Naunyn-Schmiedeberg's archives of pharmacology最新文献

This study was aimed at elucidating the therapeutic effects of hirudin on renal interstitial fibrosis (RIF) and at delineating the molecular mechanisms underlying its antifibrotic actions. A comprehensive research approach was adopted, integrating network pharmacology, molecular docking, molecular dynamics simulations, and in vitro experimental validation, to explore the mechanisms through which hirudin alleviates RIF. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified 185 enriched signalling pathways, with the primary ones being the VEGF signalling pathway, TNFA signalling pathway and NF-κB signalling pathway. Gene Ontology (GO) analysis revealed that hirudin's antifibrotic effects were associated with inflammatory responses, canonical NF-κB signal transduction, and cellular responses to oxidative stress. Protein-protein interaction (PPI) network analysis identified TNF, HIF1A, HO-1, CASP3, IKBA, KEAP1, and RELA as key hub proteins. Experimental validation demonstrated that hirudin significantly reduced the protein levels of fibronectin (FN) and collagen I (Col I) in TGF-β1-stimulated HK-2 cells. Additionally, hirudin downregulated pro-inflammatory markers (TNF-α, MCP-1, p-P65, and p-IκBα) while upregulating antioxidant proteins (Nrf2, HO-1, and SOD-1). These findings suggest that hirudin mitigates TGF-β1-induced inflammation and oxidative stress in HK-2 cells by modulating the Nrf2 and NF-κB signalling pathways, thereby impeding the progression of RIF.

The vast majority of peer-reviewed journals rely on specialists' voluntary services in order to ensure that work they publish is as advertised, i.e., peer reviewed. In the real, commercial world, work that relies on expert opinions, i.e., in the form of consultancy, carries a financial cost and is usually very well remunerated. However, exceptionally, in the world of academic publishing, this reliance on experts has been reduced to an art of exploitation, although it has been marketed as a necessary community service, duty or professional obligation. Ultimately, a journal that claims to conduct peer review must do so, or risk the label of engaging in fake peer review or worse-predatory publishing behavior-by claiming peer review when none has been conducted, so there is constant pressure on editors (and to a lesser extent, publishers) to secure a constant stream of peer reviewers to match or exceed the influx of submissions. Although relying on free labor has its benefits, the most obvious being the absence of costs, the risks are incalculable and can include the use of individuals who are tardy, unprofessional, abusive, frustrated, only provide superficial feedback, or may engage in this task exclusively for rewards even if they do not deliver quality reports. Editors may even have to contend with those that agree to complete the task but then fail to deliver on time, or at all. Although the issue of paying reviewers is a well-debated topic and one with seemingly no sustainable solution, it may have become a rather miniscule issue now that large language models and generative AI are reaching prominence in academic publishing, with the risk that free human peer reviewers will be substituted by free AI-driven "reviewers".

Intervertebral disc degeneration (IVDD) is a leading cause of chronic low back pain, in which fibrotic transformation of nucleus pulposus cells (NPCs) plays a critical pathological role. However, the regulatory mechanisms underlying NP cell fibrosis remain poorly understood. This study aimed to explore the role of NP cell fibrosis in IVDD and identify natural compounds capable of targeting this process. Bulk and single-cell transcriptomic data were integrated to explore the role of NP cell fibrosis in IVDD and to identify natural compounds capable of targeting this pathological process. Cellular and animal experiments were conducted for validation. Transcriptomic analysis revealed that the intersection of differentially expressed genes (DEGs), WGCNA-identified module genes, and fibrosis-related genes-termed fibrosis-related differentially expressed genes (FRDEGs)-was significantly enriched in the TGF-β signaling pathway. Based on FRDEGs, quercetin (QUE), a natural flavonoid, was identified as a candidate compound. TGF-β and TGF-βR2 were identified as hub genes. Single-cell analysis confirmed high expression of these genes in NP cells, especially within fibrotic subpopulations (Fibro-NPCs), where TGF-β pathway activity was notably elevated. Molecular docking indicated strong binding affinity between QUE and TGF-β. In vitro, QUE treatment suppressed IL-1β-induced expression of TGF-β/TGF-βR2 in degenerative NP cells. In vivo, QUE administration attenuated NP fibrosis and mitigated IVDD progression in a rat puncture model. This study uncovers the critical role of NP cell fibrosis in IVDD and demonstrates that QUE mitigates disc degeneration by targeting the TGF-β signaling pathway. These findings suggest a novel anti-fibrotic therapeutic strategy for IVDD based on natural compound intervention.

Hepatocellular carcinoma (HCC) is difficult to treat, and gefitinib (GEF) monotherapy may offer limited therapeutic benefits. Combination or multimodal approaches are often required to achieve therapeutic efficacy in such cases. Betulin (BET), a naturally occurring triterpene, is used in combination with GEF to enhance therapeutic efficacy against HCC, but its clinical translation is not possible due to poor bioavailability and lack of targeted delivery. Therefore, we developed non-targeted and lactoferrin (Lf) grafted targeted liposomes of GEF (GEF-Lipo and GEF-Lf-Lipo) and BET (BET-Lipo and BET-Lf-Lipo) by the ethanol injection method and subsequently characterized them. The vesicular size of GEF-Lipo, GEF-Lf-Lipo, BET-Lipo, and BET-Lf-Lipo was found to be 119.5 ± 6.5, 159.1 ± 16.4, 140.7 ± 16.4, and 181.6 ± 4.8 nm, respectively. Polydispersity index (PDI) of GEF-Lipo, GEF-Lf-Lipo, BET-Lipo, and BET-Lf-Lipo was found to be 0.329 ± 0.1, 0.371 ± 0.05, 0.33 ± 0.14, and 0.399 ± 0.030, respectively. Encapsulation efficiencies (EE%) of GEF-Lipo, GEF-Lf-Lipo, BET-Lipo, and BET-Lf-Lipo were found to be 84.7 ± 1.22%, 90.08 ± 1.73%, 91.4 ± 2.63%, and 93.21 ± 1.88%, respectively. Furthermore, the in vivo study has been performed to assess the effectiveness of mixtures of GEF-BET, GEF-BET-Lipo, and asialoglycoprotein receptor (ASGPR) targeted GEF-BET-Lf-Lipo. Physiological parameters and HCC biomarker AFP were quantified. AFP levels were significantly increased in the cancer control versus normal control (p < 0.0001) and were significantly reduced by treatment with pristine drugs, non-targeted liposomes, and targeted liposomes (p < 0.0001), supporting the therapeutic effects of the formulations. Morphological changes in liver tissue were evaluated through histopathological examination and scanning electron microscopy (SEM). Western blotting and immunohistochemistry (IHC) showed that both GEF-BET-Lipo and GEF-BET-Lf-Lipo treatments significantly reduced pSTAT3 expression and increased the levels of the apoptotic marker caspase-3. Overall, the findings support the enhanced antitumor potential of GEF-BET-Lf-Lipo against HCC in animals.

Cholic acid-derived hydrazones represent a promising scaffold for multifunctional drug discovery. We synthesized and characterized two novel cholic acid-based hydrazone derivatives: DFBCH (2,4-difluorobenzylidene conjugate) and MEBCH (3-methoxybenzylidene conjugate) through various spectroscopic techniques, confirming the structural integrity of the synthesized compounds, followed by their comprehensive biological evaluation. In vitro screening showed a greater antibacterial zone of inhibition of MEBCH compound as compared to DFBCH against the tested strains. MEBCH demonstrated potent antioxidant activity (IC₅₀ 1.87 ± 0.20 mg/mL) relative to ascorbic acid (IC₅₀ 7.3 ± 1.40 mg/mL) by DPPH assay illustrating superior antioxidant activity. Both the compounds exhibited greater % inhibition against Hela cell line as compared to doxorubicin, suggesting greater inhibitory activity. MEBCH was the superior inhibitor of acetylcholinesterase (IC₅₀ 1.67 ± 0.61 µM), surpassing the standard donepezil (IC₅₀ 3.13 ± 0.1 µM), and demonstrated effective tyrosinase inhibition (IC₅₀ 1.87 ± 0.88 µM), comparable to kojic acid (IC₅₀ 2.38 ± 0.75 µM). Both of these compounds demonstrated effective β-glucosidase inhibition with an IC₅₀ ≈ 2.23 µM, comparable to standard miglustat (IC₅₀ 2.02 ± 1.05 µM). Molecular docking (Glide) revealed MEBCH producing a favorable docking score with AChE (- 6.711; E-model - 57.480), indicating a stable predicted binding pose relative to DFBCH. BioTransformer 3.0 predicted CYP 450-mediated pathways for both analogues; docking of predicted metabolites showed retained or improved affinity (MEBCH metabolite to AChE - 6.3 kcal/mol) and lower RMSD bounds (AChE; lb/ub ≈ 5.8/6.2 Å; β-glucosidase lb/ub ≈ 5.25/5.73 Å). DFT calculations revealed small HOMO-LUMO gaps and solvent-sensitive dipole moments consistent with moderate chemical reactivity and solvent stabilization. Single-dose oral pharmacokinetics (10 mg/kg) in rats revealed MEBCH with higher C_max, AUC, longer t_1/2, and greater oral bioavailability than DFBCH. Collectively, these data nominate MEBCH as a lead cholic-hydrazone for further preclinical development against enzyme targets relevant to neurological and oxidative-stress pathways.

Research excellence in pharmacology and pharmacy remains insufficiently studied compared with broader analyses of productivity, despite its centrality to advancing drug discovery and health outcomes. This study investigated the multilevel determinants of pharmacology and pharmacy research excellence, defined by membership in the Stanford-Elsevier Top 2% Scientists Lists (SEL). We analyzed 56,358 records in SELs between 2017 and 2023 using a multilevel socio-ecological model. Independent variables spanned national determinants (e.g., health system capacity, human development, gender inequality, R&D investment), institutional factors (global and field-specific rankings), and individual characteristics (gender and academic age). Core bibliometric outcomes included citation counts excluding self-citations, modified H-index, and composite scores. Excellence was disproportionately concentrated in high-income countries and a limited number of elite institutions, although contributions from middle-income countries expanded over time. National R&D investment, Universal Health Coverage, and Human Development Index values consistently predicted higher bibliometric outcomes, while gender inequality was negatively associated with excellence. Disease burdens mirrored these inequities: conditions common in high-income settings (e.g., cancers, COPD) correlated positively with excellence, whereas major global burdens (e.g., HIV/AIDS, diabetes) correlated negatively. Institutional concentration illustrated the Matthew effect, with the top 20 institutions accounting for over one-tenth of global excellence. At the individual level, female scholars remained underrepresented (16.8% in career-long, 25.0% in single-year lists) and showed lower bibliometric performance and younger academic ages than men. Academic age emerged as the strongest positive predictor of research impact, with consistent gains across both datasets. Pharmacology and pharmacy research excellence is conditioned by systemic disparities in resources, prestige, and representation. Policy interventions must target these entrenched capacity-based advantages by strengthening research capacity in underrepresented countries and institutions and implementing frameworks for gender-equitable career progression.

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.