Chemical Biology & Drug Design最新文献

{"title":"Exploring the Effect of Gomisin A on Non-Small Cell Lung Cancer With Network Pharmacology, Molecular Docking, In Vitro and In Vivo Assays","authors":"Mei Liu,&nbsp;Kai Yang,&nbsp;Huibing Qiu","doi":"10.1111/cbdd.70014","DOIUrl":"10.1111/cbdd.70014","url":null,"abstract":"<div>\u0000 \u0000 <p>Gomisin A is an active ingredient of <i>Schisandra chinensis</i>. Pre-clinical studies suggest Gomisin A has good anti-cancer activities against a variety of cancers, but its mechanism of action in non-small cell lung cancer (NSCLC) is unclear. This study aims to explore the potential mechanism of Gomisin A in treating NSCLC. The SwissTargetPrediction, CTD, HERB and PharmMapper databases were used to collect related targets of Gomisin A. NSCLC-related genes were obtained using the GEO, CTD, DisGeNET, OMIM, GeneCards, NCBI, and PharmGKB databases. The central targets and potential mechanisms of Gomisin A against NSCLC were screened using network pharmacology and molecular docking. Finally, the therapeutic activity of Gomisin A on NSCLC was verified by experiments. A total of 161 potential targets of Gomisin A against NSCLC were identified. TNF, AKT1, STAT3, and IL6 were identified as the central targets of Gomisin A. The binding energy of Gomisin A and the central targets was less than −5 kcal/mol. Gomisin A could inhibit NSCLC cell viability, migration and invasion and induce cell cycle arrest and apoptosis. Gomisin A also inhibited in vivo metastasis of NSCLC cells. In addition, Gomisin A could also reduce the expression level of the central targets and inhibit the PI3K-Akt signaling pathway. In summary, Gomisin A may be a candidate drug for the treatment of NSCLC, and TNF, AKT1, STAT3, and IL6 are potential targets for Gomisin A in NSCLC treatment, and its therapeutic mechanism may be related to the PI3K-Akt signaling pathway.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploration of the Active Components and Mechanism of Jiegeng (Platycodonis Radix) in the Treatment of Influenza Virus Pneumonia Through Network Pharmacology Analysis and Experimental Verification","authors":"Zhiying Feng,&nbsp;Kangyu Wang,&nbsp;Jiawang Huang,&nbsp;Zhuolin Liu,&nbsp;Jingmin Fu,&nbsp;Jianing Shi,&nbsp;Xinyue Ma,&nbsp;Ling Li,&nbsp;Qiong Wu","doi":"10.1111/cbdd.70007","DOIUrl":"10.1111/cbdd.70007","url":null,"abstract":"<div>\u0000 \u0000 <p>This study aimed to explore the pathogenesis of platycodin D and luteolin, which are both active components in <i>Jiegeng</i> (<i>Platycodonis Radix</i>), in the treatment of influenza virus pneumonia through network pharmacology analysis combined with experimental verification. The bioactive components of <i>Jiegeng</i> (<i>Platycodonis Radix</i>) were screened by TCMSP and literature mining, and the results were standardized via the UniProt database. The action targets for the disease were identified from databases including OMIM, GeneCards, TTD, DisGeNET, and PharmGKB. Then, the visualized key target regulatory network and protein–protein interaction (PPI) network for the active components were established using Cytoscape3.7.1 software. The findings were illustrated through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The intervention concentrations of platycodin D and luteolin were screened by the CCK8 method, and the important signaling pathways of platycodin D and luteolin for treating influenza virus pneumonia were verified by RT-qPCR and Western blot tests. From data mining, 89 common drug-disease targets were screened out, and five major active components of <i>Jiegeng</i> (<i>Platycodonis Radix</i>), including platycodin D and luteolin, were obtained. Besides, 11 therapeutic targets including IL-17, IL-6, TNF-<i>α</i>, JUN, and MAKP1 were identified by PPI network analysis. GO and KEGG enrichment analyses showed that the pathways most related to the mechanisms of <i>Jiegeng</i> (<i>Platycodonis Radix</i>) against influenza virus pneumonia included the TNF and IL-17 signaling pathways and apoptosis. In vitro experiments demonstrated that the model group exhibited a notable elevation in mRNA levels of IL-6, IL-17, TNF-<i>α</i>, JUN, MAPK1, and the IL-17/−acting protein ratio, as compared to the control group (<i>p</i> &lt; 0.05). In contrast to the model group, the IL-6, IL-17, TNF-α, JUN, MAPK1 mRNA expression levels, and the IL-17 protein ratio in both the platycodin D group and luteolin group were considerably decreased (<i>p &lt; 0.05</i>). Combined with network pharmacology and experimental verification, this study revealed that platycodin D and luteolin in <i>Jiegeng</i> (<i>Platycodonis Radix</i>) may treat influenza virus pneumonia by regulating inflammation through the IL-17 signaling pathway.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis and Evaluation of Benzimidazole Derivatives as IL-6 Inhibitors and Their Role in Rheumatoid Arthritis","authors":"Shivam Mishra,&nbsp;Saurabh Gupta,&nbsp;Sukhvir Kaur,&nbsp;Yogita Bansal,&nbsp;Gulshan Bansal","doi":"10.1111/cbdd.70008","DOIUrl":"10.1111/cbdd.70008","url":null,"abstract":"<div>\u0000 \u0000 <p>Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a major role in the development of Rheumatoid Arthritis (RA). In the present study, benzimidazole and benzene sulfonyl scaffold were identified as pharmacophore by analysis of literature reports and novel small molecule IL-6 inhibitors were designed. These were screened via docking with IL-6 (PDB: 1ALU), then and through Lipinski's rule of 5. Based on docking score, 10 best compounds (<b>4a–4e</b> and <b>7a–7e</b>) were selected for synthesis and evaluated for IL-6 inhibitory activity in vitro. Compounds <b>4b</b> and <b>7b</b> showed the maximum inhibition of IL-6 (87.55% and 82.75%, respectively). These compounds were further explored for anti-arthritic activity in vivo using the Incomplete Freund's Adjuvant Model and by morphological and histopathological studies of the inflamed paw. Compound <b>4b</b> was significantly more active than compound <b>7b</b> and both were found to be slightly less active than methotrexate. These findings indicate that a benzimidazole nucleus linked to a benzene sulphonyl moiety may prove to be a useful template for the development of new chemical moieties against RA.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Comprehensive Analysis on Galantamine Based Hybrids for the Management of Alzheimer's Disease","authors":"Yash Pal Singh,&nbsp;Sonima Prasad,&nbsp;Harish Kumar","doi":"10.1111/cbdd.70004","DOIUrl":"10.1111/cbdd.70004","url":null,"abstract":"<div>\u0000 \u0000 <p>Alzheimer's disease (AD) is a progressive chronic age-related neurodegenerative brain disorder characterized by the loss of memory and other cognitive functions. The exact etiology of AD is still under investigation, however several factors such as low level of neurotransmitter acetylcholine (ACh), aggregation of amyloid beta (Aβ) in the form of Aβ plaques, hyperphosphorylation of tau protein into neurofibrillary tangles (NFTs), oxidative stress, and metal ion imbalance are the major hallmarks of this disease. Of the multiple hypotheses for AD, the amyloid-β (Aβ) and cholinergic hypothesis are the main targeting hypotheses for AD. Some researchers hypothesized that the primary event associated with the cholinergic neurotransmitter (acetylcholine) is memory loss and cognitive impairment. Due to the disease's complicated pathogenesis, long-term therapy with a single target candidate is futile. As a result, multitargeted and multifunctional therapies have emerged. Various research teams are concentrating on addressing multiple disease factors through hybridization techniques. Consequently, this hybridization approach has been applied to all core scaffolds, including galantamine. In this article, we tried to provide a thorough overview of the most recent developments on galantamine, a prospective AChE inhibitor, and its hybrid analogs as possible therapeutic agents for treating AD. Furthermore, we also provided the design, synthesis, and SAR analysis of the galantamine-based compounds used in the last decades for the management of AD.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142570587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRBN-PROTACs in Cancer Therapy: From Mechanistic Insights to Clinical Applications","authors":"Riya Thapa,&nbsp;Asif Ahmad Bhat,&nbsp;Gaurav Gupta,&nbsp;S. Renuka Jyothi,&nbsp;Irwanjot Kaur,&nbsp;Sachin Kumar,&nbsp;Naveen Sharma,&nbsp;G. V. Siva Prasad,&nbsp;Atreyi Pramanik,&nbsp;Haider Ali","doi":"10.1111/cbdd.70009","DOIUrl":"10.1111/cbdd.70009","url":null,"abstract":"<div>\u0000 \u0000 <p>Cereblon (CRBN), a member of the E3 ubiquitin ligase complex, has gained significant attention as a therapeutic target in cancer. CRBN regulates the degradation of various proteins in cancer progression, including transcription factors and signaling molecules. PROTACs (proteolysis-targeting chimeras) are a novel approach that uses the cell's degradation system to remove disease-causing proteins selectively. CRBN-dependent PROTACs work by tagging harmful proteins for destruction through the ubiquitin–proteasome system. This strategy offers several advantages over traditional protein inhibition methods, including the potential to overcome drug resistance. Recent progress in developing CRBN-based PROTACs has shown promising preclinical results in both hematologic malignancies and solid tumors. Additionally, CRBN-based PROTACs have enhanced our understanding of CRBN's role in cancer, potentially serving as biomarkers for patient stratification and predicting therapeutic responses. In this review, we delineate the mechanisms of action for CRBN-dependent PROTACs (CRBN-PROTACs), summarize recent advances in preclinical and clinical applications, and provide our perspective on future development.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142577188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Vitro Cytotoxicity and Mechanistic Investigation of Quinazolin-4(1H)-One Linked Coumarin as a Potent Anticancer Agent","authors":"Dinesh Singla,&nbsp;Palak Sharma,&nbsp;Vijay Luxami,&nbsp;Kamaldeep Paul","doi":"10.1111/cbdd.70011","DOIUrl":"10.1111/cbdd.70011","url":null,"abstract":"<div>\u0000 \u0000 <p>Quinazolinone-coumarin conjugates synthesized through Late-Stage Functionalization approach are evaluated for their in vitro biological activity for 60 human cancer cell lines representing nine different cancer types. Among the synthesized compounds, eight displayed significant growth inhibitory activity across a spectrum of cancer types, with compound <b>23</b> demonstrating particularly notable cytotoxicity. Further investigation involved a five-dose assay of compound <b>23</b> against NCI-60 cancer cell lines, revealing its efficacy at different concentrations. Additionally, binding studies elucidated its interaction with Human Serum Albumin (HSA) and DNA. The results indicated a strong binding affinity of <b>23</b> with HSA, evidenced by a high binding constant (2.26 × 10⁵ M⁻¹). Moreover, its interaction with DNA occurred via intercalation, specifically between the base pairs of DNA strands, with a binding constant of 5.51 × 10⁴ M⁻¹. This suggests that compound <b>23</b> has the ability to bind to both DNA and transport proteins, making it a promising pharmacophore with potential therapeutic applications.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142577189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitotic Arrest Deficient 2 Like 1 Contributes to Colorectal Cancer Cell Migration, Invasion, and Oxaliplatin Resistance Through the Wnt/β-Catenin Pathway","authors":"Xiang Ding,&nbsp;Yonggui Zhou,&nbsp;Linfang He,&nbsp;Hubin Kang,&nbsp;Youwu Wen,&nbsp;Jia Xu,&nbsp;Congbo Zhu,&nbsp;Libing Luo,&nbsp;Qingjun Zeng","doi":"10.1111/cbdd.70012","DOIUrl":"10.1111/cbdd.70012","url":null,"abstract":"<div>\u0000 \u0000 <p>Colorectal cancer (CRC) is a highly prevalent malignancy, requiring chemotherapy for advanced stages of the disease. Previously, we found that mitotic arrest deficient 2 like 1 (MAD2L1) was upregulated and facilitated malignant proliferation in CRC. However, the association between MAD2L1 expression and tumor progression, as well as chemotherapy resistance in CRC, remains unclear. The progression capacities of CRC cells were assessed using transwell and wound healing assays, and the resistance to cisplatin in oxaliplatin-resistant CRC cells was assessed using CCK-8 assay and flow cytometry. Relevant protein levels of epithelial-to-mesenchymal transition (EMT) and Wnt/β-catenin pathway were analyzed using western blotting. Revealing the impact of MAD2L1 on metastasis and drug resistance in CRC through inhibition of the Wnt/β-catenin pathway. Knockdown of MAD2L1 attenuated the malignant progression of CRC cells, inhibited EMT, and blocked the Wnt/β-catenin pathway. MAD2L1 was significantly upregulated in oxaliplatin-resistant CRC cells, accompanied by the activation of the Wnt/β-catenin pathway. Knockdown of MAD2L1 effectively reversed oxaliplatin resistance, leading to apoptosis and downregulation of the protein expression levels of β-catenin, P-glycoprotein (P-gp), and ABCG2. After the knockdown of MAD2L1, the inhibition of the Wnt/β-catenin pathway exhibited a synergistic effect, effectively suppressing malignant progression and reversing oxaliplatin resistance in CRC cells. So, knockdown of MAD2L1 suppressed cell malignant progression, equally sensitized resistant CRC cells to oxaliplatin, potentially by blocking the activation of the Wnt/β-catenin pathway.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive Analysis of NADH:Ubiquinone Oxidoreductase Subunit B3 in Gynecological Tumors and Identification of Its Natural Inhibitor Wedelolactone","authors":"Huiping Li,&nbsp;Yangli Jin,&nbsp;Yanyan Zhang,&nbsp;Xiaohua Xie,&nbsp;Nan Li","doi":"10.1111/cbdd.70006","DOIUrl":"10.1111/cbdd.70006","url":null,"abstract":"<div>\u0000 \u0000 <p>The aim of this study was to explore the role of NADH:ubiquinone oxidoreductase subunit B3 (NDUFB3) in human gynecological malignancies and to screen potential natural compounds targeting it. GEPIA and HPA databases were used to study the expression characteristics of NDUFB3. GO and KEGG enrichment analyses were performed using the R software clusterProfiler package. GSEA for NDUFB3 was performed using the LinkedOmics database. Natural compounds targeting NDUFB3 were screened by virtual screening and molecular docking. After NDUFB3 was depleted or wedelolactone treatment, cell proliferation was detected by CCK-8 assay. The production of reactive oxide species (ROS) in tumor cells was detected by dihydroethidium fluorescent probe. The cell cycle and apoptosis were evaluated by flow cytometry. It was revealed that NDUFB3 was highly expressed in ovarian cancer (OV), uterine corpus endometrial carcinoma (UCEC), and cervical squamous cell carcinoma (CESC). NDUFB3 expression was associated with multiple immunomodulators in CESC, OV, and UCEC. NDUFB3 was predicted to modulate MAPK signaling pathways in CESC, OV, and UCEC. Knocking down NDUFB3 inhibited the proliferation of CESC, OV, and UCEC cells, increased intracellular ROS production, and induced cell cycle arrest and apoptosis. Wedelolactone was a potential small molecule with a strong ability to bind with the active pocket of NDUFB3, and wedelolactone could kill CESC, OV, and UCEC cells partly via NDUFB3. In conclusion, NDUFB3 may be a potential biomarker and a new target for gynecological tumors, and wedelolactone may exert antitumor activity via targeting NDUFB3.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and Synthesis of 1,4-Diformyl-Piperazine Ferrostatin-1 Derivatives as Novel Ferroptosis Inhibitors","authors":"Yi-Fan Zhang,&nbsp;Wei Guo,&nbsp;Hui Zheng,&nbsp;Nai-Yu Zhang,&nbsp;Hua-Long Ji,&nbsp;Ning Meng,&nbsp;Juan Zhang,&nbsp;Cheng-Shi Jiang","doi":"10.1111/cbdd.70000","DOIUrl":"10.1111/cbdd.70000","url":null,"abstract":"<div>\u0000 \u0000 <p>The present study focuses on the design and synthesis of novel 1,4-diformyl-piperazine-based ferrostatin-1 (Fer-1) derivatives, and their evaluation against ferroptosis activity. The synthesized compounds demonstrated significant anti-ferroptosis activity in human umbilical vascular endothelial cells (HUVECs), with Compound <b>24</b> showing the highest potency. Mechanistic studies revealed that Compound <b>24</b> effectively reduced intracellular reactive oxygen species (ROS) levels, mitigated mitochondrial damage, and enhanced glutathione peroxidase 4 (GPX4) expression. Additionally, Compound <b>24</b> exhibited improved solubility and plasma stability compared to control compounds, Fer-1 and JHL-12. These findings suggest that 1,4-diformyl-piperazine-based Fer-1 derivatives hold promise as therapeutic agents for ferroptosis-associated cardiovascular diseases.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination of Diosmetin With Chrysin Against Hepatocellular Carcinoma Through Inhibiting PI3K/AKT/mTOR/NF-кB Signaling Pathway: TCGA Analysis, Molecular Docking, Molecular Dynamics, In Vitro Experiment","authors":"Xiang Yu,&nbsp;Di Zhang,&nbsp;Chengming Hu,&nbsp;Zejun Yu,&nbsp;Yang Li,&nbsp;Cheng Fang,&nbsp;Yinsheng Qiu,&nbsp;Zhinan Mei,&nbsp;Lingyun Xu","doi":"10.1111/cbdd.70003","DOIUrl":"10.1111/cbdd.70003","url":null,"abstract":"<div>\u0000 \u0000 <p>Hepatocellular carcinoma (HCC) is the sixth most prevalent malignant tumor. Hepatocellular carcinogenesis is closely linked to apoptosis, autophagy, and inflammation. Diosmetin and chrysin, are two flavonoid compounds, exhibit anti-inflammatory and anticancer properties. In this study, the TCGA database was utilized to identify differentially expressed genes between normal subjects and HCC patients. Molecular docking and molecular dynamics analyses were employed to assess the binding affinity of chrysin and diosmetin to key proteins in the PI3K/AKT/mTOR/NF-κB signaling pathway. Western blotting and RT-qPCR were used to measure the protein and gene expression within this pathway. The results indicated that HCC patients had elevated levels of PI3K, AKT, mTOR, and P65 proteins compared to normal subjects, which adversely affected patient survival. Molecular docking and dynamics studies demonstrated that diosmetin and chrysin are effectively bound to these four proteins. In vitro experiments revealed that the combination of diosmetin and chrysin could induce apoptosis, enhance autophagy, reduce inflammatory mediator production, and improve the tumor cell microenvironment by inhibiting the PI3K/AKT/mTOR/NF-κB signaling pathway. Notably, the synergy score for the combination of diosmetin (25 μM) and chrysin (10 μM) was 16. Thus, the diosmetin–chrysin combination shows promise as an effective therapeutic approach for hepatocellular carcinoma due to its strong synergistic effect.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}