Wei Shi, Min Hu, Jiale Han, Lei Wang, Yining Jiang, Hongmei Wu, Wei Liu, Biao Xiong, Yunyun Wang
{"title":"Design, synthesis, and evaluation of novel pinane-based thiazolidione derivatives with anti-glioblastoma activity.","authors":"Wei Shi, Min Hu, Jiale Han, Lei Wang, Yining Jiang, Hongmei Wu, Wei Liu, Biao Xiong, Yunyun Wang","doi":"10.1080/14756366.2025.2553691","DOIUrl":"10.1080/14756366.2025.2553691","url":null,"abstract":"<p><p>A series of pinane-based thiazolidione derivatives were synthesised, and their anti-proliferative effects were investigated by CCK-8 assay. All these compounds exhibited anti-proliferation activity against three glioblastoma cell lines (U87, T98G, and U251). Compound <b>C5</b> exhibited the strongest inhibition effect against all three cell lines. Through cellular thermal shift (CETSA) assay and drug affinity responsive target stability (DARTS) assay, compound <b>C5</b> was demonstrated to directly interact with the CDK2 protein. Additional analyses revealed that <b>C5</b> inhibited cell migration and arrested the cell cycle in glioblastoma cells while also induced mitochondrial apoptosis and autophagy. Immunoblotting analysis indicated that <b>C5</b> induced the up-regulation of Bax, cleaved caspase 3, cleaved PARP-1, P62, and LC3B, and the down-regulation of Bcl-2, caspase 3, and PARP-1. Importantly, <b>C5</b> also demonstrated efficacy in a 3D cell culture model. Together, these results highlight the potential of <b>C5</b> as a lead compound for the development of novel therapies for glioblastoma.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2553691"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12412324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992731","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}
Enrique Madruga, Cecilia Sanchez-Santos, Ignacio Valenzuela-Martínez, David Ramírez, Carmen Gil, Ana Martínez
{"title":"Discovery of a brain penetrant SGK1 inhibitor using a ligand- and structure-based virtual screening methodology.","authors":"Enrique Madruga, Cecilia Sanchez-Santos, Ignacio Valenzuela-Martínez, David Ramírez, Carmen Gil, Ana Martínez","doi":"10.1080/14756366.2025.2546591","DOIUrl":"10.1080/14756366.2025.2546591","url":null,"abstract":"<p><p>Serum and glucocorticoid-regulated kinase 1 (SGK1) is an underexplored kinase involved in several neurodegenerative diseases. Although SGK1 inhibitors are not available on the market, the absence of side effects in two SGK1 knockout mouse models supports the development of brain-penetrant SGK1 inhibitors to explore their therapeutic potential. Through a combined ligand- and target-based virtual screening using the ECBL, we identified a small heterocyclic molecule with SGK1 inhibitory activity (IC<sub>50</sub> = 0.66 ± 0.25 μM). Molecular dynamics simulations revealed two potential binding modes for the candidate compound, offering valuable insights for the further optimisation of this hit. The compound was predicted to be brain-permeable by both <i>in silico</i> methods and experimental assays. It also demonstrated a neuroprotective profile in a cellular model of Alzheimer's disease (AD) and showed a favourable cardiovascular safety profile. Finally, systems pharmacology analysis identified the FOXO1/FOXO3/CREB1 axis as the principal signalling pathway regulated by SGK1 in the context of AD.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2546591"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956608","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}
Peng Guo, Chenchun Wu, Tong Wang, Yajuan Song, Xiaozi Liu, Xiang Wang, Yuhan Zhu, Binyu Song, Yifu Zhu, Juan Zhang, Lei Guo, Rui Tao, Zhou Yu, Baoqiang Song
{"title":"The key enzyme PYCR1 in proline metabolism: a dual driver of cancer progression and fibrotic remodeling.","authors":"Peng Guo, Chenchun Wu, Tong Wang, Yajuan Song, Xiaozi Liu, Xiang Wang, Yuhan Zhu, Binyu Song, Yifu Zhu, Juan Zhang, Lei Guo, Rui Tao, Zhou Yu, Baoqiang Song","doi":"10.1080/14756366.2025.2545620","DOIUrl":"10.1080/14756366.2025.2545620","url":null,"abstract":"<p><p>Pyrroline-5-Carboxylate Reductase 1 (PYCR1), a member of the PYCR family, is a key enzyme in the proline biosynthesis pathway. Notably, PYCR1 was originally identified via genetic disease research, linking its mutations to the occurrence of cutis laxa. PYCR1 contributes to the pathogenesis of malignancies and fibrotic diseases via mechanisms involving metabolic reprogramming, Extracellular Matrix (ECM) remodelling, and redox homeostasis maintenance. PYCR1 upregulation has been reported in multiple malignancies including Hepatocellular Carcinoma (HCC), Lung Cancer (LC), Breast Cancer (BC), Bladder Cancer (BlC), and Gastric Cancer (GC), where it has been shown to promote cancer proliferation, migration, and therapy resistance, correlating significantly with advanced cancer stages and poor prognosis. On the other hand, in fibrotic disorders, PYCR1-mediated proline metabolism has been linked to the progression of pulmonary, myocardial, and cutaneous fibroses. Notably, although PYCR1-targeted small-molecule inhibitors have demonstrated therapeutic potential in preclinical studies, their clinical translation is yet to be validated.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2545620"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956654","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":"Discovery and characterization of novel hematopoietic prostaglandin D synthase inhibitors from traditional Chinese medicine: the bioactive potential of dihydroberberine in treatments of Duchenne muscular dystrophy and inflammation-related diseases.","authors":"Cheng-Han Li, Min-Che Tung, Cheng-Kuan Tsai, Tz-Chuen Ju, Tien-Sheng Tseng","doi":"10.1080/14756366.2025.2555624","DOIUrl":"10.1080/14756366.2025.2555624","url":null,"abstract":"<p><p>Inflammation plays a central role in various diseases, necessitating effective anti-inflammatory agents. Prostaglandin D2 (PGD2), a key mediator synthesised by haematopoietic prostaglandin D synthase (H-PGDS), is linked to allergic and inflammatory conditions. This study employed pharmacophore-based screening to identify inhibitors targeting H-PGDS. The model <b>Phar-A2HR2</b> identified <b>EMy</b> (IC50 = 88.9 ± 1.1 µM) as a potential inhibitor. Further analysis revealed that its analog <b>EMy-5</b> (dihydroberberine) demonstrated the most potent inhibitory activity (IC<sub>50</sub> = 3.7 ± 1.1 µM) and binding affinity (KD = 3.2 ± 0.74 µM). Molecular dynamics simulations revealed stabilising interactions, including π-π stacking, hydrogen bonding, and hydrophobic contacts, in the H-PGDS-<b>EMy-5</b> complex. Functional assays confirmed that <b>EMy-5</b> significantly reduced PGD2 production in KU812 cells. These findings highlight <b>EMy-5</b> as a promising candidate for the treatment of inflammatory and allergic diseases, including Duchenne muscular dystrophy, demonstrating both potent inhibitory activity and strong binding characteristics.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2555624"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12444937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075434","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":"Farnesiferol C enhances the effects of chemotherapy and ionising radiation in human melanoma cells via targeting topoisomerase II alpha.","authors":"Negin Moosavinejad, Zahra Nasiri Sarvi, Hamid Gholamhosseinian, Mehrdad Iranshahi, Fatemeh B Rassouli","doi":"10.1080/14756366.2025.2565463","DOIUrl":"10.1080/14756366.2025.2565463","url":null,"abstract":"<p><p>This study evaluated Farnesiferol C (FC), a natural coumarin, as a potential topoisomerase IIα (TOP2A) inhibitor to enhance chemotherapy and ionising radiation (IR) efficacy in melanoma cells. Key targets were identified, followed by enrichment and gene expression analyses, and molecular docking and dynamics simulations. Upon extraction of FC from <i>Ferula szowitsiana</i>, cell treatment with FC, alone or combined with IR or temozolomide (TMZ), was performed, and viability and apoptosis were assessed. TOP2A emerged as a hub target, showing elevated expression in melanoma and a negative correlation with patient survival. Simulations demonstrated stable binding of FC at the ATP-binding site of TOP2A. Experimental data revealed selective cytotoxicity of FC on A375 melanoma cells (IC<sub>50</sub>: 76.9 µM, SI: 4.97), sparing normal fibroblasts. Combination treatments with IR or TMZ further increased cytotoxicity and apoptosis. These findings suggest FC as a promising TOP2A inhibitor that potentiates the DNA damage effects of chemoradiotherapy in melanoma.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2565463"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199583","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}
Alessia Caputo, Gian Marco Elisi, Elisabetta Levati, Giulia Barotti, Sara Sartini, Jerome Wagner, Dominique Y Burnouf, Simone Ottonello, Silvia Rivara, Barbara Montanini
{"title":"Small molecules targeting the eubacterial β-sliding clamp discovered by combined <i>in silico</i> and <i>in vitro</i> screening approaches.","authors":"Alessia Caputo, Gian Marco Elisi, Elisabetta Levati, Giulia Barotti, Sara Sartini, Jerome Wagner, Dominique Y Burnouf, Simone Ottonello, Silvia Rivara, Barbara Montanini","doi":"10.1080/14756366.2024.2440861","DOIUrl":"https://doi.org/10.1080/14756366.2024.2440861","url":null,"abstract":"<p><p>Antibiotic resistance stands as the foremost post-pandemic threat to public health. The urgent need for new, effective antibacterial treatments is evident. Protein-protein interactions (PPIs), owing to their pivotal role in microbial physiology, emerge as novel and attractive targets. Particularly promising is the α-subunit/β-sliding clamp interaction, crucial for the replicative competence of bacterial DNA polymerase III holoenzyme. Through pharmacophore-based virtual screening, we identified 4,000 candidate small molecule inhibitors targeting the β-clamp binding pocket. Subsequently, these candidates underwent evaluation using the BRET assay in yeast cells. Following this, three hits and 28 analogues were validated via Protein Thermal Shift and competitive ELISA assays. Among them, thiazolo[4,5-<i>d</i>]-pyrimidinedione and benzanilide derivatives exhibited micromolar potency in displacing the β-clamp protein partner and inhibiting DNA replication. This screening campaign unveiled new chemical classes of α/β-clamp PPI disruptors capable of inhibiting DNA polymerase III activity, which lend themselves for further optimisation to improve their antibacterial efficacy.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2440861"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921611","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":"Profiling and cheminformatics bioprospection of curcurbitacin I and momordin Ic from <i>Momordica balsamina</i> on α-amylase and α-glucosidase.","authors":"Viruska Jaichand, Adedayo Ayodeji Lanrewaju, Himansu Baijnath, Saheed Sabiu, Viresh Mohanlall","doi":"10.1080/14756366.2025.2492706","DOIUrl":"https://doi.org/10.1080/14756366.2025.2492706","url":null,"abstract":"<p><p><i>Momordica</i> spp. has been traditionally used to manage type 2 diabetes mellitus, but the mechanisms and metabolites remain unclear. This study evaluated the inhibitory potential of Momordica <i>balsamina</i> extracts on α-amylase and α-glucosidase <i>in vitro</i>, identifying cucurbitacin I and momordin Ic via high-performance liquid chromatography-photo diode array, and their inhibitory potential <i>in silico</i>. Ethyl acetate seed extract (14.46 µg/ml) and hexane fruit flesh extract (16.79 µg/ml) exhibited lower IC<sub>50</sub> values against α-amylase and α-glucosidase, respectively, compared to acarbose (reference standard). Comparatively, momordin Ic concentrations (36.57-605.98 µg/ml) were higher than cucurbitacin I (17.08-44.34 µg/ml). A 140 ns simulation showed that cucurbitacin I (-63.06 kcal/mol) and momordin Ic (-66.53 kcal/mol) exhibited stronger binding to α-amylase than acarbose (-36.46 kcal/mol), whereas cucurbitacin I (-38.08 kcal/mol) and momordin Ic (-54.87 kcal/mol) displayed weaker binding to α-glucosidase, relative to acarbose (-63.73 kcal/mol). Generally, momordin Ic demonstrated better thermodynamic properties, hence further <i>in vitro</i> and <i>in vivo</i> studies are needed to validate their antidiabetic potential.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2492706"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022271","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":"Activity guided discovery of dual inhibitors of α-glucosidase and β-glucuronidase from the leaves of <i>Millettia pachycarpa</i> Benth.","authors":"Yanxi He, Huanran Xu, Shaoqian Tan, Jing Long, Hui Lei, Ling Xiao, Xiaoyi Qi, Mingming Deng, Xia Xiong, Jingcan You, Liangliang Zhu, Muhan Lü, Sicheng Liang","doi":"10.1080/14756366.2025.2501041","DOIUrl":"10.1080/14756366.2025.2501041","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) and cancers are two globally prevalent diseases which can increase the incidence of each other. Intestinal α-glucosidase and β-glucuronidase are key targets for glycaemic control and chemotherapy detoxification, respectively. This study first found that the leaf methanol extract of <i>Millettia pachycarpa</i> displayed dual inhibition to the two enzymes. The dually active constituents were then isolated and identified as two prenylated isoflavones of 6,8-diprenylorobol and 6,8-diprenylgenistein. Diprenylorobol exhibits competitive inhibition to both the two enzymes with <i>K<sub>i</sub></i> values of 21.6 μM (α-glucosidase) and 1.41 μM (β-glucuronidase). Diprenylgenistein is an uncompetitive inhibitor of α-glucosidase (<i>K<sub>i</sub></i> = 11.4 μM) but a competitive inhibitor of β-glucuronidase (<i>K<sub>i</sub></i> = 1.69 μM). Molecular docking studies showed that both the two isoflavones tightly bind into the active pockets via various hydrogen bonds and hydrophobic interactions. In summary, the current study identifies two promising dual inhibitors of α-glucosidase and β-glucuronidase from the leaves of <i>Millettia pachycarpa</i>.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2501041"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12082738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078334","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}
José L Pereira Filho, Renato B Pereira, Tatiana F Vieira, Sérgio F Sousa, José R A Coelho, Nuno F S Pinto, Catarina M M Coelho, Maria José G Fernandes, Elisabete M S Castanheira, Maria S T Gonçalves, David M Pereira
{"title":"Development of eugenol derivatives with 5-LOX inhibitory activity.","authors":"José L Pereira Filho, Renato B Pereira, Tatiana F Vieira, Sérgio F Sousa, José R A Coelho, Nuno F S Pinto, Catarina M M Coelho, Maria José G Fernandes, Elisabete M S Castanheira, Maria S T Gonçalves, David M Pereira","doi":"10.1080/14756366.2025.2535586","DOIUrl":"https://doi.org/10.1080/14756366.2025.2535586","url":null,"abstract":"<p><p>Eugenol (4-allyl-2-methoxyphenol), is the major chemical constituent in the essential oil of numerous plant species. Several biological properties have been described for this molecule, including modulation of enzymatic targets relevant for the inflammatory response, such as 5-lipoxygenase (5-LOX). As so, there is interest in expanding the chemical space of this molecule to develop new molecules to be used in inflammatory conditions. We describe the chemometric analysis of several eugenol derivatives, which show that the chemical space of the parent molecule was successfully expanded. All molecules were evaluated for their inhibition towards 5-LOX, an important player in inflammatory pathways. Four derivatives exhibited significant 5-LOX inhibitory activity, which prompted further studies. The most promising compounds, 4-allylbenzene-1,2-diol <b>2</b>, ethyl-4-(4-allyl-2-methoxyphenoxy)butanoate <b>4e</b>, 3-(2-methoxy-4-(oxiran-2-ylmethyl)phenoxy)propyl acetate <b>5d</b> and 4-(3-(<i>tert</i>-butoxy)-2-hydroxypropyl)-2-methoxyphenol <b>7c</b>, were submitted to <i>in silico</i> assays to validate their affinity and stability towards 5-LOX, which helped clarify the mechanism by which these molecules interact and inhibit this enzyme.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2535586"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12377105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956587","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":"Inhibition of 12/15-LOX hyperactivation mitigates cognitive decline in a chronic cerebral hypoperfusion mouse model and in H<sub>2</sub>O<sub>2</sub>-induced HT22 cells: therapeutic effects of brozopine.","authors":"Xuening Wang, Zhizai Lu, Qiuji Shao, Yi Wang, Zixin Zhang, Zhiyu Wang, Qingran Jia, Jinpeng Zhu, Yiran Song, Lingxu Yuan, Yiming Wang, Shaoyang Xu, Lirou He, Junbiao Chang, Yuan Gao","doi":"10.1080/14756366.2025.2547259","DOIUrl":"https://doi.org/10.1080/14756366.2025.2547259","url":null,"abstract":"<p><p>Brozopine (BZP), a novel inhibitor of 12/15-lipoxygenase (12/15-LOX), has previously demonstrated efficacy in mitigating inflammatory and oxidative stress-related injury in cerebral ischaemia models. This study aimed to evaluate the therapeutic potential and underlying mechanisms of BZP in a mouse model of vascular dementia induced by chronic cerebral hypoperfusion. BZP was administered for 28 days following right unilateral common carotid artery occlusion (rUCCAO) in mice. BZP significantly alleviated cognitive impairment, behavioural deficits, and fine motor function. Mechanistically, BZP inhibited 12/15-LOX, cPLA<sub>2</sub>, p-p38 MAPK/p38 MAPK ratio, tumour necrosis factor-α, interlukin-1β, Aβ<sub>1-42</sub> deposition, and Tau hyperphosphorylation in the brain and serum of rUCCAO mice. Similar protective effects were observed in both 12/15-LOX-overexpressed and H<sub>2</sub>O<sub>2</sub>-induced HT22 cell models. These findings suggest that BZP exerts its neuroprotective effects by targeting the 12/15-LOX/cPLA<sub>2</sub>/p38 MAPK pathway, offering a promising therapeutic strategy for mitigating the progression of cognitive impairment.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2547259"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12372482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956637","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}