Naunyn-Schmiedeberg's archives of pharmacology最新文献

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.

Assessing the biological activities of some potential drugs and comparing their suitability for in vitro and in vivo combination therapy or in silico drug repositioning against important targets is essential for minimizing labor, costs, and time in drug development. Herein, dose- and time-dependent in vitro anticancer activity studies of anti-inflammatory drugs, including celecoxib (C), indomethacin (I), and meloxicam (M), in combination with natural products (taxifolin (T), quercetin (Q), and rutin (R)) and doxorubicin (Dox), were carried out in MDA-MB-231, BT-20, MCF-7, and HT-29 human cancer cell lines. Drug C demonstrated significant anticancer activity in cancer cells with natural products (< 40 µM) and Dox (< 5 µM). The antiulcerative effect of the most promising drug C in combination with T and R in rats was carried out. The histopathological analysis suggests that the substitution of R with T, when combined with drug C, leads to a statistically significant improvement in the amelioration of gastric mucosal injury. Additionally, in silico studies have been conducted against the important cancer drug target sphingosine kinase 1 (SphK1). The obtained results highlight that drug C and T may be potential inhibitor candidates as SphK1 inhibitors for targeted cancer therapy. Overall, the combination of drug C with T has shown promising results, anticancer effects in breast and colon cancer cells and antiulcerative effects in rats.

Gastric ulcer (GU) is primarily caused by Helicobacter pylori (H. pylori) infection, ethanol-induced oxidative stress, and excessive gastric acid secretion. This is a significant global health burden. Lifetime prevalence of peptic ulcer disease (including GU and duodenal ulcer) in the general population has been estimated to be about 5-10%, and incidence 0.1-0.3% per year. Kahweol (a coffee-derived diterpene) exhibits broad pharmacological effects. Although Kahweol has strong antioxidant, anti-inflammatory and cytoprotective effects, its gastroprotective potential against ethanol-induced GU has remained unexplored. This is the first study demonstrating the multifaceted gastroprotective effects of Kahweol using an integrated computational, in vitro, and in vivo approaches, including direct comparison with omeprazole and evidence of dual acid-suppressive and anti-H. pylori activity. Molecular docking and 100 ns molecular dynamics simulations demonstrated stable Kahweol binding to H⁺/K⁺-ATPase, nuclear factor-kappa B, NOD-like receptor protein 3, and cyclooxygenase-2. Kahweol exhibits inhibition of inflammatory pathways and acid secretion, having the highest affinity for H⁺/K⁺-ATPase (-7.92 kcal/mol). In vitro assays revealed that Kahweol has dose-dependent antibacterial activity against H. pylori clinical isolates. In vivo, Kahweol significantly decreased the ethanol-induced ulcer index in a dose-dependent manner. Kahweol pretreatment inhibited GU up to 80% with 10 mg/kg dose, which was comparable to that of omeprazole (85%). Histopathological analysis in Kahweol-treated groups confirmed preserved mucosal architecture, reduced vacuolation, and restored epithelial boundaries, which were comparable to those of omeprazole. Biochemical assays of Kahweol-treated groups showed enhanced antioxidant defenses, with increased levels of reduced glutathione, glutathione S-transferase, and catalase, along with decreased levels of nitric oxide and malondialdehyde. Results from the enzyme-linked immunosorbent assay of the Kahweol-treated group showed that the pro-inflammatory cytokines interleukin-1 beta and tumor necrosis factor-alpha were suppressed, confirming anti-inflammatory effects. Quantitative real-time polymerase chain reaction verified that the expression of H⁺/K⁺-ATPase was downregulated by Kahweol, indicating the acid-inhibition effect of Kahweol. These findings suggest Kahweol is the potential natural agent for the prevention and treatment of ethanol-induced GU, highlighting the comprehensive gastroprotective effects of Kahweol through its antioxidant, anti-inflammatory, anti-secretory, and anti-H. pylori activity.

Complex systemic immune dysregulation and chronic inflammation in rheumatological diseases lead to long-term inflammation and morbidity, which are primarily controlled by systemic immunosuppressant agents with diverse effects, underscoring the need for more precise and innovative treatments. The unmatched specificity in targeting disease-driving genes and pathways makes small interfering RNA (siRNA) a transformative treatment approach. This review examines how siRNA can precisely transform the therapy of rheumatological diseases by targeting critical molecular pathways associated with inflammation, immunological dysregulation, and tissue damage. While this study elucidates siRNA therapies targeting inflammatory pathways to treat rheumatological diseases, it moves beyond the conventional therapeutic application of siRNAs targeting pro-inflammatory cytokines; it explicitly focuses on upstream signaling hubs within synovial fibroblasts, T cells, and plasma cells, as well as on non-inflammatory mechanisms that lead to bone damage. The review also integrates in vitro and in vivo, as well as preclinical siRNA studies, to identify the most promising targets and determine whether these siRNA modifications, combined with delivery systems, achieve body-wide and joint-specific immune-stromal network reprogramming through targeted delivery without causing total immune system breakdown.

Gestational diabetes mellitus (GDM) is a prevalent metabolic disorder during pregnancy associated with adverse maternal and fetal outcomes, highlighting the urgent need for novel, genetically supported drug targets due to suboptimal glycemic control and safety concerns with existing therapies. This study integrated cis-expression quantitative trait loci (cis-eQTL) of druggable genes with genome-wide association data to identify putative causal genes for GDM through two-sample Mendelian randomization (MR), with significant associations further validated using multi-tissue summary data-based Mendelian randomization (SMR), colocalization analysis, cis-protein quantitative trait loci (cis-pQTL) MR, and single-cell RNA sequencing (scRNA-seq) to confirm tissue- and cell type specific expression. MR analysis identified 15 genes significantly associated with GDM risk after Bonferroni correction, with SMR and colocalization analyses confirming robust associations for five key genes: higher expression of NRBP1, LPL, and BTN3A2 was causally linked to reduced GDM risk, while elevated GSTM1 and GRINA levels were associated with increased risk. ScRNA-seq revealed distinct expression patterns in placental cell types, with NRBP1 and GRINA highly expressed in trophoblasts and certain immune cell populations. Phenome-wide association studies revealed no significant pleiotropic effects, and pharmacological drug-target databases identified several compounds with potential regulatory interactions. This multi-omics study successfully identifies several genetically supported, druggable targets for GDM, providing a robust foundation for developing mechanism-based therapeutics and precision prevention strategies in pregnancy metabolism.

Cocaine use disorder (CUD) remains a major public health challenge with limited effective therapeutic options. Cannabidiol (CBD) has been proposed as a potential treatment due to its neuroprotective and anti-craving properties. This scoping review aims to synthesize and map the existing evidence from clinical trials evaluating CBD's effects on craving reduction, relapse prevention, cognitive function, and emotional regulation in individuals with CUD. Although CBD was well tolerated and associated with fewer adverse events than conventional pharmacological treatments, clinical studies included in this review did not demonstrate significant efficacy over placebo in reducing cocaine craving, preventing relapse, or improving cognitive performance, despite promising preclinical outcomes. The review also highlights methodological limitations across studies, including variability in dosage, treatment duration, and study design. Although current evidence does not support CBD as a standalone treatment for CUD, its favorable safety profile suggests potential utility within a broader, multimodal therapeutic framework. Future research should prioritize standardized protocols and explore synergistic combinations with behavioral or pharmacological interventions to enhance treatment efficacy.

Hepatitis C virus remains a pressing global health issue that has driven extensive research for introducing advanced therapeutic regimens. Among these, the sofosbuvir (SFV)/ribavirin (RBV) drug regimen has had a profound effect on reducing the viral load. Nevertheless, this drug regimen has led to adverse testicular alterations. This study aimed to investigate the restorative effects of SFV/RBV over different durations to determine the possibility of restoring normal histological and histophotometrical testicular tissue. Swiss Albino mice were grouped as total n = 80 with subgroups of n = 5 per timepoint per group, into control group, SFV group received 41mg/kg once daily of SFV, RBV group administered with RBV 41 mg/kg twice daily, and SFV-RBV group received a combined dose of SFV + RBV, identical to those used separately. All drugs were administered by oral gavage for 5 successive days. Testicular tissue in the SFV, RBV, and SFV-RBV groups, at 5 and 70 days after administration, exhibited pronounced alterations, including spermatocyte degeneration, Leydig cell impairment, and disrupted spermatogenesis. Moreover, altered morphometric parameters were observed, characterized by a reduction in testicular area, a diminished seminiferous diameter, and a regression in spermatic epithelium thickness, which collectively contributed to a decline in the spermatogenic index and the conception index. Conversely, starting from day 140 and persisting through day 175 post-treatment, testicular architecture demonstrated substantial recovery, with restoration of spermatogenesis and improvements across morphometric parameters. The administration of SFV and/or RBV for 5 days induced significant testicular injury, which was reversed after 175 treatments. Restorative effects underscore the potential safety of SFV/RBV regimens in human males.

The present study aimed to formulate and evaluate, both in vitro and in vivo, enteric-coated mucoadhesive microspheres of pantoprazole using xanthan gum and Eudragit L100-55 in order to protect pantoprazole from gastric acid degradation and to create a temporary drug reservoir in the gastrointestinal tract, thereby achieving enhanced targeting. The goal was to assess their potential in preventing ketorolac-induced gastric ulcers in rats. Various formulations of pantoprazole microspheres were prepared and developed via an extrusion method using ionotropic gelation and dip coating. The formulations were evaluated for encapsulation efficiency, particle size, mucoadhesive properties, swelling percentage, resistance to gastric acid, and drug release over six hours in vitro. The optimized formulation (10 mg/kg) was subsequently tested in vivo on rats with ketorolac-induced (30 mg/kg) gastric ulcers, and the gastric tissue was examined for histopathological changes. The formulation containing 1% xanthan gum showed the highest drug release (80% w/w) and suitable loading (77.58% w/w), with a swelling index of 50.84% w/w, average particle size of 1.19 mm, an adhesion strength of 2.71 ± 0.87 N per 0.1 g and was fully resistant to acidic conditions. In vivo, it prevented gastric ulcers as effectively as the marketed product and, unlike the marketed product, also prevented vascular rupture in all ketorolac-induced ulcer rats. The optimized formulation performed well, suggesting its potential as an oral delivery alternative.