Frontiers in Pharmacology
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2022
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IF 5.988
Xue Tian,Xu Chen,Qianqian Jiang,Qianbin Sun,Tiantian Liu,Yiqin Hong,Yawen Zhang,Yanyan Jiang,Mingyan Shao,Ran Yang,Chun Li,Qiyan Wang,Yong Wang
Aims: Cardiac lipotoxicity is the common consequence of lipid metabolism disorders in cardiomyocytes during development of heart failure (HF). Adenosine 5′monophosphate-activated protein kinase (AMPK) acts as an energy sensor and has a beneficial effect in reducing lipotoxicity. Notoginsenoside R1 (NGR1) is extracted from the traditional Chinese medicine Panax notoginseng (Burkill) F.H.Chen (P. notoginseng) and has definite cardioprotective effects. However, whether NGR1 can attenuate HF by mitigating lipotoxicity has not been elucidated yet. This study aimed to explore whether NGR1 plays a protective role against HF by ameliorating cardiac lipotoxicity via the AMPK pathway.
Methods: In this study, HF mice model was established by left anterior descending (LAD) ligation. palmitic acid (PA) stimulated H9C2 cell model was applied to clarify the effects and potential mechanism of NGR1 on lipotoxicity. In vivo, NGR1 (7.14 mg/kg/days) and positive drug (simvastatin: 2.9 mg/kg/days) were orally administered for 14 days. Echocardiography was applied to assess heart functions. Lipid levels were measured by Enzyme-linked immunosorbent assay (ELISA) and key proteins in the AMPK pathway were detected by western blots. In vitro, NGR1 (40 μmol/L) or Compound C (an inhibitor of AMPK, 10 μmol/L) was co-cultured with PA stimulation for 24 h in H9C2 cells. CCK-8 assay was used to detect cell viability. Key lipotoxicity-related proteins were detected by western blots and the LipidTOX™ neutral lipid stains were used to assess lipid accumulation. In addition, Apoptosis was assessed by Hoechst/PI staining.
Results: NGR1 could significantly improve the cardiac function and myocardial injury in mice with HF and up-regulate the expression of p-AMPK. Impressively, NGR1 inhibited the synthesis of diacylglycerol (DAG) and ceramide and promoted fatty acid oxidation (FAO) in vivo. Moreover, NGR1 significantly promoted expression of CPT-1A, the key enzyme in FAO pathway, and down-regulated the expression of GPAT and SPT, which were the key enzymes catalyzing production of DAG and ceramide. In vitro experiments showed that NGR1 could significantly attenuate lipid accumulation in PA-induced H9C2 cells and the Hoechst/PI staining results showed that NGR1 ameliorated lipotoxicity-induced apoptosis in PA-stimulated H9C2 cell model. Furthermore, co-treatment with inhibitor of AMPK abrogated the protective effects of NGR1. The regulative effects of NGR1 on lipid metabolism were also reversed by AMPK inhibitor.
Conclusion: NGR1 could significantly improve the heart function of mice with HF and reduce cardiac lipotoxicity. The cardio-protective effects of NGR1 are mediated by the activation of AMPK pathway.Keywords: heart failure, cardiac lipotoxicity, NGR1, AMPK, apoptosis
研究领域:
心脏病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Xiaoning Zhang,Jingxian Zhu,Xiaoya Kang,Xiaoqing Hu,Qiang Gao,Ming Li,Jingyao Sun,Jian Zhuang
The healing of linear skin wounds is a complex biological process, and traditional treatment methods have certain limitations. This study proposes a wireless power supply near-infrared light drug-loaded microneedle system (NIR-LED-NG-R1-MN), which utilizes microneedles (MNs) to achieve targeted delivery of the active component of traditional Chinese medicine, Notoginsenoside R1 (NG-R1), and combines the biological regulatory effect of near-infrared light (NIR) to achieve efficient synergistic treatment for linear skin wounds. Experimental results show that the device can significantly promote the wound closure rate and reduce the levels of inflammatory factors and the risk of scar formation. By comparing the wound repair conditions of different treatment groups, it was found that the group treated with the NIR-LED-NG-R1-MN patch for NG-R1 and NIR synergistic treatment (MN@NG-R1@LED group) showed superior wound repair effects compared to other groups, thus confirming the synergistic therapeutic advantages of NG-R1 and NIR in skin wound healing. In addition, the application of wireless power supply technology used in this system eliminates the dependence on external power sources, enhancing the convenience of treatment. This study clearly demonstrates that the NIR-LED-NG-R1-MN has the potential to become a new clinical method for the treatment of linear skin wound healing.
研究领域:
生物医学工程
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药学
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伤口愈合
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产品关联
DOI
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2024
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IF 6.9
Qi Chen,Ziwei Huang,Jing Chen,Xiaoyu Tian,Rong Zhang,Qi Liang,Zhongqiu Liu,Yuanyuan Cheng
β2 adrenergic receptor (β2AR) is a G-protein-coupled receptor involved in cardiac protection. In chronic heart failure (CHF), persistent sympathetic nervous system activation occurs, resulting in prolonged β2AR activation and subsequent receptor desensitization and downregulation. Notoginsenoside R1 (NGR1) has the functions of enhancing myocardial energy metabolism and mitigating myocardial fibrosis. The mechanisms of NGR1 against ischemic heart failure are unclear. A left anterior descending (LAD) artery ligation procedure was performed on C57BL/6 J mice for four weeks. From the 4th week onwards, they were treated with various doses (3, 10, 30 mg/kg/day) of NGR1. Subsequently, the impacts of NGR1 on ischemic heart failure were evaluated by assessing cardiac function, morphological changes in cardiac tissue, and the expression of atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). H9c2 cells were protected by NGR1 when exposed to OGD/R conditions. H9c2 cells were likewise protected from OGD/R damage by NGR1. Furthermore, NGR1 increased β2AR levels and decreased β2AR ubiquitination. Mechanistic studies revealed that NGR1 enhanced MDM2 protein stability and increased the expression of MDM2 and β-arrestin2 while inhibiting their interaction. Additionally, under conditions produced by OGD/R, the protective benefits of NGR1 on H9c2 cells were attenuated upon administration of the MDM2 inhibitor SP141. According to these findings, NGR1 impedes the interplay between β-arrestin2 and MDM2, thereby preventing the ubiquitination and degradation of β2AR to improve CHF.
研究领域:
心脏病学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Pharmaceutical Investigation
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2024
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IF 5.3
Zhou Limei,Shang Yunxia,Wang Yaru,Wei Xiaohui
Purpose Ulcerative colitis (UC) is a chronic and non-specific inflammatory bowel disease that poses a serious threat to individuals' health and lives. Notoginsenoside R1 (R1) alleviates various symptoms caused by UC effectively. However, the application of R1 is somewhat restricted due to its low bioavailability and nontargeted delivery in vivo. Consequently, it is imperative to develop novel strategies to overcome the aforementioned limitations and enhance the efficacy of this drug. To enhance R1's efficacy and targeting ability, polyethylene glycol poly (lactic-co-glycolic acid) nanoparticles loaded with R1 (R1@PEG–PLGA NPs) modified by transferrin (Tf) were prepared in this study and named R1@Tf–PEG–PLGA NPs. Methods R1@PEG–PLGA NPs and R1@Tf–PEG–PLGA NPs were prepared through nanoprecipitation, and the characterization methods were as follows: First, the surface morphology of the NPs was studied through transmission electron microscopy. Second, particle size, polydispersity index (PDI), and zeta potential were measured with a Malvern particle size analyzer, and the Tf grafting rate on the surface of the NPs was determined by using a bicinchoninic acid protein quantification kit. Third, high-performance liquid chromatography was used in determining the drug load (DL), entrapment efficiency (EE), and in vitro release of the prepared preparation. In addition, the fluorescence intensities of fluorescent-labeled NPs absorbed and ingested in Caco-2 cells were observed through in vitro experiments using fluorescence microscopy; the effects of incubation time, incubation temperature, and endocytosis inhibitors on the uptake of nanoparticles were compared; and the uptake-transport mechanism was explored. Finally, in vivo experiments were performed using the oxazolone (OXZ)-induced UC model in Sprague–Dawley (SD) rats to assess the pharmacodynamic effects and tissue distribution of the prepared NPs. Results The experimentally prepared R1@Tf–PEG–PLGA NPs were round particles with particle size and PDI of 153.50 ± 2.01 and 0.11 ± 0.01, respectively. In addition, the DL of R1@Tf-PEG-PLGA NPs was 24.26% ± 0.18%, and the EE was 50.32% ± 0.86%. Furthermore, R1@Tf–PEG–PLGA NPs had a slower cumulative release rate in vitro than R1 and R1@PEG–PLGA NPs. Fluorescence results showed that under the same conditions, Caco-2 cells took up more Tf-PEG–PLGA NPs than they took up PEG–PLGA NPs. Studies on the cellular uptake mechanism of absorption and uptake determined that the PEG–PLGA NPs entered the cells mainly through fovea-mediated endocytosis, whereas the Tf–PEG–PLGA NPs entered the cells mainly through fovea-mediated and lattice protein-mediated endocytosis. In vivo intestinal tissue distribution results in OXZ-induced SD rats showed that R1@Tf–PEG–PLGA NPs were more enriched in the colon than R1 and R1@PEG–PLGA NPs, and pharmacodynamic evaluation showed that R1@Tf–PEG–PLGA NPs exhibited more pronounced effects in ameliorating colonic injury. Conclusion R1@Tf–PEG–PLGA NPs showed significant colonic targeting and anti-UC effect, showing promising applications.
研究领域:
药学
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纳米技术
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炎症性肠病
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药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）