Amyloidosis is characterized by the deposition of fibrillar aggregates,with a specific peptide or protein as the primary component,in affected tissues or organs.Excessive proliferation and deposition of amyloid fibril...Amyloidosis is characterized by the deposition of fibrillar aggregates,with a specific peptide or protein as the primary component,in affected tissues or organs.Excessive proliferation and deposition of amyloid fibrils can cause organismal dysfunction and lethal pathological outcomes associated with amyloidosis.In this study,a nanochaperone(nChap-NA)was developed to inhibit protein misfolding and fibrillation by simulating the function of natural molecular chaperones.The nanochaperone was prepared by self-assembly of two block copolymers PEG-b-PCL and PCL-b-P(NIPAM-co-AANTA),which had a phase-separated surface consisting of hydrophobic PNIPAM microdomains with coordinative NTA(Zn)moieties and hydrophilic PEG chains.The hydrophobic interaction of the PNIPAM microdomain and the coordination of NTA(Zn)synergistically work together to effectively trap the amyloid monomer and block its fibrillation site.Insulin and human islet amyloid polypeptide(hIAPP)were used as model proteins to investigate the nanochaperone's inhibition of amyloid misfolding and fibrillation.It was proved that the nanochaperone could stabilize the natural conformation of the trapped insulin and hIAPP,and effectively inhibit their fibrillation.In vivo study demonstrated that the nanochaperone could effectively preserve the bioactivity of insulin and reduce the cytotoxicity caused by hIAPP aggregation.This study may provide a promising strategy for the prophylactic treatment of amyloidosis.展开更多
AIM： To evaluate the impact of the ITGA2 gene polymorphism on gastric cancer risk. METHODS： A hospital-based case-control study was conducted, including 307 gastric cancer patients and 307 age- and gender-matched co...AIM： To evaluate the impact of the ITGA2 gene polymorphism on gastric cancer risk. METHODS： A hospital-based case-control study was conducted, including 307 gastric cancer patients and 307 age- and gender-matched control subjects. The genotypes were identified by polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS： The frequencies of the wild and variant genotypes in cases were significantly different from those of controls （P = 0.019）. Compared with individuals with the wild genotype CC, subjects with the variant genotypes （CT ＋ IT） had a significantly higher risk of gastric cancer （adjusted odds ratio = 1.57, 95% CI = 1.13-2.17, P = 0.007）. In stratified analyses, the elevated gastric cancer risk was especially evident in older individuals aged 〉 58 years, nonsmokers and rural subjects. Further analyses revealed that the variant genotypes were associated with poor tumor differentiation and adjacent organ invasion in the sub-analysis of gastric cancer patients. CONCLUSION： The ITGA2 gene C807T polymorphism may be associated with an increased risk of gastric cancer, differentiation and invasion of gastric cancer.展开更多
After repeated frustrations with amyloid beta(Aβ)-targeted clinical trials for Alzheimer’s disease(AD)in recent years,the therapeutic focus of AD has gradually shifted from Aβto tau protein.The misfolding and aggre...After repeated frustrations with amyloid beta(Aβ)-targeted clinical trials for Alzheimer’s disease(AD)in recent years,the therapeutic focus of AD has gradually shifted from Aβto tau protein.The misfolding and aggregation of tau protein into neurofibrillary tangles(NFTs)cause neuron death and synaptic dysfunction,and the deposition of NFTs is more closely related to the severity of AD than Aβplaques.Thus,it has great potential to target tau protein aggregation for AD treatment.The hexapeptide VQIVYK(known as PHF6)in tau protein has been found to play a dominant role for tau aggregation and was widely used as a model to design tau protein aggregation inhibitors.Here,inspired by natural heat shock protein(HSPs),we fabricated a self-assembly nanochaperone based on mixed-shell polymeric micelle(MSPM)as a novel tau-targeted AD therapy.With tunable phase-separated microdomains on the surface,the nanochaperone could effectively bind with PHF6 aggregates,inhibit PHF6 aggregation,block neuronal internalization of PHF6 species,thus significantly alleviating PHF6 mediated neurotoxicity.Moreover,the as-prepared nanochaperone could work with proteinase to facilitate the degradation of PHF6 aggregates.This bioinspired nanochaperone demonstrated a new way to target tau protein and provided a promising strategy for AD treatment.展开更多
Alzheimer’s disease(AD),one of the most prevalent progressive neurodegenerative disorders,is characterized by neurological dysfunction and is closely linked to learning and memory impairment.Despite tremendous effort...Alzheimer’s disease(AD),one of the most prevalent progressive neurodegenerative disorders,is characterized by neurological dysfunction and is closely linked to learning and memory impairment.Despite tremendous effort being involved,several anti-AD drugs come into clinical trials difficult to succeed due to the complex AD pathogenesis and the blood-brain barrier(BBB).展开更多
A palladium/chiral N,N0-disulfonyl bisimidazoline(Bim)-catalyzed asymmetric addition of arylboronic acids to isoquinoline-1,3,4-trione-derived ketimines is reported,leading to the generation of a series of functionali...A palladium/chiral N,N0-disulfonyl bisimidazoline(Bim)-catalyzed asymmetric addition of arylboronic acids to isoquinoline-1,3,4-trione-derived ketimines is reported,leading to the generation of a series of functionalized isoquinoline-1,3(2H,4H)-diones bearing one quaternary carbon-amino functionality in good to excellent yields with95%ee in most cases.The reaction has remarkable compatibility with both substrate scopes,providing a highly enantioselective entry to chiral heterocyclicα-tertiary amines.展开更多
基金financially supported by the National Key R&D Program of China(No.2022YFA1205700)the National Natural Science Foundation of China(Nos.51933006,52293383 and 52303188)+1 种基金the Natural Science Foundation of Tianjin,China(No.23JCYBJC01780)China Postdoctoral Science Foundation Funded Project(No.2023M731786)。
文摘Amyloidosis is characterized by the deposition of fibrillar aggregates,with a specific peptide or protein as the primary component,in affected tissues or organs.Excessive proliferation and deposition of amyloid fibrils can cause organismal dysfunction and lethal pathological outcomes associated with amyloidosis.In this study,a nanochaperone(nChap-NA)was developed to inhibit protein misfolding and fibrillation by simulating the function of natural molecular chaperones.The nanochaperone was prepared by self-assembly of two block copolymers PEG-b-PCL and PCL-b-P(NIPAM-co-AANTA),which had a phase-separated surface consisting of hydrophobic PNIPAM microdomains with coordinative NTA(Zn)moieties and hydrophilic PEG chains.The hydrophobic interaction of the PNIPAM microdomain and the coordination of NTA(Zn)synergistically work together to effectively trap the amyloid monomer and block its fibrillation site.Insulin and human islet amyloid polypeptide(hIAPP)were used as model proteins to investigate the nanochaperone's inhibition of amyloid misfolding and fibrillation.It was proved that the nanochaperone could stabilize the natural conformation of the trapped insulin and hIAPP,and effectively inhibit their fibrillation.In vivo study demonstrated that the nanochaperone could effectively preserve the bioactivity of insulin and reduce the cytotoxicity caused by hIAPP aggregation.This study may provide a promising strategy for the prophylactic treatment of amyloidosis.
基金Supported by The National Natural Science Foundation of Chi-na,No. 30873099Nanjing Medical University start-up research fund for Wang XRthe Natural Science Foundation of education Department,Jiangsu Province,No. 08KJB320004
文摘AIM： To evaluate the impact of the ITGA2 gene polymorphism on gastric cancer risk. METHODS： A hospital-based case-control study was conducted, including 307 gastric cancer patients and 307 age- and gender-matched control subjects. The genotypes were identified by polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS： The frequencies of the wild and variant genotypes in cases were significantly different from those of controls （P = 0.019）. Compared with individuals with the wild genotype CC, subjects with the variant genotypes （CT ＋ IT） had a significantly higher risk of gastric cancer （adjusted odds ratio = 1.57, 95% CI = 1.13-2.17, P = 0.007）. In stratified analyses, the elevated gastric cancer risk was especially evident in older individuals aged 〉 58 years, nonsmokers and rural subjects. Further analyses revealed that the variant genotypes were associated with poor tumor differentiation and adjacent organ invasion in the sub-analysis of gastric cancer patients. CONCLUSION： The ITGA2 gene C807T polymorphism may be associated with an increased risk of gastric cancer, differentiation and invasion of gastric cancer.
基金financially supported by the National Natural Science Foundation of China (Nos. 51933006 and 52073306)Young Elite Scientists Sponsorship Program by Tianjin (No. TJSQNTJ-2020-18)+1 种基金the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2019-RC-HL-014)Wenzhou Key Laboratory of Biomaterials and Engineering (No. WIUCASSWCL21004)
文摘After repeated frustrations with amyloid beta(Aβ)-targeted clinical trials for Alzheimer’s disease(AD)in recent years,the therapeutic focus of AD has gradually shifted from Aβto tau protein.The misfolding and aggregation of tau protein into neurofibrillary tangles(NFTs)cause neuron death and synaptic dysfunction,and the deposition of NFTs is more closely related to the severity of AD than Aβplaques.Thus,it has great potential to target tau protein aggregation for AD treatment.The hexapeptide VQIVYK(known as PHF6)in tau protein has been found to play a dominant role for tau aggregation and was widely used as a model to design tau protein aggregation inhibitors.Here,inspired by natural heat shock protein(HSPs),we fabricated a self-assembly nanochaperone based on mixed-shell polymeric micelle(MSPM)as a novel tau-targeted AD therapy.With tunable phase-separated microdomains on the surface,the nanochaperone could effectively bind with PHF6 aggregates,inhibit PHF6 aggregation,block neuronal internalization of PHF6 species,thus significantly alleviating PHF6 mediated neurotoxicity.Moreover,the as-prepared nanochaperone could work with proteinase to facilitate the degradation of PHF6 aggregates.This bioinspired nanochaperone demonstrated a new way to target tau protein and provided a promising strategy for AD treatment.
文摘Alzheimer’s disease(AD),one of the most prevalent progressive neurodegenerative disorders,is characterized by neurological dysfunction and is closely linked to learning and memory impairment.Despite tremendous effort being involved,several anti-AD drugs come into clinical trials difficult to succeed due to the complex AD pathogenesis and the blood-brain barrier(BBB).
基金grateful for financial support from the National Natural Science Foundation of China(Nos.21971090 and 22271123)the Top-Notch Academic Programs Project of Jiangsu Higher Education Institution(TAPP).
文摘A palladium/chiral N,N0-disulfonyl bisimidazoline(Bim)-catalyzed asymmetric addition of arylboronic acids to isoquinoline-1,3,4-trione-derived ketimines is reported,leading to the generation of a series of functionalized isoquinoline-1,3(2H,4H)-diones bearing one quaternary carbon-amino functionality in good to excellent yields with95%ee in most cases.The reaction has remarkable compatibility with both substrate scopes,providing a highly enantioselective entry to chiral heterocyclicα-tertiary amines.
