JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Yifu Lyu,Xiuyi Yang,Lei Yang,Jinyu Dai,Huanyu Qin,Yunuo Zhou,Yunan Huang,Yanmei Wang,Di Wu,Qindai Shuai,Qilong Li,Xiaofei Xin,Lifang Yin
Lipid nanoparticle-mediated co-delivery of siRNA and small molecule holds a great potential to treat metabolic dysfunction-associated steatotic liver disease (MASLD). However, targeted delivery of therapeutics to hepatocytes remains challenging. Taking the advantage of rising low density lipoprotein receptor/very-low density lipoprotein receptor (LDLR/VLDR) levels in MASLD, the biological fate of dinonylamine-ethylene glycol chlorophosphate-1-nonanol (DNNA-COP-NA) based lipid nanoparticles (LNPs) was oriented to liver tissues via apolipoprotein E (ApoE)-LDLR/VLDLR pathway. We then adopted a three-round screening strategy to optimize the formulation with both high potency and selectivity to deliver siRNA-HIF-1α (siHIF1α) and silibinin (SLB) payloads to hepatocytes. The optimized SLB/siHIF1α-LNPs mediates great siRNA delivery and transfection of hepatocytes. In high fat diet (HFD)- and carbon tetrachloride (CCl 4 )-induced mouse models of MASLD, SLB/siHIF1α-LNPs enabled the silencing of hypoxia inducible factor-1α (HIF-1α), a therapeutic target primarily expressed by hepatocytes, leading to significantly reduced inflammation and liver fibrosis synergized with SLB. Moreover, it is demonstrated the hepatocyte-targeting delivery of SLB/siHIF1α-LNPs has the potential to restore the immune homeostasis by modulating the population of Tregs and cytotoxic T cells in spleen. This proof-of-concept study enable siRNA and small molecule co-delivery to hepatocytes through intrinsic variation of targeting receptors for MASLD therapy.
研究领域:
药学
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分子生物学
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肝病学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2022
·Vol. 36
·期 6
·2463-2480
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IF 6.388
Yun Wang,Yuanyuan Xu,Xiaowei Xu,Hong Wang,Dong Wang,Wenchao Yan,Jiaying Zhu,Haiping Hao,Guangji Wang,Lijuan Cao,Jun Zhang
The Ginkgo biloba leave extract (GbE) is widely applied in the prevention and treatment of atherosclerotic cardiovascular diseases in clinical practice. However, its mechanism of actions has not been totally elucidated. In this study, we confirmed the beneficial effects of GbE in alleviating hypercholesterolemia, inflammation and atherosclerosis in Ldlr −/− mice, which were fed 12 weeks of Western diet (WD). Moreover, 16S rRNA sequencing revealed that GbE treatment reshaped the WD-perturbed intestinal microbiota, particularly decreased the Firmicutes / Bacteroidetes ratio and elevated the abundance of Akkermansia , Alloprevotella , Alistipes , and Parabacteroides . Furthermore, GbE treatment downregulated the intestinal transcriptional levels of proinflammatory cytokines and enhanced the expression of tight junction proteins, exerting the roles of attenuating the intestinal inflammation as well as repairing the gut barrier. Meanwhile, the targeted metabolomic analysis displayed that GbE treatment significantly reversed the dysfunction of the microbial metabolic phenotypes, including promoting the production of short chain fatty acids, indole-3-acetate and secondary bile acids, which were correlated with the atherosclerotic plaque areas. Finally, we confirmed GbE-altered gut microbiota was sufficient to alleviate atherosclerosis by fecal microbiota transplantation. In summary, our findings provide important insights into the pharmacological mechanism underlying the antiatherogenic efficacy of GbE.
研究领域:
药理学
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心血管疾病
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微生物学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
LETTERS IN APPLIED MICROBIOLOGY
·
2021
·Vol. 73
·期 6
·779-792
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IF 2.858
Yang R.,Yin D.,Yang D.,Liu X.,Zhou Q.,Pan Y.,Li J.,Li S.
This study aims to explore the potential mechanisms of Xinnaokang in atherosclerosis treatment. Firstly, the active components of Xinnaokang were analysed by HPLC, which contains ginsenoside Rg1, puerarin, tanshinone, notoginsenoside R1, ammonium glycyrrhizate and glycyrrhizin. Network pharmacology analysis showed there were 145 common targets of Xinnaokang, including the chemical stress, lipid metabolite, lipopolysaccharide, molecules of bacterial origin, nuclear receptor and fluid shear stress pathways. Then, the animal experiment showed that Xinnaokang reduced the body weight and blood lipid levels of atherosclerotic mice. Vascular plaque formation was increased in atherosclerotic mice, which was markedly reversed by Xinnaokang. In addition, Xinnaokang reduced CAV‐1 expression and increased ABCA1, SREBP‐1 and LXR expressions in the vasculature. Xinnaokang promoted SREBP‐2 and LDLR expressions in the liver but decreased IDOL and PCSK9 expressions, indicating that Xinnaokang regulated lipid transport‐related protein expression. Cecal microbiota diversity was reduced in atherosclerotic mice but increased after Xinnaokang treatment. Xinnaokang treatment also improved gut microbiota communities by enriching Actinobacteria, Bifidobacteriales and Bifidobacteriaceae abundances. Metabolic profile showed that Xinnaokang significantly reduced homogentisate, phenylacetylglycine, alanine and methionine expressions in the liver of atherosclerotic mice. Xinnaokang effectively alleviated atherosclerosis, and this effect might be linked with the altered features of the liver metabolite profiles and cecal microbiota.
研究领域:
药理学
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心血管疾病
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微生物学
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代谢组学
✓ 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）