British Journal of Pharmacology最新文献

{"title":"A p75 neurotrophin receptor-sparing nerve growth factor protects retinal ganglion cells from neurodegeneration by targeting microglia","authors":"Laura Latini,&nbsp;Daniel Souza Monteiro De Araujo,&nbsp;Rosario Amato,&nbsp;Alessio Canovai,&nbsp;Lucia Buccarello,&nbsp;Francesco De Logu,&nbsp;Elena Novelli,&nbsp;Anastasiia Vlasiuk,&nbsp;Francesca Malerba,&nbsp;Ivan Arisi,&nbsp;Rita Florio,&nbsp;Hiroki Asari,&nbsp;Simona Capsoni,&nbsp;Enrica Strettoi,&nbsp;Gino Villetti,&nbsp;Bruno Pietro Imbimbo,&nbsp;Massimo Dal Monte,&nbsp;Romina Nassini,&nbsp;Pierangelo Geppetti,&nbsp;Silvia Marinelli,&nbsp;Antonino Cattaneo","doi":"10.1111/bph.17316","DOIUrl":"10.1111/bph.17316","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Retinal ganglion cells (RGCs) are the output stage of retinal information processing, via their axons forming the optic nerve (ON). ON damage leads to axonal degeneration and death of RGCs, and results in vision impairment. Nerve growth factor (NGF) signalling is crucial for RGC operations and visual functions. Here, we investigate a new neuroprotective mechanism of a novel therapeutic candidate, a p75-less, TrkA-biased NGF agonist (hNGFp) in rat RGC degeneration, in comparison with wild type human NGF (hNGFwt).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Both neonate and adult rats, whether subjected or not to ON lesion, were treated with intravitreal injections or eye drops containing either hNGFp or hNGFwt. Different doses of the drugs were administered at days 1, 4 or 7 after injury for a maximum of 10 days, when immunofluorescence, electrophysiology, cellular morphology, cytokine array and behaviour studies were carried out. Pharmacokinetic evaluation was performed on rabbits treated with hNGFp ocular drops.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>hNGFp exerted a potent RGC neuroprotection by acting on microglia cells, and outperformed hNGFwt in rescuing RGC degeneration and reducing inflammatory molecules. Delayed use of hNGFp after ON lesion resulted in better outcomes compared with treatment with hNGFwt. Moreover, hNGFp-based ocular drops were less algogenic than hNGFwt. Pharmacokinetic measurements revealed that biologically relevant quantities of hNGFp were found in the rabbit retina.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Our data point to microglia as a new cell target through which NGF-induced TrkA signalling exerts neuroprotection of the RGC, emphasizing hNGFp as a powerful treatment to tackle retinal degeneration.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17316","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219166","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":"Serotonergic transmission plays differentiated roles in the rapid and sustained antidepressant-like effects of ketamine","authors":"Yong-Yu Yin,&nbsp;Jiao-Zhao Yan,&nbsp;Qian-Qian Wei,&nbsp;Si-Rui Sun,&nbsp;Yu-Qiang Ding,&nbsp;Li-Ming Zhang,&nbsp;Yun-Feng Li","doi":"10.1111/bph.17324","DOIUrl":"10.1111/bph.17324","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The emerging antidepressant effects of ketamine have inspired tremendous interest in its underlying neurobiological mechanisms, although the involvement of 5-HT in the antidepressant effects of ketamine remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental approach</h3>\u0000 \u0000 <p>The chronic restraint stress procedure was performed to induce depression-like behaviours in mice. OFT, FST, TST, and NSFT tests were used to evaluate the antidepressant-like effects of ketamine. <i>Tph2</i> knockout or depletion of 5-HT by PCPA and 5,7-DHT were used to manipulate the brain 5-HT system. ELISA and fibre photometry recordings were used to measure extracellular 5-HT levels in the brain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>60 min after injection, ketamine (10 mg·kg⁻¹, i.p.) produced rapid antidepressant-like effects and increased brain 5-HT levels. After 24 h, ketamine significantly reduced immobility time in TST and FST tests and increased brain 5-HT levels, as measured by ELISA and fibre photometry recordings. The sustained (24 h) but not rapid (60 min) antidepressant-like effects of ketamine were abrogated by PCPA and 5,7-DHT, or by <i>Tph2</i> knockout. Importantly, NBQX (10 mg·kg⁻¹, i.p.), an AMPA receptor antagonist, significantly inhibited the effect of ketamine on brain 5-HT levels and abolished the sustained antidepressant-like effects of ketamine in naïve or CRS-treated mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>This study confirms the requirement of serotonergic neurotransmission for the sustained antidepressant-like effects of ketamine, which appears to involve AMPA receptors, and provides avenues to search for antidepressant pharmacological targets.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139367","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":"Schwann cell transient receptor potential ankyrin 1 (TRPA1) ortholog in zebrafish larvae mediates chemotherapy-induced peripheral neuropathy","authors":"Elisa Bellantoni,&nbsp;Matilde Marini,&nbsp;Martina Chieca,&nbsp;Chiara Gabellini,&nbsp;Erica Lucia Crapanzano,&nbsp;Daniel Souza Monteiro de Araujo,&nbsp;Daniele Nosi,&nbsp;Lorenzo Roschi,&nbsp;Lorenzo Landini,&nbsp;Gaetano De Siena,&nbsp;Pasquale Pensieri,&nbsp;Alessandra Mastricci,&nbsp;Irene Scuffi,&nbsp;Pierangelo Geppetti,&nbsp;Romina Nassini,&nbsp;Francesco De Logu","doi":"10.1111/bph.17318","DOIUrl":"10.1111/bph.17318","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The oxidant sensor transient receptor potential ankyrin 1 (TRPA1) channel expressed by Schwann cells (SCs) has recently been implicated in several models of neuropathic pain in rodents. Here we investigate whether the pro-algesic function of Schwann cell TRPA1 is not limited to mammals by exploring the role of TRPA1 in a model of chemotherapy-induced peripheral neuropathy (CIPN) in zebrafish larvae.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We used zebrafish larvae and a mouse model to test oxaliplatin-evoked nociceptive behaviours. We also performed a TRPA1 selective silencing in Schwann cells both in zebrafish larvae and mice to study their contribution in oxaliplatin-induced CIPN model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>We found that zebrafish larvae and zebrafish TRPA1 (zTRPA1)-transfected HEK293T cells respond to reactive oxygen species (ROS) with nociceptive behaviours and intracellular calcium increases, respectively. TRPA1 was found to be co-expressed with the Schwann cell marker, SOX10, in zebrafish larvae. Oxaliplatin caused nociceptive behaviours in zebrafish larvae that were attenuated by a TRPA1 antagonist and a ROS scavenger. Oxaliplatin failed to produce mechanical allodynia in mice with Schwann cell TRPA1 selective silencing (<i>Plp1</i>⁺<i>-Trpa1</i> mice). Comparable results were observed in zebrafish larvae where TRPA1 selective silencing in Schwann cells, using the specific Schwann cell promoter myelin basic protein (MBP), attenuated oxaliplatin-evoked nociceptive behaviours.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>These results indicate that the contribution of the oxidative stress/Schwann cell/TRPA1 pro-allodynic pathway to neuropathic pain models seems to be conserved across the animal kingdom.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17318","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139339","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":"Deficiency of 5-HT_2B receptors alleviates atherosclerosis by regulating macrophage phenotype through inhibiting interferon signalling.","authors":"Yahan Liu, Zhipeng Wang, Li Fang, Yaohua Xu, Beilei Zhao, Xuya Kang, Yanqing Zhao, Jintao Han, Yan Zhang, Erdan Dong, Nanping Wang","doi":"10.1111/bph.17315","DOIUrl":"https://doi.org/10.1111/bph.17315","url":null,"abstract":"<p><strong>Background and purpose: </strong>Elevated levels of 5-HT have been correlated with coronary artery disease and cardiac events, suggesting 5-HT is a potential novel factor in the development of atherosclerotic cardiovascular disease. However, the underlying pathological mechanisms of the 5-HT system in atherosclerosis remain unclear. The 5-HT_2B receptor (5-HT2BR), which establishes a positive feedback loop with 5-HT, has been identified as a contributor to pathophysiological processes in various vascular disorders. In this study, we investigated the immunological impact of 5-HT2BR in atherosclerosis-prone apolipoprotein E-deficient (ApoE^-/-) mice.</p><p><strong>Experimental approach: </strong>Plasma levels of 5-HT were measured in mice using an ELISA kit. Atherosclerotic plaque formation, macrophage infiltration and inflammatory signalling were assessed in ApoE^-/- mice by employing both pharmacological inhibition and genetic deficiency of 5-HT2BR. Inflammasome activation was elucidated using peritoneal macrophages isolated from 5-HT2BR-deficient mice.</p><p><strong>Key results: </strong>An upregulation of 5-HT2BR expression was observed in the aortas of ApoE^-/- mice, exhibiting a strong correlation with the presence of macrophages in plaques. Atherosclerosis was attenuated in mice through pharmacological inhibition and genetic deficiency of 5-HT2BR. Additionally, a significant reduction in atherosclerotic plaque size was achieved through bone marrow reconstitution with 5-HT2BR-deficient cells. 5-HT2BR-deficient macrophages showed attenuated interferon (IFN) signalling, NLRP3 inflammasome activation, and interleukin-1β release. Moreover, macrophages primed with 5-HT2BR deficiency displayed an anti-inflammatory phenotype.</p><p><strong>Conclusion and implications: </strong>These findings support the hypothesis that 5-HT2BR in macrophages plays a causal role in the development of atherosclerosis, revealing a novel perspective for potential therapeutic strategies in atherosclerosis-related diseases.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131897","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":"Tert-butylhydroquinone promotes skin flap survival by inhibiting oxidative stress mediated by the Nrf2/HO-1 signalling pathway","authors":"Kaitao Wang,&nbsp;An Wang,&nbsp;Jiapeng Deng,&nbsp;Jialong Yang,&nbsp;Guodong Chen,&nbsp;Qingyu Chen,&nbsp;Minle Ye,&nbsp;Dingsheng Lin","doi":"10.1111/bph.17321","DOIUrl":"10.1111/bph.17321","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Skin flaps are among the most important means of wound repair in clinical settings. However, partial or even total distal necrosis may occur after a flap operation, with severe consequences for both patients and doctors. This study investigated whether <i>tert</i>-butylhydroquinone (TBHQ), a known agonist of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), and an antioxidant, could promote skin flap survival.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>McFarlane skin flap models were established in male Sprague–Dawley rats and then randomly divided into control, low-dose TBHQ, and high-dose TBHQ treatment groups. On postoperative day 7, the survival and blood flow of the skin flaps were assessed. Using flap tissue samples, angiogenesis, inflammation, apoptosis, autophagy, and Nrf2/haem oxygenase 1 (HO-1) signalling pathway activity were measured with immunohistochemical techniques and western blotting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>TBHQ dose-dependently stimulated the Nrf2/HO-1 signalling pathway, inducing autophagy through the up-regulation of LC3B and beclin 1 and concurrently suppressing p62 expression. Additionally, TBHQ hindered apoptosis by enhancing Bcl-2 expression while inhibiting the expression of Bax. It suppressed inflammation by inhibiting the expression of interleukin 1β, interleukin 6, and tumour necrosis factor-α and enhanced angiogenesis by promoting the expression of vascular endothelial growth factor.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>In summary, TBHQ promoted flap survival in rats by up-regulating the Nrf2/HO-1 signalling pathway. As TBHQ is already widely used as a food additive, it could offer an acceptable means of improving clinical outcomes following skin flap surgery in patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131898","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":"Advancing the field of viroporins—Structure, function and pharmacology: IUPHAR Review 39","authors":"Kira Devantier,&nbsp;Viktoria M. S. Kjær,&nbsp;Stephen Griffin,&nbsp;Birthe B. Kragelund,&nbsp;Mette M. Rosenkilde","doi":"10.1111/bph.17317","DOIUrl":"10.1111/bph.17317","url":null,"abstract":"<p>Viroporins possess important potential as antiviral targets due to their critical roles during virus life cycles, spanning from virus entry to egress. Although the antiviral amantadine targets the M2 viroporin of influenza A virus, successful progression of other viroporin inhibitors into clinical use remains challenging. These challenges relate in varying proportions to a lack of reliable full-length 3D-structures, difficulties in functionally characterising individual viroporins, and absence of verifiable direct binding between inhibitor and viroporin. This review offers perspectives to help overcome these challenges. We provide a comprehensive overview of the viroporin family, including their structural and functional features, highlighting the moldability of their energy landscapes and actions. To advance the field, we suggest a list of best practices to aspire towards unambiguous viroporin identification and characterisation, along with considerations of potential pitfalls. Finally, we present current and future scenarios of, and prospects for, viroporin targeting drugs.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17317","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119022","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":"Targeting RNA with small molecules, from RNA structures to precision medicines: IUPHAR review: 40","authors":"Yuquan Tong,&nbsp;Jessica L. Childs-Disney,&nbsp;Matthew D. Disney","doi":"10.1111/bph.17308","DOIUrl":"10.1111/bph.17308","url":null,"abstract":"<p>RNA plays important roles in regulating both health and disease biology in all kingdoms of life. Notably, RNA can form intricate three-dimensional structures, and their biological functions are dependent on these structures. Targeting the structured regions of RNA with small molecules has gained increasing attention over the past decade, because it provides both chemical probes to study fundamental biology processes and lead medicines for diseases with unmet medical needs. Recent advances in RNA structure prediction and determination and RNA biology have accelerated the rational design and development of RNA-targeted small molecules to modulate disease pathology. However, challenges remain in advancing RNA-targeted small molecules towards clinical applications. This review summarizes strategies to study RNA structures, to identify small molecules recognizing these structures, and to augment the functionality of RNA-binding small molecules. We focus on recent advances in developing RNA-targeted small molecules as potential therapeutics in a variety of diseases, encompassing different modes of actions and targeting strategies. Furthermore, we present the current gaps between early-stage discovery of RNA-binding small molecules and their clinical applications, as well as a roadmap to overcome these challenges in the near future.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119023","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":"The plant extract PNS mitigates atherosclerosis via promoting Nrf2-mediated inhibition of ferroptosis through reducing USP2-mediated Keap1 deubiquitination","authors":"Yun Zhao,&nbsp;Guobin Zheng,&nbsp;Shu Yang,&nbsp;Shangjing Liu,&nbsp;Yifan Wu,&nbsp;Yaodong Miao,&nbsp;Zhen Liang,&nbsp;Yunqing Hua,&nbsp;Jing Zhang,&nbsp;Jia Shi,&nbsp;Dan Li,&nbsp;Yanfei Cheng,&nbsp;Yunsha Zhang,&nbsp;Yuanli Chen,&nbsp;Guanwei Fan,&nbsp;Chuanrui Ma","doi":"10.1111/bph.17311","DOIUrl":"10.1111/bph.17311","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and purpose</h3>\u0000 \u0000 <p>Atherosclerosis is the basis of cardiovascular disease. Ferroptosis is a form of programmed cell death characterized by lipid peroxidation, which contributes to atherogenesis. The plant extract PNS (<i>Panax notoginseng saponins</i>), containing the main active ingredients of <i>Panax notoginseng</i>, exhibits anti-atherogenic properties. Herein, we determined whether PNS and its major components could attenuate atherosclerosis by suppressing ferroptosis and revealed the underlying mechanism(s).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental approach</h3>\u0000 \u0000 <p>The anti-atherogenic effects of PNS and their association with inhibition of ferroptosis was determined in apoE^−/− mice. In vitro, the anti-ferroptotic effect and mechanism(s) of PNS components were demonstrated in the presence of ferroptosis inducers. Expression of ferroptosis markers and the ubiquitination of Keap1 were evaluated in USP2^−/− macrophages. Finally, the anti-atherogenic effect of USP2 knockout was determined by using USP2^−/− mice treated with high-fat diet (HFD) and AAV-PCSK9.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key results</h3>\u0000 \u0000 <p>PNS inhibited ferroptosis and atherosclerosis in vivo. PNS suppressed ferroptosis and ferroptosis-aggravated foam cell formation and inflammation in vitro. Mechanistically, PNS and its components activated Nrf2 by antagonizing Keap1, which was attributed to the inhibition of USP2 expression. USP2 knockout antagonized ferroptosis and ferroptosis-aggravated foam cell formation and inflammation, thus mitigating atherosclerosis. USP2 knockout abolished inhibitory effects of PNS on foam cell formation and inflammation in vitro.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and implications</h3>\u0000 \u0000 <p>PNS reduced USP2-mediated Keap1 de-ubiquitination and promoted Keap1 degradation, thereby activating Nrf2, improving iron metabolism and reducing lipid peroxidation, thus contributing to an anti-atherosclerotic outcome. Our study revealed the mechanism(s) underlying inhibition of ferroptosis and atherosclerosis by PNS.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel inhibitor of class IIa histone deacetylases attenuates collagen-induced arthritis","authors":"Eunice K. Poon,&nbsp;Ligong Liu,&nbsp;Kai-Chen Wu,&nbsp;Junxian Lim,&nbsp;Matthew J. Sweet,&nbsp;Rink-Jan Lohman,&nbsp;Abishek Iyer,&nbsp;David P. Fairlie","doi":"10.1111/bph.17306","DOIUrl":"10.1111/bph.17306","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Most inhibitors of histone deacetylases (HDACs) are not selective and are cytotoxic. Some have anti-inflammatory activity in disease models, but cytotoxicity prevents long-term uses in non-fatal diseases. Inhibitors selective for class IIa HDACs are much less cytotoxic and may have applications in management of chronic inflammatory diseases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>LL87 is a novel HDAC inhibitor examined here for HDAC enzyme selectivity. It was also investigated in macrophages for cytotoxicity and for inhibition of lipopolysaccharide (LPS)-stimulated cytokine secretion. In a rat model of collagen-induced arthritis, LL87 was investigated for effects on joint inflammation in Dark Agouti rats. Histological, immunohistochemical, micro-computed tomography and molecular analyses characterise developing arthritis and anti-inflammatory efficacy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>LL87 was significantly more inhibitory against class IIa than class I or IIb HDAC enzymes. In macrophages, LL87 was not cytotoxic and reduced both LPS-induced secretion of pro-inflammatory cytokines, and IL6-induced class IIa HDAC activity. In rats, LL87 attenuated paw swelling and clinical signs of arthritis, reducing collagen loss and histological damage in ankle joints. LL87 decreased immune cell infiltration, especially pro-inflammatory macrophages and osteoclasts, into synovial joints and significantly reduced expression of pro-inflammatory cytokines and tissue-degrading proteases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>A novel inhibitor of class IIa HDACs has been shown to have an anti-inflammatory and anti-arthritic profile distinct from current therapies. It is efficacious in reducing macrophage infiltration and joint inflammation in a chronic model of rat arthritis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17306","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119021","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 of natural product derivative triptolidiol as a direct NLRP3 inhibitor by reducing K63-specific ubiquitination.","authors":"Mo-Yu Ding, Chengqing Ning, Shao-Ru Chen, Hao-Ran Yin, Jing Xu, Ying Wang","doi":"10.1111/bph.17320","DOIUrl":"https://doi.org/10.1111/bph.17320","url":null,"abstract":"<p><strong>Background and purpose: </strong>NLRP3 is up-regulated in inflammatory and autoimmune diseases. The development of NLRP3 inhibitors is challenged by the identification of compounds with distinct mechanisms of action avoiding side effects and toxicity. Triptolide is a natural product with multiple anti-inflammatory activities, but a narrow therapeutic window.</p><p><strong>Experimental approach: </strong>Natural product triptolide derivatives were screened for NLRP3 inhibitors in human THP-1 and mouse bone marrow-derived macrophages. The efficacy of potent NLRP3 inhibitors was evaluated in LPS-induced acute lung injury and septic shock models.</p><p><strong>Key results: </strong>Triptolidiol was identified as a selective inhibitor of NLRP3 with high potency. Triptolidiol inactivated the NLRP3 inflammasome in human THP-1 and mouse primary macrophages primed with LPS. Triptolidiol specifically inhibited pro-caspase 1 cleavage downstream of NLRP3, but not AIM2 or NLRC4 inflammasomes. Based on the structure-activity relationship study, the C8-β-OH group was critical for its binding to NLRP3. Triptolidiol exhibited a submicromolar K_D for NLRP3, binding to residue C280. This binding prevented the interaction of NLRP3 with NEK7, the key regulator of NLRP3 inflammasome oligomerization and assembly, but not with the inflammasome adaptor protein ASC. Triptolidiol decreased the K63-specific ubiquitination of NLRP3, leading NLRP3 to a \"closed\" inactive conformation. Intraperitoneal administration of triptolidiol significantly attenuated LPS-induced acute lung injury and lethal septic shock.</p><p><strong>Conclusion and implications: </strong>Triptolidiol is a novel NLRP3 inhibitor that regulates inflammasome assembly and activation by decreasing K63-linked ubiquitination. Triptolidiol has novel structural features that make it distinct from reported NLRP3 inhibitors and represents a viable therapeutic lead for inflammatory diseases.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104565","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}