The main proteases(M^(pro)s)are hydrolases playing essential roles in the replication ofβ-coronaviruses including SARS-CoV-2.Herein,a highly efficient strategy was developed for discovering the M^(pro)inactivators fr...The main proteases(M^(pro)s)are hydrolases playing essential roles in the replication ofβ-coronaviruses including SARS-CoV-2.Herein,a highly efficient strategy was developed for discovering the M^(pro)inactivators from crude plant extract integrating target-based biochemical assay and chemoproteomic approaches.Firstly,Pu-erh tea was found to potently suppress SARS-CoV-2 M^(pro)in a time-dependent manner.Next,global chemical analysis coupling with peptide-modification profiling were used to identify the cysteine-modified constituents in Pu-erh tea.The results suggested that seven constituents in Pu-erh tea could modify SARSCoV-2 M^(pro),which turned out that epigallocatechin,gallocatechin and gallic acid were the most efficacious M^(pro)inactivators.Further investigations demonstrated that epigallocatechin and gallocatechin could inactivate S ARS-CoV-2 M^(pro)via blocking the formation of the homodimers.Collectively,this work proposed a novel and practical strategy for highly efficient discovery of time-dependent inhibitors of SARS-CoV-2 M^(pro)from plant extracts,while 3 constituents in Pu-erh tea have emerged as robust SARS-CoV-2 M^(pro)inactivators.展开更多
Introduction:With the incidence of chronic kidney disease(CKD)increasing year by year,it is particularly important to intervene in the early stage of CKD(stages 1–3).Unfortunately,the effective drug treatment methods...Introduction:With the incidence of chronic kidney disease(CKD)increasing year by year,it is particularly important to intervene in the early stage of CKD(stages 1–3).Unfortunately,the effective drug treatment methods for CKD(stages 1–3)are lacking.Guben Tongluo Formula(GTF)is the experience formula of Professor Liqun He,a famous traditional Chinese medicine(TCM)doctor in Shanghai.Our previous studies demonstrated that GTF might effectively alleviate CKD via multi-mechanisms.As the first angiotensin-2 receptor antagonist for treating hypertension,losartan potassium(LP)could effectively reduce blood pressure,decrease cardiovascular risk,and delay the occurrence of end-stage renal disease.Thus,we design this clinical protocol of GTF combining LP to observe the efficacy and safety of GTF and try to provide a novel drug treatment method for treating CKD(stages 1–3)patients.Methods and analysis:This is a multicenter randomized controlled clinical trial.160 participants will be enrolled in this trial and divided into LP group,GTF group,LP+GTF group,and placebo group randomly assigning 1:1:1:1 principle.LP group will receive general treatments combining LP,GTF group will receive general treatments combining GTF,and the GTF+LP group will receive general treatments combining GTF and LP.Placebo group will receive general treatments combining placebo treatment.The primary evaluation index will be the change of serum creatinine after treatment.Secondary evaluation indexes include changes in blood urea nitrogen,serum uric acid,estimated glomerular filtration rate,etc.;immune indicators and renal fibrosis indicators,as well as TCM symptoms.Besides,vital sign indicators and adverse events will be closely observed.Ethics and dissemination:The protocol has been approved by the Ethics Committee of Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine(reference number:2024-7th-HIRB-094)and other ethics committees at each center.With the implementation of this clinical trial,it would offer a TCM formula for the treatment of CKD(stages 1–3)and clarify the underlying mechanism of GTF for alleviating CKD.Trial registration:This trial is registered with ChiCTR2400090125 and registered on September 24,2024.展开更多
Although herbal medicines(HMs)are widely used in the prevention and treatment of obesity and obesity-associated disorders,the key constituents exhibiting anti-obesity activity and their molecular mechanisms are poorly...Although herbal medicines(HMs)are widely used in the prevention and treatment of obesity and obesity-associated disorders,the key constituents exhibiting anti-obesity activity and their molecular mechanisms are poorly understood.Recently,we assessed the inhibitory potentials of several HMs against human pancreatic lipase(hPL,a key therapeutic target for human obesity),among which the root-extract of Rhodiola crenulata(ERC)showed the most potent anti-hPL activity.In this study,we adopted an integrated strategy,involving bioactivity-guided fractionation techniques,chemical profiling,and biochemical assays,to identify the key anti-hPL constituents in ERC.Nine ERC fractions(retention time=12.5e35 min),obtained using reverse-phase liquid chromatography,showed strong anti-hPL activity,while the major constituents in these bioactive fractions were subsequently identified using liquid chromatography-quadrupole time-of-flight mass spectrometry(LC-Q-TOF-MS/MS).Among the identified ERC constituents,1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose(PGG)and catechin gallate(CG)showed the most potent anti-hPL activity,with pIC50 values of 7.59±0.03 and 7.68±0.23,respectively.Further investigations revealed that PGG and CG potently inhibited hPL in a non-competitive manner,with inhibition constant(Ki)values of 0.012 and 0.082 mM,respectively.Collectively,our integrative analyses enabled us to efficiently identify and characterize the key anti-obesity constituents in ERC,as well as to elucidate their anti-hPL mechanisms.These findings provide convincing evidence in support of the anti-obesity and lipid-lowering properties of ERC.展开更多
Glycosyl imidates are among the pioneering donors for catalytic glycosylation.We report a new generation of imidates featuring the presence of a pentafluorophenyl group,introduced via substitution on imidoyl fluoride ...Glycosyl imidates are among the pioneering donors for catalytic glycosylation.We report a new generation of imidates featuring the presence of a pentafluorophenyl group,introduced via substitution on imidoyl fluoride which is easily prepared,stable and user-friendly.The resulting donors exhibit exceptional shelf stability while can be readily activated to achieve high-yielding glycosylation,encompassing comprehensively aldosyl,ketosyl and ulosonyl donors,and both O-and N-glycosylation acceptors.Notably,the reactivity gradient across different generations of imidates,coupled with the accessible imidate acceptor from selective reaction of imidoyl fluoride at the anomeric hydroxyl group,enables a fully catalytic one-pot synthesis of oligosaccharides.展开更多
Human cytochrome P4501B1(h CYP1B1),an extrahepatic heme-dependent monooxygenase,has been validated as a key target for overcoming chemotherapy resistance and tumorigenesis.Herein,to discover novel efficacious h CYP1B1...Human cytochrome P4501B1(h CYP1B1),an extrahepatic heme-dependent monooxygenase,has been validated as a key target for overcoming chemotherapy resistance and tumorigenesis.Herein,to discover novel efficacious h CYP1B1 inhibitors,a suite of 1,8-naphthalimide derivatives was designed,synthesized,and biologically evaluated,via integrating structure-based drug design(SBDD)and biochemical assays.After two rounds of structural modifications and structure-activity relationship(SAR)studies,the results suggested that introducing a benzene ring at the north part and a halogen atom at the C-4 site significantly enhanced the anti-h CYP1B1 effects of naphthalimides.Among all tested 1,8-naphthalimides,NB-10showed the most potent anti-h CYP1B1 effect(half maximal inhibitory concentration(IC_(50))=0.41 nmol/L)and excellent specificity,while this agent did not activate Ah R transcription activity in living cells.Further cellular assays and in vivo tests in paclitaxel(PTX)-resistance xenograft mice showed that NB-10could significantly potentiate the anti-cancer effects of PTX both in vitro and in vivo,while this agent also showed high safety profiles in mice.Mechanistically,NB-10 potently inhibited h CYP1B1-catalyzed 7-ethoxyresorufin O-deethylation in a competitive manner,with an estimated Kivalue of 0.15 nmol/L.Docking simulations showed that NB-10 could be well-fitted in the catalytic pocket of h CYP1B1 to form a stable conformation with a high binding affinity.Collectively,several potent 4-halogenated naphthalimides were developed as novel h CYP1B1 inhibitors,while NB-10 showed high safety profiles and impressive efficacy for overcoming h CYP1B1-associated PTX resistance both in vitro and in vivo.展开更多
Background There have been no effective treatments for slowing or reversing Alzheimer’s disease(AD)until now.Growing preclinical evidence,including this study,suggests that mesenchymal stem cells-secreted exosomes(MS...Background There have been no effective treatments for slowing or reversing Alzheimer’s disease(AD)until now.Growing preclinical evidence,including this study,suggests that mesenchymal stem cells-secreted exosomes(MSCs-Exos)have the potential to cure AD.Aims The first three-arm,drug-intervention,phase I/II clinical trial was conducted to explore the safety and efficacy of allogenic human adipose MSCs-Exos(ahaMSCs-Exos)in patients with mild to moderate AD.Methods The eligible subjects were assigned to one of three dosage groups,intranasally administrated with ahaMSCs-Exos two times per week for 12 weeks,and underwent follow-up visits at weeks 16,24,36 and 48.Results No adverse events were reported.In the medium-dose arm,Alzheimer’s Disease Assessment Scale–Cognitive section(ADAS-cog)scores decreased by 2.33(1.19)and the basic version of Montreal Cognitive Assessment scores increased by 2.38(0.58)at week 12 compared with baseline levels,indicating improved cognitive function.Moreover,the ADAS-cog scores in the medium-dose arm decreased continuously by 3.98 points until week 36.There were no significant differences in altered amyloid or tau deposition among the three arms,but hippocampal volume shrank less in the medium-dose arm to some extent.Conclusions Intranasal administration of ahaMSCs-Exos was safe and well tolerated,and a dose of at least 4×10^(8)particles could be selected for further clinical trials.展开更多
The Chinese herb Ephedra(also known as Mahuang)has been extensively utilized for the prevention and treatment of coronavirus-induced diseases,including coronavirus disease 2019(COVID-19).However,the specific anti-SARS...The Chinese herb Ephedra(also known as Mahuang)has been extensively utilized for the prevention and treatment of coronavirus-induced diseases,including coronavirus disease 2019(COVID-19).However,the specific anti-SARS-CoV-2 compounds and mechanisms have not been fully elucidated.The main protease(M^(pro))of SARS-CoV-2 is a highly conserved enzyme responsible for proteolytic processing during the viral life cycle,making it a critical target for the development of antiviral therapies.This study aimed to identify naturally occurring covalent inhibitors of SARS-CoV-2 M^(pro)from Ephedra and to investigate their covalent binding sites.The results demonstrated that the non-alkaloid fraction of Ephedra(ENA)exhibited a potent inhibitory effect against the SARS-CoV-2 M^(pro)effect,whereas the alkaloid fraction did not.Subsequently,the chemical constituents in ENA were identified,and the major constituents'anti-SARS-CoV-2 M^(pro)effects were evaluated.Among the tested constituents,herbacetin(HE)and gallic acid(GA)were found to inhibit SARS-CoV-2 M^(pro)in a time-and dose-dependent manner.Their combination displayed a significant synergistic effect on this key enzyme.Additionally,various techniques,including inhibition kinetic assays,chemoproteomic methods,and molecular dynamics simulations,were employed to further elucidate the synergistic anti-M^(pro)mechanisms of the combination of HE and GA.Overall,this study deciphers the naturally occurring covalent inhibitors of SARS-CoV-2 M^(pro)from Ephedra and characterizes their synergistic anti-M^(pro)synergistic effect,providing robust evidence to support the anti-coronavirus efficacy of Ephedra.展开更多
As a vital negative regulator of Wnt signaling pathway,human Notum(hNotum)plays a crucial regulatory role in the progression of many human diseases.Deciphering the relevance of h Notum to human diseases requires pract...As a vital negative regulator of Wnt signaling pathway,human Notum(hNotum)plays a crucial regulatory role in the progression of many human diseases.Deciphering the relevance of h Notum to human diseases requires practical and reliable tools for visualizing h Notum activity in living systems.Herein,an enzyme-activatable fluorogenic tool(IR-783 octanoate)was rationally engineered for sensing and imaging h Notum activity in living systems by integrating computer-aided molecular design and biochemical assays.IR-783 octanoate showed good optical properties,excellent specificity and high binding-affinity towards h Notum(K_(m)=0.98μmol/L).IR-783 octanoate could be well up-taken into the cancerous cells or tumors that over-expressed organic anion transporting polypeptides(OATPs),and then hydrolyzed by cellular h Notum to release free IR-783 ketone,which created brightly fluorescent signals around 646 nm.Further investigations showed that IR-783 octanoate achieved a good performance for in-situ functional imaging of h Notum in both living cells,cancerous tissues and organs.It was also found that some SW620cells with multipolar spindles could be stained by IR-783 octanoate to emit extremely bright signals,suggesting that this agent could be used as a novel visualizing tool for tracing the cells undergoing abnormal cell mitoses.Collectively,this study devises a highly specific fluorogenic tool for in-situ functional imaging of hNotum in living systems,which offers a practical and reliable tool to dynamically track the changes in h Notum activity under various conditions.展开更多
Traditional Chinese medicine(TCM)is considered as a unique treasure of Chinese civilization for its profound theoretical system and extensive experience in clinical practice for more than two thousand years.As one of ...Traditional Chinese medicine(TCM)is considered as a unique treasure of Chinese civilization for its profound theoretical system and extensive experience in clinical practice for more than two thousand years.As one of the most commonly used folk medicines,Chinese medicines have made indelible contributions to well-being maintenance and disease treatment,as well as the progress of human civilization[1].展开更多
Human serum albumin(HSA) has emerged as a pivotal biomarker and prognostic indicator for various human diseases. Real-time sensing and visual tracking of HSA in plasma or other biological systems will immensely facili...Human serum albumin(HSA) has emerged as a pivotal biomarker and prognostic indicator for various human diseases. Real-time sensing and visual tracking of HSA in plasma or other biological systems will immensely facilitate the basic researchers and clinicians to better understand HSA-associated biological processes. Herein, a novel near-infrared(NIR) fluorescent probe(7-HTCF) was rationally constructed for light-up sensing and in-situ imaging of HSA in real samples, based on the principle of twisted intramolecular charge transfer(TICT). Under physiological conditions, 7-HTCF could be efficiently trapped by HSA to form a stable complex via binding on a non-drug binding site, while the complex emitted strong fluoresce signals around 670 nm. Further investigations demonstrated that 7-HTCF displayed a great combination of excellent selectivity and good chemical stability, as well as rapid fluorescent response and ultra-high sensitivity for HSA detection. Particularly, the newly developed light-up probe has been successfully utilized for quantitative detection of HSA in diluted plasma samples, while its readouts are hardly affected by the addition of therapeutic agents and herbal medicines. 7-HTCF is also successfully used for in-situ imaging of the reabsorbed HSA in living renal cells, while this dye exhibits good cell permeability and high resolution for in-situ imaging in living cells. Collectively, a novel TICT-based near-infrared fluorescent probe was devised for highly selective and ultra-sensitive sensing of HSA in plasma samples or imaging HSA in living cells, which offered a practical tool for clinical tests and for exploring HSA-associated biological processes.展开更多
Artificial intelligence(AI)has emerged as a transformative technology in accelerating drug discovery and development within natural medicines research.Natural medicines,characterized by their complex chemical composit...Artificial intelligence(AI)has emerged as a transformative technology in accelerating drug discovery and development within natural medicines research.Natural medicines,characterized by their complex chemical compositions and multifaceted pharmacological mechanisms,demonstrate widespread application in treating diverse diseases.However,research and development face significant challenges,including component complexity,extraction difficulties,and efficacy validation.AI technology,particularly through deep learning(DL)and machine learning(ML)approaches,enables efficient analysis of extensive datasets,facilitating drug screening,component analysis,and pharmacological mechanism elucidation.The implementation of AI technology demonstrates considerable potential in virtual screening,compound optimization,and synthetic pathway design,thereby enhancing natural medicines’bioavailability and safety profiles.Nevertheless,current applications encounter limitations regarding data quality,model interpretability,and ethical considerations.As AI technologies continue to evolve,natural medicines research and development will achieve greater efficiency and precision,advancing both personalized medicine and contemporary drug development approaches.展开更多
Despite ongoing advancements in cancer treatment,the emergence of primary and acquired resistance poses a significant challenge for both traditional chemotherapy and immune checkpoint blockade therapies.The demand for...Despite ongoing advancements in cancer treatment,the emergence of primary and acquired resistance poses a significant challenge for both traditional chemotherapy and immune checkpoint blockade therapies.The demand for targeted therapeutics for multidrug-resistant cancer is more important than ever.Peptides,as emerging alternatives to current anticancer drugs,offer exquisite versatility in facilitating the design of novel oncology drugs,with the core superiorities of good biocompatibility and a low tendency to induce drug resistance.This review comprehensively introduces the pharmacological mechanisms of peptide-based drugs and strategies for overcoming multidrug resistance(MDR)in cancers,including inducing cell membrane lysis,targeting organelles,activating anticancer immune responses,enhancing drug uptake,targeting ATP-binding cassette(ABC)transporters,and targeting B-cell lymphoma-2(BCL-2)family proteins.Additionally,the current clinical applications of representative peptides in combating MDR cancers and their potential directions for medicinal chemistry research have been thoroughly discussed.This review offers essential insights into the novel treatment approaches for MDR cancers and highlights the trends and perspectives in this field.展开更多
Hyperlipidemia is a risk factor for clinically significant thrombotic events in cardiovascular diseases.Platelet reactivity in hyperlipidemic conditions is enhanced when platelet scavenger receptor CD36 recognizes oxi...Hyperlipidemia is a risk factor for clinically significant thrombotic events in cardiovascular diseases.Platelet reactivity in hyperlipidemic conditions is enhanced when platelet scavenger receptor CD36 recognizes oxidized lipids in oxidized low-density lipoprotein(ox-LDL)particles,a process that induces atherothrombosis.Sulforaphane(SFN)is a dietary isothiocyanate enriched in cruciferous vegetables and exerts multiple biological activities.The current study sought to investigate the efficacy of SFN on platelet hyperreactivity under hyperlipidemic conditions in vitro and in vivo.Using a series of platelet functional assays in human platelets in vitro,we demonstrated that SFN attenuated ox-LDL-increased platelet aggregation and activation(surface CD62P expression).Mechanistically,studies using pharmacological inhibitors clarified that these inhibitory effects of SFN were mainly modulated by down-regulating CD36-mediated activation of Src kinases,leading to enhanced activation of cyclic adenosine monophosphate/protein kinase A(cAMP/PKA)signaling,and resultant inhibition of NADPH oxidase 2(NOX2)-dependent generation of reactive oxygen species(ROS).Moreover,12-week supplementation of SFN-enriched broccoli sprout extract(BSE,0.06%diet)in hyperlipidemic C57BL/6J mice also decreased platelet hyperreactivity.Studies using pharmacological inhibitors of CD36,protein kinase A(PKA)and NOX2 showed that the efficacy of BSE supplementation was mainly through modulating CD36-mediated the cAMP/PKA/NOX2 signaling.Thus,through modulating the cAMP/PKA/NOX2 pathway and attenuating CD36-mediated platelet hyperreactivity,SFN may play important protective roles in atherothrombosis under hyperlipidemic conditions.展开更多
Immunotherapy of triple-negative breast cancer(TNBC)is significantly hindered by the immunosuppressive tumor microenvironment(TME).Notably,tumor-associated macrophages(TAMs),which constitute the predominant infiltrati...Immunotherapy of triple-negative breast cancer(TNBC)is significantly hindered by the immunosuppressive tumor microenvironment(TME).Notably,tumor-associated macrophages(TAMs),which constitute the predominant infiltrating immune cell type in TNBC,represent a critical target for“turning off”immunosuppressive TME.Despite numerous ongoing clinical trials,current strategies exhibit limited efficacy in overcoming immunosuppressive TME.Interestingly,regulation of son of sevenless 1(SOS1),which is overexpressed in TNBC patients,shows promising potential for TAM repolarization.Herein,we developed a biomimetic liposomal platform(CCM/Cil-lipo@TD),which integrates cilengitide(Cil)-functionalized breast cancer cell membranes(CCM)to co-deliver tetrandrine(TET)and low-dose docetaxel(DTX)for TNBC therapy.This system synergistically enhanced immunotherapy by coupling SOS1 blockade-driven TAM repolarization with immune cell death(ICD)-mediated dendritic cell(DC)maturation,thereby reshaping the highly immunosuppressive TME in TNBC.Critically,the low-density Cil-anchored,CCM-fused liposomes overcome the penetration limitations inherent to conventional CCM-based delivery systems,achieving deep intratumoral accumulation of therapeutic payloads.Mechanistically,the CCM/Cil-lipo@TD ensured that TET-mediated SOS1 inhibition in tumor cells efficiently polarized TAM2(protumor)toward TAM1(antitumor).Furthermore,SOS1 blockade synergized with low-dose DTX-induced ICD to remodel TME,as evidenced by sustained cytotoxic T-cell infiltration and suppression of regulatory T cells.The CCM/Cil-lipo@TD exerted superior tumor inhibition(82.9%)in 4T1 orthotopic models and effectively inhibited postoperative local recurrence and distant metastasis.Taken together,the Cil-engineered,cellmembrane-anchoring CCM/Cil-lipo@TD provides a promising approach for TNBC immunotherapy.展开更多
Human Notum(hNotum)inhibitors could be used for treating Wnt signalling-associated diseases including colorectal cancer.Herein,two series of chalcone derivatives were designed and synthesized aiming to find selective ...Human Notum(hNotum)inhibitors could be used for treating Wnt signalling-associated diseases including colorectal cancer.Herein,two series of chalcone derivatives were designed and synthesized aiming to find selective and potent hNotum inhibitors.Structure–activity relationship(SAR)studies showed that 2-methoxyl and 5-bromine substitutions on A-ring significantly enhanced anti-hNotum effect,while 4’-ethoxyl and 3’-alkyl substitutions on B-ring were beneficial for hNotum inhibition.Among all tested chalcones,B11 displayed the most potent anti-Notum effect(IC_(50)=3.6 nmol/L),good selectivity,excellent chemical stability and suitable metabolic stability.Further investigations showed that B11 acted as a competitive inhibitor of hNotum,while this agent(5μmol/L)significantly weaken the migration abilities of colorectal cancer cells.Collectively,this study deciphers the SARs of chalcones as hNotum inhibitors and reports a novel and potent hNotum inhibitor with the anti-migration effect on colorectal cancer cells,which offers a promising lead compound to develop novel anti-cancer agents.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 aryl hydrocarbon receptor(AhR)plays a crucial role in regulating many physiological processes.Activating the AhReCYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases.Here,a...The aryl hydrocarbon receptor(AhR)plays a crucial role in regulating many physiological processes.Activating the AhReCYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases.Here,a practical in situ cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators,via functional sensing of CYP1A1 activities in live cells.Firstly,a cell-permeable,isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for in-situ visualizing the dynamic changes of CYP1A1 function in living systems,which was subsequently used for discovering the efficacious modulators of the AhReCYP1A1 axis.Following screening of a compound library,LAC-7 was identified as an efficacious activator of the AhReCYP1A1 axis,which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines.LAC-7 also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages.Animal tests showed that LAC-7 could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice,and markedly reduced the levels of multiple inflammatory factors.Collectively,an optimized fluorometric cell-based assay was devised for in situ functional imaging of CYP1A1 activities in living systems,which strongly facilitated the discovery of efficacious modulators of the AhReCYP1A1 axis as novel antiinflammatory agents.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
Ferroptosis induced by ferrous ions(Fe^(2+))and lipid peroxidation accumulation is a novel form of regulated cell death that has become a hot topic in tumor therapy research.Identifying small-molecule drugs that can i...Ferroptosis induced by ferrous ions(Fe^(2+))and lipid peroxidation accumulation is a novel form of regulated cell death that has become a hot topic in tumor therapy research.Identifying small-molecule drugs that can induce ferroptosis in tumor cells is a very attractive therapeutic strategy.Here,we screened a natural product,acevaltrate(ACE),which rapidly and strongly induces ferroptosis in colorectal cancer cells.ACE not only increases Fe^(2+)levels in colorectal cancer cells by targeting iron chaperones PCBP1/2 and reducing their expression but also disrupts the antioxidant system of colorectal cancer cells by targeting GPX4 and inhibiting its enzymatic activity,leading to its ubiquitin-mediated degradation.展开更多
Objective:To characterize the oxidative metabolic pathway(s)of pectolinarigenin(PEC)and reveal the effect of PEC oxidative metabolism on its biological activities including peroxisome proliferatoractivated receptors(P...Objective:To characterize the oxidative metabolic pathway(s)of pectolinarigenin(PEC)and reveal the effect of PEC oxidative metabolism on its biological activities including peroxisome proliferatoractivated receptors(PPAR)and nuclear factor erythroid 2-related factor 2(Nrf2)agonist effects,as well as the anti-oxidative and hepatoprotective activities.Methods:The oxidative metabolites of PEC were identified by liquid chromatography-time of flight-mass spectrometry(LC-TOF-MS/MS).The key enzymes involved in oxidative metabolism of PEC were assigned by P450 reaction phenotyping assays and enzymatic kinetics assays.Luciferase reporter assays and western blotting analysis were used to evaluate the Nrf2 and PPAR agonist effects of PEC and its oxidative metabolites.The intracellular levels of total reactive oxygen species(ROS),mitochondrial membrane potential(MMP),lactate dehydrogenase(LDH)and glutathione(GSH)in acetaminophen(APAP)-challenged hepatocytes were also tested.Results:PEC could be readily metabolized to form two O-demethylated metabolites including hispidulin(HIS,4′-O-demethylated PEC)and 6-O-demethylated PEC in human liver microsomes(HLM)in the presence of nicotinamide adenine dinucleotide phosphate(NADPH),while HIS was identified as the major oxidative metabolite of PEC.At least nine human cytochrome P450 enzymes(CYP)enzymes could catalyze PEC-4′-O-demethylation,while CYP1A2 and CYP2D6 showed the highest binding affinities and rapid metabolic clearance rates in the oxidative metabolism of PEC.Biological assays showed that PEC4′-O-demethylation slightly decreased the PPAR agonist effects of PEC,while HIS showed more potent Nrf2 agonist effect.Compared with PEC,HIS showed more efficacious hepatoprotective effect against APAP-induced hepatocyte injury,evidenced by more potent ability to reduce intracellular ROS and LDH levels,as well as more effective ability to elevate the intracellular levels of both MPP and GSH in APAP-challenged hepatocytes.Conclusion:CYPs catalyze PEC-4′-O-demethylation to generate a more active Nrf2 agonist(HIS),which shows more efficacious hepatoprotective effects against APAP-induced hepatocyte injury.展开更多
基金the supporting of Shanghai Science and Technology Innovation Action Plans(21S21900600,20S21901500,20S21900900)supported by Shanghai Science and Technology Committee+5 种基金the NSF of China(82273897,81922070,81973286,82104281,82173798)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTDD-202004)the Three-year Action Plan for Shanghai TCM Development and Inheritance Program(ZY(2021-2023)-0401)Shanghai Municipal Health Commission’s TCM Research Project(2022CX005)Shanghai Municipal Science and Technology Major Project(ZD2021CY001)Excellent Doctoral Student Cultivation Projects in Key Fields(GJ2022012)。
文摘The main proteases(M^(pro)s)are hydrolases playing essential roles in the replication ofβ-coronaviruses including SARS-CoV-2.Herein,a highly efficient strategy was developed for discovering the M^(pro)inactivators from crude plant extract integrating target-based biochemical assay and chemoproteomic approaches.Firstly,Pu-erh tea was found to potently suppress SARS-CoV-2 M^(pro)in a time-dependent manner.Next,global chemical analysis coupling with peptide-modification profiling were used to identify the cysteine-modified constituents in Pu-erh tea.The results suggested that seven constituents in Pu-erh tea could modify SARSCoV-2 M^(pro),which turned out that epigallocatechin,gallocatechin and gallic acid were the most efficacious M^(pro)inactivators.Further investigations demonstrated that epigallocatechin and gallocatechin could inactivate S ARS-CoV-2 M^(pro)via blocking the formation of the homodimers.Collectively,this work proposed a novel and practical strategy for highly efficient discovery of time-dependent inhibitors of SARS-CoV-2 M^(pro)from plant extracts,while 3 constituents in Pu-erh tea have emerged as robust SARS-CoV-2 M^(pro)inactivators.
基金supported by grants from Pudong New Area Traditional Chinese Medicine Brand Multiplication Plan-Chronic Nephropathy(PDZY-2021-0302)Construction of He Liqun’s famous TCM studio(PDZY-2022-0703)+2 种基金Clinical Observation on the Efficacy of Guben Tongluo Formula in Treating Chronic Kidney Disease Phase 1-3(PW2022D-12)Pilot Project of Inheritance,Innovation and Development of Traditional Chinese Medicine in Pudong New Area(YC-2023-0602)Pudong New Area’s Peak and Plateau Discipline Development in Clinical Medicine for Novel and Special Diseases(2025-PWXZ-15).
文摘Introduction:With the incidence of chronic kidney disease(CKD)increasing year by year,it is particularly important to intervene in the early stage of CKD(stages 1–3).Unfortunately,the effective drug treatment methods for CKD(stages 1–3)are lacking.Guben Tongluo Formula(GTF)is the experience formula of Professor Liqun He,a famous traditional Chinese medicine(TCM)doctor in Shanghai.Our previous studies demonstrated that GTF might effectively alleviate CKD via multi-mechanisms.As the first angiotensin-2 receptor antagonist for treating hypertension,losartan potassium(LP)could effectively reduce blood pressure,decrease cardiovascular risk,and delay the occurrence of end-stage renal disease.Thus,we design this clinical protocol of GTF combining LP to observe the efficacy and safety of GTF and try to provide a novel drug treatment method for treating CKD(stages 1–3)patients.Methods and analysis:This is a multicenter randomized controlled clinical trial.160 participants will be enrolled in this trial and divided into LP group,GTF group,LP+GTF group,and placebo group randomly assigning 1:1:1:1 principle.LP group will receive general treatments combining LP,GTF group will receive general treatments combining GTF,and the GTF+LP group will receive general treatments combining GTF and LP.Placebo group will receive general treatments combining placebo treatment.The primary evaluation index will be the change of serum creatinine after treatment.Secondary evaluation indexes include changes in blood urea nitrogen,serum uric acid,estimated glomerular filtration rate,etc.;immune indicators and renal fibrosis indicators,as well as TCM symptoms.Besides,vital sign indicators and adverse events will be closely observed.Ethics and dissemination:The protocol has been approved by the Ethics Committee of Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine(reference number:2024-7th-HIRB-094)and other ethics committees at each center.With the implementation of this clinical trial,it would offer a TCM formula for the treatment of CKD(stages 1–3)and clarify the underlying mechanism of GTF for alleviating CKD.Trial registration:This trial is registered with ChiCTR2400090125 and registered on September 24,2024.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82160739,81922070,81973286,and 81973393)Sailing Special Project of Shanghai Rising-Star Program(Grant No.:22YF1441500)+6 种基金Program for Innovative Leading Talents of Qinghai Province(2018&2019)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(Grant No.:ZYYCXTD-D-202004)Shanghai Science and Technology Innovation Action Plans(Grant Nos.:20S21901500 and 20S21900900)supported by the Shanghai Science and Technology CommitteeProject of the National Multidisciplinary Innovation Team of Traditional Chinese Medicine supported by the National Administration of Traditional Chinese MedicineKey R&D and Transformation Science and Technology Cooperation Project of Qinghai Province(Grant No.:2019-HZ-819)Basic Public Welfare Research Program of Zhejiang Province(Grant No.:LGF22H280012).
文摘Although herbal medicines(HMs)are widely used in the prevention and treatment of obesity and obesity-associated disorders,the key constituents exhibiting anti-obesity activity and their molecular mechanisms are poorly understood.Recently,we assessed the inhibitory potentials of several HMs against human pancreatic lipase(hPL,a key therapeutic target for human obesity),among which the root-extract of Rhodiola crenulata(ERC)showed the most potent anti-hPL activity.In this study,we adopted an integrated strategy,involving bioactivity-guided fractionation techniques,chemical profiling,and biochemical assays,to identify the key anti-hPL constituents in ERC.Nine ERC fractions(retention time=12.5e35 min),obtained using reverse-phase liquid chromatography,showed strong anti-hPL activity,while the major constituents in these bioactive fractions were subsequently identified using liquid chromatography-quadrupole time-of-flight mass spectrometry(LC-Q-TOF-MS/MS).Among the identified ERC constituents,1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose(PGG)and catechin gallate(CG)showed the most potent anti-hPL activity,with pIC50 values of 7.59±0.03 and 7.68±0.23,respectively.Further investigations revealed that PGG and CG potently inhibited hPL in a non-competitive manner,with inhibition constant(Ki)values of 0.012 and 0.082 mM,respectively.Collectively,our integrative analyses enabled us to efficiently identify and characterize the key anti-obesity constituents in ERC,as well as to elucidate their anti-hPL mechanisms.These findings provide convincing evidence in support of the anti-obesity and lipid-lowering properties of ERC.
基金the National Natural Science Foundation of China(No.21672147)Shanghai University of Traditional Chinese Medicine for financial support。
文摘Glycosyl imidates are among the pioneering donors for catalytic glycosylation.We report a new generation of imidates featuring the presence of a pentafluorophenyl group,introduced via substitution on imidoyl fluoride which is easily prepared,stable and user-friendly.The resulting donors exhibit exceptional shelf stability while can be readily activated to achieve high-yielding glycosylation,encompassing comprehensively aldosyl,ketosyl and ulosonyl donors,and both O-and N-glycosylation acceptors.Notably,the reactivity gradient across different generations of imidates,coupled with the accessible imidate acceptor from selective reaction of imidoyl fluoride at the anomeric hydroxyl group,enables a fully catalytic one-pot synthesis of oligosaccharides.
基金supported by the National Natural Science Foundation of China(Nos.82273897,U23A20516,32101202)Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine(No.2023YZZ02)+5 种基金Shanghai Municipal Health Commission’s TCM research project(No.2022CX005)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTDD-202004)Pudong Institute of Clinical Chinese Medicine(No.YC-2023-0603)The“Fourteenth Five-Year Plan”Traditional Chinese Medicine Specialty Project for the Construction of Andrology Departments in TCM(No.ZYTSZK1-4)the State Key Laboratory of Fine Chemicals,Dalian University of Technology(No.KF2202)the Fundamental Research Funds for the Central Universities(No.G2024KY05106)。
文摘Human cytochrome P4501B1(h CYP1B1),an extrahepatic heme-dependent monooxygenase,has been validated as a key target for overcoming chemotherapy resistance and tumorigenesis.Herein,to discover novel efficacious h CYP1B1 inhibitors,a suite of 1,8-naphthalimide derivatives was designed,synthesized,and biologically evaluated,via integrating structure-based drug design(SBDD)and biochemical assays.After two rounds of structural modifications and structure-activity relationship(SAR)studies,the results suggested that introducing a benzene ring at the north part and a halogen atom at the C-4 site significantly enhanced the anti-h CYP1B1 effects of naphthalimides.Among all tested 1,8-naphthalimides,NB-10showed the most potent anti-h CYP1B1 effect(half maximal inhibitory concentration(IC_(50))=0.41 nmol/L)and excellent specificity,while this agent did not activate Ah R transcription activity in living cells.Further cellular assays and in vivo tests in paclitaxel(PTX)-resistance xenograft mice showed that NB-10could significantly potentiate the anti-cancer effects of PTX both in vitro and in vivo,while this agent also showed high safety profiles in mice.Mechanistically,NB-10 potently inhibited h CYP1B1-catalyzed 7-ethoxyresorufin O-deethylation in a competitive manner,with an estimated Kivalue of 0.15 nmol/L.Docking simulations showed that NB-10 could be well-fitted in the catalytic pocket of h CYP1B1 to form a stable conformation with a high binding affinity.Collectively,several potent 4-halogenated naphthalimides were developed as novel h CYP1B1 inhibitors,while NB-10 showed high safety profiles and impressive efficacy for overcoming h CYP1B1-associated PTX resistance both in vitro and in vivo.
基金supported by the Ministry of Science and Technology of the People's Republic of China(2021ZD0201804,GW)National Natural Science Foundation of China(92068111,81973272,XG,81903582,QS)+1 种基金Natural Science Foundation of Shanghai(219ZR1431500,GW)Shanghai Science and Technology Committee(121XD1422200,XG)and Cellular Biomedicine Group(CBMG,Shanghai,China).
文摘Background There have been no effective treatments for slowing or reversing Alzheimer’s disease(AD)until now.Growing preclinical evidence,including this study,suggests that mesenchymal stem cells-secreted exosomes(MSCs-Exos)have the potential to cure AD.Aims The first three-arm,drug-intervention,phase I/II clinical trial was conducted to explore the safety and efficacy of allogenic human adipose MSCs-Exos(ahaMSCs-Exos)in patients with mild to moderate AD.Methods The eligible subjects were assigned to one of three dosage groups,intranasally administrated with ahaMSCs-Exos two times per week for 12 weeks,and underwent follow-up visits at weeks 16,24,36 and 48.Results No adverse events were reported.In the medium-dose arm,Alzheimer’s Disease Assessment Scale–Cognitive section(ADAS-cog)scores decreased by 2.33(1.19)and the basic version of Montreal Cognitive Assessment scores increased by 2.38(0.58)at week 12 compared with baseline levels,indicating improved cognitive function.Moreover,the ADAS-cog scores in the medium-dose arm decreased continuously by 3.98 points until week 36.There were no significant differences in altered amyloid or tau deposition among the three arms,but hippocampal volume shrank less in the medium-dose arm to some extent.Conclusions Intranasal administration of ahaMSCs-Exos was safe and well tolerated,and a dose of at least 4×10^(8)particles could be selected for further clinical trials.
基金supported by the National Key Research and Development Program of China(No.2022YFC-3502000)the Basic Public Welfare Research Program of Zhejiang Province(No.LGF22H280012)+4 种基金Zhejiang Provincial TCM Science and Technology Plan Project(Nos.2023ZR064,GZY-ZJ-KJ-24004,2024ZL007 and 2022ZB017)the Medical Science and Technology Project of Zhejiang Province(Nos.2022495401,2021KY040 and2022KY069)Zhejiang Provincial Key Projects in Chinese Medicine(Nos.2020ZZ003 and 2021ZZ001)Shanghai Science and Technology Innovation Action Plans(Nos.21S21900600)Zhejiang Province"Ten Thousand People Plan"Science and Technology Innovation Leading Talents Project(No.2020R52029)。
文摘The Chinese herb Ephedra(also known as Mahuang)has been extensively utilized for the prevention and treatment of coronavirus-induced diseases,including coronavirus disease 2019(COVID-19).However,the specific anti-SARS-CoV-2 compounds and mechanisms have not been fully elucidated.The main protease(M^(pro))of SARS-CoV-2 is a highly conserved enzyme responsible for proteolytic processing during the viral life cycle,making it a critical target for the development of antiviral therapies.This study aimed to identify naturally occurring covalent inhibitors of SARS-CoV-2 M^(pro)from Ephedra and to investigate their covalent binding sites.The results demonstrated that the non-alkaloid fraction of Ephedra(ENA)exhibited a potent inhibitory effect against the SARS-CoV-2 M^(pro)effect,whereas the alkaloid fraction did not.Subsequently,the chemical constituents in ENA were identified,and the major constituents'anti-SARS-CoV-2 M^(pro)effects were evaluated.Among the tested constituents,herbacetin(HE)and gallic acid(GA)were found to inhibit SARS-CoV-2 M^(pro)in a time-and dose-dependent manner.Their combination displayed a significant synergistic effect on this key enzyme.Additionally,various techniques,including inhibition kinetic assays,chemoproteomic methods,and molecular dynamics simulations,were employed to further elucidate the synergistic anti-M^(pro)mechanisms of the combination of HE and GA.Overall,this study deciphers the naturally occurring covalent inhibitors of SARS-CoV-2 M^(pro)from Ephedra and characterizes their synergistic anti-M^(pro)synergistic effect,providing robust evidence to support the anti-coronavirus efficacy of Ephedra.
基金supported by National Natural Science Foundation of China(Nos.81922070,81973286,82273897,U23A20516,81801818)Shanghai Municipal Health Commission’s TCM research project(No.2022CX005)+4 种基金Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTDD-202004)Three-year Action Plan for Shanghai TCM Development and Inheritance Program(No.ZY(2021-2023)-0401)Department of Science&Technology of Liaoning Province Grant(No.2022JH2/20200056)supported by the State Key Laboratory of Fine ChemicalsDalian University of Technology(No.KF 2202)。
文摘As a vital negative regulator of Wnt signaling pathway,human Notum(hNotum)plays a crucial regulatory role in the progression of many human diseases.Deciphering the relevance of h Notum to human diseases requires practical and reliable tools for visualizing h Notum activity in living systems.Herein,an enzyme-activatable fluorogenic tool(IR-783 octanoate)was rationally engineered for sensing and imaging h Notum activity in living systems by integrating computer-aided molecular design and biochemical assays.IR-783 octanoate showed good optical properties,excellent specificity and high binding-affinity towards h Notum(K_(m)=0.98μmol/L).IR-783 octanoate could be well up-taken into the cancerous cells or tumors that over-expressed organic anion transporting polypeptides(OATPs),and then hydrolyzed by cellular h Notum to release free IR-783 ketone,which created brightly fluorescent signals around 646 nm.Further investigations showed that IR-783 octanoate achieved a good performance for in-situ functional imaging of h Notum in both living cells,cancerous tissues and organs.It was also found that some SW620cells with multipolar spindles could be stained by IR-783 octanoate to emit extremely bright signals,suggesting that this agent could be used as a novel visualizing tool for tracing the cells undergoing abnormal cell mitoses.Collectively,this study devises a highly specific fluorogenic tool for in-situ functional imaging of hNotum in living systems,which offers a practical and reliable tool to dynamically track the changes in h Notum activity under various conditions.
基金supported by the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTDD-202004)the Threeyear Action Plan for Shanghai TCM Development and Inheritance Program[No.ZY(2021-2023)-0401]Shanghai Science and Technology InnovationActionPlans(Nos.20S21901500,21S21900600)supported by Shanghai Science and Technology Committee。
文摘Traditional Chinese medicine(TCM)is considered as a unique treasure of Chinese civilization for its profound theoretical system and extensive experience in clinical practice for more than two thousand years.As one of the most commonly used folk medicines,Chinese medicines have made indelible contributions to well-being maintenance and disease treatment,as well as the progress of human civilization[1].
基金financially supported by the National Key Research and Development Program of China (No. 2021YFE0200900)National Natural Science Foundation of China (Nos. 81922070, 81973286, 82003847, 81703604)+3 种基金Shanghai Science and Technology Innovation Action Plans (Nos. 20S21901500 and 20S21900900)supported by Shanghai Science and Technology Committee, Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (No. ZYYCXTD-D-202004)Shanghai Talent Development Fund (No. 2019093)Shanghai University of Traditional Chinese Medicine Postgraduate Innovation Training Special (No. Y2021034)。
文摘Human serum albumin(HSA) has emerged as a pivotal biomarker and prognostic indicator for various human diseases. Real-time sensing and visual tracking of HSA in plasma or other biological systems will immensely facilitate the basic researchers and clinicians to better understand HSA-associated biological processes. Herein, a novel near-infrared(NIR) fluorescent probe(7-HTCF) was rationally constructed for light-up sensing and in-situ imaging of HSA in real samples, based on the principle of twisted intramolecular charge transfer(TICT). Under physiological conditions, 7-HTCF could be efficiently trapped by HSA to form a stable complex via binding on a non-drug binding site, while the complex emitted strong fluoresce signals around 670 nm. Further investigations demonstrated that 7-HTCF displayed a great combination of excellent selectivity and good chemical stability, as well as rapid fluorescent response and ultra-high sensitivity for HSA detection. Particularly, the newly developed light-up probe has been successfully utilized for quantitative detection of HSA in diluted plasma samples, while its readouts are hardly affected by the addition of therapeutic agents and herbal medicines. 7-HTCF is also successfully used for in-situ imaging of the reabsorbed HSA in living renal cells, while this dye exhibits good cell permeability and high resolution for in-situ imaging in living cells. Collectively, a novel TICT-based near-infrared fluorescent probe was devised for highly selective and ultra-sensitive sensing of HSA in plasma samples or imaging HSA in living cells, which offered a practical tool for clinical tests and for exploring HSA-associated biological processes.
基金supports from the National Key Research and Development Program of China(No.2020YFE0202200)the National Natural Science Foundation of China(Nos.81903538,82322073,92253303)+1 种基金the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTD-D-202004)the Science and Technology Commission of Shanghai Municipality(Nos.22ZR1474200,24JS2830200).
文摘Artificial intelligence(AI)has emerged as a transformative technology in accelerating drug discovery and development within natural medicines research.Natural medicines,characterized by their complex chemical compositions and multifaceted pharmacological mechanisms,demonstrate widespread application in treating diverse diseases.However,research and development face significant challenges,including component complexity,extraction difficulties,and efficacy validation.AI technology,particularly through deep learning(DL)and machine learning(ML)approaches,enables efficient analysis of extensive datasets,facilitating drug screening,component analysis,and pharmacological mechanism elucidation.The implementation of AI technology demonstrates considerable potential in virtual screening,compound optimization,and synthetic pathway design,thereby enhancing natural medicines’bioavailability and safety profiles.Nevertheless,current applications encounter limitations regarding data quality,model interpretability,and ethical considerations.As AI technologies continue to evolve,natural medicines research and development will achieve greater efficiency and precision,advancing both personalized medicine and contemporary drug development approaches.
基金supported by the Science and Technology Innovation Program of Hunan Province(No.2022RC1168)National Natural Science Foundation of China(Nos.82322073,82173846,82304533)+12 种基金CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2023-I2M-3-009)Key project at central government level:The ability establishment of sustainable use for valuable Chinese medicine resources(No.2060302)China Postdoctoral Science Foundation(No.2021M702215)Oriental Scholars of Shanghai Universities(No.TP2022081)Jiangxi Province Thousand Talents Program(No.jxsq2023102168)Young Talent Lifting Project of China Association of Chinese Medicine(No.CACM-(2021-QNRC2-A08))Shanghai Rising-Star Program(No.22QA1409100)Shanghai Sailing Program(No.22YF1445000)2021 Shanghai Science and Technology Innovation Action Plan(No.21S11902800)Three-year Action Plan for Shanghai TCM Development and Inheritance Program(Nos.ZY(2021-2023)-0208,ZY(2021-2023)-0401)High level Key Discipline of National Administration of Traditional Chinese Medicine(No.71)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTD-D-202004)Innovation team of high-level local universities in Shanghai:Strategic Innovation Team of TCM Chemical Biology。
文摘Despite ongoing advancements in cancer treatment,the emergence of primary and acquired resistance poses a significant challenge for both traditional chemotherapy and immune checkpoint blockade therapies.The demand for targeted therapeutics for multidrug-resistant cancer is more important than ever.Peptides,as emerging alternatives to current anticancer drugs,offer exquisite versatility in facilitating the design of novel oncology drugs,with the core superiorities of good biocompatibility and a low tendency to induce drug resistance.This review comprehensively introduces the pharmacological mechanisms of peptide-based drugs and strategies for overcoming multidrug resistance(MDR)in cancers,including inducing cell membrane lysis,targeting organelles,activating anticancer immune responses,enhancing drug uptake,targeting ATP-binding cassette(ABC)transporters,and targeting B-cell lymphoma-2(BCL-2)family proteins.Additionally,the current clinical applications of representative peptides in combating MDR cancers and their potential directions for medicinal chemistry research have been thoroughly discussed.This review offers essential insights into the novel treatment approaches for MDR cancers and highlights the trends and perspectives in this field.
基金supported by the National Natural Science Foundation of China(82003451 and 82003455)Yunnan Fundamental Research Projects(202101AT070033)the Start-Up Fund for Introduction of High-level Talents to Dali University(YBS2021015).
文摘Hyperlipidemia is a risk factor for clinically significant thrombotic events in cardiovascular diseases.Platelet reactivity in hyperlipidemic conditions is enhanced when platelet scavenger receptor CD36 recognizes oxidized lipids in oxidized low-density lipoprotein(ox-LDL)particles,a process that induces atherothrombosis.Sulforaphane(SFN)is a dietary isothiocyanate enriched in cruciferous vegetables and exerts multiple biological activities.The current study sought to investigate the efficacy of SFN on platelet hyperreactivity under hyperlipidemic conditions in vitro and in vivo.Using a series of platelet functional assays in human platelets in vitro,we demonstrated that SFN attenuated ox-LDL-increased platelet aggregation and activation(surface CD62P expression).Mechanistically,studies using pharmacological inhibitors clarified that these inhibitory effects of SFN were mainly modulated by down-regulating CD36-mediated activation of Src kinases,leading to enhanced activation of cyclic adenosine monophosphate/protein kinase A(cAMP/PKA)signaling,and resultant inhibition of NADPH oxidase 2(NOX2)-dependent generation of reactive oxygen species(ROS).Moreover,12-week supplementation of SFN-enriched broccoli sprout extract(BSE,0.06%diet)in hyperlipidemic C57BL/6J mice also decreased platelet hyperreactivity.Studies using pharmacological inhibitors of CD36,protein kinase A(PKA)and NOX2 showed that the efficacy of BSE supplementation was mainly through modulating CD36-mediated the cAMP/PKA/NOX2 signaling.Thus,through modulating the cAMP/PKA/NOX2 pathway and attenuating CD36-mediated platelet hyperreactivity,SFN may play important protective roles in atherothrombosis under hyperlipidemic conditions.
基金the National Facility for Protein Science in Shanghai(NFPS),Shanghai Advanced Research Institute,Chinese Academy of Science,China for providing the Electron Microscopy System technical support and assistance in data collection and analysisfunded by“Shuguang Program”supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission(22SG41)the combination of the medical care and health project of the Shanghai University of Traditional Chinese Medicine(YYKC-2021-01-008).
文摘Immunotherapy of triple-negative breast cancer(TNBC)is significantly hindered by the immunosuppressive tumor microenvironment(TME).Notably,tumor-associated macrophages(TAMs),which constitute the predominant infiltrating immune cell type in TNBC,represent a critical target for“turning off”immunosuppressive TME.Despite numerous ongoing clinical trials,current strategies exhibit limited efficacy in overcoming immunosuppressive TME.Interestingly,regulation of son of sevenless 1(SOS1),which is overexpressed in TNBC patients,shows promising potential for TAM repolarization.Herein,we developed a biomimetic liposomal platform(CCM/Cil-lipo@TD),which integrates cilengitide(Cil)-functionalized breast cancer cell membranes(CCM)to co-deliver tetrandrine(TET)and low-dose docetaxel(DTX)for TNBC therapy.This system synergistically enhanced immunotherapy by coupling SOS1 blockade-driven TAM repolarization with immune cell death(ICD)-mediated dendritic cell(DC)maturation,thereby reshaping the highly immunosuppressive TME in TNBC.Critically,the low-density Cil-anchored,CCM-fused liposomes overcome the penetration limitations inherent to conventional CCM-based delivery systems,achieving deep intratumoral accumulation of therapeutic payloads.Mechanistically,the CCM/Cil-lipo@TD ensured that TET-mediated SOS1 inhibition in tumor cells efficiently polarized TAM2(protumor)toward TAM1(antitumor).Furthermore,SOS1 blockade synergized with low-dose DTX-induced ICD to remodel TME,as evidenced by sustained cytotoxic T-cell infiltration and suppression of regulatory T cells.The CCM/Cil-lipo@TD exerted superior tumor inhibition(82.9%)in 4T1 orthotopic models and effectively inhibited postoperative local recurrence and distant metastasis.Taken together,the Cil-engineered,cellmembrane-anchoring CCM/Cil-lipo@TD provides a promising approach for TNBC immunotherapy.
基金financially supported by the National Natural Science Foundation of China(Nos.82104281,81922070,81973286,81801818 and 82273897)Shanghai Municipal Health Commission’s TCM research project(No.2022CX005)+1 种基金Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTD-D-202004)Three-year Action Plan for Shanghai TCM Development and Inheritance Program[No.ZY(2021–2023)-0401]。
文摘Human Notum(hNotum)inhibitors could be used for treating Wnt signalling-associated diseases including colorectal cancer.Herein,two series of chalcone derivatives were designed and synthesized aiming to find selective and potent hNotum inhibitors.Structure–activity relationship(SAR)studies showed that 2-methoxyl and 5-bromine substitutions on A-ring significantly enhanced anti-hNotum effect,while 4’-ethoxyl and 3’-alkyl substitutions on B-ring were beneficial for hNotum inhibition.Among all tested chalcones,B11 displayed the most potent anti-Notum effect(IC_(50)=3.6 nmol/L),good selectivity,excellent chemical stability and suitable metabolic stability.Further investigations showed that B11 acted as a competitive inhibitor of hNotum,while this agent(5μmol/L)significantly weaken the migration abilities of colorectal cancer cells.Collectively,this study deciphers the SARs of chalcones as hNotum inhibitors and reports a novel and potent hNotum inhibitor with the anti-migration effect on colorectal cancer cells,which offers a promising lead compound to develop novel anti-cancer agents.
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 National Natural Science Foundation of China(Nos.U23A20516,81922070,82273897 and 52303191)National Key Research and Development Program of China(No.2022YFC3502000)+5 种基金Shanghai Science and Technology Innovation Action Plans(21S21900600,China)the Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine(No.2023YZZ02,China)Shanghai Municipal Health Commission’s TCM research project(No.2022CX005,China)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTDD-202004,China)the State Key Laboratory of Fine Chemicals,Dalian University of Technology(No.KF 2202,China)Shanghai University of Traditional Chinese Medicine(No.2021LK023,China).
文摘The aryl hydrocarbon receptor(AhR)plays a crucial role in regulating many physiological processes.Activating the AhReCYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases.Here,a practical in situ cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators,via functional sensing of CYP1A1 activities in live cells.Firstly,a cell-permeable,isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for in-situ visualizing the dynamic changes of CYP1A1 function in living systems,which was subsequently used for discovering the efficacious modulators of the AhReCYP1A1 axis.Following screening of a compound library,LAC-7 was identified as an efficacious activator of the AhReCYP1A1 axis,which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines.LAC-7 also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages.Animal tests showed that LAC-7 could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice,and markedly reduced the levels of multiple inflammatory factors.Collectively,an optimized fluorometric cell-based assay was devised for in situ functional imaging of CYP1A1 activities in living systems,which strongly facilitated the discovery of efficacious modulators of the AhReCYP1A1 axis as novel antiinflammatory agents.
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funded by the National Natural Science Foundation of China(No.82374086,82141203,82104459,82430116)National Key Research and Development Program of China(2022YFC3502000)+5 种基金hanghai Municipal Science and Technology Major Project(ZD2021CY001)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTDD-202004)Science and Technology Commission of Shanghai Municipality(20YF1458700)Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine(2023YZZ02)CAMS Innovation Fund for Medical Sciences(CIFMS)(2023-I2M-3-009)Key Project at Central Government Level:The Ability Establishment of Sustainable Use for Valuable Chinese Medicine Resources(2060302-2305-02)。
文摘Ferroptosis induced by ferrous ions(Fe^(2+))and lipid peroxidation accumulation is a novel form of regulated cell death that has become a hot topic in tumor therapy research.Identifying small-molecule drugs that can induce ferroptosis in tumor cells is a very attractive therapeutic strategy.Here,we screened a natural product,acevaltrate(ACE),which rapidly and strongly induces ferroptosis in colorectal cancer cells.ACE not only increases Fe^(2+)levels in colorectal cancer cells by targeting iron chaperones PCBP1/2 and reducing their expression but also disrupts the antioxidant system of colorectal cancer cells by targeting GPX4 and inhibiting its enzymatic activity,leading to its ubiquitin-mediated degradation.
基金supported by National Key Research and Development Program of China(No.2022YFC3502000)National Natural Science Foundation of China(No.U23A20516,82273897,82304616)+6 种基金Shanghai Science and Technology Innovation Action Plans(No.21S21900600)supported by Shanghai Science and Technology Committee,Shanghai Municipal Health Commission’s Traditional Chinese Medicine Research Project(No.2022CX005)Yangfan Program of Science and Technology Commission of Shanghai Municipality(No.23YF1447400)the Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine(No.2023YZZ02)Department of Science&Technology of Liaoning Province(No.2022JH2/20200056)New Quality Clinical Specialty Program of High-end Medical Disciplinary Construction in Shanghai Pudong New Area(No.2025-PWXZ-15)the Project for Inheritance,Innovation and Development of Traditional Chinese Medicine in Pudong New Area(No.YC-2023-0602)。
文摘Objective:To characterize the oxidative metabolic pathway(s)of pectolinarigenin(PEC)and reveal the effect of PEC oxidative metabolism on its biological activities including peroxisome proliferatoractivated receptors(PPAR)and nuclear factor erythroid 2-related factor 2(Nrf2)agonist effects,as well as the anti-oxidative and hepatoprotective activities.Methods:The oxidative metabolites of PEC were identified by liquid chromatography-time of flight-mass spectrometry(LC-TOF-MS/MS).The key enzymes involved in oxidative metabolism of PEC were assigned by P450 reaction phenotyping assays and enzymatic kinetics assays.Luciferase reporter assays and western blotting analysis were used to evaluate the Nrf2 and PPAR agonist effects of PEC and its oxidative metabolites.The intracellular levels of total reactive oxygen species(ROS),mitochondrial membrane potential(MMP),lactate dehydrogenase(LDH)and glutathione(GSH)in acetaminophen(APAP)-challenged hepatocytes were also tested.Results:PEC could be readily metabolized to form two O-demethylated metabolites including hispidulin(HIS,4′-O-demethylated PEC)and 6-O-demethylated PEC in human liver microsomes(HLM)in the presence of nicotinamide adenine dinucleotide phosphate(NADPH),while HIS was identified as the major oxidative metabolite of PEC.At least nine human cytochrome P450 enzymes(CYP)enzymes could catalyze PEC-4′-O-demethylation,while CYP1A2 and CYP2D6 showed the highest binding affinities and rapid metabolic clearance rates in the oxidative metabolism of PEC.Biological assays showed that PEC4′-O-demethylation slightly decreased the PPAR agonist effects of PEC,while HIS showed more potent Nrf2 agonist effect.Compared with PEC,HIS showed more efficacious hepatoprotective effect against APAP-induced hepatocyte injury,evidenced by more potent ability to reduce intracellular ROS and LDH levels,as well as more effective ability to elevate the intracellular levels of both MPP and GSH in APAP-challenged hepatocytes.Conclusion:CYPs catalyze PEC-4′-O-demethylation to generate a more active Nrf2 agonist(HIS),which shows more efficacious hepatoprotective effects against APAP-induced hepatocyte injury.
