Chemical Biology & Drug Design
·
2025
·Vol. 106
·期 6
·e70214
·
IF 3.3
Guihua Jia,Jiayi Li,Abbas Khan,Aman Chandra Kaushik,Diyi Wu,Hongyu Chen,Rongpei Li,Jian Wang,Chen Zhang,Adil Farooq,Xueying Mao,Aamir Mehmood,Weidong Zhang,Heng Wang,Dong-Qing Wei
WGX-50, a previously reported drug candidate for Alzheimer's disease, is derived from Zanthoxylum bungeanum Maxim commonly called Sichuan pepper. Its pharmacological actions for the long run benefit of human health have been extensively investigated. However, in terms of its anti-aging effect, it totally remains unexplored. In this work, WGX-50 was first reported to promote healthy aging in Caenorhabditis elegans with insights from drug target prediction and molecular dynamics simulations. Further investigations have experimentally demonstrated that: Firstly, both daf-16 and skn-1 genes are causative to WGX-50 mediated longevity. WGX-50 failed to extend lifespan upon depletion of these genes in transgenic worms. Their orthologs Foxo1 and Nrf2 were also activated even in D-galactose (D-gal) induced aging and Zmpste24 −/− progeria mice intestines. Secondly, WGX-50 inhibits IIS signaling via downregulating daf-2 , and activating daf-16 and skn-1 genes, which thus enable downstream pro-longevity effectors increasing stress resistance and promoting healthier aging. WGX-50 increased expression levels of sod-3 , ctl-1 , gst-7/8/12/33 , gsto-1 , and heat shock protein genes such as hsp-12.2 , hsp-90 , F44E5.4/0.5 , T05E11.9 and their inducer hsf-1 . In addition, the accumulation of lipofuscin, fat, and reactive oxygen species levels with age was decreased significantly upon WGX-50 supplementation without physiological impairments. Thirdly, in progeria, D-gal and naturally aged mice, WGX-50 is incapable of inducing aging. Senescent genes and SASP factors were not produced at higher levels in livers and small intensities. No impact was observed on key organ indices, blood biochemistry parameters, and bone histomorphometry. WGX-50 perhaps prolongs lifespan through other mechanisms such as reducing fertility, inducing dietary restriction, and improving proteostasis with lowered levels of polyQ35 aggregates. Our findings thus provide primary insights for the potential medical use of WGX-50 in anti-aging and long-term healthcare.
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Evidence-based Complementary and Alternative Medicine
·
2019
·
IF 1.984
Ling Zhou,Pan-Pan Huang,Lin-Lin Chen,Ping Wang
The deposition of amyloid beta (Aβ) is the main hallmark of Alzheimer’s disease (AD) and there is no effective drug to cure the progressive cognitive loss or memory deficits caused by the aggregative toxicity of Aβ protein. Oxidative stress has been hypothesized to play a role in progressive neurodegenerative diseases like AD. Panax notoginseng saponin (PNS) from the rhizome of “pseudo-ginseng” exhibits potent antioxidant effects on aging process in neuron cells and animals. By using C. elegans as an ideal model organism, the present study shows that PNS (0.5–4 mg/mL) can significantly inhibit AD-like symptoms of worm paralysis and enhance resistance to oxidative stress induced by paraquat and aging conditions. Additionally, PNS extends lifespan and maintains healthspan of C. elegans by improving the swimming prowess and fertility at old age. It markedly activates the expression of SKN-1 mRNA, which further supports SKN-1 signaling pathway which is involved in the therapeutic effect of PNS on AD C. elegans. Our results provide direct evidence on PNS for treating AD on gene level and theoretical foundation for reshaping medicinal products of PNS in the future.
研究领域:
神经科学
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药理学
·
分子生物学
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Weimin Zuo,Tingting Lin,Hehuan Zhu,Xiaobi Huang,Yudong Guo,Qihe Long,Yanfeng Liang,Yongyang Chen,Xiaoqing Xu,Yanhong Su,Wenmei Su
As a widely used chemical raw material, the potential exposure threat of bisphenol A is inevitable. At present, there is no effective treatment for the toxicity caused by bisphenol A (BPA). Therefore, it is necessary to find a natural drug to alleviate the toxicity of BPA. In this study, Caenorhabditis elegans was applied to evaluate the protective effect of tremella polysaccharide (TPC) on BPA. The results showed that TPC regained the locomotion and chemotaxis ability induced by BPA. Also TPC protected the dopamine neuron cells against the BPA-induced damage. Moreover, TPC also regulated IIS/PI3K/AKT and MAPK/AMPK pathways to activate daf-16 and skn-1 (homolog to Nrf-2) increase the antioxidant ability in C. elegans . TPC treatment obviously increased the expression of GST-4 as well as the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) to sharply reduced the high reactive oxygen species (ROS) level to help the C. elegans to against the toxicity induced by BPA. Altogether, these results indicated TPC is a promising natural drug to alleviate the toxicity induced by BPA.
研究领域:
毒理学
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分子生物学
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药理学
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环境健康
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神经科学
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高影响因子
BIOGERONTOLOGY
·
2026
·Vol. 27
·期 2
·72
·
IF 5.3
Zhang Xiaoli,Wang Chengniu,Chen Weiguan
Aging is a major risk factor for the onset and progression of many neurodegenerative diseases. Inflammation is the body’s natural defense mechanism against harmful stimuli . A growing body of research has highlighted the intricate relationship between aging and inflammation, with chronic low - grade inflammation, often referred to as “inflammaging,” being a hallmark of the aging process. Cycloneolitsol (CL) is a C-32 cycloartane-type triterpene from Taxodium ascendens which has been reported to possess the anticancer, neuroprotection and antibacterial activities. Its specific role and the underlying molecular mechanisms in modulating the aging process remain unclear. Our study aimed to explore the possible anti-aging effect and mechanisms of CL. Network pharmacology predicted core targets and several potential pathways, which are associated with the anti-aging effect of CL. RAW264.7 macrophages and Caenorhabditis elegans were selected for evaluating its anti-aging and anti-inflammation activity. The results showed that CL exerted obvious anti-inflammatory effects against LPS-induced M1-type polarization of RAW264.7 cells via NF-κB signaling pathway. In C. elegans , CL improved Biological Characteristics and prolonged the lifespan without reproductive toxicity. Furthermore, experiments on different mutant C. elegans strains and the nuclear translocation of SKN-1 confirmed that CL activates autophagy and enhances the antioxidant stress response ability through the SEK-1/PMK-1/SKN-1 signaling pathway. This study provides novel insights into the biological activities of CL, highlighting its potential as a natural product for treating inflammation-related diseases and delay aging.
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BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Xin Tan,Rui Xu,Ai-Pei Li,Dan Li,Yun Wang,Qian Zhao,Li-Ping Long,Yu-Zhou Fan,Chen-Xiao Zhao,Yan Liu,Sheng-Hong Li
1,8-Cineole is a bicyclic monoterpene widely distributed in the essential oils of various medicinal plants, and it exhibits significant anti-inflammatory and antioxidant activities. We aimed to investigate the therapeutic effect of 1,8-cineole on anti-Alzheimer's disease by using transgenic Caenorhabditis elegans models. Our studies demonstrated that 1,8-cineole significantly relieved A β 1–42 -induced paralysis and exhibited remarkable antioxidant and anti-A β 1–42 aggregation activities in transgenic nematodes CL4176, CL2006 and CL2355. We developed a 1,8-cineole/cyclodextrin inclusion complex, displaying enhanced anti-paralysis, anti-A β aggregation and antioxidant activities compared to 1,8-cineole. In addition, we found 1,8-cineole treatment activated the SKN-1/Nrf-2 pathway and induced autophagy in nematodes. Our results demonstrated the antioxidant and anti-Alzheimer's disease activities of 1,8-cineole, which provide a potential therapeutic approach for Alzheimer's disease.
研究领域:
神经科学
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药理学
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分子生物学
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2026
·Vol. 27
·期 5
·
IF 5.6
Tong Chen,Jing Zhang,Shaoqin Jian,Bocen Chen,Yingjie Ma,Wenguang Wang,Tianpeng Ma,Jiran Shi,Jin Yang,Man Xiao
Paederia scandens(Lour.)Merris a substance exhibiting medicine–food homology (MFH), commonly used in China. However, the antioxidant and anti-aging effects ofpaederoside(PSG) have not been thoroughly investigated; therefore, in this study,Caenorhabditis elegans(C. elegans) was treated with PSG to investigate these effects. We found that 50, 80, and 100 μg/mL of PSG could prolong the lifespan ofC. elegans, and administration of 100 μg/mL PSG significantly reduced the accumulation of lipofuscin. Under conditions of oxidative stress, RT-qPCR analysis revealed that PSG treatment significantly up-regulated the expression of key antioxidant geneskn-1and longevity-associated genedaf-16. In addition, PSG increased the activity of the antioxidant enzymes SOD and CAT and reduced the level of MDA. When DAF-2 activity is reduced or inhibited inC. elegans, DAF-16 and SKN-1 are activated and translocate to the nucleus to promote stress resistance and prolong lifespan. Finally, by utilizing HeLa cell models, we demonstrated that the core component ofPaederia scandens, PSG, promotes targeted degradation of IGF1R through the ubiquitin–proteasome system. Our results suggest that feedingC. elegansPSG is effective in extending this organism’s lifespan by improving oxidative stress resistance; thus, PSG has significant potential for development as an anti-aging food product and drug.
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高影响因子
Frontiers in Aging Neuroscience
·
2024
·
IF 4.1
Yu Xingzhi,Tao Jie,Xiao Tian,Duan Xiaohua
Introduction: Gastrodia elata Blume is a widely used medicinal and edible herb with a rich chemical composition. Moreover, prescriptions containing Gastrodia elata are commonly used for the prevention and treatment of cardiovascular, cerebrovascular, and aging-related diseases. Recent pharmacological studies have confirmed the antioxidant and neuroprotective effects of Gastrodia elata, and, in recent years, this herb has also been used in the treatment of Alzheimer’s disease (AD) and other neurodegenerative disorders. We have previously shown that 4,4′-methylenediphenol, a key active ingredient of Gastrodia elata, can mitigate amyloid-β (Aβ)-induced paralysis in AD model worms as well as prolong the lifespan of the animals, thus displaying potential as a treatment of AD.Methods: We investigated the effects of 4,4′-methylenediphenol on AD and aging through paralysis, lifespan, and behavioral assays. In addition, we determined the anti-AD effects of 4,4′-methylenediphenol by reactive oxygen species (ROS) assay, lipofuscin analysis, thioflavin S staining, metabolomics analysis, GFP reporter gene worm assay, and RNA interference assay and conducted in-depth studies on its mechanism of action.Results: 4,4′-Methylenediphenol not only delayed paralysis onset and senescence in the AD model worms but also enhanced their motility and stress tolerance. Meanwhile, 4,4′-methylenediphenol treatment also reduced the contents of reactive oxygen species (ROS) and lipofuscin, and decreased Aβ protein deposition in the worms. Broad-spectrum targeted metabolomic analysis showed that 4,4′-methylenediphenol administration had a positive effect on the metabolite profile of the worms. In addition, 4,4′-methylenediphenol promoted the nuclear translocation of DAF-16 and upregulated the expression of SKN-1, SOD-3, and GST-4 in the respective GFP reporter lines, accompanied by an enhancement of antioxidant activity and a reduction in Aβ toxicity; importantly, our results suggested that these effects of 4,4′-methylenediphenol were mediated, at least partly, via the activation of DAF-16.Conclusion: We have demonstrated that 4,4′-methylenediphenol can reduce Aβ-induced toxicity in AD model worms, suggesting that it has potential for development as an anti-AD drug. Our findings provide ideas and references for further research into the anti-AD effects of Gastrodia elata and its active ingredients.
研究领域:
神经科学
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药理学
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老年学
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分子生物学
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代谢组学
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Food & Function
·
2021
·Vol. 12
·期 23
·12127-12141
·
IF 5.396
Yue Ge,Huibin Chen,Jilite Wang,Guishan Liu,Steve W. Cui,Ji Kang,Yumei Jiang,Hao Wang
Naringenin (NN) is one of the most abundant flavonoids in citrus and grapefruits and has been shown to have antioxidant properties in vitro. The purpose of the study is to examine the antioxidant and anti-aging activities of NN in C. elegans, and to further explore the molecular mechanism. The results showed that NN enhanced the lifespan under normal and oxidative stress induced by H2O2. After treatment with NN, locomotion capability was improved and aging pigment accumulation was suppressed. NN also delayed the paralysis and reversed the defective chemotaxis behavior induced by Aβ protein. Meanwhile, the treatment with NN enhanced the activities of antioxidant enzymes and reduced the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA) content. The possible targets and pathways interacting with NN were predicted by network pharmacology. Real-time PCR analysis indicated that NN upregulated the expression levels of daf-16, sek-1 and skn-1, downregulated the expression levels of daf-2, age-1 and akt-1, and further activated sod-3, ctl-1, ctl-2, gst-4 and mtl-1. Moreover, the selected mutant strains were used and molecular docking was conducted to further suggest that IIS and MAPK pathways could be involved in the NN-mediated longevity-promoting effect.
研究领域:
老年学
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分子生物学
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药理学
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JOURNAL OF APPLIED TOXICOLOGY
·
2024
·
IF 2.7
Jia-Jun Tu,Zhen-Zhen Yu,Mei-Ling Ou,Jin-Xiong Cen,Kun Xue,Jing Zhou,Shao-Jun Li,Guo-Dong Lu
Aging and age-related diseases are intricately associated with oxidative stress and inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown their promise in mitigating age-related conditions and potentially extending lifespan in various model organisms. However, the efficacy of NSAIDs in older individuals may be influenced by age-related changes in drug metabolism and tolerance, which could result in age-dependent toxicities. This study aimed to evaluate the potential risks of toxicities associated with commonly used NSAIDs (aspirin, ibuprofen, acetaminophen, and indomethacin) on lifespan, healthspan, and oxidative stress levels in both young and old Caenorhabditis elegans . The results revealed that aspirin and ibuprofen were able to extend lifespan in both young and old worms by suppressing ROS generation and enhancing the expression of antioxidant SOD genes. In contrast, acetaminophen and indomeacin accelerated aging process in old worms, leading to oxidative stress damage and reduced resistance to heat stress through the pmk-1/skn- 1 pathway. Notably, the harmful effects of acetaminophen and indomeacin were mitigated when pmk-1 was knocked out in the pmk-1 (km25) strain. These results underscore the potential lack of benefit from acetaminophen and indomeacin in elderly individuals due to their increased susceptibility to toxicity. Further research is essential to elucidate the underlying mechanisms driving these age-dependent responses and to evaluate the potential risks associated with NSAID use in the elderly population.
研究领域:
衰老
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药理学
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分子生物学
·
遗传学
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高影响因子
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