Fundamental & Clinical Pharmacology最新文献

{"title":"Fluoxetine-induced downregulation of circMap2k1 signaling cascade to improve neurological function after ischemic stroke","authors":"Langtao He,&nbsp;Hui Zhang,&nbsp;Jian Deng,&nbsp;Yibo He,&nbsp;Zhili Cai,&nbsp;Yitao He","doi":"10.1111/fcp.13048","DOIUrl":"10.1111/fcp.13048","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Ischemic stroke (IS) is known for its high incidence, disability, and mortality, and there is an urgent need to investigate the pathophysiological mechanisms and develop novel treatment strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We aimed to investigate the mechanisms of the novel circMap2k1/miR-135b-5p/Pidd1 axis in the treatment of IS progression with fluoxetine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The middle cerebral artery occlusion (MCAO) model was done in adult male Sprague–Dawley (SD) rats and followed by fluoxetine treatment and the injection of adeno-associated virus (AAV)-sh-ctr and AAV-sh-circMap2k1 into the bilateral hippocampal tissues of rats. Dual-luciferase reporter gene assay was employed to confirm the binding between miR-135b-5p and Pidd1. Enzyme-linked immunosorbent assay was performed to measure the concentrations of the inflammatory factors TNF-α, IL-6, and IL-1β in the plasma. The role of circMap2k1 in cells was tested by overexpression of circMap2k1. Cell viability was assessed using Cell Counting Kit-8 assay, while apoptosis was measured by flow cytometry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Knockdown of circMap2k1 enhanced the therapeutic and protective effect of fluoxetine on IS injury in rats. Dual-luciferase reporter gene assay confirmed the targeting of miR-135b-5p to Pidd1. Additionally, fluoxetine deactivated the adsorption of miR-135b-5p by downregulating circMap2k1, and miR-135b-5p further exerted its inhibitory effect on Pidd1 and finally attenuated the inflammatory response caused by microglial polarization after IS. Cell experiments revealed that overexpression of circMap2k1 repressed cell viability and promoted cell apoptosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Fluoxetine downregulated of circMap2k1 was associated ameliorate neurological injury and inflammatory responses induced by microglial polarization after IS. The manuscript is available as a preprint at this link: doi.org/10.21203/rs.3.rs-3209057/v1.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fundamental and Clinical Pharmacology of drug repositioning","authors":"Lars Petter Jordheim","doi":"10.1111/fcp.13046","DOIUrl":"10.1111/fcp.13046","url":null,"abstract":"","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142947256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term evaluation of rheumatoid arthritis activity with erythrocyte methotrexate-polyglutamate 3","authors":"Jean Escal,&nbsp;Marion Poudret,&nbsp;Sophie Hodin,&nbsp;Tiphany Neel,&nbsp;Irina Coman,&nbsp;Hervé Locrelle,&nbsp;Adamah Amouzougan,&nbsp;Thierry Thomas,&nbsp;Xavier Delavenne,&nbsp;Hubert Marotte","doi":"10.1111/fcp.13050","DOIUrl":"10.1111/fcp.13050","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Methotrexate (MTX) is the first-line treatment for Rheumatoid Arthritis (RA), yet 30%–50% of RA patients develop resistance to MTX, which can manifest several years after treatment initiation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study investigates the relationship between erythrocyte methotrexate polyglutamates (MTX-PGs) subtype concentrations and clinical disease activity in RA patients undergoing long-term MTX treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this cross-sectional study, patients on a stable dose of subcutaneous MTX for several years were included. The study protocol was registered in the European Medicines Agency's clinical trials register (n°2017-004348-39). Patients were classified as either in clinical remission (DAS28 &lt;2.6) or having active disease (DAS28 &gt;3.2). Erythrocyte MTX-PGs concentrations were measured using liquid chromatography coupled with mass spectrometry. Multivariate logistic regression analysis assessed the probability of remission status based on MTX-PG3 concentrations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The study included 34 patients with active RA and 25 in remission. The remission group had a median MTX treatment duration of 6.4 years compared to 2.6 years for the active group (<i>p</i> = 0.001). Patients in remission had a longer median disease duration (<i>p</i> = 0.02) and a lower Body Mass Index (BMI) (<i>p</i> = 0.03) than those with active RA. A positive correlation was found between remission status and high MTX-PG3 concentrations in patients with a BMI &lt;25 kg/m².</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Erythrocyte MTX-PG3 concentrations may serve as a marker for RA activity after prolonged treatment. However, BMI could limit their utility as a biomarker.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Body mass index affects imatinib exposure: Real-world evidence from TDM with adaptive dosing","authors":"Paul Maroselli,&nbsp;Raphaelle Fanciullino,&nbsp;Julien Colle,&nbsp;Laure Farnault,&nbsp;Pauline Roche,&nbsp;Geoffroy Venton,&nbsp;Régis Costello,&nbsp;Joseph Ciccolini","doi":"10.1111/fcp.13049","DOIUrl":"10.1111/fcp.13049","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Imatinib is the treatment of elderly or frail patients with chronic myeloid leukemia (CML). Trough levels of around 1000 ng/ml are considered as the target exposure.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We searched for baseline parameters associated with imatinib pharmacokinetics, and studied the clinical impact of subsequent adaptive dosing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We present data from 60 adult CML patients upon imatinib with therapeutic drug monitoring (TDM) and adaptive dosing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Mean trough levels after treatment initiation were 994.2 ± 560.6 ng/ml with 56% inter-patient variability). Only 29% of patients were in the therapeutic range. Body weight, height, body surface area, body mass index (BMI), and age were associated with imatinib plasma levels on univariate analysis. Age and BMI remained the only parameters associated with imatinib trough levels on multivariate analysis. As severe toxicities have been previously reported in patients with low BMI treated with standard imatinib, we evaluated the extent to which low BMI may lead to plasma overexposure. We found a statistically significant difference in trough imatinib levels in patients with BMI &lt; 18.5 kg/m², with exposure +61.5% higher than in patients with 18.5 &lt; BMI ≤  24.9 and +76.3% higher than in patients with BMI ≥ 25. After TDM with adaptive dosing, a statistically significant difference in dosing between patients was observed, with doses ranging from 200 to 700 mg. No difference in toxicity or efficacy was observed regardless of BMI after adaptive dosing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our data suggest that low BMI has a significant impact on imatinib exposure but that pharmacokinetically-guided dosing limits its clinical impact in patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel naphthylchalcone ([E]-4-(3-[naphthalen-2-yl]-3-oxoprop-1-en-1-yl) induces intrinsic and extrinsic apoptosis in human acute leukemia cell lines","authors":"Amanda V. Jacques,&nbsp;Natália M. Stefanes,&nbsp;Laura O. Walter,&nbsp;Stephanie M. Syracuse,&nbsp;Alisson Bigolin,&nbsp;Louise D. Chiaradia-Delatorre,&nbsp;Luiz F. S. de Souza,&nbsp;Ana C. R. de Moraes,&nbsp;Ricardo J. Nunes,&nbsp;Maria C. Santos-Silva","doi":"10.1111/fcp.13047","DOIUrl":"10.1111/fcp.13047","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Chalcones have been described in the literature as promising antineoplastic compounds.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Therefore, the objective of this study was to analyze the cytotoxic effect of 23 synthetic chalcones on human acute leukemia (AL) cell lines (Jurkat and K562).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Cytotoxicity assessment was performed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Cell death was evaluated using fluorescence microscopy, the DNA fragmentation technique, and the assessment of proteins involved in apoptosis by flow cytometry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The most cytotoxic chalcone (<b>R32</b>) showed no cytotoxicity towards peripheral blood mononuclear cells (PBMC). It exhibited no hemolytic activity, did not alter platelet aggregation after adenosine diphosphate (ADP) and epinephrine stimulation, and did not affect blood coagulation as measured by prothrombin time (PT) and activated partial thromboplastin time (APTT). <b>R32</b> demonstrated cytotoxic activity by inducing both intrinsic and extrinsic apoptosis, leading to caspase-3 activation and DNA fragmentation. In Jurkat and K562 cells, intrinsic apoptosis was associated with changes in mitochondrial membrane potential (MMP). There was a decreased expression of Bcl-2, increased expression of Bax, decreased expression of survivin, and increased expression of apoptosis-inducing factor (AIF). Extrinsic apoptosis involvement was also observed in both cell lines, characterized by increased expression of the Fas receptor. Additionally, Jurkat cells exhibited decreased expression of the KI-67 cell proliferation marker.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings suggest <b>R32</b> as a potential compound for the development of novel drugs for the treatment of AL.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knockdown of RFC3 enhances the sensitivity of colon cancer cells to oxaliplatin by inducing ferroptosis","authors":"Youyi Wu,&nbsp;Tingting Chen,&nbsp;Songsong Wu,&nbsp;Yiwei Huang,&nbsp;Fuyao Li","doi":"10.1111/fcp.13044","DOIUrl":"10.1111/fcp.13044","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The development of resistance to oxaliplatin is a multifaceted process, often involving modifications in drug transport, DNA repair mechanisms, and the ability of cells to evade drug-induced apoptosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To evaluate whether knocking down RFC3 promotes the sensitivity of colorectal cancer (CRC) cells to oxaliplatin, potentially offering a new approach to combat drug resistance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>siRNA-mediated knockdown of RFC3 was employed in colorectal cancer cell lines to assess the impact on oxaliplatin responsiveness. Cell viability assays, clonogenic survival assays, and flow cytometry were conducted to evaluate the effects on cell growth and apoptosis. Additionally, immunoblot analysis was used to scrutinize modifications in the expression of pivotal protein expression in the Wnt/β-catenin/GPX4 axis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>RFC3 is highly expressed in CRC tissues and associated with prognosis. Knocking down RFC3 enhances the sensitivity of CRC cells to oxaliplatin. Additionally, the reduction of RFC3 promotes the susceptibility of chemoresistant tumor cells to oxaliplatin by inducing ferroptosis. Furthermore, the knockdown of RFC3 disrupts the Wnt/β-catenin/GPX4 axis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Depletion of RFC3 enhances the sensitivity of CRC cells to oxaliplatin via inducing ferroptosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breastfeeding and contrast agents—A critical review and presentation of new aspects","authors":"Sina Lemmenmeier,&nbsp;Ingrid Boehm","doi":"10.1111/fcp.13045","DOIUrl":"10.1111/fcp.13045","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>There are discrepancies between guidelines of scientific societies and information of the package inserts of contrast media concerning breastfeeding following the application of a contrast agent to the mother.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The contents of different review articles reflect the opinion of scientific societies. Consequently, in clinical routine settings it is difficult to find the optimal advice for a breastfeeding woman and her baby.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Therefore, the paper carefully summarized important information dealing with the topic ‘breastfeeding and contrast media’ from the literature. Among other things, the paper focuses on topics that are not yet taken into account in other reviews (e.g. approval for breastfeeding women, contrast agents that have been analysed in human breast milk).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In this way, the review shows new aspects. It has been revealed that data concerning the amount of contrast agents in human breast milk as well as contrast medium absorption by the infants' intestine are sparse. Instead of them, a lot of speculations and incorrect conclusions do exist in the literature. Because studies are rare or missing, contrast media are not approved for breastfeeding women (off-label-use).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Although breastfeeding women 100% prefers a break from breastfeeding, in current decision-making processes, their preference plays a minor role. However, this should change in the future. In addition, it would be very important to inform breastfeeding women in the future about the missing data concerning ‘breastfeeding and contrast media’.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The synergy between alkylating agents and ERCC1–XPF inhibitors is p53 dependent","authors":"Gloria Ciniero,&nbsp;Tiago Marques Pedro,&nbsp;Charles Dumontet,&nbsp;Ahmed H. Elmenoufy,&nbsp;Frederick G. West,&nbsp;Michael Weinfeld,&nbsp;Francesco Gentile,&nbsp;Jack A. Tuszynski,&nbsp;Emeline Cros-Perrial,&nbsp;Lars Petter Jordheim","doi":"10.1111/fcp.13043","DOIUrl":"10.1111/fcp.13043","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>DNA repair plays a major role in maintaining genomic stability, thus limiting the transformation of normal cells into cancer cells. However, in cancer patients treated with DNA-targeting drugs, DNA repair can decrease efficacy by removing the damage generated by such molecules that is needed to induce pharmacological activity. Inhibiting DNA repair thus represents an interesting approach to potentiating the activity of chemotherapy in this setting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Here, we continue the characterization of an inhibitor of the interaction between Excision Repair Cross-Complementing Rrodent repair deficiency complementation group 1 (ERCC1) and Xeroderma Pigmentousum group F (XPF) (<b>B9</b>), two key proteins of nucleotide excision repair.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used various cell lines and co-incubation studies for the determination of cell survival and DNA repair capacities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We show that it is synergistic with other platinum derivatives than previously described, and that synergy is lacking in cells not expressing ERCC1 or XPF. Finally, a series of experiments show that potentiation is observed only in cells expressing wild-type p53.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our results confirm the mechanism of action of our ERCC1–XPF inhibitor and give important additional data on this approach to enhance the activity of already existing cancer drugs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.13043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Capivasertib augments chemotherapy via Akt inhibition in preclinical small cell lung cancer models","authors":"Cheng Long,&nbsp;Hui Shen,&nbsp;Hui Li,&nbsp;Lan Han","doi":"10.1111/fcp.13042","DOIUrl":"10.1111/fcp.13042","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer for which platinum-based chemotherapy is the standard of care. Despite an initial response to this therapy, patients eventually develop resistance to the chemotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To investigate the potential of capivasertib, an approved drug for advanced breast cancer, to enhance the efficacy of cisplatin in preclinical SCLC models and explore the underlying mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>SCLC cell lines were treated with capivasertib and cisplatin, alone or in combination, to assess cell viability, proliferation, colony formation, and apoptosis. Next, capivasertib's effects, alone and combined with cisplatin, were evaluated in an SCLC mouse model. Mechanistic studies focused on Akt and MYC signaling, with constitutively active Akt overexpression used to assess its role.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Capivasertib is active against a panel of SCLC cell lines regardless of cellular origin and genetic profiling with IC50 at a clinically achievable range. Particularly, capivasertib inhibits proliferation and anchorage-independent colony formation and induces apoptosis in SCLC cells. It significantly augments cisplatin's inhibitory effects in all tested cell lines. Importantly, capivasertib at a non-toxic dose is effective in delaying SCLC growth in mice and its combination with cisplatin achieves nearly complete tumor growth inhibition. Mechanistic studies confirm that capivasertib inhibits Akt and MYC signaling, and furthermore, that overexpression of constitutively active Akt reversed anti-SCLC activity of capivasertib.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our work is the first to reveal that Akt inhibition can augment chemotherapy in SCLC, and capivasertib is a useful addition to the treatment armamentarium for SCLC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New ways to repurpose salmeterol in an animal model of fibromyalgia","authors":"Mena Z. Shafiek,&nbsp;Hala F. Zaki,&nbsp;Ahmed F. Mohamed","doi":"10.1111/fcp.13041","DOIUrl":"10.1111/fcp.13041","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Fibromyalgia (FM) is a syndrome of pervasive chronic pain accompanied by low mood, sleep disorders, and cognitive decline. The dysfunction of central pain processing systems along with neurotransmitter disturbances are possible contributing mechanisms. Genetic polymorphism of the 𝛽2 adrenergic receptors is reported in FM patients. It is reported that chronic β2 agonists administration is effective for neuropathic pain alleviation. No current information, however, exists on their potential to alleviate nociplastic pain, such as FM. Therefore, the purpose of the current study is to examine salmeterol's potential antiallodynic effects in experimentally produced FM and explore some of the possible contributing mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Thirty rats are allocated into three groups (<i>n</i> = 10): a normal group, a reserpine group that received reserpine (1 mg/kg; s.c.) for 3 days, and a reserpine + salmeterol group that received salmeterol (1 mg/kg; i.p.) for 21 consecutive days following last reserpine injection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Reserpine administration resulted in behavioral and biochemical changes consistent with FM, including thermal and mechanical hyperalgesia, depressive behavior, and motor incoordination. This is coupled with disturbed spinal monoamine levels, depressed cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling, disturbed mitochondrial function/dynamics, and compromised blood-nerve barrier integrity. Treatment with salmeterol conceivably reversed these effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>β2 receptor agonists such as salmeterol could be regarded as a promising strategy for the management of FM.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}