Using chemoproteomic techniques,we first identified EIF2AK2,eEF1A1,PRDX3 and VPS4B as direct targets of berberine(BBR)for its synergistically anti-inflammatory effects.Of them,BBR has the strongest affinity with EIF2A...Using chemoproteomic techniques,we first identified EIF2AK2,eEF1A1,PRDX3 and VPS4B as direct targets of berberine(BBR)for its synergistically anti-inflammatory effects.Of them,BBR has the strongest affinity with EIF2AK2 via two ionic bonds,and regulates several key inflammatory pathways through EIF2AK2,indicating the dominant role of EIF2AK2.Also,BBR could subtly inhibit the dimerization of EIF2AK2,rather than its enzyme activity,to selectively modulate its downstream pathways including JNK,NF-κB,AKT and NLRP3,with an advantage of good safety profile.In EIF2AK2 gene knockdown mice,the inhibitory IL-1β,IL-6,IL-18 and TNF-a secretion of BBR was obviously attenuated,confirming an EIF2AK2-dependent anti-inflammatory efficacy.The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target,and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammationrelated disorders.展开更多
Helicobacter pylori(H.pylori)is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis,and its high prevalence and resistance make it difficult to tackle.A graph neural network...Helicobacter pylori(H.pylori)is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis,and its high prevalence and resistance make it difficult to tackle.A graph neural network-based deep learning model,employing different training sets of 13,638 molecules for pre-training and fine-tuning,was aided in predicting and exploring novel molecules against H.pylori.A positively predicted novel berberine derivative 8 with 3,13-disubstituted alkene exhibited a potency against all tested drug-susceptible and resistant H.pylori strains with minimum inhibitory concentrations(MICs)of 0.25-0.5μg/mL.Pharmacokinetic studies demonstrated an ideal gastric retention of 8,with the stomach concentration significantly higher than its MIC at 24 h post dose.Oral administration of 8 and omeprazole(OPZ)showed a comparable gastric bacterial reduction(2.2-log reduction)to the triple-therapy,namely OPZ+amoxicillin(AMX)+clarithromycin(CLA)without obvious disturbance on the intestinal flora.A combination of OPZ,AMX,CLA,and 8 could further decrease the bacteria load(2.8-log reduction).More importantly,the mono-therapy of 8 exhibited comparable eradication to both triple-therapy(OPZ+AMX+CLA)and quadrupletherapy(OPZ+AMX+CLA+bismuth citrate)groups.SecA and BamD,playing a major role in outer membrane protein(OMP)transport and assembling,were identified and verified as the direct targets of 8 by employing the chemoproteomics technique.n summary,by targeting the relatively conserved OMPs transport and assembling system,8 has the potential to be developed as a novel anti-H.pylori candidate,especially for the eradication of drug-resistant strains.展开更多
A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria.Compound 33a(IMBZ18G)is highly effective in vitro and in vivo against c...A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria.Compound 33a(IMBZ18G)is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant(MDR)Gram-negative strains,with a highly druglike nature.The checkerboard assay reveals its significant synergistic effect withβ-lactamase inhibitor avibactam,and the MIC values against MDR enterobacteria were reduced up to 4—512folds.X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and Cβ-lactamases.Accordingly,preclinical studies of 33a alone and 33a-avibactam combination as potential innovative candidates are actively going on,in the treatment ofβ-lactamase-producing MDR Gram-negative bacterial infections.展开更多
Orthodontic forces can cause stress and strain concentration and microcracks on tooth root surfaces.This study aimed to analyze whether a lingual orthodontic appliance was more likely to cause root stress concentratio...Orthodontic forces can cause stress and strain concentration and microcracks on tooth root surfaces.This study aimed to analyze whether a lingual orthodontic appliance was more likely to cause root stress concentration and root resorption than the traditional buccal appliance.A finite element model of the root of the maxillary central incisor with straight,buccal,and lingual curvatures was established.A load perpendicular to the tooth surface on the buccal and lingual surfaces of the central incisor was applied,and the stress and strain concentration at the root apex was compared.The stress and strain at the root apex of the lingual cingulum group were lesser than those of the buccal group;little difference was observed between the lingual and buccal clinical crown central augmentation groups.The stress and strain at the root apex of the lingual direction movement group were greater than those of the buccal direction movement group.The direction of the root curvature also influenced the amount of stress and strain at the root apex.The difference in the risk of root resorption between lingual and buccal orthodontics is dependent on the height of the bracket placement.The loading direction of the orthodontic force and direction of the root curvature also affect the stress and strain at the root apex.展开更多
目的研究不同类型高冲击运动对于骨密度（bone mineral density,BMD）和骨矿含量（bone mineral content,BMC）的影响。方法招募39名志愿者,其中伞兵、篮球运动员和作为对照组的普通大学生各13名,将其分成两组（第1组：20～22岁;第2组...目的研究不同类型高冲击运动对于骨密度（bone mineral density,BMD）和骨矿含量（bone mineral content,BMC）的影响。方法招募39名志愿者,其中伞兵、篮球运动员和作为对照组的普通大学生各13名,将其分成两组（第1组：20～22岁;第2组：23～25岁）,分别测量跟骨、第1～5跖骨、髋关节和腰椎（L1～4）BMD和BMC。结果篮球运动员跟骨、第1、2跖骨、总腰椎和髋部BMC显著大于伞兵和对照组;篮球运动员在腰椎、髋关节和股骨颈处BMD也显著大于其他组;伞兵和对照组在测量部位的BMD和BMC无显著性差异。结论 BMC与BMD并非总是正比于平时运动时的垂直地面反作用力。相比跳伞训练,篮球运动能更好提高BMC和BMD,这种变载荷运动作为训练方法,更有利于降低骨质疏松性骨折的风险。展开更多
The authors regret that there are some misplaced figure numbers in the body of this article due to negligence in the layout and proofreading of the figures.Although it does not affect the conclusion,it is an obvious e...The authors regret that there are some misplaced figure numbers in the body of this article due to negligence in the layout and proofreading of the figures.Although it does not affect the conclusion,it is an obvious error.The authors have now modified as below.The authors apologize for any inconvenience caused to the journal and readers.展开更多
基金the CAMS initiative for innovative medicine(2022-I2M-2-002,China)National Natural Science Foundation of China(32141003)。
文摘Using chemoproteomic techniques,we first identified EIF2AK2,eEF1A1,PRDX3 and VPS4B as direct targets of berberine(BBR)for its synergistically anti-inflammatory effects.Of them,BBR has the strongest affinity with EIF2AK2 via two ionic bonds,and regulates several key inflammatory pathways through EIF2AK2,indicating the dominant role of EIF2AK2.Also,BBR could subtly inhibit the dimerization of EIF2AK2,rather than its enzyme activity,to selectively modulate its downstream pathways including JNK,NF-κB,AKT and NLRP3,with an advantage of good safety profile.In EIF2AK2 gene knockdown mice,the inhibitory IL-1β,IL-6,IL-18 and TNF-a secretion of BBR was obviously attenuated,confirming an EIF2AK2-dependent anti-inflammatory efficacy.The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target,and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammationrelated disorders.
基金This research project was supported by grants from National Natural Science Foundationof China(32141003,82330110,61976050,61972384,and 82003575)CAMS Initiative for Innovative Medicine(2021-1-12M-030).
文摘Helicobacter pylori(H.pylori)is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis,and its high prevalence and resistance make it difficult to tackle.A graph neural network-based deep learning model,employing different training sets of 13,638 molecules for pre-training and fine-tuning,was aided in predicting and exploring novel molecules against H.pylori.A positively predicted novel berberine derivative 8 with 3,13-disubstituted alkene exhibited a potency against all tested drug-susceptible and resistant H.pylori strains with minimum inhibitory concentrations(MICs)of 0.25-0.5μg/mL.Pharmacokinetic studies demonstrated an ideal gastric retention of 8,with the stomach concentration significantly higher than its MIC at 24 h post dose.Oral administration of 8 and omeprazole(OPZ)showed a comparable gastric bacterial reduction(2.2-log reduction)to the triple-therapy,namely OPZ+amoxicillin(AMX)+clarithromycin(CLA)without obvious disturbance on the intestinal flora.A combination of OPZ,AMX,CLA,and 8 could further decrease the bacteria load(2.8-log reduction).More importantly,the mono-therapy of 8 exhibited comparable eradication to both triple-therapy(OPZ+AMX+CLA)and quadrupletherapy(OPZ+AMX+CLA+bismuth citrate)groups.SecA and BamD,playing a major role in outer membrane protein(OMP)transport and assembling,were identified and verified as the direct targets of 8 by employing the chemoproteomics technique.n summary,by targeting the relatively conserved OMPs transport and assembling system,8 has the potential to be developed as a novel anti-H.pylori candidate,especially for the eradication of drug-resistant strains.
基金supported by CAMS Innovation Fund for Medical Sciences(2021-12M-1-070)National Natural Science Foundation of China(32141003)。
文摘A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria.Compound 33a(IMBZ18G)is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant(MDR)Gram-negative strains,with a highly druglike nature.The checkerboard assay reveals its significant synergistic effect withβ-lactamase inhibitor avibactam,and the MIC values against MDR enterobacteria were reduced up to 4—512folds.X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and Cβ-lactamases.Accordingly,preclinical studies of 33a alone and 33a-avibactam combination as potential innovative candidates are actively going on,in the treatment ofβ-lactamase-producing MDR Gram-negative bacterial infections.
基金This work was supported by the National Natural Science Foundation of China(No.U20A20390 and 11827803).
文摘Orthodontic forces can cause stress and strain concentration and microcracks on tooth root surfaces.This study aimed to analyze whether a lingual orthodontic appliance was more likely to cause root stress concentration and root resorption than the traditional buccal appliance.A finite element model of the root of the maxillary central incisor with straight,buccal,and lingual curvatures was established.A load perpendicular to the tooth surface on the buccal and lingual surfaces of the central incisor was applied,and the stress and strain concentration at the root apex was compared.The stress and strain at the root apex of the lingual cingulum group were lesser than those of the buccal group;little difference was observed between the lingual and buccal clinical crown central augmentation groups.The stress and strain at the root apex of the lingual direction movement group were greater than those of the buccal direction movement group.The direction of the root curvature also influenced the amount of stress and strain at the root apex.The difference in the risk of root resorption between lingual and buccal orthodontics is dependent on the height of the bracket placement.The loading direction of the orthodontic force and direction of the root curvature also affect the stress and strain at the root apex.
文摘目的研究不同类型高冲击运动对于骨密度（bone mineral density,BMD）和骨矿含量（bone mineral content,BMC）的影响。方法招募39名志愿者,其中伞兵、篮球运动员和作为对照组的普通大学生各13名,将其分成两组（第1组：20～22岁;第2组：23～25岁）,分别测量跟骨、第1～5跖骨、髋关节和腰椎（L1～4）BMD和BMC。结果篮球运动员跟骨、第1、2跖骨、总腰椎和髋部BMC显著大于伞兵和对照组;篮球运动员在腰椎、髋关节和股骨颈处BMD也显著大于其他组;伞兵和对照组在测量部位的BMD和BMC无显著性差异。结论 BMC与BMD并非总是正比于平时运动时的垂直地面反作用力。相比跳伞训练,篮球运动能更好提高BMC和BMD,这种变载荷运动作为训练方法,更有利于降低骨质疏松性骨折的风险。
文摘The authors regret that there are some misplaced figure numbers in the body of this article due to negligence in the layout and proofreading of the figures.Although it does not affect the conclusion,it is an obvious error.The authors have now modified as below.The authors apologize for any inconvenience caused to the journal and readers.
