Current medicinal chemistry最新文献

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.

Introduction: Bladder cancer (BLCA) remains a leading urological malignancy with rising incidence and a dismal prognosis; therefore, reliable prognostic markers and actionable therapeutic targets are urgently needed. The extracellular-matrix-related gene Zona-Pellucida-like Domain-containing Protein 1 (ZPLD1) has not been investigated in BLCA. We therefore aimed to delineate the expression landscape, prognostic value, immune contexture, and druggability of ZPLD1 in BLCA.

Methods: A multi-level integrative design was employed. RNA-seq (TPM) and clinical data were retrieved from TCGA-BLCA (n = 412 tumors, 19 normals) and GSE121711 (n = 8 tumors, 10 normals). We performed differential expression, ROC analysis, and logistic regression in R. Kaplan-Meier and multivariate Cox regression (with VIF control) defined survival associations; a nomogram was built. Gene set enrichment analysis (GSEA) explored pathways; ssGSEA and ESTIMATE characterized immune infiltration and checkpoint gene expression. The mRNA expression-based stemness index (mRNAsi) and drug sensitivity (RNAactDrug, CCLE/GDSC) were correlated. We inspected Genomic alterations via cBioPortal. Quantitative real-time PCR (qRT-PCR) validated ZPLD1 in 5637 and HT-1376 cell lines versus SV-HUC-1 normal urothelial cells.

Results: ZPLD1 was markedly up-regulated in BLCA compared with normal tissues (mean 0.200 ± 0.019 vs 0.033 ± 0.010; p = 0.003) with an AUC of 0.704 for discriminating tumor from normal. High ZPLD1 independently predicted poorer overall survival (HR 2.004; 95% CI 1.037-3.874; p = 0.039) and disease-specific survival (HR 1.64; p = 0.007). GSEA revealed enrichment of focal adhesion, chemokine signaling, and PPAR pathways. ZPLD1 positively correlated with Th1 cells, macrophages, neutrophils, NK CD56dim cells, PD-L1, CTLA-4, LAG-3 and PD-1 (all p < 0.001) but negatively with SIGLEC15. Higher ZPLD1 was associated with lower cancer stemness (r = -0.23; p < 0.001) and altered sensitivity to TKI258, Topotecan, Paclitaxel, 5-FU, and Vorinostat. ZPLD1 was altered in 2% of TCGA-BLCA cases, mostly as missense mutations and amplifications. qRT-PCR confirmed elevated ZPLD1 in BLCA cell lines (p < 0.001).

Discussion: ZPLD1 emerges as a novel, independent poor-prognosis biomarker that orchestrates an inflamed but checkpoint-restricted microenvironment and modulates drug response in BLCA. These findings position ZPLD1 as a candidate for risk stratification and combination immunotherapy, although prospective multi-center validation and mechanistic studies are required.

Conclusion: This study establishes ZPLD1 as a prognostic indicator and potential therapeutic target in BLCA, paving the way for precision oncology strategies integrating ZPLD1-guided patient selection and immune-drug combinations.

Introduction: The objective of this study is to characterize plasma metabolites and identify potential clinical indicators of sarcopenia in individuals with Type 2 Diabetes (T2D).

Methods: This cross-sectional, observational study included 122 individuals with T2D recruited from a university hospital clinic between October 2022 and December 2023. Demographic and health data were obtained through questionnaires and electronic health records. Plasma metabolites were analyzed using liquid chromatography-mass spectrometry. Predictive probability of the identified metabolite was assessed using the Receiver Operating Characteristic-Area Under the Curve (ROC-AUC). Statistical analyses were conducted with SPSS version 29 and R version 4.4.2.

Results: We identified 23 metabolites, including 21 that were unique to individuals with sarcopenia compared with the general population. Plasma 4-Hydroxyproline and homocysteine levels were significantly different between the sarcopenia and non-sarcopenia groups, as defined by the Asian Working Group for Sarcopenia criteria. A model combining 4-Hydroxyproline, age, body mass index, and educational levels achieved an ROC-AUC of 0.825 (95% CI: 0.726-0.923) for predicting sarcopenia.

Discussion: The metabolic features of sarcopenic status are distinctive among individuals with T2D compared to the general population. Plasma 4-Hydroxyproline and Homocysteine are clinical indicators in sarcopenia in T2D.

Conclusions: Individuals with T2D and sarcopenia exhibit distinct metabolite profiles compared with the general population. Plasma 4-Hydroxyproline and homocysteine may serve as clinical indicators for sarcopenia in T2D. Further studies are needed to validate these findings and assess their potential as diagnostic and therapeutic targets.

Introduction: Esophageal cancer(EC) is a significant clinical challenge due to its aggressiveness and poor prognosis. CD47, a transmembrane protein, inhibits macrophage phagocytosis and is linked to tumor advancement and poor outcomes. The interaction between curcumin(CUR) and CD47 and its effects on EC need further studies.

Methods: This study identified common target genes of CUR and EC through network pharmacology, and then found core genes via protein-protein interaction (PPI) analysis. in vitro experiments were conducted to investigate the effects of CUR on cell proliferation, apoptosis, and migration, and to explore the underlying mechanisms. in vivo xenograft experiments were also carried out to evaluate the effects and mechanisms of CUR on tumor growth.

Results: CD47 was highly expressed in EC, and CUR shared ten common target genes with EC. Enrichment analysis and PPI network supported PTGS2 and BAX as core genes. in vitro, CUR could inhibit the proliferation and migration of CD47-overexpressing EC cells and induce apoptosis. In the xenograft model, CUR could inhibit tumor growth (p = 0.0144). The mechanism of CUR may be related to multiple components of the MAPK signaling pathway, especially ERK1/2 and its phosphorylation. Additionally, CUR treatment reduced the COX-2 expression level. Immunohistochemistry showed that both BAX and Bcl-2 proteins were upregulated, but the upregulation of BAX protein was significantly more pronounced than that of Bcl-2.

Discussion: Our study has confirmed that CUR inhibits CD47-overexpressing esophageal cancer cells. This mechanism may be achieved by blocking ERK1/2 and its phosphorylation, reducing COX2 levels, and enhancing BAX protein expression.

Conclusion: This study highlights CUR's potential in treating EC, particularly in CD47 overexpression cases. These results clarify the molecular interactions and provide a basis for future research on CUR-based therapies targeting EC progression pathways.

Background: Interleukin-33 (IL-33), a tissue-derived alarmin released during sterile and infectious stress, modulates inflammatory responses in an organ-specific manner. Although IL-33 is implicated in hepatic pathophysiology, its functional mechanism in sepsis-induced liver injury (SILI) remains insufficiently characterized.

Method: SILI was modeled in vivo via cecal ligation and puncture (CLP) and in vitro using lipopolysaccharide (LPS)-stimulated primary hepatocytes. The multimodal evaluations included oxidative stress analysis, inflammatory cytokine measurements, liver functional biomarker analysis, and histomorphological studies. IL-33 signaling was investigated by combining transcriptomic pathway analysis with pharmacological interventions with soluble ST2 decoy receptor (sST2) and ST2-neutralizing (anti-ST2) antibodies. The SILI model dynamically increased the IL-33 level.

Results: Exogenous IL-33 conserved liver architecture, improved function, and reduced both inflammation and oxidative damage. Critically, blocking IL-33/ST2 signaling with an anti-ST2 antibody or sST2 eliminated the protective effect of IL-33, worsening hepatocellular damage. Mechanistic investigations revealed that IL-33/ST2 stimulation reduced NF-κB pathway activity, improved BCL-2 expression, and inhibited caspase-3-- mediated apoptosis. The lack of the antiapoptotic effects of IL-33 on NF-κB pathway activation validated its regulatory axis specificity.

Discussion: This study identifies IL-33/ST2-NF-κB-BCL-2 as a key axis mitigating hepatocyte apoptosis in SILI. IL-33-based therapies may offer dual control of inflammation and cell death, though clinical translation requires temporal optimization.

Conclusion: Our results suggest that the pharmacologically targeted IL-33/ST2-NF-κB-BCL-2 pathway decreases sepsis-induced hepatocyte apoptosis. These findings indicate that IL-33-based treatments may be feasible for treating SILI and that this axis coordinates cytoprotection by concurrently controlling inflammatory signals and apoptotic processes.

Introduction: Chitosan nanoparticles (CNPs) are broadly explored for drug delivery due to their biocompatibility, biodegradability, and non-toxicity. This study encapsulated Brugmansia suaveolens leaf ethanol extract (BSLEE) into CNPs to enhance antioxidant and antibacterial activity.

Materials and methods: The optimization of synthesis, such as chitosan concentration of (1:1) to cross-link BSLEE, maintaining an optimal acidic pH (~4.5-5.5), and applying mild stirring at 50 rpm resulted in an encapsulation efficiency ranging from 26.33 to 48.58%,indicating the successful encapsulation of BSLEE within the CNPs. Characterization by UV-Vis, FTIR, SEM, XRD, EDX, and zeta potential confirmed successful formulation, with semi-crystalline, porous nanoparticles.

Results: DPPH, FRAP, and total phenolics assay indicate BSLEE CNPs exhibited stronger antioxidant activity in the range of 30.42 ±0.77% to 55.85± 0.69% of DPPH inhibition, 34.73±2.71 to 121.44±1.83 µg/ml FSE, and 58±2.27 to 149.5±2.48 µg GAE/ml, respectively, when compared to crude BSLEE. The antibacterial effectiveness of BSLEE CNPs against S. aureus and E. coli was more significant when compared to the BSLEE and chitosan alone, attributed to enhanced membrane permeability and disruption of the bacterial cell membrane.

Discussion: Antibacterial studies showed significant inhibition against S. aureus and E. coli, linked to improved membrane disruption. The BSLEE CNPs demonstrated promising biocompatibility and potential for application in antimicrobial and antioxidant therapies, warranting further clinical validation and in vitro findings of BSLEE-conjugated chitosan nanoparticles.

Conclusion: The BSLEE CNPs showed promising pharmacological properties like antibacterial efficacy against E. coli and S. aureus, indicating their potential as an alternative approach to combat bacterial infections.