70 results on '"Gaoyun Hu"'
Search Results
2. Corrigendum: Protective effects of Mefunidone on ischemia-reperfusion injury/folic acid-induced acute kidney injury
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Jiajia Li, Yupeng Jiang, Qin Dai, Yue Yu, Xin Lv, Yan Zhang, Xiaohua Liao, Liyun Ao, Gaoyun Hu, Jie Meng, Zhangzhe Peng, Lijian Tao, and Yanyun Xie
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Pharmacology ,Pharmacology (medical) - Published
- 2023
3. Imidazo[1,2‐ a ]pyridine Derivatives as AMPK Activators: Synthesis, Structure–Activity Relationships, and Regulation of Reactive Oxygen Species in Renal Fibroblasts
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Siming Wu, Zhihong Xiao, Junling Wei, Lei Zhang, Yuanyuan Cao, Zhuo Chen., Qianbin Li, and Gaoyun Hu
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Pharmacology ,Organic Chemistry ,Drug Discovery ,Molecular Medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Biochemistry - Published
- 2023
4. Design, synthesis, and biological evaluation of quinoline (quinolinone) derivatives as NADPH oxidase (NOX) inhibitors
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Lei Zhang, Siming Wu, Xinliang Yang, Rui Yi, gaoyun Hu, Qianbin Li, and Zhuo Chen
- Abstract
NADPH oxidase (NOX) is the only enzyme in the human body that can directly produce reactive oxygen species. Recent studies have shown that NADPH oxidase is a very potential target for the treatment of Diabetic Nephropathy (DN). Here, a series of quinoline (quinolinone) derivatives were designed and synthesized based on pharmacophore modelling. And the antiproliferative effect against NRK-49F cell-line was evaluated as their potential anti-DN activity. 19d, the most potent compounds with an effective cell proliferation inhibitory activity (IC50 = 5.25 uM), showed a promising inhibitory activity on NOXs (IC50 = 1.12 µM). The 3D-QSAR model based on the anti-proliferation activity of NRK-49F exhibited the good predictive ability. In conclusion, 19d may have therapeutic effects on diabetic nephropathy like other NOX inhibitors in clinical trials.
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- 2023
5. Fluorofenidone protects against acute liver failure in mice by regulating MKK4/JNK pathway
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Lei Gu, Xin He, Yanqiu Zhang, Shenglan Li, Jie Tang, Ruixue Ma, Xinyi Yang, Hao Huang, Yu Peng, Yanyun Xie, Zhangzhe Peng, Jie Meng, Gaoyun Hu, Lijian Tao, Xiaowei Liu, and Huixiang Yang
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Pharmacology ,General Medicine - Published
- 2023
6. Dual inhibitors of ASK1 and PDK1 kinases: Design, synthesis, molecular docking and mechanism studies of N-benzyl pyridine-2-one containing derivatives as anti-fibrotic agents
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Jia Qin, Meng Cao, Xinlan Hu, Wenhua Tan, Binghao Ma, Yuanyuan Cao, Zhuo Chen, Qianbin Li, and Gaoyun Hu
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Pharmacology ,Organic Chemistry ,Drug Discovery ,General Medicine - Abstract
Utilizing fragment-based hybrid designing strategies, 24 N-benzyl pyridine-2-one containing derivatives were synthesized by successfully incorporating 6-(4H-1,2,4-triazol-3-yl) pyridin-2-amine of scaffold of ASK1 inhibitor (GS-444217). These newly synthesized compounds were screened in cell-free ASK1 and PDK1 kinase and cellular vitality assays. Among all compounds tested, both 21c and 21d displayed single digit potency of 9.13, 1.73 nM in inhibiting ASK1, and exhibited excellent enzyme inhibitory activity against PDK1 (the inhibition rates at 10 μM were 13.63% and 23.80%, respectively). Specifically, both compounds inhibited the TGF-β1 induced fibrotic response and blocked the up-regulated protein expression levels of ASK1-p38/JNK signaling pathways and possessed the potency in reducing PDK1/Akt phosphorylation. The results herein showed the potential lead characteristics of 21c or 21d as dual inhibitors ASK1/PDK1 kinases.
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- 2022
7. Protective effects of mefunidone on ischemia-reperfusion injury/Folic acid-induced acute kidney injury
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Jiajia Li, Yupeng Jiang, Qin Dai, Yue Yu, Xin Lv, Yan Zhang, Xiaohua Liao, Liyun Ao, Gaoyun Hu, Jie Meng, Zhangzhe Peng, Lijian Tao, and Yanyun Xie
- Subjects
Pharmacology ,Pharmacology (medical) - Abstract
Renal ischemia-reperfusion injury (IRI) is one of the most common causes of acute kidney injury (AKI). It poses a significant threat to public health, and effective therapeutic drugs are lacking. Mefunidone (MFD) is a new pyridinone drug that exerts a significant protective effect on diabetic nephropathy and the unilateral ureteral obstruction (UUO) model in our previous study. However, the effects of mefunidone on ischemia-reperfusion injury-induced acute kidney injury remain unknown. In this study, we investigated the protective effect of mefunidone against ischemia-reperfusion injury-induced acute kidney injury and explored the underlying mechanism. These results revealed that mefunidone exerted a protective effect against ischemia-reperfusion injury-induced acute kidney injury. In an ischemia-reperfusion injury-induced acute kidney injury model, treatment with mefunidone significantly protected the kidney by relieving kidney tubular injury, suppressing oxidative stress, and inhibiting kidney tubular epithelial cell apoptosis. Furthermore, we found that mefunidone reduced mitochondrial damage, regulated mitochondrial-related Bax/bcl2/cleaved-caspase3 apoptotic protein expression, and protected mitochondrial electron transport chain complexes III and V levels both in vivo and in vitro, along with a protective effect on mitochondrial membrane potential in vitro. Given that folic acid (FA)-induced acute kidney injury is a classic model, we used this model to further validate the efficacy of mefunidone in acute kidney injury and obtained the same conclusion. Based on the above results, we conclude that mefunidone has potential protective and therapeutic effects in both ischemia-reperfusion injury- and folic acid-induced acute kidney injury.
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- 2022
8. Pulmonary artery smooth muscle cell phenotypic switching: A key event in the early stage of pulmonary artery hypertension
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Binghao Ma, Yuanyuan Cao, Jia Qin, Zhuo Chen, Gaoyun Hu, and Qianbin Li
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Pharmacology ,Drug Discovery - Published
- 2023
9. Discovery of Ureido-Based Apcin Analogues as Cdc20-specific Inhibitors against Cancer
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Yiqin He, Xiangyang Le, Gaoyun Hu, Qianbin Li, and Zhuo Chen
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docking ,Drug Discovery ,Cdc20-specific inhibitor ,Pharmaceutical Science ,Molecular Medicine ,ureido analogues ,anticancer ,Apcin analogues - Abstract
Cdc20 is a promising drug target that plays an important role in the mid-anaphase process of cellular mitosis, and Apcin is the only reported core structure of the Cdc20-specific inhibitor. Some potent Apcin derivatives were obtained in our previous research, and a structure–activity relationship was determined. In this study, we designed and synthesized a series of ureido-based Apcin derivatives. The proliferation-inhibition experiments on four cancer-cell lines showed that ureido skeleton could promote the anti-proliferation activity of purine-substituted compounds, whereas the ureido analogues with pyrimidine substitutes showed no significant improvement in the inhibitory effect compared with the original ones. Further tests confirmed that ureido-based compounds can enhance the binding affinity to Cdc20 by increasing the levels of Cdc20 downstream proteins. Compound 27 revealed a remarkably antitumor activity pattern against Hela (IC50 = 0.06 ± 0.02 μM) and potent binding affinity to Cdc20. Moreover, compound 20 induced caspase-dependent apoptosis and cell-cycle arrest at the G2/M phase, and compound 27 induced caspase-dependent apoptosis and promoted microtubule polymerization. Finally, a molecular-docking simulation was performed for compounds 20 and 27 to predict the potential ligand–protein interactions with the active sites of the Cdc20 proteins.
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- 2023
10. Fluorofenidone attenuates renal fibrosis by inhibiting the mtROS-NLRP3 pathway in a murine model of folic acid nephropathy
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Gaoyun Hu, Xiaohua Liao, Yan Zhang, Lijian Tao, Yue Yu, Zhangzhe Peng, Jie Meng, Yupeng Jiang, Qin Dai, and Yanyun Xie
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Male ,0301 basic medicine ,Inflammasomes ,Pyridones ,Biophysics ,Pharmacology ,Kidney ,Biochemistry ,Nephropathy ,Extracellular matrix ,03 medical and health sciences ,Folic Acid ,0302 clinical medicine ,Fibrosis ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Renal fibrosis ,Animals ,Molecular Biology ,NADPH oxidase ,biology ,Chemistry ,NOX4 ,Inflammasome ,Cell Biology ,medicine.disease ,Extracellular Matrix ,Mitochondria ,Mice, Inbred C57BL ,Fibronectin ,Disease Models, Animal ,030104 developmental biology ,030220 oncology & carcinogenesis ,Macrophages, Peritoneal ,biology.protein ,Kidney Diseases ,Reactive Oxygen Species ,medicine.drug - Abstract
Fluorofenidone (AKF-PD) is a novel pyridone agent that reduces the deposition of extracellular matrix (ECM) in various models of renal fibrosis. However, there are no reports on the effect of AKF-PD in preventing fibrosis in the folic acid nephropathy model. Besides, the mechanisms of action of AKF-PD in preventing renal fibrosis are not fully understood. In the study, we observed that AKF-PD reduced folate-induced kidney injury, ameliorated the deterioration of renal function, and suppressed the deposition of ECM by decreasing the expression of collagen I, collagen III, transforming growth factor-β (TGF-β), fibronectin (FN), and alpha smooth muscle actin (α-SMA) in the folic acid nephropathy model. Additionally, AKF-PD suppressed the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome to reduce the production of caspase-1 and IL-1β, and alleviated mitochondrial oxidative damage by promoting mitochondrial energy metabolism and reducing the expression of NADPH oxidase 4 (NOX4). The results of in vitro experiments demonstrated that AKF-PD suppressed NLRP3 inflammasome activation in activated peritoneal-derived macrophages (PDMs) and renal tubular epithelial cells (RTECs). AKF-PD increased the intracellular ATP content and decreased the expression of NOX4, while preventing the excessive production of mitochondrial reactive oxygen species (mtROS) in activated PDMs. In conclusion, this study demonstrated that AKF-PD inhibited renal fibrosis by suppressing the mtROS-NLRP3 pathway in the folic acid nephropathy model. These findings provide new evidence in support of the clinical use of AKF-PD in the treatment of diseases related to renal fibrosis.
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- 2021
11. Novel pyrazolo[3,4-b]pyridine derivatives: Synthesis, structure-activity relationship studies, and regulation of the AMPK/70S6K pathway
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Yating Guo, Xiaoding Jiang, Qi Chang, Zhihong Xiao, Zhuo Chen, Dejian Jiang, Gaoyun Hu, and Qianbin Li
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Structure-Activity Relationship ,Molecular Structure ,Pyridines ,Cell Line, Tumor ,Drug Discovery ,Pharmaceutical Science ,Humans ,Antineoplastic Agents ,AMP-Activated Protein Kinases ,Cell Proliferation - Abstract
A series of novel pyrazolo[3,4-b]pyridine derivatives were designed, synthesized, and biologically evaluated for anti-lung cancer activity. Structure-activity relationship and AutoGPA models were constructed based on the in vitro antiproliferative potency of the compounds against a human lung adenocarcinoma cell line (A549). Compound 9d exhibits improved potency for A549 cell growth inhibition (3.06 ± 0.05 μM) compared with A-769662 (45.29 ± 2.14 μM). Compound 9d can elevate the phosphorylation levels of adenosine monophosphate-activated protein kinase (AMPK) and its substrate acetyl-CoA carboxylase and reduce the level of phosphorylated ribosomal S6 kinase (p-70S6K) at 1 μM, which is comparable to the activity of A-769662 at 20 μM. 9d induced G2/M cell cycle arrest, which was rescued when co-incubated with "Compound C," a potent AMPK inhibitor. Taken together, compound 9d showed potential anti-lung cancer activity via inducing cell cycle arrest by regulation of the AMPK/70S6K pathway in A549 cells, which could provide a new lead for the discovery of anti-lung cancer agents.
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- 2022
12. Discovery of Novel Pyrazolo[3,4-b] Pyridine Derivatives with Dual Activities of Vascular Remodeling Inhibition and Vasodilation for the Treatment of Pulmonary Arterial Hypertension
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Jia Qin, Qinglian Liu, Songsen Fu, Qi Chang, Qianbin Li, Zhuo Chen, Gaoyun Hu, Lijun Li, Xiaohui Li, and Liqing Hu
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Chemistry ,AMPK ,Vasodilation ,Pharmacology ,medicine.disease ,Riociguat ,Right ventricular hypertrophy ,In vivo ,medicine.artery ,Drug Discovery ,Pulmonary artery ,medicine ,Ventricular pressure ,Molecular Medicine ,Protein kinase A ,medicine.drug - Abstract
Current pulmonary arterial hypertension (PAH) therapeutic strategies mainly focus on vascular relaxation with less emphasis on vascular remodeling, which results in poor prognosis. Hence, dual pathway regulators with vasodilation effect via soluble guanylate cyclase (sGC) stimulation and vascular remodeling regulation effect by AMP-activated protein kinase (AMPK) inhibition provide more advantages and potentialities. Herein, we designed and synthesized a series of novel pyrazolo[3,4-b] pyridine derivatives based on sGC stimulator and AMPK inhibitor scaffolds. In vitro, 2 exhibited moderate vasodilation activity and higher proliferation and migration suppressive effects compared to riociguat. In vivo, 2 significantly decreased right ventricular systolic pressure (RVSP), attenuated pulmonary artery medial thickness (PAMT), and right ventricular hypertrophy (RVH) in hypoxia-induced PAH rat models (i.g.). Given the unique advantages of significant vascular remodeling inhibition and moderate vascular relaxation based on the dual pathway regulation, we proposed 2 as a promising lead for anti-PAH drug discovery.
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- 2020
13. In vitro metabolic characterization of orbitazine, a novel derivative of the PAC-1 anticancer agent
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Gaoyun Hu, Yanfen Chen, Xuhua Han, Shanshan Wang, Fang Li, Qubo Zhu, Zeneng Cheng, and Wenjie Liu
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Male ,CYP2D6 ,CYP2B6 ,Pharmaceutical Science ,Antineoplastic Agents ,Piperazines ,03 medical and health sciences ,chemistry.chemical_compound ,Dogs ,0302 clinical medicine ,Cytochrome P-450 Enzyme System ,Species Specificity ,Tandem Mass Spectrometry ,Animals ,Humans ,Cells, Cultured ,Chromatography, High Pressure Liquid ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Dose-Response Relationship, Drug ,CYP3A4 ,Hydrazones ,CYP1A2 ,Haplorhini ,Metabolism ,In vitro ,Rats ,Piperazine ,chemistry ,Biochemistry ,030220 oncology & carcinogenesis ,Hepatocytes ,Microsomes, Liver ,Microsome ,Chromatography, Liquid - Abstract
Objectives The in vitro evaluation of new drugs is an important step in the drug development pipeline. Orbitazine is a derivative of PAC-1 that has substituted the functional group homopiperazine ring with a piperazine ring. The purpose of this study was to assess the metabolic profile of orbitazine. Methods Metabolism was characterized in vitro by incubating liver microsomes with metabolize orbitazine or the classical metabolic enzyme substrates. High performance liquid chromatography (HPLC) and LC-MS/MS were used to identify the parent drugs and metabolites of orbitazine or metabolic enzyme substrates. Key findings There was no difference in metabolic stability or metabolites across different species. The metabolites included a debenzyl compound and several hydroxyl compounds, defined as M1(316), M2(440), M3(422), M4(422) and M5(422). We found that orbitazine was metabolized by CYP3A4, CYP2C9 and CYP2D6 in a human liver microsomes incubation system. Orbitazine had no significant inhibitory effect on CYP1A2, CYP2B6, CYP2C9, or CYP2C19 in human liver microsomes, but showed a dose-dependent inhibition of CYP2C8, CYP2D6 and CYP3A4; and there was no orbitazine-mediated induction of CYP1A2, CYP2B6, CYP3A4 or mRNA expression in hepatocytes. Conclusions This in vitro data on the metabolism of orbitazine may provide valuable information to support further clinical progression as a potential therapeutic molecule.
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- 2020
14. Identification of selective homeodomain interacting protein kinase 2 inhibitors, a potential treatment for renal fibrosis
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Liqing Hu, Guangying Wang, Congke Zhao, Zhangzhe Peng, Lijian Tao, Zhuo Chen, Gaoyun Hu, and Qianbin Li
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Molecular Docking Simulation ,Mice ,Organic Chemistry ,Drug Discovery ,Animals ,Apoptosis ,Protein Serine-Threonine Kinases ,Molecular Biology ,Biochemistry ,Fibrosis ,Cell Line - Abstract
Homeodomain interacting protein kinase 2 (HIPK2) has emerged as a promising target for the discovery of anti-renal fibrosis drugs. Herein, to develop specific pharmacologic inhibitors of HIPK2, we designed and synthesized a series of compounds containing benzimidazole and pyrimidine scaffolds via fragment-based drug design strategy. Kinase assay was applied to evaluate the inhibitory activity of target compounds against HIPKs enzyme. The molecular docking study suggest the contribution of tyrosine residues beside the active sites of HIPK1-3 to the selectivity of active compounds. Compound 15q displayed good selectivity and potent inhibitory activity against HIPK2 compared to other two subtype enzymes. 15q could downregulate phosphorylated p53, the direct substrate of HIPK2, and decrease the fibrosis-related downstream of HIPK2, such as p-Smad3 and α-SMA in NRK-49F cells. 15q showed no effect on the cell apoptosis in fibrotic or cancer cell lines, suggesting little cancer risk of 15q. Notably, 15q displayed encouraging in vivo anti-fibrotic effects in the unilateral ureteral obstruction mouse model, which could be used as a potential lead for structural optimization and candidate for the development of selective HIPK2 inhibitors.
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- 2021
15. An emerging strategy for targeted therapy of pulmonary arterial hypertension: Vasodilation plus vascular remodeling inhibition
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Liqing Hu, Congke Zhao, Zhuo Chen, Gaoyun Hu, Xiaohui Li, and Qianbin Li
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Pharmacology ,Vasodilation ,Pulmonary Arterial Hypertension ,Hypertension, Pulmonary ,Drug Discovery ,Humans ,Vascular Remodeling - Abstract
Pulmonary arterial hypertension (PAH) is a rapidly progressing disease with limited therapeutic options. Studies have elucidated the multifactorial pathological characteristics of PAH, indicating the complexity and difficulty of PAH treatment. Currently available treatments focus primarily on vasodilation rather than on vascular remodeling, although several drugs have been developed for the latter. This paradigm for management leads to PAH remaining an incurable disease; thus, there is an urgent need to explore new strategies for coping with this devastating disease. In this review, we discuss current strategies and options for PAH therapy and emerging novel therapeutic approaches in PAH treatment. This viewpoint suggests a shift in PAH treatment strategy from mono-activity to dual effects on vasoconstriction and vascular remodeling.
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- 2021
16. Mefunidone Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice
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Yuanyuan Han, Mao Jiang, Rongling He, Xin Lv, Xiaohua Liao, Yijun He, Fan Zhang, Lingzhi Long, Guoliang Jiang, Zhangzhe Peng, Lijian Tao, Gaoyun Hu, and Jie Meng
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TGF-β ,epithelial-mesenchymal transition ,Inflammation ,Vimentin ,RM1-950 ,Bleomycin ,Idiopathic pulmonary fibrosis ,chemistry.chemical_compound ,Pulmonary fibrosis ,medicine ,Pharmacology (medical) ,Epithelial–mesenchymal transition ,Original Research ,Pharmacology ,Lung ,pulmonary fibrosis ,medicine.diagnostic_test ,biology ,business.industry ,apoptosis ,respiratory system ,medicine.disease ,respiratory tract diseases ,mefunidone ,medicine.anatomical_structure ,Bronchoalveolar lavage ,chemistry ,Cancer research ,biology.protein ,Therapeutics. Pharmacology ,medicine.symptom ,business - Abstract
Idiopathic pulmonary fibrosis (IPF) is one of the most common and devastating interstitial lung diseases with poor prognosis. Currently, few effective drugs are available for IPF. Hence, we sought to explore the role of mefunidone (MFD), a newly synthesized drug developed by our team, in lung fibrosis. In this study, MFD was found to attenuate bleomycin (BLM) -induced lung fibrosis and inflammation in mice according to Ashcroft and alveolitis scoring. The protein contents and total cell counts in bronchoalveolar lavage fluids of BLM-treated mice were also lowered by MFD. Moreover, the elevation of TGF-β/Smad2 and phosphorylation of MAPK pathways was repressed by MFD. Additionally, MFD attenuated the swelling and vacuolization of mitochondria, lowered the ratio of apoptotic cells, restored the mitochondrial membrane potential, and reversed the expression of cleaved-caspase 3, Bcl-2 and Bax. Meanwhile, the level of epithelial marker, E-cadherin, was restored by MFD, while the levels of mesenchymal markers such as Snail and vimentin were down-regulated by MFD. Besides, MFD inhibited the expression of fibronectin and α-smooth muscle actin in TGF-β treated normal human lung fibroblasts. Thus, our findings suggested that MFD could ameliorate lung fibrosis, cell apoptosis and EMT potentiallyviasuppression of TGF-β/Smad2 and MAPK pathways.
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- 2021
17. Protective Effect of Fluorofenidone Against Acute Lung Injury Through Suppressing the MAPK/NF-κB Pathway
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Xin Lv, Tingting Yao, Rongling He, Yijun He, Mengyu Li, Yuanyuan Han, Yan Zhang, Lingzhi Long, Guoliang Jiang, Xiaoyun Cheng, Yanyun Xie, Ling Huang, Zhangzhe Peng, Gaoyun Hu, Qianbin Li, Lijian Tao, and Jie Meng
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Pharmacology ,acute lung injury ,inflammation ,lipopolysaccharide ,apoptosis ,fluorofenidone ,Pharmacology (medical) ,Therapeutics. Pharmacology ,RM1-950 ,respiratory system ,respiratory tract diseases ,Original Research - Abstract
Acute lung injury (ALI) is a severe disease that presents serious damage and excessive inflammation in lungs with high mortality without effective pharmacological therapy. Fluorofenidone (AKFPD) is a novel pyridone agent that has anti-fibrosis, anti-inflammation, and other pharmacological activities, while the effect of fluorofenidone on ALI is unclarified. Here, we elucidated the protective effects and underlying mechanism of fluorofenidone on lipopolysaccharide (LPS)-induced ALI. In this study, fluorofenidone alleviated lung tissue structure injury and reduced mortality, decreased the pulmonary inflammatory cell accumulation and level of inflammatory cytokines IL-1β, IL-6, and TNF-α in the bronchoalveolar lavage fluid, and attenuated pulmonary apoptosis in LPS-induced ALI mice. Moreover, fluorofenidone could block LPS-activated phosphorylation of ERK, JNK, and P38 and further inhibited the phosphorylation of IκB and P65. These results suggested that fluorofenidone can significantly contrast LPS-induced ALI through suppressing the activation of the MAPK/NF-κB signaling pathway, which indicates that fluorofenidone could be considered as a novel therapeutic candidate for ALI.
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- 2021
18. Fluorofenidone protects against acute kidney injury
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Xiaohua Liao, Yang Chen, Jie Meng, Gaoyun Hu, Rong Lu, Jiao Quan, Qianbin Li, Yue Yu, Yupeng Jiang, Yanyun Xie, Zhangzhe Peng, Qin Dai, and Lijian Tao
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Male ,0301 basic medicine ,Lipopolysaccharide ,Pyridones ,Antineoplastic Agents ,Pharmacology ,Kidney ,Biochemistry ,Cell Line ,Nephrotoxicity ,Rats, Sprague-Dawley ,Mice ,Random Allocation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Genetics ,medicine ,Animals ,Molecular Biology ,Beneficial effects ,Copper Transporter 1 ,Peroxidase ,Inflammation ,Mitogen-Activated Protein Kinase Kinases ,Cisplatin ,business.industry ,Acute kidney injury ,Organic Cation Transporter 2 ,Acute Kidney Injury ,medicine.disease ,Rats ,Mice, Inbred C57BL ,030104 developmental biology ,Gene Expression Regulation ,chemistry ,Reperfusion Injury ,Fluorofenidone ,Reactive Oxygen Species ,business ,030217 neurology & neurosurgery ,Biotechnology ,medicine.drug - Abstract
Cisplatin (CP) is one of the most effective chemotherapeutics in the treatment of human cancers. However, the beneficial effects of CP are limited by the toxic effects, especially nephrotoxicity. Fluorofenidone (AKFPD) is a promising multifunctional antifibrosis pyridinone drug discovered by our group. But there is no evidence of its protective effects against acute kidney injury (AKI). Therefore, we investigated the protective effects of AKFPD on CP-induced AKI
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- 2019
19. Cost-effectiveness Analysis of Pembrolizumab Plus Axitinib Versus Sunitinib in First-line Advanced Renal Cell Carcinoma in China
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Xiaohui Zeng, Gaoyun Hu, Zhuo Chen, Chongqing Tan, Jun Chen, Xiaomin Wan, and Zeneng Cheng
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Oncology ,China ,medicine.medical_specialty ,Axitinib ,Cost effectiveness ,Cost-Benefit Analysis ,Pembrolizumab ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,030226 pharmacology & pharmacy ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Renal cell carcinoma ,Internal medicine ,Sunitinib ,Humans ,Medicine ,Pharmacology (medical) ,Carcinoma, Renal Cell ,health care economics and organizations ,business.industry ,Hazard ratio ,General Medicine ,Cost-effectiveness analysis ,medicine.disease ,Kidney Neoplasms ,Quality-adjusted life year ,Drug Therapy, Combination ,Quality-Adjusted Life Years ,business ,medicine.drug - Abstract
In first-line treatment of advanced renal cell carcinoma (aRCC), the KEYNOTE-426 study demonstrated a significant progression-free survival and overall survival for pembrolizumab plus axitinib in comparison with sunitinib. The objective of the current study was to evaluate the cost effectiveness of pembrolizumab plus axitinib versus sunitinib for previously untreated patients with aRCC in China. A Markov model was used to estimate the costs and health outcomes of treatment of aRCC with sunitinib or pembrolizumab plus axitinib. Univariable and probabilistic sensitivity analyses were performed to determine the robustness of the model outcomes. Additional subgroup analyses were also performed. The primary outputs of the model included the total cost, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER). Pembrolizumab plus axitinib provided an additional 2.461 LYs (1.650 QALYs). The total cost per patient was US$178,725 for pembrolizumab plus axitinib and US$87,693 for sunitinib. The ICER for pembrolizumab plus axitinib was US$55,185/QALY versus sunitinib. Sensitivity analyses found the results to be most sensitive to pembrolizumab cost and overall hazard ratio. The results of subgroup analyses showed that the ICER remained greater than US$32,000/QALY across the all patient subgroups. Pembrolizumab plus axitinib is not likely to be cost effective versus sunitinib for patients with previously untreated aRCC at a threshold value of US$29,306/QALY.
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- 2019
20. Retracted : 9za plays cytotoxic and proapoptotic roles and induces cytoprotective autophagy through the PDK1/Akt/mTOR axis in non‐small‐cell lung cancer
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Hong-Hao Zhou, Xi Li, Xinan Yi, Zhao-Qian Liu, Gaoyun Hu, Fengying Huang, Rangru Liu, Danqi Liu, and Zhuo Chen
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0301 basic medicine ,Indoles ,Lung Neoplasms ,Cell Survival ,Physiology ,Clinical Biochemistry ,Antineoplastic Agents ,3-Phosphoinositide-Dependent Protein Kinases ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Autophagy ,medicine ,Humans ,Cytotoxic T cell ,Benzodioxoles ,Protein kinase A ,Lung cancer ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Aniline Compounds ,Molecular Structure ,Chemistry ,TOR Serine-Threonine Kinases ,Cancer ,Cell Biology ,Fibroblasts ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Phosphorylation ,Proto-Oncogene Proteins c-akt - Abstract
Non-small-cell lung cancer (NSCLC) is an aggressive subtype of pulmonary carcinomas with high mortality. However, chemotherapy drug resistance and high recurrence rates hinder the curative effect of platinum-based first-line chemotherapy, which makes it urgent to develop new antitumor drugs for NSCLC. 9za, a new candidate drug synthesized by our research group, has been verified with potent antilung cancer activity in preliminary experiments. However, the underlying molecular mechanism of 9za remains largely vague. This work revealed that 9za could play important cytotoxic and proapoptotic roles in NSCLC cells. Moreover, 9za could induce autophagy and promote autophagy flux. Interestingly, the cytotoxic and proapoptotic roles were significantly dependent on 9za-induced cytoprotective autophagy. That is, the coadministration of 9za with an autophagy inhibitor such as chloroquine or 3-methyladenine exhibited increased cytotoxic and proapoptotic effects compared with 9za treatment alone. In addition, 9za exposure suppressed the phosphorylation of phosphoinositide-dependent protein kinase 1 (PDK1), protein kinase B (Akt), mammalian targets of rapamycin (mTOR), p70 S6 kinase, and 4E binding protein 1 by a dose-dependent way, manifesting that the Akt/mTOR axis was implicated in 9za-induced autophagy. In addition, the overexpression of PDK1 resulted in increased phosphorylation of PDK1 and Akt and blocking of 9za-mediated autophagy. These data showed that the PDK1/Akt/mTOR pathway was involved in 9za-induced autophagy. Hence, this work provides a theoretical basis for exploiting 9za as a new antilung cancer candidate drug and hints that the combination of 9za with an autophagy inhibitor is a feasible alternative approach for the therapy of NSCLC.
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- 2019
21. Dual inhibitors of RAF-MEK-ERK and PI3K-PDK1-AKT pathways: Design, synthesis and preliminary anticancer activity studies of 3-substituted-5-(phenylamino) indolone derivatives
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Shiqi Ye, Meng Lv, Zhuo Chen, Qianbin Li, Gaoyun Hu, Zhijun Tu, Qiongli Su, Zutao Yu, Mengni Kuai, Rangru Liu, Xiaoping Yang, and Hongbo Yuan
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MAPK/ERK pathway ,Indoles ,Lung Neoplasms ,MAP Kinase Signaling System ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Apoptosis ,01 natural sciences ,Biochemistry ,Cell Line, Tumor ,Drug Discovery ,Humans ,Structure–activity relationship ,Benzodioxoles ,Protein Kinase Inhibitors ,Molecular Biology ,Protein kinase B ,IC50 ,PI3K/AKT/mTOR pathway ,Amination ,A549 cell ,Aniline Compounds ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Pyruvate Dehydrogenase Acetyl-Transferring Kinase ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,A549 Cells ,Drug Design ,Cancer research ,Molecular Medicine ,Phosphorylation ,raf Kinases ,Phosphatidylinositol 3-Kinase ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
The dysfunction and mutual compensatory activation of RAF-MEK-ERK and PI3K-PDK1-AKT pathways have been demonstrated as the hallmarks in several primary and recurrent cancers. The strategy of concurrent blocking of these two pathways shows clinical merits on effective cancer therapy, such as combinatory treatments and dual-pathway inhibitors. Herein, we report a novel prototype of dual-pathway inhibitors by means of merging the core structural scaffolds of a MEK1 inhibitor and a PDK1 inhibitor. A library of 43 compounds that categorized into three series (Series I–III) was synthesized and tested for antitumor activity in lung cancer cells. The results from structure-activity relationship (SAR) analysis showed the following order of antitumor activity that 3-hydroxy-5-(phenylamino) indolone (Series III) > 3-alkenyl-5-(phenylamino) indolone (Series I) > 3-alkyl-5-(phenylamino) indolone (Series II). A lead compound 9za in Series III showed most potent antitumor activity with IC50 value of 1.8 ± 0.8 µM in A549 cells. Moreover, antitumor mechanism study demonstrated that 9za exerted significant apoptotic effect, and cellular signal pathway analysis revealed the potent blockage of phosphorylation levels of ERK and AKT in RAF-MEK-ERK and PI3K-PDK1-AKT pathways, respectively. The results reported here provide robust experimental basis for the discovery and optimization of dual pathway agents for anti-lung cancer therapy.
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- 2019
22. The Protective Effect of Fluorofenidone against Cyclosporine A-Induced Nephrotoxicity
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Jiao Qin, Yang Chen, Gaoyun Hu, Qiongjing Yuan, Yanyun Xie, Lijian Tao, Zhangzhe Peng, Qianbin Li, and Nasui Wang
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Male ,lcsh:Diseases of the circulatory (Cardiovascular) system ,Pyridones ,medicine.medical_treatment ,030232 urology & nephrology ,Apoptosis ,Pharmacology ,lcsh:RC870-923 ,Kidney ,Protective Agents ,Fas ligand ,Nephrotoxicity ,Rats, Sprague-Dawley ,Cyclosporine A ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,lcsh:Dermatology ,medicine ,Animals ,Renal tubulointerstitial fibrosis ,Dose-Response Relationship, Drug ,Chemistry ,Growth factor ,General Medicine ,Pirfenidone ,lcsh:RL1-803 ,lcsh:Diseases of the genitourinary system. Urology ,medicine.disease ,Rats ,medicine.anatomical_structure ,Fluorofenidone ,lcsh:RC666-701 ,Nephrology ,Cyclosporine ,Cardiology and Cardiovascular Medicine ,Transforming growth factor ,medicine.drug - Abstract
Background/Aims: Cyclosporine A (CsA) is an immunosuppressant drug that is used during organ transplants. However, its utility is limited by its nephrotoxic potential. This study aimed to investigate whether fluorofenidone (AKF-PD) could provide protection against CsA-induced nephrotoxicity. Methods: Eighty-five male Sprague-Dawley rats were divided into 5 groups: drug solvent, CsA, CsA with AKF-PD (250, 500 mg/kg/day), and CsA with pirfenidone (PFD, 250 mg/kg/day). Tubulointerstitial injury index, extracellular matrix (ECM) deposition, expression of type I and IV collagen, transforming growth factor (TGF)-β1, platelet-derived growth factor (PDGF), Fas ligand (FASL), cleaved-caspase-3, cleaved-poly(ADP-ribose) polymerase (PARP)-1, and the number of transferase-mediated nick end-labeling (TUNEL)-positive renal tubule cells were determined. In addition, levels of TGF-β1, FASL, cleaved-caspase-3, cleaved-PARP-1, and number of annexin V-positive cells were determined in rat proximal tubular epithelial cells (NRK-52E) treated with CsA (20 μmol/L), AKF-PD (400 μg/mL), PFD (400 μg/mL), and GW788388 (5 μmol/L). Results: AKF-PD (250, 500 mg/kg/day) significantly reduced tubulointerstitial injury, ECM deposition, expression of type I and IV collagen, TGF-β1, PDGF, FASL, cleaved-caspase-3, cleaved-PARP-1, and number of TUNEL-positive renal tubule cells in the CsA-treated kidneys. In addition, AKF-PD (400 μg/mL) significantly decreased TGF-β1, FASL, cleaved-caspase-3, and PARP-1 expression in NRK-52E cells and further reduced the number of annexin V-positive cells. Conclusion: AKF-PD protect kidney from fibrosis and apoptosis in CsA-induced kidney injury.
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- 2019
23. Discovery of Novel Pyrazolo[3,4
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Liqing, Hu, Lijun, Li, Qi, Chang, Songsen, Fu, Jia, Qin, Zhuo, Chen, Xiaohui, Li, Qinglian, Liu, Gaoyun, Hu, and Qianbin, Li
- Subjects
Vasodilation ,Structure-Activity Relationship ,Pyridines ,Drug Design ,Hypertension, Pulmonary ,Adenylate Kinase ,Animals ,Humans ,Pyrazoles ,Vascular Remodeling ,Cell Line ,Rats - Abstract
Current pulmonary arterial hypertension (PAH) therapeutic strategies mainly focus on vascular relaxation with less emphasis on vascular remodeling, which results in poor prognosis. Hence, dual pathway regulators with vasodilation effect via soluble guanylate cyclase (sGC) stimulation and vascular remodeling regulation effect by AMP-activated protein kinase (AMPK) inhibition provide more advantages and potentialities. Herein, we designed and synthesized a series of novel pyrazolo[3,4
- Published
- 2020
24. Targeted degradation of CD147 proteins in melanoma
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Chen Xiang, Gaoyun Hu, Zhuo Chen, Li Yayun, Ling Tang, Wang Yuan, Qi Chang, Xu Zhang, Jing Long, Peng Cong, Zhe Zhou, Shuo Hu, and Qianbin Li
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Alkylation ,Proteolysis ,Mice, Nude ,Antineoplastic Agents ,Biochemistry ,chemistry.chemical_compound ,Mice ,Pseudolaric acid B ,In vivo ,Cell Movement ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Molecular Biology ,Melanoma ,Wound Healing ,Natural product ,medicine.diagnostic_test ,Molecular Structure ,Organic Chemistry ,Cancer ,Neoplasms, Experimental ,medicine.disease ,In vitro ,chemistry ,Cancer research ,Basigin ,Immunoglobulin superfamily ,Female ,Diterpenes ,Drug Screening Assays, Antitumor - Abstract
CD147 is a transmembrane glycoprotein and a member of immunoglobulin superfamily, is strongly expressed in melanoma cells. CD147 has a pivotal role in tumor development. Therefore, it is a potential drug target for melanoma. In this article, we report the discovery of the first CD147 protein proteolysis targeting chimeras (PROTACs) derived from the natural product pseudolaric acid B (PAB). The representative compound 6a effectively induced degradation of CD147 and inhibited melanoma cells in vitro and in vivo. 6a could be used as the novel type of anticancer agent or as a part of the molecular biology research toolkit used in the gain-of-function study of the dynamic roles of CD147 in cancer networks.
- Published
- 2020
25. Fluorofenidone attenuates interleukin-1β production by interacting with NLRP3 inflammasome in unilateral ureteral obstruction
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Sisi Qiu, Jie Meng, Yanyun Xie, Linfeng Zheng, Juan Tang, Yiting Tang, Qiongjing Yuan, Wenjuan Mei, Gaoyun Hu, Lijian Tao, Zhangzhe Peng, Xiangning Yuan, and Jin Zhang
- Subjects
0301 basic medicine ,integumentary system ,medicine.diagnostic_test ,business.industry ,Inflammasome ,General Medicine ,Pharmacology ,Cleavage (embryo) ,medicine.disease ,In vitro ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Western blot ,Nephrology ,In vivo ,030220 oncology & carcinogenesis ,medicine ,Renal fibrosis ,Fluorofenidone ,business ,Infiltration (medical) ,medicine.drug - Abstract
Aim We explored whether Fluorofenidone reduced interleukin-1β (IL-1β) production by interacting with NLRP3 inflammasome in unilateral ureteral obstruction (UUO). Methods Ureteral obstruction rats were treated with Fluorofenidone (500 mg/kg per day) for 3, 7 days. Morphologic analysis and leukocytes infiltration were assessed in ligated kidneys. Furthermore, plasmids of NLRP3, ASC, pro-Caspase-1, pro-IL-1β were co-transfected into 293 T cells, and then treated with Fluorofenidone (2 mM). The expression of NLRP3, ASC, pro-caspase-1, cleavage caspase-1, pro-IL-1β and cleavage IL-1β were measured by Western blot or real-time PCR in vivo and in vitro. Moreover the interaction of NLRP3 inflammasome-assembly was detected by co-immunoprecipitation and confocal immunofluorescence. Results Fluorofenidone treatment significantly attenuated renal fibrosis and leukocytes infiltration in UUO model. Fluorofenidone had no effect on the expression of pro-IL-1β. Interestingly, Fluorofenidone inhibited the activation of NLRP3 inflammasome, downregulated Caspase-1 levels and thereby decreased the cleavage of pro-IL-1β into IL-1β in vivo and in vitro. Fluorofenidone treatment distinctively weakened the interaction between NLRP3 and ASC, as well as ASC and pro-Caspase-1 in vivo. However, Fluorofenidone treatment only significantly weakened the interaction between ASC and pro-Caspase-1 in co-transfected 293 T cells. Conclusion Fluorofenidone serves as a novel anti-inflammatory agent that attenuates IL-1β production in UUO model by interacting with NLRP3 inflammasome.
- Published
- 2018
26. Discovery of 1-(4-((3-(4-methylpiperazin-1-yl)propyl)amino)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one, an orally active multi-target agent for the treatment of diabetic nephropathy
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Jun Chen, Zeneng Cheng, Xuan Xiong, Zhuo Chen, Gaoyun Hu, Lijian Tao, Dejian Jiang, Qianbin Li, Miaomiao Lu, and Zhangzhe Peng
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Male ,0301 basic medicine ,Pyridones ,Stereochemistry ,medicine.drug_class ,Clinical Biochemistry ,Administration, Oral ,Pharmaceutical Science ,030204 cardiovascular system & hematology ,Pharmacology ,medicine.disease_cause ,Biochemistry ,Piperazines ,Anti-inflammatory ,Diabetes Mellitus, Experimental ,Diabetic nephropathy ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Fibrosis ,Drug Discovery ,medicine ,Animals ,Hypoglycemic Agents ,Diabetic Nephropathies ,Molecular Biology ,IC50 ,Trifluoromethyl ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Anti-Inflammatory Agents, Non-Steroidal ,Organic Chemistry ,Pirfenidone ,medicine.disease ,Rats ,Oxidative Stress ,030104 developmental biology ,NIH 3T3 Cells ,Kidney Failure, Chronic ,Molecular Medicine ,Lead compound ,Oxidative stress ,medicine.drug - Abstract
Oxidative stress, inflammation and fibrosis can cause irreversible damage on cell structure and function of kidney and are key pathological factors in Diabetic Nephropathy (DN). Therefore, multi-target agents are urgently need for the clinical treatment of DN. Using Pirfenidone as a lead compound and based on the previous research, two novel series (5-trifluoromethyl)-2(1H)-pyridone analogs were designed and synthesized. SAR of (5-trifluoromethyl)-2(1H)-pyridone derivatives containing nitrogen heterocyclic ring have been established for in vitro potency. In addition, compound 8, a novel agent that act on multiple targets of anti-DN with IC50 of 90μM in NIH3T3 cell lines, t1/2 of 4.89±1.33h in male rats and LD50>2000mg/kg in mice, has been advanced to preclinical studies as an oral treatment for DN.
- Published
- 2018
27. Multistep virtual screening based identification of homeodomain-interacting protein kinase 2 inhibitors: An opportunity for treating Chronic Kidney Disease
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Yuanyuan Cao, Dong-Sheng Cao, Xiaomei Shi, Xiangyang Le, Qianbin Li, Gaoyun Hu, Chao Hao, Zhuo Chen, and Binghao Ma
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Virtual screening ,Chemistry ,Process Chemistry and Technology ,Regulator ,Biological activity ,medicine.disease ,Computer Science Applications ,Analytical Chemistry ,Biochemistry ,Docking (molecular) ,medicine ,Viability assay ,Binding site ,Protein kinase A ,Spectroscopy ,Software ,Kidney disease - Abstract
Homeodomain-Interacting Protein Kinase 2 (HIPK2) is a critical regulator of multiple pathways upstream of Chronic Kidney Disease (CKD). With the purpose of seeking HIPK2 inhibitors with novel scaffolds, a multistep virtual screening from the SPECS library was conducted. The screening process generally included similarity screening, random forest modeling, docking and ADMET prediction. Ten compounds were finally purchased and evaluated in biological activity test. The activity results demonstrated that the compound 1 (SPECS ID AG-401/37408043) can inhibit enzymatic activity and cell viability of high-glucose-induced rat normal renal interstitial fibroblast cells (NRK49F) with moderate activity. Its binding modes with the HIPK2 ATP binding site were analyzed. Overall, the compound 1 with a rather new scaffold might be used as the lead for the future structural optimization to seek potent HIPK2 inhibitors.
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- 2021
28. Synthesis, anti-lung cancer activity and molecular docking study of 3-methylene-2-oxoindoline-5-carboxamide derivatives
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Zhuo Chen, Gaoyun Hu, Meng Lv, Ai Juntao, Qianbin Li, and Xiaohui Li
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0301 basic medicine ,MAPK/ERK pathway ,medicine.diagnostic_test ,medicine.drug_class ,Chemistry ,Kinase ,Organic Chemistry ,Carboxamide ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Biochemistry ,Western blot ,Docking (molecular) ,030220 oncology & carcinogenesis ,Extracellular ,medicine ,Phosphorylation ,MTT assay ,General Pharmacology, Toxicology and Pharmaceutics - Abstract
A series of 3-methylene-2-oxoindoline-5-carboxamide derivatives were synthesized in appreciable yield by using 4-aminobenzoic acid as a starting material. The preliminary biological test results showed that most compounds displayed potent inhibitory activity against proliferation of human lung adenocarcinoma epithelial cell line (A549) in MTT assay. Compound 6l displayed the highest potency (IC50 = 3.0 μM). The western blot analysis demonstrated a correlation between anti-proliferative activity of active compounds and blockade of the phosphorylation of extracellular signal-regulated kinases (ERK1/2). The docking study also provides new insights into further optimization of 3-methylene-2-oxoindoline-5-carboxamide derivatives for the discovery of more potent RAF/MEK/ERK pathway regulators as anti-lung cancer agents.
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- 2017
29. Fluorofenidone Inhibits the Proliferation of Lung Adenocarcinoma Cells
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Juan Tang, Jie Meng, Gaoyun Hu, Zhenghao Deng, and Lijian Tao
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0301 basic medicine ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Carcinoma ,medicine ,STAT3 ,Lung cancer ,Lung ,Stat3 ,biology ,medicine.diagnostic_test ,business.industry ,NUPR1 ,lung adenocarcinoma ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Fluorofenidone ,Oncology ,Apoptosis ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Adenocarcinoma ,business ,Research Paper - Abstract
Background: Lung carcinoma is the leading cause of malignant tumor related mortality in China in recent decades, and the development of new and effective therapies for patients with advanced lung carcinoma is needed. We recently found that fluorofenidone (FD), a newly developed pyridine compound, reduced the activation of Stat3 (Signal transducer and activator of transcription 3) in fibroblasts. Stat3 plays a crucial role in the development of lung cancer and may represent a new therapeutic target. In this study, we examined the effect of FD on human lung adenocarcinoma cells in vivo and in vitro. Methods: The effect of FD on the growth of lung cancer cells was measured with a CCK-8 assay, colony formation assay and xenograft tumor model. A flow cytometry analysis was performed to study cell cycle arrest and apoptosis. Western blotting and immunohistochemistry were used to observe the expression of Stat3. Changes in the expression of RNA induced by FD were assessed using gene chip and real-time RT-PCR assays. Results: In vitro, FD inhibited the growth of lung adenocarcinoma A549 and SPC-A1 cells in a dose-dependent manner. After treatment with FD, the A549 and SPC-A1 cells were arrested in the G1 phase, and apoptosis was induced. In vivo, this compound significantly inhibited the growth of tumors that were subcutaneously implanted in mice. Moreover, FD decreased Stat3 activity in lung cancer cells and xenograft tumor tissue, and microarray chip results showed that FD altered the gene expression profile of lung cancer cells. Specifically, NUPR1, which plays a significant role in cancer development, was down-regulated by FD in lung cancer cells. Conclusion: Our study supports the clinical evaluation of FD as a potential lung adenocarcinoma therapy.
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- 2017
30. Mefunidone ameliorates renal inflammation and tubulointerstitial fibrosis via suppression of IKKβ phosphorylation
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Lijian Tao, Jie Meng, Jin Zhang, Chunyan Liu, Feifei Xie, Gaoyun Hu, Linfeng Zheng, Jiao Qin, Xiangning Yuan, Zhangzhe Peng, Sisi Qiu, Yiting Tang, and Qiongjing Yuan
- Subjects
Lipopolysaccharides ,Male ,0301 basic medicine ,Lipopolysaccharide ,Cell Survival ,Pyridones ,Interleukin-1beta ,NALP3 ,Inflammation ,urologic and male genital diseases ,Biochemistry ,Piperazines ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Fibrosis ,Animals ,Medicine ,Lymphocytes ,Phosphorylation ,Kidney ,biology ,Tumor Necrosis Factor-alpha ,business.industry ,NF-kappa B ,Cell Biology ,medicine.disease ,I-kappa B Kinase ,Rats ,Kidney Tubules ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,chemistry ,030220 oncology & carcinogenesis ,Immunology ,Macrophages, Peritoneal ,Tubulointerstitial fibrosis ,biology.protein ,Cancer research ,Tumor necrosis factor alpha ,medicine.symptom ,business ,Ureteral Obstruction - Abstract
Mefunidone is a new pyridone agent that attenuates renal tubulointerstitial fibrosis. However, the signaling pathways involved in the effect of mefunidone on renal tubulointerstitial fibrosis have not been well explained. Inflammatory response initiates and promotes renal tubulointerstitial fibrosis, and the inhibitor of nuclear factor kappa-B kinase beta (IKKβ) is a master regulator of inflammation. This study is determined to clarify the influence of mefunidone on renal inflammation and the phosphorylation of IKKβ. Experimental renal tubulointerstitial fibrosis was induced by unilateral ureteral obstruction (UUO) for 3, 7 and 14days in sprague dawley rat. Treatment with mefunidone was conducted simultaneously. Obstructed kidneys were harvested for the assessment. Our results showed that treatment with mefunidone ameliorated renal inflammatory injury, renal tubular lesions and interstitial fibrosis. Further studies indicated that treatment with mefunidone mitigated the expressions of tumor necrosis factorα (TNFα) and interleukin-1β (IL-1β) in the kidney. The phosphorylation of IKKβ and inhibitor of kappa-B (IκB) and the expression of NOD-like receptor family, pyrin domain containing 3 (NALP3) were also reduced in vivo after treatment with mefunidone. In vitro, peritoneal macrophages were incubated with necrotic cells or lipopolysaccharide in the presence or absence of mefunidone. Mefunidone markedly decreased necrotic cell or LPS induced IL-1β production and LPS induced TNFα production in primary peritoneal macrophages. Furthermore, mefunidone significantly inhibited the phosphorylation of IKKβ/IκB and nuclear transition of NF-κB p65 in peritoneal macrophages stimulated by necrotic cell or lipopolysaccharide. In conclusion, mefunidone serves as a novel anti-inflammatory agent that attenuates UUO-induced renal interstitial inflammation and fibrosis, possibly through suppressing IKKβ phosphorylation.
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- 2016
31. Soluble Guanylate Cyclase Stimulators and Activators: Where are We and Where to Go?
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Qi Chang, Qianbin Li, Sijia Xiao, Zutao Yu, Liqing Hu, Jie Yang, Gaoyun Hu, and Zhuo Chen
- Subjects
inorganic chemicals ,Enzyme Activators ,030204 cardiovascular system & hematology ,Guanosine triphosphate ,Pharmacology ,Nitric Oxide ,Riociguat ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,medicine ,Benzene Derivatives ,Humans ,heterocyclic compounds ,Cyclic guanosine monophosphate ,Cyclic GMP ,030304 developmental biology ,0303 health sciences ,Activator (genetics) ,Phosphodiesterase ,General Medicine ,chemistry ,Cardiovascular Diseases ,Guanylate Cyclase ,Second messenger system ,cardiovascular system ,Nervous System Diseases ,cGMP-dependent protein kinase ,medicine.drug - Abstract
Soluble Guanylate Cyclase (sGC) is the intracellular receptor of Nitric Oxide (NO). The activation of sGC results in the conversion of Guanosine Triphosphate (GTP) to the secondary messenger cyclic Guanosine Monophosphate (cGMP). cGMP modulates a series of downstream cascades through activating a variety of effectors, such as Phosphodiesterase (PDE), Protein Kinase G (PKG) and Cyclic Nucleotide-Gated Ion Channels (CNG). NO-sGC-cGMP pathway plays significant roles in various physiological processes, including platelet aggregation, smooth muscle relaxation and neurotransmitter delivery. With the approval of an sGC stimulator Riociguat for the treatment of Pulmonary Arterial Hypertension (PAH), the enthusiasm in the discovery of sGC modulators continues for broad clinical applications. Notably, through activating the NO-sGC-cGMP pathway, sGC stimulator and activator potentiate for the treatment of various diseases, such as PAH, Heart Failure (HF), Diabetic Nephropathy (DN), Systemic Sclerosis (SS), fibrosis as well as other diseases including Sickle Cell Disease (SCD) and Central Nervous System (CNS) disease. Here, we review the preclinical and clinical studies of sGC stimulator and activator in recent years and prospect for the development of sGC modulators in the near future.
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- 2019
32. Design, synthesis, and biological evaluation of 1,2,4‐oxadiazole‐containing pyrazolo[3,4‐ b ]pyridinones as a new series of AMPKɑ1β1γ1 activators
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Qi Chang, Yajun Peng, Bifeng Zheng, Zhihong Xiao, Qianbin Li, Yating Guo, Zhuo Chen, and Gaoyun Hu
- Subjects
Pyridones ,Enzyme Activators ,Pharmaceutical Science ,Apoptosis ,AMP-Activated Protein Kinases ,Kidney ,01 natural sciences ,Cell Line ,Structure-Activity Relationship ,Enzyme activator ,Drug Discovery ,medicine ,Animals ,Humans ,Binding site ,Protein kinase A ,chemistry.chemical_classification ,Oxadiazoles ,Reactive oxygen species ,010405 organic chemistry ,Activator (genetics) ,AMPK ,Fibroblasts ,Adenosine ,In vitro ,Rats ,0104 chemical sciences ,Enzyme Activation ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,chemistry ,Biochemistry ,Drug Design ,Pyrazoles ,Reactive Oxygen Species ,medicine.drug - Abstract
Adenosine monophosphate-activated protein kinase (AMPK) plays a key role in maintaining whole-body homeostasis and has been regarded as a therapeutic target for the treatment of diabetic nephropathy (DN). Herein, a series of 1,2,4-oxadiazole-containing pyrazolo[3,4-b]pyridinone derivatives is reported as AMPKɑ1β1γ1 activators. The in vitro biological assay demonstrated that compounds 12k (EC50 [AMPKα1γ1β1] = 180 nM) and 13q (EC50 [AMPKα1γ1β1] = 2 nM) displayed significant enzyme activation. Mechanism studies indicated that both compounds reduced the levels of reactive oxygen species in a rat kidney fibroblast cell line (NRK-49F) stimulated by transforming growth factor-β and induced early apoptosis of NRK-49F cells at 10 μM. Molecular docking studies suggested that 13q exhibited critical hydrogen-bond interactions with the critical amino acid residues Lys29, Lys31, Asn111, and Asp88 at the binding site of the AMPK protein. These results enrich the structure pool of AMPK activators and provide novel lead compounds for the subsequent development of compounds with a promising therapeutic potential against DN.
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- 2021
33. Synthesis, preliminary biological evaluation and 3D-QSAR study of novel 1,5-disubstituted-2(1H)-pyridone derivatives as potential anti-lung cancer agents
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Chuo Chen, Qianbin Li, Qifei Xu, Weixing Zhu, Gaoyun Hu, and Xiaoding Jiang
- Subjects
0301 basic medicine ,Quantitative structure–activity relationship ,Chemistry(all) ,General Chemical Engineering ,Pharmacology ,3D-QSAR models ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,A549 cell line ,medicine ,Potency ,Lung cancer ,IC50 ,Cisplatin ,010405 organic chemistry ,Chemistry ,Cancer ,Anti-lung cancer activity ,General Chemistry ,medicine.disease ,In vitro ,0104 chemical sciences ,030104 developmental biology ,Chemical Engineering(all) ,Lead compound ,2(1H)-pyridone derivatives ,medicine.drug - Abstract
Twenty-eight novel 1,5-disubstituted-2(1H)-pyridone derivatives were designed and synthesized for discovering more potent anti-lung cancer agents combined with anti-fibrotic profiles. The in vitro antiproliferative activities of the derivatives against A549 and NIH3T3 cell lines were tested by MTT assays. The majority of the tested analogues exhibited equivalent or an improved anti-lung cancer activity. Prominently, compound 4l displayed the best potency and selectivity toward A549 with an IC50 value of 20 μM, nearly comparable to the positive control cisplatin (IC50 = 10 μM) and even superior to the lead compound 22 (IC50 = 130 μM). Simultaneously, compound 4l showed significant inhibitory activity against NIH3T3 (IC50 = 55 μM), which may contribute to hindering the proliferation of lung cancer cells fundamentally. What is more, the 3D-QSAR models established on the activity data may provide new insights into the design of novel 2(1H)-pyridone derivatives and lay a theoretical foundation for further studies of promising anti-lung cancer activity with the maintenance of anti-fibrotic effect.
- Published
- 2016
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34. Fluorofenidone attenuates pulmonary inflammation and fibrosis via inhibiting the activation of <scp>NALP</scp> 3 inflammasome and <scp>IL</scp> ‐1β/ <scp>IL</scp> ‐1R1/MyD88/ <scp>NF</scp> ‐κB pathway
- Author
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Lujuan He, Gaoyun Hu, Cheng Song, Xiangning Yuan, Jin Zhang, Hong Ma, Jian Zhang, Jie Meng, and Lijian Tao
- Subjects
0301 basic medicine ,biology ,medicine.diagnostic_test ,Monocyte ,Interleukin ,NALP3 ,Inflammasome ,Cell Biology ,medicine.disease ,Molecular biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Western blot ,Fibrosis ,030220 oncology & carcinogenesis ,Myeloperoxidase ,Pulmonary fibrosis ,medicine ,biology.protein ,Molecular Medicine ,medicine.drug - Abstract
Interleukin (IL)-1β plays an important role in the pathogenesis of idiopathic pulmonary fibrosis. The production of IL-1β is dependent upon caspase-1-containing multiprotein complexes called inflammasomes and IL-1R1/MyD88/NF-κB pathway. In this study, we explored whether a potential anti-fibrotic agent fluorofenidone (FD) exerts its anti-inflammatory and anti-fibrotic effects through suppressing activation of NACHT, LRR and PYD domains-containing protein 3 (NALP3) inflammasome and the IL-1β/IL-1R1/MyD88/NF-κB pathway in vivo and in vitro. Male C57BL/6J mice were intratracheally injected with Bleomycin (BLM) or saline. Fluorofenidone was administered throughout the course of the experiment. Lung tissue sections were stained with haemotoxylin and eosin and Masson's trichrome. Cytokines were measured by ELISA, and α-smooth muscle actin (α-SMA), fibronectin, collagen I, caspase-1, IL-1R1, MyD88 were measured by Western blot and/or RT-PCR. The human actue monocytic leukaemia cell line (THP-1) were incubated with monosodium urate (MSU), with or without FD pre-treatment. The expression of caspase-1, IL-1β, NALP3, apoptosis-associated speck-like protein containing (ASC) and pro-caspase-1 were measured by Western blot, the reactive oxygen species (ROS) generation was detected using the Flow Cytometry, and the interaction of NALP3 inflammasome-associated molecules were measured by Co-immunoprecipitation. RLE-6TN (rat lung epithelial-T-antigen negative) cells were incubated with IL-1β, with or without FD pre-treatment. The expression of nuclear protein p65 was measured by Western blot. Results showed that FD markedly reduced the expressions of IL-1β, IL-6, monocyte chemotactic protein-1 (MCP-1), myeloperoxidase (MPO), α-SMA, fibronectin, collagen I, caspase-1, IL-1R1 and MyD88 in mice lung tissues. And FD inhibited MSU-induced the accumulation of ROS, blocked the interaction of NALP3 inflammasome-associated molecules, decreased the level of caspase-1 and IL-1β in THP-1 cells. Besides, FD inhibited IL-1β-induced the expression of nuclear protein p65. This study demonstrated that FD, attenuates BLM-induced pulmonary inflammation and fibrosis in mice via inhibiting the activation of NALP3 inflammasome and the IL-1β/IL-1R1/MyD88/ NF-κB pathway.
- Published
- 2016
35. Inhibitors of 11β-Hydroxylase (CYP11B1) for Treating Diseases Related to Excess Cortisol
- Author
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Weixing Zhu, Gaoyun Hu, Qianbin Li, Zhuo Chen, and Gui-Shan Tan
- Subjects
0301 basic medicine ,Pharmacology ,Chronic wound ,Drug discovery ,business.industry ,Organic Chemistry ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,Drug Discovery ,Molecular Medicine ,Medicine ,Wound closure ,Steroid 11-beta-hydroxylase ,medicine.symptom ,business ,Beneficial effects ,Cortisol level ,Medical therapy ,Therapeutic strategy - Abstract
The overproduction of cortisol is associated with many severe and life-threatening diseases, such as Cushing’s syndrome (CS) and chronic wound healing. 11β-Hydroxylase (CYP11B1) is considered as an attractive target for treating these diseases, since it is a key enzyme responsible for the last step in cortisol biosynthesis. Nowadays, medical therapy has become increasingly important for CS patients, especially for those who are in need of surgery or suffer from surgery failure and those in early phases of radiation therapy. In clinic, steroidogenesis blockers including CYP11B1 inhibitors are utilized most frequently. Nevertheless, drugs that inhibit CYP11B1 are inevitable with side effects due to lack of selectivity over other steroidogenesis enzymes. Recent advances in the development of novel CYP11B1 inhibitors might overcome these limitations. In addition, the beneficial effects of down-regulation of cortisol levels to wound closure have been recently disclosed and have stimulated topical application of CYP11B1 inhibitors as a novel therapeutic strategy for curing chronic wounds. Herein, we provide a review of the current CYP11B1 inhibitors in clinic combating CS and the latest development of novel CYP11B1 inhibitors for treating CS and chronic wounds.
- Published
- 2016
36. Drug repurposing and rediscovery: Design, synthesis and preliminary biological evaluation of 1-arylamino-3-aryloxypropan-2-ols as anti-melanoma agents
- Author
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Qi Chang, Liqing Hu, Jing Long, Qianbin Li, Gaoyun Hu, and Zhuo Chen
- Subjects
Skin Neoplasms ,Cell cycle checkpoint ,Cell Survival ,Propanols ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Apoptosis ,Propranolol ,Pharmacology ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Humans ,Melanoma ,Molecular Biology ,Cell Proliferation ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Cell growth ,Organic Chemistry ,Drug Repositioning ,medicine.disease ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Drug repositioning ,Tubulin ,Docking (molecular) ,Cardiovascular agent ,biology.protein ,Molecular Medicine ,Drug Screening Assays, Antitumor ,medicine.drug - Abstract
Malignant melanoma (MM) presents as the highest morbidity and mortality type in skin cancer. Herein, inspired by the previously reported anti-melanoma effect of propranolol, a widely applied β adrenergic receptor antagonist as cardiovascular drug, we set out to exploit its potential as anti-melanoma therapy based on the drug repurposing strategy. Structural optimization of propranolol yielded 5m, which exhibits dramatically improved potency on human melanoma cell growth (1.98–3.70 μM), compared to propranolol (59.5–75.8 μM). Further investigation demonstrated that 5m could inhibit colony formation of melanoma cell line (completely abolished at 2 μM for 5m, partially inhibited at 50 μM for propranolol), induce cell apoptosis and cell cycle arrest in the G2/M phase (both observed at 1 μM). Preliminary mechanism study indicated that 5m could disrupt the cellular microtubule network, which suggested tubulin as a potential target. Docking study provided a structural insight into the interaction between 5m and tubulin. In summary, our study presents a drug repurposing case that redirects a cardiovascular agent to an anti-melanoma agent.
- Published
- 2020
37. Fluorofenidone affects hepatic stellate cell activation in hepatic fibrosis by targeting the TGF-β1/Smad and MAPK signaling pathways
- Author
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Yu Peng, Hong Shen, Lijian Tao, Sha Tu, Mingyan Xie, Congying Yang, Huixiang Yang, Gaoyun Hu, Xin Zhang, and Li Li
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Cancer Research ,Kinase ,Chemistry ,p38 mitogen-activated protein kinases ,fluorofenidone ,Articles ,General Medicine ,SMAD ,Hepatic stellate cell activation ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immunology and Microbiology (miscellaneous) ,030220 oncology & carcinogenesis ,Hepatic stellate cell ,Cancer research ,hepatic fibrosis ,extracellular signal-regulated kinase/mitogen-activated protein kinase ,hepatic stellate cells ,Hepatic fibrosis ,Protein kinase A ,transforming growth factor-β1/mothers against decapentaplegic homolog - Abstract
The aim of the present research was to study the therapeutic impacts of fluorofenidone (AKF-PD) on pig serum (PS)-induced liver fibrosis in rats and the complex molecular mechanisms of its effects on hepatic stellate cells (HSCs). Wistar rats were randomly divided into normal control, PS and PS/AKF-PD treatment groups. The activated human HSC LX-2 cell line was also treated with AKF-PD. The expression of collagen I and III, and α-smooth muscle actin (α-SMA) was determined by immunohistochemical staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Western blotting and/or RT-qPCR analyses were used to determine the expression of transforming growth factor (TGF)-β1, α-SMA, collagen I, mothers against decapentaplegic homolog (Smad)-3, extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK). AKF-PD attenuated the degree of hepatic fibrosis and liver injury in vivo, which was associated with the downregulation of collagen I and III, and α-SMA at the mRNA and protein levels. In vitro, AKF-PD treatment significantly reduced the TGF-β1-induced activation of HSCs, as determined by the reduction in collagen I and α-SMA protein expression. The TGF-β1-induced upregulation of the phosphorylation of Smad 3, ERK1/2, p38 and JNK was attenuated by AKF-PD treatment. These findings suggested that AKF-PD attenuated the progression of hepatic fibrosis by suppressing HSCs activation via the TGF-β1/Smad and MAPK signaling pathways, and therefore that AKF-PD may be suitable for use as a novel therapeutic agent against liver fibrosis.
- Published
- 2017
38. Fluorofenidone inhibits macrophage IL-1β production by suppressing inflammasome activity
- Author
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Hong Ma, Wenjun Yang, Zhangzhe Peng, Juan Tang, Chunyan Liu, Gaoyun Hu, Lijian Tao, Ben Lv, Jie Meng, Xiangning Yuan, Jin Zhang, Jishi Liu, Wenjuan Mei, and Miaomiao Lu
- Subjects
Male ,Salmonella typhimurium ,Inflammasomes ,Pyridones ,medicine.medical_treatment ,Interleukin-1beta ,Immunology ,Anti-Inflammatory Agents ,Biology ,Cleavage (embryo) ,Mice ,Adenosine Triphosphate ,In vivo ,medicine ,Renal fibrosis ,Animals ,Humans ,Immunology and Allergy ,Cells, Cultured ,Immunosuppression Therapy ,Pharmacology ,Antigens, Bacterial ,Mice, Inbred BALB C ,Caspase 1 ,Inflammasome ,In vitro ,Cell biology ,Cytokine ,Biochemistry ,Proteolysis ,Macrophages, Peritoneal ,Fluorofenidone ,Nephritis, Interstitial ,medicine.drug - Abstract
Interleukin-1 beta (IL-1β) is a potent pro-inflammatory and pro-fibrotic cytokine that plays an important role in renal fibrosis. Fluorofenidone (AKF-PD) is a novel pyridone agent that exerts a strong renal anti-fibrotic effect. We previously found that administration of AKF-PD could significantly attenuate IL-1β production in vitro and in vivo. However, the underlying mechanism is not fully understood. Here we show that AKF-PD has no effect on the expression of pro-IL-1β in activated mouse macrophages in vitro. Instead, AKF-PD inhibits the inflammasome, lowering caspase-1 levels and thereby decreasing cleavage of pro-IL-1β into IL-1β. AKF-PD was found to block inflammasome activity induced by various signals, including ATP, alum crystals, and Salmonella typhimurium. These results provide a novel mechanistic insight into how AKF-PD exerts its anti-inflammatory and anti-fibrotic activities, and suggest that AKF-PD might block IL-1β production via suppression of inflammasomes in renal fibrosis. In addition, the results suggest that AKF-PD may be of therapeutic potential in other inflammasome-related diseases.
- Published
- 2015
39. The RAF-MEK-ERK pathway: targeting ERK to overcome obstacles to effective cancer therapy
- Author
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Shiqi Ye, Zutao Yu, Zhijun Tu, Gaoyun Hu, Meng Lv, Kun Zhou, and Qianbin Li
- Subjects
Pharmacology ,MAPK/ERK pathway ,Mutation ,MAP Kinase Signaling System ,business.industry ,Cancer therapy ,Drug resistance ,medicine.disease_cause ,Proto-Oncogene Proteins c-raf ,Clinical trial ,Preclinical research ,Neoplasms ,Drug Discovery ,Cancer research ,Animals ,Humans ,Molecular Medicine ,Medicine ,MEK-ERK Pathway ,Clinical efficacy ,Extracellular Signal-Regulated MAP Kinases ,business ,Protein Kinase Inhibitors - Abstract
Aim: Currently, dozens of BRAF inhibitors and MEK inhibitors targeting RAF-MEK-ERK pathway have been introduced into clinical trials for cancer therapy. However, after 6–8 months of initial response, acquired drug resistance among the majority of those treated patients sharply diminished their clinical efficacy. Discussion: Important mechanisms responsible for acquired resistance of BRAF inhibitors and MEK inhibitors have been elucidated. Continually, ERK1/2 locates in the critical position and features unique characteristics, such as activating hundreds of substrates, participating in feedback regulation, being catalyzed by MEK specifically and no acquired resistant mutation. Conclusion: Taking in account the inspiring outcomes of ERK inhibitors in preclinical research, ERK1/2 might be the optimal target to overcome acquired drug resistance in RAF-MEK-ERK pathway.
- Published
- 2015
40. Fluorofenidone attenuates interleukin-1β production by interacting with NLRP3 inflammasome in unilateral ureteral obstruction
- Author
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Linfeng, Zheng, Jin, Zhang, Xiangning, Yuan, Juan, Tang, Sisi, Qiu, Zhangzhe, Peng, Qiongjing, Yuan, Yanyun, Xie, Wenjuan, Mei, Yiting, Tang, Jie, Meng, Gaoyun, Hu, and Lijian, Tao
- Subjects
Male ,Nephritis ,Time Factors ,Inflammasomes ,Pyridones ,Caspase 1 ,Interleukin-1beta ,Anti-Inflammatory Agents ,Down-Regulation ,Kidney ,Fibrosis ,CARD Signaling Adaptor Proteins ,Rats, Sprague-Dawley ,Chemotaxis, Leukocyte ,Disease Models, Animal ,HEK293 Cells ,NLR Family, Pyrin Domain-Containing 3 Protein ,Animals ,Humans ,Signal Transduction ,Ureteral Obstruction - Abstract
We explored whether Fluorofenidone reduced interleukin-1β (IL-1β) production by interacting with NLRP3 inflammasome in unilateral ureteral obstruction (UUO).Ureteral obstruction rats were treated with Fluorofenidone (500 mg/kg per day) for 3, 7 days. Morphologic analysis and leukocytes infiltration were assessed in ligated kidneys. Furthermore, plasmids of NLRP3, ASC, pro-Caspase-1, pro-IL-1β were co-transfected into 293 T cells, and then treated with Fluorofenidone (2 mM). The expression of NLRP3, ASC, pro-caspase-1, cleavage caspase-1, pro-IL-1β and cleavage IL-1β were measured by Western blot or real-time PCR in vivo and in vitro. Moreover the interaction of NLRP3 inflammasome-assembly was detected by co-immunoprecipitation and confocal immunofluorescence.Fluorofenidone treatment significantly attenuated renal fibrosis and leukocytes infiltration in UUO model. Fluorofenidone had no effect on the expression of pro-IL-1β. Interestingly, Fluorofenidone inhibited the activation of NLRP3 inflammasome, downregulated Caspase-1 levels and thereby decreased the cleavage of pro-IL-1β into IL-1β in vivo and in vitro. Fluorofenidone treatment distinctively weakened the interaction between NLRP3 and ASC, as well as ASC and pro-Caspase-1 in vivo. However, Fluorofenidone treatment only significantly weakened the interaction between ASC and pro-Caspase-1 in co-transfected 293 T cells.Fluorofenidone serves as a novel anti-inflammatory agent that attenuates IL-1β production in UUO model by interacting with NLRP3 inflammasome.
- Published
- 2017
41. Soluble Guanylate Cyclase: A New Therapeutic Target for Fibrotic Diseases
- Author
-
Zhuo Chen, Ze-yu Wang, Qianbin Li, Rui Yi, Liqing Hu, Sijia Xiao, Gaoyun Hu, and Honghong Yi
- Subjects
inorganic chemicals ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Protein Conformation ,Enzyme Activators ,Stimulation ,Biochemistry ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Soluble Guanylyl Cyclase ,Fibrosis ,Transforming Growth Factor beta ,Drug Discovery ,Medicine ,Animals ,Humans ,heterocyclic compounds ,Molecular Targeted Therapy ,Pharmacology ,Kidney ,Lung ,business.industry ,Organic Chemistry ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Mechanism of action ,030220 oncology & carcinogenesis ,cardiovascular system ,Cancer research ,Molecular Medicine ,medicine.symptom ,Signal transduction ,business ,Transforming growth factor ,Signal Transduction - Abstract
Fibrosis occurs in a variety of organs and frequently brings great harm to patients, even contributes to their death. Despite great efforts made in the field of fibrosis over the past decades and considerable understanding of the pathogenesis of fibrotic reactions attained, there is still lack of effective anti-fibrotic treatments. A growing body of evidence indicates a significant anti-fibrotic potential of activated soluble guanylate cyclase (sGC), which emphasizes the importance of sGC in fibrogenesis of diverse organs including skin, kidney, liver and lung. While sGC has been well known for its role in the regulation of vascular tone and vascular remodeling, its possible implication in fibrosis remains to be illustrated. Emerging evidence in recent years provides new insights into anti-fibrotic effect of sGC stimulation by blocking non-canonical TGF-β signaling. In this review we will discuss the key role of sGC and its mechanism of action in fibrosis. Herein, sGC signaling pathway may represent a promising target for treating tissue fibrosis.
- Published
- 2016
42. Synthesis and structure–activity relationships of pyrazolo‐[3,4‐ b ]pyridine derivatives as adenosine 5'‐monophosphate‐activated protein kinase activators
- Author
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Bifeng Zheng, Weihong Wu, Yu Guo, Shengjie Sun, Gaoyun Hu, Junlong Ma, Zhuo Chen, Qianbin Li, Yajun Peng, and Yuzhao Zhang
- Subjects
Models, Molecular ,Adenosine monophosphate ,Pyridines ,Stereochemistry ,Pharmaceutical Science ,AMP-Activated Protein Kinases ,Pyrazole ,01 natural sciences ,Cell Line ,Structure-Activity Relationship ,chemistry.chemical_compound ,Enzyme activator ,Drug Discovery ,medicine ,Humans ,Protein kinase A ,Cell Proliferation ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Cell growth ,Activator (genetics) ,AMPK ,Adenosine ,Recombinant Proteins ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Pyrazoles ,medicine.drug - Abstract
A series of pyrazolo[3,4-b]pyridine derivatives were designed, synthesized, and evaluated for their activation activity toward adenosine 5'-monophosphate-activated protein kinase (AMPK). According to the enzyme activity, the pyrazole N-H exposure and para substitution on the diphenyl group were proved to be essential for the activation potency. Compound 17f showed equal activation compared with A-769662. In the molecular modeling study, compound 17f exhibited important hydrogen bond interaction with Lys29, Asp88, and Arg83. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays on the NRK-49F cell line showed that potent enzyme activators could effectively inhibit cell proliferation, especially for 17f (EC50 [AMPKα1γ1β1] = 0.42 μM, efficacy = 79%; IC50 [NRK-49F cell line] = 0.78 μM). These results might provide new insights to explore novel AMPK activators.
- Published
- 2019
43. Novel potent 2,5-pyrrolidinedione peptidomimetics as aminopeptidase N inhibitors. Design, synthesis and activity evaluation
- Author
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Hao Fang, Gaoyun Hu, Wenfang Xu, Qiang Wang, Qianbin Li, and Xuejian Wang
- Subjects
Models, Molecular ,Stereochemistry ,Peptidomimetic ,Phenylalanine ,Clinical Biochemistry ,Cell ,Succinimides ,Pharmaceutical Science ,Antineoplastic Agents ,CD13 Antigens ,Biochemistry ,Aminopeptidase ,Structure-Activity Relationship ,In vivo ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Protease Inhibitors ,Enzyme kinetics ,Molecular Biology ,IC50 ,Cell Proliferation ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Aminopeptidase N ,Organic Chemistry ,In vitro ,medicine.anatomical_structure ,Drug Design ,Molecular Medicine ,Peptidomimetics ,Drug Screening Assays, Antitumor - Abstract
A series of novel aminopeptidase N inhibitors with 2,5-pyrrolidinedione scaffold were chemically synthesized. Their preliminary biological activities in enzyme kinetics and cell assay in vitro and anti-metastasis profile in vivo were also evaluated. The results indicated that all the compounds displayed potent inhibitory activity against aminopeptidase N. Compound 8f inhibited aminopeptidase N activity with IC50 value of 1.0 μM and displayed better activity profile in vivo than that of bestatin.
- Published
- 2012
44. Fluorofenidone attenuates pulmonary inflammation and fibrosis via inhibiting the activation of NALP3 inflammasome and IL-1β/IL-1R1/MyD88/NF-κB pathway
- Author
-
Cheng, Song, Lujuan, He, Jin, Zhang, Hong, Ma, Xiangning, Yuan, Gaoyun, Hu, Lijian, Tao, Jian, Zhang, and Jie, Meng
- Subjects
Male ,Inflammasomes ,Pyridones ,NALP3 inflammasome ,Pulmonary Fibrosis ,Interleukin-1beta ,Down-Regulation ,fluorofenidone ,Collagen Type I ,Bleomycin ,NLR Family, Pyrin Domain-Containing 3 Protein ,Animals ,Humans ,IL‐1β/IL‐1R1/MyD88/NF‐κB pathway ,Lung ,Chemokine CCL2 ,Peroxidase ,Interleukin-6 ,Caspase 1 ,NF-kappa B ,Pneumonia ,Receptors, Interleukin ,Original Articles ,Actins ,Fibronectins ,Uric Acid ,Mice, Inbred C57BL ,Myeloid Differentiation Factor 88 ,Original Article ,Reactive Oxygen Species ,Signal Transduction - Abstract
Interleukin (IL)‐1β plays an important role in the pathogenesis of idiopathic pulmonary fibrosis. The production of IL‐1β is dependent upon caspase‐1‐containing multiprotein complexes called inflammasomes and IL‐1R1/MyD88/NF‐κB pathway. In this study, we explored whether a potential anti‐fibrotic agent fluorofenidone (FD) exerts its anti‐inflammatory and anti‐fibrotic effects through suppressing activation of NACHT, LRR and PYD domains‐containing protein 3 (NALP3) inflammasome and the IL‐1β/IL‐1R1/MyD88/NF‐κB pathway in vivo and in vitro. Male C57BL/6J mice were intratracheally injected with Bleomycin (BLM) or saline. Fluorofenidone was administered throughout the course of the experiment. Lung tissue sections were stained with haemotoxylin and eosin and Masson's trichrome. Cytokines were measured by ELISA, and α‐smooth muscle actin (α‐SMA), fibronectin, collagen I, caspase‐1, IL‐1R1, MyD88 were measured by Western blot and/or RT‐PCR. The human actue monocytic leukaemia cell line (THP‐1) were incubated with monosodium urate (MSU), with or without FD pre‐treatment. The expression of caspase‐1, IL‐1β, NALP3, apoptosis‐associated speck‐like protein containing (ASC) and pro‐caspase‐1 were measured by Western blot, the reactive oxygen species (ROS) generation was detected using the Flow Cytometry, and the interaction of NALP3 inflammasome‐associated molecules were measured by Co‐immunoprecipitation. RLE‐6TN (rat lung epithelial‐T‐antigen negative) cells were incubated with IL‐1β, with or without FD pre‐treatment. The expression of nuclear protein p65 was measured by Western blot. Results showed that FD markedly reduced the expressions of IL‐1β, IL‐6, monocyte chemotactic protein‐1 (MCP‐1), myeloperoxidase (MPO), α‐SMA, fibronectin, collagen I, caspase‐1, IL‐1R1 and MyD88 in mice lung tissues. And FD inhibited MSU‐induced the accumulation of ROS, blocked the interaction of NALP3 inflammasome‐associated molecules, decreased the level of caspase‐1 and IL‐1β in THP‐1 cells. Besides, FD inhibited IL‐1β‐induced the expression of nuclear protein p65. This study demonstrated that FD, attenuates BLM‐induced pulmonary inflammation and fibrosis in mice via inhibiting the activation of NALP3 inflammasome and the IL‐1β/IL‐1R1/MyD88/ NF‐κB pathway.
- Published
- 2015
45. Fluorofenidone attenuates bleomycin-induced pulmonary fibrosis by inhibiting eukaryotic translation initiation factor 3a (eIF3a) in rats
- Author
-
Dai Li, Wenqun Li, Xian-Wei Li, Yuan-Jian Li, Gaoyun Hu, Yue-Han Wu, Xiao-Hui Li, and Zhao-Qian Liu
- Subjects
0301 basic medicine ,Male ,Pyridones ,Eukaryotic Initiation Factor-3 ,Pulmonary Fibrosis ,Biology ,Bleomycin ,Rats, Sprague-Dawley ,Transforming Growth Factor beta1 ,03 medical and health sciences ,chemistry.chemical_compound ,Western blot ,In vivo ,Pulmonary fibrosis ,medicine ,Initiation factor ,Animals ,Lung ,Cell Proliferation ,Pharmacology ,medicine.diagnostic_test ,Cell growth ,Cell Differentiation ,Pirfenidone ,Fibroblasts ,medicine.disease ,Molecular biology ,In vitro ,Rats ,030104 developmental biology ,chemistry ,Gene Expression Regulation ,Collagen ,medicine.drug - Abstract
Fluorofenidone is a novel derivative of l-mimosine. It has remarkable anti-fibrotic properties. In this study, we established that fluorofenidone ameliorates pulmonary fibrosis (PF) both in vivo and in vitro by specifically inhibiting the expression of eukaryotic translation initiation factor 3a (eIF3a). eIF3a plays an important role in the development and progression of PF. An animal model of PF was induced by intratracheal instillation of bleomycin (5mg/kg) in rats. Rats were orally administered with fluorofenidone (250, 500 mg/kg/d·[i.g.]) and pirfenidone (500 mg/kg/d·[i.g.]) for 28 days. Primary pulmonary fibroblasts were cultured to determine the effect of fluorofenidone on TGF-β1-induced (5 ng/ml) proliferation and differentiation of fibroblasts. The expression/level of eIF3a, TGF-β1, α-SMA, collagen I, and collagen III were analyzed by ELISA, real-time PCR, and western blot. The cell proliferation rate was determined by MTS assay. The results indicate that fluorofenidone significantly improves the pathological changes in lung tissues and reduces the deposition of collagen by inhibiting eIF3a in rats with bleomycin-induced PF. Moreover, in a culture of pulmonary fibroblasts, fluorofenidone decreased the up-regulation of TGF-β1-induced eIF3a by inhibiting the proliferation of cells and reducing the expression of α-SMA, collagen I, and collagen III. These findings suggest that eIF3a is a new and special target of fluorofenidone, which could be potentially used in the development of a drug that treats PF.
- Published
- 2015
46. Identification of the human liver cytochrome P450 isoenzymes responsible for the 5-methylhydroxylation of the novel anti-fibrotic drug AKF-PD
- Author
-
Xiaoai He, Xi Luo, Gaoyun Hu, Zeneng Cheng, and Zhi Liu
- Subjects
CYP2D6 ,Pyridones ,Health, Toxicology and Mutagenesis ,Metabolite ,Debrisoquin ,Pharmacology ,Toxicology ,Biochemistry ,chemistry.chemical_compound ,Cytochrome P-450 Enzyme System ,Cytochrome P-450 CYP1A2 ,medicine ,Humans ,Drug Interactions ,CYP3A4 ,biology ,CYP1A2 ,Cytochrome P450 ,General Medicine ,Isoenzymes ,chemistry ,Chlorzoxazone ,Microsomes, Liver ,Microsome ,biology.protein ,Metabolic Networks and Pathways ,medicine.drug - Abstract
Identification of cytochrome P450 isoforms (CYPs) involved in flourofenidone (5-methyl-1-(3-fluorophenyl)-2-[1H]-pyridone, AKF-PD) 5-methylhydroxylation was carried out using human liver microsomes and cDNA-expressed human CYPs (supersomes). The experiments were performed in the following in vitro models: (A) a study of AKF-PD metabolism in liver microsomes: (a) correlations study between the rate of AKF-PD 5-methylhydroxylation and activity of CYPs; (b) the effect of specific CYPs inhibitors on the rate of AKF-PD 5-methylhydroxylation; (B) AKF-PD biotransformation by cDNA-expressed human CYPs (1A2, 2D6, 2C9, 2C19, 2E1, 3A4). In human liver microsomes, the formation of AKF-PD 5-methylhydroxylation metabolite significantly correlated with the caffeine N3-demethylase (CYP1A2), chlorzoxazone 6-hydroxylase (CYP2E1), midazolam 1'- hydroxylase (CYP3A4), tolbutamide 4-hydroxylase (CYP2C9), and debrisoquin 4-hydroxylase (CYP2D6) activities. The production of AKF-PD 5-methylhydroxylation metabolite was completely inhibited by a-naphthoflavone (a CYP1A2 inhibitor) with the IC50 value of 0.12 μM in human liver microsomes. The cDNA-expressed human CYPs generated different amounts of AKF-PD 5-methylhydroxylation metabolites, but the preference of CYP isoforms to catalyze AKF-PD metabolism was as follows: 2D6 2C19 1A2 2E1 2C9 3A4. The results demonstrated that CYP1A2 is the main isoform catalyzing AKF-PD 5-methylhydroxylation while CYP3A4, CYP2C9, CYP2E1, CYP2C19, and CYP2D6 are engaged to a lesser degree. Potential drug-drug interactions involving CYP1A2 may be noticed when AKF-PD is used combined with CYP1A2 inducers or inhibitors.
- Published
- 2011
47. Fluorofenidone attenuates renal interstitial fibrosis in the rat model of obstructive nephropathy
- Author
-
Gaoyun Hu, Wei Wang, Zhangzhe Peng, Yiting Tang, Qiongjing Yuan, Yanyun Xie, Bingxin Li, Lijian Tao, Fangfang Zhang, and Nasui Wang
- Subjects
Male ,medicine.medical_specialty ,Transcription, Genetic ,Pyridones ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Connective tissue ,urologic and male genital diseases ,Collagen Type I ,Rats, Sprague-Dawley ,Transforming Growth Factor beta1 ,Extracellular matrix ,Fibrosis ,Internal medicine ,medicine ,Animals ,Enalapril ,Molecular Biology ,Platelet-Derived Growth Factor ,Tissue Inhibitor of Metalloproteinase-1 ,biology ,business.industry ,Connective Tissue Growth Factor ,Cell Biology ,General Medicine ,Pirfenidone ,medicine.disease ,Actins ,Obstructive Nephropathy ,Rats ,CTGF ,Collagen Type III ,Kidney Tubules ,Endocrinology ,medicine.anatomical_structure ,Matrix Metalloproteinase 9 ,biology.protein ,Kidney Diseases ,business ,Platelet-derived growth factor receptor ,Ureteral Obstruction ,medicine.drug - Abstract
Fluorofenidone (FD) is a novel pyridone agent with significant antifibrotic effects in vitro. The purpose of this study is to investigate the effects of FD on renal interstitial fibrosis in rats with obstructive nephropathy caused by unilateral ureteral obstruction (UUO). With pirfenidone (PD, 500 mg/kg/day) and enalapril (10 mg/kg/day) as the positive treatment controls, the rats in different experimental groups were administered with FD (500 mg/kg/day) from day 4 to day 14 after UUO. The tubulointerstitial injury, interstitial collagen deposition, and expression of type I and type III collagen, transforming growth factor-β(1) (TGF-β(1)), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), α-smooth muscle actin (α-SMA), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were assessed. FD treatment significantly attenuated the prominently increased scores of tubulointerstitial injury, interstitial collagen deposition, and protein expression of type I and type III collagen in ureter-obstructed kidneys, respectively. As compared with untreated rats, FD also significantly reduced the expression of α-SMA, TGF-β(1), CTGF, PDGF, and inhibitor of TIMP-1 in the obstructed kidneys. Fluorofenidone attenuates renal interstitial fibrosis in the rat model of obstructive nephropathy through its regulation on fibrogenic growth factors, tubular cell transdifferentiation, and extracellular matrix.
- Published
- 2011
48. Fluorofenidone Attenuates Tubulointerstitial Fibrosis by Inhibiting TGF-β1-Induced Fibroblast Activation
- Author
-
Wei Wang, Zhaohe Wang, Zhangzhe Peng, Xiao Fu, Fangfang Zhang, Qiongjing Yuan, Linghao Wang, Rui Wang, Yu Peng, Lijian Tao, Gaoyun Hu, and Wangbin Ning
- Subjects
Male ,medicine.medical_specialty ,MAP Kinase Kinase 4 ,Pyridones ,Smad Proteins ,Kidney ,urologic and male genital diseases ,Rats, Sprague-Dawley ,Transforming Growth Factor beta1 ,Internal medicine ,Renal fibrosis ,Animals ,Medicine ,Phosphorylation ,Fibroblast ,Regulation of gene expression ,biology ,urogenital system ,business.industry ,Body Weight ,Kidney metabolism ,Fibroblasts ,Fibrosis ,female genital diseases and pregnancy complications ,Rats ,Kidney Tubules ,Endocrinology ,medicine.anatomical_structure ,Gene Expression Regulation ,Nephrology ,Mitogen-activated protein kinase ,Tubulointerstitial fibrosis ,Cancer research ,biology.protein ,business ,Transforming growth factor - Abstract
Background: Novel therapeutic agents are urgently needed to combat renal fibrosis. The purpose of this study was to assess, using complete unilateral ureteral obstruction (UUO) in rats, whether fluorofenidone (AKF-PD) [1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone] inhibits renal fibrosis, and to determine whether it exerts its inhibitory function on renal fibroblast activation. Methods: Sprague-Dawley rats were randomly divided into 3 groups: sham operation, UUO and UUO/AKF-PD (500 mg/kg/day). Renal function, tubulointerstitium damage index score, extracellular matrix (ECM) deposition, and the expressions of TGF-β1, collagen III, α-SMA, p-Smad2, p-Smad3, p-ERK1/2, p-JNK and p-p38 were measured. In addition, the expressions of α-SMA, fibronectin, CTGF, p-Smad2/3, p-ERK1/2, p-p38 and p-JNK were measured in TGF-β1-stimulated normal rat renal fibroblasts (NRK-49F). Results: AKF-PD treatment significantly attenuated tubulointerstitium damage, ECM deposition, the expressions of TGF-β1, collagen III, α-SMA, p-ERK1/2, p-p38 and p-JNK in vivo. In vitro, AKF-PD dose-dependently inhibited expressions of α-SMA, fibronectin and CTGF. Furthermore, AKF-PD did not inhibit Smad2/3 phosphorylation or nuclear accumulation, but rather attenuated ERK, p38 and JNK activation. Conclusion: AKF-PD treatment inhibits the progression of renal interstitial fibrosis in obstructed kidneys; this is potentially achieved by suppressing fibroblast activation. Therefore, AKF-PD is a special candidate for the treatment of renal fibrosis.
- Published
- 2011
49. Fluorofenidone protects mice from lethal endotoxemia through the inhibition of TNF-α and IL-1β release
- Author
-
Wangbin Ning, Gaoyun Hu, Yiting Tang, Qiongjing Yuan, Yanyun Xie, Zhangzhe Peng, Bingxin Li, Jing Li, Fangfang Zhang, Lijian Tao, Ling Wang, Linghao Wang, Jiao Qin, and Nasui Wang
- Subjects
Male ,Pyridones ,medicine.medical_treatment ,Interleukin-1beta ,Immunology ,Anti-Inflammatory Agents ,Down-Regulation ,Inflammation ,Pharmacology ,Proinflammatory cytokine ,Sepsis ,Pathogenesis ,Mice ,medicine ,Animals ,Immunology and Allergy ,Macrophage ,Cells, Cultured ,Mice, Inbred BALB C ,Tumor Necrosis Factor-alpha ,business.industry ,Septic shock ,Macrophages ,medicine.disease ,Endotoxemia ,Cytokine ,Tumor necrosis factor alpha ,medicine.symptom ,business - Abstract
The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release proinflammatory factors like TNF-alpha and IL-1beta. Fluorofenidone (AKF-PD) is a novel pyridone agent, which exerts a strong antifibrotic effect. In this work, we showed that AKF-PD also exert an inhibitory effect on acute systemic inflammatory response. AKF-PD treatment significantly increased survival in animals with established endotoxemia. In addition, AKF-PD treatment significantly reduced circulating levels of TNF-alpha and IL-1beta during endotoxemia. In macrophage cultures, AKF-PD inhibited the release of TNF-alpha and IL-1beta in a dose-dependent manner. In conclusion, these results indicate that AKF-PD inhibits the release of the proinflammatory cytokines (TNF-a and IL-1beta) and improves survival during lethal endotoxemia, which suggest this new pyridone agent can be a novel candidate for therapy of septic shock.
- Published
- 2010
50. Fluorofenidone attenuates collagen I and transforming growth factor-β1 expression through a nicotinamide adenine dinucleotide phosphate oxidase-dependent way in NRK-52E cells
- Author
-
Gaoyun Hu, Lijian Tao, Wangbin Ning, Yi-Ting Tang, Nasui Wang, Zhangzhe Peng, Hong Shen, Yanyun Xie, Ling Wang, and Bingxin Li
- Subjects
Pyridones ,Kidney ,Collagen Type I ,Kidney Tubules, Proximal ,Transforming Growth Factor beta1 ,Superoxide dismutase ,chemistry.chemical_compound ,Superoxides ,Dichlorofluorescein ,Animals ,Medicine ,Cells, Cultured ,chemistry.chemical_classification ,Reactive oxygen species ,Oxidase test ,NADPH oxidase ,biology ,business.industry ,Cytochrome c ,NADPH Oxidases ,General Medicine ,Fibrosis ,Molecular biology ,Rats ,chemistry ,Nephrology ,biology.protein ,P22phox ,business ,Nicotinamide adenine dinucleotide phosphate - Abstract
SUMMARY: Aim: Fluorofenidone (1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone) is a novel pyridone agent. The aim of the present study is to investigate the effects of fluorofenidone on angiotensin (Ang)II-induced fibrosis and the involved molecular mechanism in rat proximal tubular epithelial cells. Methods: NRK-52E cells, a rat proximal tubular epithelial cell line, were incubated with medium containing AngII, with or without nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium (DPI), losartan, fluorofenidone (2, 4 and 8 mmol/L) and pirfenidone (8 mmol/L) for 24 h. Cells in the serum-free medium were controls. The expression of three subunits of NADPH oxidase, including p47phox, Nox-4 and p22phox, were determined by real-time reverse transcription polymerase chain reaction (RT–PCR) and western blot. NADPH oxidase activity was measured directly by superoxide dismutase (SOD) inhibitable cytochrome C reduction assay. The generation of reactive oxygen species (ROS) was measured by dichlorofluorescein fluorescence analysis. The mRNA and protein expression of collagen I and transforming growth factor (TGF)-β1 were determined by real-time RT–PCR and enzyme-linked immunosorbent assay. Results: Fluorofenidone significantly inhibited TGF-β1 and collagen I expression upregulation induced by AngII or TGF-β1 respectively. Moreover, fluorofenidone greatly reduced the elevation of expression and activity of NADPH oxidase and inhibited ROS generation induced by AngII in rat proximal tubular epithelial cells. These responses were also attenuated by DPI, losartan, and pirfenidone. Conclusion: Fluorofenidone acted as an anti-oxidative and anti-fibrotic agent through the mechanisms of blocking NADPH oxidase-dependent oxidative stress and inhibiting TGF-β1 expression in rat proximal tubular epithelial cells.
- Published
- 2009
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