Pharmacological Reports最新文献

{"title":"WIN55,212-2 attenuates intestinal fibrosis in a DSS-induced mouse model.","authors":"Zofia Misztal, Maria Wołyniak, Ewa Małecka-Wojciesko, Adam Fabisiak","doi":"10.1007/s43440-026-00822-0","DOIUrl":"10.1007/s43440-026-00822-0","url":null,"abstract":"<p><p>BACKGROUND: Inflammatory bowel diseases (IBD) are often associated with intestinal fibrosis. There is increased interest in new methods for managing intestinal fibrosis, among which the endocannabinoid system (ECS) is an interesting therapeutic target. The primary purpose of the study was to evaluate the effect of CB1/2 agonist, WIN 55,212-2 (WIN) on expression of fibrosis regulatory proteins: alpha smooth muscle Actin 2 (ACTA2), Collagen I (COLIA1), Fibronectin 1 (FN1) and SMAD family member 3 (SMAD3) in a mice model of dextran sulfate sodium (DSS)-induced intestinal fibrosis. METHODS: Chronic intestinal fibrosis was induced by oral administration of 1.5% DSS in rotation with tap water for 3 weeks in three cycles. WIN was administered intraperitoneally, once daily starting from day 10th and continued every other day until day 77th. The expression of genes encoding ACTA2, COL1A1, FN1, SMAD3, Col1a1, Fn1 both in mouse and human colon, was assessed with real-time PCR. RESULTS: We found lower relative expression of genes encoding fibrosis regulatory proteins in colonic mucosa of mice treated with WIN than in inflamed mice: ACTA2 (–51%), COL1A1 (–44%), FN1 (–60%), and SMAD3 (–22%). Human colonic mucosal patients with UC showed higher expression of COL1A1 (+ 57%) and SMAD3 (+ 34%) compared to healthy controls. CONCLUSIONS: Our results show that regulation of ECS activity may play a role in the inhibition of intestinal fibrosis in IBD and appears as a potential therapeutic target in patients at high risk of developing strictures. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"479-486"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12975791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053376","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":"The PERK inhibitor GSK2606414 evokes developmental defects in zebrafish consistent with Wolcott-Rallison syndrome phenotypes.","authors":"Liliana M Almeida, Leonor Pereira Lima, Nuno A S Oliveira, Rui F O Silva, Bruno Sousa, José Bessa, Brígida R Pinho, Jorge M A Oliveira","doi":"10.1007/s43440-026-00837-7","DOIUrl":"10.1007/s43440-026-00837-7","url":null,"abstract":"<p><p>BACKGROUND: Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is an endoplasmic reticulum stress kinase whose loss of function disturbs human development, leading to skeletal dysplasia and permanent neonatal diabetes, as in the Wolcott-Rallison Syndrome (WRS). The lack of effective, less invasive therapies for developmental diseases highlights the need for animal models that replicate complex pathological phenotypes, while allowing scalable drug screening. Zebrafish high fecundity and rapid development enable efficient in vivo drug testing. We assessed zebrafish’s potential for studying PERK and its pharmacological modulation in developmental diseases like WRS. METHODS: To assess the similarity between human and zebrafish PERK we used bioinformatic analyses. To inhibit PERK we used GSK2606414. To evaluate effects on skeletal, neuromuscular, and cardiac development we combined behavioural and functional assays. To assess diabetic-like phenotypes we used fluorescent pancreatic markers and a glucose probe. RESULTS: Zebrafish PERK conserves 11 of 12 critical GSK2606414‑binding residues (predicted 3D structures highly similar). Functionally, GSK2606414 (10 µM) decreased levels of PERK pathway markers and induced WRS-relevant phenotypes: reduced body length, increased trunk–tail curvature, decreased cranial cartilage staining; neuromuscular impairment (altered reflexes, reduced muscle birefringence) and cardiac dysfunction (pericardial oedema, reduced stroke volume and cardiac output). However, parameters not associated with WRS like otolith area and eye/body ratio remained unaffected. Moreover, GSK2606414 decreased 𝛽-cell mass and lowered 2-NBDG-glucose uptake in neuromasts, consistent with diabetic-like phenotypes. CONCLUSION: These findings evidence zebrafish’s potential for studying PERK function and its pharmacological modulation in developmental disorders like WRS, aiding research on pathophysiology and experimental treatments. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"487-504"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12975795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181585","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":"The synaptic triad in depression: how stress-related pathways converge on BDNF, NMDA receptor, and MMP-9.","authors":"Bartosz Adam Frycz, Magdalena Dutsch-Wicherek, Olga Płaza, Agata Szulc, Monika Bijata, Jakub Wlodarczyk, Joanna Dzwonek","doi":"10.1007/s43440-026-00827-9","DOIUrl":"10.1007/s43440-026-00827-9","url":null,"abstract":"<p><p>Chronic stress is a major precipitating factor in depression, engaging interconnected central and peripheral pathways. In this review, we propose an integrative model that organizes the neurobiological consequences of stress around five major mechanistic domains: neurotrophic dysfunction, disturbances in inhibition-excitation (E/I) balance, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, neuroinflammatory activation, and monoaminergic alterations. Although each hypothesis highlights distinct aspects of stress-related pathology, we argue that they ultimately converge on shared molecular mediators, including matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and N-methyl-D-aspartate (NMDA) receptor-dependent signalling, that govern synaptic plasticity.In this model, synaptic plasticity emerges as the final common mechanism through which chronic stress produces enduring alterations in brain structure and function. Context-dependent modulation of MMP-9 activity, dysregulated BDNF processing, NMDA-dependent control of synaptic strength, and monoaminergic influences on neurotrophic and glial function collectively impair synaptic plasticity. As a result, stress-driven pathways lead to altered dendritic spine architecture, reduced neurogenesis, and maladaptive network-level changes underlying depressive behavior. By positioning synaptic plasticity as the convergent endpoint of diverse stress-responsive mechanisms, the model highlights common therapeutic targets, including MMP-9 modulation, BDNF-enhancing strategies, HPA-axis regulators, anti-inflammatory approaches, and NMDA receptor-based interventions, offering new directions for mechanism-based and personalized treatments in depression.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"351-373"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146065909","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":"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}