ABSTRACT
Polo-like kinase 1 (PLK1), which is crucial in cell cycle regulation, is considered a promising anticancer drug target. Herein, we present the N-degron pathway-based proteolysis targeting chimera (PROTAC) for PLK1 degradation, targeting the Polo-box domain (PBD). We identified DD-2 as the most potent PROTAC that selectively induces PLK1 degradation in cancer cells, including HeLa and nonsmall cell lung cancer (NSCLC), through the N-degron pathway. DD-2 exhibited significant in vitro anticancer effects, inducing G2/M arrest and apoptosis in HeLa and NSCLC cell lines. DD-2 showed significant tumor growth inhibition in a xenograft mouse model using HeLa and NSCLC cell lines, highlighting its potential in cancer treatment. Furthermore, the combination of DD-2 with tyrosine kinase inhibitor (TKI), osimertinib, effectively suppressed tumor growth in double-mutated H1975 cell lines, emphasizing DD-2's potential in combination cancer therapies. Collectively, this study demonstrates the potential of the N-degron pathway, especially using DD-2, for targeted cancer therapies.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Animals , Mice , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Cell Cycle Proteins , Proteolysis Targeting Chimera , Protein Serine-Threonine Kinases , Polo-Like Kinase 1 , Apoptosis , Degrons , Cell Line, Tumor , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , G2 Phase Cell Cycle Checkpoints , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic useABSTRACT
The effectiveness of natural bioresources at enhancing exercise performance is of interest to those in sports and health care. The use of 29 common seaweed species as supplements to enhance exercise performance and the recovery from physical fatigue was evaluated. The ethanol extract of the red seaweed Gloiopeltis furcata (GFE) had the greatest effect on forelimb grip strength and swimming endurance in mice. The optimal daily dose of GFE was 0.1 mg per 10 µl per g of body weight. GFE significantly increased muscle mass but had little effect on body weight and fatty deposits. The extract also significantly raised the blood superoxide dismutase and high-density lipoprotein cholesterol levels, while reducing the lactate and urea levels (p < 0.05). Docosahexaenoic acid (DHA) from GFE made the greatest contribution to improving physical exercise performance. These results support the use of GFE and DHA in health food products for enhancing physical performance. PRACTICAL APPLICATIONS: The study shows the exercise enhancement and anti-fatigue activities of GFE using the forelimb grip strength test, forced swimming endurance test, muscle mass measurement, and blood biochemical parameters. These results support the use of GFE and its active constituent DHA in functional foods or nutraceuticals for enhancing physical performance.
Subject(s)
Docosahexaenoic Acids/pharmacology , Ethanol/chemistry , Physical Conditioning, Animal , Plant Extracts/pharmacology , Rhodophyta/chemistry , Animals , Docosahexaenoic Acids/chemistry , Mice , Mice, Inbred ICR , Muscle Strength/drug effects , Physical Endurance/drug effects , Plant Extracts/chemistry , Seasons , SwimmingABSTRACT
Freshwater softshell turtle (Trionyx sinensis) extract has been used traditionally as a tonic soup, and to recover from physical fatigue. To support these claims, the forelimb grip strength of mice was measured after feeding a soft-shell turtle extract for 7 days. The T. sinensis extract significantly increased the grip strength to 1.25±0.07 N (P<0.01), which is 16.8% higher than the force on day 0. After exercising, the blood glucose levels in extract-fed mice were 202% higher and urea levels were 73% lower, which were both significantly different than the levels observed after control treatment. Lactate dehydrogenase was significantly higher by 314%, and glutathione peroxidase increased by 165%. In addition, the obesity markers, serum triglyceride and cholesterol, decreased to 62% and 49%, respectively, after mice were fed the extract. These data show that the T. sinensis extract provided more energy for forelimb exercise, prevented protein catabolism and muscle fatigue, and decreased the oxidative stress caused by an exhaustive workout.
ABSTRACT
The hot water extract of leather carp (Cyprinus carpio nudus) has been used as a nourishing tonic soup and as an aid for recovery from physical fatigue. In this study, we investigated the effect of leather carp extract on exercise performance in mice. Swimming endurance and forelimb grip strength were assessed following oral administration of the extract (once per day for 7 days) at a dose of 0.5 mg/10 µL/g body weight. After 7 days, mice given the leather carp extract had significantly greater swimming endurance [105±18 s (P<0.05); 52% longer than day 0] and forelimb grip strength [1.18±0.05 Newton (P<0.01); 17% greater than day 0]. The extract increased muscle mass, but had little effect on body weight. Following the swimming exercise, blood glucose, glutathione peroxidase, and superoxide dismutase levels in extract-fed mice were significantly higher (145%, 131%, and 106%, respectively) than in the saline control group. Blood levels of high-density lipoprotein cholesterol were also significantly increased (128%) in mice given the extract compared to the controls. These results suggest that leather carp extract can improve physical exercise performance and prevent oxidative stress caused by exhaustive workouts.
