Our previous study has revealed that procyanidin A_(1)(A_(1))and its simulated digestive product(D-A,)can alleviate acrylamide(ACR)-induced intestine cell damage.However,the underlying mechanism remains unknown.In thi...Our previous study has revealed that procyanidin A_(1)(A_(1))and its simulated digestive product(D-A,)can alleviate acrylamide(ACR)-induced intestine cell damage.However,the underlying mechanism remains unknown.In this study,we elucidated the molecular mechanism for and D-A_(1) to alleviate ACR-stimulated IPEC-J2 cell damage.ACR slightly activated nuclear factor erythroid 2-related factor 2(Nrf2)signaling and its target genes,but this activation could not reduce intestine cell damage.A_(1) and D-A_(1) could alleviate ACR-induced cell damage,but the effect was abrogated in cells transiently transfected with Nrf2 small interfering RNA(siRNA).Further investigation confirmed that A_(1) and D-A_(1) interacted with Ketch-like ECH-associated protein 1(Keapl),which boosted the stabilization of Nrf2,subsequently promoted the translocation of Nrf2 into the nucleus,and further increased the expression of antioxidant proteins,thereby inhibiting glutathione(GSH)consumption,maintaining redox balance and eventually alleviating ACR-induced cell damage.Importantly,there was no difference between A_(1) and D-A_(1) treated groups,indicating that A_(1) can tolerate gastrointestinal digestion and may be a potential compound to limit the toxicity of ACR.展开更多
The present work is to construct the potential energy function of isotopic molecules. The so-called molecular potential energy function is the electronic energy function under Born-Oppenheimer approximation,in which t...The present work is to construct the potential energy function of isotopic molecules. The so-called molecular potential energy function is the electronic energy function under Born-Oppenheimer approximation,in which the nuclear motions(translational,rotational and vibration motions) are not included,therefore,its nuclear vibration motion and isotopic effect need to be considered. Based on group theory and atomic and molecular reactive statics(AMRS),the reasonable dissociation limits of D2O(1A1)are determined,its equilibrium geometry and dissociation energy are calculated by density-functional theory(DFT) B3lyp,and then,using the many-body expansion method the potential energy function of D2O(1A1) is obtained for the first time. The potential contours are drawn,in which it is found that the reactive channel D + OD→D2O has no threshold energy,so it is a free radical reaction. But the reactive channel O + DD→D2O has a saddle point. The study of collision for D2O(1A1) is under way.展开更多
An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease prog...An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease progression,demonstrating the need for novel approaches in PD.Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson's disease.However,the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown.The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling.Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test.Immunoblot,quantitative reverse transcription polymerase chain reaction,immunohistochemistry,and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen.Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals.A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen.Treatment with intermittent theta burst stimulation began 7 days after the lesion,coinciding with the onset of motor symptoms.After treatment with prolonged intermittent theta burst stimulation,complete motor recovery was observed.This improvement was accompanied by downregulation of the e N/CD73-A_(2A)R pathway and a return to physiological levels of A_(1)R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation.Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A_(1)R and elevated the expression of A_(2A)R.Intermittent theta burst stimulation reversed these effects by restoring the abundances of A_(1)R and A_(2A)R to control levels.The shift in ARs expression likely restored the balance between dopamine-adenosine signaling,ultimately leading to the recovery of motor control.展开更多
The bioactive constituents found in natural products(NPs)are crucial in protein-ligand interactions and drug discovery.However,it is difficult to identify ligand molecules from complex NPs that specifically bind to ta...The bioactive constituents found in natural products(NPs)are crucial in protein-ligand interactions and drug discovery.However,it is difficult to identify ligand molecules from complex NPs that specifically bind to target protein,which often requires time-consuming and labor-intensive processes such as isolation and enrichment.To address this issue,in this study we developed a method that combines ultra-high performance liquid chromatography-electrospray ionization-mass spectrometry(UHPLCESI-MS)with molecular dynamics(MD)simulation to identify and observe,rapidly and efficiently,the bioactive components in NPs that bind to specific protein target.In this method,a specific protein target was introduced online using a three-way valve to form a protein-ligand complex.The complex was then detected in real time using high-resolution MS to identify potential ligands.Based on our method,only 10 molecules from green tea(a representative natural product),including the commonly reported epigallocatechin gallate(EGCG)and epicatechin gallate(ECG),as well as the previously unreported eepicatechin(4β→8)-epigallocatechin 3-O-gallate(EC-EGCG)and eepiafzelechin 3-O-gallate-(4β→8)-epigallocatechin 3-O-gallate(EFG-EGCG),were screened out,which could form complexes with Aβ_(1-42)(a representative protein target),and could be potential ligands of Aβ_(1-42).Among of them,EC-EGCG demonstrated the highest binding free energy with Aβ_(1-42)(−68.54±3.82 kcal/mol).On the other side,even though the caffeine had the highest signal among green tea extracts,it was not observed to form a complex with Aβ_(1-42).Compared to other methods such as affinity selection mass spectrometry(ASMS)and native MS,our method is easy to operate and interpret the data.Undoubtedly,it provides a new methodology for potential drug discovery in NPs,and will accelerate the research on screening ligands for specific proteins from complex NPs.展开更多
基金supported by the project from National Natural Science Foundation of China (31671962)Fundamental Research Funds for the Central Universities (2662019PY034)。
文摘Our previous study has revealed that procyanidin A_(1)(A_(1))and its simulated digestive product(D-A,)can alleviate acrylamide(ACR)-induced intestine cell damage.However,the underlying mechanism remains unknown.In this study,we elucidated the molecular mechanism for and D-A_(1) to alleviate ACR-stimulated IPEC-J2 cell damage.ACR slightly activated nuclear factor erythroid 2-related factor 2(Nrf2)signaling and its target genes,but this activation could not reduce intestine cell damage.A_(1) and D-A_(1) could alleviate ACR-induced cell damage,but the effect was abrogated in cells transiently transfected with Nrf2 small interfering RNA(siRNA).Further investigation confirmed that A_(1) and D-A_(1) interacted with Ketch-like ECH-associated protein 1(Keapl),which boosted the stabilization of Nrf2,subsequently promoted the translocation of Nrf2 into the nucleus,and further increased the expression of antioxidant proteins,thereby inhibiting glutathione(GSH)consumption,maintaining redox balance and eventually alleviating ACR-induced cell damage.Importantly,there was no difference between A_(1) and D-A_(1) treated groups,indicating that A_(1) can tolerate gastrointestinal digestion and may be a potential compound to limit the toxicity of ACR.
基金Supported by the National Natural Science Foundation of China (Grant No. NSAF10676022)
文摘The present work is to construct the potential energy function of isotopic molecules. The so-called molecular potential energy function is the electronic energy function under Born-Oppenheimer approximation,in which the nuclear motions(translational,rotational and vibration motions) are not included,therefore,its nuclear vibration motion and isotopic effect need to be considered. Based on group theory and atomic and molecular reactive statics(AMRS),the reasonable dissociation limits of D2O(1A1)are determined,its equilibrium geometry and dissociation energy are calculated by density-functional theory(DFT) B3lyp,and then,using the many-body expansion method the potential energy function of D2O(1A1) is obtained for the first time. The potential contours are drawn,in which it is found that the reactive channel D + OD→D2O has no threshold energy,so it is a free radical reaction. But the reactive channel O + DD→D2O has a saddle point. The study of collision for D2O(1A1) is under way.
基金supported by a grant from Ministry of Science,Technological Development and Innovation,Serbia,No.451-03-68/2022-14/200178(to NN)University of Defence,No.MFVMA/02/22-24(to MN)。
文摘An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease progression,demonstrating the need for novel approaches in PD.Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson's disease.However,the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown.The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling.Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test.Immunoblot,quantitative reverse transcription polymerase chain reaction,immunohistochemistry,and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen.Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals.A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen.Treatment with intermittent theta burst stimulation began 7 days after the lesion,coinciding with the onset of motor symptoms.After treatment with prolonged intermittent theta burst stimulation,complete motor recovery was observed.This improvement was accompanied by downregulation of the e N/CD73-A_(2A)R pathway and a return to physiological levels of A_(1)R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation.Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A_(1)R and elevated the expression of A_(2A)R.Intermittent theta burst stimulation reversed these effects by restoring the abundances of A_(1)R and A_(2A)R to control levels.The shift in ARs expression likely restored the balance between dopamine-adenosine signaling,ultimately leading to the recovery of motor control.
文摘作者发现并从蟾蜍血清中的高密度脂蛋白(HDL MW=400 000)中,提取出可水解强有机磷毒剂梭曼的酶蛋白,SDS-聚丙烯酰胺凝胶电泳(SDS-PAGE)为一条区带,分子量28 000,与蟾蜍血清 HDL 中的载脂蛋白 A_1(apo A_1)分子量相同,与已知的人及鸭血清中 HDL 的 apo A_1分子量很接近。还进行了酶蛋白与鸭血清 apo A_1氨基酸组份对比。作者认为,蟾蜍血清中的梭曼水解酶与 apo A_1密切相关,但是否能肯定梭曼水解酶(A-酯酶)和 apo A_1是同一物质还需进一步的实验证明。
基金supported by the National Key R&D Program of China(No.2018YFA0800900).
文摘The bioactive constituents found in natural products(NPs)are crucial in protein-ligand interactions and drug discovery.However,it is difficult to identify ligand molecules from complex NPs that specifically bind to target protein,which often requires time-consuming and labor-intensive processes such as isolation and enrichment.To address this issue,in this study we developed a method that combines ultra-high performance liquid chromatography-electrospray ionization-mass spectrometry(UHPLCESI-MS)with molecular dynamics(MD)simulation to identify and observe,rapidly and efficiently,the bioactive components in NPs that bind to specific protein target.In this method,a specific protein target was introduced online using a three-way valve to form a protein-ligand complex.The complex was then detected in real time using high-resolution MS to identify potential ligands.Based on our method,only 10 molecules from green tea(a representative natural product),including the commonly reported epigallocatechin gallate(EGCG)and epicatechin gallate(ECG),as well as the previously unreported eepicatechin(4β→8)-epigallocatechin 3-O-gallate(EC-EGCG)and eepiafzelechin 3-O-gallate-(4β→8)-epigallocatechin 3-O-gallate(EFG-EGCG),were screened out,which could form complexes with Aβ_(1-42)(a representative protein target),and could be potential ligands of Aβ_(1-42).Among of them,EC-EGCG demonstrated the highest binding free energy with Aβ_(1-42)(−68.54±3.82 kcal/mol).On the other side,even though the caffeine had the highest signal among green tea extracts,it was not observed to form a complex with Aβ_(1-42).Compared to other methods such as affinity selection mass spectrometry(ASMS)and native MS,our method is easy to operate and interpret the data.Undoubtedly,it provides a new methodology for potential drug discovery in NPs,and will accelerate the research on screening ligands for specific proteins from complex NPs.
