ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Euonymus alatus (Thunb.) Siebold. (EA), a traditional Chinese medicine, is widely used in the treatment of diabetes. Our group has previously found that EA could treat diabetic retinopathy (DR) and stigmast-4-en-3-one (Numbered E6) is the active substance responsible for inhibiting angiogenesis in vitro by EA. However, the effects and mechanisms of E6 in the treatment of DR is still unknown. AIM OF THE STUDY: The aim of this study was to investigate the effects and mechanisms of E6 in EA on DR. Additionally, a comparison was made between the effects of E6 and triamcinolone acetonide (TA), as well as the side effects of E6 and dexamethasone. MATERIALS AND METHODS: Ocular affinity assessment and pharmacokinetic parameter prediction were conducted to evaluate the potential of E6 to treat DR. Retinal endothelial cells were used to investigate the in vitro inhibitory effect of E6 on vascular proliferation. Additionally, chicken embryos, zebrafish, and mice were used to investigate the in vivo anti-vascular proliferation effect of E6. Finally, diabetic mice were used to investigate whether E6 improves diabetic retinopathy and to compare its efficacy with that of TA. We then used network pharmacology to study the targets of E6 and performed molecular docking; followed by immunofluorescence experiments, ELISA, Western blot, and tube formation experiments to further investigate its mechanism. Finally, we compared the side effects of E6 with those of dexamethasone. RESULTS: E6 was found to have an affinity for the eye and to inhibit vascular proliferation both in vivo and in vitro. Moreover, E6 was found to be more efficacious than TA in the treatment of DR. Molecular docking experiments predicted that the glucocorticoid receptor (GR) is a potential target of E6, and immunofluorescence analyses confirmed that E6 upregulated the expression of the GR in the retina of hyperglycemic mice. In addition, western blotting results and tube formation experiments showed that E6 also attenuated angiogenesis by inhibiting the Hippo and VEGF pathways. Finally, by comparing the effects of E6 and dexamethasone on glucose regulation and osteoporosis, E6 was found to have fewer side effects. CONCLUSIONS: E6 is a highly effective drug for the treatment of DR, superior to TA and with fewer side effects than dexamethasone. Its mechanism involves the activation of glucocorticoid receptor and inhibition of Hippo and VEGF pathways to alleviate angiogenesis and inflammation. This study is the first to investigate the role and mechanism of E6 in improving DR. The findings suggest that E6 has unique advantages in the treatment of DR.
ABSTRACT
Magnolol (M), a hydroquinone containing an allyl side chain, is one of the major active components of Houpoea officinalis for antioxidation and anti-aging. To enhance the antioxidant activity of magnolol, the different sites of magnolol were structurally modified in this experiment, and a total of 12 magnolol derivatives were obtained. Based on the preliminary exploration of the anti-aging effect of magnolol derivatives in a Caenorhabditis elegans (C. elegans) model. Our results indicate that the active groups of magnolol exerting anti-aging effects were allyl groups and hydroxyl on the phenyl. Meanwhile, the anti-aging effect of the novel magnolol derivative M27 was found to be significantly superior to that of magnolol. To investigate the effect of M27 on senescence and the potential mechanism of action, we investigated the effect of M27 on senescence in C. elegans. In this study, we investigated the effect of M27 on C. elegans physiology by examining body length, body curvature and pharyngeal pumping frequency. The effect of M27 on stress resistance in C. elegans was explored by acute stress experiments. The mechanism of M27 anti-aging was investigated by measuring ROS content, DAF-16 nuclear translocation, sod-3 expression, and lifespan of transgenic nematodes. Our results indicate that M27 prolonged the lifespan of C. elegans. Meanwhile, M27 improved the healthy lifespan of C. elegans by improving pharyngeal pumping ability and reducing lipofuscin accumulation in C. elegans. M27 increased resistance to high temperature and oxidative stress in C. elegans by reducing ROS. M27 induced DAF-16 translocation from cytoplasm to nucleus in transgenic TJ356 nematodes and upregulated the expression of sod-3 (a gene downstream of DAF-16) in CF1553 nematodes. Furthermore, M27 did not extend the lifespan of daf-16, age-1, daf-2, and hsp-16.2 mutants. This work suggests that M27 may ameliorate aging and extend lifespan in C. elegans through the IIS pathway.
ABSTRACT
Rat sarcoma (RAS), as a frequently mutated oncogene, has been studied as an attractive target for treating RAS-driven cancers for over four decades. However, it is until the recent success of kirsten-RAS (KRAS)G12C inhibitor that RAS gets rid of the title "undruggable". It is worth noting that the therapeutic effect of KRASG12C inhibitors on different RAS allelic mutations or even different cancers with KRASG12C varies significantly. Thus, deep understanding of the characteristics of each allelic RAS mutation will be a prerequisite for developing new RAS inhibitors. In this review, the structural and biochemical features of different RAS mutations are summarized and compared. Besides, the pathological characteristics and treatment responses of different cancers carrying RAS mutations are listed based on clinical reports. In addition, the development of RAS inhibitors, either direct or indirect, that target the downstream components in RAS pathway is summarized as well. Hopefully, this review will broaden our knowledge on RAS-targeting strategies and trigger more intensive studies on exploiting new RAS allele-specific inhibitors.
ABSTRACT
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is an evolutionarily conserved protein kinase and the most studied member of the Dual-specificity tyrosine-regulated kinase (DYRK) family. It has been shown that it participates in the development of plenty of diseases, and both the low or high expression of DYRK1A protein could lead to disorder. Thus, DYRK1A is recognized as a key target for the therapy for these diseases, and the studies on natural or synthetic DYRK1A inhibitors have become more and more popular. Here, we provide a comprehensive review for DYRK1A from the structure and function of DYRK1A, the roles of DYRK1A in various types of diseases, including diabetes mellitus, neurodegenerative diseases, and kinds of cancers, and the studies of its natural and synthetic inhibitors.
Subject(s)
Tyrosine , Humans , Phosphorylation , Tyrosine/metabolismABSTRACT
To alleviate the deteriorating environment and protect biodiversity, China has implemented a natural forest protection system, demonstrating the importance of sustainable forest management for ecological conservation and socio-economic development, including the complete cessation of commercial logging of natural forests. Financial compensation is adopted to increase farmers' enthusiasm within the commercial Logging Ban of Natural Forests framework. This study used the contingent valuation method and the Heckman two-stage model to explore farmers' willingness to participate in the Logging Ban of Natural Forests and the willingness to accept by survey data on 486 farming households. 72% of farmers are willing to join the Logging Ban of Natural Forests. Their willingness to accept is 517.95 yuan/ha per year, higher than the current state subsidy standard (225 yuan/ha per year). The key factors influencing willingness to accept include the education and degree of fragmentation of woodland and village collective willingness to accept. The age of the rural household head, the fragmentation of the forest, and the evaluation of the Logging Ban of Natural Forests policies have inhibited the increase of farmers' compensation. Farmers' assessment of the Logging Ban of Natural Forests policy only impacts the medium level of compensation. The age and the degree of forest fragmentation would affect the higher compensation amount. The results from this study suggest more financial sources and increased compensation standards are needed. The government should also strengthen ecological awareness and adopt different compensation standards for other groups to achieve sustainable forestry.