Combinatorial chemistry & high throughput screening最新文献

Introduction: Sex hormones are important factors in maintaining brain function and acting as brain protectors. Recent research suggests that neuronal damage in brain aging may be linked to the methylation of the estrogen receptor α (ERα). However, the mechanism of Zuogui Pills (ZGW) in brain-aging ERα DNA methylation and neuronal repair remains unknown.

Materials and methods: D-galactose-induced ovary removal mice were used as a model of aging. Changes in estrous cycle were detected in mice by vaginal cell smear. Animal behavior tests, including the Morris water maze (MWM) and new object recognition (NOR) test, were conducted. Hematoxylin-eosin (HE) and Nissl-staining were carried out to assess hippocampal neurogenesis. Enzyme-linked immunosorbent assay (ELISA) was performed for 5- methylcytosine methylation levels, and immunohistochemistry (IHC) and western blotting (WB) experiments were performed to assess ERα/DNA methyltransferase 1 (DNMT1) expression after ZGW treatment. Finally, bisulfite sequencing PCR (BSP) analysis was performed to identify methylated differentially expressed estrogen receptor 1 (ESR1) gene in D-gal-induced senescent neurons before and after ZGW treatment.

Results: We found that ERα methylation was involved in the delayed brain ageing process of ZGW. Mechanistically, ZGW can improve the learning and memory ability of brain-aging mice, reduce the expression of 5-methylcytosine (5-mc) in serum, increase the amount of ERα, inhibit the expression of DNMT1, and significantly reduce methylated expression of the ESRI gene.

Conclusion: Our data suggested that ZGW slowed down D-gal-induced brain aging in mice, and these results showed that ZGW is beneficial for aging. It may be used for neuronal protection in aging.

Introduction: In the ongoing fight against bacterial resistance to antibiotics, this study focuses on synthesizing and evaluating 1,2,4-triazole derivatives to explore their potential as new antibacterial agents. 1,2,4-Triazole compounds are promising drug candidates with a wide range of therapeutic effects, including pain relief, antiseptic, antimicrobial, antioxidant, antiurease, anti-inflammatory, diuretic, anticancer, anticonvulsant, antidiabetic, and antimigraine properties.

Method: The structures of all the synthesized compounds were identified using their physicochemical properties and spectral techniques, such as IR and NMR. These compounds were then evaluated in molecular docking studies against antimicrobial activity in vitro and further supported by molecular dynamics studies.

Result: Compound 7, featuring a 6-chloro group on the phenyl ring, emerged as the most effective against Gram-positive S. aureus compared to the standard antibiotic ciprofloxacin. Docking studies revealed high and comparable affinities for all ten ligands, with compounds 4 and 6 showing the best-docked activity against Penicillin Acylase mutants. Further, compounds 6 and 10 displayed significant affinity against D-alanine-D-alanine ligase (DDL) from Yersinia pestis during 100 ns MD simulation.

Conclusion: Notably, compound 7 demonstrated the highest binding score to the 5C1P protein, suggesting its potential as a lead molecule for the development of potent and safer antimicrobial agents. This research contributes valuable insights into addressing the escalating challenge of bacterial resistance.

Background: A major factor in type 1 diabetes mortality is Ischemic Heart Disease (IHD). In order to treat IHD, blood flow must be restored to the heart, which results in myocardial ischemia-reperfusion (MI/R) damage. While rosmanol inhibits MI/R damage, its role in diabetic- MI/R (D-MI/R) injury remains unclear. Both microRNA (miR) 126 and the PI3K/AKT signaling pathway have been linked to preventing MI/R damage.

Objective: The objective of the present study was to investigate whether rosmanol inhibits DMI/ R-injury in diabetic rats and whether miR-126-phosphatidylinositol 3-kinase (PI3K)/ protein kinase B axis (miR-126-PI3K/AKT) is implicated in this protective effect.

Methods: For 30 days, diabetic rats received either distilled water or the drug rosmanol (40 mg/kg, orally) before being subjected to MI/R.

Results: The findings from the current study demonstrated how rosmanol reduced MI/R damage in rats with diabetes caused by streptozotocin (STZ). Using spectrophotometry, it was possible to measure the decrease in myocardial enzyme levels, the rise in cardiac viability, the inhibition of myocardial oxidative stress, the increase in cardiac function, and the detection of these changes using a hemodynamic monitoring system. In addition, rosmanol augmented the miR- 126-PI3K/AKT in the hearts of ischemic rats. After stimulating the myocardial miR-126- PI3K/AKT axis, our results showed that rosmanol protected the heart against MI/R in STZinduced diabetic rats.

Conclusion: According to the most recent research, rosmanol may be a useful tool in the therapy of diabetic IHD since it is an effective agent against D-MI/R damage.

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Ethnopharmacological relevance: Dispel-Scar Ointment is used in Traditional Chinese Medicine to treat scarred tissue and increasing evidence has shown that DSO has potent therapeutic; however, its exact mechanism remains unexplored.

Aim of the study: This study explored the molecular mechanisms of action of DSO in scarring using network pharmacology, molecular docking, and experimental validation.

Materials and methods: Public databases were used to predict the bioactive ingredients and putative targets of DSO against scars. A compounds-targets network was constructed using the Cytoscape software. Enrichment analysis was performed using ClueGo and FunRich to specify the biological functions and associated pathways of hub targets. Molecular docking was used to verify the correlation between the major active components and hub targets, visualised using PyMol 2.3. Experimental validations were conducted to elucidate the influence of DSO on keloid fibroblast cells using the CCK-8, wound-scratch, cell reactive oxygen species, and western blot assays. Results：Network pharmacological analysis of DSO for scar treatment identified 146 ingredients and 1078 gene targets. Major targets included, prostaglandin-endoperoxide synthase 2 matrix metallopeptidases, and nitric oxide synthase 2. ClueGo analysis revealed 29 pathways (p<0.05) and FunRich 345 pathways (p<0.05), mainly toll-like receptor, TGF-β, interleukin-4/13, glypican, and tumour necrosis factor-related apoptosis-inducing ligand pathways. Molecular docking showed MMP2-flavoxanthin, MMP9-luteolin and MMP-9-kaempferol bound best to DSO. DSO could inhibit the proliferation and migration of scar fibroblasts and promote their apoptosis in a concentration-dependent manner. DSO also decreased TGF-β1, -βR2, pSMAD2, pSMAD3, SMAD4, CoL1a1, and MMP2 expression.

Conclusions: Network pharmacology, molecular docking, and experimental validation showed DSO's potential in treating scars. It may inhibit scars via the TGF-β1/SMADs/MMPs signalling pathway, providing a basis for DSO's scar treatment application.

Tropical fruits are often studied to determine their content of bioactive compounds that contain health-enhancing properties and are often identified to hold a rich nutritional composition. Their bioactive compounds are classified through their phenolic, flavonoid, and antioxidant properties, while some tropical fruits are known to have other properties such as anticancer and anti-inflammatory activity. Sri Lanka is an island with abundant resources. One such resource is exotic fruits. Exotic fruits are known as edible fruits, which are not necessarily native but consist of a unique flavor profile, fragrance, shape, or appearance. Exotic fruits are usually consumed on their own or consumed as beverages, pickles, jams, salads, and desserts. The market-friendly tropical fruits in Sri Lanka include a vast number, and some of them are mango, Ceylon olives, durian, jackfruit, rambutan, soursop, passion fruit, and star fruit. These fruits contribute to the rice culinary heritage of Sri Lanka, and most of them are exported worldwide. At present, the traditional medicine system is quite popular among the public due to its less toxic nature and easy access. This review is aimed at evaluating the antioxidant, cytotoxic, anticancer, and anti-inflammatory properties of eight selected exotic fruits mentioned above and their traditional usage, which is based on the literature of various scientific studies conducted on these tropical fruits.

The plant kingdom offers a wealth of molecules with potential efficacy against various human, animal, and plant crop infections and illnesses. Cannabis sativa L. has garnered significant attention in recent decades within the scientific community due to its broad biological activity. Key bioactive compounds such as cannabinoids and phenolic compounds have been isolated from this plant, driving its bioactivity. Numerous studies have highlighted the impact of different agronomic practices, particularly fertilization, on the phytochemical composition, notably altering the percentage of various chemical groups. This review aims to present updated fertilization recommendations, crop requirements, and their implications for the chemical composition of C. sativa plants, along with major biological properties documented in the literature over the past five years. Various databases were utilized to summarize information on fertilization and crop requirements, chemical composition, bioassays employed, natural products (extracts or isolated compounds), and bioactivity results. Through this review, it is evident that C. sativa holds promise as a source of novel molecules for treating diverse human diseases. Nonetheless, careful consideration of agronomic practices is essential to optimize chemical composition and maximize therapeutic potential.

Background: Current evidence highlights clear cell renal carcinoma (ccRCC) as the most prevalent form of kidney cancer despite ongoing challenges in treating advanced-stage disease. Integrin subunit beta 3 (ITGB3) has recently emerged as a critical player in tumorigenesis, prompting our investigation into its role in ccRCC. This study aimed to elucidate the mechanisms responsible for ITGB3 downregulation and evaluate its clinical significance, particularly regarding its impact on the immune landscape within ccRCC.

Methods: We first conducted analyses utilizing data from both TCGA and GEO datasets to explore ITGB3 expression in ccRCC tissues. Subsequently, we evaluated the association between ITGB3 expression levels and patient prognosis and pathological staging. Pathway and functional enrichment analyses were performed to assess correlations between ITGB3 and immune and methylation-related pathways. Additionally, we examined the relationship between ITGB3 transcriptional expression and DNA hypermethylation. A prognostic risk model was developed using LASSO-based analysis on selected ITGB3-associated DNA methylation probes. Immunohistochemistry (IHC) analysis, alongside TIMER and ssGSEA results, was utilized to investigate ITGB3 expression and its association with immune cell infiltration.

Results: Our analyses revealed significant downregulation of ITGB3 mRNA expression in ccRCC tissues compared to other members of the ITGB family, consistent across TCGA and GEO datasets. Higher ITGB3 expression correlated with improved prognosis and lower pathological stage in ccRCC patients. Pathway and functional enrichment analyses demonstrated positive correlations between ITGB3 and immune and methylation-related pathways, while ITGB3 transcriptional expression showed a negative correlation with DNA hypermethylation. The established prognostic risk model identified a high-risk group with poorer survival probabilities than the low-risk group. Immunohistochemical quantification revealed a positive correlation between CD4+ and CD8+ immune cell infiltration and ITGB3 expression.

Conclusion: Overall, our study provides compelling evidence supporting the significant role of ITGB3 in ccRCC immunity. The downregulation of ITGB3, coupled with its association with better prognosis and immune activation, suggests its potential as a therapeutic target and prognostic marker for this patient population.

Background: In this study, we used immune repertoire (IR) sequencing technology to profile the diversity of peripheral blood T cell receptors and used transcriptomics to profile the gene expression of peripheral blood neutrophil mRNA in patients with mild-moderate knee osteoarthritis (KOA) before and after electroacupuncture (EA) treatment.

Methods: An 8-week intervention with EA was performed on 3 subjects with KOA. IR sequencing of complementarity determining region 3 (CDR3) was performed using RNA extracted from peripheral blood T cells of KOA subjects prior to and at the end of the intervention, as well as healthy volunteers (controls) who matched the subjects in sex and age. Neutrophils were extracted from the plasma of healthy individuals, pretreatment patients, and posttreatment patients for further transcriptome sequencing.

Results: The D50, diversity index (DI), and Shannon entropy values of circulatory T-cells were significantly lower in pretreatment KOA patients compared to healthy controls. Posttreatment KOA samples displayed significant decreases in serum proinflammatory factors, IL-8 and IL-18 (P < 0.01), as well as a substantial reduction in serum matrix MMP-3 and MMP-13 (P < 0.01, P < 0.05). Transcriptome analysis revealed that the expression of CXCL2, IRF8, and PEAR1 (P < 0.05) was significantly higher in patients before the treatment than in the healthy population and was significantly down-regulated after the treatment. In contrast, the expression of SMPD3 (P < 0.05) showed the opposite trend.

Conclusion: EA may alleviate KOA by rebalancing T-cell homeostasis and improving systemic inflammation. At the same time, EA treatment can significantly enhance TCR diversity, reduce levels of proinflammatory factors, and increase levels of anti-inflammatory factors, thereby achieving therapeutic effects.