Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, joint destruction, and functional impairment. Angiogenesis plays a key role in the pathological progression of RA with dysfunction of endothelial cells to promote synovial inflammation, sustain pannus formation, subsequently leading to joint damage. Colquhounia Root Tablets (CRT), a Chinese patent drug, has shown a satisfying clinical efficacy in treating RA, while the underlying mechanism by which CRT inhibits RA-associated angiogenesis remains unclear. In this study, we applied a research approach combining transcriptomic data analysis, bio-network mapping, and in vivo and in vitro experiments to explore the molecular mechanisms of CRT in suppressing angiogenesis in RA. Animal welfare and experimental procedures follow the regulations of the Animal Ethics Committee of Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences (ratification number: IBTCMCACMS21-2307-06). Network analysis identified that key genes such as nucleotide-binding oligomerization domain-containing protein 2 (NOD2), SMAD family member 3 (SMAD3), and vascular endothelial growth factor A (VEGFA) significantly enriched in pathways related to NOD-like receptor signaling and VEGF signaling, indicating that CRT may inhibit angiogenesis by regulating vascular endothelial cell function with modulating angiogenesis-related pathways. In vivo data showed that CRT significantly reduced the positive expression of CD31 and VEGF in the ankle joint of adjuvant-induced arthritis (AIA) rats. In vitro data further confirmed that CRT effectively inhibited VEGF-induced migration, invasion, and tube formation in HUVECs, while significantly reduced the expression of angiogenesis-related factors VEGF/CD31/Ang-1, as well as the positive expression of VEGF and CD31 in HUVECs. Furthermore, CRT markedly decreased the protein expression of NOD2, VEGFA, and SMAD3. In conclusion, these findings indicate that CRT may inhibit the RA-related angiogenesis by targeting the NOD2/SMAD3/VEGF signaling axis to improve endothelial cell function, enriching the scientific connotation of CRT in inhibiting pathological angiogenesis in RA and also offer new insights for clinical prevention and treatment of RA.

Humans ; Vascular Stiffness ; Coal Mining ; Occupational Diseases/epidemiology* ; Risk Factors ; Coal ; Miners

Humans ; PPAR gamma/metabolism* ; Multiple Sclerosis ; Transcription Factors/metabolism* ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha

Child ; Humans ; Mpox (monkeypox)/prevention & control* ; Disease Outbreaks

Three 2,3-diketoquinoxaline alkaloids were isolated from Heterosmilax yunnanensis Gagnep. Their structures were determined through 1D and 2D NMR, HR-ESI-MS, UV, and IR as 1-[5′-(3″-hydroxy-3″-methyl) glutaryl] ribityl-2,3-diketo-1,2,3,4-tetrahydro-6,7-dimethylquinoxaline (1), 1-[2′-(3″-hydroxy-3″-methyl) glutaryl]ribityl-2,3-diketo-1,2,3,4-tetrahydro-6,7-dimethylquinoxaline (2), and 1-ribityl-2,3-diketo-1,2,3,4-tetrahydro-6,7-dimethylquinoxaline (3). Compounds 1 and 2 are novel compounds, and 3 was isolated from H. yunnanensis for the first time. The hepatoprotective activity of these three compounds was evaluated, with compound 3 showing promising hepatoprotective activity.

BACKGROUND:Astrocytes are the most abundant cells in the central nervous system,and various subsets of astrocytes are heterogeneous,performing a variety of special functions.Single-cell RNA sequencing(scRNA-seq)technology developed in recent years has extended our understanding of astrocyte heterogeneity from the perspective of transcriptome profiling. OBJECTIVE:To summarize the heterogeneity of scRNA-seq technology in different time and space,and pathological states and expand our knowledge of astrocyte heterogeneity on both molecular and functional levels. METHODS:The relevant articles on astrocyte heterogeneity and scRNA-seq were searched on PubMed,Elsevier,and CNKI databases.The search terms were"astrocytes,scRNA-seq,heterogeneity,Alzheimer disease,spinal cord injury,multiple sclerosis"in Chinese and English.Finally,74 articles were selected for viewing after screening according to inclusion criteria. RESULTS AND CONCLUSION:scRNA-seq studies related to the heterogeneity of astrocytes have shown that astrocyte is significantly heterogeneous across four aspects:species,developmental stage,central nervous system region,and pathological state.(1)Unique expression of certain genes occurs in astrocytes of different species,and the discovery of species-specific genes is beneficial for the translation of clinical studies.(2)During astrocyte development,differential gene expression emerged in the cellular subtypes identified at each stage,which further refined the cellular lineage of astrocytes and laid the foundation for the study of astrocyte developmental trajectories and mechanisms.(3)The discovery of differential gene expression allows regional localization of different astrocyte subpopulations and assists in the diagnosis and treatment of neurological diseases.(4)Astrocyte heterogeneity revealed by scRNA-seq can provide specific markers at the time of disease diagnosis and identify potential therapeutic targets.(5)The heterogeneity of astrocytes exists in many aspects,interacts with each other and is complex.The mechanisms of its generation,maintenance and transformation remain unclear.At present,molecular research on the single-cell level is still lacking.Linking transcriptionally defined astrocyte subpopulations to cellular activity,behavior and disease markers in real time remains one of the great challenges in the field.

Understanding the research methods for drug protein targets is crucial for the development of new drugs, clinical applications of drugs, drug mechanisms, and the pathogenesis of diseases. Cellular thermal shift assay (CETSA), a target research method without modification, has been widely used since its development. Now, there are various CETSA-based technology combinations, such as mass spectrometry-based cellular thermal shift assay (MS-CETSA), isothermal dose response-cellular thermal shift assay (ITDR-CETSA), amplified luminescent proximity homogeneous assay-cellular thermal shift assay (Alpha-CETSA), etc., which combine their respective advantages and further expand the application scope of CETSA. These technologies are suitable for the entire drug development chain, from drug screening to monitoring the target binding and off-target toxicity of drugs in patients. Based on the author's research experience, this paper reviews the principles of CETSA and related binding technologies, their application in target discovery, and the progress of data processing and analysis in recent years, aiming to provide reference and reference for the further application of CETSA.

The p53 protein is an essential tumor suppressor in the human body that plays a critical role in preventing tumor formation by controlling cell cycle arrest and promoting apoptosis. Mutations in the p53 gene are frequently observed in more than 50% of tumor tissues and lead to the generation of mutant p53 proteins, which not only have a dominant-negative effect (DN) that hinders the function of wild-type p53 protein but also have gain-of-function (GOF) effects that stimulate tumor development by regulating cell metabolism, invasion, migration, and other processes. Therefore, mutant p53 protein has become a specific drug target for cancer therapy. However, the lack of a drug-binding pocket and smooth surface of mutant p53 proteins have made them undruggable targets for a long time. In recent years, with the development of high-throughput screening technology and an enhanced understanding of the structure and conformational changes exhibited by mutant p53 proteins, a multitude of small molecule compounds directed against mutant p53 protein have been identified, exhibiting substantial in vitro anti-tumor efficacy. Moreover, some of these compounds have entered clinical trials. This review summarized the direct and indirect strategies for the treatment of cancers targeting mutant p53, with a primary focus on the mechanisms of action of small molecule compounds that reactivate mutant p53 protein or degrade mutant p53 protein. The aim is to provide assistance for the development of innovative drugs targeting mutant p53 protein in the future.

AIM To study the chemical constituents from Ganoderma angustisporum J.H.Xing,B.K.Cui&Y.C.Dai and their α-glucosidase inhibitory activities.METHODS The ethyl acetate extract from G.angustisporum was isolated and purified by silica gel,ODS,TLC and HPLC,then the structures of obtained compounds were identified by physicochemical properties and spectral data.pNPG method was used to evaluate their α-glucosidase inhibitory activities.RESULTS Seven compounds were isolated and identified as N-acetyl-L-phenylalanine ethyl ester(1),N-acetyl-L-phenylalanine methyl ester(2),4-hydroxy-17R-methylincisterol(3),6,8-di-O-methylaverufin(4),aversin(5),methyl 2-(4-hydroxyphenyl)aceate(6),5-toluene-1,3-diol(7).Compounds 1-2,4-7 showed inhibitory activities of α-glucosidase with IC50 values being(33.80±0.47),(45.45±7.95),(48.80±5.86),(39.48±2.82),(41.47±6.68),(55.38±10.12)μmol/L,and compound 1 showed good inhibitory activity.CONCLUSION Compound 1 is a new natural product.Compounds 2-7 are isolated from genus Ganoderma for the first time.Compounds 1-2,4-7 have α-glucosidase inhibitory activities.

AIM To establish a GC-MS method for the simultaneous content determination of sixteen pesticide residues in Lycii Fructus and perform safety assessment.METHODS The analysis was performed on DB-5MS chromatographic column(30 m×0.25 mm,0.25 μm)subjected to the programmed heating,with splitless injection of 1.0 μL dissolved sample at a flowing rate of 1.0 mL/min.Other parameters were as follows:injection port temperature of 250℃,electron impact ionization(EI),electron energy of 70 eV;ion source temperature of 230℃,multi-reaction monitoring mode,and collision gas.of high-purity N2.Pesticide residues with relatively high dietary risk were analyzed and discussed with regard to residue levels,dietary intake risk,risk ranking and cumulative exposure assessment.RESULTS Sixteen pesticides showed good linear relationships within their own ranges(r≥0.994 4),whose average recoveries were 70%-114%,with the RSDs of less than 2%.The highest average cyfluthrin residue of 0.999 2 mg/kg in Lycii Fructus of production regions and the highest average cypermethrin residue of 0.088 4 mg/kg in Lycii Fructus commodities were both detected.In Lycii Fructus of production regions with chronic hazard index(HI)value of 0.012 9 and acute HI value of 0.065 5 and their commodities with chronic HI of 0.001 2 and acute HI of 0.005 4,the pesticide residue of cypermethrin was the leading cause of chronic and acute dietary risk,and additionally,pyridaben within maximum residue limit(MRL)was the only detectectable highly toxic pesticide among the other most concerning pestcides of deltamethrin,pyridaben,chlorpyrifos,dichlorvos and methidathion.CONCLUSION There exist pesticide residues within MRL values in some samples of Lycii Fructus and the use of cypermethrin should be well-controlled.