Combinatorial Chemistry & High Throughput Screening - Online First

Ferroptosis is a recently identified iron-dependent programmed cell death closely linked to the progression of diffuse large B-cell lymphoma (DLBCL). While studies have shown that FA-2-b-β extracted from Agaricus blazei Murill affects various malignancies, its specific role in modulating ferroptosis in DLBCL and the underlying mechanisms are not yet clear. Objectives: This study aims to elucidate the anticancer properties and mechanisms of FA-2-b-β in inducing ferroptosis in DLBCL cells.

The cell counting kit 8 assay was carried out to evaluate the inhibition of cellular proliferation. Ferroptosis was evaluated using the ferrous colorimetric method, together with kits for measuring malondialdehyde (MDA), reduced glutathione (GSH), reactive oxygen species (ROS), western blotting, JC-1 assays, and transmission electron microscopy. Reverse transcription-quantitative polymerase chain reaction and western blot were conducted to determine whether FA-2-b-β affected nuclear factor erythroid 2- related factor 2 (Nrf2) and heme oxygenase 1 (HO-1).

FA-2-b-β induced ferroptosis in DLBCL cells by elevating the ROS and MDA levels, facilitating the accretion of Fe²⁺, diminishing GSH, upregulating the expression of PTGS2, and downregulating the expression of FTH1, SLC7A11, and GPX4. Furthermore, FA-2-b-β caused structural damage to mitochondria and diminished the mitochondrial membrane potential. The ferroptosis triggered by FA-2-b-β also led to the downregulation of Nrf2 and HO-1, thereby regulating the Nrf2/HO-1 pathway.

FA-2-b-β suppressed DLBCL cell growth by inducing ferroptosis through the Nrf2/HO-1 pathway, making it an attractive potential therapeutic option.

Quantitative Structure–Property Relationship (QSPR) models play a crucial role in predicting the chemical and physical characteristics of molecules.

This study introduces Zagreb rho indices derived from graph theory to assess the physico-chemical properties of benzenes. The rho degree of vertices in connected graphs was formulated and used to compute these indices.

Strong correlations (R> 0.94) were observed between Zagreb rho indices and various molecular properties such as boiling point, molecular weight, and electron energy.

The findings demonstrate that Zagreb rho indices can serve as reliable predictors within QSPR frameworks, offering structural sensitivity and outperforming traditional topological indices in several aspects.

Osteosarcoma (OS), a malignant tumor originating in bone or cartilage, primarily affects children and adolescents. Notably, substantial alterations in mitochondrial energy metabolism have been observed in OS; however, the specific contribution of mitochondrial-related genes (MRGs) to OS pathogenesis and prognosis remains unclear. Herein, we identified novel diagnostic biomarkers associated with mitochondrial-related processes in OS via comprehensive bioinformatics analysis.

OS mRNA expression profiles were retrieved from GSE16088 and GSE19276 databases. Mitochondrial-related differentially expressed genes (MitoDEGs) were identified by integrating differentially expressed analysis with mitochondrial-localized genes. A protein-protein interaction network was constructed, and machine learning algorithms (LASSO regression analysis and SVM-RFE) identified characteristic MitoDEGs. Subsequently, immune cell infiltration, microenvironment analysis, and single-cell RNA sequencing (scRNA-seq) analyzed differences in characteristic MitoDEGs, and RT-PCR was used for in vitro verification of characteristic MitoDEGs.

MitoDEGs in OS were significantly enriched in the pathways associated with mitochondrial function and immune regulation. Two MitoDEGs, UCP2 and PRDX4, were identified via LASSO and SVM-RFE. Correlation analysis demonstrated a close association between UCP2 and PRDX4 expression levels and immune cell infiltration, particularly in CD8+ T and native CD4+ T cells, as observed in both immune cell and scRNA-seq analyses. Furthermore, RT-PCR confirmed the expression levels of UCP and PRDX4 at the cellular level, which was consistent with the bioinformatics results.

This study identified UCP2 and PRDX4 as characteristic MitoDEGs and potential diagnostic biomarkers for OS using machine learning algorithms. These findings provide novel insights into the clinical applications of these biomarkers for OS diagnosis.

This study aimed to assess the safety and effectiveness of carbamazepine in treating trigeminal neuralgia in contrast to gabapentin. Hence, a systematic review and meta-analysis of randomised controlled trials had been carried out.

The relevant studies were searched in PubMed and filtered according to the inclusion and exclusion criteria. Independently, two reviewers chose the studies, evaluated the quality of the investigations, and retrieved the data. RevMan was used for analysis when the data were collected and entered into the data extraction sheet. In addition to heterogeneity, the overall estimate measures were computed as mean differences with a 95% confidence interval for continuous data and relative risk for dichotomous data. To investigate the impact of outliers on the result, a sensitivity analysis was performed. A funnel plot was used to qualitatively evaluate the publishing bias. A total of 1,650 participants from 19 randomised controlled trials were evaluated.

The meta-analysis revealed that the group receiving gabapentin therapy had a similar overall effective rate to the group receiving carbamazepine therapy (OR = 1.94, 95% CI 1.46, 2.57, P = 0.32). Additionally, our meta-analysis revealed that the group receiving gabapentin therapy witnessed a significantly lower risk of adverse reactions than the group receiving carbamazepine therapy (OR= 0.29, 95% CI 0.22, 0.387, P<0.00001).

In summary, the current trials comparing carbamazepine and gabapentin have had inadequate methodological quality. It is not possible to conclude that gabapentin is more effective than carbamazepine in terms of adverse effects based on the evidence that is currently available.

This study aimed to examine the impact of quercetin on a mouse model of endometriosis and elucidate its underlying mechanisms.

An endometriosis model was established using C57BL/6 mice, which were divided into three groups: 1) sham group, 2) model group, and 3) model group treated with daily gavage administration of 100 mg/kg/d quercetin. Histopathological examination was performed using hematoxylin and eosin (HE) staining. The microstructure of the lesions was examined using electron microscopy. The expressions levels of related proteins, such as the peroxisome proliferator-activated receptor-γ (PPARγ), methionine adenosyl-transferase 2A (MAT2A), Ki67 and VEGF was measured using Western blotting or Immunohistochemistry.

Compared to the model group, the medication group showed sparse endometrial stromal cells, irregular morphology, and numerous vacuoles, indicating apoptosis. Compared to the sham group, SAM expression was unchanged (P > 0.05), while PPARγ decreased. MAT2A, PRMT5, cyclin D1, and C-MYC increased, and vimentin, Ki67, VEGF, and caspase-1 were strongly positive (P < 0.05). Quercetin intervention reduced ectopic lesion weights, increased PPARγ, and decreased MAT2A, PRMT5, SAM, cyclin D1, and C-MYC. Vimentin, Ki67, VEGF, and caspase-1 were weakly positive (P < 0.05).

These results indicate that quercetin effectively reduced endometriosis lesions by modulating key protein expressions and promoting apoptosis.

Quercetin modulated the transcription of the MAT2A/PRMT5 gene by activating PPARγ activity, thereby influencing the ectopic implantation and growth of endometrial cells.

Age-related Macular Degeneration (AMD) is a predominant cause of blindness in the elderly. The present study is the first to investigate the alteration of lncRNAs and mRNAs in neovascular AMD.

Nine patients with neovascular AMD were included in the study. The control group comprised seven patients with epiretinal membranes. RNA sequencing was performed to obtain the differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs). Then, the DElncRNA-DEmRNA co-expression network, ceRNA network, and immune-related ceRNA subnetwork were constructed. Functional annotation of DEmRNAs between the two groups and DEmRNAs in networks was conducted. The immune cell distribution in neovascular AMD was also evaluated. Real-time qPCR (RT-qPCR) was used to validate the expression levels of key markers.

A total of 342 DEmRNAs and 157 DElncRNAs were obtained in neovascular AMD. Functional annotation indicated that these DEmRNAs significantly enriched immune system-related processes, such as positive regulation of B cell activation, immunoglobulin receptor binding, complement activation, and classical pathway. The DElncRNA-DEmRNA co-expression network, including 185 DElncRNA-DEmRNA co-expression pairs, and the ceRNA (DElncRNA-miRNA-DEmRNA) network, containing 45 lncRNA-miRNA pairs and 73 miRNA-mRNA pairs, were constructed. The immune-related ceRNA subnetwork, including 2 lncRNAs, 5 miRNAs, and 3 mRNAs, was constructed. In addition, the distribution of immune cells was slightly different between the neovascular AMD group and the control group. RT-qPCR validation indicated the consistency between the RT-qPCR results and RNA sequencing results.

In conclusion, STC1, S100A1, MEG3, MEG3-hsa-miR-608-S100A1, and MEG3-hsa-miR-130b-3p/hsa-miR-149-3p-STC1 may be related to the occurrence and development of neovascular AMD.

Atherosclerosis, a leading cause of death globally, is characterized by the buildup of immune cells and lipids in medium to large-sized arteries. However, its precise mechanism remains unclear. The purpose of this study is to explore innovative and reliable biomarkers as a viable approach for the identification and management of atherosclerosis.

The atherosclerosis-related datasets GSE100927 and GSE66360 were retrieved from the Gene Expression Omnibus (GEO) database. The Limma package in the R programming language was utilized, applying the criteria of |logFC| > 1 and P < 0.05. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the 127 identified DEGs using R. Machine learning techniques were then applied to these data to explore and pinpoint potential biomarkers. The diagnostic potential of these markers was assessed via Receiver Operating Characteristic (ROC) curve analysis. Finally, western blot, real-time quantitative PCR (qRT-PCR), and immunohistochemistry (IHC) were employed to confirm the key biomarkers.

Our research indicated that a total of 127 DEGs linked to atherosclerosis were successfully identified. Through the application of machine learning methods, eight critical genes were highlighted. Among these, Nuclear Receptor Subfamily 4 Group A Member-2 (NR4A2) emerged as the most promising marker for further investigation. CIBERSORT analysis revealed that NR4A2 expression levels were significantly correlated with multiple immune cell types, including B cells, plasma cells, and macrophages. Additional validation experiments confirmed that NR4A2 expression was indeed elevated in atherosclerotic plaques, supporting its potential as a biomarker for atherosclerosis.

Our study identified NR4A2 as a potential immune-related biomarker for the diagnosis and treatment of atherosclerosis.

The phylum Thermotogae is composed of five families: Fervidobacteriaceae, Thermatogaceae, Kosmotogaceae, Petrotogaceae, and Mesoaciditogaceae; one class: Thermotogae; and four orders: Kosmotogales, Petrotogales, and Mesoaciditogales. There are thirteen genera in all. The physical and metabolic characteristics of the Thermotogae species reflect the extreme heat from which they were separated. Thermotogae members have a broad spectrum of metabolic capacities, resulting in a pool of valuable chemicals with potential uses in many different sectors.

A 1.5-liter operating capacity bioreactor with a 2.3-liter double-jacket glass volume was utilised to culture Thermotoga maritima in both oxic and anoxic conditions. In addition to temperature, pH, and redox potential, sensors that were installed within the fermentor monitored additional parameters. RNA extraction and cDNA synthesis A total of RNAs was extracted utilising Roche's High Pure RNA reagent. Analysis of glycolysis pathways in T. maritima was performed by NMR spectroscopy

Based on NMR analysis, our findings demonstrate that T. maritima uses the EM route to metabolize 90% of glucose in anoxia and the ED pathway for 10%. On the other hand, T. maritima continues to employ the EM and ED glycolysis routes concurrently when exposed to extended oxidative stress; however, the ED pathway's contribution drops from 10% to around 5%.

Compared to the EM route, the ED pathway has more strongly repressed transcripts that encode its unique enzymes.

Zhishi decoction (ZSD) is one of the most common herb decoctions in traditional Chinese medicine (TCM), and it is used for the treatment of FC. However, its main therapeutic mechanism is not yet clear. This study aims to explore the possible pharmacodynamic material basis and potential molecular mechanism from network pharmacology and molecular docking and verify them through animal experiments.

Firstly, the effective ingredients, potential targets, and key targets of ZSD in the treatment of FC were screened through network pharmacology. Go and KEGG analyses were performed for potential targets. Secondly, molecular docking was used to link the main active components of ZSD with target genes to predict their possible molecular mechanisms. Finally, 30 male BALB/c mice (20±2g) were randomly divided into five groups (n=6), including the blank group, ZSD groups with two dosages (7.15, 14.3g/kg), FC model group, and positive group (lactulose group). All the mice were given difenoxate tablets for 14 days to establish FC model except the blank group. Moreover, the mice in the blank group were given the same volume of normal saline. After admination for 14 days, the whole colon tissues were obtained for the analysis of small intestinal propulsion rate, and the expression of P38MAPK in colon tissues of mice was observed via immunohistochemistry and WesterBlot.

In this study, 43 active ingredients in ZSD were identified. Four hundred and thirty potential therapeutic targets were selected, among which AKT1, MAPK12, and MAPK14 were key targets. 164 GO biological processes and 123 KEGG signaling pathways were identified after analysis, such as MAPK signaling pathway, TNF signaling pathway etc. The molecular docking results showed that Prangenin, 4-Hydroxyhomopterocarpin, isoponcimarin, and AKT1, MAPK12, MAPK14 had good binding degree. Additionally, ZSD could relieve the symptoms of FC in mice significantly. Compared with the model group, p38/MAPK positive expression cells and protein expression levels in the colon tissues of ZSD groups significantly increased in a dose-dependent manner (p<0.01).

This study confirmed that ZSD could act on AKT1, MAPK12, and MAPK14 targets to activate the p38/MAPK signaling pathway to relieve FC induced by defenoxate tablets. The further development of ZSD provided a theoretical basis.