Naunyn-Schmiedeberg's archives of pharmacology最新文献

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. The "mild" clinical behavior of PTC often leads to underestimation of the complexity of its treatment. Ruminococcus (Rum) is a cancer-related intestinal flora. Further study on its functional mechanism is expected to provide a new direction for microbial targeted therapy of cancer. Therefore, the aim of this study was to investigate the therapeutic effect of Rum on PTC and its related mechanism. Rum upregulated the mRNA expression level of RBM15 in BCPAP and KTC-1 cells, decreased their cell viability, promoted pyroptotic signaling, and inhibited their invasion and migration, as well as reduced the volume and weight of tumor tissue and aggravated their pathological injuries. Moreover, Rum downregulated MMP2 and MMP9 mRNA and protein expression levels and upregulated IFN-γ, IL-1β, and IL-18 expression levels, as well as NLRP3, ASC, Caspase-1 mRNA and protein expression levels, the m6A methylation content, and the m6A methylation of NLRP3 in vivo and in vitro. In addition, knocking down RBM15 effectively reversed the effects of Rum mentioned above in vivo and in vitro. Mechanistically, Rum activates the NLRP3/ASC/Caspase-1 axis-mediated pyroptotic signaling in PTC by upregulating RBM15 to increase the N6-methyladenosine methylation modulation of NLRP3, thereby providing a novel strategy and target for the clinical treatment of PTC.

This study investigated lacosamide (LCM), a third-generation antiepileptic drug, as a potential gonadoprotective agent against cyclophosphamide (CP)-induced testicular injury. The research addressed the critical need for safer antiepileptic alternatives in cancer patients requiring concurrent chemotherapy and seizure control. Male Wistar rats underwent comprehensive biochemical and histopathological analyses including Western blot, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry, steroidogenic enzyme activity assessments, sexual hormone measurements, sperm quality evaluations, and molecular docking studies to evaluate LCM's protective mechanisms against CP-induced testicular damage. CP administration significantly elevated oxidative stress markers, pro-inflammatory mediators (Nuclear factor kappa B [NF-κB], Tumor necrosis factor-α [TNF-α], Interleukin-6 [IL-6], Interleukin-1β [IL-1β]), and apoptotic signaling (Bcl-2-associated x protein [Bax], caspase-3), while activating regulatory proteins c-jun N-terminal kinase 1 (JNK1) and Signal transducer and activator of transcription 3 (STAT-3) (identified as novel markers in CP-induced testicular injury). CP suppressed antioxidant defenses, steroidogenic factors (steroidogenic acute regulatory protein [StAR], 3β-hydroxysteroid dehydrogenase [3β-HSD], 17β-hydroxysteroid dehydrogenase [17β-HSD]), Heme oxygenase 1 (HO-1) expression, and androgen receptor (AR) functionality, resulting in decreased testosterone, gonadotropin levels, and compromised spermatogenesis. LCM treatment effectively mitigated these deleterious effects through multi-target protective mechanisms including c-jun N-terminal kinase 1(JNK1)-mediated apoptosis inhibition, HO-1 upregulation, IL-6/ signal transducer and activator of transcription 3 (STAT-3) signaling suppression, prevention of p-JNK1/STAT-3 crosstalk, and AR preservation. This study establishes LCM's multi-target protective efficacy, supporting its potential as a safer antiepileptic alternative providing dual benefits of seizure control and reproductive preservation during chemotherapy.

Obesity is a chronic disease caused by the accumulation of cholesterol, which often requires long-term management strategies, such as dietary changes, increased physical activity, and psychological support. Obesity associated neurobehavioral disorders are a growing global health concern, emphasizing the need for innovative therapeutic strategies. Our study evaluates the therapeutic efficacy of (Z)-1-(furan-2-yl)-N-(4-(2-nitrophenyl)-6-(p-tolyl)pyrimidin-2-yl)methanimine referred as BN3 derivative, in treating high-fat diet-induced metabolic and behavioral dysfunctions in a zebrafish model. The research focused on reducing oxidative stress, lipid accumulation, and neurobehavioral deficits, which are closely linked to obesity-related metabolic stress. In this study, zebrafish were divided into five separate experimental groups: control group, model of obesity caused by high-fat diets, BN3 (50 µM and 100 µM), and Positive Control (PC) Group treated with Lovastatin 100 µM. Initially, fish were fed a high-fat diet for 14 days and followed by 30 days of exercise and simultaneously administering BN3 treatments via oral gavage. Assessment of biochemical, histopathology, gene expression, and behavioral were carried out. The results indicated that BN3 treatment significantly decreased oxidative stress levels by enhancing the activity of four antioxidant enzymes (Superoxide Dismutase, Catalase, Glutathione Transferase and Glutathione Peroxidase). BN3 also decreased lipid accumulation as evidenced through histological staining analysis, and total cholesterol estimation. BN3 enhanced locomotion, social interaction, and exploratory behaviors, and reduced anxiety, with the 100 µM treatment group exhibiting the same results as the PC. Gene expression analysis indicates that BN3 is modulating pparγ, fas, pik3cd, src-3, and bdnf pathways (metabolic and neuroinflammation pathways). BN3 impacted these multiple metabolic and neurobehavioral impairments associated with obesity through a multisite treatment approach. BN3 demonstrates significant therapeutic potential, assuring further studies to explore its long-term safety, pharmacokinetics, and translational application in managing obesity and related disorders.

Przewaquinone A (PrA), a natural active substance extracted from Salvia przewalskii Maxim, has been shown to have antitumor activity and can act as a STAT3 inhibitor to modulate the Src/STAT3 pathway. However, its role in colorectal cancer (CRC), along with its related mechanisms, has not yet been clarified. This study aims to explore whether PrA inhibits the malignant advancement of CRC via the Src/STAT3 pathway, and to provide new drug candidates and molecular targets for CRC clinical treatment. The toxic effects of PrA on normal cells NCM460 and on CRC cells (SW480, HCT116, etc.) were explored by Cell Counting Kit-8 (CCK-8) assay. The malignant phenotype, cell cycle distribution, and apoptosis rate were analyzed with the help of Transwell assay, clone formation assay, and flow cytometry. The impact of PrA on autophagic flow in CRC cells was analyzed by GFP-RFP-LC3 dual fluorescent labeling. Plasmid transfection was used to modulate Src expression to verify whether PrA acts through the Src/STAT3 pathway. Finally, subcutaneous graft tumor and carcinoma in situ models were constructed in nude mice, and cell proliferation and apoptosis were detected by pathological staining, and the expression of indicator proteins and Src/STAT3 pathway-related proteins were evaluated via western blot. PrA at 1 ~ 4 µM did not markedly impact NCM460 cell viability, but it dose-dependently reduced CRC cell viability. PrA also diminished the migration and invasion ability of CRC cells, induced G0/G1 phase cycle block, apoptosis, and autophagy, and inhibited Src/STAT3 pathway activation and nuclear translocation of STAT3. Furthermore, overexpression of Src reversed the regulatory impacts of PrA described above. In vivo, PrA treatment hindered tumor growth in nude mice, inhibited cell proliferation, and promoted apoptosis, whereas Src overexpression attenuated the tumor-suppressive effects of PrA. By suppressing the Src/STAT3 pathway, PrA regulates cell cycle and autophagy in CRC cells, thereby inhibiting CRC malignant progression.

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.