Combinatorial chemistry & high throughput screening最新文献

Background: Atopic dermatitis is a common inflammatory skin disease worldwide that is characterized by skin barrier dysfunction, itching, and a reduced quality of life.

Objective: The research at hand aimed to delve into the anti-atopic dermatitis mechanism of Herba Siegesbeckiae, a traditional medicinal herb, using a metabolomic approach.

Methods: The molecular mechanism by which Herba Siegesbeckiae acts against atopic dermatitis was investigated by establishing a mouse model of atopic dermatitis while conducting a metabolomics analysis on its metabolites.

Results: Interleukin IL-13, IL-17A, IL-3, IL-31, IL-33, IL4, IL-5, TSLP, IgE, and histamine levels in serum, participating in inhibiting itching and regulating immunity signaling were found to be restored to varying degrees in AD treating with HS. A total of 31 differential metabolites were selected from metabolomics results, among which N-acetyl-L-alanine (VIP = 1.62), Nacetyl- L-methionine (VIP = 1.5), uracil (VIP = 1.47), and prostaglandin E2 (VIP = 1.4) play important roles in the anti-AD regulatory mechanisms of HS and can be used as biomarkers. In addition, the mechanisms of HS anti-AD have been shown to be associated with seven metabolic pathways, including β-alanine metabolism, glycerophospholipid metabolism, histidine metabolism, and so on.

Conclusion: In conclusion, HS demonstrated properties that counteract Atopic Dermatitis by suppressing itchiness and boosting the immune system, subsequently controlling the concentrations of related metabolites.

Neutrophils release neutrophil extracellular traps (NETs), a reticular structure mainly composed of antimicrobial peptides, DNA, and histones. Neutrophil elastase (NE), matrix metalloproteinase- 9, and histone G are the key components of NETs critically involved in breast cancer invasion and migration, which suggests an important role of NETs in tumorigenesis and metastasis. Studies have reported that NETs significantly promote breast cancer invasion, intravascular infiltration, and distant metastasis by inducing epithelial-mesenchymal transition (EMT), remodeling the extracellular matrix, and modulating the immune microenvironment. Meanwhile, NETs also function crucially in capturing circulating tumor cells, forming a pre-metastatic microenvironment, and awakening dormant cancer cells. Notably, NETs are also closely associated with chemotherapy and immunotherapy resistance in breast cancer. Therapeutic strategies targeting NETs, including DNase I, PAD4 inhibitors, elastase inhibitors, and histone C inhibitors, have been widely studied. These targeted therapies can effectively suppress the generation of NETs, improve drug efficacy, and delay tumor metastasis. This review aimed to systematically elucidate the mechanism of action of NETs in the progression and drug resistance of breast cancer and explore potential targeted therapeutic strategies against NETs. These strategies could effectively inhibit the generation of NETs, delay the progression of breast cancer, and improve therapeutic efficacy. An indepth study of the mechanism of action of NETs and the clinical significance of their targeted interventions is expected to provide a new direction for breast cancer treatment.

Introduction: The specific role of necroptosis in the pathogenesis of cataracts remains unclear. This study aimed to identify and validate the genes related to necroptosis in the development of cataracts through bioinformatics analysis.

Method: We utilized RNA sequencing data (GSE161701) from the Gene Expression Omnibus (GEO) database and employed R software to perform differential expression analysis of necroptosis- related genes (NRGs) in lens epithelial cells (LECs) under oxidative stress. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to evaluate the functions of necroptosis-related differentially expressed genes (NRDEGs) and their associated pathways. Additionally, a diagnostic model was established using LASSO regression to select hub genes, and protein-protein interaction (PPI) networks, mRNA-miRNA, and mRNAdrug regulatory networks were constructed. Immune infiltration analysis was performed using the xCell and CIBERSORT algorithms, and the differential expression of hub genes was validated in a UVB-induced rat cataract model using RT-qPCR and immunohistochemistry.

Results: The results indicated that oxidative stress promoted necroptosis in LECs, involving 86 NRDEGs and nine hub genes. GO and KEGG analyses revealed significant enrichment in necroptosis- associated pathways. Furthermore, we identified 58 mRNA-miRNA interactions and 131 potential molecular compounds or drugs. The immune infiltration analysis showed that certain immune cells exhibited significantly elevated expression in the cataract group, with notable correlations between some immune cells and hub genes. RT-qPCR and immunohistochemistry confirmed the expression of 9 hub genes and 3 key necroptosis genes. BAX, CXCL1, EPAS1, JUN, LRP1, RBM14, SERTAD1, and TNFAIP3 were highlighted as potential diagnostic and therapeutic targets.

Conclusion: This study identified key NRDEGs involved in the pathogenesis of cataracts under oxidative stress through bioinformatics analyses, potentially providing new targets and research directions for future cataract prevention and treatment.

Background: The triazole analogues are molecules of immense attraction because of their wide pharmacological applications.

Methods: Present research deals with the synthesis of triazole-2-thione analogues and their QSAR study. The synthesized analogs are also evaluated for their antimicrobial, anti-inflammatory, and antioxidant effect.

Results: It was revealed that the benzamide analogues (3a, 3d) and triazolidine analogue (4b) were found to be most active against P. aeruginosa and E. coli with pMIC values of 1.69, 1.69 and 1.72, respectively. The antioxidant study of the derivatives showed that 4b was the most active antioxidant with 79% protein denaturation inhibition. The highest anti-inflammatory activity was shown by 3f, 4a and 4f.

Conclusion: This study provides certain potent leads for further development of more potential anti- inflammatory, antioxidant and antimicrobial agents.

Background: GBM is an aggressive brain tumor with limited treatment options. Prior research has indicated FOLR1 as a pivotal gene involved in cancer pathogenesis.

Aim: This study aimed to explore the involvement of folate receptor alpha (FOLR1) in glioblastoma (GBM) and evaluate its potential as a therapeutic target.

Objective: This study investigated the expression pattern of FOLR1 in GBM, its impact on patient prognosis, and its role in GBM cell growth and the SRC/ERK1/2 signaling axis.

Methods: Initially, we conducted an expression analysis of FOLR1 based on public databases and examined its expression pattern in GBM and its impact on patient prognosis. Subsequently, cell experiments were carried out to evaluate the regulation of GBM cells by differential FOLR1 expression. We then downloaded 100 FOLR1 co-expressed genes from the Linkedomics data repository and performed an enrichment analysis. Finally, the role of FOLR1 and SRC/ERK1/2 axis in GBM was analyzed again by cell experiments.

Results: FOLR1 was found to be substantially expressed in GBM patients and was linked to a poor prognosis. Cell experiments showed that overexpression of FOLR1 promoted GBM cell growth, while low expression of FOLR1 inhibited cell growth. Additionally, genes related to FOLR1 were enriched in the lysosome, toxoplasmosis, and other pathways. This study further indicated that FOLR1 facilitates the activation of the SRC/ERK1/2 signaling pathway in GBM cells, and the attenuation of these pathways can effectively impede the malignancy-promoting effects triggered by FOLR1 in GBM cells.

Conclusions: We revealed that FOLR1 orchestrates the malignant advancement of GBM by stimulating the SRC/ERK1/2 signaling axis, underscoring its pivotal role in the pathogenesis of GBM.

Background: The incidence and mortality rates of lung cancer in China have significantly increased in recent years, and lung adenocarcinoma (LUAD) accounts for about 40% of all lung cancers. Metformin (MET) has been used as a therapeutic drug for type 2 diabetes, and a recent study revealed that MET can play an anti-tumor role by inhibiting cell proliferation, but its specific mechanism of action in LUAD is still unclear.

Methods: The key genes and signaling pathways of MET acting on LUAD were screened by bioinformatics, and the effects of MET on LUAD cell proliferation, invasion, migration, and apoptosis were detected. We then constructed small interfering RNAs for CCNA2 and combined them with MET to verify whether MET inhibits LUAD cell growth by affecting the expression of CCNA2. The binding ability of MET to E2F1 was predicted by molecular docking, and the correlation between E2F1 and CCNA2 was analyzed by bioinformatics. Finally, it was verified by interfering with the expression of E2F1 whether MET down-regulated the expression of CCNA2 by regulating E2F1, thus exerting anti-tumor effects.

Results: MET can inhibit the proliferation of LUAD cells and induce apoptosis, exerting its anticancer activity. Moreover, MET reduced the expression of CCNA2 in LUAD cells, and when the expression of CCNA2 was down-regulated, the anti-tumor cell activity of MET was promoted. In addition, MET had a good binding ability with E2F1, and MET down-regulated the expression of E2F1 in LUAD. Down-regulating the expression of E2F1 could reduce the expression of CCNA2 and enhance the inhibitory effect of MET on the proliferation of LUAD cells.

Conclusion: In conclusion, our findings revealed a novel mechanism for LUAD treatment in which MET can down-regulate CCNA2 expression via E2F1 and thus exert its anti-tumor effects.

Introduction: ARL6IP1 has been linked to cancer progression, but its precise role in BC, particularly in metabolism and its interaction with an OLFM4, remains unclear.

Aims: This study aimed to investigate the role of ADP-ribosylation factor-like 6 interacting protein 1 (ARL6IP1) in breast cancer (BC) cell behavior and metabolism and explore its interaction with an olfactomedin-4 (OLFM4) as a potential therapeutic target.

Objective: The objective of this study was to determine the effects of ARL6IP1 knockdown on BC cell proliferation, invasion, migration, apoptosis, oxidative stress, and glycolysis. Additionally, this study also explored the interaction between ARL6IP1 and OLFM4 and their combined role in BC progression and metabolism.

Methods: Key gene modules in the GSE73540 dataset were identified through weighted gene co-expression network analysis (WGCNA). Three BC-related datasets (GSE73540, GSE22820, and GSE36295) and The Cancer Genome Atlas (TCGA) were applied for additional examination of differentially expressed genes (DEGs). Intersection analysis selected ARL6IP1 as a hub gene for prognostic analysis. In vitro experiments investigated how ARL6IP1 knockdown influences BC cell proliferation, invasion, migration, apoptosis, epithelial-mesenchymal transition (EMT), oxidative stress, and glycolysis. The connection between ARL6IP1 and an OLFM4 was confirmed using Co-immunoprecipitation (Co-IP), and their roles in BC tumor progression and glycolysis were evaluated.

Results: ARL6IP1 was elevated in BC datasets and linked with poor BC prognosis. Experiments demonstrated that knockdown of ARL6IP1 significantly reduced BC cell growth while promoting apoptosis and oxidative stress. Besides, ARL6IP1 knockdown reduced glycolysis, as manifested by decreased extracellular acidification rate (ECAR), glucose consumption, adenosine triphosphate (ATP) levels, and lactate production while increasing mitochondrial respiration (OCR). Co-IP validated the connection between ARL6IP1 and OLFM4, and OLFM4 overexpression partially counteracted the suppression of glycolysis and cell behavior resulting from ARL6IP1 knockdown.

Conclusion: ARL6IP1 is a critical regulator of BC progression, influencing glycolysis, mitochondrial function, and key cellular behaviors. Targeting the ARL6IP1-OLFM4 axis offers a promising therapeutic strategy for managing BC.

The current core theory of rhinitis and asthma is referred to as the antigen-antibody theory. However, the academic perspective is insufficient to explain the issues that arise in the epidemiology, pathophysiology, and clinical treatment of these diseases. So, the academic field of lipid metabolism disorders emerged. This perspective aims to explore two aspects: firstly, the overall approach and definition (starting with a new origin of the digestive tract rather than antigens from the respiratory tract; the non-digestion of various nutrients and the effects of probiotics result in a series of pathological and physiological changes in the body) and secondly, key aspects, such as 1. Dietary factors and lipid disorders that occur first, followed by airway hyperresponsiveness and asthma; 2. The prominent role of lipid droplet morphology in mast cells manifested as a bridge between lipid metabolites and lipid mediators released during allergies; and 3. Low-energy diet intervention with a significant effect on patients. This perspective offers valuable insights into new factors for the primary prevention of these diseases and exploring new avenues for the treatment of such diseases.

Introduction/objective: Antibodies have broad applications in various fields, such as biology and medicine. The screening and preparation of highly specific and sensitive antibodies are essential research areas. Several techniques for the preparation of mouse-derived antibodies have been developed, but limited studies on rabbit-derived antibodies with a broader antibody profile and easier humanization are reported. An improved yeast surface display technique was used for rapid screening of rabbit-derived Fab antibodies.

Methods: After RNA extraction from peripheral rabbit blood, a cDNA library was obtained by reverse transcription. After recombinant vector construction, the expressed sequence in the form of Fab antibody structure was fused to the N-terminal end of Aga2p in the vector; a bidirectional promoter was inserted and successfully expressed in brewer's yeast EBY100. In addition, sequences, such as leucine zipper and inulinase signal peptide (INU), were inserted into the recombinant vector to improve the expression and stability of Fab antibody further.

Results: A biotin-labeled salbutamol marker was synthesized, and two rabbit-derived salbutamol- Fab antibodies were screened in three weeks using fluorescence-activated cell sorting (FACS).

Conclusion: After antigen-binding kinetic studies, the screened antibodies demonstrated good affinity and specificity.