Chemical Biology & Drug Design最新文献

Osteosarcoma is a prevalent form of cancer that develops in growing bones. The precise cause of this multifaceted disease remains uncertain. Yet, genetic, genomic and proteomic research has enhanced our understanding of the disruption in its molecular signaling pathways. In this review, we attempted to highlight the regulation of autophagy pathways by a range of biocompounds (chemical compounds of biological origin) in osteosarcoma. Autophagy is a degradation mechanism, maintaining cellular homeostasis under basal and stress conditions. However, the role of autophagy is variable in cancer. There is a delicate balance between autophagy and apoptosis, and disruption of this balance is one of the causes of tumor formation and development. Autophagy and apoptosis can reciprocally activate or inhibit each other. Thus, autophagy works synergistically or antagonistically with apoptosis. In osteosarcoma, different biocompounds involve in the regulation of autophagy and/or apoptosis, triggering cellular signaling pathways, convenient or inconvenient for growth, proliferation, invasion and metastasis of cancer cells in a tumor. Also, some of the biocompounds have been shown to affect the therapeutic response of osteosarcoma cells. Therefore, biocompounds are promising candidates for the regulation of autophagy and may play critical roles in the crosstalk between autophagy and apoptosis in osteosarcoma.

This study aimed to develop a noninvasive nomogram that integrates deep learning-pathomics, radiomics, and immunoscore to predict lymph node metastasis (LNM) in breast cancer. Pathological features from 1133 TCGA-BRCA slides were extracted via ResNet50 and Lasso. Radiomics features from 137 MRI images (TCIA) were analyzed using pyradiomics. Immunoscore was calculated via ESTIMATE. A nomogram was constructed and validated with 10-fold cross-validation. The pathomics model achieved an AUC of 0.65 (95% CI: 0.61–0.68), sensitivity 0.62, specificity 0.67; radiomics 0.61 (95% CI: 0.50–0.72), sensitivity 0.59, specificity 0.63; and the combined nomogram 0.69 (95% CI: 0.59–0.79), sensitivity 0.66, specificity 0.71. Radiomics score was the strongest predictor. The nomogram provides a reliable noninvasive tool for predicting lymph node involvement, potentially reducing unnecessary biopsies.

Obstructive sleep apnea (OSA) is characterized by recurrent chronic intermittent hypoxia (CIH), which induces oxidative stress, inflammatory responses, and mitochondrial damage in bronchial epithelial cells. Tetramethylpyrazine (TMP) has been shown to exert lung-protective effects in other pathological models, but its role in mitigating CIH-induced 16HBE cell injury and the underlying molecular mechanisms have not been previously investigated. PTEN-induced putative kinase 1 (PINK1)-mediated mitophagy is a critical endogenous mechanism that defends against CIH-induced epithelial damage. However, whether TMP alleviates CIH-induced injury by regulating the PINK1 pathway remains unknown. CIH significantly reduced 16HBE cell viability, increased apoptosis rate, elevated inflammatory responses (IL-6 and TNF-α levels upregulated), and oxidative stress (ROS and MDA levels increased), and inhibited mitophagy (reduced PINK1 and LC3-II/LC3-I ratio, increased p62). TMP treatment improved cell viability in a dose-dependent manner; notably, 20 μg/mL TMP reversed CIH-induced apoptosis, inflammation, and oxidative stress, accompanied by upregulated PINK1 and restored mitophagy. Moreover, HDAC6 knockdown mimicked TMP's benefits (enhanced PINK1 and mitophagy, reduced injury), while concurrent PINK1 silencing reversed this effect. TMP protected 16HBE cells from CIH-induced injury by inhibiting HDAC6-mediated PINK1 deacetylation. This mechanism stabilized PINK1 protein, enhanced mitophagy, and thereby suppressed apoptosis, oxidative stress, and inflammation, identifying the HDAC6/PINK1 axis as a key regulatory pathway in CIH-induced cell injury.

Acute lung injury (ALI) is a severe inflammatory condition often triggered by infections. Glycolysis and macrophage polarization play critical roles in ALI pathogenesis. This study investigates the effects of Daucosterol on lipopolysaccharide (LPS)-stimulated lung injury and its potential mechanisms. In this research, BEAS-2B lung epithelial cells and MH-S alveolar macrophages were exposed to LPS and various concentrations of Daucosterol. Cell viability was assessed using CCK-8 assay. Glycolytic activity was evaluated by detecting ATP production, lactate level, and extracellular acidification rate. Macrophage polarization was assessed using flow cytometry. Tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels were detected by enzyme-linked immunosorbent assay. Gene expression was evaluated by reverse transcription-quantitative polymerase chain reaction and western blotting. A cecal ligation and puncture (CLP)-induced ALI mouse model was used to validate the protective effect of Daucosterol in vivo. Results showed that Daucosterol prevented the reduction in cell viability in LPS-stimulated BEAS-2B cells. In MH-S macrophages, Daucosterol inhibited LPS-induced glycolysis and M1 polarization while promoting M2 polarization. Mechanistically, Daucosterol reversed the LPS-induced upregulation of PFKFB3. Overexpression of PFKFB3 counteracted the inhibitory effects of Daucosterol on glycolysis and M1 polarization. In vivo, Daucosterol significantly alleviated CLP-induced ALI by improving lung histopathology, reducing pulmonary edema, enhancing oxygenation, inhibiting myeloperoxidase and caspase-3 activity, and decreasing TNF-α and IL-6 levels in bronchoalveolar lavage fluid. In conclusion, Daucosterol targets PFKFB3 to mitigate sepsis-induced ALI by inhibiting glycolysis and M1 macrophage polarization, offering a potential therapeutic strategy for ALI.

Tormentic acid (TA) has demonstrated potential anti-hepatocellular carcinoma (HCC) effects. This study aimed to explore the anti-HCC effect and underlying mechanisms of TA via network pharmacology, molecular docking, molecular dynamics simulation and in vitro experiments. In this study, HCC-related genes were obtained from the GeneCards OMIM, and GEO databases. The targets of TA were collected from Swiss Target Prediction, TargetNet, and the PharmMapper database. A protein–protein interaction network of TA anti-HCC target genes was constructed using the STRING database and visualized by Cytoscape. The potential anti-HCC targets of TA were then identified through GO and KEGG pathway enrichment analyses using the DAVID database. Molecular docking and molecular dynamics simulation were performed to evaluate the binding affinity and structural stability of TA-target complexes. For the in vitro experiments, the CCK-8 assay was employed to assess the effects of TA on HepG2 cell viability. Apoptosis in HepG2 cells was detected via flow cytometry. Western blotting was used to elucidate the underlying molecular mechanisms of TA. Integrating network pharmacology and bioinformatics analyses revealed that the anti-HCC effect of TA was closely associated with apoptosis and the PI3K/AKT/HSP90 pathway. Molecular docking and molecular dynamics simulation demonstrated that TA-target protein complexes maintained marked structural stability and exhibited favorable kinetic properties. In vitro experiments showed that TA significantly inhibited the proliferation of HepG2 cells and induced apoptosis. Western blot results further indicated that TA treatment increased the expression of Bax while decreasing the expression levels of PI3K, AKT, HSP90, and Bcl-2. TA suppressed the proliferation of HepG2 cells and induced apoptosis, possibly by regulating the PI3K/AKT/HSP90 signaling pathway.

Globally, colorectal cancer (CRC) is the second most common cause of cancer-related deaths and the third most common cancer. Thymidylate synthase (TS), a key enzyme involved in DNA biosynthesis, has emerged as a promising molecular target for anticancer therapy. In the present study, we designed and synthesized a series of 22 benzylated pyrrole-based pyrido[2,3-d]pyrimidines using Claisen Schmidt and Michael addition reactions, and evaluated their anticancer potential against four human cancer cell lines: HCT 116 (colorectal), A549 (lung), MCF-7 (breast), and MDA-MB-231 (triple-negative breast cancer) as well as for TS inhibitory potential. Compounds 1c and 2i exhibited potent TS inhibition with IC₅₀ values of 11.50 ± 1.08 nM and 17.12 ± 0.91 nM, respectively, comparable to the standard drug raltitrexed (IC₅₀ = 12.51 ± 0.91 nM). Molecular docking studies revealed stronger binding affinities of these compounds compared to raltitrexed, involving key interactions with the catalytic residue Cys195 of TS. Additionally, compounds 1c and 2i exhibited good stability in 300 ns molecular dynamics simulations along with acceptable drug-like properties and oral bioavailability. These findings suggest that compounds 1c and 2i are promising lead candidates for the development of TS inhibitors.

This study aimed to investigate the impact of the RNA-binding protein eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) gene, also known as PKR, on the condition of islet beta cells. In this study, EIF2AK2 was overexpressed in INS1 cells, and transcriptome data following EIF2AK2 overexpression were obtained using RNA-seq technology. Additionally, potential target genes that bind to EIF2AK2 were identified through iRIP-seq technology. The proteins interacting with EIF2AK2 were characterized using co-immunoprecipitation (CO-IP) combined with mass spectrometry to elucidate the molecular regulatory mechanisms of EIF2AK2 in INS1 cells. RNA-seq results indicated that in INS1 cells overexpressing EIF2AK2, 1171 genes were differentially expressed, and 2161 alternative splicing events were significantly altered. iRIP-seq data demonstrated that reads from the immunoprecipitated samples were significantly enriched in the intronic and coding sequence (CDS) regions. EIF2AK2 preferentially binds to the GCGGCGG motif in RNA. Comprehensive analysis suggests that EIF2AK2 may directly bind to and regulate the expression of Dusp8, Btg1, and Prkce, thereby affecting pancreatic islet cell functions. Furthermore, EIF2AK2 may influence islet cell function by modulating the alternative splicing of Zfr and Pias2. Additionally, combined with Co-IP mass spectrometry data, it was discovered that EIF2AK2 can interact with 649 proteins, including various differentially expressed RNA-binding proteins, transcription factors, and histones, which may be associated with diabetes. Our results indicate that EIF2AK2 may regulate the expression or alternative splicing of mRNA related to type 2 diabetes through direct or indirect binding. Additionally, it may influence the progression of type 2 diabetes by interacting with other proteins. We propose that EIF2AK2 plays a significant role in diabetic islet beta cells, and its aberrant regulatory pattern is closely associated with the onset and progression of type 2 diabetes.

Laryngeal cancer (LC) is one of the most common malignant tumors of the head and neck, with high morbidity and mortality rates worldwide. Oridonin (Ori), a natural tetracyclic diterpenoid, exhibits notable anti-tumor properties. However, its efficacy and underlying mechanism in LC remain to be elucidated. This study employed comprehensive network pharmacology, molecular docking, and molecular dynamic simulation to investigate the molecular targets and mechanisms underlying the anti-LC effects of Ori, followed by in vitro validation of its key mechanisms. A total of 172 potential therapeutic targets of Ori for LC were identified. GO and KEGG analyses indicated that Ori's anti-LC mechanism primarily involved the PI3K-Akt, Ras, MAPK, and Rap1 signaling pathways. The PPI network and molecular docking analyses revealed that AKT1, EGFR, and MAPK1 are potential core targets of Ori. Additionally, molecular dynamics simulations and bioinformatics analyses further confirmed that these proteins are key candidate targets. In vitro, Ori inhibited the proliferation of LC Hep-2 and TU212 cells, induced apoptosis, arrested the cell cycle at the G1 phase, and suppressed migration and invasion. WB assays further showed that Ori significantly downregulated p-AKT expression in the PI3K/AKT pathway. These findings indicate that Ori represents a promising therapeutic candidate for LC.

This study aimed to investigate the molecular mechanism by which tripartite motif-containing 24 (TRIM24) regulates the ubiquitination of sirtuin 1 (SIRT1) and to explore the protective effect of paeoniflorin (PF) on pulmonary arterial hypertension (PAH). Bioinformatics analysis identified TRIM24 and SIRT1 as key targets of PF. A PAH rat model was established by SU5416 (Su) injection combined with chronic hypoxia (Hx). These model rats were then treated with PF and/or subjected to overexpression of TRIM24 or SIRT1. TRIM24 and SIRT1 expression were assessed by reverse transcription quantitative PCR (RT-qPCR) and immunohistochemistry. Lung vascular remodeling was evaluated by hemodynamic analysis and hematoxylin–eosin (HE) staining. Inflammatory cytokine levels (interleukin-1β, interleukin-6, tumor necrosis factor-α) in lung tissues were measured. In vitro, hypoxia-exposed human pulmonary artery endothelial cells (HPAECs) were used to evaluate PF effects on cell viability (CCK-8), migration (scratch assay), and protein expression (Western blot). Ubiquitination and protein stability assays demonstrated that TRIM24 promoted SIRT1 protein degradation. TRIM24 inhibited SIRT1-mediated autophagy, thereby activating the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Conversely, SIRT1 upregulation enhanced autophagy and suppressed NLRP3 activation. PF alleviated PAH and endothelial dysfunction by downregulating TRIM24 and preserving SIRT1 function. These findings reveal a novel mechanism by which PF protects against PAH via the TRIM24/SIRT1/NLRP3 axis.

The emergence of multidrug-resistant microorganisms and the limited therapeutic options for hepatocellular carcinoma (HCC) highlight the urgent need for new molecular scaffolds with dual pharmacological potential. In this study, a novel series of benzimidazole-urea phenylalanine hybrids was designed and synthesized using a rational structure-based approach to integrate antimicrobial and anticancer functionalities within a single pharmacophore. All synthesized compounds were characterized by spectroscopic methods and evaluated for their antimicrobial and cytotoxic activities. Among the series, CPN305 exhibited the most potent cytotoxicity against hepatocellular carcinoma cell lines (PLC/PRF/5 and HuH7) while maintaining minimal toxicity toward normal human fibroblasts (BJ-1). Additionally, the compound demonstrated promising antimicrobial efficacy against Staphylococcus aureus. Molecular docking simulations revealed favorable binding interactions within the Hsp90 active site, supporting the observed in vitro anticancer effects, while ADME predictions indicated desirable physicochemical and pharmacokinetic properties. Collectively, these findings suggest that the benzimidazole-urea phenylalanine scaffold represents a promising lead framework for further structural optimization and mechanistic exploration as a dual-acting antimicrobial and anticancer agent.