a novel and promising antitumor target,AXL plays an important role in tumor growth,metastasis,immunosuppression and drug resistance of various malignancies,which has attracted extensive research interest in recent yea...a novel and promising antitumor target,AXL plays an important role in tumor growth,metastasis,immunosuppression and drug resistance of various malignancies,which has attracted extensive research interest in recent years.In this study,by employing the structure-based drug design and bioisosterism strategies,we designed and synthesized in total 54 novel AXL inhibitors featuring a fusedpyrazolone carboxamide scaffold,of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions.Notably,compound 59 showed a desirable AXL kinase inhibitory activity(IC_(50):3.5 nmol/L)as well as good kinase selectivity,and it effectively blocked the cellular AXL signaling.In turn,compound 59 could potently inhibit BaF3/TEL-AXL cell viability(IC_(50):1.5 nmol/L)and significantly suppress GAS6/AXL-mediated cancer cell invasion,migration and wound healing at the nanomolar level.More importantly,compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency,in which we observed significant AXL phosphorylation suppression,and its antitumor efficacy at 20 mg/kg(qd)was comparable to that of BGB324 at 50 mg/kg(bid),the most advanced AXL inhibitor.Taken together,this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.展开更多
Oncogenes are critical factors in tumorigenesis of diverse cancer types and play essential roles in tumor immune escape.Mutations in Kirsten rat sarcoma viral oncogene homolog(KRAS)and epidermal growth factor receptor...Oncogenes are critical factors in tumorigenesis of diverse cancer types and play essential roles in tumor immune escape.Mutations in Kirsten rat sarcoma viral oncogene homolog(KRAS)and epidermal growth factor receptor(EGFR)are among the most frequent gain-of-function alterations[1].After many years of in-depth research,inhibitors targeting EGFR or KRAS mutations have been successfully developed,however,their clinical benefit is relatively limited,and they will inevitably encounter the challenge of drug resistance.The emergence of resistance is attributed to secondary mutations in driver genes and other complicated factors.展开更多
Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia,which results in atherosclerosis and cardiovascular disease(CVD).ATP-citrate lyase(ACLY)is a key lipogenic enzyme that converts cyto...Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia,which results in atherosclerosis and cardiovascular disease(CVD).ATP-citrate lyase(ACLY)is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle(TCA cycle)to acetyl-CoA in the cytoplasm.Therefore,ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis.In this study,we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor,and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC_(50)=5.31±1.2μmol/L in vitro.326E treatment reduced de novo lipogenesis,and increased cholesterol efflux in vitro and in vivo.326E was rapidly absorbed after oral administration,exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid(BA)used for hypercholesterolemia.Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia.Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE^(-/-)mice to a greater extent than that of BA treatment.Taken together,our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.展开更多
Eight polycyclic furanobutenolide-containing norcembrane diterpenoids featuring C19 frameworks(1–8)were rapidly recognized and isolated from the Hainan soft coral Sinularia sp. by the HSQC-based small molecule accura...Eight polycyclic furanobutenolide-containing norcembrane diterpenoids featuring C19 frameworks(1–8)were rapidly recognized and isolated from the Hainan soft coral Sinularia sp. by the HSQC-based small molecule accurate recognition technology. Yonarolide A(1a), featuring an unprecedented 5/6/4/4/7 pentacyclic ring skeleton, was surprisingly obtained as a transformed product by leaving compound 1 under indoor natural light, and was further proved to be a [2 + 2] cycloaddition product of 1 by photochemical reaction. The absolute stereochemistry of 1a and the three known norcembrane diterpenoids 1, 4, and7 were determined by using X-ray diffraction(XRD) analyses. Further, with the aid of XRD analysis, the structure of scabrolide B(2), which was previously reported of possessing 5/6/7 tricyclic skeleton, was firmly revised as 2a with the rare inelegane skeleton featured by the highly oxygenated 5/7/6 tricyclic carbocycle.展开更多
Biliary atresia is a rare infant disease that predisposes patients to liver transplantation and death if not treated in time.However,early diagnosis is challenging because the clinical manifestations and laboratory te...Biliary atresia is a rare infant disease that predisposes patients to liver transplantation and death if not treated in time.However,early diagnosis is challenging because the clinical manifestations and laboratory tests of biliary atresia overlap with other cholestatic diseases.Therefore,it is very important to develop a simple,safe and reliable method for the early diagnosis of biliary atresia.Herein,a novel NIR-Ⅱfluorescence probe,HZL2,with high quantum yield,excellent biocompatibility,low cytotoxicity and rapid excretion through the liver and gallbladder was developed based on the oil/water partition coefficient and permeability.A simple fecal sample after injection of HZL2 can be used to efficiently identify the success of the mouse model of biliary atresia for the first time,allowing for an early diagnosis of the disease.This study not only developed a simple and safe method for the early diagnosis of biliary atresia with great potential in clinical translation but also provides a research tool for the development of pathogenesis and therapeutic medicines for biliary atresia.展开更多
Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety,low cost,and outstanding hypoglycemic effect clinically.The mechanisms underlying these benefits are complex and sti...Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety,low cost,and outstanding hypoglycemic effect clinically.The mechanisms underlying these benefits are complex and still not fully understood.Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin,leading to reduced ATP production and activation of AMP-activated protein kinase(AMPK).Meanwhile,many novel targets of metformin have been gradually discovered.In recent years,multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes.Herein,we summarized the benefits of metformin in four types of diseases,including metabolic associated diseases,cancer,aging and age-related diseases,neurological disorders.We comprehensively discussed the pharmacokinetic properties and the mechanisms of action,treatment strategies,the clinical application,the potential risk of metformin in various diseases.This review provides a brief summary of the benefits and concerns of metformin,aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research.Although there have been countless studies of metformin,longitudinal research in each field is still much warranted.展开更多
Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal physiological processes.Through metabolic engineering,bioorthogonal groups can be tagged onto cell membranes,which se...Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal physiological processes.Through metabolic engineering,bioorthogonal groups can be tagged onto cell membranes,which selectively attach to cargos with paired groups via bioorthogonal reactions.Due to its simplicity,high efficiency,and specificity,bioorthogonal chemistry has demonstrated great application potential in drug delivery.On the one hand,bioorthogonal reactions improve therapeutic agent delivery to target sites,overcoming off-target distribution.On the other hand,nanoparticles and biomolecules can be linked to cell membranes by bioorthogonal reactions,providing approaches to developing multi-functional drug delivery systems(DDSs).In this review,we first describe the principle of labeling cells or pathogenic microorganisms with bioorthogonal groups.We then highlight recent breakthroughs in developing active targeting DDSs to tumors,immune systems,or bacteria by bioorthogonal chemistry,as well as applications of bioorthogonal chemistry in developing functional bio-inspired DDSs(biomimetic DDSs,cell-based DDSs,bacteria-based and phage-based DDSs)and hydrogels.Finally,we discuss the difficulties and prospective direction of bioorthogonal chemistry in drug delivery.We expect this review will help us understand the latest advances in the development of active targeting and multi-functional DDSs using bioorthogonal chemistry and inspire innovative applications of bioorthogonal chemistry in developing smart DDSs for disease treatment.展开更多
Nanosized drug delivery systems(NDDSs)have emerged as a powerful tool to optimize drug delivery in complex diseases,including cancer and inflammation.However,the therapeutic effect of NDDSs is still far from satisfact...Nanosized drug delivery systems(NDDSs)have emerged as a powerful tool to optimize drug delivery in complex diseases,including cancer and inflammation.However,the therapeutic effect of NDDSs is still far from satisfactory due to their poor circulation time,low delivery efficiency,and innate toxicity.Fortunately,biomimetic approaches offer new opportunities to develop nanomedicine,which is derived from a variety of native biomolecules including cells,exosomes,bacteria,and so on.Since inheriting the superior biocompatibility and versatile functions of natural materials,biomimetic nanomedicine can mimic biological processes,prolong blood circulation,and lower immunogenicity,serving as a desired platform for precise drug delivery for treating cancer and inflammatory disease.In this review,we outline recent advances in biomimetic NDDSs,which consist of two concepts:biomimetic exterior camouflage and bioidentical molecule construction.We summarize engineering strategies that further functionalized current biomimetic NDDSs.A series of functional biomimetic NDDSs created by our group are introduced.We conclude with an outlook on remaining challenges and possible directions for biomimetic NDDSs.We hope that better technologies can be inspired and invented to advance drug delivery systems for cancer and inflammation therapy.展开更多
Metastatic triple-negative breast cancer(TNBC)is the most aggressive type of breast cancer.Combination of systemic chemotherapy and immune checkpoint blockade is effective but of limited benefit due to insufficient in...Metastatic triple-negative breast cancer(TNBC)is the most aggressive type of breast cancer.Combination of systemic chemotherapy and immune checkpoint blockade is effective but of limited benefit due to insufficient intratumoral infiltration of cytotoxic T lymphocytes(CTLs)and the accumulation of immunosuppressive cells.Herein,we designed a lenvatinib-and vadimezan-loaded synthetic high-density lipoprotein(LV-sHDL)for combinational immunochemotherapy of metastatic TNBC.The LV-sHDL targeted scavenger receptor class B type 1-overexpressing 4T1 cells in the tumor after intravenous injection.The multitargeted tyrosine kinase inhibitor(TKI)lenvatinib induced immunogenic cell death of the cancer cells,and the stimulator of interferon genes(STING)agonist vadimezan triggered local inflammation to facilitate dendritic cell maturation and antitumor macrophage differentiation,which synergistically improved the intratumoral infiltration of total and active CTLs by 33-and 13-fold,respectively.LV-sHDL inhibited the growth of orthotopic 4T1 tumors,reduced pulmonary metastasis,and prolonged the survival of animals.The efficacy could be further improved when LV-sHDL was used in combination with antibody against programmed cell death ligand 1.This study highlights the combination use of multitargeted TKI and STING agonist a promising treatment for metastatic TNBC.展开更多
The occurrence of obesity has increased across the whole world. Many epidemiological studies have indicated that obesity strongly contributes to the development of cancer, cardiovascular diseases, type 2 diabetes, liv...The occurrence of obesity has increased across the whole world. Many epidemiological studies have indicated that obesity strongly contributes to the development of cancer, cardiovascular diseases, type 2 diabetes, liver diseases and other disorders, accounting for a heavy burden on the public and on health-care systems every year. Excess energy uptake induces adipocyte hypertrophy, hyperplasia and formation of visceral fat in other non-adipose tissues to evoke cardiovascular disease, liver diseases. Adipose tissue can also secrete adipokines and inflammatory cytokines to affect the local microenvironment,induce insulin resistance, hyperglycemia, and activate associated inflammatory signaling pathways. This further exacerbates the development and progression of obesity-associated diseases. Although some progress in the treatment of obesity has been achieved in preclinical and clinical studies, the progression and pathogenesis of obesity-induced diseases are complex and unclear. We still need to understand their links to better guide the treatment of obesity and associated diseases. In this review, we review the links between obesity and other diseases, with a view to improve the future management and treatment of obesity and its co-morbidities.展开更多
Epithelial to mesenchymal transition (EMT) plays a crucial role in cancer metastasis, accompanied with vast epigenetic changes.AMP-activated protein kinase (AMPK), a cellular energy sensor, plays regulatory roles in m...Epithelial to mesenchymal transition (EMT) plays a crucial role in cancer metastasis, accompanied with vast epigenetic changes.AMP-activated protein kinase (AMPK), a cellular energy sensor, plays regulatory roles in multiple biological processes. Although afew studies have shed light on AMPK regulating cancer metastasis, the inside epigenetic mechanisms remain unknown. Herein weshow that AMPK activation by metformin relieves the repressive H3K9me2-mediated silencing of epithelial genes (e.g., CDH1)during EMT processes and inhibits lung cancer metastasis. PHF2, a H3K9me2 demethylase, was identified to interact with AMPKα2.Genetic deletion of PHF2 aggravates lung cancer metastasis and abolishes the H3K9me2 downregulation and anti-metastasis effectof metformin. Mechanistically, AMPK phosphorylates PHF2 at S655 site, enhancing PHF2 demethylation activity and triggering thetranscription of CDH1. Furthermore, the PHF2-S655E mutant that mimics AMPK-mediated phosphorylation status further reducesH3K9me2 and suppresses lung cancer metastasis, while PHF2-S655A mutant presents opposite phenotype and reverses the antimetastasiseffect of metformin. PHF2-S655 phosphorylation strikingly reduces in lung cancer patients and the higherphosphorylation level predicts better survival. Altogether, we reveal the mechanism of AMPK inhibiting lung cancer metastasis viaPHF2 mediated H3K9me2 demethylation, thereby promoting the clinical application of metformin and highlighting PHF2 as thepotential epigenetic target in cancer metastasis.展开更多
Comprehensive Summary,Compounds 1—12,including seven complex monoterpenoid indole-quinoline and bisindole alkaloids,suadimins D—J(1—7)with previously unreported carbon-carbon linkages,were isolated and identified f...Comprehensive Summary,Compounds 1—12,including seven complex monoterpenoid indole-quinoline and bisindole alkaloids,suadimins D—J(1—7)with previously unreported carbon-carbon linkages,were isolated and identified from the twigs and leaves of Melodinus suaveolens.Their structures were elucidated by a combination of diverse methods,especially the extensive spectroscopic data analysis and electric circular dichroism(ECD)calculations.The cytotoxicity of these compounds against three cancer cell lines was evaluated,some of which showed moderate activities with IC50 values ranging from 2.4 to 8.0μM.展开更多
Five new terpenoids,including two vibsane-type diterpenoids(1,2)and three iridoid allosides(3-5),together with eight known ones,were isolated from the leaves and twigs of Viburnum odoratissimum var.sessiliflorum.Their...Five new terpenoids,including two vibsane-type diterpenoids(1,2)and three iridoid allosides(3-5),together with eight known ones,were isolated from the leaves and twigs of Viburnum odoratissimum var.sessiliflorum.Their planar structures and relative configurations were determined by spectroscopic methods,especially 2D NMR techniques.The sugar moieties of the iridoids were confirmed asβ-D-allose by GC analysis after acid hydrolysis and acetylation.The absolute configurations of neovibsanin Q(1)and dehydrovibsanol B(2)were determined by quantum chemical calculation of their theoretical electronic circular dichroism(ECD)spectra and Rh2(OCOCF_(3))_(4)-induced ECD analysis.The anti-inflammatory activities of compounds 1,3,4,and 5 were evaluated using an LPS-induced RA W264.7 cell model.Compounds 3 suppressed the release of NO in a dose-dependent manner,with an IC_(50) value of 55.64μmol·L^(-1).The cytotoxicities of compounds 1-5 on HCT-116 cells were assessed and the results showed that compounds 2 and 3 exhibited moderate inhibitory activities with IC_(50) values of 13.8 and 12.3μmol·L^(-1),respectively.展开更多
Chemical investigation of Hedyosmum orientale led to the identification of two terpenoid derivatives,dyosmunoids A and B(1 and 2)featuring two different 3/5/6/6/5-fused pentacyclic ring systems,respectively.Compound 1...Chemical investigation of Hedyosmum orientale led to the identification of two terpenoid derivatives,dyosmunoids A and B(1 and 2)featuring two different 3/5/6/6/5-fused pentacyclic ring systems,respectively.Compound 1 is the second natural product of this C_(25) terpenoid compound class,and compound 2 is a rare dinor-C25 terpenoid with a peroxide bridge.Their structural elucidation was achieved by the comprehensive analysis of spectroscopic data,single-crystal X-ray diffraction,and ECD calculation.Putative biosynthetic pathways for compounds 1 and 2 are proposed.Compound 2 exhibited strong antimalarial activity with an IC_(50) value of 0.42μmol·L^(-1).展开更多
1 Introduction Natural products(NPs)historically serve as a valuable and productive source of bioactive compounds for drug development.The discovery of a range of alkaloids in the early1800s,including strychnine,morph...1 Introduction Natural products(NPs)historically serve as a valuable and productive source of bioactive compounds for drug development.The discovery of a range of alkaloids in the early1800s,including strychnine,morphine,etc.,heralded a new era of isolating plant-derived bioactive compounds in the field of NPs[1].展开更多
A detailed chemical investigation of the South China Sea nudibranch Hexabranchus sanguineus,as well as its possible sponge-prey Acanthella cavernosa,led to the isolation of fifteen new nitrogenous sesquiterpenoids,nam...A detailed chemical investigation of the South China Sea nudibranch Hexabranchus sanguineus,as well as its possible sponge-prey Acanthella cavernosa,led to the isolation of fifteen new nitrogenous sesquiterpenoids,namely ximaocavernosins A-0,including seven cadinanes(1-7),seven spiroaxanes(12-18)and one aromadendrane(19),together with thirteen known related compounds(8-11 and 20-28).展开更多
Dichagelinoids A—C(1—3),three unusual dichapetalin-type triterpenoids,together with two biogenetically related derivatives dichagelinoids D and E(4 and 5)were isolated and characterized by solid data from Dichapetal...Dichagelinoids A—C(1—3),three unusual dichapetalin-type triterpenoids,together with two biogenetically related derivatives dichagelinoids D and E(4 and 5)were isolated and characterized by solid data from Dichapetalum gelonioides.Compounds 1—3 possess a common rearranged C ring and different C6—C2 modified motifs at the A rings.Biological evaluation revealed that compounds 1—3 showed distinct cytotoxic activity against the tested human cancer cell lines.展开更多
Multiple myeloma(MM) is still an incurable hematologic malignancy, which is eagerly to the discovery of novel therapeutic targets and methods. N-acetyltransferase 10(NAT10) is the first reported regulator of mRNA acet...Multiple myeloma(MM) is still an incurable hematologic malignancy, which is eagerly to the discovery of novel therapeutic targets and methods. N-acetyltransferase 10(NAT10) is the first reported regulator of mRNA acetylation that is activated in many cancers. However, the function of NAT10 in MM remains unclear. We found significant upregulation of NAT10 in MM patients compared to normal plasma cells, which was also highly correlated with MM poor outcome. Further enforced NAT10 expression promoted MM growth in vitro and in vivo, while knockdown of NAT10 reversed those effects. The correlation analysis of acetylated RNA immunoprecipitation sequencing(ac RIP-seq) and ribosome profiling sequencing(Ribo-seq) combined with RIP-PCR tests identified centrosomal protein 170(CEP170) as an important downstream target of NAT10. Interfering CEP170 expression in NAT10-OE cells attenuated the acceleration of cellular growth caused by elevated NAT10. Moreover,CEP170 overexpression promoted cellular proliferation and chromosomal instability(CIN) in MM.Intriguingly, remodelin, a selective NAT10 inhibitor, suppressed MM cellular growth, induced cellular apoptosis in vitro and prolonged the survival of 5TMM3VT mice in vivo. Collectively, our data indicate that NAT10 acetylates CEP170 mRNA to enhance CEP170 translation efficiency, which suggests that NAT10 may serve as a promising therapeutic target in MM.展开更多
Ten new cembrane-type diterpenoids,namely xishaglaucumins A—J(1—10),along with ten known related ones(11—20),have been isolated from the soft coral Sarcophyton glaucum collected off the Xisha Island in the South Ch...Ten new cembrane-type diterpenoids,namely xishaglaucumins A—J(1—10),along with ten known related ones(11—20),have been isolated from the soft coral Sarcophyton glaucum collected off the Xisha Island in the South China Sea.Their structures were elucidated by extensive spectroscopic analysis,quantum mechanical nuclear magnetic resonance(QM-NMR)methods,X-ray diffraction analysis,chemical methods and comparison with the reported data in the literature.The absolute configuration of new compounds 1,5 and known compounds 11,12,16 and 20 were determined either by chemical methods or by X-ray diffraction analysis using Cu Kα(λ=1.5417A).In in vitro bioassay,compound 4 exhibited inhibitory effects on lipopolysaccharide(LPS)-induced inflammatory responses in BV-2 microglial cells.展开更多
The natural products of dispirocochlearoids are complex Ganoderma meroterpenoids featuring a 6/6/5/6/6/6 ring system and are selective cox-2 inhibitors.Herein,we describe our progress regarding the total synthesis of ...The natural products of dispirocochlearoids are complex Ganoderma meroterpenoids featuring a 6/6/5/6/6/6 ring system and are selective cox-2 inhibitors.Herein,we describe our progress regarding the total synthesis of dispirocochlearoids A-C,in which a hexacyclic skeleton was constructed firstly.The key steps of this work involve an intermolecular[4+2]cycloaddition reaction,a ring cleavage approach via Ticla,and the installation of a profoundly sterically hindering lactone.展开更多
基金supported by the Natural Science Foundation of China for Innovation Research Group(81821005)the National Natural Science Foundation of China(21977106 and 82173834)+4 种基金the Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning(2020CXJQ02)the Shanghai Post-doctoral Excellence Program(2022231,China)the Shanghai Sail Program(22YF1460700,China)Lingang Laboratory(LG202103-02-07,China)Lingang Laboratory(LGGG-202204-02,China).
文摘a novel and promising antitumor target,AXL plays an important role in tumor growth,metastasis,immunosuppression and drug resistance of various malignancies,which has attracted extensive research interest in recent years.In this study,by employing the structure-based drug design and bioisosterism strategies,we designed and synthesized in total 54 novel AXL inhibitors featuring a fusedpyrazolone carboxamide scaffold,of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions.Notably,compound 59 showed a desirable AXL kinase inhibitory activity(IC_(50):3.5 nmol/L)as well as good kinase selectivity,and it effectively blocked the cellular AXL signaling.In turn,compound 59 could potently inhibit BaF3/TEL-AXL cell viability(IC_(50):1.5 nmol/L)and significantly suppress GAS6/AXL-mediated cancer cell invasion,migration and wound healing at the nanomolar level.More importantly,compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency,in which we observed significant AXL phosphorylation suppression,and its antitumor efficacy at 20 mg/kg(qd)was comparable to that of BGB324 at 50 mg/kg(bid),the most advanced AXL inhibitor.Taken together,this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.
基金This research was supported by grants from the Natu-ral Science Foundation of China for Innovation Research Group(81821005)the National Natural Science Founda-tionofChina(82273948,81573271and81903638)+3 种基金High-level Innovative Research Institute(2021B0909050003)State Key Laboratory of Drug Research(SKLDR-2023-TT-01 and SIMM2205KF-09)Lingang Laboratory(LG202103-02-02)Institutes for Drug Discovery and Development,Chinese Academy of Sciences(CASIMM0120225003-1 and-2).
文摘Oncogenes are critical factors in tumorigenesis of diverse cancer types and play essential roles in tumor immune escape.Mutations in Kirsten rat sarcoma viral oncogene homolog(KRAS)and epidermal growth factor receptor(EGFR)are among the most frequent gain-of-function alterations[1].After many years of in-depth research,inhibitors targeting EGFR or KRAS mutations have been successfully developed,however,their clinical benefit is relatively limited,and they will inevitably encounter the challenge of drug resistance.The emergence of resistance is attributed to secondary mutations in driver genes and other complicated factors.
基金supported by grants from the National Natural Science Foundation of China(92057116 and 82170872)the Medical Guidance Project of Shanghai Science and Technology Commission(20S11903400,China)+3 种基金the“Personalized Medicines-Molecular Signature-based Drug Discovery and Development”Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12040328,China)the“State Key Laboratory of Drug Research”Shanghai Institute of Materia Medica,Chinese Academy of Sciences(SIMM2105KF-02,China)Natural Science Foundation of Shanghai’s 2021“Science and Technology Innovation Action Plan”(21ZR1475300,China)the Lingang Laboratory(LG-QS-202205-01,China)。
文摘Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia,which results in atherosclerosis and cardiovascular disease(CVD).ATP-citrate lyase(ACLY)is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle(TCA cycle)to acetyl-CoA in the cytoplasm.Therefore,ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis.In this study,we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor,and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC_(50)=5.31±1.2μmol/L in vitro.326E treatment reduced de novo lipogenesis,and increased cholesterol efflux in vitro and in vivo.326E was rapidly absorbed after oral administration,exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid(BA)used for hypercholesterolemia.Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia.Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE^(-/-)mice to a greater extent than that of BA treatment.Taken together,our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.
基金financially supported by the National Key Research and Development Program of China (No. 2021YFF0502400)the National Natural Science Foundation of China (Nos. 81991521, 82022069 and 42076099)+2 种基金the Shanghai Rising-Star Program (No. 20QA1411100)“Youth Innovation Promotion Association” of Chinese Academy of Sciences (No. Y202065)the SKLDR/SIMM Project (No. SIMM2103 ZZ-06)。
文摘Eight polycyclic furanobutenolide-containing norcembrane diterpenoids featuring C19 frameworks(1–8)were rapidly recognized and isolated from the Hainan soft coral Sinularia sp. by the HSQC-based small molecule accurate recognition technology. Yonarolide A(1a), featuring an unprecedented 5/6/4/4/7 pentacyclic ring skeleton, was surprisingly obtained as a transformed product by leaving compound 1 under indoor natural light, and was further proved to be a [2 + 2] cycloaddition product of 1 by photochemical reaction. The absolute stereochemistry of 1a and the three known norcembrane diterpenoids 1, 4, and7 were determined by using X-ray diffraction(XRD) analyses. Further, with the aid of XRD analysis, the structure of scabrolide B(2), which was previously reported of possessing 5/6/7 tricyclic skeleton, was firmly revised as 2a with the rare inelegane skeleton featured by the highly oxygenated 5/7/6 tricyclic carbocycle.
基金partially supported by grants from the National Key R&D Program of China(2020YFA0908800)NSFC(82273796)+6 种基金Special Funds for Guiding Local Science and Technology Development of Central Government(XZ202202YD0021C,China)Tibet Autonomous Region COVID-19 Prevention and Control Programs for Science and Technology Development(XZ202201ZY0046G,China)Guangdong Basic and Applied Basic Research Foundation(2023A1515012649,China)Shenzhen Science and Technology Research Grant(JCYJ20220530140605012,China)Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University(ZNJC202209,China)Project Funded by China Postdoctoral Science Foundation(2022M712091,China)the Fundamental Research Funds for the Central Universities。
文摘Biliary atresia is a rare infant disease that predisposes patients to liver transplantation and death if not treated in time.However,early diagnosis is challenging because the clinical manifestations and laboratory tests of biliary atresia overlap with other cholestatic diseases.Therefore,it is very important to develop a simple,safe and reliable method for the early diagnosis of biliary atresia.Herein,a novel NIR-Ⅱfluorescence probe,HZL2,with high quantum yield,excellent biocompatibility,low cytotoxicity and rapid excretion through the liver and gallbladder was developed based on the oil/water partition coefficient and permeability.A simple fecal sample after injection of HZL2 can be used to efficiently identify the success of the mouse model of biliary atresia for the first time,allowing for an early diagnosis of the disease.This study not only developed a simple and safe method for the early diagnosis of biliary atresia with great potential in clinical translation but also provides a research tool for the development of pathogenesis and therapeutic medicines for biliary atresia.
基金founded by China Postdoctoral Science Foundation(No.2021M703345)the National Natural Science Foundation of China(Nos.82130099,81971265,and 81821005)+3 种基金Shanghai Science and Technology Development Funds(Nos.22YF1457100 and 22ZR1415200)National Key R&D Program of China(No.2022YFA1303802)the National Natural Science Foundation of China for Innovation Research Group(No.81821005)the Lingang Laboratory(Nos.LG202103-03-04,LG202103-03-01,and LG202103-03-05).
文摘Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety,low cost,and outstanding hypoglycemic effect clinically.The mechanisms underlying these benefits are complex and still not fully understood.Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin,leading to reduced ATP production and activation of AMP-activated protein kinase(AMPK).Meanwhile,many novel targets of metformin have been gradually discovered.In recent years,multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes.Herein,we summarized the benefits of metformin in four types of diseases,including metabolic associated diseases,cancer,aging and age-related diseases,neurological disorders.We comprehensively discussed the pharmacokinetic properties and the mechanisms of action,treatment strategies,the clinical application,the potential risk of metformin in various diseases.This review provides a brief summary of the benefits and concerns of metformin,aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research.Although there have been countless studies of metformin,longitudinal research in each field is still much warranted.
基金Financial supports from the National Natural Science Foundation of China(81903548,32170935,32070927 and 81690265)the Strategic Priority Research Program of CAS(XDA12050307)the Youth Innovation Promotion Association of CAS(2019283)are gratefully acknowledged.
文摘Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal physiological processes.Through metabolic engineering,bioorthogonal groups can be tagged onto cell membranes,which selectively attach to cargos with paired groups via bioorthogonal reactions.Due to its simplicity,high efficiency,and specificity,bioorthogonal chemistry has demonstrated great application potential in drug delivery.On the one hand,bioorthogonal reactions improve therapeutic agent delivery to target sites,overcoming off-target distribution.On the other hand,nanoparticles and biomolecules can be linked to cell membranes by bioorthogonal reactions,providing approaches to developing multi-functional drug delivery systems(DDSs).In this review,we first describe the principle of labeling cells or pathogenic microorganisms with bioorthogonal groups.We then highlight recent breakthroughs in developing active targeting DDSs to tumors,immune systems,or bacteria by bioorthogonal chemistry,as well as applications of bioorthogonal chemistry in developing functional bio-inspired DDSs(biomimetic DDSs,cell-based DDSs,bacteria-based and phage-based DDSs)and hydrogels.Finally,we discuss the difficulties and prospective direction of bioorthogonal chemistry in drug delivery.We expect this review will help us understand the latest advances in the development of active targeting and multi-functional DDSs using bioorthogonal chemistry and inspire innovative applications of bioorthogonal chemistry in developing smart DDSs for disease treatment.
基金Financial supports from National Key R&D Program of China(2022YFC3401404)National Natural Science Foundation of China(32170935 and 31930066)the Youth Innovation Promotion Association of CAS(2019283)are gratefully acknowledged.
文摘Nanosized drug delivery systems(NDDSs)have emerged as a powerful tool to optimize drug delivery in complex diseases,including cancer and inflammation.However,the therapeutic effect of NDDSs is still far from satisfactory due to their poor circulation time,low delivery efficiency,and innate toxicity.Fortunately,biomimetic approaches offer new opportunities to develop nanomedicine,which is derived from a variety of native biomolecules including cells,exosomes,bacteria,and so on.Since inheriting the superior biocompatibility and versatile functions of natural materials,biomimetic nanomedicine can mimic biological processes,prolong blood circulation,and lower immunogenicity,serving as a desired platform for precise drug delivery for treating cancer and inflammatory disease.In this review,we outline recent advances in biomimetic NDDSs,which consist of two concepts:biomimetic exterior camouflage and bioidentical molecule construction.We summarize engineering strategies that further functionalized current biomimetic NDDSs.A series of functional biomimetic NDDSs created by our group are introduced.We conclude with an outlook on remaining challenges and possible directions for biomimetic NDDSs.We hope that better technologies can be inspired and invented to advance drug delivery systems for cancer and inflammation therapy.
基金the National Natural Science Foundation of China (32171374, 31870995 and 81671808)the Shandong Provincial Natural Science Foundation (ZR2019ZD25, China) for financial support
文摘Metastatic triple-negative breast cancer(TNBC)is the most aggressive type of breast cancer.Combination of systemic chemotherapy and immune checkpoint blockade is effective but of limited benefit due to insufficient intratumoral infiltration of cytotoxic T lymphocytes(CTLs)and the accumulation of immunosuppressive cells.Herein,we designed a lenvatinib-and vadimezan-loaded synthetic high-density lipoprotein(LV-sHDL)for combinational immunochemotherapy of metastatic TNBC.The LV-sHDL targeted scavenger receptor class B type 1-overexpressing 4T1 cells in the tumor after intravenous injection.The multitargeted tyrosine kinase inhibitor(TKI)lenvatinib induced immunogenic cell death of the cancer cells,and the stimulator of interferon genes(STING)agonist vadimezan triggered local inflammation to facilitate dendritic cell maturation and antitumor macrophage differentiation,which synergistically improved the intratumoral infiltration of total and active CTLs by 33-and 13-fold,respectively.LV-sHDL inhibited the growth of orthotopic 4T1 tumors,reduced pulmonary metastasis,and prolonged the survival of animals.The efficacy could be further improved when LV-sHDL was used in combination with antibody against programmed cell death ligand 1.This study highlights the combination use of multitargeted TKI and STING agonist a promising treatment for metastatic TNBC.
基金supported by the Natural Science Foundation of China (No. 82073759, China)Qingdao Postdoctoral Science Foundation (No. 862105040014, China)+1 种基金Special funds of Shandong Province for Qingdao National Laboratory of Marine Science and Technology (No. 2022QNLM030003, China)National Science and Technology Major Project for Significant New Drugs Development (No. 2018ZX09735004, China)。
文摘The occurrence of obesity has increased across the whole world. Many epidemiological studies have indicated that obesity strongly contributes to the development of cancer, cardiovascular diseases, type 2 diabetes, liver diseases and other disorders, accounting for a heavy burden on the public and on health-care systems every year. Excess energy uptake induces adipocyte hypertrophy, hyperplasia and formation of visceral fat in other non-adipose tissues to evoke cardiovascular disease, liver diseases. Adipose tissue can also secrete adipokines and inflammatory cytokines to affect the local microenvironment,induce insulin resistance, hyperglycemia, and activate associated inflammatory signaling pathways. This further exacerbates the development and progression of obesity-associated diseases. Although some progress in the treatment of obesity has been achieved in preclinical and clinical studies, the progression and pathogenesis of obesity-induced diseases are complex and unclear. We still need to understand their links to better guide the treatment of obesity and associated diseases. In this review, we review the links between obesity and other diseases, with a view to improve the future management and treatment of obesity and its co-morbidities.
基金China Postdoctoral Science Foundation(Grant 2021M703345)the National Natural Science Foundation of China(Grant 31871414,81821005)+3 种基金Shanghai Science and Technology Development Funds(Grant 22YF1457100,22ZR1415200)the Lingang Laboratory(Grant Nos.LG202103-03-04,LG202103-03-05)Shanghai Special Program for Research on Aging and Women and Children’s Health(No.2020YJZX0136)Talent Program of Shanghai Pulmonary Hospital(No.fkgg1809,fkzr2317).
文摘Epithelial to mesenchymal transition (EMT) plays a crucial role in cancer metastasis, accompanied with vast epigenetic changes.AMP-activated protein kinase (AMPK), a cellular energy sensor, plays regulatory roles in multiple biological processes. Although afew studies have shed light on AMPK regulating cancer metastasis, the inside epigenetic mechanisms remain unknown. Herein weshow that AMPK activation by metformin relieves the repressive H3K9me2-mediated silencing of epithelial genes (e.g., CDH1)during EMT processes and inhibits lung cancer metastasis. PHF2, a H3K9me2 demethylase, was identified to interact with AMPKα2.Genetic deletion of PHF2 aggravates lung cancer metastasis and abolishes the H3K9me2 downregulation and anti-metastasis effectof metformin. Mechanistically, AMPK phosphorylates PHF2 at S655 site, enhancing PHF2 demethylation activity and triggering thetranscription of CDH1. Furthermore, the PHF2-S655E mutant that mimics AMPK-mediated phosphorylation status further reducesH3K9me2 and suppresses lung cancer metastasis, while PHF2-S655A mutant presents opposite phenotype and reverses the antimetastasiseffect of metformin. PHF2-S655 phosphorylation strikingly reduces in lung cancer patients and the higherphosphorylation level predicts better survival. Altogether, we reveal the mechanism of AMPK inhibiting lung cancer metastasis viaPHF2 mediated H3K9me2 demethylation, thereby promoting the clinical application of metformin and highlighting PHF2 as thepotential epigenetic target in cancer metastasis.
基金financial support from the National Natural Science Foundation of China(Nos.22007095 and 82293685)the CAMS Innovation Fund for Medical Sciences(2019-12M-5-080)the Biological Resources Program,CAS(KFJ-BRP-008-001)is gratefully acknowledged.
文摘Comprehensive Summary,Compounds 1—12,including seven complex monoterpenoid indole-quinoline and bisindole alkaloids,suadimins D—J(1—7)with previously unreported carbon-carbon linkages,were isolated and identified from the twigs and leaves of Melodinus suaveolens.Their structures were elucidated by a combination of diverse methods,especially the extensive spectroscopic data analysis and electric circular dichroism(ECD)calculations.The cytotoxicity of these compounds against three cancer cell lines was evaluated,some of which showed moderate activities with IC50 values ranging from 2.4 to 8.0μM.
基金supported by the National Natural Science Foundation of China(Nos.22077111,22177016,81872756,and 81901678)Department of Education of Guangdong Province(No.2020KZDZX1203)。
文摘Five new terpenoids,including two vibsane-type diterpenoids(1,2)and three iridoid allosides(3-5),together with eight known ones,were isolated from the leaves and twigs of Viburnum odoratissimum var.sessiliflorum.Their planar structures and relative configurations were determined by spectroscopic methods,especially 2D NMR techniques.The sugar moieties of the iridoids were confirmed asβ-D-allose by GC analysis after acid hydrolysis and acetylation.The absolute configurations of neovibsanin Q(1)and dehydrovibsanol B(2)were determined by quantum chemical calculation of their theoretical electronic circular dichroism(ECD)spectra and Rh2(OCOCF_(3))_(4)-induced ECD analysis.The anti-inflammatory activities of compounds 1,3,4,and 5 were evaluated using an LPS-induced RA W264.7 cell model.Compounds 3 suppressed the release of NO in a dose-dependent manner,with an IC_(50) value of 55.64μmol·L^(-1).The cytotoxicities of compounds 1-5 on HCT-116 cells were assessed and the results showed that compounds 2 and 3 exhibited moderate inhibitory activities with IC_(50) values of 13.8 and 12.3μmol·L^(-1),respectively.
基金The financial support from the National Natural Science Foundation of China(Nos.82122062,81861138045,22177121)the CAMS Innovation Fund for Medical Sciences(2019-12M-5-080)+2 种基金the Biological Resources Program(CAS,KFJ-BRP-008)Science and Technology Commission of Shanghai Municipality(20ZR1467800)Youth Innovation Promotion Association CAS,is gratefully acknowledged.
文摘Chemical investigation of Hedyosmum orientale led to the identification of two terpenoid derivatives,dyosmunoids A and B(1 and 2)featuring two different 3/5/6/6/5-fused pentacyclic ring systems,respectively.Compound 1 is the second natural product of this C_(25) terpenoid compound class,and compound 2 is a rare dinor-C25 terpenoid with a peroxide bridge.Their structural elucidation was achieved by the comprehensive analysis of spectroscopic data,single-crystal X-ray diffraction,and ECD calculation.Putative biosynthetic pathways for compounds 1 and 2 are proposed.Compound 2 exhibited strong antimalarial activity with an IC_(50) value of 0.42μmol·L^(-1).
基金supported by the National Natural Science Foundation of China(81872758,22237007)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2019-I2M-5-080)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2022282)。
文摘1 Introduction Natural products(NPs)historically serve as a valuable and productive source of bioactive compounds for drug development.The discovery of a range of alkaloids in the early1800s,including strychnine,morphine,etc.,heralded a new era of isolating plant-derived bioactive compounds in the field of NPs[1].
基金This research work was financially supported by the National Natural Science Foundation of China(Nos.81991521,82022069,42076099)the Shanghai Rising-Star Program(No.20QA1411100)+1 种基金"Youth Innovation Promotion Association"of Chinese Academy of Sciences(No.Y202065)the SKLDR/SIMM Project(No.SIMM2103ZZ-06).
文摘A detailed chemical investigation of the South China Sea nudibranch Hexabranchus sanguineus,as well as its possible sponge-prey Acanthella cavernosa,led to the isolation of fifteen new nitrogenous sesquiterpenoids,namely ximaocavernosins A-0,including seven cadinanes(1-7),seven spiroaxanes(12-18)and one aromadendrane(19),together with thirteen known related compounds(8-11 and 20-28).
基金Financial support from the National Natural ScienceFoundation of China(No.22007095)the CAMS Innovation Fund for Medical Sciences(2019-12M-5-080)the Biological Resources Program,CAS(KFJ-BRP-008-001)of People's Republic of China,and the Youth Innovation Promotion Associationof CAS(2022283),is gratefully acknowledged.
文摘Dichagelinoids A—C(1—3),three unusual dichapetalin-type triterpenoids,together with two biogenetically related derivatives dichagelinoids D and E(4 and 5)were isolated and characterized by solid data from Dichapetalum gelonioides.Compounds 1—3 possess a common rearranged C ring and different C6—C2 modified motifs at the A rings.Biological evaluation revealed that compounds 1—3 showed distinct cytotoxic activity against the tested human cancer cell lines.
基金supported by National Key R&D Program of China (2020YFA0509400) (to Ye Yang)National Natural Science Foundation of China 81970196 (to Chunyan Gu) and 82073885 (to Ye Yang)+4 种基金Natural Science Foundation of Jiangsu Province (China) BK20200097 (to Chunyan Gu)National Natural Science Foundation of China 82073888 (to Hongbo Wang)the Science and Technology Support Program for Youth Innovation in Universities of Shandong (China) (2019KJM009) (to Hongbo Wang)Bohai rim Advanced Research Institute for Drug Discovery (China) (LX211011) (to Hongbo Wang)Jiangsu Postgraduate Research and Practice Innovation Program (China) KYCX21_1769 (to Rongfang Wei)。
文摘Multiple myeloma(MM) is still an incurable hematologic malignancy, which is eagerly to the discovery of novel therapeutic targets and methods. N-acetyltransferase 10(NAT10) is the first reported regulator of mRNA acetylation that is activated in many cancers. However, the function of NAT10 in MM remains unclear. We found significant upregulation of NAT10 in MM patients compared to normal plasma cells, which was also highly correlated with MM poor outcome. Further enforced NAT10 expression promoted MM growth in vitro and in vivo, while knockdown of NAT10 reversed those effects. The correlation analysis of acetylated RNA immunoprecipitation sequencing(ac RIP-seq) and ribosome profiling sequencing(Ribo-seq) combined with RIP-PCR tests identified centrosomal protein 170(CEP170) as an important downstream target of NAT10. Interfering CEP170 expression in NAT10-OE cells attenuated the acceleration of cellular growth caused by elevated NAT10. Moreover,CEP170 overexpression promoted cellular proliferation and chromosomal instability(CIN) in MM.Intriguingly, remodelin, a selective NAT10 inhibitor, suppressed MM cellular growth, induced cellular apoptosis in vitro and prolonged the survival of 5TMM3VT mice in vivo. Collectively, our data indicate that NAT10 acetylates CEP170 mRNA to enhance CEP170 translation efficiency, which suggests that NAT10 may serve as a promising therapeutic target in MM.
基金financially supported by the National Natural Science Foundation of China(Nos.81991521,41776093)the National Key Research and Development Program of China(No.2018YFC0310903)+2 种基金the Key Research and Development Project of Hainan Province(ZDYF2021SHFZ107)Financial Fund of the Ministry of Agriculture and Rural Affairs,P.R.China(NFZX2021)the SKLDR/SIMM Project(No.SIMM2103ZZ-06).
文摘Ten new cembrane-type diterpenoids,namely xishaglaucumins A—J(1—10),along with ten known related ones(11—20),have been isolated from the soft coral Sarcophyton glaucum collected off the Xisha Island in the South China Sea.Their structures were elucidated by extensive spectroscopic analysis,quantum mechanical nuclear magnetic resonance(QM-NMR)methods,X-ray diffraction analysis,chemical methods and comparison with the reported data in the literature.The absolute configuration of new compounds 1,5 and known compounds 11,12,16 and 20 were determined either by chemical methods or by X-ray diffraction analysis using Cu Kα(λ=1.5417A).In in vitro bioassay,compound 4 exhibited inhibitory effects on lipopolysaccharide(LPS)-induced inflammatory responses in BV-2 microglial cells.
文摘The natural products of dispirocochlearoids are complex Ganoderma meroterpenoids featuring a 6/6/5/6/6/6 ring system and are selective cox-2 inhibitors.Herein,we describe our progress regarding the total synthesis of dispirocochlearoids A-C,in which a hexacyclic skeleton was constructed firstly.The key steps of this work involve an intermolecular[4+2]cycloaddition reaction,a ring cleavage approach via Ticla,and the installation of a profoundly sterically hindering lactone.