Naunyn Schmiedebergs Arch. Pharmacol. [JOURNAL]
Sun
200 papers
Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: a bibliometric analysis of global research trends and research hotspots from 2006 to 2025.
Bi Q, Zhang L, Zhang J … +6 more , Wang X, Zuo C, Zhao S, Wang Z, Zhao Z, Wan H
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42384167 · Publisher ↗
This study aimed to systematically characterize the global research landscape, collaboration patterns, knowledge structure, and emerging hotspots of glucagon-like peptide-1 receptor agonists in neurodegenerative diseases...
This study aimed to systematically characterize the global research landscape, collaboration patterns, knowledge structure, and emerging hotspots of glucagon-like peptide-1 receptor agonists in neurodegenerative diseases using bibliometric methods. Publications related to glucagon-like peptide-1 receptor agonists and neurodegenerative diseases were retrieved from the Web of Science Core Collection from 2006 to 2025. Only English-language articles and reviews were included. Bibliometric analyses were performed using Bibliometrix, VOSviewer, and CiteSpace to evaluate annual publication trends, country and institutional contributions, author collaborations, journal distribution, citation structures, keyword co-occurrence, thematic evolution, and citation bursts. A Scopus-based sensitivity analysis was conducted to assess the robustness of the main bibliometric findings. A total of 1,202 publications were included, with annual output increasing from 2 in 2006 to 241 in 2025, particularly after 2020. China, the USA, and England were the leading contributors and major collaboration hubs. Shanxi Medical University, Lancaster University, and the National Institute on Aging were among the most productive institutions, while major journals included International Journal of Molecular Sciences, Neuropharmacology, European Journal of Pharmacology, Frontiers in Endocrinology, Frontiers in Pharmacology, and Journal of Alzheimer's Disease. Keyword and citation analyses indicated a thematic shift from exendin-4, Alzheimer's disease, Parkinson's disease, and neuroprotection toward semaglutide, neuroinflammation, cognitive impairment, clinical efficacy, evidence synthesis, and combination therapy. Research on glucagon-like peptide-1 receptor agonists in neurodegenerative diseases has expanded rapidly over the past two decades. Current bibliometric evidence suggests that this field has evolved from preclinical exploration toward broader translational and clinical research, with increasing attention to neuroinflammation, metabolic dysfunction, cognitive outcomes, and newer incretin-based therapies. However, the therapeutic implications of glucagon-like peptide-1 receptor agonists for neurodegenerative diseases remain to be further validated by high-quality mechanistic studies and well-designed clinical trials.
Contractile effects of dulaglutide in the human atrium.
Neumann J, Jarikova M, Hofmann B … +2 more , Kirchhefer U, Gergs U
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42380521 · Publisher ↗
Dulaglutide is a glucagon-like peptide 1 receptor (GLP-1R) agonist. Dulaglutide (LY2189265) is a GLP-1(7-37) analogue fused by a linker to a modified immunoglobulin G. GLP-1R agonists like dulaglutide can be used to trea...
Dulaglutide is a glucagon-like peptide 1 receptor (GLP-1R) agonist. Dulaglutide (LY2189265) is a GLP-1(7-37) analogue fused by a linker to a modified immunoglobulin G. GLP-1R agonists like dulaglutide can be used to treat diabetes type 2 and obesity. We tested the hypothesis that dulaglutide directly increased force of contraction in the human heart via GLP-1R. To this end, we conducted contraction experiments in paced (1 Hz) isolated human right atrial muscle preparations (HAP). HAP were obtained during open-heart surgery from adult patients with severe coronary heart disease. We detected a concentration- and time-dependent positive inotropic effect of dulaglutide in HAP. Dulaglutide augmented the rate of tension development, the rate of tension relaxation and accelerated the relaxation time in HAP. Dulaglutide (100 nM) augmented the phosphorylation state of phospholamban at serine 16 and the phosphorylation state of the inhibitory subunit of troponin. The positive inotropic effect of 100 nM dulaglutide in HAP was attenuated by 100 nM exendin (9-39). In contrast, dulaglutide alone or in the presence of phosphodiesterase inhibitor rolipram up to 100 nM failed to exert a positive inotropic effect in isolated electrically paced (1 Hz) mouse left atrial preparations and did not increase the beating rate of spontaneously beating mouse right atrial preparations. Our data suggest that dulaglutide raised force of contraction in the isolated paced human atrium via GLP-1R involving cAMP-dependent protein kinase in HAP.
Young Investigator Award 2026: Extent and incidence of pseudo-worsening of kidney function due to oral antitumor therapeutics in the AMBORA cohort: an analysis of real-world data.
Sponfeldner MI
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42380520 · Publisher ↗
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A new chapter in the history of Naunyn-Schmiedebergs Archives of Pharmacology: appointment of international deputy editors.
Seifert R, El-Mas MM, Hattori Y … +1 more , Kapoor DU
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42380519 · Publisher ↗
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Deacetyl xylopic acid exhibits synergistic antidepressant-like effects and augments fluoxetine activity in a chronic restraint-induced depression model in mice.
Benneh CK, Abotsi WKM, Moomin A … +6 more , Biney RP, Ofosu JO, Abeka MK, Tandoh A, Adongo DW, Woode E
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42377453 · Publisher ↗
Xylopic acid (XA) and the deacetyl derivative (dXA) have been shown to exhibit antidepressant activity in acute models of depression in mice. This study evaluated and compared the effect of the deacetyl derivative in a c...
Xylopic acid (XA) and the deacetyl derivative (dXA) have been shown to exhibit antidepressant activity in acute models of depression in mice. This study evaluated and compared the effect of the deacetyl derivative in a chronic restrain model of depression. In the first phase of the study, the synergistic potential of dXA was evaluated using the mouse tail suspension test (TST) and forced swim test (FST). In the second phase, mice were subjected to chronic restraint stress for 42 days, starting from day 0, in ventilated tubes (0800-1400 h). On day 42, stress-naïve and stressed mice were assessed using both the FST and TST to identify the more sensitive behavioural assay for subsequent evaluation of treatment effects. Stressed mice were then administered fluoxetine, XA, dXA, vehicle for 72 h or single acute dosing of combinations of fluoxetine with XA or dXA, followed by repeat behavioural testing 90 min after the last dose of either a single acute or a chronic dosing regimen. The interaction index (γ), together with the significantly lower ED compared to the ED, for the dXA combinations, with fluoxetine, sertraline, imipramine and ketamine is indicative of synergistic effect. An 8-hourly dosing, for 72 h of XA (100 mg kg) and dXA (100 mg kg) in the acute models did not reverse the behavioural traits of chronic restrain. However, fluoxetine (30 mg kg), given 12 hourly for 72 h, and the acute administration of combinations of fluoxetine (100 mg kg) and dXA (100 mg kg) significantly reversed the duration of immobility. The present study demonstrates that deacetyl xylopic acid (dXA) exerts synergistic antidepressant-like effects with selective antidepressants and augments the antidepressant effects of fluoxetine in a mouse model of chronic restraint stress-induced depression. These findings suggest that dXA may represent a promising adjunctive agent for improving antidepressant efficacy, particularly in stress-related depressive disorders.
Protective in vitro effects of antioxidants against DNA damage induced by metabolites accumulated in propionic and methylmalonic acidemias.
Dos Reis BG, Lopes FF, Tedesco LMB … +3 more , de Moura Sarmento SM, Manfredini V, Vargas CR
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42377452 · Publisher ↗
Methylmalonic acidemia and propionic acidemia are inborn errors of metabolism caused by genetic mutations in mitochondrial enzymes involved in propionate metabolism. When these enzymes fail to function properly, organic...
Methylmalonic acidemia and propionic acidemia are inborn errors of metabolism caused by genetic mutations in mitochondrial enzymes involved in propionate metabolism. When these enzymes fail to function properly, organic acids accumulate in tissues and biological fluids. The brain is the primary tissue affected in these disorders, particularly due to the accumulation of organic acids. Oxidative stress and DNA damage play an important role in the pathophysiology of these diseases and may contribute to neurological impairment. In this context, the present study aimed to evaluate the in vitro effects of L-carnitine, N-acetylcysteine, and coenzyme Q10 on DNA damage induced by metabolites accumulated in methylmalonic and propionic acidemias. Leukocytes isolated from whole blood were used, and DNA damage was assessed using the comet assay. Our results demonstrated that metabolites accumulated in these disorders were responsible for inducing DNA damage, individually and in combination. In addition, all tested antioxidants exhibited protective effects against DNA damage. This study is the first to demonstrate the genotoxic effects of other metabolites beyond methylmalonic and propionic acids and to show the protective potential effect of different antioxidants in mitigate DNA damage. Taken together, these findings reinforce the need for clinical trials evaluating antioxidant-based therapies to improve prognosis and clinical outcomes in patients with methylmalonic acidemia and propionic acidemia.
From molecular mechanisms to digital surveillance: the 2010-2025 evolution of benzodiazepine and Z-drug misuse research.
Liu J, Zhu W, Zhang Z … +2 more , Zhao Q, Wang Y
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42373974 · Publisher ↗
The misuse of benzodiazepines (BZDs) and Z-drugs poses significant global public health challenges. This study maps the scientific evolution and paradigm shifts in this field from 2010 to 2025. A bibliometric analysis of...
The misuse of benzodiazepines (BZDs) and Z-drugs poses significant global public health challenges. This study maps the scientific evolution and paradigm shifts in this field from 2010 to 2025. A bibliometric analysis of 6,311 publications from the Web of Science Core Collection was performed using VOSviewer and CiteSpace to identify collaboration networks, research hotspots, and emerging frontiers. The USA and Harvard Medical School dominated global contributions. Research hotspots evolved through three distinct phases: (1) 2010-2014 focused on GABA receptor subtype-specific pharmacology, specifically the role of the alpha1 subunit in midbrain disinhibition and the biological basis of addiction; (2) 2015-2019 shifted toward the pharmacodynamic synergy of BZD-opioid interactions and the implementation of mass spectrometry-based toxicological surveillance; and (3) 2020-2025 centered on integrated computational pharmacology (QSAR and docking) for designer BZDs, alongside digital governance using electronic health records (EHR) and machine learning for precision deprescribing. Burst detection reveals a trajectory shifting from retrospective mechanistic deconstruction to prospective, data-driven risk prediction. BZD research has undergone a paradigm shift from molecular pharmacology to multidimensional digital and computational surveillance. Future directions prioritize utilizing big data and in silico modeling for individualized risk forecasting and precision clinical intervention to address the complex landscape of designer analogs and improve public mental health governance.
Bisphenol A promotes esophageal carcinogenesis by activating the MMP1-PCOLCE regulatory axis and remodeling the tumor immune microenvironment.
Cui Y, Shen G, Chen H … +8 more , Wang R, Zhang C, Han L, Wang K, Chen Y, Li J, Gao X, Dai Y
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42373973 · Publisher ↗
Bisphenol A (BPA), a ubiquitous environmental endocrine-disrupting chemical extensively used in plastic products, has been increasingly recognized for its carcinogenic potential. However, the molecular mechanisms underly...
Bisphenol A (BPA), a ubiquitous environmental endocrine-disrupting chemical extensively used in plastic products, has been increasingly recognized for its carcinogenic potential. However, the molecular mechanisms underlying BPA-associated esophageal carcinogenesis remain incompletely understood. In this study, we integrated transcriptomic differential expression profiling, weighted gene co-expression network analysis (WGCNA), and a comprehensive machine-learning framework incorporating 127 predictive models to systematically identify critical molecular targets involved in BPA-driven esophageal cancer initiation. Single-cell RNA sequencing datasets were further employed to characterize the cell-type-specific distribution of these candidate targets within the tumor microenvironment. Molecular docking and molecular dynamics simulations were conducted to evaluate the binding affinity and interaction stability between BPA and target proteins. SHAP-based interpretability analysis was applied to pinpoint the core regulatory target. Subsequently, scTenifoldKnk virtual gene knockout analysis was utilized to explore downstream signaling mediators. A total of twelve key targets were identified, predominantly enriched in immune and epithelial cell subpopulations at the single-cell level. Docking analyses demonstrated strong binding affinities between BPA and multiple target proteins. Notably, SHAP analysis highlighted MMP1 as the central target mediating BPA-induced esophageal tumorigenesis, which was further supported by molecular dynamics simulations indicating a highly stable interaction. scTenifoldKnk analysis revealed PCOLCE as a potential downstream effector of MMP1 signaling. Collectively, our findings elucidate a previously unrecognized mechanism by which BPA promotes esophageal carcinogenesis through activation of the MMP1-PCOLCE regulatory axis and remodeling of the tumor immune microenvironment. This study provides novel molecular insights and potential therapeutic targets for future toxicological and translational investigations.
Integrative multi-omics and network toxicology reveal candidate molecular targets of deoxynivalenol in melanoma.
Wang Z, Yang C, Wang W … +3 more , Zhang Z, Sun Z, Diao Z
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42373972 · Publisher ↗
Deoxynivalenol (DON) has been reported to exhibit skin toxicity and carcinogenic potential; however, its effects on melanoma remain unclear. We integrated network toxicology, single-cell transcriptomic analysis, molecula...
Deoxynivalenol (DON) has been reported to exhibit skin toxicity and carcinogenic potential; however, its effects on melanoma remain unclear. We integrated network toxicology, single-cell transcriptomic analysis, molecular docking, and publicly available Human Protein Atlas immunohistochemical evidence to investigate the potential toxicological effects of DON on melanoma and identify candidate molecular targets. A total of 5283 DON-related genes were identified from the SwissTargetPrediction, CTD, and SEA databases, and 5101 melanoma-related genes were obtained from the GeneCards, TTD, and OMIM databases. Differentially expressed genes from the GSE15605 dataset were used for intersection validation. After further screening with three machine learning algorithms, MYEF2 was identified as a core target potentially involved in DON-induced melanoma. ROC analysis showed that MYEF2 achieved AUC values above 0.75 in both the training and validation cohorts. Single-cell transcriptomic analysis revealed the expression and distribution of MYEF2 across melanoma cell subtypes. Immune infiltration analysis further showed significant associations between MYEF2 and multiple immune cell populations. Molecular docking supported a stable interaction between DON and MYEF2, and HPA validation confirmed its elevated expression in melanoma. These findings suggest that MYEF2 may represent a candidate molecular target involved in DON-associated melanoma progression, providing a theoretical basis for future studies on the mechanisms and risk assessment of DON exposure.
The endothelin-1/TLR4/NF-κB/NLRP3 inflammasome axis in preeclampsia: a review of a pathological feed-forward loop and therapeutic frontier.
Alshaikh ABA, Al-Kuraishy HM, Hasanain RS … +5 more , Kafy S, Albar MH, Sebghatallah A, Shokr MM, Batiha GE
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42373971 · Publisher ↗
Preeclampsia remains a primary cause of maternal and neonatal mortality, yet no definitive therapy targets the placenta itself, and current management is largely limited to delivery. Recent research has identified a self...
Preeclampsia remains a primary cause of maternal and neonatal mortality, yet no definitive therapy targets the placenta itself, and current management is largely limited to delivery. Recent research has identified a self-sustaining, feed-forward molecular loop involving exaggerated placental endothelin-1 (ET-1) signaling, amplified by the TLR4/NF-κB/NLRP3 inflammasome axis, as a central driver of the disease. This axis translates placental hypoxia and oxidative stress into sustained maternal endothelial injury; while ET-1 acts as a potent vasoconstrictor that stimulates the NLRP3 inflammasome, the resulting inflammasome-driven IL-1β further upregulates ET-1 production. This inflammatory engine promotes the release of anti-angiogenic factors such as sFlt-1 and soluble endoglin. Evidence from human primary trophoblast cultures, placental explants, and animal models demonstrates that interrupting this axis can collapse the pathological cycle. Selective ET1_A receptor antagonists and direct NLRP3 inhibitors have shown high efficacy in reducing anti-angiogenic output and restoring maternal vascular function, while repurposed drugs like sulfasalazine and pravastatin offer immediate translational opportunities. Ultimately, the ET-1/NLRP3 axis represents a highly actionable target for modifying the course of preeclampsia in a significant subset of patients, particularly those with hypoxic, metabolic, or TLR4-driven inflammatory phenotypes. Genetically stratified trials are now needed to identify who benefits most. However, the relative contribution of this axis varies across the clinical and genetic heterogeneity of preeclampsia, necessitating biomarker-guided trial design.
Zingerone attenuates aluminum chloride/D-galactose-induced hippocampal neurotoxicity in mice: Modulation of oxidative stress, astrogliosis, cholinergic function, ATP hydrolysis, and neurotrophic signaling.
Oria RS, Akpang KE, Ugbem LP … +5 more , Ojie AP, Obu T, Oge PA, Ohaegbulam CM, Igiri AO
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42365121 · Publisher ↗
Neurodegenerative disorders constitute a growing global health concern, with oxidative stress, cholinergic dysfunction, and compromised neuroplasticity identified as key pathological contributors. Zingerone, a bioactive...
Neurodegenerative disorders constitute a growing global health concern, with oxidative stress, cholinergic dysfunction, and compromised neuroplasticity identified as key pathological contributors. Zingerone, a bioactive phenolic compound from ginger (Zingiber officinale), possesses antioxidant and anti-inflammatory properties, but its neuroprotective capacity against combined aluminum chloride (AlCl₃) and D-galactose (D-Gal)-induced hippocampal neurotoxicity remains poorly characterized. This study evaluated the neuroprotective effects of zingerone (100 mg/kg) on spatial memory, brain antioxidant enzyme activities, acetylcholinesterase (AChE) activity, ATP hydrolysis and nitric oxide levels, together with hippocampal neuronal integrity, astrocytic reactivity, and brain-derived neurotrophic factor (BDNF) expression, in mice co-exposed to AlCl₃ and D-Gal, with donepezil (10 mg/kg) as the standard reference drug. Twenty male Swiss mice were randomly assigned to four groups (n = 5): Control, AlCl₃/D-Gal, AlCl₃/D-Gal + Zingerone, and AlCl₃/D-Gal + Donepezil. AlCl₃/D-Gal co-exposure significantly impaired Y-maze and Morris water maze performance, depleted catalase and superoxide dismutase activities, elevated AChE activity, ATP hydrolysis, and nitric oxide levels, reduced Nissl substance staining, increased glial fibrillary acidic protein (GFAP) immunoreactivity, and suppressed BDNF expression. Zingerone significantly reversed these deficits, producing significantly greater restoration of superoxide dismutase activity than donepezil (p < 0.01) and numerically greater catalase and BDNF responses, whereas donepezil produced greater AChE inhibition and a greater reduction in nitric oxide. These contrasting profiles indicate complementary mechanisms rather than therapeutic superiority of either agent, and provide a rationale for evaluating a zingerone-donepezil combination in future studies. These findings position zingerone as a promising multi-target neuroprotective agent.
Pseudomonas aeruginosa ST4936 with extensive antibacterial drug resistance and virulence determinants from ureteral stent biofilms: whole-genome insights.
Khan N, Faryal R, Khan MH … +1 more , Ali L
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42365120 · Publisher ↗
Newly emerging Pseudomonas aeruginosa sequence types carrying diverse antibacterial resistance and virulence determinants pose serious clinical concerns. This study aimed to characterize the genomic features of P. aerugi...
Newly emerging Pseudomonas aeruginosa sequence types carrying diverse antibacterial resistance and virulence determinants pose serious clinical concerns. This study aimed to characterize the genomic features of P. aeruginosa isolates recovered from ureteral stent biofilms, focusing on antibacterial drug resistance genes, virulence determinants, and mobile genetic elements. P. aeruginosa isolates were confirmed phenotypically and underwent whole-genome sequencing. Multilocus sequence typing and phylogenomic, pangenomic analysis, and comprehensive bioinformatics tools were used to investigate the genomic determinants. All isolates belonged to ST4936 and clustered together phylogenetically, while exhibiting notable genomic variations. Resistome analysis identified acquired resistance genes, including bla, bla, aac(6')-Ib, aadA6, rmtF, sul1, dfrA15, and crpP, in addition to several intrinsic resistance genes. A total of 207 virulence-associated genes were detected, including type III secretion system (exoU, exoY, and exoT), alginate (algU, algW, mucA, mucD), flagellar genes (fliC, fliD, fleI, fleP), quorum sensing (lasI, lasR, rhlR), pyoverdine (pvdA, pvdE, pvdD, pvdS) and type IV pili (pilA, pilB). Four insertion sequences (ISPa6, ISPa7, ISPa32, and ISPa26) and multiple prophages were identified. Pangenomic analysis revealed extensive accessory gene content and genome rearrangements. To the best of our knowledge, this is the first genomic characterization of ST4936 P. aeruginosa isolated from ureteral stent biofilms in Pakistan. The combination of extensive antibacterial resistance determinants, numerous virulence factors, and mobile genetic elements suggests that ST4936 might have the potential to persist in ureteral stent-associated infections and limit antibacterial treatment options. However, multicenter surveillance studies are required to determine its epidemiological significance in Pakistan.
Ferric ion-mediated biomimetic mineralization of human serum albumin with doxorubicin and celastrol for enhanced antitumor therapy.
Liu J, Chen J, Zhang L … +1 more , Xia C
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42365119 · Publisher ↗
Doxorubicin (DOX) efficacy in breast cancer is limited by dose-dependent cardiotoxicity and the development of multidrug resistance, while celastrol (Cel) suffers from poor solubility, low bioavailability and systemic to...
Doxorubicin (DOX) efficacy in breast cancer is limited by dose-dependent cardiotoxicity and the development of multidrug resistance, while celastrol (Cel) suffers from poor solubility, low bioavailability and systemic toxicity. Their combination offers synergistic potential, but effective co-delivery remains challenging. We designed a protein-based nanoplatform via ferric ion-mediated biomimetic mineralization co-assembly of DOX, Cel, and human serum albumin (HSA) for enhanced antitumor therapy. HSA-Fe(III)-Cel-DOX nanoparticles were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Drug loading and encapsulation efficiencies were determined by high-performance liquid chromatography (HPLC). In vitro drug release was evaluated with or without glutathione (GSH). Cytotoxicity against 4T1 murine breast cancer cells was assessed by CCK-8 assay. The optimized HSA-Fe(III)-Cel-DOX NPs (8 mM Fe⁺) exhibited uniform spherical morphology with an average diameter of approximately 64.6 nm and narrow size distribution (PDI = 0.103). The nanoparticles demonstrated exceptionally high drug encapsulation efficiencies (96.7 ± 1.9% for DOX and 94.5 ± 1.4% for Cel) and drug loading capacities (19.7 ± 0.5% for DOX and 17.3 ± 0.4% for Cel). The formulation exhibited excellent colloidal stability over 28 days of storage. In vitro release studies revealed remarkable GSH-responsive behavior, with cumulative release reaching 77.0 ± 3.3% for DOX and 64.0 ± 2.9% for Cel at 12 h under reducing conditions, while negligible release (< 5%) under non-reducing conditions was observed in the absence of GSH. Cytotoxicity assays demonstrated that HSA-Fe(III)-Cel-DOX NPs exerted significantly enhanced antitumor effect against 4T1 cells compared to free DOX or free Cel alone. At an equivalent DOX concentration of 0.5 μg/mL, the nanoparticles reduced cell viability to 29.2 ± 1.2%, substantially lower than free DOX (89.7 ± 2.0%) or free Cel (100.4 ± 2.2%). We successfully constructed a ferric ion-mediated biomimetic nanoplatform via co-assembly of DOX, Cel, and HSA. This nanoplatform offers facile preparation, excellent stability, GSH-responsive drug release, and significantly enhanced in vitro cytotoxicity, representing a promising strategy for synergistic breast cancer therapy.
Real-world analysis of fibrinolytics-associated bleeding and literature synthesis.
Hong X, Wei Q, Wang ZL … +3 more , Wang YZ, Li LC, Jiang Q
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42365118 · Publisher ↗
Fibrinolytic agents are essential for acute thrombotic diseases, yet their significant bleeding risks pose a critical clinical challenge, underscoring the need to understand and quantify these risks to optimize outcomes...
Fibrinolytic agents are essential for acute thrombotic diseases, yet their significant bleeding risks pose a critical clinical challenge, underscoring the need to understand and quantify these risks to optimize outcomes and ensure patient safety. This study leveraged real-world data from the FDA Adverse Event database to analyze global bleeding events associated with fibrinolytic agents from 2004 to 2024. Using disproportionality analysis with multiple complementary statistical algorithms, we identified robust signals linking specific bleeding events to fibrinolytic therapies. The analysis revealed that the majority of bleeding events occurred within the first 30 days of therapy, with severe outcomes such as death, hospitalization, and life-threatening complications predominating. Notably, neurological indications, including ischemic stroke and cerebrovascular accident, exhibited the highest bleeding reporting signal, while significant variations in reporting trends and outcomes were observed across different indications and demographics. Procedural and intracranial bleeding emerged as critical concerns, with strong statistical signals highlighting their clinical relevance. The insights advance the understanding of fibrinolytic-associated bleeding signals and provide an evidence base to support individualized risk-benefit assessments and targeted interventions to enhance patient outcomes in thrombotic disease management.
Structure-based immunopharmacological design of a multi-epitope vaccine candidate against Naegleria fowleri targeting TLR3: a pan-genomic and molecular dynamics approach.
Faizan R, Naveed M, Estevez IB … +7 more , Rehman HM, Latif A, Hammad HM, Khan AR, Alsulami SO, Aljumaa MA, Tombozara N
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42365117 · Publisher ↗
Naegleria fowleri is a highly lethal free-living protozoan responsible for primary amoebic meningoencephalitis (PAM), a rapidly progressive central nervous system infection with a mortality rate exceeding 95%, for which...
Naegleria fowleri is a highly lethal free-living protozoan responsible for primary amoebic meningoencephalitis (PAM), a rapidly progressive central nervous system infection with a mortality rate exceeding 95%, for which no licensed vaccine or effective preventive therapy currently exists. The absence of prophylactic strategies demands development of novel immunopharmacological interventions. In this study, a comprehensive pan-genomic and structure-guided immunoinformatics approach was employed to design a multi-epitope vaccine candidate against N. fowleri. Four genomes of N. fowleri were subjected to an integrative pan-genomic-immunoinformatics pipeline involving orthologous clustering, subtractive genomics, and immunological relevance screening. From 1427 predicted membrane proteins, 885 antigenic, non-allergenic, and non-toxic candidates were identified. Epitope prediction yielded 7 B-cell epitopes, 26 MHC class I-restricted CTL epitopes, and 22 MHC class II-restricted HTL epitopes, which were assembled into a multi-epitope vaccine construct with immunostimulatory adjuvants. The resulting 320-amino acid construct demonstrated high antigenicity and global population coverage of 91.75%. Structural validation confirmed 98.9% of residues in favorable Ramachandran regions and an ERRAT quality score of 92.484. Molecular docking with Toll-like receptor 3 (TLR3) revealed a highly stable complex with a weighted energy score of - 1475.4 kcal/mol, featuring 24 hydrogen bonds and 5 salt bridges. Molecular dynamics simulations over 100 ns demonstrated structural stability with low RMSD and RMSF values, indicating dynamic stability and coordinated residue motions. Immune simulations predicted strong humoral and cellular immune responses with sustained antibody levels and memory cell generation. Codon optimization achieved a CAI of 0.99 and 53.4% GC content, supporting heterologous expression in Escherichia coli. This multi-epitope vaccine candidate exhibits strong immunogenic potential, structural stability, and favorable interactions with innate immune receptors, positioning it as a promising candidate for experimental validation against N. fowleri infection.
Unveiling the potential of solid lipid nanoparticles of apigenin-Cu(II) coordinated nanocomplex in colon cancer.
Kasture K, Shende P
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42365116 · Publisher ↗
To engineer biocompatible, colon-targeted delivery vehicle utilizing octadecanol-dextran (Odl-Dex)-coated apigenin-copper (Apg-Cu(II)) loaded solid lipid nanoparticles (SLNs). The main research study was based on enzyme-...
To engineer biocompatible, colon-targeted delivery vehicle utilizing octadecanol-dextran (Odl-Dex)-coated apigenin-copper (Apg-Cu(II)) loaded solid lipid nanoparticles (SLNs). The main research study was based on enzyme-responsive system to prevent premature gastrointestinal drug degradation while maximizing localised therapeutic potential against colon cancer. The Apg-Cu(II) SLNs were formulated via hot-melt emulsification and surface-coated with Odl-Dex. The nanoparticles were characterised for particle size, surface charge, and entrapment efficiency (%). Enzyme-triggered release was evaluated using simulated gastrointestinal fluid with dextranase. In vitro cytotoxicity and cellular apoptosis were assessed on human HCT-116 colon cancer cells, followed by in vivo pharmacokinetic evaluation in Wistar rats to determine oral bioavailability. The optimised Odl-Dex-coated Apg-Cu(II) SLNs exhibited the particle size of 374 ± 2.03 nm, surface charge of -25.6 ± 0.36 mV, and entrapment efficiency of 84.54 ± 0.05%. The formulation maintained robust stability in gastric and intestinal environments, triggering precise release upon exposure to colonic dextranase. Cu(II) complexation significantly enhanced the anticancer efficacy, lowered the IC against HCT-116 cells to 0.8 ± 0.6 µg/mL compared to free Apg (3.00 ± 1.53 µg/mL) and Apg-Cu(II) loaded SLNs (1.5 ± 0.2 µg/mL), and then, profoundly induced sub-G1 phase apoptosis. Furthermore, in vivo studies demonstrated a remarkable improvement in oral bioavailability (AUC: 484.28 ± 5.21). Apg-Cu(II)-Odl-Dex SLNs effectively bypass premature upper gastrointestinal release and significantly improve oral bioavailability. This novel and enzyme-modulated nanocarrier serves as a highly promising and advanced targeted therapeutic strategy for colon cancer.
Resveratrol-loaded novasomal gel for sustained dermal delivery against monobenzone-induced vitiligo-like depigmentation in black chicks.
El-Ela FIA, Eid HM, Hassan WH … +6 more , Ragab Ibrahim R, Abdel-Razik AH, Baroni S, Attia ME, Soliman AG, Habib AGK
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42365115 · Publisher ↗
Vitiligo is a multifactorial depigmenting disorder characterized by melanocyte loss, oxidative stress, and impaired melanogenesis. Resveratrol (RVT) exhibits potent antioxidant and cytoprotective properties; however, its...
Vitiligo is a multifactorial depigmenting disorder characterized by melanocyte loss, oxidative stress, and impaired melanogenesis. Resveratrol (RVT) exhibits potent antioxidant and cytoprotective properties; however, its topical application is limited by its poor cutaneous penetration, rapid degradation, and limited local bioavilability. To overcome these limitations, we developed a resveratrol-loaded novasomal formulation (RVT-NVS) and evaluated its physicochemical properties, in vitro release behavior, repigmentation efficacy in a 40% monobenzone (MZ)-induced vitiligo-like depigmentation model in black chicks. Dermal tolerability was additionally assessed in rats. RVT-NVS exhibited nanoscale vesicles with an average size of 386 nm, a a relatively narrow size distribution (PDI = 0.31), high entrapment efficiency of 79%, and a negative zeta potential of - 37 mV. The RVT-NVS gel showed sustained RVT release over 12 h compared with the free RVT gel. MZ induced marked depigmentation, hematological alterations, reduced body weight gain, histopathological skin damage, reduced tyrosinase immunoreactivity, and altered behavioral readouts. RVT-NVS significantly improved visible repigmentation, normalized hematological parameters, improved body weight gain, preserved epidermal and feather follicle architecture, and restored tyrosinase-positive melanocyte-associated staining more effectively than free RVT, blank nanovehicle, or natural composite formulations. RVT-NVS also improved several MZ-associated behavioral readouts, including sweet-solution consumption, locomotor activity, social-response measures, freezing behavior, and tonic immobility duration. Molecular docking suggested possible interactions of RVT with targets related to redox regulation, melanogenesis, inflammation, and apoptosis, with favorable predicted interactions observed for catalase (CAT) and selected melanogenesis-associated targets. These findings suggest that RVT-NVS may represent a promising nanoscale topical delivery system for chemically induced oxidative melanocyte injury and vitiligo-like depigmentation.
Serum-based untargeted metabolomics reveals the therapeutic mechanism of asiatic acid against atherosclerosis in ApoE mice.
Wu Z, Yang L, Yang J … +3 more , Gou Z, Yu H, Ren W
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42363947 · Publisher ↗
Atherosclerosis (AS) is a leading cause of cardiovascular morbidity and mortality worldwide. This study investigated the protective effects and underlying mechanisms of asiatic acid (AA), a bioactive triterpenoid from Ce...
Atherosclerosis (AS) is a leading cause of cardiovascular morbidity and mortality worldwide. This study investigated the protective effects and underlying mechanisms of asiatic acid (AA), a bioactive triterpenoid from Centella asiatica, in high-fat diet (HFD)-fed ApoE mice and in ox-LDL-stimulated RAW264.7 macrophages. In vivo, AA, particularly at the high dose, was associated with reduced aortic atherosclerotic lesions and attenuated hepatic steatosis, accompanied by an improved serum lipid profile (lower TC, TG, and LDL-C; higher HDL-C) and by attenuated systemic inflammation (IL-6, IL-1β, and TNF-α) and oxidative stress. Mechanistically, AA was associated with upregulation of the PPARγ/LXRα/ABCG1 axis in the liver; consistently, in ox-LDL-induced macrophage-derived foam cells, AA dose-dependently reduced intracellular total and free cholesterol in parallel with restoration of the same PPARγ/LXRα/ABCG1 axis, findings that may reflect improved macrophage cholesterol efflux. Untargeted serum metabolomics further showed that AA reversed a focused set of disease-associated metabolites enriched in pro-inflammatory arachidonic acid-derived oxylipins (e.g., 12R-HETE, 15(S)-HPETE, leukotriene B4, and PGE2-related metabolites). Collectively, these findings suggest that AA exerts multi-target anti-atherosclerotic activity, integrating lipid-regulating, antioxidant, and anti-inflammatory actions, and support its potential as a candidate agent for the prevention and management of atherosclerotic cardiovascular disease.
Potential efficacy of repurposed drugs for treating drug-resistant visceral leishmaniasis.
Ghousepeer GD, Singh SK, Singh S … +8 more , Basu S, Priyadarshini A, Rani M, Kumar A, Singh N, Raj VS, Pandey K, Pandey RP
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42363946 · Publisher ↗
Visceral leishmaniasis is a life-threatening parasitic disease that predominantly affects socioeconomically backward populations in the Indian subcontinent. Increasing rates of treatment relapse and reduced drug suscepti...
Visceral leishmaniasis is a life-threatening parasitic disease that predominantly affects socioeconomically backward populations in the Indian subcontinent. Increasing rates of treatment relapse and reduced drug susceptibility among Leishmania donovani parasites have emerged as major challenges in endemic regions. In addition, immunosuppressive conditions further increase susceptibility to infection and complicate disease management. Current therapeutic options are limited by drug resistance, toxicity, high treatment costs, and the persistence of post-treatment complications. Drug repurposing offers a promising strategy by identifying new antileishmanial applications for existing drugs with established safety profiles. Therefore, this study evaluated the efficacy of Artemisinin, Chloroquine, Disulfiram, and Buparvaquone against clinical isolates of Leishmania donovani with reduced susceptibility to Miltefosine. The study is aimed at addressing the treatment failure and drug resistance among the Leishmania donovani clinical isolates. Due to the emergence of resistance among the clinical isolates, this study has focused on alternative medicines by considering drug repurposing. The in vitro efficacy of Artemisinin (ART), Chloroquine (CQ), Disulfiram (DIS), and Buparvaquone (BQ) was tested against both promastigote and amastigote stages of L. donovani CI (clinical isolates) that are less susceptible to Miltefosine and Amphotericin B, and their IC50 values were determined via MTT assays. The toxicity of the repurposed drugs was analyzed against PBMCs. All the repurposed drugs exhibited significant antileishmanial activity. Among these drugs, Buparvaquone was effective against the promastigote stage, with the lowest IC50 of 2.67 ± 0.15 nM, and against the amastigote stage, with an IC50 of 1.839 ± 0.228 nM. Compared to other drugs, Buparvaquone showed the highest efficacy against both the promastigote and amastigote stage of L. donovani Clinical isolate and all the repurposed drugs are cytotoxically safe. This study reports the potential efficacy of Artemisinin (ART), Chloroquine (CQ), Disulfiram (DIS), and Buparvaquone (BQ) for treating drug-resistant visceral leishmaniasis. Their in vitro efficacy and ability to modulate the immune response underscore their therapeutic promise. Further in vivo studies and clinical trials are recommended to confirm these findings and pave the way for new treatment formulations against susceptible strains of Leishmania donovani (Ld).
Rational design of pyrazole-oxime hybrids as dual-targeting agents for glioma and breast cancer brain metastasis.
Gul M, Alagoz MA, Hepokur C … +1 more , Algul O
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42363945 · Publisher ↗
To design, synthesize, and biologically evaluate a novel series of 1-(4-chlorophenyl)-2-(4-methylpyrazol-1-yl)ethenone oxime derivatives (5-15) as targeted anticancer agents, focusing on their selectivity for glioma, mec...
To design, synthesize, and biologically evaluate a novel series of 1-(4-chlorophenyl)-2-(4-methylpyrazol-1-yl)ethenone oxime derivatives (5-15) as targeted anticancer agents, focusing on their selectivity for glioma, mechanistic action, and blood-brain barrier (BBB) permeability. The oxime derivatives were synthesized and characterized using H-NMR, C-NMR, and mass spectrometry. In vitro cytotoxicity was assessed against C6 (glioma), MCF-7 (breast cancer), and SH-SY5Y (human neuroblastoma) cell lines. Flow cytometry evaluated apoptosis and cell cycle arrest for the lead compound. Molecular docking simulations were performed against CDK6 (PDB: 5L2I) and P-glycoprotein/ABCB1 (PDB: 7A6E). All derivatives exhibited selective potency against C6 glioma cells. Compound 14 demonstrated the highest antiproliferative activity (IC₅₀: 31.23 µM) against tumor lines while sparing SH-SY5Y cells. Flow cytometry confirmed that compound 14 triggers apoptosis and induces cell cycle arrest in C6 cells. Molecular docking predicted the most favorable docking scores for compound 14 against both CDK6 and P-glycoprotein. Structure-activity relationships (SAR) analysis validates the 4-methylpyrazole core as a viable scaffold for targeted glioma therapy. These results suggest that further functionalization of the O-alkyl oxime moiety merits further investigation as a starting point for potentially brain-penetrant scaffolds, although in vivo and target-level validation are required.
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