Combinatorial chemistry & high throughput screening最新文献

Background: Ligusticum striatum DC. (LDC) is often prescribed for Cerebral Ischemia (CI) and is commonly combined with Borneolum (BO) to enhance therapeutic outcomes. However, its specific active ingredients and underlying mechanisms remain unclear.

Objective: This study aimed to identify the active ingredients and mechanisms of LDC and BO combination therapy against CI using network pharmacology, molecular docking, and in vivo experiments.

Methods: Potential active ingredients and targets were sourced from relevant databases, and a drug-component-target-disease network was constructed to pinpoint key ingredients. Subsequently, a protein-protein interaction analysis was conducted to confirm the key targets. Following enrichment analyses of Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), molecular docking was employed to evaluate binding energies. Finally, the therapeutic effects and mechanisms of the combination against CI were validated through in vivo experiments using male ICR mice.

Results: Venn analysis identified a total of 41 components and 292 potential targets. The drugcomponent-target-disease network revealed that the key components in LDC were palmitic acid, tetramethylpyrazine, and (Z)-ligustilide, while those in BO were (+)-borneol, β-elemene, and (-)- borneol. The PPI analysis highlighted seven crucial targets. Docking results confirmed a stable affinity between these components and their targets. KEGG enrichment analysis indicated that the mechanism involved the PI3K/AKT signaling pathway. Subsequently, in vivo experiments confirmed that the combination ameliorated abnormal hippocampus morphology and reduced the release of inflammatory factors through the activation of the PI3K/AKT signaling pathway.

Conclusion: The combination of LDC and BO markedly improved CI and inhibited inflammation response via activating the PI3K/AKT pathway.

Most cancers have become immune to normal cancer therapy, like chemotherapy and radiation. Therefore, exploring more effective and economical treatment options is important. Plants and herbs contain substances called phytochemicals, which have biological effects. Many phytochemicals having antioxidant and anticancer properties have been studied previously. There is increasing evidence that phytochemicals' anti-carcinogenic benefits originate from their ability to inhibit oxidation, inflammation, cell proliferation, and angiogenesis. These phytochemicals inhibit the spread of cancer by controlling the cell cycle and other molecular processes, such as metastasis. Along with therapeutic potential, other advantages, like their abundance, greater tolerability, and economic use, increase their utility in cancer therapeutics. In recent years, a number of scientists have examined lycophytes and ferns for their potential medicinal and phytochemical properties. This analysis emphasizes the significance of chemicals obtained from ferns and their derivatives in therapeutics. The authors discuss the pteridophyte's anti-cancer properties and other medical uses in this article. This information may help researchers in further research related to the most promising anticancer phytochemicals and their possibility as alternative drugs against cancer.

Objective: This study aimed to investigate the differential expression of mitophagyrelated genes in osteosarcoma patients with distinct prognostic outcomes and explore potential molecular regulatory mechanisms.

Methods: We analyzed microarray data from metastatic and nonmetastatic osteosarcoma patients using the UCSC dataset. Differential gene screening and intersection of mitophagy-related genes were performed using NetworkAnalyst. Random forest and LASSO regression were employed to screen selected genes and establish a risk prediction model. Functional enrichment analysis, protein- protein interaction (PPI) networks, immunoassays, and in vitro experiments were conducted to validate the findings.

Results: Seven differentially expressed genes were identified, and a robust risk prediction model was developed (AUC=0.886). PPI and functional enrichment analyses provided insights into relevant molecules and regulatory pathways. The immunoassay results revealed differences in the immune environment between the metastatic and nonmetastatic groups. Immunohistochemistry demonstrated significant downregulation of EPHA3 expression in the metastatic group, and in vitro experiments indicated that inhibiting EPHA3 increased the proliferative activity and migration ability of osteosarcoma cells.

Conclusion: Our study suggests that the downregulation of EPHA3 may contribute to mitochondrial autophagy dysfunction, thereby increasing the risk of osteosarcoma metastasis.

Background: Verbascoside, a compound classified as a phenylethanol glycoside in Dihuang, has been the subject of modern pharmacological investigations. These studies have revealed its noteworthy antioxidant, anti-inflammatory, memory-enhancing, neuroprotective, antitumor, and various other pharmacological properties. While verbascoside exhibits favorable antioxidant effects, its precise mechanism of action in ameliorating osteoporosis through the treatment of oxidative stress remains unclear.

Methods: This study employed CCK8, ALP, ELISA, and ROS staining techniques to examine the osteoporotic effects of verbascoside on zebrafish and MC3T3-E1 cells. Additionally, this study aimed to investigate the molecular mechanism by which verbascoside improves osteoporosis by mitigating oxidative stress. To identify the common targets of verbascoside in relation to oxidative stress and osteoporosis, network pharmacology and molecular dynamics simulation were employed. The construction of the verbascoside - oxidative stress - osteoporosis - potential target gene network aimed to identify the core targets, while the mechanism of action was elucidated through KEGG analysis, and the accuracy was confirmed by assessing the mRNA expression of the targets.

Results: In vivo experiments demonstrated that verbascoside exhibited therapeutic effects on osteoporosis and reduced ROS production in zebrafish. In vitro experiments further revealed that verbascoside enhanced the proliferation and differentiation of MC3T3-E1 cells, thereby improving the oxidative stress status of osteoblasts. Thirteen core targets and estrogen signaling pathways were identified through the application of network pharmacology. The pivotal role of the estrogen signaling pathway in facilitating the ability of verbascoside to mitigate oxidative stressinduced osteoporosis was substantiated by the modulation of target protein mRNA expression.

Conclusion: The findings underscore the considerable therapeutic potential of verbascoside in ameliorating osteoporosis through the alleviation of oxidative stress, thus establishing it as a promising compound for the treatment of this condition.

Introduction/objective: The incidence of metabolic-associated fatty liver disease (MAFLD) increases annually. Modified Zexie Decoction (MZXD) can treat this disease; however, their mechanisms of action are uncertain. This study evaluated the mechanisms of MZXD against MAFLD based on network pharmacology, molecular docking, and in vivo experiments.

Methods: The main active compounds, targets and signaling pathways of MZXD against MAFLD were obtained using network pharmacological analysis. Underlying mechanisms were validated by molecular docking and in vivo assays.

Results: Forty-one active ingredients and 197 intersection targets were identified. The main active ingredients include quercetin, luteolin, isorhamnetin, 3-methylhexane, and 3β- acetoxyatractylone. The main targets were TP53, JUN, HSP90AA1, MAPK1, MAPK3, AKT1, NF-κB p65, TNF, ESR1, FOS, and IL-6. The pathway enrichment analysis indicated that MZXD was related to the IL-17, TNF, and PI3K-AKT signaling pathways. Molecular docking suggested that these active ingredients bound strongly to TNF, IL-6, and NF-κB p65, which are integral components of the TNF pathway. In the rat MAFLD model, MZXD attenuated high-fat diet( HFD)-induced liver injury and lipid accumulation, decreased the serum levels of the inflammatory mediators TNF-α, IL6, and IL-1β, and inhibited the protein expression of TNF-α, IL6, p- IKB-α and p-NF-κB p65. Furthermore, immunohistochemistry results showed that MZXD attenuated the F4/80 staining intensity of the liver compared with the model group.

Conclusion: Collectively, our results suggested that MZXD could improve MAFLD by downregulating TNF/NF-κB signaling mediated macrophage activation.

Background: The establishment and validation of methods for testing biological samples are crucial steps in pharmacokinetic studies. Currently, several methodological reports have been published on the detection of rapamycin plasma concentrations.

Objective: The objective of this study was to explore an effective method for detecting rapamycin in rat whole blood biological samples.

Method: In this study, we designed a rapid, sensitive, and specific liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS) methodology for detecting rapamycin in rat whole blood biological samples. We comprehensively validated the specificity, linear range, lower limit of quantification (LLOQ), precision, accuracy, recovery, and stability of this method.

Results: The findings of this study confirmed the successful implementation of LC-MS/MS for the detection of rapamycin, demonstrating its sensitivity, specificity, and reliability in quantitative analysis. This method ensures the accuracy and reliability of subsequent study data through our validated LC-MS/MS approach.

Conclusion: The results demonstrated the successful implementation of an LC-MS/MS method for sensitive, specific, and reliable quantitative analysis of rapamycin in rat whole blood samples. This method ensures the accuracy and reliability of subsequent study data.

Significance: The importance of this study lies in the successful establishment of a rapid, sensitive, and specific LC-MS/MS method for detecting rapamycin concentration in rat whole blood, ensuring the accuracy and reliability of subsequent research data. This provides a crucial tool and foundation for further understanding the metabolism and pharmacological effects of rapamycin in vivo, aiding in the advancement of drug research and clinical applications in related fields.