Archiv der Pharmazie最新文献

Accumulating evidence has demonstrated that the overactivation of phosphoinositide 3-kinase (PI3K) is closely linked to the development and progression of pancreatic cancer, establishing it as a potential therapeutic target. Although several PI3K inhibitors have been developed, few have shown efficacy in treating pancreatic cancer. Consequently, there is an ongoing need for a deeper understanding of the anticancer effects exerted by PI3K inhibitors in this context. In this study, we selected copanlisib, the first marketed PI3K inhibitor, as a research tool to systematically evaluate its antipancreatic cancer effects, with the aim of validating the feasibility of using PI3K inhibitors for the treatment. In vitro studies demonstrated that copanlisib inhibited the proliferation and colony-forming ability of typical pancreatic ductal adenocarcinoma cell lines. Additionally, it induced G2/M phase arrest in pancreatic cancer cells, thereby promoting apoptosis in tumor cells. In in vivo studies, copanlisib treatment effectively inhibited pancreatic cancer growth and reduced Ki-67 expression by suppressing the PI3K signaling pathway in a xenograft mouse model. Collectively, these findings provide preliminary validation for the concept that PI3K inhibitor copanlisib significantly inhibits pancreatic cancer cell proliferation and tumor growth in both in vitro and in vivo settings, promoting apoptosis and suppressing the PI3K signaling pathway, which indicates its potential in pancreatic cancer treatment. We anticipate that these findings will serve as a reference for the clinical application of PI3K inhibitors in managing pancreatic cancer.

In the current study, a series of 22 prenylated arylidene appended thiazolidinedione derivatives were designed, synthesized, and evaluated for pancreatic lipase (PL) inhibitory activity. The study led to the identification of compounds exhibiting potent to moderate inhibitory activities with IC₅₀ values ranging between 6.18 ± 0.46 and 52.75 ± 2.34 µM. Among them, compound 22b demonstrated remarkable PL inhibitory activity with an IC₅₀ value of 6.18 ± 0.46 µM. Enzyme kinetics studies revealed a reversible competitive mode of inhibition for 22b with a K_i value of 4.1 μM. The results of in vitro findings further supported the outcome of in silico studies, which correlate the strong binding affinity of compound 22b for PL. Molecular docking studies confirmed satisfactory binding mode of compounds within the active site of PL by exhibiting various interactions such as H-bonding, π–π stacking, and hydrophobic interactions. A 100 ns molecular dynamics simulation study of protein–ligand complex with compound 22b revealed good binding and stability. The MM-GBSA analysis revealed strong binding affinity toward the active site of PL as compared with the reference ligand. Further, all derivatives were predicted to exhibit good pharmacokinetic properties, devoid of toxicity (toxicity class 4) and drug likeness.

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.