Biochemical pharmacology最新文献

Discovery of a novel BCL-2 inhibitor GW806742X for the treatment of TNBC.

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-04-06 DOI: 10.1016/j.bcp.2025.116925

Wenjun Liu, Jia Xu, Li Chen, Dongze Zhang, Juan Zhang, Linlin Lu, Xiaoming Zhang, Xue Huang, Guangbo Zhang

{"title":"Discovery of a novel BCL-2 inhibitor GW806742X for the treatment of TNBC.","authors":"Wenjun Liu, Jia Xu, Li Chen, Dongze Zhang, Juan Zhang, Linlin Lu, Xiaoming Zhang, Xue Huang, Guangbo Zhang","doi":"10.1016/j.bcp.2025.116925","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.116925","url":null,"abstract":"<p><p>Triple-negative breast cancer（TNBC） lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), and traditional treatments cannot accurately target TNBC. Anthracycline- and paclitaxel-based chemotherapeutic agents are still the mainstay of treatment for TNBC, but these chemotherapeutic agents have major toxic side effects and are prone to drug resistance during the treatment of TNBC. In this study, we investigated the efficacy and potential mechanisms of action of GW806742X in the treatment of TNBC. We screened a library of 600 FDA-approved small molecule compounds to identify GW806742X, a small molecule that inhibits the viability of triple-negative breast cancer cells. In vitro, GW806742X was found to be cytotoxic to TNBC cells in a dose-dependent manner and to inhibit the growth of MDA-MB-468 tumors in vivo. Mechanistically, we used PharmMapper to predict the possible targets of GW806742X and demonstrated that the small molecule drug could directly bind to BCL-2 by molecular docking simulations and ITC experiments. Western blot analysis demonstrated that GW806742X could reduce BCL-2 protein levels and possibly promote BCL-2 degradation through the lysosomal pathway. Moreover, GW806742X disrupts NF-κB signaling In conclusion, this study demonstrates that GW806742X can be a potential therapeutic agent for triple-negative breast cancer by targeting BCL-2.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116925"},"PeriodicalIF":5.3,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810055","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}

引用次数: 0

Exploring the biological functions and disease implications of OSGINs: A journey from discovery to clinical relevance.

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-04-06 DOI: 10.1016/j.bcp.2025.116921

Qian-Fei Cui, Chong Liu, Xue-Man Dong, Zhao-Qian Liu

{"title":"Exploring the biological functions and disease implications of OSGINs: A journey from discovery to clinical relevance.","authors":"Qian-Fei Cui, Chong Liu, Xue-Man Dong, Zhao-Qian Liu","doi":"10.1016/j.bcp.2025.116921","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.116921","url":null,"abstract":"<p><p>Oxidative stress-induced growth inhibitors (OSGINs) represent a new category of proteins that respond to oxidative stress and modulate redox balance. Growing evidence indicates that OSGINs have extensive physiological and pathological functions by regulating essential cellular processes, including proliferation, autophagy, apoptosis, and ferroptosis, thus influencing the progression of various diseases such as cancer, atherosclerosis, and pulmonary fibrosis. Moreover, research indicates that some contaminants, biomaterials, active compounds, and drugs can induce the expression of OSGINs, thereby exerting toxicity or therapeutic effects on the organism. These many functions make OSGINs attractive targets. However, a thorough analysis of the topic is still lacking. This paper presents a systematic review of current OSGINs research, with an emphasis on their molecular functions, regulatory mechanisms, disease roles, and environmental stressors. Furthermore, using virtual screening tools, we identified a series of active molecules with potential inhibitory effects on OSGINs, providing valuable references for further drug development. Our review presents novel insights and guidance for the ongoing investigation of the biological significance and potential clinical applications of OSGINs.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116921"},"PeriodicalIF":5.3,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810166","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}

引用次数: 0

Increased SUMO-activating enzyme subunit 1 promotes glycolysis and fibrotic phenotype of diabetic nephropathy

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-04-05 DOI: 10.1016/j.bcp.2025.116920

Reziwanguli Wusiman , Shayila Haimiti , Hanikezi Abuduaini , Miaoyan Yang , Yitian Wang , Meijun Gu , Ali Sailike , Lei Gao

{"title":"Increased SUMO-activating enzyme subunit 1 promotes glycolysis and fibrotic phenotype of diabetic nephropathy","authors":"Reziwanguli Wusiman , Shayila Haimiti , Hanikezi Abuduaini , Miaoyan Yang , Yitian Wang , Meijun Gu , Ali Sailike , Lei Gao","doi":"10.1016/j.bcp.2025.116920","DOIUrl":"10.1016/j.bcp.2025.116920","url":null,"abstract":"<div><div>Renal fibrosis is a prominent feature of diabetic nephropathy (DN), and the connection between renal fibrosis and abnormal glycolysis is not fully understood. SUMO-activating enzyme subunit 1 (SAE1) plays a crucial role in the SUMO modification process and is related to abnormal glycolysis. Despite this, the specific role of SAE1 in DN and its mechanism are not well defined. To investigate this, a streptozotocin-induced diabetic CD1 mice model was used, with SAE1 suppression achieved through systemic administration of SAE1 siRNA. In parallel, human renal proximal tubular tubule HK2 cells transfected with siSAE1 were exposed to high glucose for <em>in vitro</em> studies. The study revealed that SAE1 levels were elevated in diabetic kidney, and the deletion of SAE1 mitigated renal fibrosis in DN mice. Such suppression in SAE1 was associated with the lower expression of hypoxia inducible factor-1α (HIF-1α) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), these alterations subsequently improved abnormal glycolysis and mesenchymal transformations <em>in vivo</em> and <em>in vitro</em>. Further experiments discovered that SAE1 stabilized transcription factor HIF-1α expression through SUMOylation, promoting PFKFB3 transcription, which enhanced glycolysis characterized by increased PFK1 activity and lactate production. Additionally, pharmacological inhibition of PFKFB3 reduced renal fibrosis in DN mice, while overexpression of PFKFB3 partly restored the glycolysis and mesenchymal transformations inhibited by SAE1 knockdown <em>in vitro</em>. These data demonstrate that SAE1 promotes abnormal glycolysis by HIF-1α/PFKFB3 which is responsible for the fibrotic phenotype of diabetic kidney. Inhibition of SAE1 could be an alternative strategy in combating diabetes associated-kidney fibrosis via improving aberrant glycolysis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116920"},"PeriodicalIF":5.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143800489","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}

引用次数: 0

Relief of loperamide-induced constipation by peptidic and small molecule RXFP4 agonists in mice.

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-04-05 DOI: 10.1016/j.bcp.2025.116924

Shiyu Yan, Yan Chen, Jiang Wang, Qiuying Wang, Qingtong Zhou, Hong Liu, Ming-Wei Wang, Dehua Yang

{"title":"Relief of loperamide-induced constipation by peptidic and small molecule RXFP4 agonists in mice.","authors":"Shiyu Yan, Yan Chen, Jiang Wang, Qiuying Wang, Qingtong Zhou, Hong Liu, Ming-Wei Wang, Dehua Yang","doi":"10.1016/j.bcp.2025.116924","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.116924","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"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}

引用次数: 0

Blocking the LRH-1/LCN2 axis by ML-180, an LRH-1 inverse agonist, ameliorates osteoarthritis via inhibiting the MAPK pathway.

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-04-05 DOI: 10.1016/j.bcp.2025.116922

Jianwen Li, Yayun Zhang, Xin Gan, Junhong Li, Ganqing Xia, Lingxiao He, Chengyan Xia, Weikai Zhang, Khan Akhtar Ali, Meipeng Zhu, Hui Huang

{"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, Yayun Zhang, Xin Gan, Junhong Li, Ganqing Xia, Lingxiao He, Chengyan Xia, Weikai Zhang, Khan Akhtar Ali, Meipeng Zhu, Hui Huang","doi":"10.1016/j.bcp.2025.116922","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.116922","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"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}

引用次数: 0

Phosphocreatine alleviates monocrotaline-induced liver injury dependent on PSRC1-regulated endoplasmic reticulum stress

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-04-05 DOI: 10.1016/j.bcp.2025.116915

Sinuo Chen , Yifan Ma , Mingyan Ji , Heming Wang , Yun Chen , Dongping Li , Hongyue Jiang , Guangqi Song , Jinglin Xia , Hong Gao

{"title":"Phosphocreatine alleviates monocrotaline-induced liver injury dependent on PSRC1-regulated endoplasmic reticulum stress","authors":"Sinuo Chen , Yifan Ma , Mingyan Ji , Heming Wang , Yun Chen , Dongping Li , Hongyue Jiang , Guangqi Song , Jinglin Xia , 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}

引用次数: 0

Serum-derived extracellular vesicles mediate acquired multidrug resistance of MCF-7 breast cancer cells induced by chemotherapeutic drugs

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-04-05 DOI: 10.1016/j.bcp.2025.116923

Mi Zhou , Jiahuan Hong , Xiaofeng Qiu , Zixian Xiong , Xiaoyong Liu , Zhuan Qin , Zhesi Luo , Qi Chen , Mianjie Lin , Ling Min , Xiaorong Yang , Xinmin Guo , Bin Xu , Jianwen Mao

{"title":"Serum-derived extracellular vesicles mediate acquired multidrug resistance of MCF-7 breast cancer cells induced by chemotherapeutic drugs","authors":"Mi Zhou , Jiahuan Hong , Xiaofeng Qiu , Zixian Xiong , Xiaoyong Liu , Zhuan Qin , Zhesi Luo , Qi Chen , Mianjie Lin , Ling Min , Xiaorong Yang , Xinmin Guo , Bin Xu , 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}

引用次数: 0

A novel IgD-FcδR blocker, IgD-Fc-Ig fusion protein, effectively alleviates abnormal activation of T cells the disease progression in systemic lupus erythematosus.

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-04-05 DOI: 10.1016/j.bcp.2025.116930

Jingjing He, Danyan Liu, Li Jiang, Mengqin Chen, Xi Ling, Manling Dong, Tiantian Wu, Tingting Guo, Nuo Xu, Jing Zhang, Tao Li, Yueye Wang, Jiemin Zhao, Wei Wei, Shangxue Yan, Yujing Wu

{"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, Danyan Liu, Li Jiang, Mengqin Chen, Xi Ling, Manling Dong, Tiantian Wu, Tingting Guo, Nuo Xu, Jing Zhang, Tao Li, Yueye Wang, Jiemin Zhao, Wei Wei, Shangxue Yan, Yujing Wu","doi":"10.1016/j.bcp.2025.116930","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.116930","url":null,"abstract":"<p><p>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<sup>+</sup> 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, in vivo 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.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"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}

引用次数: 0

Scutellarein ameliorates pulmonary arterial hypertension via sirtuin 1 mediated deacetylation of nicotinamide nucleotide transhydrogenase

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-04-04 DOI: 10.1016/j.bcp.2025.116932

Heng Tang , Ke Ning , Boji Wu , Xuhong Wang , Jingyu He , Pingping Li , Lina Pan , Jiawen Zhang , Yi He , Shizhu Bian , Xingyu Ma , Jihang Zhang , Chuan Liu , Zhexue Qin , Houyuan Hu

{"title":"Scutellarein ameliorates pulmonary arterial hypertension via sirtuin 1 mediated deacetylation of nicotinamide nucleotide transhydrogenase","authors":"Heng Tang , Ke Ning , Boji Wu , Xuhong Wang , Jingyu He , Pingping Li , Lina Pan , Jiawen Zhang , Yi He , Shizhu Bian , Xingyu Ma , Jihang Zhang , Chuan Liu , Zhexue Qin , 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<sup>+</sup> axis to restore mitochondrial homeostasis: it upregulated SIRT1 expression and elevated NAD<sup>+</sup> levels by promoting SIRT1-mediated deacetylation of nicotinamide nucleotide transhydrogenase (NNT), thereby enhancing NNT activity. Elevated NAD<sup>+</sup> further activated SIRT1, forming a self-reinforcing SIRT1/NNT/NAD<sup>+</sup> 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<sup>+</sup> 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}

引用次数: 0

Insights into 2D and 3D cell culture models for nanoparticle-based drug delivery to glioblastoma

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-04-03 DOI: 10.1016/j.bcp.2025.116931

Girstautė Dabkevičiūtė , Vilma Petrikaitė

{"title":"Insights into 2D and 3D cell culture models for nanoparticle-based drug delivery to glioblastoma","authors":"Girstautė Dabkevičiūtė , 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}

引用次数: 0