Biochemical pharmacology最新文献

{"title":"Phosphocreatine alleviates monocrotaline-induced liver injury dependent on PSRC1-regulated endoplasmic reticulum stress","authors":"Sinuo Chen ,&nbsp;Yifan Ma ,&nbsp;Mingyan Ji ,&nbsp;Heming Wang ,&nbsp;Yun Chen ,&nbsp;Dongping Li ,&nbsp;Hongyue Jiang ,&nbsp;Guangqi Song ,&nbsp;Jinglin Xia ,&nbsp;Hong Gao","doi":"10.1016/j.bcp.2025.116915","DOIUrl":"10.1016/j.bcp.2025.116915","url":null,"abstract":"<div><div>Monocrotaline (MCT), a pyrrolizidine alkaloid (PA), is naturally found in certain plants and known for its hepatotoxic effects. In our prior research, we identified that phosphocreatine (PCr) mitigates PA-induced liver damage. However, the specific mechanism of PCr remains unknown. The objective of the present study was to elucidate the mechanism through which PCr shields against MCT-induced hepatic injury. In vitro assays demonstrated that PCr mitigated the MCT-induced ER stress and apoptosis. This alleviation was similarly observed with the use of the ER stress inhibitor 4-PBA, hinting at the role of ER stress in the protective mechanism of PCr against MCT-induced hepatic damage. In the MCT group, an upregulation of proline/serine-rich coiled-coil protein 1 (PSRC1) was evident, but this was notably downregulated following PCr treatment in vitro. The silencing of PSRC1 diminished the ER stress and apoptosis triggered by MCT, and the protective effect of PCr on liver injury remained evident. Overexpressing PSRC1 increased MCT-induced apoptosis and ER stress, and PCr still plays a protective role. In vivo experiments, we observed a notable attenuation of MCT-induced liver damage by PCr. Employing RNA sequencing and immunohistochemical staining techniques, we ascertained that endoplasmic reticulum (ER) stress, apoptosis and PSRC1 were significantly elevated in the liver samples treated with MCT. Notably, these alterations were counteracted by the presence of PCr. In conclusion, our findings suggest that PCr counteracts ER stress via modulation of PSRC1, which consequently confers protection against MCT-induced liver injury. Furthermore, this study offers potential therapeutic avenues for addressing hepatic damages attributable to MCT.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116915"},"PeriodicalIF":5.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relief of loperamide-induced constipation by peptidic and small molecule RXFP4 agonists in mice","authors":"Shiyu Yan ,&nbsp;Yan Chen ,&nbsp;Jiang Wang ,&nbsp;Qiuying Wang ,&nbsp;Qingtong Zhou ,&nbsp;Hong Liu ,&nbsp;Ming-Wei Wang ,&nbsp;Dehua Yang","doi":"10.1016/j.bcp.2025.116924","DOIUrl":"10.1016/j.bcp.2025.116924","url":null,"abstract":"<div><div>Constipation is a common gastrointestinal disorder often treated symptomatically as the existing therapies all have significant side-effects. The relaxin/insulin-like family peptide receptor 4 (RXFP4), a class A G protein-coupled receptor, has emerged as a potential drug target for this indication as it regulates intestinal motility. Here, we investigated the therapeutic effects of both peptidic (insulin-like peptide 5, INSL5) and small molecule (DC591053) RXFP4 agonists on loperamide-induced constipation in mice. Fecal water content, fecal weight, colonic transit time, and serum levels of neurotransmitters such as nitric oxide (NO), serotonin (5-HT), and vasoactive intestinal peptide (VIP) were assessed, in conjunction with the examination of colon tissue histology and expression levels of aquaporin 3 (AQP3), transient receptor potential vanilloid 1 (TRPV1), and calcitonin gene-related peptide (CGRP). It was found that both INSL5 and DC591053 dose-dependently increased fecal water content and weight, accelerated colonic transit, and improved colon morphology in constipated mice, accompanied by the altered expression levels of factors related to constipation. Comparative analysis revealed that while the two agonists produced similar beneficial outcomes, their different chemical nature may affect pharmacokinetics property and receptor engagement. Our results suggest that the activation of RXFP4 presents a novel approach to alleviating constipation.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116924"},"PeriodicalIF":5.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blocking the LRH-1/LCN2 axis by ML-180, an LRH-1 inverse agonist, ameliorates osteoarthritis via inhibiting the MAPK pathway","authors":"Jianwen Li ,&nbsp;Yayun Zhang ,&nbsp;Xin Gan ,&nbsp;Junhong Li ,&nbsp;Ganqing Xia ,&nbsp;Lingxiao He ,&nbsp;Chengyan Xia ,&nbsp;Weikai Zhang ,&nbsp;Khan Akhtar Ali ,&nbsp;Meipeng Zhu ,&nbsp;Hui Huang","doi":"10.1016/j.bcp.2025.116922","DOIUrl":"10.1016/j.bcp.2025.116922","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a chronic and degenerative disease marked by inflammation and extracellular matrix (ECM) degeneration, contributing to synovial inflammation and cartilage destruction. Accumulating evidence has demonstrated that Liver receptor homolog-1 (LRH-1), an orphan nuclear receptor, mediates inflammatory response. However, there is a lack of evidence regarding the regulatory role of LRH-1 in OA pathogenesis. In this study, we confirmed that chondrocytes expressed LRH-1, and observed its upregulation in both IL-1β-treated chondrocytes and cartilage of destabilization of the medial meniscus (DMM)-operated mice. Overexpression of LRH-1 promoted inflammation and dysregulation of ECM metabolism in IL-1β-induced chondrocytes, reversed by inhibition of LRH-1 with ML-180 or gene silencing to protect chondrocytes. Moreover, ML-180 treatment in vivo improved the deteriorated OA phenotypes in mouse models, alleviating OA development. Mechanistically, RNA sequencing revealed that Lipocalin-2 (LCN2), a member of the lipocalin family associated with inflammation, is located downstream of LRH-1 and is positively regulated by it. Furthermore, the LRH-1/LCN2 axis mainly relied on activating the mitogen-activated protein kinase (MAPK) signaling pathway to promote inflammation and dysregulation of ECM metabolism, ultimately damaging chondrocytes. Our findings demonstrate that LRH-1 positively modulates LCN2,<!--> <!-->activating the MAPK pathway, indicating that targeting the LRH-1/LCN2/MAPK axis may represent a potential therapeutic strategy for OA.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116922"},"PeriodicalIF":5.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum-derived extracellular vesicles mediate acquired multidrug resistance of MCF-7 breast cancer cells induced by chemotherapeutic drugs","authors":"Mi Zhou ,&nbsp;Jiahuan Hong ,&nbsp;Xiaofeng Qiu ,&nbsp;Zixian Xiong ,&nbsp;Xiaoyong Liu ,&nbsp;Zhuan Qin ,&nbsp;Zhesi Luo ,&nbsp;Qi Chen ,&nbsp;Mianjie Lin ,&nbsp;Ling Min ,&nbsp;Xiaorong Yang ,&nbsp;Xinmin Guo ,&nbsp;Bin Xu ,&nbsp;Jianwen Mao","doi":"10.1016/j.bcp.2025.116923","DOIUrl":"10.1016/j.bcp.2025.116923","url":null,"abstract":"<div><div>Multidrug resistance (MDR) in tumor cells presents a significant challenge in cancer therapy. This study investigates the role of serum-derived extracellular vesicles (EVs) in mediating MDR during chemotherapeutic exposure. The findings indicate that short- or long-term co-incubation of doxorubicin (Dox)-pretreated serum derived EVs (EVs(S-PT)) caused drug-sensitive MCF-7 breast cancer cells to develop a MDR phenotype. In addition, serum EVs contain a high concentration of unglycosylated P-glycoprotein (P-gp). Chemotherapy treatment of tumor patients or exposure to chemotherapeutic drugs in vitro activates serum glycosyltransferases, inducing glycosylation of EVs P-gp and giving it drug-pumping activity. Furthermore, damage caused by Dox to the vascular endothelial barrier facilitates the crossing of serum EVs into the tumor microenvironment. These EVs are then taken up by tumor cells, providing them with access to a significant quantity of glycosylated P-gp proteins that possess transporter activity and the ability to evade degradation by the ubiquitin proteasome system. The results indicate that EVs(S-PT) transfers glycosylated P-gp across the damaged vascular endothelial barrier into MCF-7 cells and that these glycosylated P-gp remain intracellular for a long period of time, inducing MDR in the cells. Our study highlights a novel mechanism of acquired MDR and provides a potential avenue for therapeutic interventions targeting the serum EVs pathway in cancer therapy.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116923"},"PeriodicalIF":5.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143800488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel IgD-FcδR blocker, IgD-Fc-Ig fusion protein, effectively alleviates abnormal activation of T cells the disease progression in systemic lupus erythematosus","authors":"Jingjing He ,&nbsp;Danyan Liu ,&nbsp;Li Jiang ,&nbsp;Mengqin Chen ,&nbsp;Xi Ling ,&nbsp;Manling Dong ,&nbsp;Tiantian Wu ,&nbsp;Tingting Guo ,&nbsp;Nuo Xu ,&nbsp;Jing Zhang ,&nbsp;Tao Li ,&nbsp;Yueye Wang ,&nbsp;Jiemin Zhao ,&nbsp;Wei Wei ,&nbsp;Shangxue Yan ,&nbsp;Yujing Wu","doi":"10.1016/j.bcp.2025.116930","DOIUrl":"10.1016/j.bcp.2025.116930","url":null,"abstract":"<div><div>Systemic lupus erythematosus (SLE) is a chronic, multi-organ autoimmune disease with complex pathogenesis and unclear causes. Elevated levels of IgD have been observed in the peripheral blood of SLE patients, suggesting a potential role for IgD through its interaction with the IgD Fc receptor (FcδR). This study aimed to explore the impact of IgD on T cell function in SLE and evaluate the therapeutic potential of targeting the IgD-FcδR pathway using an IgD-Fc-Ig fusion protein. In SLE patients, biomarkers such as BAFF, ESR, anti-dsDNA and SLEDAI-2k, which are used to assess disease activity and clinical presentations, were significantly correlated with sIgD levels. As an IgD-FcδR blocker, IgD-Fc-Ig effectively suppressed the activation and proliferation of CD4⁺ T cells stimulated by IgD, restored the balance between Th17 and Treg cell subsets, and reduced the expression and interaction of phosphorylated Lck (p-Lck) and JAK2 (p-JAK2). Moreover, <em>in vivo</em> study demonstrated that IgD-Fc-Ig may also ameliorates disease manifestations in MRL/lpr mice with lupus nephritis. IgD-Fc-Ig could reduce serum IgD levels, proteinuria level and the kidney deposition of immune complex C3, ameliorate histopathological changes in kidney and spleen tissue. Additionally, it reversed the state of excessive activation and imbalance of Th17/Treg cell subsets, reduced cytokine levels, and downregulated p-JAK2 and p-STAT3 expression. In conclusion, our study revealed a correlation between abnormally increased sIgD and SLE pathogenesis, IgD-FcδR-Lck-JAK2-STAT3 may act as an important mechanism contributing to T cell activation in SLE. IgD-Fc-Ig fusion protein may represent a promising targeted therapy for SLE.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116930"},"PeriodicalIF":5.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scutellarein ameliorates pulmonary arterial hypertension via sirtuin 1 mediated deacetylation of nicotinamide nucleotide transhydrogenase","authors":"Heng Tang ,&nbsp;Ke Ning ,&nbsp;Boji Wu ,&nbsp;Xuhong Wang ,&nbsp;Jingyu He ,&nbsp;Pingping Li ,&nbsp;Lina Pan ,&nbsp;Jiawen Zhang ,&nbsp;Yi He ,&nbsp;Shizhu Bian ,&nbsp;Xingyu Ma ,&nbsp;Jihang Zhang ,&nbsp;Chuan Liu ,&nbsp;Zhexue Qin ,&nbsp;Houyuan Hu","doi":"10.1016/j.bcp.2025.116932","DOIUrl":"10.1016/j.bcp.2025.116932","url":null,"abstract":"<div><div>Scutellarein (Sc), a natural flavonoid, holds potential for treating pulmonary arterial hypertension (PAH), yet its mechanisms remain unexplored. This study investigated Sc’s therapeutic effects and underlying pathways in PAH. In vivo experiments demonstrated that Sc significantly attenuated right ventricular hypertension, pulmonary arterial remodeling, αSMA expression, and vascular inflammation in PAH models. In vitro, Sc suppressed hypoxia-induced proliferation, migration, inflammation, and pyroptosis in human pulmonary artery smooth muscle cells (HPASMCs). Mechanistically, Sc activated the SIRT1/NAD⁺ axis to restore mitochondrial homeostasis: it upregulated SIRT1 expression and elevated NAD⁺ levels by promoting SIRT1-mediated deacetylation of nicotinamide nucleotide transhydrogenase (NNT), thereby enhancing NNT activity. Elevated NAD⁺ further activated SIRT1, forming a self-reinforcing SIRT1/NNT/NAD⁺ feedback loop that mitigated hypoxia-induced mitochondrial dysfunction. This study identifies Sc as a novel regulator of the SIRT1-dependent NNT deacetylation pathway, which stabilizes NAD⁺ homeostasis to counteract HPASMCs dysregulation in PAH. These findings highlight Sc’s potential as a therapeutic candidate for PAH, offering insights into targeting mitochondrial-metabolic pathways for vascular remodeling diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116932"},"PeriodicalIF":5.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into 2D and 3D cell culture models for nanoparticle-based drug delivery to glioblastoma","authors":"Girstautė Dabkevičiūtė ,&nbsp;Vilma Petrikaitė","doi":"10.1016/j.bcp.2025.116931","DOIUrl":"10.1016/j.bcp.2025.116931","url":null,"abstract":"<div><div>Glioblastoma (GBM) remains a formidable challenge due to its aggressive nature, protected location within the brain, and resistance to conventional treatments. Its complex tumor microenvironment (TME), coupled with the blood–brain barrier (BBB), hinders drug delivery leading to poor treatment outcomes. Nanoparticles (NPs) offer a promising solution, as they can improve the pharmacokinetic properties of anticancer agents. By functionalizing NPs with targeting molecules, researchers aim to enhance drug concentration in the brain. However, developing effective NP-based therapies requires robust in vitro models that accurately capture the complexities of GBM.</div><div>Two-dimensional (2D) and three-dimensional (3D) cell culture models provide a versatile platform for studying NP-cell interactions. By customizing cell types, incorporating TME components, and adjusting flow conditions, researchers can tailor these models to specific research questions. While 2D models offer a simpler starting point, 3D models, such as multicellular spheroids and organoids, can more accurately replicate the complex TME, including the BBB and tumor heterogeneity. These models enable a more comprehensive evaluation of NP efficacy and safety, ultimately accelerating drug development and reducing reliance on animal testing.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116931"},"PeriodicalIF":5.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NUF2 activated by YY1 promotes prostate cancer malignancy via p38/MAPK signaling axis and serves as a therapeutic target","authors":"Chengqi Jin ,&nbsp;Jing Xu ,&nbsp;Wentao Luo ,&nbsp;Hanxu Guo ,&nbsp;Li Ding ,&nbsp;Yongqiang Liu ,&nbsp;Ji Liu ,&nbsp;Libin Zou ,&nbsp;Yang Yu ,&nbsp;Yajuan Hao ,&nbsp;Bin Yang","doi":"10.1016/j.bcp.2025.116919","DOIUrl":"10.1016/j.bcp.2025.116919","url":null,"abstract":"<div><div>Prostate cancer (PCa) is one of the most prevalent malignancies in the male urogenital system. Despite extensive research into its mechanisms of initiation and progression, the full scope of its pathophysiology remains insufficiently understood. This study demonstrated that NUF2 was significantly overexpressed in PCa, with its elevated levels correlating with poor patient survival outcomes. Silencing NUF2 notably impaired PCa cell proliferation and metastasis in both in vitro and in vivo models, whereas its overexpression promoted these processes. Additionally, YY1 was identified as a direct transcriptional activator of NUF2, binding to its promoter and enhancing its oncogenic effects through activation of downstream targets. Moreover, NUF2 promoted PCa progression by recruiting p38, accelerating its phosphorylation, and activating the p38/MAPK signaling pathway. Through the PubChem database, fisetin was identified as a small molecule inhibitor of NUF2. Fisetin effectively inhibited PCa cell proliferation, and NUF2 overexpression reversed this inhibitory effect. In conclusion, our results suggest that NUF2 overexpression accelerated PCa progression via the p38/MAPK pathway, regulated by YY1. The identification of fisetin as a NUF2 inhibitor offers a promising therapeutic strategy for targeting NUF2 to impede PCa growth. NUF2 may thus serve as a valuable prognostic biomarker and a potential therapeutic target for PCa.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116919"},"PeriodicalIF":5.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vascular cellular senescence in human atherosclerosis: The critical modulating roles of CDKN2A and CDK4/6 signaling pathways","authors":"Guofu Hu ,&nbsp;Haihua Zhou ,&nbsp;Zihui Yuan ,&nbsp;Jian Wang","doi":"10.1016/j.bcp.2025.116916","DOIUrl":"10.1016/j.bcp.2025.116916","url":null,"abstract":"<div><div>Vascular cellular senescence promotes vascular aging and atherogenesis. Mitigating vascular cellular senescence serves as a promising therapy for atherosclerosis. Transcriptomic analysis was conducted to reveal the differentially expressed genes (DEGs) regulating cell proliferation, growth, senescence, and death in human atherosclerotic lesions <em>vs.</em> normal vessels. The key DEGs were screened out using Venn diagrams. Ox-LDL induced umbilical vein endothelial cells (HUVECs) and high fat diet-fed <em>ApoE^-/-</em> mice were utilized to construct model. We identified CDKN2A as a senescence-related DEG. The upregulated CDKN2A depressed the downstream CDK4/6 in ox-LDL treated HUVECs. Ox-LDL aggravated cell-cycle arrest, decreased cellular viability, inhibited migration, led to flattened and enlarged senescent morphology, generated ROS, and elevated β-galactosidase activity along with increment in β-galactosidase expression, which were ameliorated by CDKN2A knockdown and, conversely, were exacerbated by the addition of CDK4/6 inhibitor palbociclib. β-galactosidase activity and ROS production were significantly elevated in human and mice atherosclerotic lesions. β-galactosidase, co-localized with CD31, was obviously upregulated in atherosclerotic lesions, indicating endothelial cellular senescence <em>in vivo</em>. CDKN2A, co-localized with CD31, was markedly increased in atherosclerotic lesions, indicating the CDKN2A immunopositivity in endothelial cells <em>in vivo</em>. Colocalization of CDKN2A with CDK4/6 revealed the potential connection <em>in vivo</em>. Palbociclib exacerbated vascular cell senescence and atherogenesis in mice. Endothelial cellular senescence is present in atherosclerotic lesions. CDKN2A and CDK4/6 pathway is active in endothelial cellular senescence and atherogenesis, and altering CDKN2A and CDK4/6 pathway plays a critical role in alleviating endothelial cellular senescence and atherosclerosis, implying novel targets for prevention of vascular aging and atherogenesis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116916"},"PeriodicalIF":5.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relevance of transportome among the mechanisms of chemoresistance in hepatoblastoma","authors":"Candela Cives-Losada ,&nbsp;Maitane Asensio ,&nbsp;Oscar Briz ,&nbsp;Luis Miguel Chinchilla-Tábora ,&nbsp;María Manuela Barranco ,&nbsp;Álvaro del Río-Álvarez ,&nbsp;Maria Luz Martinez-Chantar ,&nbsp;Matias A. Avila ,&nbsp;Stefano Cairo ,&nbsp;Carolina Armengol ,&nbsp;Jose J.G. Marin ,&nbsp;Rocio I.R. Macias","doi":"10.1016/j.bcp.2025.116914","DOIUrl":"10.1016/j.bcp.2025.116914","url":null,"abstract":"<div><div>Approximately 20 % of hepatoblastomas (HBs) exhibit a poor response to conventional chemotherapy due to mechanisms of chemoresistance (MOCs), such as reduced intracellular drug accumulation. This study evaluated the role of transportome in the multidrug resistance (MDR) of HB. Paired HB and adjacent liver tissue samples (n = 19) and HB-derived cell lines (HepG2, HuH6) were analyzed for their resistome characterization at mRNA (RT-qPCR, Taqman Low-Density Array, sequencing) and protein (western blot, immunohistochemistry, immunofluorescence) levels. Cell viability (MTT test) proliferation and migration (holographic microscopy) were determined. The impact of short-term (72 h) and long-term (&gt;10 months) exposure of HB cells to cisplatin or doxorubicin on the transportome was investigated. Solute carrier (SLC) family of transporters showed minor relevance in HB MDR, while drug export pumps, particularly MRP2, were associated with poor response to chemotherapy. Exposure of HB cells to doxorubicin or cisplatin up-regulated MDR1, MRP1 and MRP2. In cells with induced persistent chemoresistance, the expression of genes involved in other MOCs, and epigenetic machinery was altered. Chemoresistant cells showed cross-resistance to several anticancer drugs but maintained sensitivity to cabozantinib. In conclusion, drug export pumps, but not SLC uptake transporters, are key contributors to HB chemoresistance. Cabozantinib emerges as a potential therapeutic option for HBs resistant to conventional chemotherapy.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116914"},"PeriodicalIF":5.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}