Chronic heart failure(CHF)impairs cognitive function.Xijiaqi Formula(XJQ),a traditional Chinese medicine(TCM)used clinically to treat CHF,demonstrates potential for improving cognition in CHF patients.However,its prec...Chronic heart failure(CHF)impairs cognitive function.Xijiaqi Formula(XJQ),a traditional Chinese medicine(TCM)used clinically to treat CHF,demonstrates potential for improving cognition in CHF patients.However,its precise mechanism in treating post-CHF cognitive dysfunction remains unclear.This study systematically investigates XJQ’s effects on post-CHF cognitive dysfunction and the underlying mechanisms.The components of XJQ were identified through liquid chromatography-mass spectrometry.CHF was induced in rats via ligation of the left anterior descending coronary artery,followed by six weeks of XJQ treatment.Cardiac function was evaluated through echocardiography and hemodynamic parameters,while cognitive function was assessed using Morris water maze(MWM)and open field tests(OFT).XJQ treatment enhanced both cardiac and cognitive functions in CHF rats.Network pharmacology identified 12 core active components of XJQ and indicated its effect on cognitive dysfunction involved regulating synapses,inflammation,and phosphodiesterase 4(PDE4)-dependent cyclic adenosine monophosphate(cAMP)signaling.XJQ inhibited microglial and astrocyte activation,decreased proinflammatory cytokines,and mitigated neuronal damage.Notably,XJQ promoted synaptic repair and dendritic growth by downregulating PDE4 and upregulating cAMP,protein kinase A(PKA),cAMP-response element binding protein(CREB),brain-derived neurotrophic factor(BDNF),PSD95,and synapsin I levels.Molecular docking and Bio-layer interferometry assays confirmed direct binding of quercetin,kaempferol,isorhamnetin,and darutoside to PDE4.In conclusion,XJQ alleviates neuroinflammation and enhances synaptic plasticity to improve cognitive dysfunction in CHF rats via the PDE4/cAMP/PKA/CREB signaling pathway.These findings provide valuable insight into the heart-brain axis.展开更多
Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease and its incidence rate is rapidly rising.However,effective therapies for the treatment of IPF are still lacking.Phosphodiesterase 4(PDE4)inhibitors were ...Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease and its incidence rate is rapidly rising.However,effective therapies for the treatment of IPF are still lacking.Phosphodiesterase 4(PDE4)inhibitors were reported to be potential anti-fibrotic agents.Herein,structure-based hit-to-lead optimization of natural isoaurostatin(8.98μmol/L)resulted in several potent inhibitors of PDE4 with half maximal inhibitory concentration(IC_(50))values ranging from 35 nmol/L to 126 nmol/L.Co-crystal structures revealed that isoaurostatin compounds exhibited different binding patterns from the classic PDE4 inhibitor rolipram and the analogues would favor to be Z configurations other than the corresponding E isomers.Finally,lead 2–9 showed remarkable in vitro/in vivo anti-fibrotic effects indicating its potential as a novel anti-IPF agent.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82430116 and 82574622)the Special Fund of Central Committee High Level Chinese Medicine Hospital(Nos.DZMG-LJRC-0014,DZMG-ZJXY-23013)+1 种基金Chinese Medicine Inheritance and Innovation“Thousand Million”Talents Project(Qihuang Project 2021)Qihuang Scholarsthe Medical and Health Industry Development Project of Tongzhou District(2023).
文摘Chronic heart failure(CHF)impairs cognitive function.Xijiaqi Formula(XJQ),a traditional Chinese medicine(TCM)used clinically to treat CHF,demonstrates potential for improving cognition in CHF patients.However,its precise mechanism in treating post-CHF cognitive dysfunction remains unclear.This study systematically investigates XJQ’s effects on post-CHF cognitive dysfunction and the underlying mechanisms.The components of XJQ were identified through liquid chromatography-mass spectrometry.CHF was induced in rats via ligation of the left anterior descending coronary artery,followed by six weeks of XJQ treatment.Cardiac function was evaluated through echocardiography and hemodynamic parameters,while cognitive function was assessed using Morris water maze(MWM)and open field tests(OFT).XJQ treatment enhanced both cardiac and cognitive functions in CHF rats.Network pharmacology identified 12 core active components of XJQ and indicated its effect on cognitive dysfunction involved regulating synapses,inflammation,and phosphodiesterase 4(PDE4)-dependent cyclic adenosine monophosphate(cAMP)signaling.XJQ inhibited microglial and astrocyte activation,decreased proinflammatory cytokines,and mitigated neuronal damage.Notably,XJQ promoted synaptic repair and dendritic growth by downregulating PDE4 and upregulating cAMP,protein kinase A(PKA),cAMP-response element binding protein(CREB),brain-derived neurotrophic factor(BDNF),PSD95,and synapsin I levels.Molecular docking and Bio-layer interferometry assays confirmed direct binding of quercetin,kaempferol,isorhamnetin,and darutoside to PDE4.In conclusion,XJQ alleviates neuroinflammation and enhances synaptic plasticity to improve cognitive dysfunction in CHF rats via the PDE4/cAMP/PKA/CREB signaling pathway.These findings provide valuable insight into the heart-brain axis.
基金supported by the Natural Science Foundation of China(Nos.22277019,82150204,22307031,22377023,22077143,and 82003594)Key Project of Guangdong Natural Science Foundation(No.2016A030311033)+2 种基金Fundamental Research Funds for Hainan University(Nos.KYQD(ZR)-21031,KYQD(ZR)-21108,KYQD(ZR)-23003,and XTCX2022JKA01)Guangdong Provincial Key Laboratory of Construction Foundation(No.2023B1212060022)Science Foundation of Hainan Province(Nos.KJRC2023B10,824YXQN420,and 324MS018)。
文摘Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease and its incidence rate is rapidly rising.However,effective therapies for the treatment of IPF are still lacking.Phosphodiesterase 4(PDE4)inhibitors were reported to be potential anti-fibrotic agents.Herein,structure-based hit-to-lead optimization of natural isoaurostatin(8.98μmol/L)resulted in several potent inhibitors of PDE4 with half maximal inhibitory concentration(IC_(50))values ranging from 35 nmol/L to 126 nmol/L.Co-crystal structures revealed that isoaurostatin compounds exhibited different binding patterns from the classic PDE4 inhibitor rolipram and the analogues would favor to be Z configurations other than the corresponding E isomers.Finally,lead 2–9 showed remarkable in vitro/in vivo anti-fibrotic effects indicating its potential as a novel anti-IPF agent.
