ACS Applied Materials & Interfaces
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2016
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IF 7.145
Hai Xiao,Altanzul Altangerel,Gerile Gerile,Yinga Wu,Huricha Baigude
RNA interference (RNAi) is a highly efficient approach for gene silencing. Regulation of gene expression at post-transcriptional level provides great potential for curing diseases caused by abnormal overexpression of disease-related genes. However, the application of RNAi in the clinic has been hindered by the lack of efficient and biocompatible delivery systems. Therefore, the development of a safe and tissue-targeted double-stranded interfering RNA (siRNA) carrier for clinical application is urgently needed. Here we report the discovery of a highly efficient liposomal siRNA delivery agent based on a novel peptidomimetic built from natural amino acids. Fine tuning of the composition of amino acids, the type of amide linkage in the peptidomimetic, as well as the formulation and the physicochemical parameters of the novel lipoplex resulted in a lipid nanoparticle (LNP) that efficiently encapsulates and carries siRNA to mouse liver. In vivo experiments showed that a single injection of unmodified siRNA complexed to one of the peptidomimetics at a clinically feasible dose induced significant RNAi in mouse liver, resulting in a 90% decrease in apolipoprotein B (ApoB) mRNA level, as well as a 60% decrease in serum ApoB protein level. Analysis of mouse serum by ELISA indicated that the novel peptidomimetic based lipoplex did not elevate the level of liver enzymes (ALT, AST) in the serum. Our novel peptidomimetic-based lipoplex demonstrated great potential for the development of a safe and efficient siRNA delivery agent for clinical applications.
研究领域:
药理学
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分子生物学
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治疗学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Microbiology
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2023
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IF 5.2
Guo Huanyu,Chen Jing,Yuan Xuemei,Zhang Jian,Wang Jiayang,Yao Jiayun,Ge Haixia
Herbal extracts have been considered as ideal alternative to antibiotics in aquaculture and application of combinatory effective extracts always can exhibit the enhanced bioactivity with high efficiency. In our study, a novel herbal extract combination GF-7, which is composed of Galla Chinensis, Mangosteen Shell extracts as well as the effective parts of Pomegranate peel and Scutellaria baicalensis Georgi extracts, was prepared and applied for the therapy of bacterial infection in aquaculture. The HPLC analysis of GF-7 was also investigated for quality control and chemical identification. In the bioassay, GF-7 had excellent antibacterial activity against various aquatic pathogenic bacteria in vitro, and the related MIC values were between 0.045 and 0.36 mg/mL. After feeding Micropterus salmoide with GF-7 (0.1, 0.3, and 0.6%, respectively) for 28 days, the activities of ACP, AKP, LZM, SOD, and CAT of the liver in each treatment group were significantly increased and the content of MDA was significantly decreased. Meanwhile, the hepatic expression of the immune regulators including IL-1β, TNF-α, and Myd88 at different times was up-regulated in varying degrees. The challenge results exhibited a good dose-dependent protective effect on M. salmoides infected with A. hydrophila, which was further confirmed by liver histopathology. Our results imply that the novel combination GF-7 is a potential natural medicine for the prevention and treatment of numerous aquatic pathogenic infectious diseases in aquaculture.
研究领域:
水产养殖
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药理学
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免疫学
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微生物学
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
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2024
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IF 4.8
Yuan Yuan,Xiaoxuan Yin,Lu Li,Ziyue Wang,Haiyang Yan
ABSTRACT Glycidol (CAS: 556-52-5), a known carcinogen and genotoxicant, is often found in refined vegetable oils. Human exposure predominantly occurs through consumption of these oils and their byproducts, which contain glycidyl esters (GEs). Upon ingestion, GEs are metabolized to release glycidol, posing substantial health hazards. Historical studies have reported the tumorigenic properties of glycidol across various organs in mice models, encompassing the stomach, liver, lungs, brain, mammary gland, and skin. In this study, we employed a Balb/c mice model to investigate the hepatotoxic effects of glycidol following exposure to escalating doses (0, 25, 50, and 100 mg/kg bw/day). The hepatotoxicity was evidenced by a significant elevation in liver enzymes (ALT, AST), indicative of liver cell damage. Furthermore, biochemical analysis revealed heightened levels of oxidative stress indicators (SOD, MDA, GSH) and the upregulation of endoplasmic reticulum stress proteins, underscoring the cellular stress response. The induction of hepatocyte apoptosis served as a direct marker of liver damage caused by glycidol exposure. Additionally, glycidol altered the composition of intestinal microbiota and short-chain fatty acids (SCFAs), which unbalanced homeostasis. Gut barrier integrity markers (ZO-1, Claudin-1, Occludin, TLR4, LPS) indicated increased permeability of harmful substances to the liver via the gut-liver axis, which exacerbated hepatic injury. These findings highlight glycidol's disruption of gut homeostasis and its hepatotoxic potential.
研究领域:
毒理学
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肝病学
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微生物学
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2023
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IF 5.8
Ziyun Hu,Di Xu,Huihui Meng,Wenya Liu,Qi Zheng,Junsong Wang
4-octyl itaconate (4-OI) is a cell-permeable itaconate derivative with anti-inflammatory and antioxidant properties. However, its therapeutic potential for oxidative stress-induced liver injury remains unknown. This study investigated the hepatoprotective effects and mechanisms of 4-OI against oxidative damage in in vitro and in vivo models. 4-OI attenuated H 2 O 2 -induced cytotoxicity, oxidative stress, and mitochondrial dysfunction in L02 and HepG2 cells. Untargeted metabolomics profiling and pathway analysis identified the PI3K/AKT/mTOR and MAPK pathways as key regulators of 4-OI's protective effects. Specifically, 4-OI induced phosphorylation of AKT and ERK1/2, leading to activation of the Nrf2 signaling pathway. Nrf2 upregulated expression of the mitochondrial deacetylase Sirt3, which subsequently alleviated H 2 O 2 -induced cell injury. In mice, 4-OI reduced acetaminophen (APAP)-induced liver injury as evidenced by attenuated hepatocellular necrosis and decreased serum liver enzymes . It also elevated hepatic expression of Nrf2, Sirt3, p-AKT and p-ERK1/2. Inhibition of AKT, ERK1/2 or Nrf2 blocked the protective effects of 4-OI in vitro, suggesting its antioxidant activity is mediated by activating the Nrf2/Sirt3 pathway via AKT and ERK1/2 phosphorylation. In summary, 4-OI exerted antioxidant and hepatoprotective effects by activating the Nrf2/Sirt3 signaling pathway through AKT and ERK1/2 phosphorylation, which were elucidated using in vitro and in vivo oxidative stress models. This provides novel insights into the mechanisms of 4-OI against oxidative stress-related liver diseases.
研究领域:
药理学
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毒理学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
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2023
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IF 4.8
Huan Xue,Hao-Jie Xing,Bin Wang,Chao Fu,Yu-Shan Zhang,Xi Qiao,Chao Guo,Xiao-Li Zhang,Bin Hu,Xin Zhao,Li-Jiao Deng,Xiao-Chan Zhu,Yi Zhang,Yun-Feng Liu
Purpose The glucagon-like peptide-1 receptor (GLP-1R) is an effective therapeutic target for type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH). Research has focused on small-molecule GLP-1R agonists because of their ease of use in oral formulations and improved patient compliance. However, no small-molecule GLP-1R agonists are currently available in the market. We aimed to screen for a potential oral small-molecule GLP-1R agonist and evaluated its effect on blood glucose and NASH.Methods The Connectivity map database was used to screen for candidate small-molecule compounds. Molecular docking was performed using SYBYL software. Rat pancreatic islets were incubated in different concentrations glucose solutions, with cinchonine or Exendin (9–39) added to determine insulin secretion levels. C57BL/6 mice, GLP-1R−/− mice and hGLP-1R mice were used to conduct oral glucose tolerance test. In addition, we fed ob/ob mice with the GAN diet to induce the NASH model. Cinchonine (50 mg/kg or 100 mg/kg) was administered orally twice daily to the mice. Serum liver enzymes were measured using biochemical analysis. Liver tissues were examined using Hematoxylin-eosin staining, Oil Red O staining and Sirius Red staining.Results Based on the small intestinal transcriptome of geniposide, a recognized small-molecule GLP-1R agonist, we identified that cinchonine exerted GLP-1R agonist-like effects. Cinchonine had a good binding affinity for GLP-1R. Cinchonine promoted glucose-dependent insulin secretion, which could be attenuated significantly by Exendin (9–39), a specific GLP-1R antagonist. Moreover, cinchonine could reduce blood glucose in C57BL/6 and hGLP-1R mice, an effect that could be inhibited with GLP-1R knockout. In addition, cinchonine reduced body weight gain and food intake in ob/ob-GAN NASH mice dose-dependently. 100 mg/kg cinchonine significantly improved liver function by reducing the ALT, ALP and LDH levels. Importantly, 100 mg/kg cinchonine ameliorated hepatic steatosis and fibrosis in NASH mice.Conclusion Cinchonine, a potential oral small-molecule GLP-1R agonist, could reduce blood glucose and ameliorate NASH, providing a strategy for developing small-molecule GLP-1R agonists.
研究领域:
药理学
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内分泌学
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肝病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Scientific Reports
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2020
·Vol. 10
·期 1
·14092-14092
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IF 3.998
Yang Chen,Juan Ni,Yun Gao,Jinghui Zhang,Xuesong Liu,Yong Chen,Zhongjian Chen,Yongjiang Wu
Colorectal cancer (CRC) is a common malignancy occurring in the digestive system. Despite progress in surgery and therapy options, CRC is still a considerable cause of cancer mortality worldwide. In this study, a colon cancer patient-derived xenograft model was established to evaluate the antitumor activity of Shikonin. The protective effect underlying Shikonin was determined through assessing serum levels of liver enzymes (ALT, AST) and kidney functions (BuN, Scr) in PDX mice. Proteomics and metabolomics profiles were integrated to provide a systematic perspective in dynamic changes of proteins and global endogenous metabolites as well as their perturbed pathways. A total of 456 differently expressed proteins (DEPs), 32 differently expressed metabolites (DEMs) in tumor tissue, and 20 DEMs in mice serum were identified. The perturbation of arginine biosynthesis, purine metabolism, and biosynthesis of amino acids may mainly account for therapeutic mechanism of Shikonin. Furthermore, the expression of mRNAs participating in arginine biosynthesis (CPS1, OTC, Arg1) and do novo purine synthesis (GART, PAICS, ATIC) were validated through RT-qPCR. Our study provides new insights into the drug therapeutic strategies and a better understanding of antitumor mechanisms that might be valuable for further studies on Shikonin in the clinical treatment of colorectal cancer.
研究领域:
肿瘤学
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药理学
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蛋白质组学
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代谢组学
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分子生物学
✓ 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）