European journal of pharmacology最新文献

{"title":"Unveiling novel molecules and therapeutic targets in hypertension – A narrative review","authors":"Jefry Winner G ,&nbsp;Surbhi Jain ,&nbsp;Dimpy Gupta","doi":"10.1016/j.ejphar.2024.177053","DOIUrl":"10.1016/j.ejphar.2024.177053","url":null,"abstract":"<div><div>Hypertension is a prevalent non-communicable disease with serious cardiovascular complications, including heart failure, myocardial infarction, and stroke, often resulting from uncontrolled hypertension. While current treatments primarily target the renin-angiotensin-aldosterone pathway, the therapeutic response remains modest in many patients, with some developing resistant hypertension. Newer therapeutic approaches aim to address hypertension from various aspects beyond conventional drugs, including targeting central nervous system pathways, inflammatory pathways, vascular smooth muscle function, and baroreceptors. Despite these advancements, each therapy faces unique clinical and mechanistic challenges that influence its clinical translatability and long-term viability. This review explores the mechanisms of novel molecules in preclinical and clinical development, highlights potential therapeutic targets, and discusses the challenges and ethical considerations related to hypertension therapeutics and their development.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177053"},"PeriodicalIF":4.2,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential MRGPRX2-dependent activation of human mast cells by polymyxins and octapeptins","authors":"Jie Ding ,&nbsp;Stephanie S. Zhang ,&nbsp;Nithya A. Fernandopulle ,&nbsp;John A. Karas ,&nbsp;Jian Li ,&nbsp;James Ziogas ,&nbsp;Tony Velkov ,&nbsp;Graham A. Mackay","doi":"10.1016/j.ejphar.2024.177050","DOIUrl":"10.1016/j.ejphar.2024.177050","url":null,"abstract":"<div><div>The emergence of multi-drug resistant Gram-negative bacteria has led to renewed interest in the antimicrobial activity of polymyxins and novel polymyxin analogues (<em>e.g.</em> nonapeptides and octapeptin). In some individuals, clinically used polymyxins can cause acute hypersensitivity reactions through mast cell activation, with a recent study attributing this effect to activation of the MAS-related G protein-coupled receptor X2 (MRGPRX2). In the present study, HEK293 cells expressing human MRGPRX2 and the human mast cell line LAD2 were used to characterize the activity of the broader family of polymyxins. Octapeptin C4, polymyxin B and colistin produced concentration-dependent calcium mobilization, degranulation, and CCL-2 (MCP-1) release in LAD2 mast cells, with the former being highly potent. CRISPR-Cas9 knockdown of MRGPRX2 in LAD2 cells and a MRGPRX2 inverse agonist caused a significant reduction in calcium mobilization, degranulation, and CCL-2 release, demonstrating dependency on MRGPRX2 expression. In contrast, polymyxin nonapeptides were far less potent calcium mobilisers and failed to induce functional degranulation in LAD2 cells. Our results confirm that activation of mast cells induced by polymyxin-related antibiotics is MRGPRX2-dependent and reveal that octapeptin C4 might be more liable, whilst nonapeptides are less liable, to trigger immediate hypersensitivity reactions clinically. The mechanism underpinning the difference in MRGPRX2 activation between polymyxin-related antibiotics is important to better understand as it may help design new, safer polymyxins and guide the optimal clinical use of existing polymyxin drugs.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177050"},"PeriodicalIF":4.2,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rhoifolin, baicalein 5,6-dimethyl ether and agathisflavone prevent amnesia induced in scopolamine zebrafish (Danio rerio) model by increasing the mRNA expression of bdnf, npy, egr-1, nfr2α, and creb1 genes","authors":"Ion Brinza ,&nbsp;Razvan Stefan Boiangiu ,&nbsp;Marius Mihasan ,&nbsp;Dragos Lucian Gorgan ,&nbsp;Alexandru Bogdan Stache ,&nbsp;Ahmed Abd-Alkhalek ,&nbsp;Heba El-Nashar ,&nbsp;Iriny Ayoub ,&nbsp;Nada Mostafa ,&nbsp;Omayma Eldahshan ,&nbsp;Abdel Nasser Singab ,&nbsp;Lucian Hritcu","doi":"10.1016/j.ejphar.2024.177013","DOIUrl":"10.1016/j.ejphar.2024.177013","url":null,"abstract":"<div><div>The increasing attention towards age-related diseases has generated significant interest in the concept of cognitive dysfunction associated with Alzheimer's disease (AD). Certain limitations are associated with the current therapies, and flavonoids have been reported to exhibit multiple biological activities and anti-AD effects in several AD models owing to their antioxidative, anti-inflammatory, and anti-amyloidogenic properties. In this study, we performed an initial in silico predictions of the pharmacokinetic properties of three flavonoids (rhoifolin, baicalein 5,6-dimethyl ether and agathisflavone). Subsequently, we evaluated the antiamnesic and antioxidant potential of flavonoids in concentrations of 1, 3, and 5 μg/L in scopolamine (100 μM)-induced amnesic zebrafish (<em>Danio rerio</em>) model. Zebrafish behavior was analyzed by novel tank diving test (NTT), Y-maze, and novel object recognition test (NOR). Acetylcholinesterase (AChE) activity, brain antioxidant status and the expression of <em>bdnf</em>, <em>npy</em>, <em>egr1</em>, <em>nrf2α</em>, <em>creb1</em> genes, and CREB-1 protein level was measured to elucidate the underlying mechanism of action. Our flavonoids improved memory and decreased anxiety-like behavior of scopolamine-induced amnesia in zebrafish. Also, the studied flavonoids reduced AChE activity and brain oxidative stress and upregulated the gene expression, collectively contributing to neuroprotective properties. The results of our study add new perspectives on the properties of flavonoids to regulate the evolution of neurodegenerative diseases, especially AD, by modulating the expression of genes involved in the regulation of synaptic plasticity, axonal growth, and guidance, sympathetic and vagal transmission, the antioxidant response and cell proliferation and growth.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177013"},"PeriodicalIF":4.2,"publicationDate":"2024-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The NF-κB pathway: Key players in neurocognitive functions and related disorders","authors":"Danfeng Yang ,&nbsp;Junwei Su ,&nbsp;Yeru Chen,&nbsp;Gang Chen","doi":"10.1016/j.ejphar.2024.177038","DOIUrl":"10.1016/j.ejphar.2024.177038","url":null,"abstract":"<div><div>Perioperative neurocognitive disorder (PND) is a common complication of surgical anesthesia, yet its precise etiology remains unclear. Neuroinflammation is a key feature of PND, influenced by both patient -related and surgical variables. The nuclear factor-κB (NF-κB) transcription factor family plays a critical role in regulating the body's immunological proinflammatory response, which is pivotal in the development of PND. Surgery and anesthesia trigger the activation of the NF-κB signaling pathway, leading to the initiation of inflammatory cascades, disruption of the blood-brain barrier, and neuronal injury. Immune cells and glial cells are central to these pathological processes in PND. Furthermore, this study explores the interactions between NF-κB and various signaling molecules, including Tlr4, P2X, α7-nAChR, ROS, HIF-1α, PI3K/Ak, MicroRNA, Circular RNA, and histone deacetylases, within the context of PND. Targeting NF-κB as a therapeutic approach for PND shows promise as a potential treatment strategy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177038"},"PeriodicalIF":4.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tulipalin A suppressed the pro-inflammatory polarization of M1 macrophage and mitigated the acute lung injury in mice via interference DNA binding activity of NF-κB","authors":"Ke-Gang Linghu ,&nbsp;Yue-Ting Tuo ,&nbsp;Wen-Qing Cui ,&nbsp;Tai-Qin Li ,&nbsp;Da-Song Wang ,&nbsp;Ya-Ya Zhang ,&nbsp;Jian Zhang ,&nbsp;Tian Zhang ,&nbsp;Yu-E Wang ,&nbsp;Hua Yu ,&nbsp;Xiang-Chun Shen ,&nbsp;Hai-Yang Li","doi":"10.1016/j.ejphar.2024.177034","DOIUrl":"10.1016/j.ejphar.2024.177034","url":null,"abstract":"<div><div>Acute lung injury (ALI) is an inflammatory disorder accompanied by higher morbidity and mortality. The pathological mechanism of ALI has been reported to be associated with the release of inflammatory cytokines by macrophages. Sesquiterpene lactones (SLs) represent the principal anti-inflammatory components of many natural products. Tulipalin A is a natural small molecule and a conserved moiety in anti-inflammatory SLs. However, the anti-inflammatory potential of Tulipalin A has yet to be fully disclosed. The present study aims to investigate TulipalinA's anti-inflammatory activity and underlying mechanisms <em>in vitro</em> and <em>in vivo</em>. Tulipalin A suppressed inflammatory responses in lipopolysaccharide (LPS)-stimulated bone marrow-derived primary macrophages and ameliorated LPS-induced ALI in mice. Mechanistically, Tulipalin A directly targets the NF-<em>κ</em>B p65 and disrupts its DNA binding activity, thereby impeding the activation of NF-<em>κ</em>B. Inhibition of NF-<em>κ</em>B attenuated M1 polarization of macrophages, consequently suppressing the production of pro-inflammatory mediators and ameliorating the onset and progression of ALI. These findings suggest Tulipalin A's potential to mitigate inflammatory disorders like ALI via targeting NF-<em>κ</em>B p65 and disrupting its DNA binding activity.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177034"},"PeriodicalIF":4.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological modulation of transglutaminase 2 in the unilateral ureteral obstruction mouse model","authors":"Judit Prat-Duran ,&nbsp;Isabela Bastos Binotti Abreu De Araujo ,&nbsp;Nina Juste ,&nbsp;Estéfano Pinilla ,&nbsp;Francisco J. Rios ,&nbsp;Augusto C. Montezano ,&nbsp;Rhian M. Touyz ,&nbsp;Ulf Simonsen ,&nbsp;Rikke Nørregaard ,&nbsp;Niels Henrik Buus","doi":"10.1016/j.ejphar.2024.177037","DOIUrl":"10.1016/j.ejphar.2024.177037","url":null,"abstract":"<div><h3>Background</h3><div>Transglutaminase 2 (TG2) is a multifunctional enzyme involved in fibrosis by promoting transforming-growth-factor-β1 and crosslinking of extracellular matrix proteins. These functions are dependent on the open conformation, while the closed state of TG2 can induce vasodilation. We explored the putative protective role of TG2 in its closed state on development of renal fibrosis and blood pressure (BP) regulation.</div></div><div><h3>Methods</h3><div>We studied the unilateral ureteral obstruction (UUO) mouse model treated with LDN27219, which promotes the closed conformation of TG2. Mice were subjected to 7 days UUO or sham operation and treated with vehicle (n = 10), LDN27219 (15 mg/kg/12 h, n = 9) or candesartan (5 mg/kg/day, n = 10) as a clinically comparator. Renal expression of TG2 and pro-fibrotic mediators were evaluated by Western blotting, qPCR and histology, and BP by tail-cuff measurements.</div></div><div><h3>Results</h3><div>Obstructed kidneys showed increased mRNA and protein expression of fibronectin, collagen 3α1 (Col3α1), α-smooth muscle actin and collagen staining. Despite increased renal TG2 mRNA, protein expression was reduced in all UUO groups, but with increased transamidase activity in the vehicle and candesartan groups. LDN27219 reduced mRNA expression of fibronectin and Col3α1, but their protein expression remained unchanged. In contrast to LDN27219, candesartan lowered BP without affecting expression of pro-fibrotic biomarkers.</div></div><div><h3>Conclusion</h3><div>Renal TG2 mRNA and protein expression levels seem dissociated, with transamidase activity being increased. LDN27219 influences kidney pro-fibrotic markers at the mRNA level and attenuates transamidase activity but without affecting collagen content or BP. Our findings suggest that TG2 in its closed conformation has anti-fibrotic effects at the molecular level.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177037"},"PeriodicalIF":4.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of hippocampal miRNA expression by intestinal flora in anxiety-like mice","authors":"Chang-qing Tong ,&nbsp;Meng-jia Li ,&nbsp;Yan Liu ,&nbsp;Qin Zhou ,&nbsp;Wen-qi Sun ,&nbsp;Jia-yi Chen ,&nbsp;Di Wang ,&nbsp;Feng Li ,&nbsp;Zi-jie Chen ,&nbsp;Yue-han Song","doi":"10.1016/j.ejphar.2024.177016","DOIUrl":"10.1016/j.ejphar.2024.177016","url":null,"abstract":"<div><div>This study investigated the possible interaction between gut flora and miRNAs and the effect of both on anxiety disorders. The model group was induced with chronic restraint stress (CRS) and each group was tested for anxiety-like behaviour by open field test and elevated plus maze test. Meanwhile, the gut flora was analysed by 16S rRNA high-throughput sequencing. The miRNAs in hippocampus were analysed by high-throughput sequencing, and the key miRNAs were obtained by using the method of bioinformatics analysis. PCR was used to verify the significantly related key miRNAs. Spearman correlation analysis was used to explore the correlation between behaviour, key miRNAs and differential gut microbiota. The 16S rRNA high-throughput sequencing result showed that the gut flora was dysregulated in the model group. In particular, Verrucomicrobia, <em>Akkermansia</em>, <em>Anaerostipes</em>, <em>Ralstonia</em>, <em>Burkholderia</em> and <em>Anaeroplasma</em> were correlated with behaviour. The results of miRNA high-throughput sequencing analysis and bioinformatics analysis showed that 7 key miRNAs influenced the pathogenesis of anxiety, and qRT-PCR results were consistent with the high-throughput sequencing results. Mmu-miR-543-3p and mmu-miR-26a-5p were positively correlated with Verrucomicrobia, <em>Akkermansia</em> and <em>Anaerostipes</em>. Therefore, we infer that chronic stress caused the decrease of <em>Akkermansia</em> abundance, which may aggravate the decrease of mmu-miR-543-3p and mmu-miR-26a-5p expression, leading to the increase of SLC1A2 expression. In conclusion, gut flora has played an important influence on anxiety with changes in miRNAs.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177016"},"PeriodicalIF":4.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unique cardiometabolic factors in women that contribute to modified cardiovascular disease risk","authors":"Kara Hetherington ,&nbsp;Jordyn Thomas ,&nbsp;Stephen J. Nicholls ,&nbsp;Giannie Barsha ,&nbsp;Kristen J. Bubb","doi":"10.1016/j.ejphar.2024.177031","DOIUrl":"10.1016/j.ejphar.2024.177031","url":null,"abstract":"<div><div>Major risk factors of cardiovascular disease (CVD) include hypertension, obesity, diabetes mellitus and metabolic syndrome; all of which are considered inflammatory conditions. Women are disproportionately affected by inflammatory conditions, with sex differences emerging as early as adolescence. Hormonal fluctuations associated with reproductive events such as menarche, pregnancy and menopause, are hypothesized to promote a pro-inflammatory state in women. Moreover, women who have experienced inflammatory-type conditions such as polycystic ovarian syndrome (PCOS), gestational diabetes or pre-eclampsia, have a cardiometabolic phenotype that pre-disposes to increased risk of myocardial infarction, stroke and coronary heart disease. Women with no notable CVD risk factors are often relatively protected from CVD pre-menopause; but overtake men in risk of major cardiovascular events when the cardiovascular protective effects of oestrogen begin to wane. Sex differences and female-specific factors have long been considered challenging to study and this has led to an underrepresentation of females in clinical trials and lack of female-specific data from pre-clinical studies. However, there is now a clear prerogative to include females at all stages of research, despite inherent complexities and potential variability in data. This review explores recent advancements in our understanding of CVD in women. We summarise the underlying factors unique to women that can promote CVD risk factors, ultimately contributing to CVD burden and the emerging therapies aimed to combat this.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177031"},"PeriodicalIF":4.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glibenclamide reverses cardiac damage and NLRP3 inflammasome activation associated with a high refined sugar diet","authors":"Renata Gomes Miranda e Castor ,&nbsp;Alexandre Santos Bruno ,&nbsp;Camila André Pereira ,&nbsp;Fernanda Luiza Menezes Bello ,&nbsp;Yuri Blanc Rodrigues ,&nbsp;Mychel Gonçalves Silva ,&nbsp;Sara Santos Bernardes ,&nbsp;Marina Gomes Miranda e Castor ,&nbsp;Anderson Jose Ferreira ,&nbsp;Rita de Cassia Tostes ,&nbsp;Stêfany Cau","doi":"10.1016/j.ejphar.2024.177035","DOIUrl":"10.1016/j.ejphar.2024.177035","url":null,"abstract":"<div><div>Increased energy intake from carbohydrates has been associated with major cardiovascular outcomes. Mice fed a highly-refined carbohydrate (HC) diet develop cardiac hypertrophy and inflammation. During cardiac injury, NLRP3 inflammasome is activated which results in a local inflammatory response. In this study, we hypothesized that a nom-hypoglycemic dose of glibenclamide may reverses sugar diet-induced cardiac damage by NRLP3 inflammasome inhibition. Mice were fed the HC diet for eight weeks and divided into a group treated with glibenclamide (20 mg/kg, gavage) and another with vehicle for four weeks. Afterward, hearts were excised for morphometric analysis and <em>ex vivo</em> function determination. NLRP3 inflammasome activation was investigated by western blotting and <em>in situ</em> fluorescent detection of reactive oxygen species (ROS) and active caspase-1. The HC diet promotes heart hypertrophy and collagen deposition, which were reverted by glibenclamide without ameliorating HC diet-induced insulin resistance. Changes in cardiac performance were observed <em>in vivo</em> by invasive catheterization and in Langendorff-perfused hearts due to the HC diet, which were prevented by glibenclamide. Hearts from HC diet mice had increased levels of NLRP3 and cleaved IL-1β. Glibenclamide reversed ROS production and caspase-1 activity induced by HC diet. These findings suggest glibenclamide's cardioprotective effects on heart damage caused by the HC diet are related to its inhibitory action on the NLRP3 inflammasome.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177035"},"PeriodicalIF":4.2,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein kinase C (PKC) inhibitor Calphostin C activates PKC in a light-dependent manner at high concentrations via the production of singlet oxygen","authors":"Tomomi Ishii ,&nbsp;Taketoshi Kajimoto ,&nbsp;Satoshi Kikkawa ,&nbsp;Soshi Narasaki ,&nbsp;Soma Noguchi ,&nbsp;Serika Imamura ,&nbsp;Kana Harada ,&nbsp;Izumi Hide ,&nbsp;Shigeru Tanaka ,&nbsp;Yasuo M. Tsutsumi ,&nbsp;Norio Sakai","doi":"10.1016/j.ejphar.2024.177036","DOIUrl":"10.1016/j.ejphar.2024.177036","url":null,"abstract":"<div><div>Calphostin C (Cal-C) is a protein kinase C (PKC) inhibitor that binds to its C1 domain. The aim of the present study was to elucidate the action of Cal-C in addition to PKC inhibition. First, we confirmed that Cal-C at low concentrations (&lt;200 nM) inhibit phorbol ester-induced PKC translocation and G-protein-coupled receptor (GPCR)-mediated PKC activation. Cal-C at higher concentrations (&gt;2 μM) increased intracellular calcium ion concentrations ([Ca²⁺]_i) in a concentration-dependent manner. The origin of this increase is the mobilization of the endoplasmic reticulum (ER), which does not involve GPCR or ryanodine receptors. Cal-C at high concentrations also cause structural changes in the ER, such as the formation of vacuoles and aggregates, and calcium leakage from the ER. At 2 μM, Cal-C translocated a calcium-sensitive PKCα. Studies using a C-kinase activity reporter and a myristoylated alanine-rich protein kinase C substrate fused with green fluorescent protein (GFP) have also revealed that Cal-C at high concentrations activate PKC in living cells. Additionally, the PKC-activating effects of Cal-C were light-dependent. Finally, studies using Si-DMA, an indicator of singlet oxygen, showed that Cal-C at high concentrations generated singlet oxygen, causing structural changes in the ER and leakage of calcium into the cytosol, which triggered PKC activation. This study confirms the novel action of Cal-C, solely considered a PKC inhibitor. Cal-C acted as a PKC inhibitor at low concentrations and a PKC activator at high concentrations by generating singlet oxygen in a light-dependent manner, suggesting that Cal-C can be used in photodynamic therapy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177036"},"PeriodicalIF":4.2,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}