Clinical and Experimental Pharmacology and Physiology最新文献

Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have improved cancer outcomes but can induce immune-related adverse events, including mycobacterial infections. This study retrospectively analysed pulmonary nontuberculous mycobacteria (NTM) infection in 91 patients with pre-existing stage II–IV lung cancer at Shanghai Pulmonary Hospital between June 2015 and June 2024. Among these patients, 78.0% [71/91] were male, and 16.5% [15/91] were receiving ICIs monotherapy at the time of initial pulmonary NTM infection diagnosis (ICIs group). Compared with the non-ICIs group, ICIs-treated patients developed pulmonary NTM infection earlier (median time: 12 months [IQR, 6–18] vs. 21.5 months [IQR, 13–30]; p = 0.004), and had a higher proportion of rapid-growing NTM isolates (73.3% [11/15] vs. 30.3% [23/76]; p = 0.003), predominantly Mycobacterium abscessus complex (40.0% [6/15]). In contrast, Mycobacterium avium complex was the predominant NTM species in the non-ICIs group (71.1% [54/76]). During 12 months of anti-NTM therapy, the ICIs group showed a lower cumulative sputum culture conversion rate (36.4% [4/11] vs. 59.6% [31/52]; p = 0.19) and a longer median time to initial sputum culture conversion (12 months vs. 6 months; p = 0.13), though these differences were not statistically significant. The most commonly administered ICIs drugs were tislelizumab (40.0% [6/15]) and sintilimab (26.7% [4/15]). These findings suggest that ICIs may be associated with earlier development of pulmonary NTM infection in lung cancer patients. Future prospective studies with larger sample sizes are needed to validate this conclusion.

The prevalence of parkinsonism is increasing worldwide, not only in age groups but now becoming a favourite of adults. As the onset is increasing in developed and underdeveloped countries, the current therapy lacks a permanent cure. Therefore, the research has used the gold-containing compound auranofin (AUF) in its neuroprotective form. The research was conducted to decipher the neuroprotective potential of AUF hybrid nanoparticles (AUFHNPs) using the in silico and in vivo 6-OHDA models. The in silico study was performed using CDOCKER software and the binding affinity of AUF with PI3K (5DXT), AKT (1UNQ), GSK-3β (1Q41), Nrf2 (2DYH), and HO-1 (1N45) were assessed. Then, intra-striatal unilateral injection of 6-OHDA (10 μg/2 μL) was given to rats with the help of stereotaxic surgery. After performing the amphetamine challenge test, rodents were treated with AUF (10 mg/kg) and AUFHNPs (5 and 10 mg/kg) for 21 days. All the behaviour parameters were performed on the last 2 days, and animals were sacrificed; brains were isolated for oxidative stress, neuroinflammatory, apoptotic, histological, and molecular marker analysis. In the docking study, AUF offered the highest binding score of −61.1231 with GSK-3β. In vivo administration of AUF and AUFHNPs significantly restored motor and behaviour alterations observed in open field tests, narrow beam walks, and grip strength meter. It also restored morphological changes and increased expression of pPI3K/pAKT, followed by inhibition of GSK-3β. Thus, the AUFHNPs were more significant than AUF alone and exerted neuroprotection via modulation of PI3K/AKT/GSK-3β signalling pathways.

Natural products and their semisynthetic derivatives possess tremendous medicinal properties and have the potential to modulate the immune system, providing new therapeutic options for drug development. In this study, we evaluated Dehydrozingerone-15, a novel dehydrozingerone derivative, for its anti-inflammatory and antioxidant properties through standardised in vitro and in vivo approaches. Dehydrozingerone-15 suppressed the stimulatory effect of LPS in RAW 264.7 cells by reducing the secretion of interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-2 (IL-2) and nitric oxide. Western blot analysis at the mechanistic level showed a reduced expression level of nitric oxide synthase (iNOS), IκB kinase beta (Ikk-β) and nuclear factor kappa-B (NF-κB/p65). Confocal microscopy studies further demonstrated that Dehydrozingerone-15 reduced the expression of NF-κB/p65 markedly. In the in vivo LPS-induced sepsis model, Dehydrozingerone-15 administration reduced TNF-α and IL-6 expression and protected vital organs (lungs, kidneys, and liver) from acute inflammation. The anti-inflammatory potential of Dehydrozingerone-15 was further validated in leukocyte migration induced by carrageenan and vascular permeability triggered by acetic acid assays, both of which showed significant inhibition. Pharmacokinetic analysis revealed that Dehydrozingerone-15 was rapidly absorbed in BALB/c mice, reaching a C_max of 10 349 ng/mL at 0.25 h. The total drug exposure (AUC_0–α) was 13 862 ng.h/mL, indicating sustained exposure, with high tissue distribution (20 L/kg) and moderate clearance. Additionally, toxicological evaluation at doses up to 2000 mg/kg body weight showed no significant alterations in haematological parameters compared with the vehicle control. Furthermore, based on a comparative evaluation of in vitro and in vivo results, Dehydrozingerone-15, relative to its parent molecule, demonstrates significant therapeutic potential with high efficacy against inflammation and oxidative stress.

Postoperative peritoneal adhesion (PA) formation is a common complication after abdominal surgery and can result in various severe outcomes. Inflammation and fibrosis are important processes in PA formation. The effectiveness of kaempferol (KF), a common component of several medications used to reduce inflammation and prevent fibrotic diseases, in preventing postoperative PA formation is unknown. This study explored the effectiveness and mechanism of KF in preventing PA formation following surgery. The animal adhesion model revealed that KF could effectively prevent adhesions formation and inhibit mesothelial–mesenchymal transition (MMT). Protein–protein interaction and pathway enrichment analyses revealed that TNF-α may be the key target through which KF prevents adhesion formation. Here, KF was found to inhibit TNF-α-induced MMT. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed that common genes between KF and PA are enriched in the TNF signalling pathway. Moreover, cyclooxygenase 2 (COX2) was identified as a downstream target of TNF-α whose expression is positively correlated with adhesion formation. Most importantly, COX2 small interfering RNA (siRNA) and overexpression plasmid (OE) transfection experiments confirmed that KF inhibits MMT by blocking the TNF-α/COX2 signalling pathway. Finally, molecular docking revealed that TNF-α is a binding target of KF. In conclusion, these results suggest that KF inhibits MMT by blocking the TNF-α/COX2 signalling pathway, thus attenuating adhesion formation. These results provide new insights into the development of antiadhesion drugs.

Molecular glues have emerged as a novel class of targeted protein degraders with broad potential in cancer therapy. By inducing proximity between E3 ubiquitin ligases and oncogenic proteins, these agents activate the ubiquitin–proteasome system to drive selective protein degradation. This review systematically explores the application strategies of molecular glues in the targeted degradation of cancer-related proteins located in different subcellular compartments: nuclear cancer proteins (Ikaros, Helios, Aiolos, B-cell lymphoma 6 protein, cyclin K, RNA binding motif protein 39) and cytoplasmic cancer proteins (β-catenin, casein kinase 1α, G1 to S phase transition factor 1). Additionally, this work discusses current challenges and optimisation strategies, offering new perspectives for the development of precision anti-cancer therapeutics.