British Journal of Pharmacology最新文献

{"title":"Fibrin induces infiltration of macrophages and neutrophils via integrin αMβ2 and triggers aortic dissection.","authors":"Jie Li, Jixiu Zhang, Lingwei Zou, Meifang Cao, Zhonghui Zhu, Li Yu, Min Zhou, Weiguo Fu, Zhihui Dong, Huiyuan Gao, Baohong Jiang","doi":"10.1111/bph.70033","DOIUrl":"https://doi.org/10.1111/bph.70033","url":null,"abstract":"<p><strong>Background and purpose: </strong>Infiltration of macrophages and neutrophils plays a crucial role in the occurrence of aortic dissection (AD), while the mechanism elucidating their infiltration remains unknown. The present study aimed to delineate the underlying mechanism and provide a potential therapeutic strategy to attenuate AD progression.</p><p><strong>Experimental approach: </strong>A model of AD was established in male mice using β-aminopropionitrile and angiotensin II. Proteomic analysis, histological evaluation, flow cytometry, western blot, multiple fluorescence staining and adhesion assays were used to evaluate fibrin and inflammatory cells during AD progression. Fibrinogen-lowering drugs and fibrinogen γ-chain knockout (Fgg^+/-) mice were also used to evaluate the fibrin-integrin αMβ2 interaction.</p><p><strong>Key results: </strong>Fibrin deposition was confirmed by proteomic analysis and histological staining, accompanied by infiltration of macrophages and neutrophils detected by flow cytometry during the progression of AD. After confirming that macrophages and neutrophils infiltrated at the sites where fibrin was deposited by immunofluorescence, an association between fibrin and the integrin αMβ2 was disclosed using protein-protein interaction analysis and immunofluorescence. The pivotal role of interactions between fibrin and integrin αMβ2 in AD progression was confirmed by cell adhesion in vitro, down-regulation of fibrin using batroxobin and Fgg^+/- mice in vivo. The relevance of fibrin and integrin αMβ2 was also found in patients with AD.</p><p><strong>Conclusion and implications: </strong>Fibrin plays a crucial role in triggering AD through recruiting macrophages and neutrophils via integrin αMβ2. Regulation of fibrin deposition or inhibition of the interaction between fibrin and integrin αMβ2 provide a potential therapy against AD.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802567","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":"Inhibition of DNA polymerase eta-mediated translesion DNA synthesis with small molecule sensitises ovarian cancer stem-like cells to chemotherapy.","authors":"Subhankar Bose, Priyanka Saha, Md Tanjim Alam, Bilash Chatterjee, Mrinmoy Sarkar, Amit Kumar Dixit, Deepak Kumar, Rakesh Kumar Pathak, Prem Prakash Tripathi, Amit Kumar Srivastava","doi":"10.1111/bph.70037","DOIUrl":"https://doi.org/10.1111/bph.70037","url":null,"abstract":"<p><strong>Background and purpose: </strong>Chemoresistance and tumour relapse pose significant challenges in achieving successful chemotherapy outcomes. Targeting DNA polymerase eta (Pol ƞ)-mediated mutagenic translesion DNA synthesis (TLS) has emerged as a promising strategy for improving chemotherapy. However, the identification of small molecule inhibitors targeting Pol ƞ -mediated TLS with high in vivo efficacy remains a challenge.</p><p><strong>Experimental approach: </strong>The small molecule was identified through in silico screening. Pol η inhibitory potential of the identified small molecule was validated by a fluorescent-based reporter strand displacement assay. Flow cytometry was conducted to analyse the CD44 + CD117 + cancer stem-like cell (CSC) population and live-dead cell population. Xenograft mouse models were used to test the CSC sensitising potential.</p><p><strong>Key results: </strong>We screened and identified chrysin as a small-molecule inhibitor that sensitises ovarian cancer stem-like cells to cisplatin treatment by inhibiting Pol ƞ -mediated TLS. Chrysin effectively inhibits Pol ƞ expression, mitigates cancer stem-like cell enrichment and enhances cisplatin-induced cell death both in vitro and in vivo. Furthermore, chrysin treatment reduces spontaneous and cisplatin-induced mutagenesis. Pre-treatment with chrysin attenuates cisplatin-induced haematological toxicity and suppresses tumour growth in human ovarian cancer xenografts.</p><p><strong>Conclusions and implications: </strong>These results establish chrysin as a novel class of TLS inhibitors and highlight its potential as a chemotherapy adjuvant for overcoming chemoresistance and improving treatment outcomes in ovarian cancer.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802569","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":"Activation of autophagy mediated by PI3K/Akt/mTOR signalling cascade alleviates impaired adipose-derived stem cell osteogenesis in a diabetic microenvironment.","authors":"Fangzhi Lou, Ting Fu, Qilin Li, Pengcheng Rao, Shuanglin Peng, Shi Lu, Tianli Wu, Qing Li, Jingang Xiao","doi":"10.1111/bph.70016","DOIUrl":"https://doi.org/10.1111/bph.70016","url":null,"abstract":"<p><strong>Background and purpose: </strong>Advanced glycation end products (AGEs) contribute to the onset and advancement of diabetic osteoporosis (DOP). Adipose-derived stem cells (ASCs) have garnered attention in the field of bone renewal; the mechanisms leading to decreased osteogenesis within a diabetic environment are not fully understood. This study explores the effects/molecular pathways of AGEs on the osteogenesis of ASCs both in vitro and in vivo.</p><p><strong>Experimental approach: </strong>A DOP mouse model was used, and ASCs were extracted from the inguinal fat of C57BL/6 mice. ASCs were cultivated in an osteogenic differentiation medium and were exposed to AGEs, Torin1 (an autophagy activator), or ibandronate (IBAN), a PI3K/Akt/mTOR signalling inhibitor. Osteogenesis and autophagy activity were measured.</p><p><strong>Key results: </strong>The expression of osteogenic markers, OPN and RUNX2, was decreased, ALP activities were impaired, and the formation of mineralised nodules was reduced in ASCs treated with AGEs. Additionally, the autophagic flux was blocked, and there was an increase in PI3K/Akt/mTOR signalling markers. After treatment with Torin1, the osteogenesis of ASCs in a diabetic microenvironment was restored by activating autophagy. Moreover, in the AGEs and DOP model, treatment with IBAN up-regulated autophagy and rescued the impaired osteogenesis of ASCs in diabetic microenvironment.</p><p><strong>Conclusion and implications: </strong>AGEs decreased the osteogenesis of ASCs by activating PI3K/Akt/mTOR signalling cascade and blocking autophagic flux. Autophagy induced by blocking the PI3K/Akt/mTOR signalling cascade could rescue the negative influences of ASCs in diabetic environment and provide a potential therapeutic strategy for bone renewal in individuals with DOP.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763029","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":"Annexin A1/FPR2 pathway modulates leukocyte function during Escherichia coli-induced pneumonia to promote resolution of inflammation and restores lung function.","authors":"Edvaldo S Lara, Antônio Felipe S Carvalho, Camila Cardoso, Isabella Zaidan, Laís C Grossi, Fernanda S Carneiro, Erick Bryan S Lima, Adelson Heric A Monteiro, Rodrigo S Caixeta, Isabella L Augusto, Ana Clara M Montuori-Andrade, Lívia Cristina R Teixeira, Celso M Queiroz-Junior, Remo C Russo, Mauro Perretti, Vivian V Costa, Mauro M Teixeira, Luciana P Tavares, Lirlândia P Sousa","doi":"10.1111/bph.70026","DOIUrl":"https://doi.org/10.1111/bph.70026","url":null,"abstract":"<p><strong>Background and purpose: </strong>Gram-negative bacteria are the main causes of pneumonia in the nosocomial environment. Inflammation triggered during pneumonia is necessary for bacterial clearance but must be spatially and temporally regulated to prevent further tissue damage and bacterial dissemination. Emerging data shows that annexin A1 (ANXA1) signalling through its receptor FPR2 promotes host resistance and resilience in preclinical models of infectious disease.</p><p><strong>Experimental approach: </strong>Using a mouse model of Escherichia coli-induced pneumonia, the role of ANXA1/FPR2 on key steps of inflammation resolution was evaluated.</p><p><strong>Key results: </strong>Anxa1 and Fpr2/3 knockout mice, intranasally infected with E. coli, exhibited exacerbated neutrophilic inflammation, higher bacterial dissemination, decreased neutrophil apoptosis/efferocytosis counts in the airways and higher levels of inflammatory cytokines/chemokines coupled to marked lung damage and dysfunction, as compared to WT mice. Treatment of WT-infected mice with the ANXA1 peptidomimetic, annexin I-(2-26), decreased inflammation, increased apoptosis/efferocytosis of neutrophils and improved bacterial clearance in the airways and lungs, resulting in an improvement of lung function. The pan-caspase inhibitor Z-VAD-FMK prevented annexin I-(2-26)-induced resolution of the neutrophilic inflammation, underlining neutrophil apoptosis as the main mechanism for annexin I-(2-26) promotion of resolution of E. coli pneumonia. In addition, annexin I-(2-26) treatment increased the numbers of airway macrophages of infected mice and promoted macrophage phagocytosis of E. coli in vitro.</p><p><strong>Conclusions and implications: </strong>In summary, these findings highlight the role for ANXA1/FPR2 pathway as a nonredundant resolution mechanism for E. coli-induced pneumonia and demonstrate that annexin I-(2-26) as a potential host-directed therapeutic approach to treat infectious lung diseases.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763031","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":"Photochemical control of cold-sensitive TRPA1 ion channel gating for modulation of pain sensation.","authors":"Junli Peng, Nan Yang, Zhen Qiao, Ningning Wei, KeWei Wang, Yanru Zhang","doi":"10.1111/bph.70038","DOIUrl":"https://doi.org/10.1111/bph.70038","url":null,"abstract":"<p><strong>Background and purpose: </strong>As a polymodal biosensor, the TRPA1 ion channel undergoes rapid opening and closing, a dynamic process known as gating that defines the fundamental function and modulation of ion channels. TRPA1 gating is primarily regulated by chemical and mechanical stimuli. However, whether and how TRPA1 gating transduces the biological function of pain sensation is poorly understood.</p><p><strong>Experimental approach: </strong>A series of photoswitchable TRPA1 probes (PSTRAPs1-4) were designed and synthesized. Whole-cell patch clamp recordings of hTRPA1 channels expressed in CHO cells were performed to test whether PSTRAPs could optically switch TRPA1 channel function. Site-directed mutagenesis was conducted to identify the binding site of PSTRAPs on the extracellular surface of TRPA1. In a mouse model of cheek pain, intracutaneous injection of PSTRAPs elicited pain sensation in response to photoswitching.</p><p><strong>Key results: </strong>PSTRAP-2 and PSTRAP-4 reversibly modulate TRPA1 channel function with spatiotemporal resolution. These azobenzene photoswitches can activate and deactivate TRPA1 currents expressed in CHO cells upon switching between blue light and darkness. Structural-activity relationship (SAR) analysis of PSTRAPs1-4 combined with site-directed mutagenesis revealed a residue Y926 between the pore helix 1 and 2 critical for the interaction between the PSTRAPs and TRPA1. In a mouse cheek pain model, photochemical gating of TRPA1 by intracutaneous injections of photoswitchable PSTRAP-2 and PSTRAP-4 induced pain perception in response to photoswitching cycles.</p><p><strong>Conclusion and implications: </strong>Our identification of these photoswitches not only provides small molecule tools for probing and understanding TRPA1 channel gating but also holds developmental potential for pain modulation.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763033","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":"Rhynchophylline as an agonist of sirtuin 3 ameliorates endothelial dysfunction via antagonizing mitochondrial damage of endothelial progenitor cells.","authors":"Lin Lin, Bowen Sun, Yuanlong Hu, Wenqing Yang, Jie Li, Danyang Wang, Lei Zhang, Mengkai Lu, Yuan Li, Yunlun Li, Dan Zhang, Chao Li","doi":"10.1111/bph.70032","DOIUrl":"https://doi.org/10.1111/bph.70032","url":null,"abstract":"<p><strong>Background and purpose: </strong>Mitochondrial dysregulation of endothelial progenitor cells (EPCs) has been implicated in endothelial destruction and hypertension. Regulation of silent information regulator 3 (sirtuin 3; SIRT3) in mitochondrial damage of EPCs and the underlying molecular mechanisms remain unclear, and evidence of selective SIRT3 agonists for the treatment of hypertension also is lacking.</p><p><strong>Experimental approach: </strong>Here, we discovered a potent SIRT3 agonist, rhynchophylline (Rhy), and explored its underlying action on mitochondrial damage of EPCs and endothelial dysfunction.</p><p><strong>Key results: </strong>In spontaneously hypertensive rats, Rhy reduced blood pressure and ameliorated vasomotion, paralleling improved EPC function in the peripheral circulation. Moreover, Rhy alleviated mitochondrial damage and inhibited apoptosis via the mitochondrial apoptotic pathway. SIRT3 knockdown interrupted the regulation of mitochondrial homeostasis induced by Rhy, thus abolishing its antagonizing effect on EPC dysfunction and endothelial damage, suggesting that Rhy protection of EPC mitochondria is mediated via the activation of SIRT3. Rhy restrained the production of mitochondrial ROS and improved the activity of superoxide dismutase 2 (SOD2) in a SIRT3-dependent manner, whereas silencing SOD2 eliminated the inhibition by Rhy of oxidative stress and apoptosis, reflecting that SOD2 was indispensable for the regulation of Rhy on mitochondrial dysfunction and the mitochondrial-mediated apoptosis pathway.</p><p><strong>Conclusion and implications: </strong>SIRT3-dependent mitochondrial homeostasis contributes to attenuating hypertension-related EPC dysfunction and endothelial injury, and Rhy itself is a potent and targeted SIRT3 agonist that prevented mitochondrial dysfunction by regulating the SIRT3/SOD2 pathway, which may provide new clues for drug candidates for hypertension therapeutics.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751199","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":"GI-Y2, a novel gasdermin D inhibitor, attenuates sepsis-induced myocardial dysfunction by inhibiting gasdermin D-mediated pyroptosis in macrophages.","authors":"Yiling Mei, Xudong Chen, Si Shi, Wante Lin, Zhenfeng Cheng, Xiaoxi Fan, Wenqi Wu, Jibo Han, Weijian Huang, Bozhi Ye, Shanshan Dai","doi":"10.1111/bph.70040","DOIUrl":"https://doi.org/10.1111/bph.70040","url":null,"abstract":"<p><strong>Background and purpose: </strong>Myocardial dysfunction is a significant complication associated with sepsis. However, there are currently no specific and effective treatments available. Inhibiting gasdermin D (GSDMD)-mediated pyroptosis has shown promise in mitigating sepsis-induced myocardial dysfunction. The GSDMD inhibitor Y2 (GI-Y2) has been demonstrated to directly bind to GSDMD. Nonetheless, it remains uncertain whether GI-Y2 offers a cardioprotective effect in the context of sepsis-induced myocardial dysfunction.</p><p><strong>Experimental approach: </strong>A mouse model of sepsis was created using lipopolysaccharide (LPS), caecal ligation and puncture. Following treatment with GI-Y2 or macrophage membrane-encapsulated GI-Y2 nanoparticles (GI-Y2@MM-NPs), myocardial dysfunction and pyroptosis levels in heart tissues were assessed. Transcriptome sequencing revealed the molecular mechanism of GI-Y2 in treating septic cardiomyopathy.</p><p><strong>Key results: </strong>We observed that GI-Y2 alleviated myocardial dysfunction and attenuated cardiac inflammation in mice induced by LPS, caecal ligation and puncture. GI-Y2 reduced macrophage pyroptosis and attenuated macrophage-mediated cardiomyocyte injury induced by LPS/nigericin. Concurrently, we confirmed the protective effect of GI-Y2 against LPS-induced cardiac dysfunction was abolished in the absence of GSDMD. Additionally, GI-Y2 attenuated the mitochondrial damage induced by LPS by inhibiting GSDMD in the mitochondria. Furthermore, we developed GI-Y2@MM-NPs to enhance the targeting capability of GI-Y2 towards macrophages in heart tissues and demonstrated its protective effect in vivo.</p><p><strong>Conclusion and implications: </strong>These findings indicate that GI-Y2 alleviates septic myocardial injury and dysfunction by specifically targeting GSDMD, thereby inhibiting GSDMD-mediated pyroptosis and mitochondrial damage. Both GI-Y2 and GI-Y2@MM-NPs may serve as promising therapeutic options for addressing septic myocardial dysfunction.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751187","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":"Efficacy of IDOR-1117-2520, a novel, orally available CCR6 antagonist in preclinical models of skin dermatitis.","authors":"Paulina Kulig, Pijus Brazauskas, Madeleine Suffiotti, Emilie Raoult, Ulrike Babilonski, Bérengère Renault, Ursula Grieder, Enrico Vezzali, Peter Blattmann, Marianne M Martinic, Mark J Murphy","doi":"10.1111/bph.70025","DOIUrl":"https://doi.org/10.1111/bph.70025","url":null,"abstract":"<p><strong>Background and purpose: </strong>The chemokine receptor CCR6 guides pathogenic T17 cells, implicated in autoimmune diseases including psoriasis, to sites of inflammation via the chemokine CCL20. Therefor, pharmacological inhibition of CCR6⁺ immune cell migration provides a novel therapeutic approach. Translatability of such an intervention has not yet been assessed in detail. We evaluated the translatability of the Aldara® mouse model induced skin inflammation to psoriasis, with particular focus on immune cell trafficking and assessed the efficacy of IDOR-1117-2520, a highly selective, potent and orally available CCR6 small inhibitor.</p><p><strong>Experimental approach: </strong>Effects of IDOR-1117-2520 were investigated in the Aldara® and IL23 mouse models of skin inflammation using flow cytometry, RNA sequencing and transcriptome-based cell type deconvolution approaches to characterise immune cell migration patterns. These results were compared to human psoriasis transcriptomics data.</p><p><strong>Key results: </strong>IDOR-1117-2520 dose dependently reduced infiltration of CCR6⁺ immune cells into inflamed skin, and was equally efficacious as IL-17 and IL-23 inhibition in models of skin inflammation. Pathway analysis showed molecular similarities in the immune response between human psoriasis and the Aldara® mouse model. IL-17/IL-23 pathway genes were expressed in both human psoriasis and the mouse model. CCR6 inhibition modulated multiple pathways associated with inflammation beyond the proximal IL-17/IL-23 pathway. A chemokine-chemokine receptor interaction map implicated CCL20-CCR6 as the dominant axis in recruiting pathogenic T17 cells in both the model and in human psoriasis.</p><p><strong>Conclusion and implications: </strong>IDOR-1117-2520 could provide a promising novel targeted approach to treating psoriasis and, potentially, other autoimmune diseases involving the CCR6/CCL20 axis and the IL-17/IL-23 pathway. IDOR-1117-2520 is currently being evaluated in a clinical phase 1 trial (ISRCTN28892128).</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742510","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":"(2R,6R)-hydroxynorketamine prevents opioid abstinence-related negative affect and stress-induced reinstatement in mice.","authors":"Andria Michael, Anna Onisiforou, Polymnia Georgiou, Morfeas Koumas, Chris Powels, Elmar Mammadov, Andrea N Georgiou, Panos Zanos","doi":"10.1111/bph.70018","DOIUrl":"https://doi.org/10.1111/bph.70018","url":null,"abstract":"<p><strong>Background and purpose: </strong>Opioid use disorder (OUD) is a pressing public health concern marked by frequent relapse during periods of abstinence, perpetuated by negative affective states. Classical antidepressants or the currently prescribed opioid pharmacotherapies have limited efficacy to reverse the negative affect or prevent relapse.</p><p><strong>Experimental approach: </strong>Using mouse models, we investigated the effects of ketamine's metabolite (2R,6R)-hydroxynorketamine (HNK) on reversing conditioning to sub-effective doses of morphine in stress-susceptible mice, preventing conditioned-place aversion and alleviating acute somatic abstinence symptoms in opioid-dependent mice. Additionally, we evaluated its effects on anhedonia, anxiety-like behaviours and cognitive impairment during protracted opioid abstinence, while mechanistic studies examined cortical EEG oscillations and synaptic plasticity markers.</p><p><strong>Key results: </strong>(2R,6R)-HNK reversed conditioning to sub-effective doses of morphine in stress-susceptible mice and prevented conditioned-place aversion and acute somatic abstinence symptoms in opioid-dependent mice. In addition, (2R,6R)-HNK reversed anhedonia, anxiety-like behaviours and cognitive impairment emerging during protracted opioid abstinence plausibly via a restoration of impaired cortical high-frequency EEG oscillations, through a GluN2A-NMDA receptor-dependent mechanism. Notably, (2R,6R)-HNK facilitated the extinction of opioid conditioning, prevented stress-induced reinstatement of opioid-seeking behaviours and reduced the propensity for enhanced morphine self-consumption in mice previously exposed to opioids.</p><p><strong>Conclusions and implications: </strong>These findings emphasize the therapeutic potential of (2R,6R)-HNK, which is currently in Phase II clinical trials, in addressing stress-related opioid responses. Reducing the time and cost required for development of new medications for the treatment of OUDs via drug repurposing is critical due to the opioid crisis we currently face.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742509","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":"Ginsenoside Rh1 mitigates mitochondrial dysfunction induced by myocardial ischaemia through its novel role as a sirtuin 3 activator.","authors":"Shuaishuai Gong, Hong Chen, Shuhua Fang, Mengyu Li, Jingui Hu, Yue Li, Boyang Yu, Junping Kou, Fang Li","doi":"10.1111/bph.70022","DOIUrl":"https://doi.org/10.1111/bph.70022","url":null,"abstract":"<p><strong>Background and purpose: </strong>The sirtuin 3 (SIRT3) signalling pathway is an essential target for various cardiovascular diseases (CVDs), although effective interventions in myocardial ischaemia-induced mitochondrial dysfunction remain to be elucidated. Here, we discovered a potent SIRT3 activator and explored its efficacy and mechanism against mitochondrial dysfunction.</p><p><strong>Experimental approach: </strong>Molecular docking screened for SIRT3 activators among the 10 more common rare ginsenosides. In vivo, left coronary artery ligation induced myocardial ischaemia injury, followed by echocardiography, histopathology and serum biochemical indicators, in C57BL/6J mice. Expression levels of mitophagy and mitochondrial dynamics-associated proteins were examined by western blot (WB), immunofluorescence (IF) and immunohistochemistry (IHC). In vitro, oxygen-glucose deprivation-induced hypoxic injury in neonatal rat ventricular myocytes, and cell viability and mitochondrial function were investigated. SIRT3 small interference RNA (siRNA) was transfected into cardiomyocytes to validate mitochondrial dynamics and mitophagy mechanism regulated by ginsenoside Rh1.</p><p><strong>Key results: </strong>Rh1 exhibited the strongest binding affinity as an effective activator of SIRT3. Rh1 improved cardiac function and mitigated myocardial ischaemia injury in vivo. Rh1 ameliorated oxidative stress, improved mitochondrial network morphology and mitochondrial respiration function in hypoxia-injured cardiomyocytes. Rh1 bound to SIRT3 and simultaneously up-regulated Foxo3a, facilitating its nuclear translocation and reducing acetylation of Foxo3a. Rh1 markedly promoted mitochondrial fusion, inhibited mitochondrial fission and accelerated mitophagy. SIRT3 siRNA abrogated the regulation of Rh1 on oxidative stress, mitochondrial dynamics and mitophagy.</p><p><strong>Conclusion and implications: </strong>Rh1 is a novel SIRT3 activator and protects against myocardial ischaemia-induced mitochondrial dysfunction, providing new clues to prevent and treat ischaemic injury-associated CVD.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728713","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}