Current medicinal chemistry最新文献

Introduction: Limited studies have explored how ferroptosis and Epithelial- Mesenchymal Transition (EMT) jointly affect the prognosis of Esophageal Squamous Cell Carcinoma (ESCC). This study aimed to develop a clinical prognostic model based on the combined impact of ESCC.

Methods: Gene expression levels and clinical data of ESCC patients were obtained from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) database. Using Cox regression analysis and Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis, we identified nine prognostic genes to build a predictive model. Immune cell infiltration was evaluated using CIBERSORT and single-sample Gene Set Enrichment Analysis methods. Finally, in vitro experiments were conducted to assess the oncogenic effects of ACSL3 and VIM.

Results: We developed a Ferroptosis-EMT Integrated Score (FEIS) based on nine key genes. High-FEIS patients had worse survival, increased immune infiltration, and higher expression of immune checkpoints. A nomogram was built for prognosis prediction, and in vitro studies confirmed the tumor-promoting roles of ACSL3 and VIM.

Discussion: The FEIS model robustly predicts ESCC prognosis by integrating ferroptosis and EMT, offering novel biomarkers for personalized immunotherapy, though further validation is warranted.

Conclusion: Our study introduced a novel prognostic tool that integrates ferroptosis and EMT-related biomarkers and offers valuable insights for developing personalized treatment strategies for ESCC patients.

As a member of the TAM family of receptor kinases, the AXL protein plays an essential role in biological processes that maintain tissue homeostasis. Deregulated AXL signalling in tumour cells is linked to cancer progression, poor prognosis, metastasis, and reduced sensitivity to anti-cancer therapies. The underlying mechanisms are the activation of downstream signalling routes that promote cell survival, invasion and epithelial-mesenchymal transition. Two major AXL isoforms are expressed in human and rodent cells due to alternative splicing. Despite extensive research on AXL in cancer, little is known regarding the functional differences between these isoforms and whether they contribute to cancer differently. This review paper first outlines the structural and functional aspects of TAM biology with a particular focus on AXL. Next, we discuss the different levels of AXL regulation in tumour cells, including proteolytic cleavage, which leads to the formation of both extracellular and nuclear forms of AXL. Finally, we review articles investigating the variations in the function of AXL isoforms and report their associations with cancer. Notably, the formation of isoform 1 is likely to determine the presence of soluble AXL, elevated levels of which have been correlated with cancer progression in several tumour types. The review identifies areas deserving further investigation, such as how changes in isoform expression impact levels of soluble AXL in cancer. Additionally, isoform-specific downstream signalling effects and their impact on metastasis and drug resistance warrant more in-depth investigation.

Background: The growing threat of bacterial drug resistance compels researchers to pursue new therapeutic strategies. Finegoldia magna secretes SufA, a subtilisin- like protease that plays a critical role in virulence by degrading host defense molecules such as fibrinogen and LL-37. This study aimed to investigate the stereoselective inhibition of SufA by pure diastereoisomers of peptidyl 1-aminoalkylphosphonate diaryl esters and to evaluate their ability to reduce bacterial virulence and growth.

Methods: We synthesized and purified the diastereoisomers and assessed their ability to inhibit SufA using a fluorescent enzymatic assay. Antibacterial activity was evaluated against Gram-positive and Gram-negative bacteria. SDS-PAGE was used to examine the inhibition of SufA-mediated degradation of fibrinogen and LL-37. Molecular docking was performed, and binding was confirmed via Western blot.

Results: Diastereoisomer XIIIA inhibited SufA activity by 63% at 50 μM, protected fibrinogen and LL-37 from degradation, and significantly suppressed the growth of F. magna and E. coli. In contrast, XIIIB showed minimal activity. Molecular docking revealed key binding interactions between XIIIA and the SufA active site, which was further confirmed by Western blot analysis.

Discussion: These results demonstrate that stereochemistry critically influences SufA inhibition, with XIIIA showing superior potency and functional protection of host defense molecules. This supports its potential as an antivirulence agent. The validated probe also provides a tool for identifying serine protease targets in other pathogens.

Conclusion: Compound XIIIA exhibits potent stereoselective inhibition of SufA and notable antimicrobial effects, supporting its development as a novel therapeutic targeting bacterial virulence.

Background: An excessive inflammatory response plays a central role in the pathogenesis of ulcerative colitis (UC), but the specific cytokines involved remain unclear. This study aimed to identify inflammatory factors associated with UC and explore the possible mechanisms of the identified targets.

Methods: Protein quantitative trait loci (pQTLs) and expression quantitative trait loci (eQTLs) for inflammatory cytokines were obtained from a genome-wide pQTL study and the eQTL consortium, respectively. Summary data for UC from the exploration and validation cohorts were derived from a genome-wide association study and the Finngen cohort. MR and colocalization analyses were conducted to identify causal associations between inflammatory cytokines and UC. Bioinformatics analyses were employed to explore the involved biological processes of candidate targets. Immunohistochemistry was used to validate the expression of these candidate targets in colon tissues.

Results: Among all inflammatory cytokines, a significant causal association was identified between C-X-C motif chemokine ligand 5 (CXCL5) and UC. Using eQTL data, a significant genetic association was established between the mRNA expression of CXCL5 and its receptor, C-X-C motif chemokine receptor 2 (CXCR2), with UC. Colocalization analysis further supported these identified links. Differential expression analysis confirmed the dysregulation of the CXCL5/CXCR2 axis in UC patients. Enrichment and immune infiltration analysis indicated that the CXCL5/CXCR2 axis was involved in neutrophil chemotaxis and immune activation in UC. Moreover, CXCL5 expression was found to correlate with neutrophil extracellular trap (NET) formation in UC. Immunohistochemistry further confirmed the dysregulation of the CXCL5/CXCR2 axis in colon tissues of UC patients.

Discussion: The CXCL5/CXCR2 axis has been implicated to play a significant role within a broader inflammatory network that includes Interleukin (IL)-17, NF-κB, and Tumor Necrosis Factor (TNF) signaling pathways. Additionally, this axis interacts with macrophages and T cells, further contributing to the complexity of inflammatory responses in UC.

Conclusion: There is a significant association between CXCL5/CXCR2 and UC under the MR assumption, which is potentially linked with colonic chemotaxis and activation of neutrophils. These findings highlight the potential of CXCL5/CXCR2 as a therapeutic target for UC. However, future functional studies are needed to validate these findings and explore the exact mechanisms by which CXCL5/CXCR2 influences immune cell crosstalk in UC.

Introduction: Malignant melanoma is a highly aggressive skin malignancy characterised by metastatic properties and resistance to conventional therapies. This indicates a necessity to explore novel, efficacious treatment modalities. Atranorin, a secondary metabolite derived from lichen, has demonstrated a diverse range of bioactivities. However, the antineoplastic mechanisms of atranorin in melanoma remain underexplored.

Methods: Human melanoma cancer cell lines (A-375, G-361, and MDA-MB-435) and normal human melanocytes were treated with various concentrations of atranorin. Cell viability and proliferation were evaluated by MTT assay, apoptosis was assessed using Annexin V-FITC/PI flow cytometry, and cell cycle distribution was determined by PI staining and flow cytometry. Gene expression of apoptosis-related markers was quantified by qRT-PCR, and protein levels were analyzed by western blot. Cell migration was evaluated by the wound healing assay.

Results: Atranorin demonstrated selective toxicity in human melanoma cancer cells, exhibiting minimal effect on normal human melanocytes. In a study on human malignant melanoma A-375 cells, it was found that atranorin, at an IC50 concentration of 12 μM, significantly increased the number of apoptotic cells by approximately 11-fold. Furthermore, the results of the study indicated that atranorin induced G1 phase arrest and inhibited migratory capacity by around 60%. Molecular profiling revealed the upregulation of the intrinsic (APAF1, BAX, and CASP9) and extrinsic (FAS, FADD, and CASP10) apoptotic pathways, and the downregulation of the anti-apoptotic genes BCL2, MCL1, and BIRC5. In line with these observations, protein analyses revealed increased levels of cleaved caspase-3, caspase-9, and PARP, thereby providing evidence for the activation of apoptotic cascades.

Discussion: In this study, the therapeutic effect of atranorin was comprehensively evaluated for the first time on A-375 melanoma cells, and it was highlighted as a natural compound with strong anti-cancer potential.

Conclusion: This study is the first to demonstrate the potent anti-melanoma effect of atranorin. This demonstrates the natural compounds' effects on cell proliferation, cell cycle progression, and the suppression of metastasis. These findings emphasize the potential of atranorin as a novel natural compound for use in adjunctive or targeted melanoma therapy, and highlight the need for further preclinical and clinical evaluation.

Introduction: Ovarian cancer (OC), characterized by high mortality and lacking early diagnostic markers, poses a significant health threat. This study investigated the expression of metabolic reprogramming and circadian rhythm-related genes (MRCRRGs) in OC and their association with clinical features.

Methods: OC datasets and MRCRRG lists were sourced from TCGA, GEO, and Gene- Cards. Comprehensive bioinformatics analyses included calculating Metabolic Reprogramming and Circadian Rhythm Scores (MRCR.Score), identifying MRCR score-related genes (MRCRSRGs), building a Cox regression model, performing clustering for subtype identification, analyzing immune cell infiltration and immune checkpoint gene expression, conducting differential expression analysis, and performing Gene Set Enrichment Analysis (GSEA).

Results: We identified 138 MRCRRGs. MRCR. Score differed significantly between OC and controls. Thirty-four MRCRSRGs were identified, and a Cox model based on four genes was developed. Clustering revealed two distinct OC subtypes with significant overall survival differences. Immune infiltration analysis showed significant expression differences in 26 immune cell types, and immune checkpoint genes differed between subtypes. Differential expression identified 89 genes (88 upregulated, 1 downregulated). A six-gene predictive model demonstrated moderate accuracy. GSEA revealed significant enrichment of key pathways, notably Fcgr3a-mediated IL-10 synthesis.

Discussion: Findings demonstrate strong links between MRCRRGs, OC subtypes, patient survival, and the tumor immune microenvironment. Enrichment of pathways like Fcgr3a-mediated IL10 synthesis suggests novel OC mechanisms. Reliant on bioinformatics, the study provides insights into OC heterogeneity.

Conclusion: This study establishes a foundation for understanding MRCRRG molecular mechanisms in OC. The identified subtypes, prognostic model, immune landscape alterations, and enriched pathways offer valuable insights for future experimental validation and potential diagnostic/therapeutic strategies.

Fat-soluble vitamins (A, D, E, and K) are crucial for pediatric health, contributing to normal cellular function, growth, immune defense, and development. Unlike water-soluble vitamins, they are absorbed with dietary fats and stored in the liver and adipose tissue, leading to risks of deficiency (hypovitaminosis) and toxicity (hypervitaminosis) in certain physiological and pathological conditions. This narrative review aimed to summarize the clinical manifestations, diagnostic considerations, and management of hypo- and hypervitaminosis of fat-soluble vitamins in pediatric populations. A comprehensive literature review was conducted, highlighting the physiological roles, symptoms of deficiency and toxicity, diagnostic strategies, and treatment options, with particular focus on high-risk groups, including neonates and children with malabsorption or dietary restrictions. Pediatric patients are especially vulnerable to vitamin imbalances due to rapid growth and specific developmental needs. Deficiencies can result in vision problems, bone disorders, immune dysfunction, and coagulation issues, while excess intake can lead to toxicity. Management strategies include clinical assessment, biochemical testing, supplementation, dietary counseling, and public health interventions. Early detection and preventive measures are essential. Future research is needed to explore non-classical roles of these vitamins and optimize supplementation guidelines.

Introduction: The pharmacological treatment of Parkinson's, an incurable disease, consists of palliative drug combinations, generally including a Dopamine Transporter (DAT) inhibitor and an exogenous source of dopamine. Benztropine has been described as a commonly used DAT inhibitor. However, the ever-increasing secondary effects led to its substitution with other, more suitable drugs. It has been described that the tropine moiety of the molecule generates most of the interaction with DAT, while other relevant interactions correspond to the benzhydryl aromatic moiety with several degrees of freedom due to the rotation of the phenyl rings.

Methods: Through organic chemistry synthesis, NMR, and other techniques, compounds are obtained and then, using in silico analysis, the interaction of DAT and the newly obtained analogs is assessed. Finally, a hemiparkinsonian animal model is generated by 6-OHDA injections and then treated with pharmaceutical concentrations of the main compound, to measure its ability to mitigate symptoms using several behavioral tests.

Results: An eight-member family of fluorenatropines was generated, and compound 9, the simplest of them, was tested in silico to see its direct interaction with DAT. Results suggest a positive and benztropine-like interaction. Behavioral results statistically demonstrated that compound 9 showed activity as a psychostimulant.

Discussion: Compound 9, with its more rigid structure, behaves as a psychostimulant, mitigating Parkinson's disease symptoms with the same efficiency as benztropine but with a quarter of the original dose.

Conclusion: The rigid aromatic sections in fluorenatropine analogs grant a superior activity over DAT, allowing motor symptom mitigation at lower concentrations.

Introduction: Sarcomas are heterogeneous mesenchymal tumors with poor responses to systemic therapies. Ubiquitination is a post-translational modification that regulates various physiological processes and cancer growth.

Methods: We analyzed the transcriptomic data of 256 sarcoma patients from The Cancer Genome Atlas (TCGA) to define the network and prognostic value of predefined ubiquitination-related genes and performed subgroup analyses. Additionally, the role of TRIM21 in sarcoma progression was explored using cellular experiments.

Results: We identified two ubiquitination-related clusters, and patients in the two clusters were characterized by different survival outcomes, enriched pathways, and characteristics of the tumor microenvironment. A ubiquitination-related signature involving LRRC41, RNF125, TRIM21, and UBE3D was identified to predict prognoses. The signature was associated with patient prognoses in the public sarcoma cohorts and our independent cohort. Immunohistochemistry analyses revealed that the risk score and CD8 could distinguish patients with different survival outcomes in our cohort. Mechanistically, different risk groups were also characterized by distinct enriched pathways and characteristics of the tumor microenvironment. Cellular experiments revealed that TRIM21 overexpression could suppress tumor progression in sarcomas.

Discussion: This study provided a novel classification for sarcoma patients based on expressions of ubiquitination-related genes. The classification and the prognostic model may facilitate the understanding of sarcoma pathogenesis, the prediction of prognosis and immunotherapy response for sarcoma patients. Meanwhile, it was confirmed that TRIM21 suppressed sarcoma progression and identified it as a potential target for therapeutic interventions.

Conclusions: The classification and signature stratify sarcoma patients for prognosis and immunotherapy response, with TRIM21 representing a promising therapeutic target.