FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Xiaomeng Ji,Jingquan Dong,Wenting Zhu,Shasha Zhang,Yaru Chen,Xiao Liu,Yan Cao,Panpan Zhao,Zibo Dong
Background Sepsis-associated encephalopathy (SAE) represents one of the most common neurological complications observed in sepsis patients, contributing to both increased mortality and long-term cognitive impairment. Microglial mitochondrial reactive oxygen species (mtROS) overproduction and NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation were key pathological drivers of SAE. Although PIM-1, a serine/threonine kinase, was known to regulate both mtROS generation and NLRP3 signaling, its specific contribution to SAE remained poorly defined. Methods This study established a SAE mouse model using cecal ligation and puncture (CLP) surgery, and screened the differentially expressed gene PIM-1 through immunohistochemistry, GEO database analysis, and etc. An in vitro model was established using Lipopolysaccharide + Adenosine(LPS + ATP) Triphosphate stimulated Mouse Microglia (BV-2), and the regulation mechanism of PIM-1 was analyzed through siRNA interference, RNA-seq, and etc. Potential drug Urolithin B (UB) targeting PIM-1 inhibition was screened through molecular docking, and its inhibitory effect on PIM-1 and therapeutic potential in SAE were evaluated through thermal stability experiments, behavioral experiments, etc. Results PIM-1 was upregulated in SAE, which was associated with brain damage. PIM-1 knockdown suppressed microglial activation and reduced inflammatory cytokines release. Further investigation indicated that PIM-1 modulated mtROS generation and facilitated NLRP3 inflammasome activation. Notably, pharmacological inhibition of PIM-1 by UB alleviated SAE both in vivo and in vitro , resulting in improved neuronal damage and cognitive impairment. Conclusion PIM-1 played a critical role in SAE progression, potentially through its mediation of microglial activation and neuroinflammation via the mtROS/NLRP3 axis. Notably, pharmacological inhibition of PIM-1 with urolithin B significantly alleviated SAE.
研究领域:
神经免疫学
·
重症医学
·
分子神经生物学
·
炎症与感染
·
转化神经科学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Carbohydrate Polymer Technologies and Applications
·
2024
·
IF 6.2
Chang Liu,Chao He,Qing Zeng,Dengqun Liao,Xianen Li
Urolithin B (UB) has significant health benefits, including a hypolipidemic effect, but its poor water solubility limits its bioavailability and pharmacological activities. In order to increase UB's water solubility, we used cyclodextrin complexation to prepare UB–methyl-β-cyclodextrin inclusion complex (UB–M-β-CD). Our result showed that water solubility of UB in inclusion complex was about 0.3 µg/mL, which was increased by 3875 folds than pure UB. In-vivo pharmacokinetic studies showed the enhanced UB content in rat plasma and the improved bioavailability with UB–M-β-CD. In hyperlipidemic hamsters, UB–M-β-CD reduced body weight and organ fat accumulation more effectively than UB alone. Both UB and UB–M-β-CD decreased serum lipid levels except that of high-density lipoprotein cholesterol. Meantime, UB–M-β-CD reversed hepatic bile acid dysregulation better than UB. Further comprehensive analysis revealed that UB–M-β-CD had the superior effects on hyperlipidemia, suggesting that cyclodextrin complexation enhances the therapeutic potential of UB in modulating liver lipid metabolism. Our results indicate that UB–M-β-CD has the great potentials in treatment of hyperlipidemia and related metabolic disorders.
研究领域:
药理学
·
药物化学
·
代谢性疾病
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF CELLULAR BIOCHEMISTRY
·
2019
·Vol. 120
·期 10
·17273-17282
·
IF 3.448
Min-yi Lv,Chuan-jian Shi,Fei-fei Pan,Jiang Shao,Lu Feng,Guoqin Chen,Caiwen Ou,Jin-fang Zhang,Wei-ming Fu
Consumption of dietary ellagitannins (ETs) has been proven to benefit multiple chronic health disorders including cancers and cardiovascular diseases. Urolithins, gut microbiota metabolites derived from ETs, are considered as the molecules responsible for these health effects. Previous studies have demonstrated that urolithins exhibit antiproliferative effects on prostate, breast, and colon cancers. However, as for hepatocellular carcinoma (HCC), it remains elusive. Herein, we aim to investigate the function of urolithin B (UB), a member of urolithins family, in HCC. The effects of UB on cell viability, cell cycle and apoptosis were evaluated in HCC cells, and we found UB could inhibit the proliferation of HCC cells, which resulted from cell cycle arrest and apoptosis. Furthermore, UB could increase phosphorylated β-catenin expression and block its translocation from nuclear to cytoplasm, thus inducing the inactivation of Wnt/β-catenin signaling. Using a xenograft mice model, UB was found to suppress tumor growth in vivo. In conclusion, our data demonstrated that UB could inhibit the proliferation of HCC cells in vitro and in vivo via inactivating Wnt/β-catenin signaling, suggesting UB could be a promising candidate in the development of anticancer drugs targeting HCC.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
MEDICINAL CHEMISTRY RESEARCH
·
2023
·Vol. 32
·期 6
·1087-1097
·
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
·
衰老生物学
·
生物医学
✓ 已验证
产品关联
DOI
高影响因子
BRAIN RESEARCH BULLETIN
·
2026
·
IF 4.5
Feifei Chen,Lingkai Tang,Ling Yuan,Jiali Xiong,Rong Kuang,Wen Qian,Yufang Kong,Yina Yin
UB alleviates CUMS-induced depressive-like behaviors and hippocampal damage in rats. • The antidepressant effect of UB may be associated with the upregulation of SLP2 expression in hippocampal neurons of rats. • SLP2 regulates the PINK1/Parkin pathway, promotes mitophagy, and maintains neuronal energy homeostasis. • Knockdown of SLP2 in vivo reverses the antidepressant and neuroprotective effects of UB. Background Depression is a highly prevalent mental disorder, with current medications often limited by delayed onset and insufficient efficacy, underscoring the urgent need to explore novel therapeutic strategies. Urolithin B (UB), a natural ellagitannin-derived metabolite, exhibits anti-inflammatory and antioxidant activities in neuroinflammation, yet its role in depression remains unclear. Objective: The present research aimed to uncover possible effects of UB on depressive-like behavior and hippocampal neuronal damage in a rat model of depression and to preliminarily elucidate its underlying molecular mechanisms. Methods: A rat model of depression was created using the chronic unpredictable mild stress (CUMS) paradigm, after which UB intervention was applied. To evaluate depressive-like behaviors, several behavioral tests were conducted, including sucrose preference test, forced swim test, tail suspension test, and open field test. Hippocampal pathological changes and related factor expression were evaluated using histopathology, immunofluorescence, and ELISA. Potential targets were screened via single-cell RNA sequencing (scRNA-seq) data obtained from the GEO database. Subsequently, the function of the identified target gene was validated through in vitro knockdown/overexpression experiments and an in vivo rescue experiment. Results: UB significantly ameliorated depressive-like behaviors in CUMS rats and alleviated hippocampal neuronal damage, synaptic loss, and neuroinflammation. scRNA-seq analysis revealed a significant upregulation of SLP2 expression in hippocampal neurons (HNs) from the treated group, along with the enrichment of mitophagy-related pathways. Functional experiments confirmed that SLP2 regulates the PINK1/Parkin pathway, promotes mitophagy, and maintains neuronal energy homeostasis. Conversely, knockdown of SLP2 reversed the antidepressant and neuroprotective effects of UB. Conclusion: UB alleviates CUMS-induced depressive-like behavior and hippocampal neuronal damage by upregulating SLP2 and regulating the PINK1/Parkin-mediated mitophagy pathway. This study presents a new potential target and theoretical basis for developing natural compound-based therapies for depression.
✓ 已验证
产品关联
DOI
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Huimin Li,Jingya Ruan,Jiayan Huang,Yijin Wu,Jiaming Cheng,Ongher Kouye,Yi Zhang,Tao Wang
Background Ulcerative colitis (UC) therapy remains challenging due to limited options. Pomegranate peel, rich in bioactive compounds, shows potential, but its key components and mechanisms underlying its action against UC are unclear. Purpose The present investigation was undertaken to assess the therapeutic efficacy of 70 % ethanolic (PPEE) and aqueous extracts (PPWE) derived from pomegranate peel, determine the primary active component, and clarify the underlying molecular mechanism. Study design and methods The anti-UC effects of PPEE and PPWE extracts were first assessed in DSS-induced mice. Differential constituents underlying their efficacy disparities were identified using LC-MS/UHPLC and chemometric analyses. Key bioactive compounds were screened via a model of Caco-2/THP-1 co-culture evaluating intestinal barrier function. The action mechanisms were further elucidated through molecular docking, surface plasmon resonance (SPR), co-immunoprecipitation (Co-IP), and other assays, validated across inflammatory cell models, DSS-induced mice, and human UC colon tissues. Results PPEE showed superior efficacy over PPWE, as evidenced by enhanced intestinal barrier function and suppressed inflammation and NLRP3 inflammasome activation. Ellagic acid (EA) was identified as the core active constituent, which directly targeted AKR1B1/AKR1B3, thereby inhibiting NLRP3-ASC oligomerization and subsequent cleavage of caspase-1 and IL-1 β . Conclusion This study unveils a novel pathogenic mechanism in UC, namely the AKR1B1/AKR1B3-NLRP3 axis, and identifies EA as its effective inhibitor. These results demonstrate the potential of pomegranate peel extracts and offer a novel therapeutic approach for UC.
研究领域:
药理学
·
胃肠病学
·
分子生物学
·
天然产物研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2023
·
IF 8.8
Yang Yang,Pui-Kei Lee,Ho-Ching Wong,Danyue Zhao
Ellagic acid (EA) is an abundant dietary polyphenol with multifarious health benefits but low bioavailability. To increase its bio-efficacy, converting EA to urolithins by supplementing urolithin-producing bacteria, e.g., Gordonibacter urolithinfaciens ( G.uro ), could be a solution. This work first tested three methods for oral delivery of live G.uro . Intestinal colonization of G.uro and its impact on local gut microbiota, EA-to-urolithin conversion and bioavailability were then investigated in C57BL/6J mice administered to EA only or a synbiotic ( G. uro + EA). In vitro results suggested that G.uro largely survived simulated gastrointestinal digestion and could be administered without protection. In vivo results showed that G.uro had little impact on local gut microbiota but could not colonize the gut. Moreover, synbiotic remarkably promoted Akkermansia , Lactobacillus and Bifidobacterium growth, and significantly enhanced the bioavailability of urolithins compared with the EA-only group. This study demonstrated the potential of oral supplementation of G.uro for enhancing EA-to-urolithin bioconversion and bioavailability.
✓ 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）