European journal of pharmacology最新文献

In vitro patient-derived models, predicting the benefit of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, have the potential to find effective drugs for cystic fibrosis patients (pwCF) through a personalized CFTR pharmacotherapeutic approach. To date, human nasal epithelial (HNE) cells and human intestinal organoids (HIOs) represent the most utilized in vitro system in Cystic Fibrosis (CF) research, carrying a patient-specific genomic background. The first one is expected to represent key processes occurring in the airways, and the second to mimic the features of the gastrointestinal tract. Both are important target tissues and are utilized as sensitive and robust tools for the diagnosis of CF. In this review, we evaluated the efficacy of nasal and intestinal models in predicting similar therapeutic responses of CFTR variants to CFTR modulators and other treatments by conducting an analysis of the published data reporting responses in both cellular models derived from the same individuals. The data confirm a high concordance in CFTR rescue across the two models, supporting their use as equally reliable and complementary theranostic tools for assessing in vitro drug efficacy of highly efficient CFTR modulator therapies (HEMT).

Sepsis is a severe systemic inflammatory condition characterized by infection, and marked by high morbidity and mortality. Injury to the spleen resulting from sepsis disrupts immune defense functions, exacerbates systemic inflammatory dysregulation, and contributes to multiple organ failure, thereby substantially increasing patient mortality. Sophoridine (SR), a naturally occurring alkaloid derived from Sophora flavescens, exhibits anti-inflammatory, antioxidant and neuroprotective effects. This study investigated the protective effects of SR against sepsis-induced splenic damage and elucidated its underlying mechanisms. A murine sepsis model was established using cecal ligation and puncture (CLP), and SR was administered to assess its efficacy. Histological analysis demonstrated that SR markedly ameliorated structural damage to splenic tissue in mice subjected to CLP. Quantitative PCR (qPCR), dihydroethidium (DHE) staining, and TUNEL assays revealed that SR significantly reduced the mRNA levels of pro-inflammatory mediators, including Tnf, Il6, Il1b and Nos2, while increasing the mRNA level of the anti-inflammatory mediator Il10. Furthermore, SR substantially reduced reactive oxygen species (ROS) production and apoptosis. We also established an in vitro model by stimulating J774A.1 cells with lipopolysaccharide (LPS). Results from Western blotting, qPCR and flow cytometry analyzes indicated that the beneficial effects of SR on LPS-induced inflammation, oxidative stress and apoptosis were substantially attenuated by overexpression of ASK1. In conclusion, SR alleviates sepsis-induced splenic injury by suppressing inflammation, oxidative stress, and apoptosis through the inhibition of ASK1, thereby offering a potential therapeutic approach for the management of splenic injury in sepsis.

Colorectal cancer (CRC) remains one of the most prevalent malignancies globally, with limited therapeutic options for advanced-stage patients due to acquired drug resistance and systemic toxicity. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic target for CRC, while cystathionine γ-lyase (CSE)-a key enzyme in hydrogen sulfide (H₂S) biosynthesis-plays a critical role in maintaining redox homeostasis and suppressing ferroptosis in cancer cells. Here, we synthesized a novel small-molecule compound, DPhA-EtOBz-TSC, and systematically evaluated its anti-CRC efficacy and underlying molecular mechanism. The chemical structure of DPhA-EtOBz-TSC was confirmed by ¹H nuclear magnetic resonance (¹H NMR), ¹³C NMR, and high-resolution mass spectrometry (HRMS). In vitro studies using human CRC cell lines (HCT8 and SW480) demonstrated that DPhA-EtOBz-TSC specifically targeted and inhibited CSE: molecular docking and cellular thermal shift assay (CETSA) confirmed direct binding between DPhA-EtOBz-TSC and CSE (binding affinity ΔG = -29.07 ± 3.85 kcal/mol), while Western blot analysis revealed a concentration-dependent reduction in CSE protein levels in SW480 and HCT8 cells treated with DPhA-EtOBz-TSC. Mechanistically, DPhA-EtOBz-TSC-induced CSE downregulation disrupted the CSE-H₂S-GPX4 axis, leading to reduced glutathione (GSH) levels, decreased glutathione peroxidase 4 (GPX4) activity, and accumulation of lipid reactive oxygen species (ROS) and malondialdehyde (MDA)-hallmarks of ferroptosis. Additionally, Electron microscopy and JC-1 staining revealed that DPhA-EtOBz-TSC induced significant alterations in mitochondrial morphology and a marked reduction in mitochondrial membrane potential (ΔΨm). Functionally, DPhA-EtOBz-TSC exhibited potent in vitro anti-CRC activity with IC₅₀ values of 25.15 μM (HCT8) and 26.11 μM (SW480) respectively, and suppressed migration and invasion. In vivo, DPhA-EtOBz-TSC (10 mg/kg/day, i.p.) significantly suppressed the growth of CT26 cell-derived xenograft tumors in BALB/c mice without causing obvious histopathological abnormalities in major organs (heart, liver, spleen, lung, kidney). Immunohistochemical staining of tumor tissues confirmed increased lipid peroxidation and decreased CSE/GPX4 expression in DPhA-EtOBz-TSC-treated mice, consistent with in vitro findings. In conclusion, DPhA-EtOBz-TSC is a novel CSE-targeting compound that induces ferroptosis in CRC cells and inhibits tumor growth in vivo. Our findings identify DPhA-EtOBz-TSC as a potential lead compound for CRC therapy and highlight the CSE-H₂S-GPX4 axis as a viable therapeutic target for ferroptosis-based anticancer strategies.

Our previous studies have demonstrated that repeated exposure of neonatal rats to sevoflurane upregulates the expression of major histocompatibility complex class I and class II (MHC-I/MHC-II) in oligodendrocyte progenitor cells (OPCs) via the Kir4.1 channel, ultimately inhibiting OPC differentiation and reducing myelin formation. However, the therapeutic strategies for these antigen-presenting OPCs remain unclear. 2',3',4'-trihydroxyflavone (2-D08) has been shown to ameliorate demyelination through targeting Kir4.1, we therefore investigate whether it could prevent sevoflurane-induced antigen presentation switching in OPCs during early development. The results showed that 2-D08 markedly reduced sevoflurane-induced upregulation of MHC-I and MHC-II expression, as well as the secretion of IL-6 and IL-1β, in OPCs. This process ameliorated deficits in OPCs differentiation, ultimately restoring motor coordination impairments in rats. In vitro experiments also indicated that Kir4.1 knockdown OPCs exhibited a significant upregulation of MHC-I and MHC-II expression, accompanied by impaired differentiation, suggesting an essential role of Kir4.1 in regulating the antigen-presenting properties of OPCs. 2-D08 significantly upregulated Kir4.1 protein expression, and its protective effect against sevoflurane-induced antigen-presenting OPCs was abolished under Kir4.1 knockdown conditions. In conclusion, our study indicates that sevoflurane induces antigen presentation switching in OPCs through the activation of the Kir4.1 channel, an effect that can be ameliorated by 2-D08.

Androgen deprivation therapy is the main treatment for prostate cancer (PCa). However, the majority of cases will advance to castration-resistant prostate cancer (CRPC) and then to metastatic CRPC (mCRPC), with bone metastasis accounting for over 90% of mCRPC cases. PCa bone metastasis appears predominantly osteosclerotic, and the processes of bone formation and bone resorption are dysregulated in the presence of PCa. It has been highlighted that cancer cells can adjust their metabolism selectively and dynamically at each stage of the metastatic cascade. More evidence has shown that metabolic reprogramming in the tumor-bone microenvironment plays a key role in promoting disease progression. Therefore, understanding the complex process between bone metastasis and metabolism in PCa could uncover novel targets to tackle these difficult questions in cancer. This review aims to present the latest discovery in the metabolic shifts (including glucose, lipid, and amino acid metabolism) in the bone microenvironment and the crosstalk between PCa cells and the bone local resident cells (such as adipocytes, osteoblasts, osteoclasts, and immune cells). The metabolism-associated and bone-targeted therapeutic strategies and biomarkers are also explored.

Tubulointerstitial fibrosis composed of epithelial-mesenchymal transition (EMT) and the resulting extracellular matrix (ECM) accumulation is the primary feature of diabetic nephropathy (DN), but its mechanism remained unclear. In the present study, sirtuin 5 (SIRT5) was screened for the key pathogenic factor by proteomics analysis in DN mice. Then SIRT5 was overexpressed and knocked down in the kidney of mice and in renal tubular epithelial cells. It was found that the elevation of SIRT5 in renal tubular epithelial cells exacerbated EMT, ECM accumulation and worsened the renal function of mice. Using real-time PCR, co-immunoprecipitation, and cycloheximide tracking assay, we found that SIRT5 increased the desuccinylation, the ubiquitination of kidney type glutaminase (GLS1), which thereby caused an increase in GLS1 protein. Meanwhile, when GLS1 protein maintained at some level, changes in SIRT5 do not impact the EMT process and the subsequent ECM accumulation. Furthermore, we found that SIRT5 was increased in kidneys of DN patients, it was also up-regulated in the urine of DN patients and had correlations with renal function of patients. Collectively, SIRT5 induces tubulointerstitial fibrosis via GLS1 in DN, which renders it a promising therapeutic target for DN.

Aging is a major risk factor for respiratory diseases, with the respiratory system demonstrating a particular vulnerability to age-related decline. This review explores the intersection between aging biology and respiratory pathophysiology, focusing on three interconnected hallmarks: cellular senescence, inflammaging, and immunosenescence. Senescent cells accumulate in aging lungs, releasing a senescence-associated secretory phenotype (SASP) that perpetuates chronic inflammation and tissue dysfunction. Natural Senotherapeutics, compounds that target senescent cells or modulate their effects, offer promising strategies to address these fundamental mechanisms. We examined the latest findings on key natural compounds (rapamycin, berberine, resveratrol, pterostilbene, quercetin, EGCG, fisetin, apigenin and curcumin) that demonstrate senomorphic and/or senolytic properties in respiratory contexts. These compounds function through diverse but overlapping molecular pathways, mainly modulating inflammation, immune dysfunction and oxidative stress. Preclinical evidence consistently supports their potential in models of chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), and respiratory infections, although their clinical translation remains limited. The challenges include bioavailability, optimal dosing regimens, and delivery methods. As global demographics shift toward an aging population, developing interventions that target fundamental aging mechanisms in the respiratory system is becoming increasingly urgent. Natural senotherapeutics may offer a paradigm shift in maintaining respiratory health in older adults, with potentially fewer adverse effects than synthetic alternatives.

Lilium brownii is a plant that can be used for medicinal and food purposes. 1-O-p-coumaroyl-3-O-feruloyl glycerol (CF) is a phenolic acid glycerol dimer isolated from Lilium brownii.

Objective: This study aims to evaluate the neuroprotective effects of CF and elucidate the possible molecular mechanisms underlying its neuroprotective effects through in vivo and in vitro models of Parkinson's disease.

Methods: 1-methyl-4-phenylpyridinium ions (MPP⁺) was used to establish in vivo and in vitro models of Parkinson's disease (PD); flow cytometry was used to detect intracellular reactive apoptosis rates and cell cycle distribution. Western blot aalysis was used to assess the expression levels of relevant proteins. Molecular docking technology was used to evaluate the binding affinity of CF with Sequestosome 1 (P62), etc. Behavioral experiments assessed motor ability and cognitive function in PD mice, and tissue sections were examined to observe the number of neurons in the substantia nigra region of the mouse brain.

Results: Following CF administration, the apoptosis rate and reactive oxygen species (ROS) levels in PC12 cells were significantly reduced. CF markedly upregulated the expression of proteins including dopamine, tyrosine hydroxylase, brain-derived neurotrophic factor (BDNF), while simultaneously downregulating the expression of proteins such as α-synuclein. Molecular docking results demonstrated favorable affinity between CF and proteins including p62. This compound not only ameliorated motor and cognitive impairments in Parkinson's disease mice but also markedly increased neuronal numbers within the substantia nigra region of these animals.

Conclusion: CF exerts a neuroprotective effect in Parkinson's disease by modulating the p62-Keap1-Nrf2 signalling pathway.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective therapies. 4,4'-Dimethoxychalcone (DMC) is a natural chalcone extracted from Angelica keiskei (Miq.) Koidz and Angelica sinensis (Oliv.) Diels, which could promote autophagy and prolong lifespan. However, the neuroprotective effects and mechanisms of DMC on AD mice have not been reported. In this study, we proved that DMC treatment significantly mitigated cognitive impairment and depressive behavior, ameliorated blood-brain barrier permeability and amyloid β pathology, and inhibited p-Tau expression in 5 × FAD mice. Also, DMC suppressed glial cell activation, enhanced neurogenesis, and decreased oxidative stress in vivo and in vitro by activating the Kelch-like ECH-associated protein1 (Keap1)/nuclear factor-erythrocyte 2-associated factor 2 (Nrf2) signaling pathway. However, Brusatol, an inhibitor of the Keap1/Nrf2 signalling, partly attenuated the neuroprotective effects of DMC on lipopolysaccharide-induced HT22 cells injury and 5 × FAD mice. In conclusion, DMC exhibited neuroprotective effects on 5 × FAD mice via the activation of Keap1/Nrf2 signalling pathway. Thus, DMC may be a promising therapeutic drug for AD.