MEDICINAL CHEMISTRY RESEARCH
·
2023
·Vol. 32
·期 6
·1087-1097
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IF 2.6
Chen Xi,Feng Xiaoqing,Kong Xiangming,Wang Hecheng,Liu Tianwen,Tang Long,Zhuang Ziheng
Aging is a natural process, but with the increase of people’s average life expectancy, aging has brought great economic pressure and social burden to many countries and regions. As urolithin B (UB) is a natural metabolite, it has shown positive effects in many disease studies, such as obesity, diabetes, osteoporosis, cancer, learning and memory disorders, and other diseases. This inspired researchers to further study and application of UB as a potential anti-aging drug. In this study, 13 amide derivatives of UB were designed and synthesized, and their anti-aging and biosafety were verified using Caenorhabditis elegans ( C. elegans ). C. elegans is a powerful model organism for anti-aging research. Finally, our results showed that Cpd. 11 had the best anti-aging activity among the thirteen amide derivatives, and the compound had good biosafety. Therefore, Cpd. 11 has the potential to be used as an anti-aging drug and needs to be further developed and applied. Graphical abstract
研究领域:
药物化学
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衰老生物学
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生物医学
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产品关联
DOI
高影响因子
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
·
2025
·
IF 4.9
Jiayin Zhang,Rong Zhang,Lemei Sun,Bingqi Chen,Xiaohan Li,Jing Duan
Urolithin A (UA), a gut microbiota-derived metabolite of ellagic acid, exhibits diverse biological activities. Emerging evidence suggests its anti-tumor potential, possibly mediated through gut microbiota modulation, yet its role in lung cancer remains unclear. In this study, UA dose- and time-dependently suppressed lung cancer cell proliferation. Mechanistically, UA triggered autophagy, as evidenced by increased LC3-II protein levels, and transcriptome analysis revealed this effect was mediated through inhibition of the PI3K/AKT/mTOR pathway. In vivo , UA supplementation markedly inhibited tumor growth in H1975 xenograft models, concomitant with enhanced autophagy and downregulation of associated proteins. Notably, 16S rRNA sequencing demonstrated that UA modulated gut microbiota composition, increasing Lactobacillus while decreasing Desulfovibrio abundance. Spearman’s correlation analysis further linked these microbial shifts to altered expression of autophagy-related genes. Collectively, our findings highlight UA as a promising gut microbial metabolite for lung cancer intervention via coordinated autophagy induction and microbiota remodeling.
研究领域:
癌症生物学
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微生物学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Chemical Biology & Drug Design
·
2025
·Vol. 105
·期 5
·e70119
·
IF 3.3
Qiulin Hu,Long Tang,Zhongqiu Xu,Fen Yan,Guoqiang Song,Xiaoqing Feng
Urolithin A (UA) is a dibenzo[ b,d ]pyran-6-one polyhydroxy derivative produced as intestinal microbe metabolize ellagitannin and ellagic acid. Because of its superior anti-inflammatory and antioxidant effects, it can cure neuronal damage in a variety of ways and play a neuroprotective role. More and more research has revealed that UA is a potential medicine for the treatment of neurodegenerative diseases. Due to UA source limitations, it is insufficient to achieve disease treatment concentrations, and the activity of UA inhibiting PDE2 needs further enhancement. As a result, we used UA as the parent nucleus structure, independently designed and used Discovery Studio software to assist in the structural design and molecular docking screening of the compounds, and tested the in vitro enzyme activity of the synthesized compounds, hoping to obtain UA-based PDE2 inhibitors. The IC 50 of 6–18, 6–19, 6–20, 6–22, and 6–29 were 0.62, 0.85, 1.51, 1.09, and 1.58 μM, respectively. In this study, UA derivatives that can bind to the crystal structure of PDE2 protein 4HTX were proposed, which laid a groundwork for further structural modification, lead design, and development of small molecule inhibitors with inhibitory activity of PDE2.
研究领域:
药理学
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生物化学
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药物化学
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DOI
PubMed
高影响因子
Scientific Reports
·
2021
·Vol. 11
·期 1
·1-12
·
IF 4.38
Tang Long,Jiang Jianchun,Song Guoqiang,Wang Yajing,Zhuang Ziheng,Tan Ying,Xia Yan,Huang Xianfeng,Feng Xiaoqing
A series of urolithins derivatives were designed and synthesized, and their structures have been confirmed by 1 H NMR, 13 C NMR, and HR-MS. The inhibitory activity of these derivatives on phosphodiesterase II (PDE2) was thoroughly studied with 3-hydroxy-8-methyl-6 H -benzo[C]chromen-6-one and 3-hydroxy-7,8,9,10-tetrahydro-6 H -benzo[C] chromen-6-one as the lead compounds. The biological activity test showed that compound 2e had the best inhibitory activity on PDE2 with an IC 50 of 33.95 μM. This study provides a foundation for further structural modification and transformation of urolithins to obtain PDE2 inhibitor small molecules with better inhibitory activity.
研究领域:
药物化学
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生物化学
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DOI
PubMed
高影响因子
Foods
·
2022
·Vol. 11
·期 17
·2621
·
IF 5.561
Haoyu Mi,Shu Liu,Yang Hai,Guang Yang,Jing Lu,Fuxiang He,Yaling Zhao,Mengjie Xia,Xiaoyue Hou,Yaowei Fang
Dietary polyphenol ellagic acid has anti-cancer and anti-inflammatory activities, and these biological activities require the conversion of ellagic acid to urolithins by intestinal microbes. However, few gut microbes are capable of metabolizing ellagic acid to produce urolithins, limiting the beneficial effects of ellagic acid on health. Here, we describe an intestinal bacteriumLactococcus garvieaeFUA009 isolated from the feces of a healthy volunteer. It was demonstrated via HPLC and UPLC-MS analysis that the end product of ellagic acid metabolism of FUA009 was urolithin A. In addition, we also examined the whole genome sequence of FUA009 and then assessed the safety and probiotic properties of FUA009 based on a complete genome and phenotype analysis. We indicated that FUA009 was safe, which was confirmed by FUA009 being sensitive to multiple antibiotics, having no hemolytic activity, and being free of aggressive putative virulence factors. Moreover, 19 stress-responsive protein genes and 8 adhesion-related genes were predicted in the FUA009 genome. Furthermore, we demonstrated that FUA009 was tolerant to acid and bile salt by determining the cell viability in a stress environment. In summary,LactococcusgarvieaeFUA009, as a novel UA-producing bacterium, not only contributes to the study of the metabolic pathway of ellagic acid but is also expected to be a novel probiotic candidate.Keywords:plant-derived activities;Lactococcusgarvieae;ellagic acid;urolithin A;complete genome;safety and probiotic characteristics
研究领域:
微生物学
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营养学
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基因组学
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药理学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
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2025
·Vol. 15
·期 1
·1-15
·
IF 3.9
Huang Zhengyuan,Ren Zhongyu,Wang Sanwang,Xiao Ling,Ling Yipeng,Xie Yinping,Wang Gaohua,Zhou Benhong
Cognitive impairment in schizophrenia occurs in the early stages of the disease and is closely associated with prognosis. Alleviation of cognitive impairment in schizophrenia faces major challenges owing to the lack of preventive and therapeutic drugs that are novel and effective. Urolithin A (UA) is a gut microbial metabolite of ellagic acid that has demonstrated neuroprotective effects in multiple neurological disease models. Nonetheless, the neuromodulatory role of UA in schizophrenia is yet to be elucidated. Wistar rat pups were separated from their mothers for 24 h on postnatal days (PNDs) 9–10 to establish an early-life stress model. The pups were pretreated with UA at different administration times (2, 4, and 6 weeks) and doses (50, 100, and 150 mg/kg) from adolescence (PND29). Behavioral tests were performed after the end of the administration. Subsequently, hippocampal samples were collected for histopathological and molecular evaluations. Male offspring rats subjected to maternal separation exhibited increased sensitivity to prepulse inhibition and cognitive impairment, accompanied by severe neuroinflammation and impaired neurogenesis. However, UA attenuated maternal separation-induced prepulse inhibition deficits and cognitive impairments and restored hippocampal neurogenesis in a dose-dependent manner. Furthermore, UA pretreatment preserved dendritic spine density, synapses, and presynaptic vesicles. In addition, it exerted anti-inflammatory effects by inhibiting microglial activation and expression of the proinflammatory cytokines tumor necrosis factor-α, interleukin-6, and interleukin-1β. Potential mechanisms included upregulation of brain-derived neurotrophic factor protein expression and activation of the extracellular signal-regulated kinase signaling pathway. This study is the first preclinical evaluation of the effects of UA on cognitive impairment in schizophrenia. The findings suggest that changes in cognitive function linked to schizophrenia are driven by the interaction among neuroinflammation, neurogenesis, and synaptic plasticity and that UA has the potential to reverse these processes. These observations provide evidence for future clinical trials of UA as a dietary supplement for preventing schizophrenia.
研究领域:
神经科学
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药理学
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精神病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Cong Zhang,Yingying Song,Ming Yuan,Liang Chen,Qianyu Zhang,Junjie Hu,Yan Meng,Shan Li,Guohua Zheng,Zhenpeng Qiu
Excessive fructose consumption exacerbates the progression of nonalcoholic fatty liver disease (NAFLD) by disrupting hepatic lipid homeostasis. This study sought to evaluate the efficacy of urolithin A (UroA) in a fructose-induced NAFLD mouse model. UroA was administered in the high-fructose-fed mice to investigate the antisteatotic effects in vivo. Fructose-stimulated HepG2 cells and primary hepatocytes were established for in vitro mechanistic assessment. The results suggested that UroA ameliorated fructose-induced hepatic steatosis in mice. Mechanistically, UroA impaired lipogenesis and enhanced β-oxidation in the livers of fructose-fed mice. Notably, UroA facilitated hepatic lipophagy through the AMPK/ULK1 pathway both in vivo and in vitro, degrading lipid droplets for fueling β-oxidation. This study indicates that UroA alleviates excessive lipid accumulation and restores lipid homeostasis in the livers of fructose-fed mice by suppressing lipid metabolic reprogramming and triggering lipophagy. Therefore, dietary supplementation of UroA or ellagitannins-rich foods may be beneficial for NAFLD individuals with high fructose intake.
研究领域:
肝病学
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代谢紊乱
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营养科学
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
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2025
·
IF 4
Peng Chen,Wenhao Xiao,Fanzhao Zou,Jiexin Lei,Fuchao Chen,Ruhong Zhang
This study explored the effects of methylated urolithin A (mUro A), on lipopolysaccharide (LPS)-induced cognitive impairment and anxiety- and depression-like behaviors, and their molecular mechanism. mUro A significantly mitigated cognitive dysfunction, anxiety- and depression-like behaviors. Furthermore, mUro A improved activities of antioxidative enzymes, regulated the release of inflammatory factors, inhibited the LPS-induced generation of Aβ 1 – 42 and restored the cholinergic system balance in the AD mouse brain. Additionally, mUro A markedly attenuated microglial activation by inhibiting the Drp1/HK1/NLRP3 pathway, thereby suppressing mitochondrial inflammation. This was evidenced by the downregulation of p-Drp1 (s616), VDACs, NLRP3, ASC, cleaved caspase 1, IL-18, and IL-1β, alongside the upregulation of HK1 expression. In conclusion, mUro A mitigates AD-associated cognitive deficits by inhibiting the Drp1/HK1/NLRP3 pathway and suppressing mitochondrial inflammation.
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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产品关联
DOI
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
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2025
·
IF 3
Feng Zhou,Xiaoqing Feng,Zhongqiu Xu,Fen Yan,Guoqiang Song,Long Tang
Urolithin A (UA) is a naturally occurring polyphenolic compound.Due to its remarkable efficacy in safeguarding the central nervous system, UA has emerged as a promising candidate for drug development targeting neurodegenerative diseases such as Alzheimer’s. However, the source of UA is limited and the activity of UA to inhibit PDE2 needs to be further improved. Therefore, this study will be optimized on the basis of UA to seek PDE2 inhibitors with better activity. In this study, we designed a series of UA derivatives based on 4HTX as the target protein and UA as the lead compound, utilizing the binding crystal structures of 4HTX and BAY60-7550 as references. After thorough screening, we successfully identified the 8-hydroxyl group as the precise site of modification. Utilizing 2-bromo-5-hydroxybenzoic acid as our primary raw material, we synthesized a series of the 8-hydroxyl modified UA. Subsequently, we evaluated the inhibitory activity of these synthesized UA derivatives using a phosphodiesterase assay kit. Ultimately, we screened a total of 34 derivatives; among them, compounds 1f, 1q, 2d, and 2j exhibited significant inhibitory activity against PDE2 with half-maximal inhibitory concentrations of 3.05 μM,0.67 μM, 0.57 μM, and 4.96 μM, respectively.
研究领域:
药物化学
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神经科学
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有机合成
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHEMICAL RESEARCH
·
2023
·
IF 1.4
Hecheng Wang,Long Tang,Wanhui Di,Feng Yan,Xianfeng Huang,Xiaoqing Feng,Guoqiang Song
Urolithins are the gut microbiota metabolites of ellagitannins which are found in natural plants such as pomegranate, strawberry, and raspberry, and in nuts. Recently, several reports have clarified the underlying mechanism of urolithins in central nervous system inflammation. Therefore, urolithins have become potential therapeutic drug candidate molecules for central nervous system diseases. Derivatives 1–1d, 1–1f, 3–2a, and 3–2b of urolithin A, urolithin B, and methoxyurolithin A were found to have had significant inhibitory activity against phosphodiesterase II with IC50 values of 35.42, 39.96, 25.58, and 13.84 μM, respectively. Herein, we report the design and synthesis of urolithin derivatives along with a biological evaluation of their activity against phosphodiesterase II.
研究领域:
药物化学
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神经科学
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生物合成
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DOI
高影响因子
Journal of Future Foods
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2025
·
IF 7.2
Ziyan Hua,Xinzhu Gong,Kexin Chi,Yajian Su,Qianyan Tan,Rui Tang,Wenjun Zhang,Shu Liu,Yaowei Fang
Ellagic acid (EA), a polyphenol found in various fruits and nuts, is converted by the gut microbiota into urolithins, including Uro-A, known for its notable bioactivities. This study utilized fecal microbiota transplantation (FMT) to establish three distinct urolithin metabotypes (UMs) in pseudo-germ-free (PGF) mice, categorized as UM-A, UM-B, and UM-0 based on their metabolic outputs. Limosilactobacillus fermentum FUA033 was administered to the FMT UMs mice, resulting in a marked increase in Uro-A production across all metabotypes. In Group-0, Uro-A concentrations increased from undetectable levels to 15.97 ± 2.21 μM, while in Group-B, levels rose from 4.13 ± 2.49 μM to 19.56 ± 1.77 μM. Additionally, L. fermentum FUA033 significantly impacted gut microbiota diversity and composition, with a notable rise in Lachnospiraceae , a group crucial for Uro-A synthesis. These results underscore the potential of probiotics in modulating urolithin metabotypes and highlight an innovative strategy to improve gut health and metabolic functions using next-generation probiotics.
研究领域:
微生物学
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营养学
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药理学
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胃肠病学
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益生菌研究
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产品关联
DOI
高影响因子
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
·
2024
·Vol. 108
·期 1
·1-14
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IF 3.9
He Fuxiang,Bian Yingying,Zhao Yaling,Xia Mengjie,Liu Shu,Gui Jiajin,Hou Xiaoyue,Fang Yaowei
Abstract The metabolite urolithin A, a metabolite of the dietary polyphenol ellagic acid (EA), has significant health benefits for humans. However, studies on the gut microbiota involved in ellagic acid metabolism are limited. In this study, we conducted in vitro fermentation of EA using human intestinal microbiome combined with antibiotics (vancomycin, polymyxin B sulfate, and amphotericin B). Liquid chromatography-mass spectrometry (LC–MS/MS) analysis demonstrated that the production capacity of urolithin A by gut microbiota co-treated with polymyxin B sulfate and amphotericin B (22.39 µM) was similar to that of untreated gut microbiota (24.26 µM). Macrogenomics (high-throughput sequencing) was used to analyze the composition and structure of the gut microbiota. The results showed that the abundance of Bifidobacterium longum , Bifidobacterium adolescentis , and Bifidobacterium bifidum in the gut microbiota without antibiotic treatment or co-treated with polymyxin B sulfate and amphotericin B during EA fermentation was higher than that in other antibiotic treatment gut microbiota. Therefore, B. longum , B. adolescentis , and B. bifidum may be new genera involved in the conversion of EA to urolithin A. In conclusion, the study revealed unique interactions between polyphenols and gut microbiota, deepening our understanding of the relationship between phenolic compounds like EA and the gut microbiota. These findings may contribute to the development of gut bacteria as potential probiotics for further development. Key points • Intestinal microbiome involved in ellagic acid metabolism. • Gram-positive bacteria in the intestinal microbiome are crucial for ellagic acid metabolism. • Bifidobacterium longum, Bifidobacterium adolescentis, and Bifidobacterium bifidum participate in ellagic acid metabolism.
研究领域:
微生物学
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营养学
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代谢组学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）