Archiv der Pharmazie最新文献

Ulcerative colitis (UC) is a persistent inflammatory bowel disorder characterized by systemic inflammation and oxidative stress. This study compared the therapeutic potential of lamotrigine and donepezil in an acetic acid (AA)-induced UC rat model. Fifty-six male Wistar rats were divided into seven groups: control, AA (4% v/v), donepezil (5 mg/kg), lamotrigine (10 mg/kg), prednisolone + AA, donepezil + AA, and lamotrigine + AA. Treatments were trans-rectally administered for 12 days before and 2 days after UC induction. Macroscopic and histological damage, oxidative stress markers (myeloperoxidase, malondialdehyde, and nitric oxide), antioxidant levels (glutathione), cytokines, and apoptotic markers were assessed. Donepezil and lamotrigine reduced AA-induced damage, decreased oxidative stress, and restored the glutathione level. Both drugs lowered proinflammatory cytokines (e.g., interleukin-1β and tumor necrosis factor-α) and increased interleukin-10. Mechanistically, they activated peroxisome proliferator-activated receptor-gamma (PPARγ), inhibited nuclear factor kappa B (NFκB), and modulated apoptosis (BAX/Bcl-2 ratio, caspase-1). Donepezil and lamotrigine show promise in UC therapy by targeting oxidative stress, inflammation, and apoptosis, supporting their potential repurposing for inflammatory bowel disease treatment. Further research is needed for clinical validation.

Hepatic ischemia/reperfusion injury (IRI) is a major complication during liver surgery, transplantation, and trauma. This study investigated the potential hepatoprotective effects of Entresto (sacubitril/valsartan), a dual angiotensin receptor-neprilysin inhibitor, in a rat model of hepatic IRI. Male Wistar rats were pretreated with Entresto before 30 min of partial hepatic ischemia followed by 2 h of reperfusion. Serum liver enzymes (ALT, AST), oxidative stress markers (GSH, GSSG, GSH/GSSG ratio, MDA), and liver histopathology were assessed. Antioxidant and signaling proteins (CAT, SOD, GPx-1, PPAR-γ, HO-1, Nrf2, IRAK-M, GCL, NQO1) were determined by ELISA. qRT-PCR assessed HO-1, GCL, NQO1, GPx-1, IL-1β, IL-6, TNF-α, BAX, and BCL-2 mRNA expression, while Western blot analysis analyzed TLR4, MyD88, and NF-κB p65 protein expression. Entresto significantly reduced serum ALT and AST, MDA, and GSSG levels, while increasing GSH and restoring the GSH/GSSG ratio. Histopathology revealed notable restoration of the hepatic architecture. Entresto downregulated proinflammatory cytokines and apoptotic markers (BAX, caspase-3), while upregulating antioxidant and antiapoptotic markers (PPAR-γ, HO-1, Nrf2, BCL-2). Additionally, key proteins in the TLR4/MyD88/NF-κB inflammatory pathway were significantly suppressed. These findings suggest that Entresto confers hepatoprotection against IRI by reducing oxidative stress, inflammation, and apoptosis, likely via modulation of TLR4/MyD88/NF-κB and PPAR-γ/Nrf2/HO-1 signaling pathways.

This study utilized an untargeted metabolomic approach using LC-MS/MS to analyze the metabolic alterations in extracellular vesicles (EVs) secreted by breast cancer cells under hypoxic conditions. EVs were isolated using an established ultracentrifugation protocol, and their homogeneity was assessed through TEM, SEM, NTA, and immunoblotting. Metabolic extracts from hypoxic EVs were found to enhance breast cancer cell migration, invasion, and epithelial–mesenchymal transition (EMT), underscoring their role in tumor progression. Metabolomic analysis identified over 400 annotated metabolites, with univariate statistical analysis (p < 0.05, Log₂FC > 0.58/< −0.58) revealing 48 significantly altered metabolites in MDA-MB-231- and MCF-7-derived EVs, respectively, indicating substantial metabolic reprogramming under hypoxia. Integrated univariate and multivariate analyses (p < 0.05, Log₂FC > 0.58/< −0.58, VIP > 1) identified key upregulated metabolites, including riboflavin, 5,6-epoxy-8,11,14-eicosatrienoic acid, and furandicarboxylic acid, in hypoxic EVs from both cell lines. Additionally, N-acetyl-l-methionine, 2,6-diamino-4-hydroxy-5-N-methylformamidopyrimidine, and 5,10-methenyltetrahydrofolic acid were identified as critical metabolites potentially influencing cell proliferation, DNA damage, and epigenetic regulation. Metabolic pathway analysis highlighted heightened activity in aromatic amino acid and riboflavin metabolism. These findings reveal significant metabolic alterations in hypoxic EVs, providing insights into their potential role in driving tumor progression.

Retinoic acid receptor-related orphan receptor gamma-t (RORγt) is one of the nuclear receptor transcription factors that plays a key role in the differentiation of pro-inflammatory IL-17⁺ T helper cells. Recently, RORγt has attracted increasing attention as a potential drug target for the treatment of several human inflammatory diseases, including psoriasis and Crohn's disease. In this study, we revealed that ergosterol (ERG) was a novel RORγt inverse agonist, which decreased RORγt transcriptional activity, to regulate collagen fiber deposition and to inhibit pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-17, IL-22, and IL-23 in the skin lesions of IMQ-induced mice with psoriasis. Furthermore, ERG could repair the epidermal barrier function by upregulating tight junction proteins, such as claudin, occludin, and ZO-1, thereby alleviating psoriasis symptoms. These findings suggested that ERG might be used as a promising novel RORγt inverse agonist in the management of psoriasis.

Acute lung injury (ALI) represents a critical medical issue typified by serious respiratory dysfunction, which frequently progresses to acute respiratory distress syndrome (ARDS), a condition linked to elevated rates of morbidity and mortality. In the present research, cumambrin B (CB), a sesquiterpene lactone extracted from Ajania fruticulosa (Ledeb.) Poljak was systematically examined, focusing on its potential anti-inflammatory molecular mechanism and therapeutic efficacy in ALI models. In vitro, lipopolysaccharide (LPS) was demonstrated to activate nuclear factor kappa B (NF-κB) or mitogen-activated protein kinase (MAPK) pathways in RAW264.7 macrophages, triggering protein phosphorylation. Conversely, treatment with CB selectively suppressed phosphorylation events and inhibited the initiation of these pathways. In vivo, CB ameliorated LPS-induced pathological alterations, including alveolar wall thickening and parenchymal structural disruption. Further analysis demonstrated that CB pretreatment alleviated LPS-induced pulmonary edema, as substantiated by a reduced pulmonary wet-to-dry ratio, and mitigated lung inflammation, indicated by decreased interleukin 6 (IL-6) mRNA expression in lung tissue, lower IL-6 levels, reduced leukocyte counts, and diminished bronchoalveolar lavage fluid (BALF) content of total protein in mice. Conclusively, our research indicates that CB exhibits potential as a viable pharmaceutical agent for managing inflammatory conditions, such as ALI.

Pregnenolone-carbamate derivatives were synthesized and evaluated as potential multifunctional agents with cholinesterase inhibitory and neuroprotective properties. Among them, P3, P5, and P9 exhibited the most promising profiles and were subjected to integrated spectroscopic, biochemical, and computational analyses. Inhibition assays revealed selective acetylcholinesterase (AChE) inhibition by P3 (IC₅₀ = 0.11 μM), butyrylcholinesterase inhibition (BuChE) selectivity for P5 (IC₅₀ = 0.47 μM), and dual inhibition by P9. Fluorescence and UV–vis studies indicated minor groove binding to DNA with log K_app values around 5.85, while static quenching with human serum albumin (HSA) was observed, with log K_A values up to 2.25. Docking studies supported these findings, showing favorable binding energies for DNA (–8.6 kcal/mol) and HSA (–9.7 kcal/mol), and predicted localization within the DNA minor groove and Sudlow sites on HSA. Cytotoxicity assays on HT22 cells indicated high viability (> 75% at 40 µM), suggesting a favorable safety margin. These results offer a molecular-level understanding of the pharmacodynamic and pharmacokinetic properties of these compounds and support their potential for further in vivo evaluation.

The antineoplastic properties of the Cu(II) coordination compound Casiopeina III-ia (Cas III-ia) are revealed using an in vivo glioma model, and its biopharmaceutical properties are predicted through an in silico analysis. C6 cells of the murine glioma allograft model were implanted in rats to form glioma tumors and treated with Cas III-ia at doses of 0.75 and 1.5 mg/kg/day for 21 days. The mean tumor volume of treated rats was reduced by 73% and 88% compared with the control, respectively. Moreover, the mitotic and proliferation indexes decreased with a simultaneous increase in the apoptotic index. We observed the generation of reactive oxygen species, lipoperoxidation, increased p21WAF/CIP, Bax, cleaved caspase 3, and decreased Cyclin D and Bcl-2. The pharmacokinetic study reveals a half-life of 12.4 h, depuration of 5.3 mL/h, and a volume of distribution of Cas III-ia of 20.3 L. In silico analysis revealed that Cas III-ia possesses potential oral bioavailability, high gastrointestinal absorption, the capacity to penetrate the blood–brain barrier, and is a potential target of glycoproteins, but not a substrate of CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4. Our findings strongly suggest that Cas III-ia holds excellent promise as a potential compound for treating human malignant glioma.

Multidrug-resistant (MDR) bacterial infections are on the rise worldwide, and there are fewer clinically available medications to treat them. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most compelling and harmful bacteria. MRSA has surfaced, spread widely, and gained recognition as a leading source of bacterial infections in both community and clinical settings. The most dangerous feature of MRSA is its quick evolution of resistance to all known antibiotics, including vancomycin. Finding novel, powerful, and less hazardous antibiotic moieties is essential to combating MRSA isolates. In medicinal chemistry, the electron-withdrawing groups—primarily the –Cl, NO₂, F, and Br groups—can play an important role. A curative or diagnostic small molecule aspirant's pharmacokinetic and physicochemical characteristics, such as increased membrane permeability for MRSA and better metabolic stability, can be improved by the selective setup of EWGs. In this study, we reviewed the benefits of using EWGs to boost antibacterial effectiveness against different types of bacterial pathogens and talked about how it might be used in antibacterial drug discovery.

Genipin is the primary active pharmacological component of several commonly used traditional Chinese medicines, and it has a variety of applications. In addition to medical uses, it has applications in food and biomaterials. However, because genipin causes dose-dependent hepatotoxicity, it is critical to identify sensitive indicators of genipin-induced dose-dependent hepatotoxicity and explain its mechanism to prevent and treat hepatotoxicity caused by genipin and similar traditional Chinese medicines. This article uses targeted metabolomics, network pharmacology, and molecular docking to screen highly relevant early diagnostic markers of genipin-induced dose-dependent liver injury and then analyzes its toxicological targets to elucidate the mechanism of genipin-induced dose-dependent liver injury. The findings demonstrated that genipin's impact on the associated liver injury targets (GSR, AKR1B1, PTGS1, MAOB, CA2, HSP90AA1, CDK1, LGALS3, HTR2C, LCK, and CASP1) was primarily linked to its disturbance of the metabolic homeostasis of the endogenous metabolites 2-phenylpropionate, 4-hydroxybenzoic acid, propionylcarnitine, and N-acetylaspartic acid. This study serves as a foundation for the early detection and prevention of liver damage brought on by genipin and associated traditional Chinese medicines. It also serves as a guide for further in-depth research into the mechanism underlying genipin-induced liver injury.

Irritable bowel disease or syndrome (IBD/IBS) is a prevalent gastrointestinal tract problem affecting approximately 4% of the total population of the world. Choosing effective pharmacological treatments for IBS is still challenging due to the existence of a heterogeneous type of patient population, diverse expectations, limited availability of effective drugs, and incompletely understood pathophysiology of the disease. Recent advancements in pharmacological research have increasingly focused on neurotransmitter dysfunctions, particularly targeting serotonin and GABA pathways. Therapeutic approaches include the use of 5-HT3 receptor antagonists and 5-HT4 receptor agonists to regulate gastrointestinal motility and sensitivity. Meanwhile, GABA-analogous medications remain underutilized despite their potential to alleviate visceral pain. This study briefly overviews IBS, highlighting its symptoms, potential causes, and chronic nature. Despite its significant societal burden, IBS often lacks attention, necessitating further research to understand its actual costs. The significance of identifying novel therapeutic agents and drug targets in IBS is underscored, offering improved treatment efficacy, reduced side effects, and the potential for personalized medicine. This article aims to explore neuro-immune interactions, evaluate new treatments, and enhance the understanding of IBS to improve treatment outcomes. It emphasizes the importance of identifying innovative therapeutic approaches and drug targets.