Naunyn-Schmiedeberg's archives of pharmacology最新文献

Angiogenesis, the production of new blood capillaries from pre-existing vasculature, is an important mechanism necessary for cancer progression and metastasis. This process may be regulated by the balance of pro-angiogenic and anti-angiogenic factors. The disruption of this balance leads to the induction of angiogenesis. Thus, there is a high necessity to identify these angiogenesis-related genes. In this study, we have used GeneCards database to obtain a list of angiogenesis-related genes followed by construction of protein-protein interaction (PPI) network using STRING database. Out of 37 angiogenesis-related genes, a single-gene cluster containing 27 genes was identified using MCODE analysis. The top ten hub genes were identified as FGF2, HIF1A, VEGFC, VEGFA, MMP9, THBS1, MMP2, KDR, IL6, and NOS, which were further analyzed. FunRich application was used to perform gene enrichment analysis and identify top interactors by constructing an interaction map. PPI map of each individual hub gene was constructed using search tool for the retrieval of interacting genes/proteins (STRING) database. The expression levels of each individual hub gene in HCC (liver hepatocellular carcinoma-LIHC dataset) and normal tissue were analyzed using the gene expression profiling interactive analysis 2 (GEPIA2) portal. The prognostic value of the hub genes was analyzed using Kaplan-Meier survival plot. The translational-level expression was analyzed using the IHC section images from the Human Protein Atlas (HPA) database. Thus, targeting these factors for therapy, diagnosis, or prognosis could be a key strategies in the field of oncology.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by relapsing mucosal inflammation. Medicine-food homologous (MFH) substances represent a promising source of therapeutic compounds. This study aimed to identify promising key MFH-derived bioactives for UC intervention. Transcriptomic datasets from GEO were analyzed to overlap differentially expressed genes (DEGs) between UC and controls with UC-related target genes from public disease databases, generating candidate genes for functional enrichment analysis. Bioactive compounds from 110 MFH substances were compiled via dual-database integration. Compound-protein interactions were predicted using GraphBAN, followed by drug-likeness and toxicity evaluations to identify candidate key compounds and their corresponding potential key genes. An MFH substance-compound-gene tripartite network was constructed. Molecular docking and molecular dynamics (MD) simulations were performed, and the expression of candidate key genes was assessed in an independent UC/control tissue dataset. We identified 266 candidate genes enriched in immune response, inflammation, and cell adhesion pathways. MOL008417 was prioritized as the candidate key compound, with CHRM3, CYP17A1, CYP3A5, MPO, and NOS1 prioritized as potential key genes. Network analysis highlighted Dangshen (Codonopsis root) as a key MFH substance. Docking suggested a feasible binding between MOL008417 and CHRM3 (- 5.3 kcal/mol), and MD simulations indicated complex stability. Gene expression analysis demonstrated significant CHRM3 upregulation and CYP3A5 downregulation in inflamed UC tissues compared with non-inflamed UC tissues and control samples. Our integrated computational workflow suggests that the MFH-derived compound MOL008417 may have multi-target potential for UC treatment through interactions with potential key genes. These predictive findings offer a mechanistic hypothesis for the development of MFH-based interventions and could inform the design of novel, UC therapeutics, pending future experimental validation.

Convallatoxin (CNT), a cardiac glycoside purified from a traditional Chinese herb Adonis amurensis Regel et Radde, has been reported to exert anti-inflammatory and antitumor effects. However, its therapeutic effect on rheumatoid arthritis (RA), a chronic inflammatory disorder, remains unexplored. Thus, this study aimed to investigate the impact of CNT on regulating key functions of fibroblast-like synoviocytes (FLS) from patients with RA, evaluate its therapeutic efficacy on collagen induced arthritis (CIA) mouse model and further elucidate the underlying molecular mechanisms. Cell viability, proliferation and apoptosis were assessed using CCK8, EdU and Annexin V-AF647/ PI assays, respectively. RA FLS migration and invasion were evaluated using wound healing assay, Transwell and Matrigel assays. mRNA and protein levels of proinflammatory cytokines and matrix metalloproteinases (MMPs) were analyzed by RT-qPCR and ELISA, respectively. Protein expression in RA FLS and synovial tissues was examined via Western blotting and immunohistochemistry. Furthermore, RNA sequencing was employed to identify the potential downstream targets of CNT. The in vivo therapeutic efficacy of CNT was investigated using a CIA mouse model. In vitro experiments demonstrated that CNT (7.5, 15 and 30 nM) dose dependently inhibited migration, invasion and expression of IL-6, CCL2, MMP-2 and MMP-13 of RA FLS, without affecting proliferation and apoptosis. In vivo study showed that CNT treatment (50ug/kg/d and 150ug/kg/d) attenuated synovial inflammation and joint destruction in mice with CIA. Mechanistically, IDH1 was identified as the potential downstream target of CNT in RA FLS. IDH1 expression was significantly elevated in RA FLS and RA synovial tissues. Moreover, both CNT treatment and IDH1 knockdown suppressed AKT and NF-κB p65 phosphorylation. CNT inhibits aggressive behavior and inflammatory response of RA FLS by inhibiting IDH1-mediated activation of the AKT and NF-κB signaling pathways. Our findings suggest that CNT may be a potential novel therapeutic agent for RA.

The association between respiratory drugs (RDs) and pediatric psychiatric adverse events (pAEs) remains insufficiently characterized. We aimed to characterize pAEs associated with RDs use in pediatric patients. RD-related pAE reports were retrieved from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. Analysis focused on pediatric patients aged 0 to 17 years. Disproportionality analysis was conducted using four algorithms, with a focus on anxiety disorders and symptoms, depressed mood disorders and disturbances, and suicidal and self-injurious behaviors. Descriptive and clinical outcome analyses were performed, along with subgroup analyses to explore potential risk differentials by age and gender. Among 6,994 cases of RD-related pAEs in pediatric patients, 16 drugs with positive signals were identified across all four algorithms, with antiallergics accounting for 75.00%. Montelukast was the most frequently reported drug (n = 6,168), primarily associated with anxiety (21.84%, reporting odds ratio [ROR] = 15.08), depression (15.86%, ROR = 12.90), and suicidal ideation (14.27%, ROR = 13.63). Promethazine demonstrated strong signals for intentional self-injury (62.99%, ROR = 127.36). The highest mortality rates were observed with hydroxyzine (50.94%) and caffeine (50.00%), while oxytetracycline (4/4, 100%) showed the highest proportions of life-threatening events. Montelukast generated signals in all age and gender groups, with the highest disproportionality observed in children aged 0 to 4 years. This study identifies statistical associations between RDs and pAEs in pediatric patients, particularly with montelukast and promethazine. The highest mortality rates were observed with hydroxyzine. These findings provide a foundation for further research but require confirmation through large-scale prospective studies.

Cyclophosphamide (CP) is a widely used chemotherapeutic agent whose clinical efficacy is often limited by its side effects, including nephrotoxicity. Oxidative stress and inflammation are central to CP-induced acute kidney injury (AKI). Ambroxol (ABX), a clinically approved mucolytic agent, has demonstrated antioxidant and anti-inflammatory properties that may be repurposed for nephroprotection. This study investigated the protective effects of ABX against CP-induced nephrotoxicity in rats and explored the underlying molecular mechanisms. Adult male rats received ABX (20 mg/kg/day) orally for seven consecutive days, with CP (100 mg/kg, i.p.) given on the fifth day. CP administration resulted in significant renal dysfunction, as indicated by elevated serum creatinine, BUN, uric acid, and Kim-1 levels. Histopathological analysis revealed glomerular degeneration, tubular damage, collagen deposition, and iron accumulation. CP also induced oxidative stress, evidenced by increased MDA and decreased GSH, SOD, and catalase, along with upregulation of NF-κB, elevated TNF-α and IL-1β levels, and increased cleaved caspase-3 expression. ABX reduced MDA, enhanced antioxidant defenses, and suppressed NF-κB and pro-inflammatory cytokines. ABX attenuated apoptosis as evidenced by reduced caspase-3 expression and concurrently modulated redox-sensitive signaling by upregulating Nrf2 and HO-1 expression and activity while downregulating Keap-1. ABX showed in silico binding affinity toward NF-κB, Keap-1, and HO-1. In conclusion, these findings suggest that ABX confers nephroprotection against CP-induced injury primarily through its antioxidant, anti-inflammatory, and anti-apoptotic actions, partly via modulation of the Keap-1/Nrf2/HO-1 pathway. These findings support potential repurposing of ABX as a nephroprotective adjuvant during CP chemotherapy and warrant further clinical investigation.

Ulcerative colitis (UC) is a chronic inflammatory disease with an unclear pathogenesis. This study aimed to investigate the therapeutic mechanism of leonurine in UC. Using network pharmacology and bioinformatics analysis, we identified the PINK1/Parkin-mediated mitophagy pathway as a key target. Validation in a DSS-induced colitis mice model showed that leonurine significantly alleviated colonic injury, reduced inflammatory cytokines, and restored intestinal barrier function. Mechanistically, leonurine upregulated the expression of mitophagy-related proteins (PINK1, Parkin, LC3II) and improved mitochondrial morphology. In conclusion, leonurine ameliorates UC by activating the PINK1/Parkin-mediated mitophagy pathway, providing a scientific basis for its development as a potential therapeutic agent.

Gambogic acid (GA), a natural active ingredient extracted from gamboge resin, has traditionally been utilized for liver-related diseases. Prior investigations have confirmed that GA holds remarkable efficacy in mitigating inflammatory response through the Nrf2 signaling pathway; also, Nrf2 acts synergistically with TGF-β₁/Smad2 in hepatocarcinogenesis. However, scientific evidence concerning how GA modulates the TGF-β₁/Smad2 and Nrf2/HO-1 signaling pathways and even Nrf2 inhibition on Smad2C/2L phosphorylation relates to the hepatoprotective ability of GA on oxidative stress remains opaque. Nowadays, DEN/CCl₄/C₂H₅OH (DCC) induced HCC in mice, and TGF-β₁ and/or Nrf2 inhibitor stimulated HepG2 cells were generated to settle the above questions. As it turns out, GA significantly inhibited the occurrence and progression of liver cancer, as reflected by amelioration in liver biopsies, liver function, and histopathology; while also markedly reducing tumor incidence and multiplicity. It had a notable effect on the activation of Nrf2/AREs-related proteins and inhibition on pSmad2C/2L expression. Cell experiments further confirmed that Nrf2 and pSmad2C/2L may simultaneously participate in the anti-HCC effect of GA, and the Nrf2 inhibitor ML385 could abate GA's anti-HCC effect on proliferation, migration, and invasion, with Nrf2 and pSmad2C/2L expression levels showing a contrary tendency. These studies highlighted that GA may inhibit oxidative stress to ameliorate hepatocellular carcinoma via the Nrf2-pSmad2C/2L pathway. However, the specific interaction regulatory mechanism deserves further exploration.

Nail diseases, including fungal infections and malignancies, pose significant health risks and may lead to severe complications if not accurately diagnosed. Conventional diagnostic methods are often subjective and time-consuming. This study introduces CapsuleSEDualNet, a novel deep learning framework designed to achieve robust and interpretable multi-class nail disease diagnosis. The proposed CapsuleSEDualNet integrates a Capsule Network head with a Squeeze-and-Excitation (SE) attention mechanism within a Dual-Backbone architecture combining MobileNetV2 and DenseNet121. The SE block enhances feature discriminability, while the Capsule head preserves spatial hierarchies for improved interpretability. To address dataset imbalance, the Synthetic Minority Over-sampling Technique (SMOTE) was applied. The model was evaluated using extensive experiments and benchmarked against existing deep learning architectures. CapsuleSEDualNet achieved an overall classification accuracy of 96%, demonstrating superior performance compared to baseline models. The integration of SE attention and Capsule networks effectively reduced misclassification rates and improved feature representation. Experimental findings confirm the framework's robustness, scalability, and interpretability for clinical applications. The proposed CapsuleSEDualNet framework provides an efficient and reliable solution for automated nail disease screening. By combining diagnostic accuracy, model interpretability, and computational efficiency, it addresses a critical clinical need for early and accessible dermatological assessment. The model shows strong potential as a computer-aided decision support tool, pending further clinical validation. Its potential integration into computer-aided dermatology systems and telemedicine platforms can enhance physician decision-making, reduce misdiagnosis risk, and improve patient outcomes in dermatological care.