Pharmacological Reports最新文献

{"title":"GNE-317 ameliorates neuroinflammation stimulated by lipopolysaccharide via PI3K/Akt/mTOR pathway.","authors":"Yoojin Lee, Namkwon Kim, Haeun Hwang, Subyn Jeon, Seung Ho Jeon, Yeongae Lee, Jeongmin Son, Sumin Ma, Sora Yoon, Min Sung Gee, Kyoung-Lim Kim, Kyung-Soo Inn, Inwha Baek, Jong Kil Lee","doi":"10.1007/s43440-026-00832-y","DOIUrl":"10.1007/s43440-026-00832-y","url":null,"abstract":"<p><p>BACKGROUND: Microglial activation in the central nervous system plays a central role in neuroinflammation and contributes to the onset and progression of neurodegenerative diseases. This study aimed to evaluate the anti-inflammatory effects of GNE-317, a phosphoinositide 3-kinase/ mammalian target of rapamycin (PI3K/mTOR) inhibitor, in lipopolysaccharide (LPS)-induced neuroinflammatory models. METHODS: BV2 microglial cells were stimulated with LPS, and the effects of GNE-317 were examined using Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), nitric oxide (NO) assays, and immunofluorescence. For in vivo experiments, C57BL/6 mice received GNE-317 (25 mg/kg/day, intraperitoneal, ip) for three days, followed by LPS injection (5 mg/kg, ip). Microglial activation was assessed by anti-ionized calcium-binding adapter molecule-1 (IBA1) immunostaining in the brain. RESULTS: GNE-317 inhibited PI3K/protein kinase B (Akt)/mTOR signaling and reduced nuclear factor-kappa B (NF-κB) nuclear translocation in LPS-stimulated BV2 cells. It decreased inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) expression and lowered tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production. In LPS-injected mice, GNE-317 reduced microglial activation in brain tissue. CONCLUSIONS: GNE-317 attenuates neuroinflammation by suppressing microglial activation through inhibition of the PI3K/Akt/mTOR and NF-κB pathways, supporting its potential as a therapeutic agent for microglia-mediated neuroinflammatory diseases. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"505-518"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146114029","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":"Impact of environmentally induced hypothermia on fentanyl and norfentanyl pharmacokinetics following intravenous administration to Wistar rats.","authors":"Paulina Stach, Kamil Skowron, Sebastian Rojek, Agnieszka Cios, Anna Wesołowska, Marilyn A Huestis, Krzysztof Gil","doi":"10.1007/s43440-026-00826-w","DOIUrl":"10.1007/s43440-026-00826-w","url":null,"abstract":"<p><strong>Background: </strong>Fentanyl, a synthetic opioid with potent analgesic and sedative properties, is widely administered in intensive care. Many critically ill patients present with, or develop, hypothermia driven by multifactorial disturbances such as sepsis, trauma, circulatory shock, or environmental exposure. Because reduced core temperature affects perfusion, metabolism, and clearance, hypothermia may meaningfully alter fentanyl disposition, although these effects remain insufficiently defined. Given these uncertainties, this study investigates how moderate hypothermia (MH) and severe hypothermia (SH) alter the pharmacokinetics of fentanyl and its primary metabolite, norfentanyl, compared with normothermic controls.</p><p><strong>Methods: </strong>Male Wistar rats were divided into three groups and subjected to different environmental temperatures: normothermic controls (37 °C), MH (30 °C), and SH (27 °C). Fentanyl (10 µg/kg) was administered via a short intravenous infusion, and serial blood samples were collected over 60 min. Serum fentanyl and norfentanyl concentrations were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Pharmacokinetic parameters were calculated using Phoenix WinNonlin software.</p><p><strong>Results: </strong>Maximum fentanyl concentration increased in both MH and SH groups, reaching statistical significance only under severe hypothermia (p < 0.001). The area under the concentration-time curve (AUC) increased markedly (p = 0.009) in SH group, indicating increased overall drug exposure. Clearance decreased by 44% (p = 0.010), and volume of distribution in steady state (V_ss) was reduced in both groups (SH: p < 0.001, MH: p = 0.029), reflecting impaired drug elimination under severe hypothermic conditions. For norfentanyl, exposure increased significantly in the SH group across all parameters, whereas in the MH group increases were limited to C_max and AUC_0-t.</p><p><strong>Conclusions: </strong>Hypothermia significantly alters fentanyl and norfentanyl pharmacokinetics in a temperature-dependent manner.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"466-478"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146029985","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":"BET inhibitors in cardiovascular diseases: from atherosclerosis to heart failure.","authors":"Moein Ala, Izat Mohammad Khawajah, Sima Shamshiri Khamene","doi":"10.1007/s43440-025-00816-4","DOIUrl":"10.1007/s43440-025-00816-4","url":null,"abstract":"<p><p>Bromodomain and extra-terminal domain (BET) proteins act as acetyl lysine ‘readers’ that summon transcriptional factors and regulate gene expression. Deregulation of bromodomain-containing protein 4 (BRD4), a transcriptional and epigenetic regulator, is associated with increased epithelial-mesenchymal transition and profibrotic changes in the cardiovascular system. Consistently, BET inhibitors were shown to attenuate cardiac and vascular remodeling induced through several signaling pathways. BRD4 upregulation has been reported in essential hypertension, dyslipidemia, myocardial infarction, heart failure, pulmonary arterial hypertension (PAH), dilated cardiomyopathy, and diabetic cardiomyopathy. Interestingly, BET inhibitors were found to lower blood pressure, downregulate low-density lipoprotein (LDL), oxidative stress markers, and inflammatory cytokine levels, upregulate high-density lipoprotein (HDL), and prevent pathologic cardiac dysfunction and hypertrophy in animal studies. Furthermore, BET inhibition improved heart transplant survival and hindered neointima formation or vascular remodeling in vivo. Moreover, compared to placebo, apabetalone, a selective bromodomain 2 (BD2) inhibitor, improved cardiovascular outcomes in some clinical trials. These promising findings warrant further studies on the efficacy and safety of BET inhibitors for cardiovascular diseases. This review aimed to discuss the efficacy of BET inhibitors for cardiovascular diseases and unravel the underlying mechanisms.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"405-422"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900901","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":"Chronic fasudil treatment induces benzodiazepine-like tolerance via modulation of GABA-A receptor γ2 subunit expression and impairs contextual fear memory in mice.","authors":"Teresa Dipol, Ornella Morsilli, Andrea Fortuna, Valentina Zecca, Gianmauro Palombelli, Zaira Maroccia, Marcello Belfiore, Gabriele Campana, Laura Ricceri, Marco Feligioni, Caterina Motta, Alessandro Martorana, Giacomo Koch, Graziano Onder, Ciro Leonardo Pierri, Rossella Canese, Stefano Loizzo","doi":"10.1007/s43440-026-00838-6","DOIUrl":"10.1007/s43440-026-00838-6","url":null,"abstract":"<p><p>BACKGROUND: Fasudil hydrochloride (FAS) is a selective Ras homologous (Rho) associated kinase (ROCK) inhibitor and vasodilator used to treat cerebral vasospasm. Owing to its neuroprotective effects in preclinical models of neurodegeneration, FAS is currently under clinical investigation for several neurological diseases. Although the precise mechanism of action of FAS remains unclear, some preclinical studies suggest that it may exert anxiolytic and anticonvulsant effects—pharmacological activities typically associated with positive allosteric modulators of the γ‑aminobutyric acid (GABA)-A ​ receptor, such as benzodiazepines. This study investigates whether FAS acts as a modulator of the GABA-A ​ receptor and examines the effects of its chronic administration. METHODS: Protein comparative analyses and in silico docking assays were performed to assess the binding affinity of FAS for the GABA-A​ receptor. CD1 mice received daily oral administration of FAS for 12 weeks. One week after treatment cessation, behavioural tests and magnetic resonance (MR) analyses were conducted to evaluate brain function and metabolism. In addition, Rho guanosine triphosphatase activity, GABA-A receptor expression, and levels of postsynaptic density protein 95 (PSD‑95) were assessed. RESULTS: The computational analysis predicted a strong binding affinity of FAS for the GABA-A​ receptor. In vivo assays revealed that FAS impaired contextual fear memory without affecting anxiety-like behaviour, motor coordination, or recognition memory. These behavioural alterations were accompanied by a reduction in the γ2 subunit of the GABA-A​ receptor in both the hippocampus and the prefrontal cortex (PFC). Within the PFC, PSD‑95 expression was decreased, whereas the activity of Ras-related C3 botulinum toxin substrate 1 was increased. MR analyses showed elevated glutamate levels in the PFC, together with a general increase in total choline and a mild impairment of white matter integrity. CONCLUSIONS: Our findings suggest that FAS influences GABA-A receptor expression and may act as an allosteric modulator. Chronic treatment in healthy mice appears to adversely affect the PFC, producing behavioural and molecular alterations resembling those observed following prolonged benzodiazepine exposure. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"446-465"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181606","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":"Potentiating anti-inflammatory and antioxidant effects in vitro: the combined action of zofenoprilat and nebivolol.","authors":"Eleonora Maceroni, Annamaria Cimini, Michele d'Angelo, Marta Sofia Scenna, Suada Meto, Simone Baldini, Paolo Fabrizzi, Giovambattista Desideri, Vanessa Castelli","doi":"10.1007/s43440-026-00833-x","DOIUrl":"10.1007/s43440-026-00833-x","url":null,"abstract":"<p><strong>Background: </strong>The present study investigated the combined effects of zofenoprilat (ZOFE) and nebivolol (NEBI) on endothelial function, focusing on their anti-inflammatory and antioxidant properties. The purpose was to evaluate whether these drugs, commonly used in clinical practice, offer a synergistic therapeutic strategy for managing hypertension and protecting vascular health. ZOFE, an ACE inhibitor, demonstrated significant anti-inflammatory activities by reducing inflammatory cytokines, thereby mitigating vascular inflammation, a key factor in hypertension and atherosclerosis. NEBI, a third-generation beta-blocker, exhibited strong antioxidant effects by enhancing nitric oxide (NO) levels, crucial for maintaining endothelial function and reducing oxidative stress.</p><p><strong>Methods: </strong>The potential effect of ZOFE and NEBI treatment was evaluated using human umbilical vein endothelial cells (HUVEC) as a model. Specifically, cells were challenged with tumor necrosis factor-α (TNF-α) to induce endothelial dysfunction. Subsequently, cell viability, NO production, protein levels of superoxide dismutase (SOD) and catalase (CAT), enzymatic activity of SOD and CAT, intracellular levels of glutathione (GSH), inflammatory status, and levels of interleukin-6 (IL-6) monocyte chemoattractant protein-1 (MCP-1), macrophage inhibitory cytokine-1 (MIC-1), and the active form of nuclear factor kappa B (p-NFκB), were analyzed.</p><p><strong>Results: </strong>Our results showed that NEBI significantly counteracted oxidative stress, increasing the main antioxidant defenses (SOD, CAT, and GSH). The combination of ZOFE and NEBI resulted in a potentiated effect, enhancing both anti-inflammatory and antioxidant activities. This dual mechanism of action provides a comprehensive approach to protecting endothelial cells and improving vascular function. The combined therapy not only lowered blood pressure more effectively but also offered greater protection against endothelial damage compared to monotherapy with either drug alone. These findings suggest that the combination of ZOFE and NEBI could be particularly beneficial for patients with hypertension, especially those with coexisting inflammatory and oxidative stress-related conditions.</p><p><strong>Conclusions: </strong>This combination therapy, by addressing multiple pathogenic pathways simultaneously, could potentially be beneficial in patients with cardiovascular risk conditions. In conclusion, the combination of ZOFE and NEBI offers a potentially promising therapeutic approach for managing hypertension and protecting vascular health, aiming at improving clinical outcomes for patients with cardiovascular diseases.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"546-557"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12975774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106732","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":"Selected tryptophan metabolites and inflammatory molecules in hemodialyzed patients.","authors":"Izabela Zakrocka, Małgorzata Kozioł, Radosław Mlak, Marta Więckowska-Deroń, Natalia Moniczewska, Sylwia Boczkowska, Renata Kloc, Tomasz Kocki, Alina Olender, Ewa M Urbańska, Wojciech Załuska, Andreas Kronbichler","doi":"10.1007/s43440-026-00821-1","DOIUrl":"10.1007/s43440-026-00821-1","url":null,"abstract":"<p><p>BACKGROUND: Clearance of selected tryptophan (Trp) metabolites and inflammatory molecules was studied in patients treated by hemodialysis (HD) or hemodiafiltration (HDF). The impact of diabetes mellitus, preserved diuresis, dialysis modality, and pharmacotherapy on the pre-dialysis concentrations and reduction ratios (RRs) of selected solutes was analyzed. METHODS: Concentration of Trp, kynurenine (KYN), kynurenic acid (KYNA) and 3-hydroxykynurenine (3-OHKYN), aryl hydrocarbon receptor (AhR), hypoxia inducible factor-1α (HIF-1α), urokinase plasminogen activator (uPA), and its soluble receptor (suPAR) were measured in the blood, before and after each HD or HDF procedure, in a cohort of 62 stable patients with end stage kidney disease (ESKD). RESULTS: The levels of KYN, KYNA, 3-OHKYN, AhRs, and suPARs, but not of HIF-1 α, significantly decreased after dialysis. In patients with diabetes mellitus, a trend towards lower AhR was observed. In patients with preserved kidney function, pre-dialysis Trp concentration was higher, whereas KYNA, AhR, and uPA levels were lower. RR for KYN and suPAR was higher after HDF compared to HD. Pharmacotherapy with angiotensin converting enzyme inhibitors (ACEi), alpha-adrenergic antagonists, and loop diuretics correlated negatively with pre-dialysis levels of selected solutes. CONCLUSIONS: In the studied cohort of patients, the KYN pathway was activated and directed mostly towards neurotoxic metabolites. Clearance of studied Trp metabolites and immune molecules was limited and differed between kidney replacement therapy modalities. Correlation between studied molecules may indirectly suggest the involvement of novel pathways in the extracellular matrix modification and vascular structure control in dialyzed patients. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"582-596"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959936","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":"Hybrids of harmine and quinoline-based antimalarials show a strong antiproliferative effect on glioblastoma cells and reverse ATP-binding cassette transporter-mediated drug resistance.","authors":"Marija Mioč, Kristina Pavić, Goran Poje, Zrinka Rajić, Marijeta Kralj","doi":"10.1007/s43440-026-00849-3","DOIUrl":"10.1007/s43440-026-00849-3","url":null,"abstract":"<p><p>BACKGROUND: Glioblastomas (GBM) are the most aggressive tumors of the nervous system, with therapy limited by multidrug resistance (MDR) and poor drug penetration across the blood-brain barrier (BBB). The BBB expresses ATP-binding cassette (ABC) transporters, particularly ABCB1 (P-glycoprotein, P-gp) and ABCG2 (BCRP), which reduce intracellular drug concentrations and contribute to MDR. The aim of this study was to evaluate a series of β-carboline-quinoline hybrid compounds as potential glioblastoma therapeutics and modulators of ABC transporter activity. METHODS: Fifteen hybrid compounds, combining harmine and quinoline-based antimalarials via triazole or ureido linkers, were tested for cytotoxicity on U251 glioblastoma and SH-SY5Y neuroblastoma cell lines using cell viability assays. ABC transporter inhibition was assessed with cell-based functional assays measuring intracellular accumulation of fluorescent P-gp and ABCG2 substrates. Selected hybrids were further evaluated for their ability to sensitize chemoresistant cells to the reference drugs doxorubicin (DOXO) and mitoxantrone (MX). RESULTS: Most hybrids exhibited stronger cytotoxic effects on glioblastoma cells than their parent compounds and the reference drug temozolomide. Several compounds significantly inhibited P-gp and ABCG2 function, with ureido-type derivatives PU-9 and MU-9 showing the most pronounced dual inhibition. Importantly, these compounds enhanced the sensitivity of resistant cells to DOXO and MX, suggesting a potential strategy to overcome MDR. CONCLUSIONS: β-Carboline-quinoline hybrids, particularly PU-9 and MU-9, represent promising dual-function agents with both cytotoxic and ABC transporter-modulating activity. Their ability to reduce glioblastoma cell survival and sensitize resistant cells highlights their potential as leads for developing therapeutics that can overcome MDR and improve CNS drug delivery. CLINICAL TRIAL NUMBER: Not applicable. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147474960","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":"CC8, a heterodimeric disintegrin from Cerastes cerastes snake venom, triggers apoptosis and restrains the dissemination of human glioblastoma cells.","authors":"Maram Morjen, Khaoula Smati, Cyrine Souissi, Sahar Ben Lamine, Mbarka Barmet, Aurelie Chantome, Marie Potier-Cartereau, Christophe Vandier, Najet Srairi-Abid, Naziha Marrakchi, Jed Jebali","doi":"10.1007/s43440-026-00846-6","DOIUrl":"https://doi.org/10.1007/s43440-026-00846-6","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM) is the most aggressive and frequent primary malignant brain tumor and remains highly resistant to existing therapies. Snake-venom disintegrins possess potent anticancer activities, yet their pharmacological potential against GBM is not fully explored. In this work, we aimed to evaluate the therapeutic potential of the disintegrin CC8 from Cerastes cerastes snake venom, toward the development of a novel anti-GBM drug.</p><p><strong>Methods: </strong>The effects of CC8 on the viability and proliferation of human GBM cell lines U87, U251, LN229, and LN18 were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet assays. Apoptosis induction was examined by annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis of pro- and anti-apoptotic gene expression. The effect of CC8 on cell-extracellular matrix (ECM) interactions was evaluated through adhesion assays and integrin-blocking antibodies. GBM cell infiltration potential was further explored using cell invasion assays and spheroid-based migration models.</p><p><strong>Results: </strong>CC8 significantly reduced the viability of U87, LN18, and LN229 cells and inhibited the proliferation of U87, whereas U251 cells showed resistance up to 200 nM. CC8 induced caspase-dependent apoptosis, as evidenced by downregulation of BCL2 apoptosis regulator (BCL2) and upregulation of BCL2-associated X, apoptosis regulator (BAX), caspase 3 (CASP3), and caspase 8 (CASP8) expression. CC8 also disrupted cell adhesion to fibrinogen (Fg) and fibronectin (Fn) through integrin interference. Furthermore, it markedly decreased GBM cell invasion and reduced U87 spheroid migration.</p><p><strong>Conclusions: </strong>These findings identify CC8 as a promising venom-derived candidate for GBM drug development, with potential to improve therapeutic outcomes for this aggressive and treatment-resistant cancer.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147433671","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":"Sex differences in the antidepressant-like response induced by the imidazoline-2 receptor compound 12d, a (3-phenylcarbamoyl-3,4-dihydro‑2H‑pyrrol-2-yl)phosphonate.","authors":"Elena Hernández-Hernández, Sandra Ledesma-Corvi, Fernando Yáñez-Gómez, Neus Mateu-Mercader, Andrea Bagán, Carmen Escolano, M Julia García-Fuster","doi":"10.1007/s43440-025-00810-w","DOIUrl":"10.1007/s43440-025-00810-w","url":null,"abstract":"<p><strong>Background: </strong>The synthesis of (3-phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates provided novel compounds with relevant affinities for imidazoline 2 (I2) receptors in human brain tissues. A selected compound, 12d, showed improved cognitive and analgesic properties at the preclinical level through the modulation of I2 receptors, but its potential innovative use as an antidepressant is still unknown.</p><p><strong>Methods: </strong>Male and female adult Sprague-Dawley rats were treated with 3 ip injections of compound 12d (10 or 20 mg/kg), or vehicle (1 ml/kg DMSO), 24, 5, and 1 h prior to scoring its antidepressant-like efficacy under the stress of the forced-swim test. Hippocampal neuroplasticity markers (i.e., FADD, p-ERK/ERK, mBDNF) were evaluated 24 h post-treatment (and post-forced-swim test exposure).</p><p><strong>Results: </strong>The novel results proved a sex-dependent efficacy of 12d, with dose-dependent antidepressant-like effects in adult male rats, and an inefficacious response for females. Moreover, compound 12d did not alter any of the hippocampal markers evaluated.</p><p><strong>Conclusions: </strong>These results presented 12d as a novel therapeutic antidepressant candidate at the tested conditions, although only for male rats, thus requiring further studies to better understand the observed sex disparities as well as its molecular underpinnings. Moreover, compound 12d joins the list of other I2 receptor ligands with known antidepressant-like efficacy, validating and strengthening this receptor as a target in this field for future drug development.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"341-349"},"PeriodicalIF":3.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145715426","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":"Novel LC-MS/MS method for measuring methotrexate in high-dose therapy: a comparative study with commercial EMIT and EIA immunoassays.","authors":"Agnieszka Czajkowska, Aleksandra Mikulska, Martyna Poniewierska, Agnieszka Suchan, Maciej Sierakowski, Tomasz Pawiński, Arkadiusz Kocur","doi":"10.1007/s43440-025-00807-5","DOIUrl":"10.1007/s43440-025-00807-5","url":null,"abstract":"<p><strong>Background: </strong>Methotrexate (MTX) is a widely used chemotherapeutic agent in pediatric oncology, where high-dose protocols (HDMTX; ≥500 mg/m²) are standard for treating hematological and central nervous system malignancies. Due to its narrow therapeutic index and potential for severe toxicity, therapeutic drug monitoring (TDM) of plasma MTX concentrations is essential to guide leucovorin rescue therapy and prevent adverse effects.</p><p><strong>Methods: </strong>The presented study aimed to compare the analytical performance of two immunoassays-enzyme-multiplied immunoassay technique (EMIT) and enzyme immunoassay (EIA)-against a newly developed and validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.</p><p><strong>Results: </strong>The LC-MS/MS assay demonstrated excellent linearity, sensitivity (LLOQ = 0.01 µmol/L), and precision, meeting ICH M10 regulatory guidelines. Clinical samples from pediatric patients receiving HDMTX were analyzed using all three methods. Results showed strong correlations (r > 0.93) between methods; however, immunoassays exhibited biases related to cross-reactivity with MTX metabolites such as DAMPA (2,4-diamino-N₁₀-methylpteroic acid) and 7-OH-MTX, which may lead to overestimation of MTX levels and unnecessary prolongation of leucovorin rescue.</p><p><strong>Conclusions: </strong>While immunoassays remain practical for routine monitoring due to their accessibility and speed, LC-MS/MS provides superior accuracy and should be the method of choice in critical clinical situations. These findings underscore the importance of selecting the appropriate assay to optimize HDMTX therapy and ensure patient safety.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"327-340"},"PeriodicalIF":3.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12795967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145549926","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}