OBJECTIVE:To investigate the protective effect of matrine on coronary microvascular dysfunction(CMD)induced by advanced glycation end products(AGEs)in a mouse model of ischemia with non-obstructive coronary artery dis...OBJECTIVE:To investigate the protective effect of matrine on coronary microvascular dysfunction(CMD)induced by advanced glycation end products(AGEs)in a mouse model of ischemia with non-obstructive coronary artery disease(INOCA),with a focus on the underlying mechanisms,particularly the endoplasmic reticulum(ER)stress protein kinase R-like ER kinase(PERK)/nuclear factor of activated T-cells(NFAT)signaling pathway.METHODS:An INOCA model was established in mice,and CMD was induced by peritoneal injections of AGEs.Matrine was administered daily via intraperitoneal injections.Coronary microcirculation was evaluated using coronary flow velocity reserve(CFVR),and cardiac microvascular endothelial cells(CMECs)were isolated for assessment of apoptosis,inflammation,oxidative stress,and microthrombosis.Markers of ER stress and the PERK/NFAT pathway were examined through immunoblotting,immunofluorescence,and enzymatic assays.The effect of matrine were further evaluated in CMECs treated with AGEs and the PERK agonist.RESULTS:Matrine treatment significantly improved CFVR and reduced CMD in AGEs-exposed INOCA mice.In CMECs,matrine attenuated AGEs-induced apoptosis,inflammation,and microthrombosis.It also suppressed intracellular reactive oxygen species(ROS)generation,ER stress markers,and PERK/NFAT signaling.Matrine's effects were concentration-dependent and partially reversed by the PERK agonist,confirming its action through the ER stress pathway.No significant toxicities were observed with matrine administration.CONCLUSION:Matrine attenuates AGEs-induced CMD in INOCA by suppressing the ROS-mediated ER stress PERK/NFAT signaling pathway in CMECs.This study highlights matrine's potential as a therapeutic agent for CMD in diabetic cardiovascular complications.展开更多
We are in an era of technological revolutions promoting personalised healthcare.Advances in medical imaging techniques with 3D imaging software and 3D printing have allowed healthcare professionals to view and documen...We are in an era of technological revolutions promoting personalised healthcare.Advances in medical imaging techniques with 3D imaging software and 3D printing have allowed healthcare professionals to view and document various geometrical structures in a brand-new way,enabling them to make meaningful 3D measurements more accurately by generating both virtual and physical models used for preoperative planning,physician-patient communication,and fabrication of surgical guides,instruments,and implants[1-5].With improvements in cost-effectiveness,efficiency,and mechanical properties,3D printing technologies have become a powerful tool for physicians to meet clinical requirements.展开更多
The structure evolution and electrochemical performance of Na SICON-type Ca_(0.5)Ti_(2)(PO_(4))_(3) for sodium batteries are presented.This phosphate was synthesized by a solid-state method,and the obtained particles ...The structure evolution and electrochemical performance of Na SICON-type Ca_(0.5)Ti_(2)(PO_(4))_(3) for sodium batteries are presented.This phosphate was synthesized by a solid-state method,and the obtained particles were coated with carbon using sucrose.This compound crystallizes in the rhombohedral system with space group R-3.The presence of carbon in the Ca_(0.5)Ti_(2)(PO_(4))_(3)/C composite was confirmed by Raman and Thermogravimetric analysis.The electrochemical performance of Ca_(0.5)Ti_(2)(PO_(4))_(3)/C was investigated in the potential window 1.5–3.0 V vs.sodium metal at different scan rates.The compound is able to initially intercalate/deintercalate 1.6/1.15 Na per formula unit,respectively.In operando synchrotron diffraction was done in the potential window 0.02–3.0 V vs.Na|Na+and revealed the occurrence of several reaction regions upon first discharge.Up to 4 Na+ion per formula unit can be inserted during the first discharge.An intensive refinement of the synchrotron X-ray diffraction(SXRD)patterns of discharged Ca_(0.5)Ti_(2)(PO_(4))_(3) evidenced the existence of five regions depending on the sodium content while the crystal structures of new phases were elucidated for the first time where sodium insertion occurs in the unusual M3 and M’3 sites of the Na SICON structure.展开更多
Combinatorial drug therapies are generally more effective than monotherapies in treating viral infections.However,it is critical for dose optimization to maximize the efficacy and minimize side effects.Although variou...Combinatorial drug therapies are generally more effective than monotherapies in treating viral infections.However,it is critical for dose optimization to maximize the efficacy and minimize side effects.Although various strategies have been devised to accelerate the optimization process,their efficiencies were limited by the high noises and suboptimal reproducibility of biological assays.With conventional methods,variances among the replications are used to evaluate the errors of the readouts alone rather than actively participating in the optimization.Herein,we present the Regression Modeling Enabled by Monte Carlo Method(ReMEMC)algorithm for rapid identification of effective combinational therapies.ReMEMC transforms the sample variations into probability distributions of the regression coefficients and predictions.In silico simulations revealed that ReMEMC outperformed conventional regression methods in benchmark problems,and demonstrated its superior robustness against experimental noises.Using COVID-19 as a model disease,ReMEMC successfully identified an optimal 3-drug combination among 10 anti-SARS-CoV-2 drug compounds within two rounds of experiments.The optimal combination showed 2-log and 3-log higher load reduction than non-optimized combinations and monotherapy,respectively.Further workflow refinement allowed identification of personalized drug combinational therapies within 5 days.The strategy may serve as an efficient and universal tool for dose combination optimization.展开更多
基金National Natural Scientific Foundation of China:Mechanisms of Macrophage-Mediated Vascular Smooth Muscle Cells Phenotypic Conversion in Advanced Glycation End Products-induced Atherosclerosis and Therapeutic Effects of Targeted Gene Silencing(82070858)Youth Scientific Research and Innovation Team Program of Shaanxi Province:Diabetes-Related Atherosclerosis Basic Research and Application Research Team(2022-SLRH-LJ-014)。
文摘OBJECTIVE:To investigate the protective effect of matrine on coronary microvascular dysfunction(CMD)induced by advanced glycation end products(AGEs)in a mouse model of ischemia with non-obstructive coronary artery disease(INOCA),with a focus on the underlying mechanisms,particularly the endoplasmic reticulum(ER)stress protein kinase R-like ER kinase(PERK)/nuclear factor of activated T-cells(NFAT)signaling pathway.METHODS:An INOCA model was established in mice,and CMD was induced by peritoneal injections of AGEs.Matrine was administered daily via intraperitoneal injections.Coronary microcirculation was evaluated using coronary flow velocity reserve(CFVR),and cardiac microvascular endothelial cells(CMECs)were isolated for assessment of apoptosis,inflammation,oxidative stress,and microthrombosis.Markers of ER stress and the PERK/NFAT pathway were examined through immunoblotting,immunofluorescence,and enzymatic assays.The effect of matrine were further evaluated in CMECs treated with AGEs and the PERK agonist.RESULTS:Matrine treatment significantly improved CFVR and reduced CMD in AGEs-exposed INOCA mice.In CMECs,matrine attenuated AGEs-induced apoptosis,inflammation,and microthrombosis.It also suppressed intracellular reactive oxygen species(ROS)generation,ER stress markers,and PERK/NFAT signaling.Matrine's effects were concentration-dependent and partially reversed by the PERK agonist,confirming its action through the ER stress pathway.No significant toxicities were observed with matrine administration.CONCLUSION:Matrine attenuates AGEs-induced CMD in INOCA by suppressing the ROS-mediated ER stress PERK/NFAT signaling pathway in CMECs.This study highlights matrine's potential as a therapeutic agent for CMD in diabetic cardiovascular complications.
文摘We are in an era of technological revolutions promoting personalised healthcare.Advances in medical imaging techniques with 3D imaging software and 3D printing have allowed healthcare professionals to view and document various geometrical structures in a brand-new way,enabling them to make meaningful 3D measurements more accurately by generating both virtual and physical models used for preoperative planning,physician-patient communication,and fabrication of surgical guides,instruments,and implants[1-5].With improvements in cost-effectiveness,efficiency,and mechanical properties,3D printing technologies have become a powerful tool for physicians to meet clinical requirements.
基金the project e-STORE(APRD Program)funded by OCP Foundationwas partially funded by the German Research Foundation(DFG)under Project ID 390874152(POLi S Cluster of Excellence)。
文摘The structure evolution and electrochemical performance of Na SICON-type Ca_(0.5)Ti_(2)(PO_(4))_(3) for sodium batteries are presented.This phosphate was synthesized by a solid-state method,and the obtained particles were coated with carbon using sucrose.This compound crystallizes in the rhombohedral system with space group R-3.The presence of carbon in the Ca_(0.5)Ti_(2)(PO_(4))_(3)/C composite was confirmed by Raman and Thermogravimetric analysis.The electrochemical performance of Ca_(0.5)Ti_(2)(PO_(4))_(3)/C was investigated in the potential window 1.5–3.0 V vs.sodium metal at different scan rates.The compound is able to initially intercalate/deintercalate 1.6/1.15 Na per formula unit,respectively.In operando synchrotron diffraction was done in the potential window 0.02–3.0 V vs.Na|Na+and revealed the occurrence of several reaction regions upon first discharge.Up to 4 Na+ion per formula unit can be inserted during the first discharge.An intensive refinement of the synchrotron X-ray diffraction(SXRD)patterns of discharged Ca_(0.5)Ti_(2)(PO_(4))_(3) evidenced the existence of five regions depending on the sodium content while the crystal structures of new phases were elucidated for the first time where sodium insertion occurs in the unusual M3 and M’3 sites of the Na SICON structure.
基金supported by the Health and Medical Research Fund(20190572)the Food and Health Bureau,The Government of the Hong Kong Special Administrative Region,General Research Fund(17122322 and 17126919)+9 种基金the Research Grants Council of the Hong Kong Special Administrative Region Government,NSFC Projects(T2122002,22077079,81871448)Ministry of Science and Technology of China Project(2022YFC2601700,2022YFF0710202)Shanghai Municipal Science and Technology Project(22Z510202478)Shanghai Jiao Tong University Projects(YG2021ZD19)Shanghai Municipal Health Commission Project(2019CXJQ03)Sanming Project of Medicine in Shenzhen,China(SZSM201911014)the High Level-Hospital Program,Health Commission of Guangdong Province,Chinathe research project of Hainan Academician Innovation Platform(YSPTZX202004)the University of Hong Kong Outstanding Young Researcher Awardand the University of Hong Kong Research Output Prize(Li Ka Shing Faculty of Medicine).
文摘Combinatorial drug therapies are generally more effective than monotherapies in treating viral infections.However,it is critical for dose optimization to maximize the efficacy and minimize side effects.Although various strategies have been devised to accelerate the optimization process,their efficiencies were limited by the high noises and suboptimal reproducibility of biological assays.With conventional methods,variances among the replications are used to evaluate the errors of the readouts alone rather than actively participating in the optimization.Herein,we present the Regression Modeling Enabled by Monte Carlo Method(ReMEMC)algorithm for rapid identification of effective combinational therapies.ReMEMC transforms the sample variations into probability distributions of the regression coefficients and predictions.In silico simulations revealed that ReMEMC outperformed conventional regression methods in benchmark problems,and demonstrated its superior robustness against experimental noises.Using COVID-19 as a model disease,ReMEMC successfully identified an optimal 3-drug combination among 10 anti-SARS-CoV-2 drug compounds within two rounds of experiments.The optimal combination showed 2-log and 3-log higher load reduction than non-optimized combinations and monotherapy,respectively.Further workflow refinement allowed identification of personalized drug combinational therapies within 5 days.The strategy may serve as an efficient and universal tool for dose combination optimization.
