Combinatorial chemistry & high throughput screening最新文献

Introduction: Ölmei-7, a traditional Mongolian medicine used for edema since the 16th century, and has remained clinically relevant. . Its mechanisms for treating cirrhotic ascites are underexplored. . This study integrates metabolomics and network pharmacology to elucidate these mechanisms and validates its taste properties using electronic tongue analysis.

Methods: Taste was analyzed using an electronic tongue. Bioactive components were identified via HILIC UHPLC-Q-TOF MS and databases (TCMSP, GeneCards). PPI networks were built with Cytoscape and STRING, followed by GO/KEGG analyses using OmicBeans. Molecular docking was performed with OpenBabel.

Results: Electronic tongue analysis confirmed Ölmei-7's bitter and umami tastes, aligning with Mongolian medical theory. Metabolomics identified 997 targets, 130 overlapping with cirrhotic ascites genes. GO analysis showed enrichment in 6200 biological processes, 513 cellular components, and 784 molecular functions. KEGG analysis identified 255 pathways, including TNF and IL-17 signaling. Molecular docking of five proteins (TNF, EGFR, MMP9, JUN, BCL2) with five compounds showed stable binding, with Rutin-MMP9 at -9.1 kcal•mol-¹.

Discussion: Ölmei-7's active components (e.g., quercetin, luteolin) likely reduce ascites by inhibiting TNF-α-mediated inflammation and vascular permeability, protecting liver function via BCL2, improving fibrosis via MMP9/EGFR, and reducing oxidative stress via JUN. These findings support its traditional use and elucidate its mechanisms.

Conclusion: Ölmei-7 alleviates cirrhotic ascites through anti-inflammatory, antifibrotic, , and antioxidative pathways, as revealed by metabolomics and network pharmacology. This study enhances understanding of its pharmacological basis and supports clinical applications.

Introduction: One of the most dangerous illnesses in the world today is hepatitis B virus (HBV) infection, which mainly affects the liver and can cause cirrhosis, hepatocellular carcinoma (HCC), and chronic infection. The primary goal of this study was to determine whether genotype polymorphisms at particular locations of the IL-18 promoter region may affect the host susceptibility to HBV infection in the North Indian population.

Methods: Genetic polymorphism of the IL-18 gene in the promoter region at positions -607 and - 137 was performed in the North Indian population (100 controls and 100 HBV patients) using the PCR-RFLP method. Genotypic, allelic, and haplotype frequencies were compared using SHEsis software.

Results: There were no significant differences in individual genotype or allele frequencies at positions -607 and -137 between HBV patients and controls. However, there were statistically significant differences with high frequencies of the -607A/-137C haplotype in HBV patients (p=0.010), whereas the -607C/-137C haplotype was more prevalent in controls (p=0.001), indicating a protective effect.

Discussion: The individual SNPs did not show significant association, but specific haplotypes of the IL-18 promoter region may influence the risk of HBV infection. These results align partially with previous studies and suggest that haplotype-based analysis provides improved insight into genetic susceptibility.

Conclusion: The present study indicates that a double mutation (polymorphism) -607A/-137C in the IL-18 gene promoter region may contribute to the onset of HBV infection, while a single nucleotide polymorphism (-607C/-137C) may provide less susceptibility to HBV and may have a protective impact.

Introduction: The main goal of this research is to determine the most proposed mechanism for the synthesis of 6-amino-3-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5- carbonitrile (P) from benzaldehyde, malononitrile, hydrazine, and ethyl acetoacetate as starting materials, which was investigated based on density functional theory (DFT).

Methods: In this report, seven possible mechanisms for the synthesis of the 1,4- dihydropyrano[2,3-c]-pyrazole have been investigated using density functional theory (DFT) at the B3LYP/6-311G** level of theory. Each synthetic route involves the condensation of ethyl acetoacetate, hydrazine hydrate, malononitrile, and benzaldehyde molecules to yield the proposed product.

Results: Herein, seven reaction mechanisms were scrutinized for the synthesis of the 6-Amino-3- methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile from benzaldehyde, malononitrile, hydrazine, and ethyl acetoacetate as starting compounds. DFT with the B3LYP basis set was used to optimize the structure of the studied molecules related to the four-component synthesis of 6-amino-3-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (P). Finally, we investigated the most favorable reaction mechanism and its corresponding steps using computational methods.

Discussion: The computational results in this research are based on transition state kinetic studies, and due to the volume of calculations, experimental or thermodynamic studies were not possible. Nevertheless, a review of the scientific literature indicates that there is strong agreement between these computational findings and the experimental data reported in the literature.

Conclusion: In summary, the best proposed mechanism for the synthesis of the 6-amino-3- methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile in ethanol has been investigated using DFT at the B3LYP/6-311G** level. This route involves the Knoevenagel condensation between benzaldehyde and ethyl acetoacetate, followed by dehydration, Michael addition reaction, imination, and intramolecular nucleophilic reaction of the hydrazine, respectively, which corresponds to proposed pathway 6.

Introduction: To investigate the clinical relevance, biological function, and molecular mechanisms of the long non-coding RNA LINC00888 in gastric cancer (GC).

Methods: Expression profiles of LINC00888 were analyzed using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Associations with clinical features-including age, sex, tumor stage, recurrence, and survival were examined. Potential downstream targets were predicted using bioinformatics, and experimental validation was performed in GC cell lines via qRT-PCR, Western blot, and luciferase reporter assays. Functional roles were assessed by proliferation and invasion assays.

Results: LINC00888 was upregulated in GC tissues and cell lines and associated with advanced stage, recurrence, and poor prognosis. Knockdown of LINC00888 reduced cell proliferation and invasion in vitro. Bioinformatics and experimental analyses indicated that LINC00888 may act as a competing endogenous RNA for miR-145-5p, potentially influencing Frizzled-7 (FZD7) expression.

Discussion: LINC00888 promotes gastric cancer progression by modulating the miR-145- 5p/FZD7 axis and is associated with poor prognosis. It may serve as a prognostic biomarker and potential therapeutic target in GC. Integration of molecular biomarkers like LINC00888 into emerging IoT-based clinical platforms may further enhance personalized cancer management.

Conclusion: LINC00888 promotes GC progression via the miR-145-5p/FZD7 ceRNA network and may serve as a prognostic biomarker and therapeutic target.

Introduction: Migraine, a primary headache disorder, is the third disabling disease of neurological disorders worldwide. The pathological mechanism underlying migraine remains poorly understood. Lipid metabolism may be related to migraine pathophysiology. We aimed to investigate the causal relationship between plasma lipids and migraine or its subtypes, including migraine with aura (MA) and migraine without aura (MO), and explore whether the circulating cytokines serve as mediators in the pathway from plasma lipids to migraine.

Methods: A two-step Mendelian randomization (MR) approach was used to assess the mediating effect. The summary genetic data for 179 lipid species were obtained from were derived from a genome-wide association studies (GWAS) summary dataset encompassing 7,174 individuals. The summary genetic data for 91 circulating cytokines were obtained from genome-wide pQTL mapping data. The summary genetic data of GWAS related to migraine and its subtypes were derived from the FinnGen Release 10 database. The MR Analysis methods included the inversevariance- weighted (IVW), MR-Egger, and weighted median.

Results: The risk of migraine was reduced mediated by CD5 with phosphatidylinositol (18:1_18:2), sphingomyelin (d34:1), and sphingomyelin (d38:1). The risk of migraine and MA was reduced mediated by CD6 with sphingomyelin (d40:1) and sphingomyelin (d42:2). The risk of migraine and MA was increased mediated by CD6 with phosphatidylethanolamine (O- 16:1_18:2).

Discussion: CD5 and CD6 were found to be related to migraine. CD5 and CD6 may affect migraine by immunological dysregulation-induced neuroinflammation. Six plasma lipids are associated with two cytokines, indicating that lipid metabolism participates in neuroinflammation, and T cells may be part of it. Plasma levels of lipids were associated with the risk of migraine. The circulating cytokines may serve as mediators in the pathway from plasma lipids to migraine.

Conclusions: CD5 and CD6 appeared to mediate the causal relationship between plasma lipids and migraine or MA, including four kinds of sphingomyelin, one phosphatidylinositol, and one phosphatidylethanolamine.

Introduction: Topological indices serve as mathematical descriptors for chemical structures, playing a crucial role in elucidating the physicochemical characteristics of compounds. Ambient- stable electroactive graphene nanoribbons are air-stable, electronically tunable and easily fabricated nanostructures, formed by the elongation of nanographene ribbon segments. This study aimed to develop precise topological formulations for three types of ambient-stable electroactive graphene nanoribbons (AEGNR) using graph-theoretical structural measures, and to evaluate their energetic properties along with their 13C NMR spectral characteristics.

Methods: The study employs the cut method, which is based on the Djoković-Winkler θ relation, to calculate topological indices.

Results: In this article, we evaluated selected spectral and energetic properties of AEGNR variants.

Discussion: The computed topological indices based on distance and vertex degree could provide important chemical insights into the properties of AEGNR(I).

Conclusions: We developed exact mathematical expressions for bond-additive molecular descriptors corresponding to three types of ambient-stable electroactive graphene nanoribbons (AEGNRs). An evaluation of HOMO-LUMO energy gaps was also performed for the AEGNR(I) chains.

Introduction: Sleep disorders (SD) affect approximately 25% of the global population. Traditional Chinese Medicine (TCM) formulas have been shown to alleviate SD by modulating endogenous melatonin. This study used data mining, network pharmacology, and meta-analysis to identify key herbal pairs from TCM formulas and the mechanism of action.

Methods: Literature was retrieved from PubMed, Web of Science, Embase, Cochrane Library, CNKI, Wanfang Data Information Site, China Science and Technology Journal Database, and SinoMed. R was used for frequency and association rule analysis, SPSS for clustering, and Cytoscape, STRING, Gene Ontology, and KEGG enrichment analyses were utilized to explore targets, protein-protein interactions, and pathways. A meta-analysis using the Metan command was performed to assess the optimal herbal pairs for SD treatment.

Results: Data mining identified 77 commonly used herbs, revealing four advantageous herbal pairs: PAEONIAE RADIX ALBA (PRA)-BUPLEURI RADIX (BR), COPTIDIS RHIZOMA (CR)- CINNAMOMI CORTEX (CC), PORIA (PA)-BUPLEURI RADIX (BR), and ZIZIPHI SPINOSAE SEMEN (ZSS)-MARGARITIFERA CONCHA (MC). Network pharmacology showed that (PRA-BR)-SD, (PA-BR)-SD, (CR-CC)-SD, and (ZSS-MC)-SD targeted CACNA1D, GRIN2A, AGT, and ATP1A1 via prion diseases, nicotine addiction, neuroactive ligand-receptor interaction, and cardiac muscle contraction pathways, respectively.

Discussion: Research shows that CACNA1D could regulate Ca²⁷ inward flow, avoid mitochondrial dysfunction in prion diseases, and reduce ROS generation, thus indirectly maintaining MT levels and sleep. GRIN2A as an amygdala hub gene closely related to daily smoking, combining brain transcriptome analysis and tobacco consumption GWAS data. The sleep regulation mechanism of MT relies on the neuroactive ligand-receptor pathway. As a neuroactive ligand, MT triggers sleep-promoting physiological responses by activating the G-protein-coupled receptors MT1 and MT2 and transmitting "night" signals to the relevant neural networks. Insufficient MT secretion or circadian rhythm disruption might lead to abnormal blood pressure rhythms accompanied by sympathetic overactivation, increasing the risk of insomnia and cardiovascular disease. ATP1A1 is a key molecule in the maintenance of electrochemical gradients in cardiac myocytes through the modulation of the Na⁷/K⁷ homeostasis affects myocardial excitability, calcium kinetics, and contractile function.

Conclusion: Meta-analysis and network pharmacology suggest that the PA-BR pair might offer superior efficacy by modulating membrane potential and nicotine addiction pathways, targeting GRIN2A, GRIN1, GRIN3A, and GRIN2B to regulate melatonin levels.

Background/objective: Observational studies have linked diabetes with cataracts, but they cannot fully elucidate the underlying causes and mechanisms. This investigation aims to evaluate the causal relationship between genetically predicted diabetes and cataract risk utilizing Mendelian randomisation (MR) techniques.

Methods: We identified single nucleotide polymorphisms (SNPs) with a significant threshold of P < 5×10^-8 as instrumental variables from genome-wide association study datasets pertaining to Type 1 (finn-b-E4_DM1, n=189,113), Type 2 diabetes (finn-b-E4_DM2, n=215,654), and cataract (ukb-b-8329, controls=136,388, cataract=14,254). Various Mendelian randomisation methods were employed, including inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode (SM), and weighted mode analyses. Additionally, sensitivity analyses were conducted to assess the robustness of the findings, encompassing tests for heterogeneity, pleiotropy, and leave-one-out assessments. A multivariable (MVMR) approach was used to account for potential confounders, such as obesity (IEUA-92, controls = 47468, obesity = 2896), smoking (ukba- 16, n = 337030), and alcohol consumption (IEUA-1283, n = 11117).

Results: The analysis included 12 SNPs, which were derived from loci specifically associated with Type 1 diabetes and known to govern immune-inflammatory and metabolic pathways. The genetically-predicted Type 1 diabetes was found to elevate cataract risk significantly (OR=1.003, 95% CI: 1.001-1.005, P=0.001). The results of the sensitivity analyses corroborated the robustness of these findings, showing no significant heterogeneity (Cochran Q, P value = 0.73) or pleiotropy (MR-Egger intercept, P value = 0.38). Furthermore, multivariable MR demonstrated that the impact of diabetes on cataract risk remained significant after adjustment for multiple lifestyle factors.

Discussion: We provide novel MR evidence that Type 1 diabetes causally increases the risk of cataract through the synergistic activity of immune dysregulation, chronic inflammation, and metabolic disturbance, with immune-metabolic crosstalk as the primary driver.

Conclusions: T1D causally increases the risk of cataract through the disruption of immuneinflammatory and metabolic pathways. Targeting immune-metabolic interactions may offer novel therapeutic strategies for preventing diabetic cataracts.

Background: Ulcerative colitis (UC) is a chronic and recurrent enteritis requiring comprehensive treatment. Artemisia annua L. (A. annua) has shown a promising role in UC therapy, yet its key components and mechanisms of action are not fully understood.

Objective: This study aimed to investigate the effects of A. annua on UC, identify bioactive components, and elucidate underlying targets and mechanisms.

Materials and methods: Candidate targets of A. annua components and UC targets were overlapped using the PPI network and GO and KEGG pathway enrichment analyses. Molecular docking, a DSS mouse model (BALB/c), and an LPS/IFNγ cell model were employed to validate the efficacy and mechanism of action of A. annua against UC.

Results: The A. annua-ingredient-target-UC network included 21 active components, 65 candidate targets, and 10 hub genes. Molecular docking showed excellent fitting of the top 9 active components in the binding pocket of the top 6 hub targets. A DSS mouse model and an LPS/IFNγ cell model revealed the weight loss, intestinal inflammation, hub targets, and critical inflammatory signaling pathways (NFκB and STAT3) to be significantly attenuated by A. annua. Furthermore, A.annua improved transcellular and paracellular epithelial permeabilities by reducing intraepithelial bacteria, enhancing TEER, and decreasing FITC-dextran permeability.

Conclusion: This study demonstrated the significant protective effects of A. annua against inflammation and its ability to preserve the integrity of the transcellular and paracellular intestinal epithelial barrier, suggesting a promising application of A. annua in UC prevention and therapy..