5 results on '"Yue, Bo"'
Search Results
2. A novel small molecule Hsp90 inhibitor, C-316-1, attenuates acute kidney injury by suppressing RIPK1-mediated inflammation and necroptosis
- Author
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Xue-qi Liu, Ming-ming Liu, Ling Jiang, Li Gao, Yao Zhang, Yue-bo Huang, Xian Wang, Wei Zhu, Han-xu Zeng, Xiao-ming Meng, and Yong-gui Wu
- Subjects
Pharmacology ,Inflammation ,Molecular Docking Simulation ,Receptor-Interacting Protein Serine-Threonine Kinases ,Immunology ,Necroptosis ,Immunology and Allergy ,Humans ,Apoptosis ,HSP90 Heat-Shock Proteins ,Acute Kidney Injury - Abstract
Acute kidney injury (AKI) is marked by a fast deterioration of the kidney function that may be caused by a variety of factors. Recently, although our group found that PPBICA alleviated programmed cell death in AKI, poor water solubility limited its bioavailability. In this research, we screened a series of derivatives and found that C-316-1 had the best suppressive effect on preventing necroptosis and inflammation in cisplatin- and ischemia/reperfusion-induced AKI in vitro and in vivo with lower toxicity and better water solubility. Mass spectrometry results showed that C-316-1 bound to heat shock protein 90 (Hsp90), which was further confirmed by molecular docking and surface plasmon resonance. Additionally, the Hsp90 expression was upregulated in the blood and tissues of AKI patients. We discovered that C-316-1 decreased the RIPK1 protein level without affecting its mRNA expression. The proteasome inhibitor, MG132 restored the level of RIPK1 reduced by C-316-1, suggesting that C-316-1 limits necroptosis by promoting the degradation of RIPK1 rather than by reducing its production. Immunoprecipitation further showed that pretreatment with C-316-1 disrupted the Hsp90-Cdc37 protein-protein Interactions (PPIs). Thereby, C-316-1 inhibited the Hsp90-Cdc37 complex formation and led to a significant decrease in RIPK1, which in turn reduced necroptosis. Moreover, C-316-1 treatment did not protect against kidney injury in vivo and in vitro when Hsp90 was knocked down and R46, E47, and S50 in Cdc37 binding site of Hsp90 might form an important active pocket with C-316-1. These findings suggest that C-316-1 is a potential therapeutic agent against RIPK1-Mediated Necroptosis in AKI.
- Published
- 2022
3. Paeoniflorin binds to VEGFR2 to restore autophagy and inhibit apoptosis for podocyte protection in diabetic kidney disease through PI3K-AKT signaling pathway
- Author
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Xian, Wang, Ling, Jiang, Xue-Qi, Liu, Yue-Bo, Huang, An-Li, Wang, Han-Xu, Zeng, Li, Gao, Qi-Jin, Zhu, Ling-Ling, Xia, and Yong-Gui, Wu
- Subjects
Vascular Endothelial Growth Factor A ,Pharmacology ,Caspase 3 ,Class I Phosphatidylinositol 3-Kinases ,Podocytes ,Pharmaceutical Science ,Apoptosis ,Vascular Endothelial Growth Factor Receptor-2 ,Molecular Docking Simulation ,Mice ,Phosphatidylinositol 3-Kinases ,Glucosides ,Complementary and alternative medicine ,Drug Discovery ,Autophagy ,Diabetes Mellitus ,Monoterpenes ,Animals ,Molecular Medicine ,Diabetic Nephropathies ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Paeoniflorin (PF) was found to exhibit renal protection from diabetic kidney disease (DKD) in previous trials, but its specific mechanism remains to be elucidated.This study furtherly explored the specific mechanism of PF in protect podocyte injury in DKD.We observed the effects of PF on renal tissue and podocytes in DKD by constructing the vitro and vivo models after measuring the pharmacokinetic characteristics of PF. Target proteins of PF were found through target prediction, and verified by molecular docking, CESTA, and SPR, and then furtherly explored the downstream regulation mechanism related to podocyte autophagy and apoptosis by network prediction and co-immunoprecipitation. Finally, by using the target protein inhibitor in vivo and knocking down the target protein gene in vitro, it was verified that PF played a role in regulating autophagy and apoptosis through the target protein in diabetic nephropathy.This study found that in STZ-induced mice model, PF could improve the renal biochemical and pathological damage and podocyte injure (p0.05), upregulate autophagy activity (p0.05), but inhibit apoptosis (p0.01). Vascular endothelial growth factor receptor 2 (VEGFR2), predicted as the target of PF, directly bind with PF reflected by molecular docking and surface plasmon resonance detection. Animal studies demonstrated that VEGFR2 inhibitors have a protective effect similar to that of PF on DKD. Network prediction and co-immunoprecipitation further confirmed that VEGFR2 was able to bind PIK3CA to regulate PI3K-AKT signaling pathway. Furthermore, PF downregulated the phosphorylation of PI3K and AKT (p0.05). In vitro, similarly to autophagy inhibitors, PF was also found to improve podocyte markers (p0.05) and autophagy activity (p0.05), decrease caspase 3 protein (p0.05) and further inhibited VEGFR2-PI3K-AKT activity (p0.05). Finally, the results of VEGFR2 knockdown were similar to the effect of PF in HG-stimulated podocytes.In conclusion, PF restores autophagy and inhibits apoptosis by targeting the VEGFR2-mediated PI3K-AKT pathway to improve renal injury in DKD, that provided a theoretical basis for PF treatment in DKD.
- Published
- 2022
4. Paeoniflorin protects against cisplatin-induced acute kidney injury through targeting Hsp90AA1-Akt protein-protein interaction.
- Author
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Zhang, Meng-ya, Ma, Li-juan, Jiang, Ling, Gao, Li, Wang, Xian, Huang, Yue-bo, Qi, Xiang-ming, Wu, Yong-gui, and Liu, Xue-qi
- Subjects
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PROTEINS , *HERBAL medicine , *POLYPHENOLS , *SEQUENCE analysis , *AUTOIMMUNE diseases , *APOPTOSIS , *PRECIPITIN tests , *CISPLATIN , *COMPUTER-assisted molecular modeling , *PHARMACEUTICAL chemistry , *CHINESE medicine , *ACUTE kidney failure - Abstract
Paeonia lactiflora Pall has been used in Chinese Medicine for thousands of years, especially having anti-inflammatory, sedative, analgesic and other ethnic pharmacological effects. Moreover, Paeoniflorin is the main active ingredient of the Paeonia lactiflora Pall , and most are used in the treatment of inflammation-related autoimmune diseases. In recent years, studies have found that Paeoniflorin has a therapeutic effect on a variety of kidney diseases. Cisplatin (CIS) is limited in clinical use due to its serious side effects, such as renal toxicity, and there is no effective method for prevention. Paeoniflorin (Pae) is a natural polyphenol which has a protective effect against many kidney diseases. Therefore, our study is to explore the effect of Pae on CIS-induced AKI and the specific mechanism. Firstly, CIS induced acute renal injury model was constructed in vivo and in vitro , and Pae was continuously injected intraperitoneally three days in advance, and then Cr, BUN and renal tissue PAS staining were detected to comprehensively evaluate the protective effect of Pae on CIS-induced AKI. We then combined Network Pharmacology with RNA-seq to investigate potential targets and signaling pathways. Finally, affinity between Pae and core targets was detected by molecular docking, CESTA and SPR, and related indicators were detected in vitro and in vivo. In this study, we first found that Pae significantly alleviated CIS-AKI in vivo and in vitro. Through network pharmacological analysis, molecular docking, CESTA and SPR experiments, we found that the target of Pae was Heat Shock Protein 90 Alpha Family Class A Member 1 (Hsp90AA1) which performs a crucial function in the stability of many client proteins including Akt. RNA-seq found that the KEGG enriched pathway was PI3K-Akt pathway with the most associated with the protective effect of Pae which is consistent with Network Pharmacology. GO analysis showed that the main biological processes of Pae against CIS-AKI include cellular regulation of inflammation and apoptosis. Immunoprecipitation further showed that pretreatment with Pae promoted the Hsp90AA1-Akt protein-protein Interactions (PPIs). Thereby, Pae accelerates the Hsp90AA1-Akt complex formation and leads to a significant activate in Akt, which in turn reduces apoptosis and inflammation. In addition, when Hsp90AA1 was knocked down, the protective effect of Pae did not continue. In summary, our study suggests that Pae attenuates cell apoptosis and inflammation in CIS-AKI by promoting Hsp90AA1-Akt PPIs. These data provide a scientific basis for the clinical search for drugs to prevent CIS–AKI. [Display omitted] • There is no effective clinical treatment for cisplatin nephrotoxicity. • Pae has a protective effect on cisplatin-induced AKI. • Pae promotes HSP90AA1-Akt Protein-Protein Interaction, reducing Cis-AKI. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
5. A novel small molecule Hsp90 inhibitor, C-316-1, attenuates acute kidney injury by suppressing RIPK1-mediated inflammation and necroptosis.
- Author
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Liu, Xue-qi, Liu, Ming-ming, Jiang, Ling, Gao, Li, Zhang, Yao, Huang, Yue-bo, Wang, Xian, Zhu, Wei, Zeng, Han-xu, Meng, Xiao-ming, and Wu, Yong-gui
- Subjects
- *
ACUTE kidney failure , *SMALL molecules , *SURFACE plasmon resonance , *APOPTOSIS , *HEAT shock proteins , *PROTEIN-protein interactions - Abstract
• Acute kidney injury (AKI) is marked by a fast deterioration of the kidney function that may be caused by a variety of factors and there is still no effective treatment for AKI. • A novel small molecule Hsp90 inhibitor, C-316-1, prevented necroptosis and inflammation in cisplatin- and ischemia/reperfusion-induced in vitro and in vivo via binding with R46, E47 and S50 in Cdc37 binding site of Hsp90. • C-316-1 is a novel Hsp90 inhibitor with high efficiency in treatment of AKI and Hsp90 may serve as a potential therapeutic target for AKI. Acute kidney injury (AKI) is marked by a fast deterioration of the kidney function that may be caused by a variety of factors. Recently, although our group found that PPBICA alleviated programmed cell death in AKI, poor water solubility limited its bioavailability. In this research, we screened a series of derivatives and found that C-316-1 had the best suppressive effect on preventing necroptosis and inflammation in cisplatin- and ischemia/reperfusion-induced AKI in vitro and in vivo with lower toxicity and better water solubility. Mass spectrometry results showed that C-316-1 bound to heat shock protein 90 (Hsp90), which was further confirmed by molecular docking and surface plasmon resonance. Additionally, the Hsp90 expression was upregulated in the blood and tissues of AKI patients. We discovered that C-316-1 decreased the RIPK1 protein level without affecting its mRNA expression. The proteasome inhibitor, MG132 restored the level of RIPK1 reduced by C-316-1, suggesting that C-316-1 limits necroptosis by promoting the degradation of RIPK1 rather than by reducing its production. Immunoprecipitation further showed that pretreatment with C-316-1 disrupted the Hsp90-Cdc37 protein–protein Interactions (PPIs). Thereby, C-316-1 inhibited the Hsp90-Cdc37 complex formation and led to a significant decrease in RIPK1, which in turn reduced necroptosis. Moreover, C-316-1 treatment did not protect against kidney injury in vivo and in vitro when Hsp90 was knocked down and R46, E47, and S50 in Cdc37 binding site of Hsp90 might form an important active pocket with C-316-1. These findings suggest that C-316-1 is a potential therapeutic agent against RIPK1-Mediated Necroptosis in AKI. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
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