PHARMACOLOGICAL RESEARCH
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2022
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IF 10.334
Bei Yan,Panpan Liu,Xiaoqin Yi,Jie Li,Nian Liu,Wu Zhu,Yehong Kuang,Xiang Chen,Cong Peng
Background Psoriasis is a chronic inflammatory disease , with lesions mainly manifesting as scaly erythematous plaques. The mild or moderate of psoriasis is the main type of patients in hospital, and topical application remains the preferred treatment option for psoriasis therapy, therefore, the development of novel topical agents has an essential role in psoriasis therapy. Objective To identify potential drugs for psoriasis topical treatment. Methods We performed drug screening by Imiquimod (IMQ)-induced psoriatic like inflammation in mouse model, followed mouse epidermis by RNA-seq to find the key molecules affecting the drug. The qRT-PCR, WB were performed to test mRNA and protein expression, and Chip assay had been conducted to examine Stat3 bound to promoter of FABP5. Results In this study, we identified VX-509, which topical application significantly attenuated IMQ-induced psoriatic like inflammation in mouse model. And then, we verified Epidermal Fatty acid binding protein (E-FABP/FABP5) was significantly decreased in VX-509 treated mouse epidermis by RNA-seq. FABP5 is a key molecule in lipid metabolism, administration of FABP5 inhibitor or knock down of FABP5 expression remarkably abrogated psoriatic inflammation as well as lipid metabolism. Mechanistically, our finding showed that VX-509 blocked IL-22 induced signaling pathway, particular in activation of Stat3. Furthermore, we identified Stat3 is a transcriptional factor associated with FABP5 promoters and VX-509 treatment remarkably attenuated IL-22-induced FABP5 expression through Stat3 in KCs. Conclusions This study demonstrated administration of VX-509 is a potential promising topical drug for treatment of psoriasis, FABP5 is a critical targeted molecule in psoriasis therapy.
研究领域:
皮肤科
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药理学
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分子生物学
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炎症
✓ 已验证
DOI
PubMed
高影响因子
Cell Reports
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2025
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IF 6.9
Rong Wu,Yunong Zeng,Jiaochan Han,Lei Li,Qing-Ming Xiong,Shuyu Li,Shanshan Fu,Ping Qin,Ze Wang,Yi He,Zhengzheng Yan,Weidong Xiao,Zhenhua Zeng,Zhe-Xiong Lian,Zhi-Bin Zhao,Wei Xiao,Yong Jiang,Shenhai Gong
Damage-associated molecular patterns (DAMPs) often cause an exaggerated immune response. Fatty acid-binding protein 5 (FABP5) is traditionally considered a cytosolic protein responsible for the transport of fatty acids. However, little is known about the role of FABP5 in sepsis. Herein, we found that circulating FABP5 levels were higher in patients with sepsis and were associated with adverse outcomes. The circulating FABP5 originated mainly from macrophage pyroptosis in the later stages of sepsis despite a decrease in cytoplasm-resident FABP5 expression. Functionally, circulating FABP5 penetrated the living macrophage membrane and bound to the intracellular domain of TLR4, ultimately inducing secondary inflammation through the NF-κB and MAPK pathways. Unlike circulating oxidized FABP5, cytoplasm-resident FABP5 was present in its reduced form and suppressed macrophage pyroptosis. Clearance of circulating DAMP FABP5 by preventing the passive release from dying macrophages or using a specific blocking antibody can improve survival in mice with sepsis.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Chinese Herbal Medicines
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2019
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IF 0
Ya-yun Liu,Jiao-jiao You,Wei Xu,Ting Zhai,Chun-yuan Du,Yong Chen,Feng-mei Han
Objective The present work was to investigate the protective effects of the aqueous extract of Gynura procumbens (GPAE) against nonalcoholic steatohepatitis (NASH) in mice and NCTC-1469 cells. Methods C57BL/6J mice were fed with methionine and choline-deficient (MCD) diet and administered simultaneously with GPAE (500 and 1000 mg/kg/d, respectively) by gavage for six weeks. The biomarkers of NASH in serum and liver were determined. NCTC-1469 cells were pretreated with 0.25 mmol/L palmitic acid (PA) plus 0.5 mmol/L oleic acid (OA) for 24 h or treated with adenovirus expressing short-hairpin RNA against CFLAR (Ad-shCFLAR) for 24 h and then treated with GPAE (80 and 160 µg/mL, respectively) for 24 h, and the content of cellular biomarkers of NASH was detected. Results In mice treated with MCD , GPAE could decrease the levels of serum ALT , AST, the content of hepatic TG , TC and MDA , repress the activities and protein expression of CYP2E1 and CYP4A and the phosphorylation of JNK, increase the activities of HO-1, CAT and GSH-Px, up-regulate the mRNA expression of PPARα, FABP5, CPT1α, ACOX, SCD-1, mGPAT, MTTP and the protein expression of CFLAR and NRF2. In NCTC-1469 cells treated with PA and OA, GPAE could decrease the content of cellular TG and ROS , promote the uptake of 2-NBDG, up-regulate the protein expression of CFLAR and NRF2. In NCTC-1469 cells treated with Ad-sh CFLAR , GPAE up-regulated the mRNA and protein expression of CFLAR, down-regulated the phosphorylation of JNK, and increased the protein expression of NRF2 and pIRS1 . Conclusion These results indicated that the activation on CFLAR-JNK pathway might be the main anti-NASH mechanism of GPAE, which on the one hand promote the β-oxidation and efflux of fatty acids in liver, and finally reduce hepatic lipid accumulation , on the other hand increase the activities of anti-oxidant enzymes and inhibit the activities of ROS generation enzymes by activating NRF2, and therefore attenuates hepatic oxidative stress damage.
研究领域:
药理学
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肝病学
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分子生物学
✓ 已验证
产品关联
DOI
JOURNAL OF ETHNOPHARMACOLOGY
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2023
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IF 5.4
Jiaqi Xie,Yihong Li,Yulu Liang,Hongqian Kui,Can Wang,Jianmei Huang
Ethnopharmacological relevance Platycladi Semen was recorded in Shen Nong's Herbal Classic and was considered a herbal medicine with low toxicity after long-term medication. Multiple traditional Chinese medicine prescriptions containing Platycladi Semen have been used to treat insomnia. Modern clinical practitioners commonly use Platycladi Semen to treat anxiety disorders, but there are few studies on its composition and anxiolytic mechanisms. Aim of the study To describe the main components of Platycladi Semen and investigate its anxiolytic effects and mechanisms. Materials and methods The main components of Platycladi Semen were characterized by liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS). The anxiolytic effects of oral Platycladi Semen were evaluated in chronic unpredictable mild stress (CUMS) induced mice. To explore the anxiolytic mechanisms of Platycladi Semen , serum non-targeted metabolomics combined with network pharmacology and molecular docking was performed. Results Fourteen compounds were identified in the 50% methanol extract and 11 fatty acid derivatives were identified in the methyl-esterified fatty oil of Platycladi Semen . In CUMS mice, both the aqueous extract and fatty oil of Platycladi Semen had anxiolytic effects, which were shown by the increase in the time and frequency of mice entering the open arm in the elevated plus maze (EPM) experiment. Through serum non-targeted metabolomics, 34 differential metabolites were identified, and lipid metabolic pathways such as sphingolipid metabolism, steroidogenesis, alpha-linoleic acid, and linoleic acid metabolism were enriched. Through network pharmacology, 109 targets of the main components in Platycladi Semen were identified, and the ‘neuroactive ligand-receptor interaction’ and ‘lipid metabolism’ were enriched. The molecular docking results showed that the main components in Platycladi Semen could bind to the key targets such as peroxisome proliferator-activated receptor delta (PPARD), peroxisome proliferator-activated receptor alpha (PPARA), fatty acid binding protein 5 (FABP5), fatty acid binding protein 3 (FABP3), peroxisome proliferator-activated receptor gamma (PPARG), arachidonate 5-lipoxygenase (ALOX5) and fatty acid amide hydrolase (FAAH). Conclusion This study indicated that Platycladi Semen has anxiolytic effects, and the anxiolytic mechanisms may be the regulation of lipid metabolism and the neuroactive ligand-receptor interaction.
研究领域:
药理学
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代谢组学
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中药学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）