Pharmaceutics
·
2022
·Vol. 14
·期 11
·2534
·
IF 6.525
Bo Wei,Yuanfang Li,Meiying Ao,Wenxiang Shao,Kun Wang,Tong Rong,Yun Zhou,Yong Chen
Previously, we found that exogenous ganglioside GM3 had an antiatherosclerotic efficacy and that its antiatherosclerotic efficacy could be enhanced by reconstituted high-density lipoprotein (rHDL). In this study, we hypothesized that GM3-functionalized rHDL (i.e., GM3-rHDL) as a nanocarrier can promote the efficacy of traditional antiatherosclerotic drugs (e.g., statins). To test this hypothesis, lovastatin (LT) was used as a representative of statins, and LT-loaded GM3-rHDL nanoparticle (LT-GM3-rHDL or[email protected]; a mean size of ~142 nm) and multiple controls (e.g., GM3-rHDL without LT, LT-loaded rHDL or LT-rHDL, and other nanoparticles) were prepared. By using two different microsphere-based methods, the presences of apolipoprotein A-I (apoA-I) and/or GM3 in nanoparticles and the apoA-I-mediated macrophage-targeting ability of apoA-I/rHDL-containing nanoparticles were verified in vitro. Moreover, LT-GM3-rHDL nanoparticle had a slowly sustained LT release in vitro and the strongest inhibitory effect on the foam cell formation of macrophages (a key event of atherogenesis). After single administration of rHDL-based nanoparticles, a higher LT concentration was detected shortly in the atherosclerotic plaques of apoE−/−mice than non-rHDL-based nanoparticles, suggesting the in vivo plaque-targeting ability of apoA-I/rHDL-containing nanoparticles. Finally, among all nanoparticles LT-GM3-rHDL induced the largest decreases in the contents of blood lipids and in the areas of atherosclerotic plaques at various aortic locations in apoE−/−mice fed a high-fat diet for 12 weeks, supporting that LT-GM3-rHDL has the best in vivo antiatherosclerotic efficacy among the tested nanoparticles. Our data imply that GM3-functionalized rHDL (i.e., GM3-rHDL) can be utilized as a novel nanocarrier to enhance the efficacy of traditional antiatherosclerotic drugs (e.g., statins).Keywords:ganglioside GM3;atherosclerosis;reconstituted high-density lipoprotein (rHDL);lovastatin (LT);drug delivery system;statins;ApoA-I
研究领域:
药理学
·
心血管疾病
·
纳米技术
·
药物递送
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产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2023
·
IF 11.2
Zhenhua Li,Xiaoqin Wang,Xiaoli Deng,Jiansen Song,Tong Yang,Yujie Liao,Guiping Gong,Linjuan Huang,Yu Lu,Zhongfu Wang
Glycosphingolipids (GSLs) in human milk regulate the immune system, support intestinal maturation, and prevent gut pathogens. The structural complexity and low abundance of GSLs limits their systematic analysis. Here, we coupled the use of monosialoganglioside 1–2-amino-N-(2-aminoethyl) benzamide (GM1-AEAB) derivatives as internal standards with HILIC-MS/MS to qualitatively and quantitatively compare GSLs in human, bovine, and goat milk. One neutral glycosphingolipid (GB) and 33 gangliosides were found in human milk, of which 22 were newly detected and three were fucosylated. Five GB and 26 gangliosides were identified in bovine milk , of which 21 were newly discovered. Four GB and 33 gangliosides were detected in goat milk, 23 of them newly reported. GM1 was the main GSL in human milk; whereas disialoganglioside 3 (GD3) and monosialogangloside 3 (GM3) were dominant in bovine and goat milk, respectively; N -acetylneuraminic acid (Neu5Ac) was detected in >88 % of GSLs in bovine and goat milk. N -hydroxyacetylneuraminic acid (Neu5Gc)-modified GSLs were 3.5 times more abundant in goat than in bovine milk; whereas GSLs modified with both Neu5Ac and Neu5Gc were 3 times more abundant in bovine than in goat milk. Given the health benefits of different GSLs, these results will facilitate the development of custom-designed human milk-based infant formula.
研究领域:
营养学
·
生物化学
·
代谢组学
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DOI
PubMed
高影响因子
Food & Function
·
2020
·Vol. 12
·期 1
·291-301
·
IF 4.171
Xiaoli Zhang,Shuhua Shan,Jiangying Shi,Hanqing Li,Zhuoyu Li
Colorectal cancer (CRC) is an aggressive malignancy with very limited therapeutic approaches. Drug resistance develops as a frequent characteristic in many patients with CRC, which leads to a decrease in the therapeutic efficacy of anticancer agents. Our previous evidences showed that bound polyphenol from millet bran (BPIS) possesses the potential of inhibiting cancer cell proliferation, and its main anticancer components are ferulic acid (FA) and p-coumaric acid (p-CA). In the present study, we found that BPIS significantly increases the sensitivity of human drug-resistant CRC cell line to oxaliplatin (OXA), a commonly used chemotherapy drug against CRC. Mechanistically, we indicated that BPIS significantly impairs the expression of a gene encoding multidrug resistance protein 1 (MDR1), a well-known permeability glycoprotein (P-gp), by preventing ganglioside GM3 catabolism. Neuraminidase 3 (NEU3) is a key enzyme catalyzing the conversion of ganglioside GM3 to ceramide trihexosides (Gb3), whose expression is increased in drug-resistant HCT-116/L cells. BPIS treatment increased GM3 level, but reduced Gb3 and P-gp levels by inhibiting NEU3 expression, which subsequently boosted the chemotherapy sensitivity of drug-resistant HCT-116/L cells to OXA. These findings reveal that BPIS increases the chemo-sensitivity by remodeling NEU3-mediated ganglioside GM3 catabolism, and it may be applied as a novel drug for facilitating the effectiveness of chemotherapeutic agents in CRC.
研究领域:
癌症生物学
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药理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2017
·Vol. 292
·期 12
·4789-4800
·
IF 4.125
Yun-Bin Han,Liu-Qing Chen,Zhuo Li,Yu-Meng Tan,Yan Feng,Guang-Yu Yang
Endoglycoceramidases (EGCases) specifically hydrolyze the glycosidic linkage between the oligosaccharide and the ceramide moieties of various glycosphingolipids, and they have received substantial attention in the emerging field of glycosphingolipidology. However, the mechanism regulating the strict substrate specificity of these GH5 glycosidases has not been identified. In this study, we report a novel EGCase I from Rhodococcus equi 103S (103S_EGCase I) with remarkably broad substrate specificity. Based on phylogenetic analyses, the enzyme may represent a new subfamily of GH5 glycosidases. The X-ray crystal structures of 103S_EGCase I alone and in complex with its substrates monosialodihexosylganglioside (GM3) and monosialotetrahexosylganglioside (GM1) enabled us to identify several structural features that may account for its broad specificity. Compared with EGCase II from Rhodococcus sp. M-777 (M777_EGCase II), which possesses strict substrate specificity, 103S_EGCase I possesses a longer α7-helix and a shorter loop 4, which forms a larger substrate-binding pocket that could accommodate more extended oligosaccharides. In addition, loop 2 and loop 8 of the enzyme adopt a more open conformation, which also enlarges the oligosaccharide-binding cavity. Based on this knowledge, a rationally designed experiment was performed to examine the substrate specificity of EGCase II. The truncation of loop 4 in M777_EGCase II increased its activity toward GM1 (163%). Remarkably, the S63G mutant of M777_EGCase II showed a broader substrate spectra and significantly increased activity toward bulky substrates (up to >1370-fold for fucosyl-GM1). Collectively, the results presented here reveal the exquisite substrate recognition mechanism of EGCases and provide an opportunity for further engineering of these enzymes.
研究领域:
生物化学
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结构生物学
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酶学
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糖鞘脂学
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产品关联
DOI
PubMed
高影响因子
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