Naunyn-Schmiedeberg's archives of pharmacology最新文献

Asthma is a chronic inflammatory airway disease characterized by Th2-driven inflammation and epithelial-mesenchymal transition (EMT)-mediated airway remodeling. Recent studies implicated that E2F transcription factor 2 (E2F2) played an important role in inflammatory diseases, yet the role of E2F2 in asthma pathogenesis is unknown. An ovalbumin (OVA)-induced asthmatic mouse model was established and E2F2-targeted shRNA was administered during OVA challenges. HE staining was used to evaluate pulmonary inflammatory infiltration, PAS staining was conducted to assess goblet cell hyperplasia and mucus secretion, and Masson staining was performed to detect collagen deposition. Immunohistochemistry (IHC) was employed to analyze E2F2 localization and expression. Bronchoalveolar lavage fluid (BALF) was collected for differential cell counting and ELISA measurement of inflammatory cytokines (IL-4, IL-5, IL-13). For in vitro experiments, TGF-β1 was used to treat human bronchial epithelial cells (BEAS-2B), with E2F2 expression was downregulated via transfecting si-E2F2. Western blot was performed to examine changes in EMT markers (E-cadherin, N-cadherin, and α-SMA) and NBR1 protein expression. Co-immunoprecipitation (Co-IP) assay was conducted to validate the interaction between E2F2 and NBR1, while cycloheximide (CHX) experiments and Thr586 site mutagenesis were employed to investigate the regulatory mechanism of E2F2 on NBR1 protein stability. The results showed that E2F2 expression was significantly upregulated in the lung tissues of asthmatic mice. E2F2 knockdown attenuated OVA-induced lung dysfunction, airway inflammation and EMT, as evidenced by reduced levels of IL-4, IL-5, and IL-13 in BALF, decreased collagen deposition, and restored expression of E-cadherin. In vitro, TGF-β1 induced E2F2 expression in BEAS-2B cells, and E2F2 knockdown inhibited TGF-β1-induced EMT, presented by reduced N-cadherin and α-SMA expressions, and promoted E-cadherin expression. Co-IP assays confirmed the interaction between E2F2 and NBR1, and E2F2 stabilized NBR1 protein through promoting its phosphorylation at Thr586. NBR1 overexpression reversed the inhibitory effects of E2F2 knockdown on EMT and inflammatory factor production. In conclusion, E2F2 promoted airway injury and remodeling by regulating NBR1-mediated EMT process. Targeting the E2F2/NBR1 axis may provide a potential therapeutic strategy for asthma patients.

Background: Vitamin D regulates cell growth and differentiation, encourages pro-apoptotic effect, stimulates antiangiogenic effect, and affects both innate and adaptive immunity. However, serum vitamin D level could differ between countries according to geographic, genetic, and dietary factors.

Aim of the work: Cosidering that most studies of relations between vitamin D level and breast cancer were conducted outside Africa and considering the fact that populations differ in sun exposure, dietary habits, and genetic construction, this study aimed to investigate the relationship between serum levels of vitamin D3 and vitamin D- binding protein (VDBP) with pathological response, clinicopathological characteristics, and various biological markers in Egyptian breast cancer patients undergoing neoadjuvant chemotherapy (NACT).

Methods: A total of 71 female breast cancer patients (mean age: 57 years) were enrolled in this prospective observational study. Fasting blood samples were collected 1 day before and 3 months after initiation of NACT. Serum levels of vitamin D3 and V DBP were quantified using high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA), respectively. Tumor expression of Ki-67, HER2, progesterone receptor (PR), and estrogen receptor (ER) was assessed via immunohistochemistry. Serum levels of CA 15-3 and Bcl-2 were also measured.

Results: Complete pathological response (pCR) was achieved in 44 patients (68.7%). A statistically significant increase in both vitamin D3 and VDBP levels was observed following NACT (p < 0.001). Lower pre- and post-treatment levels of vitamin D3 and VDBP were significantly associated with postmenopausal status, higher tumor grade and stage, triple-negative breast cancer subtype, and high Ki-67 expression (p < 0.001). Conversely, higher levels were significantly associated with achieving pCR (p < 0.001). Both vitamin D3 and VDBP levels demonstrated a significant negative correlation with tumor stage and grade (p < 0.001). Among different clinical and laboratory parameters, only triple-negative subtype and baseline vitamin D were significantly predictive for pCR by multivariable analysis (OR 1.488 and 0.506, respectively) and (95% CI 1.109-1.825 and 0.331-0.75, respectively).

Conclusion: Serum levels of vitamin D3 and VDBP significantly increased after NACT and were associated with favorable clinicopathological features and pCR. Only triple-negative subtype and baseline vitamin D were significantly predictive for pCR by multivariable analysis. These findings suggest that vitamin D3 and VDBP may serve as potential prognostic indicators in breast cancer management.

Mirtazapine is an atypical tetracyclic antidepressant drug that binds to several monoamine neurotransmitter receptors. For instance, mirtazapine binds to H₁-histamine receptors in vitro and in the brain of patients in vivo. Here, we hypothesize that mirtazapine is an antagonist at human cardiac H₁-histamine receptors. To test this hypothesis, we measured force of contraction in isolated electrically stimulated (1 Hz) left atrial preparations (LA) and spontaneously beating right atrial preparations (RA) from adult transgenic mice with cardiomyocyte-specific overexpression of the human H₁-histamine receptor (H₁-TG). These findings were compared with those in wild-type littermate mice (WT). Finally, we measured the force of contraction in isolated electrically stimulated right atrial muscle strips (HAP) gotten from adult patients who were undergoing bypass surgery. Mirtazapine concentration- and time-dependently decreased H₁-histamine receptor-stimulated force of contraction in LA and RA from H₁-TG. Importantly, mirtazapine (starting at 100 nM) concentration- and time-dependently decreased H₁-histamine receptor-stimulated force of contraction in HAP. We thus conclude that mirtazapine can antagonize human cardiac H₁-histamine receptors at therapeutic drug concentrations, and thus, mirtazapine may have cardiac untoward effects in psychiatric patients.

To develop intestinal-targeted microcapsules combining a medicine-food homology (MFH) complex with the ACE-inhibitory peptide IPP to enhance stability, achieve controlled release, and improve anti-hypertensive efficacy in an L-NAME-induced gestational hypertension rat model. Formulations were optimized by adjusting the complex-to-ACEIP ratio. Encapsulation efficiency, morphology, stability, and in vitro digestion were evaluated. Anti-hypertensive effects were assessed in L-NAME-treated pregnant rats by monitoring blood pressure, urinary protein, and renin-angiotensin system (RAS) biomarkers. The optimal 1:2 ratio showed the highest ACE-inhibitory activity. Spray-dried microcapsules reached 63.37% encapsulation efficiency, uniform morphology, and improved gastrointestinal stability. In vitro digestion showed intestinal-preferential release. In vivo, microcapsules significantly reduced L-NAME-induced hypertension and proteinuria, lowered angiotensin II, decreased ACE expression, and increased ACE2 levels. These microcapsules demonstrate enhanced stability, intestinal targeting, and strong RAS-modulating activity, effectively improving L-NAME-induced pregnancy hypertension and showing potential as a safe functional food ingredient for gestational hypertension management.

Vulvovaginal fungal infections remain a major therapeutic challenge due to poor drug penetration, recurrence, and limited efficacy of conventional formulations. Harnessing nanotechnology with a novel delivery platform offers a promising strategy to overcome these barriers. In this study, an innovative olaminogel was designed as an advanced nanocarrier for terconazole (TCZ) to enhance local antifungal therapy via the vaginal route. The formulation was prepared using the ethanol injection method and systematically optimized through a 2³ factorial design considering limonene-to-surfactant ratio (factor A), oleylamine-to-drug ratio (factor B), and oleic acid-to-surfactant ratio (factor C). Optimization targeted maximal entrapment efficiency (EE%), minimal particle size (PS), and stable zeta potential (ZP). The optimized olaminogel achieved an EE% of 82.11, nano-metric PS of 217.25 nm, and a ZP of - 33.05 mV. TEM confirmed well-formed vesicles, while FTIR verified successful encapsulation. Further in vitro characterization revealed pseudo-plastic rheology, sustained biphasic drug release, and stability for 3 months. Mucoadhesion testing demonstrated strong adhesion of the olaminogel to vaginal mucosa. Ex vivo permeation across rabbit vaginal mucosa demonstrated significantly deeper penetration (180 µm vs. 55 µm) compared with plain TCZ gel, corroborated by in vivo CLSM imaging. Histopathological studies further confirmed biocompatibility and absence of irritation. Importantly, microbiological evaluation revealed markedly reduced MIC and MFC values, alongside an accelerated fungicidal effect, outperforming TCZ control. Collectively, these findings highlight olaminogel as a novel and potent intravaginal nanocarrier capable of improving drug retention, mucosal penetration, and antifungal efficacy, thereby presenting a next-generation platform for safe and effective management of vaginal fungal infections.

Benign prostatic hyperplasia (BPH) is a prevalent urological disorder in aging men, frequently linked to hormonal fluctuations. Agomelatine (AGO), a melatonergic receptor agonist and serotonin 2C antagonist, has demonstrated anti-inflammatory and antioxidant properties. This study aimed to explore the potential of AGO in mitigating BPH induced by testosterone propionate (TP) in rats. Male rats received TP (5 mg/kg/day, subcutaneously) to induce BPH and were pretreated with AGO (80 mg/kg/day) for 28 days. AGO inhibited the rise in prostate index, serum prostate-specific antigen (PSA), and testosterone levels compared to the BPH-only group. Histological analysis revealed that AGO significantly improved the pathological alterations in prostate tissue architecture when compared to BPH-only group. Furthermore, AGO notably reduced oxidative stress induced by TP, evidenced by a decrease in lipid peroxidation and preserved levels of reduced glutathione. This reduction in oxidative stress led to a decrease in pro-inflammatory cytokines in the prostate, such as Toll-like receptor 4 (TLR4) and interleukin-1 beta (IL-1β). Additionally, AGO caused a marked decrease in of NLRP3 inflammasome and vascular endothelial growth factor-A (VEGF-A) protein expressions. When compared to the BPH group, AGO's effects also included a reduction in the immunoexpression of nuclear factor kappa B (NF-κB) and myeloid differentiation primary response 88 (MyD88) proteins. The findings from this study provide new evidence that AGO can alleviate testosterone-induced BPH in rats, likely through the inhibition of the TLR4/NFκB and NLRP3/IL-1β signaling pathways. These results suggest that AGO could be a promising therapeutic option for managing BPH.

This study aims to investigate the potential risk and possible mechanisms of Raynaud's phenomenon (RP) associated with the use of calcitonin gene-related peptide (CGRP) antagonists through a comprehensive analysis of the FDA Adverse Event Reporting System (FAERS) database combined with drug-gene network analysis methods. In this disproportionality study, we evaluated the adverse event (AE) signal of RP associated with CGRP antagonists from the FAERS covering the quarter 2 of 2018 to quarter 1 of 2025, using four methods. The gene targets of CGRP antagonists and RP targets were predicted using multiple databases and protein-protein interactions (PPI) using the STRING database. Subsequently, Kyoto Encyclopedia of genes and genomes (KEGG) enrichment analysis was performed using R software to identify the potential mechanisms of CGRP antagonists related to RP. This study retrieved a total of 149 AE reports related to CGRP antagonists and RP reports from the FAERS database, involving 7 CGRP antagonists. Erenumab has the highest number of reports. The data mining results indicate that fremanezumab resulted in the strongest AE signals of the four methods. Protein-protein interaction (PPI) network analysis revealed key nodes of non-peptide small molecule CGRP antagonists in RP, such as the key nodes of rimegepant in RP is AKT1, EGFR, ERBB2, and others. The KEGG pathway enrichment analysis showed that the most possible mechanisms of rimegepant, atogepant, and ubrogepant induce RP is the PI3K signaling pathway. Using a novel approach, we systematically integrated the FAERS database with drug-gene network analysis. Our results not only suggest a potential risk of RP associated with CGRP antagonists but also reveal that the PI3K/AKT pathway is the underlying mechanism for non-peptide small molecules. We recommend that patients receiving these antagonists, particularly those with underlying vascular dysfunction, undergo regular monitoring for RP.

Aristolochic acid I (AAI) is a known liver carcinogen, but its molecular mechanisms in hepatocellular carcinoma (HCC) remain incompletely understood. This study aimed to systematically elucidate these mechanisms. This study employed a multidisciplinary strategy: assessing AAI carcinogenicity via ProTox-3.0; identifying its targets using PubChem; and screening HCC-related genes from GEO. Core genes were filtered through network toxicology and Lasso-Cox regression. Molecular docking and dynamics simulations analyzed AAI-protein interactions, while GO, KEGG, and GSEA enrichment revealed relevant pathways. Key gene expression and clinical relevance were validated via TCGA and HPA databases. The carcinogenic potential of the AAI was 0.77. Fifty-two potential targets of AAI-induced HCC were identified. Network toxicology analysis identified 12 core genes including EZH2, FABP5, and RXRA. Lasso-Cox regression analysis identified four core genes that drive HCC progression, including EZH2. Functional enrichment analysis revealed that AAI-HCC targets were significantly enriched in lipid metabolism and the PPAR signaling pathway (p < 0.05), with the PPAR signaling pathway being significantly activated in HCC. Molecular docking and MD simulations confirmed the high affinity and stable binding of AAI to EZH2, FABP5, and RXRA. Through in silico and database-based validation, biological samples and clinical data confirmed that these genes were significantly overexpressed in HCC (p < 0.001) and were correlated with poor prognosis (p < 0.01). AAI may synergistically activate the PPAR signaling pathway by targeting EZH2, FABP5, and RXRA, driving lipid metabolism reprogramming and promoting the occurrence and development of HCC.

Fipronil (FIP), as a broad-spectrum pesticide, contributes to adverse reproductive effects. Thus, our study aimed to investigate the effect of telmisartan (TEL) as a selective angiotensin 1 receptor (AT1R) blocker on mitochondrial damage induced by FIP intoxication in male rats. Forty healthy male albino rats were allocated into 4 groups (10/ group): the control group, the TEL group received TEL (10 mg/kg b.wt.), the FIP group received FIP (1/10 of the LD50 of 97 mg/kg b.wt.), and the FIP + TEL cotreated group. All treatments were taken orally for 60 days. Before the experiment, in-silico assessments of FIP and TEL were done. FIP administration diminished relative testicular weight, sperm count, and motility, besides significantly increasing sperm abnormalities (p < 0.05). Biochemically, FIP treatment reduced considerably (p < 0.05) serum testosterone, luteinizing hormone (LH), and follicular-stimulating hormone (FSH) levels related to control animals. Furthermore, FIP administration significantly increased testicular malondialdehyde (MDA), pro-inflammatory markers as tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) levels. Also, downregulated the activities of antioxidant markers, Nrf2, HO-1, and PCNA immunostaining. Furthermore, FIP significantly upregulated (p < 0.05) DRP1 and downregulated PGC-1α, MNF2, TFAM, and mtDNA mRNA transcripts. Histopathologically, FIP induced deterioration in seminiferous tubules' histoarchitecture with upregulation in Cosentino's score and downregulation in Johnson's score. On the contrary, TEL effectively restored the testicular function hormones, testicular and epididymal histoarchitecture, antioxidant indices, PGC-1α, and TFAM, with downregulation in MDA levels and DRP1 mRNA transcript. In conclusion, TEL protects the testicular mitochondria against damage from FIP toxicosis by modulating the Nrf2/HO-1/PGC-1α/MNF2/DRP1 expressions.

Ferroptosis is a potential target for the treatment of endometriosis (EMs). The role of andrographolide (AP) in the ferroptosis has gradually attracted attention, but its mechanism of action in endometriosis has not been clarified. Here we investigated the inhibitory effect of AP on endometriosis and its mechanism. Our results showed that AP treatment inhibited progression of ectopic endometrial 12Z cells. We also demonstrated that AP treatment induced ferroptosis and apoptosis in 12Z cells. Combined metabolomics and transcriptomic analysis indicated that AP might exert its effect by down-regulating PSAT1 and PHGDH to inhibit serine synthesis. Knockdown of PSAT1 expression elevated ferroptosis level and blocked progression of 12Z cells; however, the ferroptosis inhibitor Ferrostatin-1 (Fer-1), phosphoserine, or serine mitigated these phenotypes. We also observed that AP inhibited the EMs progression and either PSAT1 or PHGDH level in mice model. Finally, AP exhibited inhibitory effects on the viability of ectopic endometrial stromal cells (EESCs) and the expression of PSAT1, as well as induced ferroptosis in EESCs. Overall, AP is a new potential drug for the treatment of endometriosis.