JOURNAL OF CELLULAR AND MOLECULAR MEDICINE最新文献

{"title":"Mib2 Regulates Lipid Metabolism in Heart Failure With Preserved Ejection Fraction via the Runx2–Hmgcs2 Axis","authors":"Zhulan Cai,&nbsp;Shunyao Xu,&nbsp;Xiaohua Xiao,&nbsp;Chen Liu,&nbsp;Lingyun Zu","doi":"10.1111/jcmm.70514","DOIUrl":"https://doi.org/10.1111/jcmm.70514","url":null,"abstract":"<p>Obesity and the mismanagement of lipids significantly contribute to the development of heart failure with preserved ejection fraction (HFpEF). However, the underlying molecular mechanisms that regulate the metabolic changes and disruptions in lipid balance within HFpEF remain to be fully understood. Transcriptome data for HFpEF were sourced from the National Center for Biotechnology Information (NCBI) database. A mouse model for HFpEF was developed utilising leptin-deficient (ob/ob) mice. The cardiac-specific mind bomb E3 ubiquitin protein ligase 2 (Mib2) overexpression in ob/ob mice was achieved by tail vein injection of a recombinant adeno-associated virus serotype 9 vector carrying Mib2 with a cTNT promoter (AAV9-cTNT-Mib2). In vitro, neonatal rat ventricular myocytes were exposed to fatty acid to induce lipotoxicity. The molecular mechanisms were investigated through proteomic analysis, dual luciferase reporter gene assay, and immunoprecipitation assays. GO and KEGG enrichment analyses indicated that the differentially expressed proteins (DEPs) in HFpEF were prominently enriched in pathways related to the fatty acid metabolic process. The transcriptomic and proteomic analyses of heart tissues from HFpEF mice presented a notable elevation in the expression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2). Immunoprecipitation assays revealed that mind bomb 2 (Mib2) directly interacted with runt-related transcription factor 2 (Runx2), ubiquitinating and degrading Runx2 to inhibit Hmgcs2 transcription, impeding the fatty acid metabolic process. Mice with cardiac-specific overexpression of Mib2 displayed a more pronounced progression of cardiac dysfunction and an accumulation of lipids compared to the control group. Our research uncovers a mechanism by which Mib2 modulates cardiac lipid metabolic homeostasis in HFpEF, implicating the Runx2-Hmgcs2 axis.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"29 7","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.70514","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine Learning Unveils Sphingolipid Metabolism's Role in Tumour Microenvironment and Immunotherapy in Lung Cancer","authors":"Lili Xu,&nbsp;Jianchun Wu,&nbsp;Jianhui Tian,&nbsp;Bo Zhang,&nbsp;Yang Zhao,&nbsp;Zhenyu Zhao,&nbsp;Yingbin Luo,&nbsp;Yan Li","doi":"10.1111/jcmm.70435","DOIUrl":"https://doi.org/10.1111/jcmm.70435","url":null,"abstract":"<p>TME is a core player in the development of a cancerous lesion, the immune evasive potential of the lesion, and its response to therapy. Sphingolipid metabolism, which governs a number of cellular processes, has been recognised as a player involved in the control of immune heterogeneity within the TME. Sphingolipid metabolism-related genes prevalent in the TME of LUAD and LUSC were identified using transcriptomic analysis and clinical samples from the TCGA and GTEx databases. Lasso regression and survival SVM in the Etra Application were employed as machine learning algorithms to determine patient outcomes and to reveal key immune factors associated with gene expression and chemotherapeutic response. Gene expression in lung cancer cells was explored through scRNA-seq data. Thereafter, mediation impact analysis was further performed to explain the defined relation between the immune cell subsets and sphingolipid metabolites and their risk impact on lung cancers. Genes involved in sphingolipid metabolism were dysregulated in lung cancer, correlating with immune cell infiltration and TME remodelling. Lasso regression identified ASAH1 and SMPD1 as strong prognostic markers. scRNA-seq revealed higher gene expression in T cells, macrophages and fibroblasts. Sphingomyelin partially mediated the link between T lymphocyte abundance and lung cancer risk. High-risk phenotypes exhibited enhanced immune evasion via altered regulatory T cell and macrophage polarisation. This research highlights the contribution of sphingolipid metabolism in shaping the TME and its implications for immunotherapy.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"29 7","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.70435","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GABRD Accelerates Tumour Progression via Regulating CCND1 Signalling Pathway in Gastric Cancer","authors":"Weibing Leng,&nbsp;Jun Ye,&nbsp;Zhenpeng Wen,&nbsp;Han Wang,&nbsp;Zhenyu Zhu,&nbsp;Xilin Song,&nbsp;Kai Liu","doi":"10.1111/jcmm.70485","DOIUrl":"https://doi.org/10.1111/jcmm.70485","url":null,"abstract":"<p>Neurotransmitters and their receptors were reported to be involved in tumour initiation and progression. However, little is known about their roles in gastric cancer (GC). Here, we first identified gamma-aminobutyric acid type A receptor subunit delta (GABRD) as a novel oncogene in GC. GABRD was preferentially upregulated in GC tissues compared with adjacent normal tissues. High GABRD expression was significantly associated with poor survival prognosis. Knockdown of GABRD could markedly induce cell apoptosis and cell cycle arrest while repressing proliferation and migration in vitro, and suppress tumour growth in vivo. The results of transcriptomic analysis and Ingenuity pathway analysis (IPA) highlighted that cyclin D1(CCND1) was a potential downstream target. Immunohistochemistry results also indicated that CCND1 expression was associated with GABRD in GC. Functional experiments also confirmed that the role of GABRD in regulating proliferation, migration, invasion, and apoptosis was dependent on CCND1. Mechanically, further research confirmed that GABRD knockdown could induce p53-dependent apoptosis through CCND1, and GABRD upregulated CCDN1 through inhibiting its ubiquitin-mediated degradation. Overall, these findings uncover a role for the neurotransmitter receptor GABRD in regulating the proliferation and apoptosis of gastric cancer cells. Our present study provides novel insights into the mechanism of tumourigenesis in gastric cancer.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"29 7","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.70485","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cinobufagin Enhances the Sensitivity of Cisplatin-Resistant Lung Cancer Cells to Chemotherapy by Inhibiting the PI3K/AKT and MAPK/ERK Pathways","authors":"Guangxin Zhang,&nbsp;Kun Zhang,&nbsp;Xin Li,&nbsp;Xiuwen Wang,&nbsp;Guangquan Li,&nbsp;Yicun Wang","doi":"10.1111/jcmm.70501","DOIUrl":"https://doi.org/10.1111/jcmm.70501","url":null,"abstract":"<p>Lung cancer patients always develop serious chemotherapy resistance after long-term use of cisplatin treatment. It has been demonstrated that the combination of cisplatin (DDP) with other chemotherapy drugs may significantly reduce drug resistance. Cinobufagin (CB) showed potent anti-tumour effect against lung cancer. However, the relevance of CB and DDP resistance in lung cancer remains unclear. This article will study the effects of CB on reversing lung cell resistance. The apoptosis was rescued by flow cytometry analysis and TUNEL staining. The invasiveness was rescued by invasion assay. The mRNA and apoptosis-related proteins were estimated by qRT-PCR analysis and Western blot analysis, respectively. In vivo antitumor activities were investigated by subcutaneous xenograft assay. The present study firstly demonstrated that the sensitivity of DDP in DDP-resistant A549 (A549/DDP) cells was enhanced when treated with CB. Moreover, CB combined with DDP weakened the proliferation and increased apoptosis of A549/DDP cells. In addition, the expression level of Bcl-2 was increased, whereas Bax and caspase-3 were activated when A549/DDP cells were treated with both drugs. After treatment with IGF1 or PMA and mixed drugs (CB + DDP), the expressions of P-AKT, P-PI3K, P-MEK1/2 and P-ERK1/2 were increased. Finally, the results of in vivo experiments showed that the combination of DDP and CB significantly reduced the growth of tumours derived from A549/DDP cells. The combination of CB and DDP can be considered an effective strategy to increase the sensitivity of DDP-resistant lung cancer cells to DDP by inhibiting the PI3K/AKT and MAPK/ERK pathways.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"29 6","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.70501","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C-Terminal Hsp90 Inhibitors Overcome MEK and BRAF Inhibitor Resistance in Melanoma","authors":"Chitra Subramanian,&nbsp;Katie K. Hohenberger,&nbsp;Ang Zuo,&nbsp;Eric Cousineau,&nbsp;Brian Blagg,&nbsp;Mark Cohen","doi":"10.1111/jcmm.70489","DOIUrl":"https://doi.org/10.1111/jcmm.70489","url":null,"abstract":"<p>Targeted therapies for melanoma MEK and BRAF inhibitors fail due to the development of chemoresistance. As Hsp90 inhibitors target client proteins of resistant pathways, we hypothesised that C-terminal Hsp90 inhibitors will target BRAF/MEK inhibitor resistant melanoma cells by overcoming the resistant pathways. Two melanoma cell lines, A375 and A375 MEK/BRAF inhibitor resistant (A375MEKi) were utilised. The inhibitory concentrations (IC₅₀) of two C-terminal Hsp90 inhibitors, KU757 and KU758, were determined by CellTiter Glo. RNA sequencing was performed after treatment with KU757. Pathways targeted by differentially expressed genes were evaluated by David, IPA, GSEA, and by evaluating the cell cycle, apoptosis and oxidative phosphorylation. Expression levels of hub genes were evaluated using Xena and validated by RT-PCR. The survival analysis was performed using UALCAN. A375MEKi was not resistant to the C-terminal Hsp90 inhibitor with a KU757 IC₅₀ of 0.59 μM versus 0.64 μM and a KU758 IC₅₀ of 0.89 μM versus 0.93 μM in A375 versus A375MEKi, respectively. RNA sequencing analysis revealed KU757 upregulates cell cycle checkpoint regulation and apoptosis and downregulates genes involved in the peroxisome, AKT/PI3K/MTOR, EIF2, fatty acid metabolism and oxidative phosphorylation. These pathways were further validated through survival analysis that demonstrated potential survival benefit in patients with dysregulated NDUFA7, CDC20, CDC25C, CDK1, VDAC2, HEATR5a, COL4A4, FLT3LG, BMP2, PRKCH and ADMST9. Melanomas often develop concurrent resistance to BRAF and MEK inhibitors. C-terminal Hsp90 inhibition with KU757 appears to overcome these chemo-resistance pathways in vitro, downregulating metabolic pathways including oxidative phosphorylation and the cell cycle, warranting further in vivo translation. The novel C-terminal HSP90 inhibitor KU757 effectively targets primary and BRAF and MEK inhibitor-resistant melanoma cells equally by affecting oxidative phosphorylation and the cell cycle.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"29 6","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.70489","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TAB2 Promotes Immune Escape and Chemoresistance Through NF-κB Pathway Activation in Cervical Cancer","authors":"Man Wu,&nbsp;Yingying Zhang,&nbsp;Xuanhui Wang,&nbsp;Yijia Zhou","doi":"10.1111/jcmm.70522","DOIUrl":"https://doi.org/10.1111/jcmm.70522","url":null,"abstract":"<p>Cervical cancer (CC) remains a major health challenge with high mortality rates due to chemoresistance and immune escape. However, the underlying mechanisms remain unclear. We investigated the role of TAB2 in CC using cisplatin-resistant and parental cell lines. Cell proliferation, migration, sphere formation and T cell-mediated killing assays were performed. Western blot and qRT-PCR analysed protein and mRNA expression. NF-κB pathway involvement was examined using the BAY 11–7082 inhibitor. TAB2 expression was significantly elevated in cisplatin-resistant CC cells. TAB2 overexpression promoted chemoresistance and immune escape through NF-κB pathway activation. Conversely, TAB2 knockdown or NF-κB inhibition sensitised resistant cells to cisplatin and enhanced T cell-mediated killing. The resistant phenotype could be rescued by restoring PD-L1 expression. Our findings reveal TAB2 as a critical regulator of both chemoresistance and immune escape in CC through NF-κB pathway activation. This suggests TAB2 as a potential therapeutic target for overcoming treatment resistance in CC.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"29 6","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.70522","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tyr1497 in the BRG1 Bromodomain of the SWI/SNF Complex is Critical for the Binding and Function of a Selective BRG1 Inhibitor","authors":"Yinan Wang,&nbsp;Chuanhe Yang,&nbsp;Gustavo A. Miranda-Carboni,&nbsp;Hannah Kelso,&nbsp;Jayaraman Seetharaman,&nbsp;Dong-Jin Hwang,&nbsp;Duane D. Miller,&nbsp;Lawrence M. Pfeffer","doi":"10.1111/jcmm.70518","DOIUrl":"https://doi.org/10.1111/jcmm.70518","url":null,"abstract":"<p>BRG1 and BRM are subunits of the SWI/SNF chromatin remodelling complex, which has DNA-stimulated ATPase activity and can destabilise histone–DNA interactions. Targeting SWI/SNF is beneficial for treating various tumours, including glioblastoma (GBM). Our research focussed on BRG1 due to its overexpression in GBM. We developed IV-255, a selective bromodomain (BRD) inhibitor that binds to BRG1 but not BRM. IV-255 sensitised GBM cells to temozolomide (TMZ), the standard GBM treatment. We identified the binding site of IV-255 within the BRG1 BRD and found that the Tyr1497 residue is crucial for IV-255's effect on TMZ-induced GBM cell death, while Asn1540 is not. Structural analyses confirmed that Tyr1497 is involved in the IV-255 binding pocket. Mechanistically, IV-255 increases γH2AX staining in GBM cell nuclei in response to TMZ, indicating an impaired DNA double-strand break response dependent on Tyr1497. IV-255 also sensitised GBM cells to TMZ-induced apoptosis, as shown by PARP and caspase-3 cleavage, which also requires Tyr1497. In conclusion, Tyr1497 within the BRD of BRG1 is critical for its interaction with IV-255 and for sensitising GBM cells to TMZ-induced DNA double-strand breaks and apoptotic cell death.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"29 6","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.70518","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Depleting Yes-Associated Protein in Gli1-Expressing Cells Attenuates Peritoneal Dialysis-Induced Peritoneal Fibrosis","authors":"Chia-Lin Wu,&nbsp;Jhih-Wen Hsu,&nbsp;Ya-Chi Chan,&nbsp;Jenn-Yah Yu,&nbsp;Yi-Liang Tsai,&nbsp;Der-Cherng Tarng","doi":"10.1111/jcmm.70516","DOIUrl":"https://doi.org/10.1111/jcmm.70516","url":null,"abstract":"<p>Long-term peritoneal dialysis (PD) leads to peritoneal damage and chronic inflammation, resulting in peritoneal fibrosis (PF). Emerging evidence suggests that yes-associated protein (YAP) is a key player in fibrogenesis across various organs. However, its role in PD-induced PF remains unclear. We used NIH/3T3 cells, primary mouse fibroblasts, and conditional YAP knockout (CKO) mice with glioma-associated oncogene 1 (<i>Gli1</i>)-specific YAP deletion. The effects of YAP knockdown and verteporfin, a YAP inhibitor, on fibroblast-to-mesenchymal transition (FMT) and angiogenesis were evaluated. Transforming growth factor-beta (TGF-β) induced YAP expression and promoted fibroblast-to-myofibroblast transition (FMT) in 3T3 fibroblasts, upregulating collagen 1A1, α-smooth muscle actin (α-SMA), and connective tissue growth factor (CTGF). YAP knockdown and verteporfin treatment reduced these FMT markers and inhibited smad2/3 phosphorylation. In vivo, YAP and <i>Gli1</i>-expressing cells were upregulated in PD-induced PF. Conditional YAP knockout in <i>Gli1</i>⁺ cells and verteporfin treatment significantly reduced fibrosis and α-SMA, collagen 1, TGF-β, CTGF, and phosphorylated smad2/3 expression in the peritoneum and peritoneal angiogenesis. YAP plays a pivotal role in FMT during PD-induced PF. Conditional YAP deletion in <i>Gli1</i>-expressing cells and verteporfin treatment represent promising antifibrotic strategies for long-term PD patients.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"29 6","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.70516","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing Splicing Variants in the PAX6 Gene: A Comprehensive Minigene Approach","authors":"Kseniya Davydenko,&nbsp;Alexandra Filatova,&nbsp;Mikhail Skoblov","doi":"10.1111/jcmm.70459","DOIUrl":"https://doi.org/10.1111/jcmm.70459","url":null,"abstract":"<p>Haploinsufficiency of the <i>PAX6</i> gene causes aniridia, a congenital eye disorder characterised by the absence or malformation of the iris and foveal hypoplasia. Previous studies indicate that pathogenic splice variants account for up to 15% of all disease-causing <i>PAX6</i> variants. However, this proportion may be significantly underestimated because the pathogenicity of splice variants can only be accurately established through experimental validation. In this study, we developed and validated a system of eight minigene constructions for the functional analysis of splicing variants in the <i>PAX6</i> gene. This system covers all <i>PAX6</i> coding exons and allows the analysis of any exon and most intronic variants of <i>PAX6</i>. Our comprehensive approach, employing fragment analysis and deep targeted sequencing, enabled us to accurately characterise 38 previously described <i>PAX6</i> variants, including challenging cases with multiple splicing events. The application of our system revealed that the number of pathogenic splicing variants might be closer to 30% of all pathogenic <i>PAX6</i> variants. This finding considerably reshapes our understanding of their significance in the genetic landscape of aniridia.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"29 6","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.70459","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and Development of Xanthone Hybrid for Potent Anti-Inflammatory Effects: Synthesis and Evaluation","authors":"Shreyasi Karmakar,&nbsp;Riya Saikia,&nbsp;Aparoop Das,&nbsp;Kalyani Pathak,&nbsp;Padmashree Das,&nbsp;Biman Bhuyan,&nbsp;Taha Alqahtani,&nbsp;Humood Al Shmrany,&nbsp;Bikram Dhara,&nbsp;Ajoy Kumer","doi":"10.1111/jcmm.70477","DOIUrl":"https://doi.org/10.1111/jcmm.70477","url":null,"abstract":"<p>Inflammatory responses, while essential for host defence, can precipitate chronic pathologies when sustained. The polyphenolic entity xanthone is distinguished by its capacity to modulate inflammation, notably via the inhibition of the COX-2 enzyme and associated inflammatory pathways. Additionally, heterocyclic frameworks such as pyrazole, triazole, and imidazole are recognised for their anti-inflammatory attributes. This investigation was conducted to engineer and synthesise a series of novel hybrid-xanthone molecules with enhanced anti-inflammatory capabilities. Utilising computational docking strategies, these hybrid-xanthone variants were virtually screened against the COX-2 enzyme structure (PDB ID:1CX2), and the 10 leading candidates were identified based on their binding affinities. These selected entities were synthesised through an optimised three-stage synthetic route. Subsequent in vitro assessments were performed using the Egg albumin denaturation assay at incremental concentrations. Complementary in vivo experiments involved the Carrageenan-induced paw edema protocol in Wistar rats, administered at 200 mg/kg to evaluate the anti-inflammatory response over a period of 6 h. The best percentage inhibition was shown by compound A127<b>(3-(5′(1,2,4-Triazole)-pentyloxy)-1,6,8-trihydroxy xanthone)</b>, A11<b>(3-(1′-(1,2,4-Triazole)-methyloxy)-1,6,8-trihydroxy xanthone)</b> and A119<b>(3-(1′-(1,2,4-Triazole)-methyloxy)-1,6,8-trihydroxy xanthone)</b> as 60 ± 0.31, 58.57 ± 0.023, and 57.14 ± 0.21 respectively. Spectroscopic characterisation of the compounds was achieved through UV, IR, NMR, and Mass spectrometry techniques. The investigation revealed that out of the synthesised cohort, nine compounds exhibited favourable <i>in silico</i> profiles, and half of these manifested substantial anti-inflammatory efficacy in both in vitro and in vivo models, outperforming the reference standard. These hybrid-xanthone molecules demonstrated precise COX-2 inhibition and maintained an acceptable safety margin in vivo, underscoring their therapeutic promise as anti-inflammatory agents.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"29 6","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.70477","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}