Naunyn-Schmiedeberg's archives of pharmacology最新文献

Anticancer drug-associated interstitial lung disease (ILD) is a serious adverse event. Identifying high-risk drugs and elucidating pathogenic mechanisms are crucial for prevention and management. Based on 21 years of the US Food and Drug Administration Adverse Event Reporting System (FAERS) data, we identified anticancer drugs strongly associated with ILD in solid tumor patients using disproportionality analysis and logistic regression. Network pharmacology identified overlapping targets between anticancer drugs and ILD. Mendelian randomization (MR) was used to assess causal links between target gene/protein expression and ILD. Molecular docking further evaluated drug-target binding. Finally, mediation MR analysis was applied to assess the role of immune cells and metabolites in mediating the causal effect of CD40 on ILD. We identified 21 anticancer drugs as independent risk factors for ILD, with the majority exhibiting an early failure mode. ILD onset was primarily observed within the first three months. Network pharmacology and MR analyses pinpointed CD40 as a key pathogenic target. Elevated CD40 expression causally increased ILD risk. Molecular docking further confirmed stable binding between gemcitabine and CD40. Mediation MR revealed CD40 influences ILD risk via specific Tregs (CD28 on secreting Treg, CD28 on activated & secreting Treg, and CD28 on CD45RA⁻ CD4 non-Treg) and metabolites (gamma-glutamylvaline, S-adenosylhomocysteine (SAH) to 5-methyluridine ratio). This integrated study reveals CD40 as a key contributor to anticancer drug-associated ILD, especially linked to gemcitabine. CD40 exerts its effect through dysregulation of specific Tregs and metabolites. These findings reveal novel disease mechanisms and identify potential therapeutic targets, providing new clues for the prevention and treatment of anticancer drug-associated ILD.

Osteosarcoma (OS) is a malignant tumor of the bone that primarily affects teenagers. Its extensive replication and metastasis are fuelled by high-energy metabolic expenditure, particularly aerobic glycolysis. The flavonol molecule quercetin has been shown to have beneficial inhibitory effects on cancer cells. Although the exact mechanism underlying the effective inhibition of OS cell growth and migration differs depending on the type of cell, it plays a significant role in this regard. Using public gene sequencing data, limma and WGCNA differential analysis, target and pathway enrichment analysis identified key targets of glycolysis in osteosarcoma. In addition, in vitro tests, including the cell viability assay, the ATP and lactate assay, the live/dead cell staining, the crystal violet staining, and the western blot, were used to examine the distinct inhibition of glycolysis by quercetin in the various fractional cell lines of OS. We pinpoint the primary glycolytic targets (PFKM, GYS1, LDHA, SLC2A1, and HK2) that set OS apart from healthy tissue. Quercetin inhibits glycolysis and tumor progression in a cell line-dependent manner, involving PI3K/AKT signaling predominantly in HOS cells. In summary, our work revealed a substantial quantitative difference between the cellular fractions of OS in which quercetin strongly slowed glycolysis.

The etiology of mental disorders continues to present a profound conundrum, with many theoretical frameworks seeking to clarify the underlying psychopathological mechanisms. Among these, the inflammatory hypothesis suggests that immune-mediated inflammation is integral to the emergence and progression of mental disorders, thus proposing a plausible mechanism. Nonetheless, bibliometric analyses that systematically aggregate and scrutinize the existing literature within this field are lacking. To address this gap in knowledge, the present study performed comprehensive bibliometric analyses and used a visualization methodology to investigate this subject using several approaches, such as analyses of publication trends, keywords, authorship patterns, and geographical distribution, collectively encompassing a dataset of 24,226 publications. Our results revealed proliferation and persistent dynamism in this area of research over the past 26 years, with the primary research focal point being the interaction between inflammation and affective disorders, particularly depression. Furthermore, emerging areas of interest include gut microbiota, neuroimaging, and metabolism. We further discussed the pharmacological potential of targeting inflammation in psychiatric disorders regarding novel drug discovery, positing that the heterogeneous outcomes of prior trials may be attributed to insufficient stratification of inflammatory phenotypes, underscoring the need for future psychopharmacological studies to precisely align intervention strategies with patient-specific inflammatory profiles. Figuring out the intricate nexus between mental disorders and inflammation is essential to improve our understanding of psychopathology and identify novel therapeutic targets.

Purpose: Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder characterized by hyperandrogenism, ovulatory dysfunction, and the formation of ovarian cysts. Key contributors to its pathophysiology include oxidative stress, inflammation, and altered intracellular signaling, especially within the PI3K/pAKT/PTEN pathway. Galangin, a dietary flavonoid derived from Alpinia galanga, exhibits antioxidant, anti-inflammatory, and estrogen- modulatory properties. This study investigated the protective effects of galangin in a PCOS rat model induced by letrozole and explored its underlying molecular mechanisms.

Methods: Thirty-six adult female Wistar rats were divided into six groups: control, galangin (8 mg/kg), letrozole (1 mg/kg), letrozole + galangin (4 or 8 mg/kg), and letrozole + metformin (20 mg/kg). All treatments were administered orally for 21 days. Serum hormones, oxidative stress biomarkers, inflammatory mediators, and key proteins in the PI3K/pAKT/PTEN pathway were assessed, along with histopathological and immunohistochemical analyses.

Results: Letrozole administration induced characteristic PCOS-like features, including cystic follicle formation, hormonal imblanaces, oxidative stress, inflammation, and suppression of PI3K/pAKT signaling, accompanied by an increase in PTEN levels. Galangin pretreatment improved ovarian morphology, restored hormonal balance, reduced oxidative and inflammatory responses, and reactivated PI3K/pAKT signaling while downregulating PTEN. These effects were comparable to those observed with metformin.

Conclusion: Galangin provides multidimensional protection against letrozole-induced ovarian dysfunction by alleviating oxidative stress, inflammation, and dysregulation of the PI3K/pAKT/PTEN pathway. These findings support the potential of galangin as a safe, multitarget natural adjunct for managing PCOS.

As the first-in-class delta-like ligand 3/cluster of differentiation 3 bispecific T-cell engager approved globally for extensive-stage small cell lung cancer, tarlatamab still lacks comprehensive post-marketing safety data from real-world settings beyond clinical trials. This study employs the US Food and Drug Administration Adverse Event Reporting System (FAERS) database to conduct a comprehensive evaluation of its safety profile, identifying potential risk signals and variations among subpopulations. A retrospective analysis was conducted using data from the FAERS prior to Q2 2025. Reports listing tarlatamab as the primary suspect drug were included. Signal detection employed quadruple disproportionality analysis (reporting odds ratio (ROR), proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker). Adverse events (AEs) were standardized using the Medical Dictionary for Regulatory Activities v27.1. Subgroup analyses focused on sex, age, and clinical outcomes. Analysis of 676 tarlatamab-associated AE reports revealed extremely strong signals for core on-target toxicities: cytokine release syndrome (CRS) (ROR = 618.54) and immune effector cell-associated neurotoxicity syndrome (ICANS) (ROR = 1014.66). New safety signals included tumor lysis syndrome (TLS) (ROR = 48.15) and respiratory failure (ROR = 6.45), both of which exhibited significant disproportionality. Sex-based analysis identified significantly higher CRS risk in females versus males (ROR = 947.46 vs 400.82), while mortality reports were more prominent in males (ROR = 2.81). The overall onset time for all AEs exhibited an early failure pattern, with a median onset time of 3 days (interquartile range, 1-10). Clinical outcomes analysis indicated death events in 12.9% of cases and hospitalization requirements in 20.9%. Leveraging FAERS, this first comprehensive real-world characterization of tarlatamab safety confirms core immune-related toxicities (CRS, ICANS) and identifies new signals (TLS, respiratory failure), with sex- and age-associated risk differences. As spontaneous-report signals are inherently hypothesis-generating, causality requires validation in robust pharmacoepidemiologic studies; meanwhile, early detection and supportive care are essential to optimize the benefit-risk profile as use expands.

Myocardial ischemia/reperfusion injury (MI/RI) is a complex state involving numerous inflammatory mediators, which significantly worsens the outcomes of patients with cardiovascular diseases. However, no standardized treatment plan for MI/RI prevails at present. Cucurbitacin B (Cb-B) is a natural bioactive substance extracted from the stem of melon flowers, and is associated with Wnt-β-Catenin, NF-κB, and PI3K/AKT signaling pathways to initiate apoptosis and inflammatory responses in various cancers. Nevertheless, its potential preventive role in MI/RI remains unclear. Here, the potential mechanism adopted by Cb-B for alleviating MI/RI was explored by network pharmacology and in vivo experiments. Firstly, network pharmacology methods, including multiple data retrieval, network construction analysis, gene ontology enrichment analysis, pathway analysis, and molecular docking, were employed to identify the target genes, signaling pathways, and potential mechanisms of Cb-B in the possible treatment of MI/RI. Simultaneously, results were validated through in vivo experiments. The results showed that the comprehensive network pharmacology identified cellular pyroptosis and apoptosis-related genes as nlrp3, caspase1, bcl-2, and caspase3. Functional enrichment analysis showed the association of these target genes with inflammatory response, positive regulation of cytokine production, and response to lipopolysaccharides in biological processes. In addition, the MI/RI rat model showed that Cb-B could alleviate myocardial injury by reducing the release of cellular pyroptosis and apoptosis-related genes. These results suggested that the mechanism of cardioprotective effects of Cb-B may be related to the regulation of PTEN/PI3K/AKT signaling pathways, which lays a foundation for further research on MI/RI treatment.

Cholangiocarcinoma (CCA) is a type of malignant tumor that originates from the bile duct epithelium and has relatively few treatment options. Paeoniflorigenone (PFG) extracted from Moutan cortex has the effect of selectively inducing tumor cell apoptosis and anti-tumor proliferation. However, its role in CCA remains unclear. Firstly, the core targets and molecular mechanisms of PFG in treating CCA were screened through network pharmacology. Subsequently, the proliferation inhibition and apoptosis induction effects of PFG acting on CCA cells were initially explored by CCK8 assay, colony formation assay, cell apoptosis, and western blot assay, while the HIF1A signaling pathway was verified by recovery experiment. Finally, the synergistic effect of PFG and cisplatin on CCA was explored in vivo. Based on network pharmacology, 20 target genes were obtained and HIF1A was the core target of PFG in treating CCA. Molecular docking and molecular dynamics simulation of PFG and HIF1A were stable, and the binding energy was - 16.9 kcal/mol. In terms of molecular mechanism, PFG could significantly inhibit proliferation and colony formation, and induce more apoptosis in RBE cells and HUCCT1 cells via HIF1A, which was verified by the recovery experiment. Furthermore, the combination of PFG and cisplatin could enhance the proliferation inhibition and apoptosis promotion of CCA in vitro and in vivo while further reducing the protein expression of HIF1A. PFG could inhibit proliferation and induce apoptosis in CCA via HIF1A. Moreover, PFG combined with cisplatin could enhance the therapeutic effect in CCA.

Benign prostatic hyperplasia (BPH) is a common public health problem in ageing men worldwide. Diarylpropionitrile, a selective ERβ agonist, favorably regulates cell proliferation and inflammation, two major hallmarks of BPH pathology. This study aimed to explore the mitigative impact of diarylpropionitrile on testosterone-driven BPH in rats. 40 Sprague Dawley male rats aged 2.5-3 months were randomly divided into 4 groups (n = 10): a normal control group, a testosterone-induced BPH group, a finasteride-treated group, and a diarylpropionitrile-treated group. BPH was induced by daily subcutaneous testosterone injections for 4 weeks, with finasteride and diarylpropionitrile administered orally once daily for the same duration, one hour before each testosterone injection. After 4 weeks of treatment, macroscopic and microscopic features of prostatic hyperplasia and androgenic, proliferative, angiogenic, apoptotic, and inflammatory biomarkers in prostatic tissue homogenates were assessed. Testosterone administration significantly increased prostate weight, prostatic index, and hyperplasia scores, while treatment with either diarylpropionitrile or finasteride effectively ameliorated these testosterone-induced changes. Both treatments significantly lowered elevated prostatic DHT, 5αR2, β-catenin, and PCNA levels, demonstrating a strong anti-proliferative effect. They also attenuated the increased pro-inflammatory cytokines IL-6, IL-27, and PGE2 and growth factors TGF-β and VEGF. Furthermore, both agents inhibited testosterone-induced ERβ upregulation and increased expression of the anti-apoptotic protein BCL2. There were no substantial differences comparing finasteride and diarylpropionitrile in the majority of the tested parameters. Diarylpropionitrile alleviates testosterone-driven BPH in rats by modulating key pathways associated with cellular proliferation and inflammation. Diarylpropionitrile, as an ERβ agonist, represents a promising alternative for the BPH treatment through multi-targeted mechanisms.

The mitochondrial-derived peptide MOTS-c regulates metabolic and cellular stress responses, but its dose-response profile and direct cardioprotective mechanisms in myocardial ischemia-reperfusion injury (MIRI) remain undefined. This proof-of-concept study aimed to identify the optimal cardioprotective dose of exogenous MOTS-c and delineate its multi-pathway mechanisms using an ex vivo rat heart IR model with in silico support. Isolated Langendorff-perfused rat hearts underwent 30-min global ischemia and 60-min reperfusion with or without MOTS-c (0.25-0.7 mg/kg) delivered via Krebs-Henseleit buffer during the first 10 min of reperfusion. Hemodynamics, infarct size (TTC), oxidative stress markers, inflammation, and apoptotic gene expression were quantified. Peptide-protein interactions with survival pathways were predicted computationally. MOTS-c at 0.5 mg per kg conferred maximal protection, producing a 73% reduction in infarct size compared with ischemia-reperfusion alone, improving heart rate, left ventricular developed pressure, and rate-pressure product, and lowering end-diastolic pressure. Lactate dehydrogenase release decreased by 65%. Antioxidant defenses improved with increased superoxide dismutase, catalase, and glutathione redox ratio, along with reduced lipid peroxidation. Myeloperoxidase activity normalized, pro-apoptotic genes including caspase 3, caspase 7, caspase 9, BAX, and PARP were downregulated, while cytoprotective genes including BCL2, GPX4, and FOXO were increased. Molecular docking demonstrated high-affinity interactions of MOTS-c with MAPK, mTOR, AMPK, NRF2, PI3K, and caspase 3. This ex vivo study identifies 0.5 mg/kg as the optimal dose within the tested range, producing coordinated anti-apoptotic, antioxidant, and anti-inflammatory effects. Although the isolated heart model isolates direct myocardial actions, the lack of systemic influences and limited dose range necessitate broader dosing and pharmacokinetic studies before translational application.