Naunyn-Schmiedeberg's archives of pharmacology最新文献

Oral lichen planus (OLP), a chronic inflammatory disease affecting the stratified squamous epithelium of oral mucosa (mucositis), presents treatment challenges due to rapid washout of conventional topical gels. This study developed prednisolone acetate-loaded mucoadhesive electrospun nanofibers using PVP K90/Eudragit RS100 via Super ES-3 technology to enhance drug retention and therapeutic efficacy. Nanofibers exhibited uniform morphology (diameter ranging from185 ± 0.3 nm to 704 ± 0.3 nm), neutral surface pH (7.4 ± 0.1), and superior mucoadhesion of 0.03N and bond strength of 0.455 Nmm². FTIR confirmed polymer-drug compatibility and XRD studies revealed crystalline state of drug in nanofibers. In vitro release from prednisolone acetate-loaded nanofibers followed zero-order kinetics (r² = 0.999, RMSE = 1.02%, 90.21% Q₁₂ₕ), ideal for sustained delivery vis a vis. prednisolone acetate dispersion that followed Korsmeyer-Peppas model (r² = 0.962, RMSE = 3.99, 51.34% Q_12h). In vivo evaluations using 4% SDS-induced mucosal irritation model in Wistar rats shown irritation score of 4.333 ± 0.58 in disease control, nanofibers achieved near-complete resolution (score 1.000 ± 0.58, equivalent to vehicle p = 0.7538), significantly outperforming marketed formulation (3.000 ± 0.58, p = 0.0015; using one-way ANOVA F = 45.2, p < 0.0001). Histopathology confirmed superiority with no signs of irritation or tissue damage of the oral mucosa showing normalized rete ridges and minimal inflammation. These findings demonstrate mucoadhesive nanofibers as a promising localized delivery system for OLP, providing sustained prednisolone acetate release, prolonged buccal retention of 7 h, and superior therapeutic outcomes while minimizing systemic corticosteroid exposure.

The short half-life of fibroblast growth factor 21 (FGF21) in vivo limits its clinical application in acetaminophen (APAP)-induced acute liver injury (ALI). This study aimed to construct a novel PLGA-based nanoparticle delivery system for FGF21 and to investigate its protective effects and underlying mechanisms in APAP-induced ALI. PLGA-FGF21 nanoparticles were prepared using a double-emulsion solvent evaporation method and characterized by transmission electron microscopy and Zetasizer Nano for morphology, size, and stability. Their release profile and cytotoxicity were evaluated in vitro using AML12 cells, while hepatoprotective effects were assessed in an APAP-induced ALI mouse model. Histopathology, biochemical assays, immunofluorescence, and Western blot were employed to examine liver function, oxidative stress, and molecular mechanisms. The nanoparticles displayed uniform spherical morphology with an average size of 222.04 ± 1.08 nm and remained stable for 7 days in aqueous suspension. Encapsulation conferred sustained-release properties, and the particles showed no cytotoxicity while maintaining biological activity for at least 28 days. In vivo, PLGA-FGF21 significantly alleviated APAP-induced liver damage, reduced serum ALT and AST, and exhibited superior hepatoprotective efficacy compared with free FGF21. Furthermore, it suppressed inflammatory responses by decreasing TNF-α and MDA levels, while enhancing antioxidant defenses through increased SOD activity. Mechanistically, PLGA-FGF21 activated the PGC-1α/Nrf2/HO-1 signaling pathway, contributing to enhanced anti-inflammatory and antioxidant effects. PLGA-FGF21 nanoparticles provide potent protection against APAP-induced ALI by reducing inflammation and oxidative stress, which may be associated with activation of the PGC-1α/Nrf2 signaling pathway, offering a promising strategy for FGF21-based therapy in liver injury.

Polycystic ovary syndrome (PCOS) is a reproductive disorder associated with infertility and causes other complications in different parts of the body. Many studies have reported reduced L-carnitine (LC) levels in these patients. The aim of the present study was to investigate the therapeutic effect of LC in an animal model of PCOS induced by estradiol valerate (EV). In this study, 15 adult female Wistar rats were divided into three groups: control group, PCOS group receiving EV (4 mg/kg body weight), and PCOS group treated with LC administered orally by gavage (100 mg/kg daily for 17 days). At the end of the treatment period, after euthanizing the animals, serum levels of LH, FSH, testosterone, insulin and glucose were analyzed, and histological, immuno-histochemical (IHC), and molecular examinations of the ovaries were performed. The results showed that LC significantly increased the expression of CYP11A1(cytochrome p450 11A1) (related to steroidogenesis) and TXNIP (thioredoxin interacting protein) (related to oxidative stress) and increased serum levels of follicle-stimulating hormone (FSH), reduced testosterone, luteinizing hormone (LH), glucose, insulin, and homeostasis model assessment-insulin resistance. Improvement in histological and morphometric changes of ovarian follicles as well as IHC expression of estrogen receptor and VEGF was observed in the treatment group. It appears that LC supplementation, through reducing weight, improving sex hormone levels, and enhancing ovarian structure, may offer a promising approach for alleviating complications associated with PCOS and reducing other related disorders. This protocol may be considered a potential future therapeutic intervention for PCOS, though further clinical investigations are required.

This study aimed to investigate the histopathological and biochemical neuroprotective effects of IL-1 receptor antagonist (anakinra) administration in an asphyxia-induced cardiac arrest model. A total of 24 Wistar albino rats were randomized into three groups: control, sham (cardiac arrest + saline), and anakinra (cardiac arrest + 50 mg/kg anakinra). Brain tissues were evaluated using a six-parameter semi-quantitative histopathological scoring system, and the composite damage score (CDS) was calculated (0-12). Levels of antioxidant and oxidative markers SOD, CAT, GSH, and MDA were analyzed spectrophotometrically. In the anakinra-treated group, neuronal degeneration, gliosis, and neuropil edema levels were significantly lower compared to the sham group (p < 0.01 for all). Although vascular congestion and perivascular edema were observed to be lower in the anakinra group, this reduction was not statistically significant in score analyses compared to the sham group (p > 0.05). No significant difference was found between the groups in terms of PMNL infiltration. In biochemical analyses, SOD, CAT, and GSH levels were found to be significantly higher in the anakinra group compared to both the sham and control groups (p < 0.001), while MDA levels were significantly lower (p < 0.001). These findings indicate that anakinra reduces oxidative stress and significantly alleviates neurohistopathological damage in the experimental model. Anakinra administration significantly reduced short-term hypoxic-ischemic brain damage following cardiac arrest, both in terms of histopathological and oxidative stress parameters. The findings suggest that targeting the IL-1-mediated inflammatory response could be an important neuroprotective approach; however, further studies are needed regarding dose, timing of administration, and long-term neurological function.

Myocardial infarction (MI) is a leading cause of death. In this study, we appraised the protective mechanisms of cuminaldehyde, a natural monocyclic terpenoid, in isoproterenol-induced myocardial infarcted rats. Our study included four groups: Group 1: normal control, Group 2: cuminaldehyde (20 mg/kg body weight) alone, Group 3: isoproterenol (100 mg/kg body weight) induced MI, Group 4: MI + cuminaldehyde (20 mg/kg body weight). Cardiac apoptosis and fibrosis were evaluated by biochemical analysis, transmission electron microscopy (TEM), ELISA, RT-PCR, and histopathology to explore the potential molecular mechanisms underlying MI protection by cuminaldehyde. Results of this study revealed that plasma thiobarbituric acid reactive substances (TBARS), heart rate, and serum cardiac troponins-T and -I were raised; heart superoxide dismutase and catalase were reduced in isoproterenol-induced MI rats. Moreover, heart lysosomal TBARS and serum and heart lysosomal enzymes were enhanced. TEM study revealed a damaged heart lysosome. By RT-PCR, the expression of B-cell lymphoma-2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), B-cell lymphoma-2 x (Bax), cytochrome c (Cyt.c), caspase-9, caspase-3, matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) was altered in the myocardium of MI rats. ELISA results revealed elevated serum MMP-2 and MMP-9. Further, histopathology of the heart revealed an accumulation of collagen. Nevertheless, MI rats treated with cuminaldehyde orally, daily for 21 days, reduced oxidative stress, thereby inhibiting apoptosis and fibrosis. Moreover, RT-PCR analysis of Bax/Bcl-2/Bcl-xL/Cyt.c/caspase-9/caspase-3, and MMP-2/MMP-9 pathways demonstrated the molecular mechanisms responsible for the anti-apoptotic and anti-fibrotic potential of cuminaldehyde and mitigated the MI provoked by isoproterenol.Therefore, cuminaldehyde may be a promising phytopharmacological agent for MI therapy.

Ovarian torsion is a gynecological emergency caused by rotation of the vascular pedicle, leading to ischemia, necrosis, and potential fertility loss. Management remains controversial, particularly regarding oophorectomy versus ovarian preservation. Detorsed ovaries continue cytokine secretion, impairing contralateral ovarian function, and no protective therapy currently exists. This study aimed to compare oophorectomy and detorsion strategies and to determine whether post-detorsion long-term pirfenidone therapy preserves ovarian function, thereby providing experimental resolution to the clinically pivotal "save or sacrifice" dilemma. Forty female rats were divided into five groups: Healthy, IR, IR + OVX, IR + Pirfenidone 50 mg/kg, and IR + Pirfenidone 100 mg/kg. Ischemia was induced in the left ovary of IR groups; in IR + OVX, the ovary was excised at 3 h, while in other groups, ovaries were reperfused. Treatments continued for 30 days. Ovarian tissues and blood were analyzed histopathologically, biochemically, and molecularly. Ovarian ischemia-reperfusion induced a persistent inflammatory and profibrotic response not only in the ischemic ovary but also in the contralateral ovary, leading to reduced estrogen levels and marked histopathological damage. Importantly, detorsion alone did not prevent contralateral injury, whereas oophorectomy attenuated molecular alterations. Post-detorsion pirfenidone therapy dose-dependently restored estrogen production, suppressed inflammasome activation (IL-1β, NLRP3, caspase-1) and fibrotic signaling (SMAD2, SMAD3, TGF-β1), and preserved normal follicular architecture in both ovaries. These findings demonstrate that the detorsed ovary remains a biologically active source of injury and identify pirfenidone as a potential adjunct therapy capable of protecting ovarian function after torsion.

Bisphenol A (BPA) is an endocrine disruptor found in plastics, particularly in food and beverages packaging materials, and can lead to excessive deposition of extracellular matrix. This may result in hepatic fibrosis by activating hepatic stellate cells (HSCs). To address this pathological condition, niclosamide (NIC), an FDA-approved anthelmintic agent, has emerged as a promising antifibrotic compound since it inhibits HSC activation. However, its poor aqueous solubility and availability at the site of action limit its therapeutic application. To overcome this limitation, NIC-loaded hyaluronic acid and mannose-grafted liposomes (NIC-HA-MN-Lipo) were developed to target CD44 on HSCs and CD206-positive mannose receptor M2 macrophages, thereby enabling site-specific delivery to fibrotic liver tissue. In this research, hepatic fibrosis was established in albino rats by oral exposure of BPA (50 mg/kg/day) for a duration of 8 weeks, and treated with free NIC, Placebo-Lipo, non-targeted liposomes (NIC-Lipo), and dual receptor targeted liposomes (NIC-HA-MN-Lipo) for alternative 21-days. After completion of the treatment liver function tests, lipid profiles, oxidative stress parameters (malondialdehyde, protein carbonyl), antioxidant levels (glutathione, catalase, superoxide dismutase), histopathology and scanning electron microscopy (SEM) was performed. Liver fibrosis scoring and immunohistochemically examination of fibrotic indicators (TGF-β1, α-SMA) and receptor expression (CD44, CD206) were also performed. NIC-HA-MN-Lipo-treated animals showed substantial betterment in liver architecture, reduced collagen deposition, and significant normalization of biochemical and oxidative stress markers in comparison to pristine NIC and NIC-Lipo. The dual targeted NIC-HA-MN-Lipo exhibited receptor targeted localization and superior anti-fibrotic efficacy, evidenced by substantial downregulation of α-SMA and TGF-β1. These findings indicate the therapeutic potential of ligand-targeted liposomal delivery of NIC in reversing hepatic fibrosis. NIC-HA-MN-Lipo demonstrated potential antifibrotic effects in BPA-induced liver injury by effectively targeting key fibrogenic cells and modulating the TGF-β-associated pathway in liver fibrosis.

Drug-induced hypokalemia is a common yet clinically insidious electrolyte disorder, but systematic evaluations of the risk profile of associated medications remain limited. This study was aimed at identifying high-risk drugs for hypokalemia via signal mining of the FAERS database, combined with bioinformatics analysis, clinical validation, and in vitro experiments, thereby elucidating the molecular basis of this condition and providing evidence for clinical risk management. Adverse event reports from 2004 Q1 to 2024 Q4 were analyzed using four disproportionality methods (ROR, PRR, BCPNN, and MGPS), integrated with multivariate logistic regression to assess drug-hypokalemia associations and risk factors. For cisplatin, the core high-risk drug identified, potassium metabolism-related differentially expressed genes were screened from the GEO dataset GSE145085. Candidate gene mRNA expression was validated by qPCR in 293 T and HK-2 cells. STRING protein-protein interaction (PPI) network analysis was performed to explore the link between candidate genes and potassium homeostasis. Additionally, ClinicalTrials.gov data were retrieved to confirm the clinical relevance of cisplatin-induced hypokalemia. FAERS analysis identified a total of 24,041 reports related to hypokalemia. The study identified 1199 suspected drugs, with 22 high-risk medications showing a significant association with hypokalemia, including cisplatin. In vitro experiments demonstrated that treatment with cisplatin for 24 h significantly altered the mRNA expression of GDF15, KCNQ1, and CLCNKB in 293 T and HK-2 cells, consistent with bioinformatics findings. STRING PPI analysis further revealed that GDF15 interacts with core components of the TGF-β/SMAD signaling pathway, while KCNQ1 and CLCNKB interact with critical regulators of renal potassium and chloride transport, collectively establishing a plausible molecular framework linking these genes to cisplatin-induced potassium homeostasis dysfunction. This study systematically identified 22 high-risk drugs associated with hypokalemia, including cisplatin. Bioinformatics analysis and in vitro experiments were further conducted to investigate the potential mechanisms underlying cisplatin-induced hypokalemia. The findings provide novel insights into the molecular basis of drug-induced hypokalemia and offer scientific support for promoting individualized rational medication and clinical management in affected patients.

Zingerone (ZO) found in Zingiber officinale, belonging to methoxyphenol family and its related derivatives, has been reported to ameliorate nonalcoholic fatty liver disease (NAFLD) by enhancing lipid metabolism and exerting hepatoprotective effects. However, the effect of ZO on hepatic AQP9 expression, along with the underlying mechanisms driving its hepatoprotective potential, remains largely unexplored. This study aims to investigate the modulatory effect of ZO on AQP9 expression in a steatosis cell model through experimental and in silico analyses, providing insights that could contribute to therapeutic interventions for NAFLD. Oleate-palmitate (OA-PA) and free fatty acids (FFA) induced hepatic steatosis was established in Hepa 1-6 cells as in vitro model of NAFLD. Cell cytotoxicity and lipid accumulation were evaluated by MTT assay and Oil-RedO staining, respectively. ZO pretreatment significantly attenuated intracellular lipid accumulation and altered the expression of aquaporins, resulting in downregulation of AQP9 and upregulation of AQP3 and AQP7, as demonstrated by qRT-PCR analysis. These findings suggest that ZO ameliorates OA-PA induced hepatic steatosis primarily by inhibiting lipid accumulation and selectively modulating aquaporin expression. Molecular docking analysis revealed that ZO forms a complex with AQP9 with the minimum binding energy of -6.2 kcal/mol. The molecular dynamics simulations showed that this complex stays stable across time with consistent RMSD and low RMSF values. In summary, pre-treatment with ZO has beneficial health effects by inhibiting lipid accumulation and selectively modulating aquaporin expression, highlighting its potential in preventing fatty liver disease.