulation of hub genes by their major ingredients.
Results:A total of 707 patients were included. TCM could decrease the metastatic recurrence associated with stage II-III CRC (HR: 0.61, log-rank p < 0.05). Among those patients in the TCM group, the core combination was Baizhu → Yinchen, Chenpi, and Fuling (C combination), and its antitumor mechanism was most likely related to the regulation of BCL2L1, XIAP, and TOP1 by its key ingredients, quercetin and tangeretin. The expression of these genes was significantly correlated with both tumor-infiltrating immune cells and hypoxia- related genes. In addition, quercetin and tangeretin down-regulated the mRNA levels of BCL2L1, XIAP, and TOP1, thereby inhibiting the growth of HCT116 cells.
Conclusion:Overall, a combination of four herbs, Baizhu → Yinchen, Chenpi, and Fuling, could reduce metastatic recurrence in postoperative patients with stage II-III CRC. The mechanism may be related to the regulation of BCL2L1, XIAP, and TOP1 by its key ingredients quercetin and tangeretin.


