Nanobelts are a rapidly developing family of macrocycles with appealing features.However,their hostvip chemistry is currently limited to the recognition of fullerenes viaπ-πinteractions.Herein,we report two hetero...Nanobelts are a rapidly developing family of macrocycles with appealing features.However,their hostvip chemistry is currently limited to the recognition of fullerenes viaπ-πinteractions.Herein,we report two heteroatom-bridged[8]cyclophenoxathiin nanobelts([8]CP-Me and[8]CP)encapsulate corannulene(Cora)to form bowl-in-bowl supramolecular structures stabilized mainly through CH-πinteractions in solid-state.The convex surface of corannulene is oriented towards the cavity due to geometry complementarity.The complex Cora⊂[8]CP exhibits a unique 2:2 capsule-like structure in crystal packing,in which corannulene adopts a concave-to-concave assembling fashion.This work enriches the molecular recognition of nanobelts and demonstrates that CH-πinteractions can act as the main driving force for nanobelts host-vip complexes.展开更多
Objective To estimate the antiviral activities of ulvan derived from Ulva pertusa,and initiate a preliminary exploration into its mechanism for the potential utilization of ulvans in the future.Methods Employing metho...Objective To estimate the antiviral activities of ulvan derived from Ulva pertusa,and initiate a preliminary exploration into its mechanism for the potential utilization of ulvans in the future.Methods Employing methodologies rooted in molecular biology and virology,such as viral infection and FACS,the effect of ulvan on virus infection and the innate immune responses in cells were evaluated.Results Ulvan significantly restricted vesicular stomatitis virus(VSV)infection.Preliminary exploration on its mechanism indicated that ulvan activated the innate immune,and induced type I interferons(IFN-Ⅰ)expression to restrict viral infection.展开更多
Triphenylamine(TPA)-based aggregation-induced emission luminogens(TPA-AIEgens),a type of photoactive material utilizing the typical TPA moiety,has recently attracted increasing attention for the diagnostics and treatm...Triphenylamine(TPA)-based aggregation-induced emission luminogens(TPA-AIEgens),a type of photoactive material utilizing the typical TPA moiety,has recently attracted increasing attention for the diagnostics and treatment of tumors due to their remarkable chemo-physical performance in optoelectronic research.TPA-AIEgens are distinguished from other photoactive agents by their strong fluorescence,good sensitivity,high signal-to-noise ratio,resistance to photobleaching,and lack of high concentration or aggregation-caused fluoresce quenching effects.In this review,we summarize the current advancements and the biomedical progress of TPA-AIEgens in tumor theranostics.First,the design principles of TPAAIEgens photoactive agents as well as the advanced targeting strategies for nuclei,cell membranes,cell organelle and tumors were introduced,respectively.Next,the applications of TPA-AIEgens in tumor diagnosis and therapeutic techniques were reviewed.Last,the challenges and prospects of TPA-AIEgens for cancer therapy were performed.The given landscape of the TPA-AIEgens hereby is meaningful for the further design and utilization of the novel photoactive material,which could be beneficial for the development of clinic applications.展开更多
Monomethyl auristatin E(MMAE)is a derivative of the marine peptide Dolastatin 10,which has therapeutic effects against various cancers according to its antimitotic activity in multiple clinical trials.The antibody dru...Monomethyl auristatin E(MMAE)is a derivative of the marine peptide Dolastatin 10,which has therapeutic effects against various cancers according to its antimitotic activity in multiple clinical trials.The antibody drug conjugate(ADC)of MMAE is currently used in clinical practice.However,the safety issues of MMAE-based ADC,such as high drug toxicity and poor bioavailability,still exist when using it for anticancer therapy.A sustained release of drug delivery approach should be used to reduce toxicity and achieve sufficient anticancer effects.Herein,PLGA-b-PEG 2000 with excellent biocompatibility and slow degradation ability was adopted to construct MMAE-loaded nanoparticles for safe and effective chemotherapy.The sustained release effect and the immunogenic cell death(ICD)effect of PLGA-MMAE nanoparticles were assessed by in vitro experiments.The PLGA-MMAE nanoparticles effectively accumulated in the tumor through the enhanced permeability and retention(EPR)effect,inducing cell apoptosis and causing a certain degree of immune response.The sustained drug release of PLGA-MMAE improved the bioavailability and effectively reduced the toxicity and development of the tumor compared to the effect of free MMAE or ADC.Overall,this study provides a safe and effective chemotherapeutic approach,as well as a simple and effective synthetic process for MMAE-based nanoparticles,improving their therapeutic efficacy and safety.展开更多
Alzheimer's disease(AD)is a typical neurodegenerative disease.β-amyloid(AβÞplaque is the most prominent pathological biomarker associated with the progression of AD.Conventional Aβprobes,including commerci...Alzheimer's disease(AD)is a typical neurodegenerative disease.β-amyloid(AβÞplaque is the most prominent pathological biomarker associated with the progression of AD.Conventional Aβprobes,including commercial probe ThT,usually suffer from tedious washing procedures.Herein,novel AIE-active Aβprobes with excellent water solubility,named DE-V1-PYC3 and DE-V1-PYOH,were developed for the detection and image of Aβwithout tedious washing procedures.Compared with commercial probe ThT,the AIE-active Aβprobes exhibited better sensitivity and a±nity to Aβaggregates.Moreover,for ThT,the washing procedures are essential to obtain high signal-to-noise ratio(SNR)images of Aβplaques in AD brain tissue slices.DE-V1-PYC3 and DE-V1-PYOH can label Aβplaques in AD brain tissue slices with high SNR even without tedious washing procedures.展开更多
Parkinson's disease(PD)is a prevalent neurodegenerative disorder that affects millions of individuals worldwide.Symptoms of PD typically manifest as movement impairments,including bradykinesia,rigidity,tremors,and...Parkinson's disease(PD)is a prevalent neurodegenerative disorder that affects millions of individuals worldwide.Symptoms of PD typically manifest as movement impairments,including bradykinesia,rigidity,tremors,and postural instability,as well as non-motor symptoms,such as cognitive decline,pain,and depression(Bloem et al.,2021).展开更多
Silver nanoparticles(AgNPs)are extensively utilized in industrial,biotechnological and medical fields because of their specific physical and chemical properties,which shown small size effects,surface and interface eff...Silver nanoparticles(AgNPs)are extensively utilized in industrial,biotechnological and medical fields because of their specific physical and chemical properties,which shown small size effects,surface and interface effects,quantum scale effects.Inevitably,wastewater containing AgNPs is leached into the soil.AgNPs in soil may be absorbed by plant roots and they affect plant growth.Understanding the complex interactions between AgNPs and plants is of crucial significance since plants are essential to the ecological environment as key players in ecosystems.Most previous reports have focused on AgNP phytotoxicity rather than positive effects in the plant field.This article reviews recent studies on the important aspects about nanoparticles including the green synthesis,absorption,migration,accumulation,biotransformation,biological effects,and the underlying molecular mechanisms of AgNPs affecting plants.We provide insights into the interactions between AgNPs and plants,helping to further understand AgNP-related effects and biosafety in agricultural production,as well as the practical application of various nanomaterials in agriculture.展开更多
Human carboxylesterase 2A(hCES2A)plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals.Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irino...Human carboxylesterase 2A(hCES2A)plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals.Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity(ITGT),but the orally active,selective,and efficacious hCES2A inhibitors are rarely reported.Here,a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design(SBDD)and structural optimization.Initially,donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration(FDA)-approved drugs.Following two rounds of SBDD and structural optimization,a donepezil derivative(B7)was identified as a strong reversible hCES2A inhibitor.Subsequently,nine B7 carbamates were rationally designed,synthesized and biologically assayed.Among all synthesized carbamates,C3 showed the most potent time-dependent inhibition on hCES2A(IC50=0.56 nmol/L),excellent specificity and favorable drug-like properties.C3 could covalently modify the catalytic serine of hCES2A with high selectivity,while this agent also showed favorable safety profiles,high intestinal exposure,and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice.Collectively,this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s),while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.展开更多
Gene expression must be precisely regulated in cells and functional nucleic acids are the most widely utilized tools for gene manipulation.Photocontrol of how these nucleic acid tools work in the cellular environment ...Gene expression must be precisely regulated in cells and functional nucleic acids are the most widely utilized tools for gene manipulation.Photocontrol of how these nucleic acid tools work in the cellular environment can precisely manipulate gene expression through a non-invasive way.Here we report a methodology on multiplex photocontrol of functional nucleic acids to achieve totally temporal and orthogonal regulation of gene expression in living cells.We select two functional nucleic acid systems as examples,DNAzyme and CRISPR/Cas9,and demonstrate the power of light control for precise gene manipulation by rational design of chemically modified oligonucleotides through introduction of two photocleavable linkers.Unlike the previous modulation of functional nucleic acids by simply activating or deactivating,we successfully achieve versatile controlling patterns using light as the governing factor.This design represents a generalized pathway towards the photo-controllable functional nucleic acids,which greatly enriches the toolbox for optogenetic studies.展开更多
Alzheimer’s disease(AD)is a common neurodegenerative disorder among the elderly,and BuChE has emerged as a potential therapeutic target.In this study,we reported the development of compound 8e,a selective reversible ...Alzheimer’s disease(AD)is a common neurodegenerative disorder among the elderly,and BuChE has emerged as a potential therapeutic target.In this study,we reported the development of compound 8e,a selective reversible BuChE inhibitor(eqBuChE IC_(50)=0.049 mmol/L,huBuChE IC_(50)=0.066 mmol/L),identified through extensive virtual screening and lead optimization.Compound 8e demonstrated favorable bloodebrain barrier permeability,good drug-likeness property and pronounced neuroprotective efficacy.Additionally,8e exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice.Further,8e significantly improved cognitive function in APP/PS1 transgenic mice.Proteomics analysis demonstrated that 8e markedly elevated the expression levels of very low-density lipoprotein receptor(VLDLR),offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway.Thus,compound 8e emerges as a novel and potent BuChE inhibitor for the treatment of AD,with significant implications for further exploration into its mechanisms of action and therapeutic applications.展开更多
The concept of gait synergy provides novel human-machine interfaces and has been applied to the control of lower limb assistive devices,such as powered prostheses and exoskeletons.Specifically,on the basis of gait syn...The concept of gait synergy provides novel human-machine interfaces and has been applied to the control of lower limb assistive devices,such as powered prostheses and exoskeletons.Specifically,on the basis of gait synergy,the assistive device can generate/predict the appropriate reference trajectories precisely for the affected or missing parts from the motions of sound parts of the patients.Optimal modeling for gait synergy methods that involves optimal combinations of features(inputs)is required to achieve synergic trajectories that improve human–machine interaction.However,previous studies lack thorough discussions on the optimal methods for synergy modeling.In addition,feature selection(FS)that is crucial for reducing data dimensionality and improving modeling quality has often been neglected in previous studies.Here,we comprehensively investigated modeling methods and FS using 4 up-to-date neural networks:sequence-to-sequence(Seq2Seq),long short-term memory(LSTM),recurrent neural network(RNN),and gated recurrent unit(GRU).We also conducted complete FS using 3 commonly used methods:random forest,information gain,and Pearson correlation.Our findings reveal that Seq2Seq(mean absolute error:0.404°and 0.596°,respectively)outperforms LSTM,RNN,and GRU for both interlimb and intralimb synergy modeling.Furthermore,FS is proven to significantly improve Seq2Seq’s modeling performance(P<0.05).FS-Seq2Seq even outperforms methods used in existing studies.Therefore,we propose FSSeq2Seq as a 2-stage strategy for gait synergy modeling in lower limb assistive devices with the aim of achieving synergic and user-adaptive trajectories that improve human-machine interactions.展开更多
Vascular dementia(VaD)is the second commonest type of dementia which lacks of efficient treatments currently.Neuroinflammation as a prominent pathological feature of VaD,is highly involved in the development of VaD.In...Vascular dementia(VaD)is the second commonest type of dementia which lacks of efficient treatments currently.Neuroinflammation as a prominent pathological feature of VaD,is highly involved in the development of VaD.In order to verify the therapeutic potential of PDE1 inhibitors against VaD,the anti-neuroinflammation,memory and cognitive improvement were evaluated in vitro and in vivo by a potent and selective PDE1 inhibitor 4a.Also,the mechanism of 4a in ameliorating neuroinflammation and VaD was systematically explored.Furthermore,to optimize the drug-like properties of 4a,especially for metabolic stability,15 derivatives were designed and synthesized.As a result,candidate 5f,with a potent IC50 value of 4.5 nmol/L against PDE1C,high selectivity over PDEs,and remarkable metabolic stability,efficiently ameliorated neuron degeneration,cognition and memory impairment in VaD mice model by suppressing NF-κB transcription regulation and activating cAMP/CREB axis.These results further identified PDE1 inhibition could serve as a new therapeutic strategy for treatment of VaD.展开更多
Our previous study demonstrated that phosphodiesterase 8(PDE8)could work as a potential target for vascular dementia(Va D)using a chemical probe 3a.However,compound 3a is a chiral compound which was obtained by chiral...Our previous study demonstrated that phosphodiesterase 8(PDE8)could work as a potential target for vascular dementia(Va D)using a chemical probe 3a.However,compound 3a is a chiral compound which was obtained by chiral resolution on HPLC,restricting its usage in clinic.Herein,a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors.Lead 15 exhibited potent inhibitory activity against PDE8A(IC_(50)=11 nmol/L),high selectivity over other PDEs,and remarkable drug-like properties(worthy to mention is that its bioavailability was up to 100%).Oral administration of 15 significantly improved the c AMP level of the right brain and exhibited dosedependent effects on cognitive improvement in a Va D mouse model.Notably,the X-ray crystal structure of the PDE8A—15 complex showed that the potent affinity and high selectivity of 15 might come from the distinctive interactions with H-pocket including T-shapedπ—πinteractions with Phe785 as well as a unique H-bond network,which have never been observed in other PDE-inhibitor complex before,providing new strategies for the further rational design of novel selective inhibitors against PDE8.展开更多
Arylalkylamine N-acetyltransferase(aaNAT),considered a potential new insecticide target,catalyzes the acetylation of arylalkylamine substrates such as serotonin and dopamine and,hence,mediates diverse functions in ins...Arylalkylamine N-acetyltransferase(aaNAT),considered a potential new insecticide target,catalyzes the acetylation of arylalkylamine substrates such as serotonin and dopamine and,hence,mediates diverse functions in insects.However,the origin of insect aaNATs(iaaNATs)and the evolutionary process that generates multiple aaNATs in mosquitoes remain largely unknown.Here,we have analyzed the genomes of 33 species to explore and expand our understanding of the molecular evolution of this gene family in detail.We show that aaNAT orthologs are present in Bacteria,Cephalochordata,Chondrichthyes,Cnidaria,Crustacea,Mammalia,Placozoa,and Teleoste,as well as those from a number of insects,but are absent in some species of Annelida,Echinozoa,and Mollusca as well as Arachnida.Particularly,more than 10 aaNATs were detected in the Culicinae subfamily of mosquitoes.Molecular evolutionary analysis of aaNAT/aaNAT-like genes in mosquitoes reveals that tandem duplication events led to gene expansion in the Culicinae subfamily of mosquitoes more than 190 million years ago.Further selection analysis demonstrates that mosquito aaNATs evolved under strongly positive pressures that generated functional diversity following gene duplication events.Overall,this study may provide novel insights into the molecular evolution of the aaNAT family in mosquitoes.展开更多
基金the National Natural Science Foundation of China(No.22171295)the Fundamental Research Funds for the Central Universities(No.23xkjc006)+1 种基金Guangzhou Science and Technology Programme(No.2024A04J6423)Innovational Fund for Scientific and Technological Personnel of Hainan Province(No.KJRC2023D34)for financial support.
文摘Nanobelts are a rapidly developing family of macrocycles with appealing features.However,their hostvip chemistry is currently limited to the recognition of fullerenes viaπ-πinteractions.Herein,we report two heteroatom-bridged[8]cyclophenoxathiin nanobelts([8]CP-Me and[8]CP)encapsulate corannulene(Cora)to form bowl-in-bowl supramolecular structures stabilized mainly through CH-πinteractions in solid-state.The convex surface of corannulene is oriented towards the cavity due to geometry complementarity.The complex Cora⊂[8]CP exhibits a unique 2:2 capsule-like structure in crystal packing,in which corannulene adopts a concave-to-concave assembling fashion.This work enriches the molecular recognition of nanobelts and demonstrates that CH-πinteractions can act as the main driving force for nanobelts host-vip complexes.
文摘Objective To estimate the antiviral activities of ulvan derived from Ulva pertusa,and initiate a preliminary exploration into its mechanism for the potential utilization of ulvans in the future.Methods Employing methodologies rooted in molecular biology and virology,such as viral infection and FACS,the effect of ulvan on virus infection and the innate immune responses in cells were evaluated.Results Ulvan significantly restricted vesicular stomatitis virus(VSV)infection.Preliminary exploration on its mechanism indicated that ulvan activated the innate immune,and induced type I interferons(IFN-Ⅰ)expression to restrict viral infection.
基金funded by the Hainan Provincial Joint Project of Sanya Yazhou Bay Science and Technology City(No.820LH027)the Hainan Provincial Natural Science Foundation of China(No.823RC472)+4 种基金the Open Project Program of Wuhan National Laboratory for Optoelectronics(No.2021WNLOKF008)the Hainan University Scientific Research Foundation(No.KYQD(ZR)19107)Natural Science Research Talent Project of Hainan Medical University(No.JBGS202101)Hainan Province Clinical Medical Center(2021)Project for Functional Materials and Molecular Imaging Science Innovation Group of Hainan Medical University。
文摘Triphenylamine(TPA)-based aggregation-induced emission luminogens(TPA-AIEgens),a type of photoactive material utilizing the typical TPA moiety,has recently attracted increasing attention for the diagnostics and treatment of tumors due to their remarkable chemo-physical performance in optoelectronic research.TPA-AIEgens are distinguished from other photoactive agents by their strong fluorescence,good sensitivity,high signal-to-noise ratio,resistance to photobleaching,and lack of high concentration or aggregation-caused fluoresce quenching effects.In this review,we summarize the current advancements and the biomedical progress of TPA-AIEgens in tumor theranostics.First,the design principles of TPAAIEgens photoactive agents as well as the advanced targeting strategies for nuclei,cell membranes,cell organelle and tumors were introduced,respectively.Next,the applications of TPA-AIEgens in tumor diagnosis and therapeutic techniques were reviewed.Last,the challenges and prospects of TPA-AIEgens for cancer therapy were performed.The given landscape of the TPA-AIEgens hereby is meaningful for the further design and utilization of the novel photoactive material,which could be beneficial for the development of clinic applications.
基金funded by the Hainan Provincial Joint Project of Sanya Yazhou Bay Science and Technology City(No.820LH027)the Hainan Provincial Natural Science Foundation of China(No.823RC472)+1 种基金the Open Project Program of Wuhan National Laboratory for Optoelectronics(No.2021WNLOKF008)the Hainan University Scientific Research Foundation(KYQD(ZR)19107).
文摘Monomethyl auristatin E(MMAE)is a derivative of the marine peptide Dolastatin 10,which has therapeutic effects against various cancers according to its antimitotic activity in multiple clinical trials.The antibody drug conjugate(ADC)of MMAE is currently used in clinical practice.However,the safety issues of MMAE-based ADC,such as high drug toxicity and poor bioavailability,still exist when using it for anticancer therapy.A sustained release of drug delivery approach should be used to reduce toxicity and achieve sufficient anticancer effects.Herein,PLGA-b-PEG 2000 with excellent biocompatibility and slow degradation ability was adopted to construct MMAE-loaded nanoparticles for safe and effective chemotherapy.The sustained release effect and the immunogenic cell death(ICD)effect of PLGA-MMAE nanoparticles were assessed by in vitro experiments.The PLGA-MMAE nanoparticles effectively accumulated in the tumor through the enhanced permeability and retention(EPR)effect,inducing cell apoptosis and causing a certain degree of immune response.The sustained drug release of PLGA-MMAE improved the bioavailability and effectively reduced the toxicity and development of the tumor compared to the effect of free MMAE or ADC.Overall,this study provides a safe and effective chemotherapeutic approach,as well as a simple and effective synthetic process for MMAE-based nanoparticles,improving their therapeutic efficacy and safety.
基金supported by the National Key R&D Program of China(2021ZD0201004)the National Natural Science Foundation of China(22165008,22077037,21474034,51673077 and 51603078)+1 种基金Hainan Provincial Natural Science Foundation of China(521RC506)the Open Project Program of Wuhan National Laboratory for Optoelectronics(No.2020WNLOKF018)。
文摘Alzheimer's disease(AD)is a typical neurodegenerative disease.β-amyloid(AβÞplaque is the most prominent pathological biomarker associated with the progression of AD.Conventional Aβprobes,including commercial probe ThT,usually suffer from tedious washing procedures.Herein,novel AIE-active Aβprobes with excellent water solubility,named DE-V1-PYC3 and DE-V1-PYOH,were developed for the detection and image of Aβwithout tedious washing procedures.Compared with commercial probe ThT,the AIE-active Aβprobes exhibited better sensitivity and a±nity to Aβaggregates.Moreover,for ThT,the washing procedures are essential to obtain high signal-to-noise ratio(SNR)images of Aβplaques in AD brain tissue slices.DE-V1-PYC3 and DE-V1-PYOH can label Aβplaques in AD brain tissue slices with high SNR even without tedious washing procedures.
基金supported by the National Natural Science Foundation of China (32160204)Major Science and Technology Projects of Hainan Province (ZDKJ2021032)STI 2030—Major Projects (2022ZD0208602)。
文摘Parkinson's disease(PD)is a prevalent neurodegenerative disorder that affects millions of individuals worldwide.Symptoms of PD typically manifest as movement impairments,including bradykinesia,rigidity,tremors,and postural instability,as well as non-motor symptoms,such as cognitive decline,pain,and depression(Bloem et al.,2021).
基金supported by the National Natural Science Foundation of China(31970525)Cultivating Fund Project of Hubei Hongshan Laboratory(2022hspy002)Advanced Foreign Experts Project(G2021157012 L)from Chinese government.
文摘Silver nanoparticles(AgNPs)are extensively utilized in industrial,biotechnological and medical fields because of their specific physical and chemical properties,which shown small size effects,surface and interface effects,quantum scale effects.Inevitably,wastewater containing AgNPs is leached into the soil.AgNPs in soil may be absorbed by plant roots and they affect plant growth.Understanding the complex interactions between AgNPs and plants is of crucial significance since plants are essential to the ecological environment as key players in ecosystems.Most previous reports have focused on AgNP phytotoxicity rather than positive effects in the plant field.This article reviews recent studies on the important aspects about nanoparticles including the green synthesis,absorption,migration,accumulation,biotransformation,biological effects,and the underlying molecular mechanisms of AgNPs affecting plants.We provide insights into the interactions between AgNPs and plants,helping to further understand AgNP-related effects and biosafety in agricultural production,as well as the practical application of various nanomaterials in agriculture.
基金supported by the National Natural Science Foundation of China(Nos.82104281,82273897,and 22367007)China Postdoctoral Science Foundation(Nos.2022M712153,and 2023M742380)+3 种基金The Fundamental Research Funds for Hainan University(KYQD(ZR)23002,China)Hainan Provincial Natural Science Foundation of China(824RC500)PhD Program in Key Fields at Shanghai University of Traditional Chinese Medicine(GJ2023004,China)Liaoning Province Science and Technology Plan Alliance Fund project(2024-BSLH-041,China).
文摘Human carboxylesterase 2A(hCES2A)plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals.Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity(ITGT),but the orally active,selective,and efficacious hCES2A inhibitors are rarely reported.Here,a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design(SBDD)and structural optimization.Initially,donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration(FDA)-approved drugs.Following two rounds of SBDD and structural optimization,a donepezil derivative(B7)was identified as a strong reversible hCES2A inhibitor.Subsequently,nine B7 carbamates were rationally designed,synthesized and biologically assayed.Among all synthesized carbamates,C3 showed the most potent time-dependent inhibition on hCES2A(IC50=0.56 nmol/L),excellent specificity and favorable drug-like properties.C3 could covalently modify the catalytic serine of hCES2A with high selectivity,while this agent also showed favorable safety profiles,high intestinal exposure,and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice.Collectively,this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s),while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.
基金supported by the National Natural Science Foundation of China(22222706,22307107,22477144)the National Key R&D Program of China(2020YFA0211200)the Guangdong Basic Research Center of Excellence(GBRCE)for Functional Molecular Engineering and the Guangdong Basic and Applied Basic Research Foundation(2024B1515040028)。
文摘Gene expression must be precisely regulated in cells and functional nucleic acids are the most widely utilized tools for gene manipulation.Photocontrol of how these nucleic acid tools work in the cellular environment can precisely manipulate gene expression through a non-invasive way.Here we report a methodology on multiplex photocontrol of functional nucleic acids to achieve totally temporal and orthogonal regulation of gene expression in living cells.We select two functional nucleic acid systems as examples,DNAzyme and CRISPR/Cas9,and demonstrate the power of light control for precise gene manipulation by rational design of chemically modified oligonucleotides through introduction of two photocleavable linkers.Unlike the previous modulation of functional nucleic acids by simply activating or deactivating,we successfully achieve versatile controlling patterns using light as the governing factor.This design represents a generalized pathway towards the photo-controllable functional nucleic acids,which greatly enriches the toolbox for optogenetic studies.
基金supported by the China Postdoctoral Science Foundation(2022M712153)The National Natural Science Foundation of China(22367007,82304384)+6 种基金The Fundamental Research Funds for Hainan University(KYQD(ZR)23002,China)Hainan Provincial Natural Science Foundation of China(824RC500)National-Local Joint Engineering Research Center for Innovative&Generic Chemical Drug,and Guizhou High-level Innovative Talents Supporting Program(2016-4015,China)The State Key Laboratory of Functions and Applications of Medicinal Plants,Guizhou Medical University(Grant number FAMP202107K,China)Guizhou Science and Technology Platform Talents(QKHRCPT[2019]5627,China)Program for Innovative Research Team in Universities of Inner Mongolia Autonomous Region(NMGIRT2216,China)Natural Science Foundation of Inner Mongolia Autonomous Region of China(2020MS08103).
文摘Alzheimer’s disease(AD)is a common neurodegenerative disorder among the elderly,and BuChE has emerged as a potential therapeutic target.In this study,we reported the development of compound 8e,a selective reversible BuChE inhibitor(eqBuChE IC_(50)=0.049 mmol/L,huBuChE IC_(50)=0.066 mmol/L),identified through extensive virtual screening and lead optimization.Compound 8e demonstrated favorable bloodebrain barrier permeability,good drug-likeness property and pronounced neuroprotective efficacy.Additionally,8e exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice.Further,8e significantly improved cognitive function in APP/PS1 transgenic mice.Proteomics analysis demonstrated that 8e markedly elevated the expression levels of very low-density lipoprotein receptor(VLDLR),offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway.Thus,compound 8e emerges as a novel and potent BuChE inhibitor for the treatment of AD,with significant implications for further exploration into its mechanisms of action and therapeutic applications.
基金supported by the National Natural Science Foundation of China(nos.32360196,and 32160204)the Key R&D Project of Hainan Province(grant nos.ZDYF2022SHFZ302 and ZDYF2022SHFZ275)+6 种基金the Major Science and Technology Projects of Hainan Province(grant no.ZDKJ2021032)Hainan Province Clinical Medical Center(no.0202067)Science,Technology,and Innovation Commission of Shenzhen Municipality(STICproject no.SGDX20220530111005036)Basic and Applied Basic Research Fund of Guangdong Province:Regional Joint Fund Project Youth Fund(project no.2021A1515110356)Shenzhen Science and Technology Plan Project(project no.JCYJ20220818101407016)by the Project of Sanya Yazhou Bay Science and Technology City(no.SCKJJYRC-2023-27).
文摘The concept of gait synergy provides novel human-machine interfaces and has been applied to the control of lower limb assistive devices,such as powered prostheses and exoskeletons.Specifically,on the basis of gait synergy,the assistive device can generate/predict the appropriate reference trajectories precisely for the affected or missing parts from the motions of sound parts of the patients.Optimal modeling for gait synergy methods that involves optimal combinations of features(inputs)is required to achieve synergic trajectories that improve human–machine interaction.However,previous studies lack thorough discussions on the optimal methods for synergy modeling.In addition,feature selection(FS)that is crucial for reducing data dimensionality and improving modeling quality has often been neglected in previous studies.Here,we comprehensively investigated modeling methods and FS using 4 up-to-date neural networks:sequence-to-sequence(Seq2Seq),long short-term memory(LSTM),recurrent neural network(RNN),and gated recurrent unit(GRU).We also conducted complete FS using 3 commonly used methods:random forest,information gain,and Pearson correlation.Our findings reveal that Seq2Seq(mean absolute error:0.404°and 0.596°,respectively)outperforms LSTM,RNN,and GRU for both interlimb and intralimb synergy modeling.Furthermore,FS is proven to significantly improve Seq2Seq’s modeling performance(P<0.05).FS-Seq2Seq even outperforms methods used in existing studies.Therefore,we propose FSSeq2Seq as a 2-stage strategy for gait synergy modeling in lower limb assistive devices with the aim of achieving synergic and user-adaptive trajectories that improve human-machine interactions.
基金supported by the National Natural Science Foundation of China(22077143,21977127,and 21877134)Science Foundation of Guangzhou City(201904020023,China)+2 种基金Fundamental Research Funds for Hainan University(KYQD(ZR)-21031,China)Science of Guangdong Province(2019A1515011883,China)Guangdong Province Higher Vocational Colleges&Schools Pearl River Scholar Funded Scheme(2016,China).
文摘Vascular dementia(VaD)is the second commonest type of dementia which lacks of efficient treatments currently.Neuroinflammation as a prominent pathological feature of VaD,is highly involved in the development of VaD.In order to verify the therapeutic potential of PDE1 inhibitors against VaD,the anti-neuroinflammation,memory and cognitive improvement were evaluated in vitro and in vivo by a potent and selective PDE1 inhibitor 4a.Also,the mechanism of 4a in ameliorating neuroinflammation and VaD was systematically explored.Furthermore,to optimize the drug-like properties of 4a,especially for metabolic stability,15 derivatives were designed and synthesized.As a result,candidate 5f,with a potent IC50 value of 4.5 nmol/L against PDE1C,high selectivity over PDEs,and remarkable metabolic stability,efficiently ameliorated neuron degeneration,cognition and memory impairment in VaD mice model by suppressing NF-κB transcription regulation and activating cAMP/CREB axis.These results further identified PDE1 inhibition could serve as a new therapeutic strategy for treatment of VaD.
基金supported by the Natural Science Foundation of China(21877134,22077143,81903542,and 21977127)Science Foundation of Guangzhou City(201904020023,China)+3 种基金Fundamental Research Funds for Hainan University(KYQD(ZR)21031,China)Science Foundation of Guangdong Province(2019A1515011883,China)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093,China)Guangdong Province Higher Vocational Colleges&Schools Pearl River Scholar Funded Scheme(2016,China)。
文摘Our previous study demonstrated that phosphodiesterase 8(PDE8)could work as a potential target for vascular dementia(Va D)using a chemical probe 3a.However,compound 3a is a chiral compound which was obtained by chiral resolution on HPLC,restricting its usage in clinic.Herein,a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors.Lead 15 exhibited potent inhibitory activity against PDE8A(IC_(50)=11 nmol/L),high selectivity over other PDEs,and remarkable drug-like properties(worthy to mention is that its bioavailability was up to 100%).Oral administration of 15 significantly improved the c AMP level of the right brain and exhibited dosedependent effects on cognitive improvement in a Va D mouse model.Notably,the X-ray crystal structure of the PDE8A—15 complex showed that the potent affinity and high selectivity of 15 might come from the distinctive interactions with H-pocket including T-shapedπ—πinteractions with Phe785 as well as a unique H-bond network,which have never been observed in other PDE-inhibitor complex before,providing new strategies for the further rational design of novel selective inhibitors against PDE8.
基金supported by the National Natural Science Foundation of China(31860702 and 31960703)by the Hainan Province Science and Technology Special Fund(ZDKJ2021035).
文摘Arylalkylamine N-acetyltransferase(aaNAT),considered a potential new insecticide target,catalyzes the acetylation of arylalkylamine substrates such as serotonin and dopamine and,hence,mediates diverse functions in insects.However,the origin of insect aaNATs(iaaNATs)and the evolutionary process that generates multiple aaNATs in mosquitoes remain largely unknown.Here,we have analyzed the genomes of 33 species to explore and expand our understanding of the molecular evolution of this gene family in detail.We show that aaNAT orthologs are present in Bacteria,Cephalochordata,Chondrichthyes,Cnidaria,Crustacea,Mammalia,Placozoa,and Teleoste,as well as those from a number of insects,but are absent in some species of Annelida,Echinozoa,and Mollusca as well as Arachnida.Particularly,more than 10 aaNATs were detected in the Culicinae subfamily of mosquitoes.Molecular evolutionary analysis of aaNAT/aaNAT-like genes in mosquitoes reveals that tandem duplication events led to gene expansion in the Culicinae subfamily of mosquitoes more than 190 million years ago.Further selection analysis demonstrates that mosquito aaNATs evolved under strongly positive pressures that generated functional diversity following gene duplication events.Overall,this study may provide novel insights into the molecular evolution of the aaNAT family in mosquitoes.
