Combinatorial chemistry & high throughput screening最新文献

Introduction: T cell exhaustion plays a critical role in the progression of hyperuricemic nephropathy. Xiebai Bining Decoction can alleviate hyperuricemic nephropathy. However, the precise multi-target mechanisms underlying its therapeutic benefits remain unclear. Therefore, the study aimed to elucidate the potential mechanisms by which Xiebai Bining Decoction regulates T cell exhaustion in hyperuricemic nephropathy and identify novel molecular targets for precise traditional Chinese medicine (TCM)-based interventions.

Methods: Network pharmacology was used to predict the active compounds and potential targets of Xiebai Bining Decoction based on oral bioavailability and drug-likeness. Transcriptomic data from a hyperuricemic nephropathy mouse model were used to validate and expand these predictions.

Results: Integrated network pharmacology and transcriptomic analyses revealed the key biological processes, including regulation of T cell activation, negative regulation of T cell activation, and negative regulation of defense responses, as well as enriched pathways.

Discussion: The integrated approach effectively revealed the molecular mechanisms underlying the therapeutic effects of the TCM Xiebai Bining Decoction in hyperuricemic nephropathy. These findings highlight the immunoregulatory effects of Xiebai Bining Decoction, particularly its ability to attenuate T cell exhaustion, and suggest promising molecular targets for targeted intervention. Additional clinical and mechanistic studies are warranted to validate these findings further and develop effective therapies for hyperuricemic nephropathy.

Conclusion: This study elucidated the therapeutic mechanisms of Xiebai Bining Decoction in hyperuricemic nephropathy, including key pathways involved in T cell exhaustion, immune modulation, and renal protection.

Introduction: Japanese encephalitis virus (JEV) hijacks the host cell's endoplasmic reticulum (ER) to form assembly and replication complexes during replication, leading to the production of multiple copies of JEV negative-sense and positive-sense RNA strands. The nonstructural protein NS5 RNA-dependent RNA polymerase (RdRp) is conserved across all Flavivirus species, and its inhibition can suppress Flavivirus replication. The objective of this study is to evaluate the inhibitory potential of 126 Aegle marmelos-derived compounds on JEV NS5 RdRp using computational methods.

Methods: A computational (in silico) approach was employed to assess the binding efficacy and inhibitory effects of Aegle marmelos compounds against the NS5 RdRp of JEV. Molecular docking and virtual screening techniques were used to identify potential inhibitors.

Results: The analysis revealed that several compounds, specifically IMPHY015072, IMPHY015047, IMPHY014838, and IMPHY011609, demonstrated significant binding affinity towards NS5 RdRp. These compounds effectively reduced JEV replication in silico, compared to control compounds. Furthermore, the selected compounds may potentially lower IL-1β serum levels and mitigate structural abnormalities in brain tissue.

Discussion: The in silico analysis in this study demonstrated the potential of Aegle marmelosderived compounds to inhibit Japanese encephalitis virus (JEV) replication by targeting the conserved NS5 RNA-dependent RNA polymerase (RdRp). The selected compounds- IMPHY015072, IMPHY015047, IMPHY014838, and IMPHY011609-showed strong binding affinity and effectively reduced JEV replication compared to control compounds.

Conclusion: The study suggests that specific Aegle marmelos-derived compounds exhibit promising inhibitory effects against JEV NS5 RdRp and could serve as potential therapeutic candidates to treat JEV infection and reduce associated inflammation and neuronal damage.

Introduction: Allergic asthma is triggered by allergens and is commonly associated with elevated IgE levels. Histamine plays a pivotal role in its pathogenesis; however, the therapeutic role of antihistamines remains controversial. Since current treatments primarily provide symptomatic relief, this review evaluates the current status of antihistamines in asthma management, with a focus on pharmacological advances, natural therapies, and novel heterocyclic compounds.

Method: A comprehensive literature search was systematically conducted across major databases, including PubMed, ScienceDirect, Scopus, and Web of Science. Studies evaluating the pharmacological potential of antihistamines, herbal compounds, and novel synthetic derivatives were included. Exclusion criteria encompassed studies unrelated to asthma or antihistamines, non-English publications, and editorials or conference abstracts lacking primary data.

Results: Second- and third-generation antihistamines effectively alleviate symptoms of allergic asthma and can reduce corticosteroid use. Combining antihistamines with leukotriene receptor antagonists has been shown to further enhance treatment outcomes. Emerging evidence also suggests that heterocyclic compounds and plant-derived phytochemicals may serve as promising antihistamines and bronchodilators, although their clinical application remains limited.

Discussion: Modern antihistamines provide added value as supportive agents in asthma management, particularly for allergic subtypes. Their improved pharmacological profiles reduce sedation and enhance patient compliance. The synergistic use of antihistamines with corticosteroids or leukotriene inhibitors exemplifies a shift toward multimodal therapy, while novel compounds continue to broaden therapeutic possibilities.

Conclusion: Antihistamines are increasingly recognized as valuable adjuvants in asthma management. Although asthma remains incurable, advanced antihistamines and natural phytochemicals provide effective symptom relief. Continued research into novel compounds and integrated therapeutic strategies holds promise for improved disease control and enhanced quality of life.

Introduction: This study aimed to explore the underlying pharmacological mechanisms of Jiao-Tai-Wan (JTW) in insomnia.

Methods: Network pharmacology approach to explore potential therapeutic targets of JTW in treating insomnia. Molecular docking was conducted to analyze the binding mechanisms of the therapeutic molecules to A2AR. Sleep- deprived model rats were treated by JTW once daily for seven days. Adenosine levels were detected via LC-MS/MS, and A1R and A2AR levels were measured via WB and qPCR.

Results: A total of 53 genes were generated. The five target genes with the greatest intersection between JTW and insomnia were ACHE, GSK3B, ADORA2A, MAOA, and APP. GO and KEGG analyses revealed the effects of the hubgenes on signaling pathways involved in neurotransmitter transmission and synaptic structure and function. Molecular docking was conducted on the A2AR. In animal experiments, JTW reduced plasma adenosine concentration and lowered it to physiological levels in the hypothalamus, prefrontal cortex, and brainstem. The A1R level in the BS and the A2AR level in the hippocampus was elevated by JTW in both protein and mRNA patterns.

Discussion: We screened potential targets for JTW in the treatment of insomnia using network pharmacology, which included adenosine receptors. Subsequently, we verified the effects of JTW on the adenosine signaling pathway through molecular docking and animal experiments and clarified the regulatory effect of JTW on the adenosine signaling pathway in animal models of insomnia Conclusion: Jiao-Tai-Wan (JTW) ameliorates insomnia through a multi-target mechanism that modulates adenosinergic signaling by reducing elevated adenosine levels and upregulating A1R/A2AR receptor expression.

Introduction: DNA microarray synthesis enables the large-scale and precise generation of DNA sequences for genomic research, data storage, and synthetic biology. However, the order of nucleotide addition significantly affects synthesis efficiency and accuracy. This study aims to model DNA microarray in situ synthesis as a traveling salesman problem (TSP) and to develop an optimized synthesis strategy.

Methods: A mathematical model for in situ microarray synthesis was established, and both greedy algorithms and a simulated annealing algorithm were applied to optimize the nucleotide addition order. The performance of these approaches was evaluated by comparing the number of synthesis cycles required at different sequence scales, ranging from 10 × 10 nt to 10000 × 120 nt arrays.

Results: The optimized synthesis schemes effectively reduced the total number of synthesis cycles. At the 10 × 10 nt scale, simulated annealing reduced cycles by 40.65% compared to the traditional scheme and by 8.52% compared to the greedy algorithm. At larger scales (100 × 100 nt to 10000 × 120 nt), cycle reductions ranged from 33.80% to 37.26%, with simulated annealing outperforming the greedy algorithm by 2.68% to 3.42%. These reductions translated into significant savings in synthesis time, reagent consumption, and overall cost.

Discussion: The simulated annealing-based optimization strategy demonstrates clear advantages in improving DNA microarray synthesis efficiency while reducing material usage and waste, thereby enhancing cost-effectiveness. Such improvements offer practical benefits for applications, including gene editing, drug development, and DNA data storage.

Introduction: The aim of this study was to investigate the potential mechanisms and therapeutic effects of Total Flavonoids of Drynaria roosii Nakaike (TFRD) on osteoporotic rats following ovariectomy, through modulation of the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis.

Methods: Ovariectomized (OVX) osteoporotic rat models were established and treated with TFRD. The effects of TFRD on Bone Mineral Density (BMD), bone microarchitecture, and the expression of genes and proteins related to the SDF-1/CXCR4 axis in rat lumbar vertebrae were assessed using BMD measurement, bone histomorphology analysis, and molecular biology techniques.

Results: In the TFRD treatment group, lumbar spine BMD significantly increased, and trabecular structure improved. Further mechanistic studies revealed that TFRD regulated SDF-1 expression, thereby promoting its binding to the CXCR4 receptor and, in turn, enhancing migration, homing, and osteogenic differentiation of BMSCs. These changes ultimately led to increased bone formation and decreased bone resorption, improving symptoms of osteoporosis.

Discussion: This study provides novel insights into the molecular mechanism of TFRD gene therapy in OVX osteoporosis rats by elucidating its involvement through the SDF-1/CXCR4 axis and BMSCs-mediated osteogenic differentiation.

Conclusion: These findings serve as a solid experimental and theoretical foundation for developing new anti-osteoporosis drugs. Furthermore, due to its natural plant extract origin, TFRD shows promising clinical application potential and requires further comprehensive investigation.

Introduction: Endometriosis (EMs), a prevalent disorder characterized by pelvic pain and infertility, affects numerous bodily systems and markedly diminishes life quality. Yiqi Huoxue formula (YQHXF) has demonstrated promising therapeutic efficacy. However, its active substances and underlying mechanisms remain ambiguous.

Methods: An innovative methodological framework incorporating NP, transcriptomics, proteomics, and molecular biology was utilized to investigate the active components and mechanisms of YQHXF. A network pharmacological analysis was conducted to identify the targets, biological processes, and pathways associated with YQHXF's effects on EMs. Additionally, transcriptomics, proteomics, and molecular biology techniques were applied for further mechanistic exploration at both the gene and protein levels.

Results: The findings suggest that YQHXF prevents EMs by modulating critical cellular processes- proliferation, invasiveness, adhesion, and apoptosis-within ectopic endometrial cells. The integration of network pharmacology, multi-omics, and molecular biology confirmed that this regulation occurs via key targets (EGFR, AKT1, FOS, MAPK3, NFKB1) and associated pathways.

Discussion: This study employed an integrated approach combining transcriptomics, proteomics, and molecular biology to analyze the effects of YQHXF on EMs. A total of 180 direct targets, 128 indirect targets, and 19 pathways related to YQHXF's anti-EMs effects were preliminarily identified. Based on these findings, it is proposed that YQHXF potentially achieves its remedial outcomes by influencing the proliferation, invasiveness, adhesion, and apoptosis of ectopic endometrial cells through the regulation of EGFR, AKT1, FOS, MAPK3, and NFKB1.

Conclusion: The findings suggest that YQHXF prevents EMs by regulating critical cellular processes, including the proliferation, invasiveness, adhesion, and apoptosis of ectopic endometrial cells.

Introduction: Shikonin, a traditional Chinese medicine monomer, exhibits potential anticancer activity. An expanding body of literature indicates that targeting ferroptosis signaling pathways can elicit antitumor effects in HCC. However, it remains unclear whether shikonin inhibits HCC by inducing ferroptosis. This study aimed to verify the anticancer effect of shikonin on HepG2 cells and elucidate its underlying mechanisms and specific therapeutic targets through an integrative approach combining network pharmacology, bioinformatics, and experimental validation.

Methods: HCC, shikonin targets, and ferroptosis-related genes were retrieved from public databases and their intersection genes were identified. PPI network and enrichment analysis were used to identify them, and "cellular response to metal ion" was a highly enriched GO biological process. Molecular docking was conducted to evaluate the binding affinity between shikonin and candidate targets, followed by in vitro validation. We also constructed a prognostic nomogram via multivariate Cox regression to estimate 1-, 3-, and 5-year overall survival.

Results: We obtained a total of 12 intersecting genes. AURKA, identified as a hub gene, showed direct binding to shikonin via molecular docking, pointing to its therapeutic targeting potential for shikonin in HCC. Validation experiments showed shikonin induced ferroptosis and inhibited proliferation in HepG2 cells, accompanied by AURKA downregulation at both mRNA and protein levels. After prognostic model construction, validation experiments confirmed that the nomogram accurately predicted survival outcomes in HCC patients.

Discussion: This study explores the therapeutic potential of shikonin in inducing ferroptosis for treating hepatocellular carcinoma (HCC). Through network pharmacology, molecular docking, and in vitro assays, AURKA was identified as a key target, demonstrating that shikonin inhibits HCC cell proliferation by triggering ferroptosis, which suggests a promising ferroptosis-based treatment strategy for HCC.

Conclusion: Together, shikonin exerts significant antitumor effects on HepG2 cells, and the underlying mechanism may involve targeting AURKA to induce ferroptosis.

Cyclin-Dependent Kinases (CDKs) are proteins that help control the cell cycle. They are considered potential targets for cancer treatment because they are often found at higher levels in cancer tissues than in normal tissues, and their presence is linked to survival rates in many cancer types. Cyclin- Dependent Kinase 1 (CDK1) is crucial for cell division and growth in cancer, as it significantly influences cell cycle progression through complexes formed with cyclins. Tumor growth can occur when CDK1 is deregulated, as its activation and phosphorylation of substrates are crucial for tumor development. Various small molecules that inhibit CDK1 have been developed and tested in preclinical studies, and some have progressed to human clinical trials. By inhibiting CDK1 activity, these drugs prevent it from changing other proteins and controlling the growth of cancer cells. Our study uses the STRING database, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and Gene Ontology (GO) analysis to reveal that CDK1 interacts with many proteins involved in cancer pathways. However, developing the best CDK1 inhibitors is challenging due to selectivity, potency, and cost, which are influenced by CDK1's structure and interactions with other proteins. This review explores the structure, function, regulation, mechanisms, and expression of CDK1, its crystal structure with various ligands, interactions with other proteins, and potential applications of CDK1 inhibitors. Future research, such as combination medicines, CRISPR, nanotechnology, and AI-driven methods and tools, should highlight their practical applications and provide a guide for efficient CDK1 discovery and drug development. Thus, this review emphasizes the significance of CDK1 targeting in cancer therapy, the difficulties in identifying potent inhibitors, and the ongoing research to enhance cancer treatment results by focusing on CDK1.