Biochemical pharmacology最新文献

{"title":"β − sitosterol promotes the SUMOylation of DRP1 in alveolar macrophages and alleviates sepsis-associated acute lung injury","authors":"Bailun Wang ,&nbsp;Ziyi Zhou ,&nbsp;Chang Sun ,&nbsp;Angran Gu ,&nbsp;Jiahan Wang ,&nbsp;Hongqian Wang ,&nbsp;Dong Wang ,&nbsp;Yizheng Yang ,&nbsp;Xinyue Li ,&nbsp;Yuelan Wang ,&nbsp;Changping Gu","doi":"10.1016/j.bcp.2026.117800","DOIUrl":"10.1016/j.bcp.2026.117800","url":null,"abstract":"<div><div>Acute lung injury (ALI) represents the most frequent complication of sepsis; however, effective drug-based interventions are still unavailable. β-sitosterol (BS) has demonstrated anti-inflammatory effects and protective properties on alveolar epithelial barriers. This study investigated the mechanism by which BS targets alveolar macrophages to attenuate sepsis-associated acute lung injury (SALI) via <em>in vivo</em> and in vitro experiments. Sepsis was induced in mice through cecal ligation and puncture (CLP), and BS was administered orally. An in vitro model of lipopolysaccharide (LPS)-induced MH-S cell infection validated the proposed mechanism. Macrophage polarization and mitochondrial function were assessed using flow cytometry, electron microscopy, and Western blot analysis. Results showed that BS suppressed reactive oxygen species (ROS) production and M1 macrophage polarization in LPS-stimulated MH-S cells. Mechanistically, BS promoted lysosomal degradation of dynamin-related protein 1 (DRP1) via SUMO2/3-mediated SUMOylation, preserving mitochondrial integrity and function. Transfection of MH-S cells with DRP1 plasmid abolished the BS-mediated mitochondrial protection mechanism, reducing inhibition of oxidative stress and M1 polarization. In summary, BS inhibits M1 polarization of alveolar macrophages by promoting DRP1 SUMOylation, effectively alleviating SALI in mice. These findings support BS as a potential therapeutic agent for SALI, providing a theoretical basis for clinical application.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117800"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146193759","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":"Exploring the mechanism of nonylphenol-induced myocardial fibrosis based on TGF-β1/Smads signaling pathway","authors":"Weichu Liu,&nbsp;Fengwen Yang,&nbsp;Jie Yu","doi":"10.1016/j.bcp.2026.117798","DOIUrl":"10.1016/j.bcp.2026.117798","url":null,"abstract":"<div><div>Myocardial fibrosis (MF) is a central feature in the terminal stages of many cardiovascular diseases. Findings from a previous study that we conducted show that when exposed to perinatal nonylphenol (NP), adult male rats developed MF. However, the underlying pathogenic mechanisms that drive its development have not been well established. This study aims to determine whether exposure to NP during the pregnancy and lactation periods causes MF in adult male offspring rats, and also to investigate the role of the TGF-β1/Smads signaling pathway in NP-induced fibrosis in cardiac fibroblasts (CFs). On postnatal day 21 (PND21), we observed a dose-dependent increase in NP levels in both the hearts and serum of the offspring rats. In comparison to the blank group, the fiber structure in the NP group was notably disorganized, and there was an occurrence of collagen deposition. Furthermore, expression levels of Collagen I/III, α-SMA, TGF-β1, MMP2, and MMP9 also increased in a dose-dependent manner in the NP group and were positively correlated with the levels of NP in the heart. In comparison to the blank control group, the levels of myocardial enzyme indicators (CK, CK-MB, LDH, and α-HBDH) as well as the levels of hydroxyproline (HYP) in both the NP and model groups showed an increase at postnatal day 90 (PND90). Furthermore, there were significant variations in the homeostasis of the outer matrix and functions related to TGF-β and Smads genes. Expression levels of Collagen I/III, TGF-β1, Smad2/3/4, α-SMA, CTGF, and MMP1 were significantly upregulated, while expression levels of Smad7 and TIMP1 were significantly downregulated. In vitro, exposure to NP significantly inhibited the activity of CFs in a dose-dependent manner and promoted abnormal expression of fibrosis-related factors and proteins related to the TGF-β1/Smads signaling pathway. TGF-β receptor type I/II inhibitors (LY2109761) reversed increased levels of NP-induced HYP and partially inhibited the expression of the TGF-β1/Smads signaling pathway and its downstream factors. This study demonstrates that exposure to NP during the pregnancy and lactation periods activates the TGF-β1/Smads signaling pathway and its downstream factors, thereby initiating the development of MF in their offspring. Moreover, the TGF-β1/Smads signaling pathway was determined to be involved in NP-induced CFs fibrosis, highlighting TGF-β1 as a critical target of NP-induced MF.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117798"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146193766","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":"Ibogalogs induce antiseizure activity in rodents by a mechanism involving 5-HT2A/2C receptor activation with a major role of 5-HT2A receptors in the hippocampal CA3 subfield","authors":"Abdeslam Chagraoui ,&nbsp;Paulina Kazmierska-Grebowska ,&nbsp;Olivia Byache ,&nbsp;Alejandro Abraham ,&nbsp;Deborah Rudin ,&nbsp;Bartosz Caban ,&nbsp;Tomasz Kowalczyk ,&nbsp;Matthias E. Liechti ,&nbsp;Daniel Wacker ,&nbsp;Chloé Aman ,&nbsp;Philippe De Deurwaerdère ,&nbsp;Hugo R. Arias","doi":"10.1016/j.bcp.2026.117799","DOIUrl":"10.1016/j.bcp.2026.117799","url":null,"abstract":"<div><div>The antiseizure properties of ibogalogs, including ibogaminalog (DM506), ibogainalog (IBG), and nor-IBG, were assessed in rodents using the pentylenetetrazol (PTZ)-induced seizure test. The behavioral findings indicated that ibogalogs exhibited mild acute antiseizure effects in mice, with endpoint- and time window-dependent differences between the compounds. The antiseizure effect was suppressed by volinanserin and SB242084, consistent with the involvement of 5-HT_2A and 5-HT_2C receptors. The antiseizure activity after repeated administration (7 and 14 days) of subthreshold doses of nor-IBG (3 mg/kg) or DM506 (5 mg/kg) was higher than that after acute treatment, indicating augmented efficacy. Subthreshold doses of DM506 and nor-IBG restored the impact of PTZ on monoamine levels in hippocampal tissue following repeated administration, but not after a single dose. Additionally, the influence of ibogalogs was evaluated on epileptiform discharges induced by kainic acid (KA) in the CA3 region of the hippocampus. The results showed that nor-IBG and DM506 decreased epileptiform discharges in a concentration-dependent manner. Nor-IBG activity was inhibited by volinanserin, supporting a role for the 5-HT_2AR. Functional studies have shown that ibogalogs are more potent agonists at 5-HT_2A/2CRs than at 5-HT_1A/1BRs, supporting the role of 5-HT_2AR. In conclusion, repetitive treatment with ibogalogs induced antiseizure activity in mice through 5-HT_2A/2CR activation, accompanied by normalization of PTZ-induced alterations in hippocampal monoamines. In the hippocampal CA3 subfield, ibogalogs reduced KA-induced epileptiform discharges, where nor-IBG activity was mediated by 5-HT_2AR activation.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117799"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197404","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":"Loss of cystathionine-β-synthase contributes to elevated OXPHOS, a vulnerability in Ara-C-resistant Myeloid Leukemia in Down syndrome","authors":"Jenna Thibodeau ,&nbsp;Jianlei Zhao ,&nbsp;Holly Edwards ,&nbsp;Lisa Polin ,&nbsp;Juiwanna Kushner ,&nbsp;Sijana H Dzinic ,&nbsp;Kathryn White ,&nbsp;Kian Hershberger ,&nbsp;Yongwei Su ,&nbsp;Tasnim Arroum ,&nbsp;Lucynda Pham ,&nbsp;Lauren Pavelich ,&nbsp;Raina Awdish ,&nbsp;Jacob LaValley ,&nbsp;Austin C. Boucher ,&nbsp;Wei Chen ,&nbsp;Jing Li ,&nbsp;Xun Bao ,&nbsp;Maik Hüttemann ,&nbsp;Jessica B. Back ,&nbsp;Yubin Ge","doi":"10.1016/j.bcp.2026.117815","DOIUrl":"10.1016/j.bcp.2026.117815","url":null,"abstract":"<div><div>Myeloid leukemia associated with Down syndrome (ML-DS), as classified by WHO 2016, includes acute myeloid leukemia (AML) and myelodysplasia in children with DS. While ML-DS patients show high sensitivity to cytarabine (Ara-C)-based chemotherapy with better overall survival than non-DS AML patients, relapsed/refractory cases have dismal outcomes. This underscores the need to understand Ara-C-resistance mechanisms and develop effective therapies. The chromosome 21 gene, <em>cystathionine-β-synthase</em> (<em>CBS</em>), is significantly overexpressed in ML-DS cells. Overexpression of CBS leads to increased hydrogen sulfide (H₂S) production, which reduces complex IV activity and oxidative phosphorylation (OXPHOS). OXPHOS has been shown to play an important role in Ara-C resistance in non-DS AML. Thus, in this study, we investigated the role of CBS as a regulator of OXPHOS and Ara-C response. We found that Ara-C-resistant ML-DS cells have lower CBS activity. Overexpression of CBS in an Ara-C-resistant ML-DS cell line resulted in increased H₂S and Ara-C sensitivity and decreased both complex IV activity and OXPHOS. Knockdown of CBS in an Ara-C-sensitive ML-DS cell line increased OXPHOS and Ara-C resistance. However, complex IV activity decreased and H₂S production was unchanged, indicating that CBS regulates OXPHOS through both a H₂S-dependent and −independent mechanism. We further demonstrate that targeting both OXPHOS, using ONC213, and apoptosis, using venetoclax, results in synergistic induction of cell death in Ara-C-resistant ML-DS cells. This study identifies CBS as a regulator of OXPHOS and Ara-C response, while the combination of ONC213 and venetoclax offers a promising therapeutic approach for relapsed/refractory ML-DS, addressing key vulnerabilities to improve patient outcomes.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117815"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146199596","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":"CUL4A promotes glycolytic metabolism of fibroblast-like synoviocytes by targeting FGF2 in rheumatoid arthritis","authors":"Dantong Sun ,&nbsp;Jun Wang ,&nbsp;Xue Yang ,&nbsp;Han Shu ,&nbsp;Yongfeng Cheng ,&nbsp;Ying Chen ,&nbsp;Qingqing Xia ,&nbsp;Facai Wang ,&nbsp;Siwei Deng ,&nbsp;Jun Li ,&nbsp;Xiao-Feng Li ,&nbsp;Biao Song","doi":"10.1016/j.bcp.2026.117783","DOIUrl":"10.1016/j.bcp.2026.117783","url":null,"abstract":"<div><div>The central role in the pathogenesis of rheumatoid arthritis (RA) is played by fibroblast-like synoviocytes (FLS), which drive disease progression through aberrant proliferation, recruitment of inflammatory cells, and subsequent degradation of cartilage and bone. Cullin 4A (CUL4A) is an important member of the Cullin family, which is a scaffolding protein for the E3 ubiquitin ligase complex. In this study, we investigated the functional significance and molecular mechanisms of CUL4A in the pathogenesis of RA. We identified elevated CUL4A expression in synovial tissues, TNFα-stimulated FLS, and peripheral blood mononuclear cells from RA patients. Furthermore, <em>CUL4A</em> mRNA expression levels showed a positive correlation with both clinical disease activity and inflammatory markers in RA. Knockdown of CUL4A led to a marked suppression of both cytokine production and glycolytic metabolism in FLS <em>in vitro.</em> RNA sequencing analysis and validation revealed the PI3K/AKT pathway as a key mediator in this process, with a significant functional interaction between CUL4A and fibroblast growth factor 2 (FGF2). Furthermore, knocking down FGF2 significantly inhibited synovial inflammation in RA FLS. <em>In vivo</em> experiments, knocking down CUL4A significantly reduced synovial inflammation in K/BxN serum transfer-induced arthritis (STA) mice and inhibited glycolytic metabolism. In conclusion, our findings reveal that CUL4A, via FGF2 binding, initiates PI3K/AKT pathway signaling, fostering the glycolysis process and synovial inflammation. Consequently, CUL4A holds significant promise as a target for early intervention against this pathogenic cascade.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117783"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146171751","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":"Exendin-4 alleviates Aβ1-40-induced apoptosis and calcium dysregulation in RPE cells through the CHP1/NHE1 complex","authors":"Qinxin Shu ,&nbsp;Yuxin Lin ,&nbsp;Wenqi Su ,&nbsp;Hui Peng,&nbsp;Xing Wang","doi":"10.1016/j.bcp.2026.117789","DOIUrl":"10.1016/j.bcp.2026.117789","url":null,"abstract":"<div><div>Age-related macular degeneration (AMD) is a leading cause of visual impairment in elderly individuals and is influenced by various factors, such as age, genetics, and environmental conditions. While research into therapies for dry AMD is rapidly advancing, effective interventions are still lacking, underscoring the urgent need for new drug development. Recent studies have highlighted the multifaceted pharmacological activities of Exendin-4 (EX-4), including its anti-inflammatory, antioxidant, and antiapoptotic properties, along with its role in maintaining calcium homeostasis. The precise effects of EX-4 on AMD and its immediate target remain unclear. In this study, we investigated whether EX-4 could protect against Aβ1-40-induced AMD and explored the underlying mechanism. Our findings indicated that pretreatment with EX-4 alleviated apoptosis and restored calcium homeostasis both in vivo and in vitro. To identify the target of EX-4, we employed proteome microarrays and pulldown LC‒MS/MS analyses. Our results revealed that EX-4 bound to Calcineurin-like EF-hand protein 1(CHP1), reducing CHP1 protein expression in a concentration-dependent manner. This interaction led to a subsequent reduction in apoptosis and the normalization of intracellular Ca²⁺ levels through the CHP1/NHE1 complex. Furthermore, we demonstrated that the inhibitory effects of EX-4 on apoptosis and calcium signaling were reversed by knocking down or overexpressing CHP1 in vitro. Finally, in AMD mice with CHP1-deficient retinas, the beneficial effects of EX-4 on apoptosis and calcium signaling were partially attenuated. In summary, our results suggest that the interaction of EX-4 with CHP1 has therapeutic potential for AMD, likely through alleviating apoptosis and restoring calcium homeostasis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117789"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146171738","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":"Abrogation of PDE7A ameliorates alveolar epithelial EMT-Driven pulmonary fibrosis","authors":"Jianqiang Guo ,&nbsp;Jiawei Zhou ,&nbsp;Anqi Cheng ,&nbsp;Weinan Hu ,&nbsp;Tianxiang Qi ,&nbsp;Dahai Zhao ,&nbsp;Ying Bai ,&nbsp;Dong Hu ,&nbsp;Jing Wu","doi":"10.1016/j.bcp.2026.117785","DOIUrl":"10.1016/j.bcp.2026.117785","url":null,"abstract":"<div><div>Epithelial-mesenchymal transition (EMT) is a key driver of idiopathic pulmonary fibrosis (IPF), yet therapies specifically targeting epithelial cells remain limited. The role of phosphodiesterase 7A (PDE7A) in IPF and its mechanism in regulating EMT are still largely unknown. This study aims to investigate the anti-fibrotic effect of BRL-50481, focusing on its target PDE7A and the associated molecular mechanism in regulating epithelial cell fibrosis and EMT. BRL-50481 was identified as a top candidate compound targeting pathogenic alveolar epithelial cells through bioinformatic screening. Its efficacy was evaluated in both a bleomycin-induced murine pulmonary fibrosis model and a TGF-β-induced A549 cell model. Drug-target interaction was characterized using molecular docking, cellular thermal shift assay (CETSA), and site-directed mutagenesis. Downstream signaling pathways were predicted via the TRRUST database and experimentally validated. PDE7A was found to be highly expressed in alveolar epithelial cells of IPF patients and mice. BRL-50481 directly bound to the ILE323 residue of PDE7A, specifically inhibiting JAK2/STAT3 signaling pathway activation. This inhibition suppressed EMT, inflammatory factor release, and collagen deposition, ultimately alleviating pulmonary fibrosis in both in vivo and in vitro models. PDE7A acts as a key upstream regulator driving JAK2/STAT3 signaling activation and the EMT process in alveolar epithelial cells. BRL-50481 exerts anti-fibrotic effects by precisely targeting this mechanism, providing novel insights into IPF pathogenesis and establishing a theoretical foundation for developing innovative therapies targeting PDE7A.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117785"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146171740","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":"Kukoamine A attenuates allergic rhinitis via H1R antagonism: Dual suppression of inflammatory signaling and epithelial barrier disruption","authors":"Panpan Lei ,&nbsp;Xiaoyu Ma ,&nbsp;Yuxiu Zhang ,&nbsp;Sifan Xie ,&nbsp;Shiling Hu ,&nbsp;Yuanji Wang ,&nbsp;Weina Ma","doi":"10.1016/j.bcp.2026.117792","DOIUrl":"10.1016/j.bcp.2026.117792","url":null,"abstract":"<div><div>Allergic rhinitis (AR) has emerged as a significant global health burden with steadily rising prevalence. As the histamine 1 receptor (H₁R) plays a central role in allergic responses, it remains a key therapeutic target for AR. In this study, we used the AlphaFold 3 platform to predict the H₁R structure and performed high-throughput molecular docking, identifying kukoamine A (KuA) as a potential ligand targeting H₁R with unique structural features. Through comprehensive cell membrane chromatography (CMC) characterization and thermal/enzymatic stabilization assays, we established that KuA specifically binds to transmembrane domain (TM) 3 and TM6 of H₁R, inducing ligand-binding pocket expansion and consequent receptor inactivation. Furthermore, KuA significantly inhibits the activity of phospholipase C (PLC) and calcium influx, thereby blocking the NF-κB/ERK signaling pathway and reducing the secretion of inflammatory factors including TNF-α, IL-8 and MCP-1. Notably, KuA also preserved epithelial barrier integrity by stabilizing F-actin cytoskeleton and upregulating Claudin-1 expression. In both acute allergy and AR mouse models, KuA effectively alleviated inflammatory responses and restored nasal epithelial integrity. In conclusion, our findings demonstrate that KuA is a novel H₁R antagonist with dual anti-inflammatory and barrier-protective effects, positioning it as a highly promising therapeutic candidate for AR.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117792"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146171752","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":"Why things get important: GPCRs in salience processing","authors":"Nina K. Blum,&nbsp;Rainer K. Reinscheid","doi":"10.1016/j.bcp.2026.117768","DOIUrl":"10.1016/j.bcp.2026.117768","url":null,"abstract":"<div><div>Perception and processing of salient sensory input is vital for every animal. While sensory systems continuously receive a vast amount of information, animal brains are challenged to distinguish between relevant, i.e. salient, and neutral or unnecessary content. Stimulus salience can depend on intensity but also motivational and attentional states. Perception of salient information affects both immediate response behaviors and memory formation, which are both critical for survival. Conversely, aberrant salience processing may contribute to disorders such as schizophrenia or drug addiction. Research in recent decades has described several G protein-coupled receptor (GPCR) systems as important regulators of salience processing in the brain. They include receptors activated by monoamines, neuropeptides and lipid molecules. Although salience attribution is a critical brain function, a comprehensive survey of involved GPCRs and their endogenous transmitters has, to our knowledge, not been compiled. This review aims to close this gap by providing an overview of GPCRs involved in salience processing.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117768"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117568","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":"Obacunone mitigates cisplatin-induced ototoxicity by activating CRHBP-mediated autophagy","authors":"Shaoqin Cen ,&nbsp;Zhenxing Hou ,&nbsp;Yuan Zhang ,&nbsp;Nan Wang ,&nbsp;Zihe Zhao ,&nbsp;Ao Li ,&nbsp;Guoqiang Wan ,&nbsp;Tianhong Zhang ,&nbsp;Xia Gao","doi":"10.1016/j.bcp.2026.117759","DOIUrl":"10.1016/j.bcp.2026.117759","url":null,"abstract":"<div><div>Cisplatin, a widely used antitumor agent, is limited in clinical application due to its ototoxicity. This study investigates the protective effects of obacunone, an active compound from Phellodendron bark, against cisplatin-induced hearing loss. Obacunone significantly improved the survival of cisplatin-treated House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, preserved the cochlear explant, and enhanced auditory function in mice upon cisplatin treatment. Mechanistically, obacunone inhibited cisplatin-induced apoptosis by activating autophagy. Transcriptome profiling revealed that the expression of corticotropin-releasing hormone-binding protein (CRHBP) was increased in the cisplatin and obacunone co-treated group compared to the cisplatin-only group. Overexpression of CRHBP significantly enhanced autophagy and inhibited apoptosis, mirroring the effects of obacunone. Our findings demonstrate that obacunone promotes autophagy by upregulating CRHBP, thereby reducing cisplatin-induced hair cell apoptosis. This study provides a novel therapeutic strategy using the natural product obacunone for preventing cisplatin-induced hearing loss and highlights the potential of CRHBP as a target for otoprotective interventions.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117759"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146083922","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}