The title compound 9S,9aS-neotuberostemonine (1) was isolated from the 95%ethanol extract of the roots of Stemona tuberosa. The crystal structure of 1, C22H33NO4, wasdetermined by single-crystal X-ray diffraction an...The title compound 9S,9aS-neotuberostemonine (1) was isolated from the 95%ethanol extract of the roots of Stemona tuberosa. The crystal structure of 1, C22H33NO4, wasdetermined by single-crystal X-ray diffraction analysis. The crystal belongs to orthorhombicsystem, space group P212121, with a-9.0115(11), b = 10.612(4), c = 22.074(3) A, V= 2110.9(8)S^3, Z= 4, Mr= 375.49, Dc= 1.182 g/cm3, λ= 0.71079 A,μ= 0.080 cm^-1, F(000) = 816, S = 1.019,R = 0.0579 and wR = 0.1358. A total of 3109 unique reflections were collected, of which 2902were observed (I〉 2σ(I)). The absolute configuration of 1 could be assigned by referring to theconserved configuration of the methyl groups at C(13) and C(20). In the solid state, the moleculeswere linked into a chain along the a-axis through weak hydrogen bond C(ll)-H(11A)…O(2).Compound 1 shows significant inhibition of cough by 24%, 44% and 65% at doses of 50, 100 and150 mg/kg, respectively.展开更多
Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases(CVDs),the world’s primary cause of death.Ginkgo biloba,a we...Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases(CVDs),the world’s primary cause of death.Ginkgo biloba,a well-known traditional Chinese medicine with notable cardiovascular actions,has been used as a cardio-and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries.Preclinical studies have shown that ginkgolide B,a bioactive component in Ginkgo biloba,can ameliorate atherosclerosis in cultured vascular cells and disease models.Of clinical relevance,several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases,such as ischemia stroke.Here,we present a comprehensive review of the pharmacological activities,pharmacokinetic characteristics,and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy.We highlight new molecular targets of ginkgolide B,including nicotinamide adenine dinucleotide phosphate oxidases(NADPH oxidase),lectin-like oxidized LDL receptor-1(LOX-1),sirtuin 1(SIRT1),platelet-activating factor(PAF),proprotein convertase subtilisin/kexin type 9(PCSK9)and others.Finally,we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis.展开更多
Chang-Kang-Fang(CKF)formula,a Traditional Chinese Medicine(TCM)prescription,has been widely used for the treatment of irritable bowel syndrome(IBS).However,its potential material basis and underlying mechanism remain ...Chang-Kang-Fang(CKF)formula,a Traditional Chinese Medicine(TCM)prescription,has been widely used for the treatment of irritable bowel syndrome(IBS).However,its potential material basis and underlying mechanism remain elusive.Therefore,this study employed an integrated approach that combined ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q/TOF-MS)with network pharmacology to systematically characterize the phytochemical components and metabolites of CKF,as well as elucidating its underlying mechanism.Through this comprehensive analysis,a total of 150 components were identified or tentatively characterized within the CKF formula.Notably,six N-acetyldopamine oligomers from Cicadae Periostracum and eight resin glycosides from Cuscutae Semen were characterized in this formula for the first time.Meanwhile,149 xenobiotics(58 prototypes and 91 metabolites)were detected in plasma,urine,feces,brain,and intestinal contents,and the in vivo metabolic pathways of resin glycosides were elaborated for the first time.Furthermore,network pharmacology and molecular docking analyses revealed that alkaloids,flavonoids,chromones,monoterpenes,N-acetyldopamine dimers,p-hydroxycinnamic acid,and Cus-3/isomer might be responsible for the beneficial effects of CKF in treating IBS,and CASP8,MARK14,PIK3C,PIK3R1,TLR4,and TNF may be its potential targets.These discoveries offer a comprehensive understanding of the potential material basis and clarify the underlying mechanism of the CKF formula in treating IBS,facilitating the broader application of CKF in the field of medicine.展开更多
We deeply regret that the representative image of invaded 143B cells treated with Z-GP-DAVLBH + AXL-KD in the lower panel of Fig. 6C was incorrect due to inadvertent mistake of copying and pasting in the process of as...We deeply regret that the representative image of invaded 143B cells treated with Z-GP-DAVLBH + AXL-KD in the lower panel of Fig. 6C was incorrect due to inadvertent mistake of copying and pasting in the process of assembling figures with Adobe Illustrator software. The image has now been corrected, and the quantification of cell invasion in Fig. 6C remains correct. The corrected version of Fig. 6C has been provided below, and the change did not affect the results and conclusions of this study. We have provided the original data of this figure to Editorial Office, and the Editorial Office or the corresponding authors can be contacted for original data access.展开更多
Heat shock protein 90(Hsp90)is a highly conserved molecular chaperone that plays a vital role in the signal transduction of cancers.Hsp90 inhibitors are able to inhibit Hsp90 or the complex of Hsp90 and co-chaperones ...Heat shock protein 90(Hsp90)is a highly conserved molecular chaperone that plays a vital role in the signal transduction of cancers.Hsp90 inhibitors are able to inhibit Hsp90 or the complex of Hsp90 and co-chaperones resulting in the degradation of Hsp90-dependent client proteins through the ubiqui tina tion-proteasome pathway,thereby leading to the growth inhibition of tumor cells.This review will briefy discuss the molecular structure and biological function of Hsp90,and focus on a summary of recent progress in the development and testing of natural Hsp90 inhibitors and their different means by which they interact with Hsp90.展开更多
Podophyllotoxone(1) was isolated from the roots of Dysosma versipellis. The structure was determined by spectroscopic analysis in combination with single-crystal X-ray analysis. The absolute configuration of compound ...Podophyllotoxone(1) was isolated from the roots of Dysosma versipellis. The structure was determined by spectroscopic analysis in combination with single-crystal X-ray analysis. The absolute configuration of compound 1 was assigned based on the Flack parameter. It showed significant inhibitory activities against human prostate cancer cells PC3 and DU145 with IC50 values being 14.7 and 20.6 μmol·L-1, respectively. It also arrested the cells at G2/M phase. Tubulin polymerization assay showed that it inhibited the tubulin polymerization in a dose-dependent manner, and molecular docking analysis revealed a different binding mode with tubulin as compared with those known tubulin inhibitors.展开更多
The relationship between chronic psychological stress and tumorigenesis has been well defined in epidemiological studies;however, the underlying mechanism remains underexplored. In this study, we discovered that impai...The relationship between chronic psychological stress and tumorigenesis has been well defined in epidemiological studies;however, the underlying mechanism remains underexplored. In this study, we discovered that impaired macrophage phagocytosis contributed to the psychological stressevoked tumor susceptibility, and the stress hormone glucocorticoid(GC) was identified as a principal detrimental factor. Mechanistically, GC disturbed the balance of the "eat me" signal receptor(low-density lipoprotein receptor-related protein-1, LRP1) and the "don’t eat me" signal receptor(signal regulatory protein alpha, SIRPa). Further analysis revealed that GC led to a direct, glucocorticoid receptor(GR)-dependent trans-repression of LRP1 expression, and the repressed LRP1, in turn, resulted in the elevatedgene level of SIRPa by down-regulating mi RNA-4695-3 p. These data collectively demonstrate that stress induces the imbalance of the LRP1/SIRPa axis and entails the disturbance of tumor cell clearance by macrophages. Our findings provide the mechanistic insight into psychological stress-evoked tumor susceptibility and indicate that the balance of LRP1/SIRPa axis may serve as a potential therapeutic strategy for tumor treatment.展开更多
Mitochondria are the energy center of cell operations and are involved in physiological functions and maintenance of metabolic balance and homeostasis in the body.Alterations of mitochondrial function are associated w...Mitochondria are the energy center of cell operations and are involved in physiological functions and maintenance of metabolic balance and homeostasis in the body.Alterations of mitochondrial function are associated with a variety of degenerative and acute diseases.As mitochondria age in cells,they gradually become inefficient and potentially toxic Acute injury can trigger the permeability of mitochondrial membranes,which can lead to apoptosis or necrosis.Transactive response DNA-binding protein 43 kDa(TDP-43)is a protein widely present in cells.It can bind to RNA,regulate a variety of RNA processes,and play a role in the formation of multi-protein/RNA complexes.Thus,the normal physiological functions of TDP-43 are particularly important for cell survival.Normal TDP-43 is located in various subcellular structures including mitochondria,mitochondrial-associated membrane,RNA particles and stress granules to regulate the endoplasmic reticulum-mitochondrial binding,mitochondrial protein translation,and mRNA transport and translation.Importantly,TDP-43 is associated with a variety of neurodegenerative diseases,including amyotrophic lateral sclerosis,frontotemporal dementia and Alzheimer's disease,which are characterized by abnormal phosphorylation,ubiquitination,lysis or nuclear depletion of TDP-43 in neurons and glial cells.Although the pathogenesis of TDP-43 proteinopathy remains unknown,the presence of pathological TDP-43 inside or outside of mitochondria and the functional involvement of TDP-43 in the regulation of mitochondrial morphology,transport,and function suggest that mitochondria are associated with TDP-43-related diseases.Autophagy is a basic physiological process that maintains the homeostasis of cells,including targeted clearance of abnormally aggregated proteins and damaged organelles in the cytoplasm;therefore,it is considered protective against neurodegenerative diseases.However,the combination of abnormal TDP-43 aggregation,mitochondrial dysfunction,and insufficient autophagy can lead to a variety of aging-related pathologies.In this review,we describe the current knowledge on the associations of mitochondria with TDP-43 and the role of autophagy in the clearance of abnormally aggregated TDP-43 and dysfunctional mitochondria.Finally,we discuss a novel approach for neurodegenerative treatment based on the knowledge.展开更多
Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties,a high incidence of pulmonary metastasis and a poor prognosis.Chemotherapy is the mainstay of treatment for osteosarcoma.Currently...Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties,a high incidence of pulmonary metastasis and a poor prognosis.Chemotherapy is the mainstay of treatment for osteosarcoma.Currently,there are no molecular targeted drugs approved for osteosarcoma treatment,particularly effective drugs for osteosarcoma with pulmonary metastases.It has been reported that fibroblast activation protein alpha(FAPa)is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis,demonstrating that FAPa-targeted agents might be a promising therapeutic strategy for osteosarcoma.In the present study,we reported that the FAPa-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPa-positive osteosarcoma cells in vitro and in vivo.Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells.Importantly,it also decreased the migration and invasion capacities and reversed epithelial-mesenchymal transition(EMT)of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo.Mechanistically,Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway,leading to inhibition of the growth and metastatic spread of osteosarcoma cells.These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPa-positive osteosarcoma,particularly osteosarcoma with pulmonary metastases.展开更多
Epidermal growth factor receptor(EGFR)activation plays a pivotal role in EGFR-driven non-small cell lung cancer(NSCLC)and is considered as a key target of molecular targeted therapy.EGFR tyrosine kinase inhibitors(TKI...Epidermal growth factor receptor(EGFR)activation plays a pivotal role in EGFR-driven non-small cell lung cancer(NSCLC)and is considered as a key target of molecular targeted therapy.EGFR tyrosine kinase inhibitors(TKIs)have been canonically used in NSCLC treatment.However,prevalent innate and acquired resistances and EGFR kinase-independent pro-survival properties limit the clinical efficacy of EGFR TKIs.Therefore,the discovery of novel EGFR degraders is a promising approach towards improving therapeutic efficacy and overcoming drug resistance.Here,we identified a 23-hydroxybetulinic acid derivative,namely DPBA,as a novel EGFR small-molecule ligand.It exerted potent in vitro and in vivo anticancer activity in both EGFR wild type and mutant NSCLC by degrading EGFR.Mechanistic studies disclosed that DPBA binds to the EGFR extracellular domain at sites differing from those of EGF and EGFR.DPBA did not induce EGFR dimerization,phosphorylation,and ubiquitination,but it significantly promoted EGFR degradation and repressed downstream survival pathways.Further analyses showed that DPBA induced clathrin-independent EGFR endocytosis mediated by flotillin-dependent lipid rafts and unaffected by EGFR TKIs.Activation of the early and late endosome markers rab5 and rab7 but not the recycling endosome marker rab11 was involved in DPBA-induced EGFR lysosomal degradation.The present study offers a new EGFR ligand for EGFR pharmacological degradation and proposes it as a potential treatment for EGFR-positive NSCLC,particularly NSCLC with innate or acquired EGFR TKI resistance.DPBA can also serve as a chemical probe in the studies on EGFR trafficking and degradation.展开更多
Oleandomycin glycosyltransferase variant P67T/S132F/A242V(ASP) was used to convert 10-hydroxycamptothecin into camptothecin-10-O-glucoside, which was confirmed by spectral analysis. Compared to the previously report...Oleandomycin glycosyltransferase variant P67T/S132F/A242V(ASP) was used to convert 10-hydroxycamptothecin into camptothecin-10-O-glucoside, which was confirmed by spectral analysis. Compared to the previously reported results, the present study reached the conversion rate up to 80% through the optimization of reaction conditions. In addition, compared with 10-hydroxycamptotheein(HCPT), camptothecin-10-O-glucoside inhibited the proliferation of Huh7 cells in a concentration-dependent manner and showed stronger antineoplastic effect but lower toxicity. Furthermore, camptothecin-10-O-glucoside induced more apoptotic cells as compared with the parent compound.展开更多
The title compound maistemonine(1)was isolated from the total alkaloid fraction of the 95%ethanol extract of the roots of Stemona japonica,followed by preparative HPLC and recrystallization from a mixture of n-hexane ...The title compound maistemonine(1)was isolated from the total alkaloid fraction of the 95%ethanol extract of the roots of Stemona japonica,followed by preparative HPLC and recrystallization from a mixture of n-hexane and ethyl acetate.The crystal structure of 1,C23H29NO)6,was determined by single-crystal X-ray diffraction analysis.The crystal belongs to orthorhombic system,space group P212121 with a=8.5698(6),b=14.0460(11),c=17.8815(17)?,V=2152.4(3)?3,Z=4,Mr=415.47,Dc=1.282 g/cm3,λ=0.71079?,μ=0.092 cm^–1,F(000)=888,S=0.995,R=0.0535 and wR=0.1067.A total of 5136 unique reflections were collected,of which 3523 were observed(Ⅰ>2σ(Ⅰ)).The absolute configuration of 1 could be assigned by referring to the conserved configuration of the methyl groups at C(2).Compound 1 shows mild cytotoxic activity against the prostate cancer cells LNCaP and PC3 with the IC50 values of 29.4±2.3 and 46.6±3.1 mM,respectively.It is noteworthy that the natural maistemonine(1)is different from the synthetic compound which was a racemic with the triclinic space group P1.The lactone rings E from the natural and synthetic 1 are almost perpendicular to each other when overlapping the remaining parts of the molecules.展开更多
Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer(LNM-CRC) cel...Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer(LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha(FAPα) expression in LNM-CRC cells. Gain-or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis(CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.展开更多
DNA damage response(DDR)is a highly conserved genome surveillance mechanism that preserves cell viability in the presence of chemotherapeutic drugs.Hence,small molecules that inhibit DDR are expected to enhance the an...DNA damage response(DDR)is a highly conserved genome surveillance mechanism that preserves cell viability in the presence of chemotherapeutic drugs.Hence,small molecules that inhibit DDR are expected to enhance the anti-cancer effect of chemotherapy.Through a recent chemical library screen,we identified shikonin as an inhibitor that strongly suppressed DDR activated by various chemotherapeutic drugs in cancer cell lines derived from different origins.Mechanistically,shikonin inhibited the activation of ataxia telangiectasia mutated(ATM),and to a lesser degree ATM and RAD3-related(ATR),two master upstream regulators of the DDR signal,through inducing degradation of ATM and ATR-interacting protein(ATRIP),an obligate associating protein of ATR,respectively.As a result of DDR inhibition,shikonin enhanced the anti-cancer effect of chemotherapeutic drugs in both cell cultures and in mouse models.While degradation of ATRIP is proteasome dependent,that of ATM depends on caspase-and lysosome-,but not proteasome.Overexpression of ATM significantly mitigated DDR inhibition and cell death induced by shikonin and chemotherapeutic drugs.These novel findings reveal shikonin as a pan DDR inhibitor and identify ATM as a primary factor in determining the chemo sensitizing effect of shikonin.Our data may facilitate the development of shikonin and its derivatives as potential chemotherapy sensitizers through inducing ATM degradation.展开更多
基金supported by Guangdong Key Scientific Project(2013A022100029)Zhongshan Scientific Scheme(2017B1134)
文摘The title compound 9S,9aS-neotuberostemonine (1) was isolated from the 95%ethanol extract of the roots of Stemona tuberosa. The crystal structure of 1, C22H33NO4, wasdetermined by single-crystal X-ray diffraction analysis. The crystal belongs to orthorhombicsystem, space group P212121, with a-9.0115(11), b = 10.612(4), c = 22.074(3) A, V= 2110.9(8)S^3, Z= 4, Mr= 375.49, Dc= 1.182 g/cm3, λ= 0.71079 A,μ= 0.080 cm^-1, F(000) = 816, S = 1.019,R = 0.0579 and wR = 0.1358. A total of 3109 unique reflections were collected, of which 2902were observed (I〉 2σ(I)). The absolute configuration of 1 could be assigned by referring to theconserved configuration of the methyl groups at C(13) and C(20). In the solid state, the moleculeswere linked into a chain along the a-axis through weak hydrogen bond C(ll)-H(11A)…O(2).Compound 1 shows significant inhibition of cough by 24%, 44% and 65% at doses of 50, 100 and150 mg/kg, respectively.
基金This work is supported by National Natural Science Foundation of China(82270500,81870324,82203304,82070464,U1401225,U21A20419)National Mega-Project for Innovative Drugs(2019ZX09735002)+1 种基金Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y036,2017BT01Y093,China)National Engineering and Technology Research Center for New drug Druggability Evaluation(Seed Program of Guangdong Province,2017B090903004,China).
文摘Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases(CVDs),the world’s primary cause of death.Ginkgo biloba,a well-known traditional Chinese medicine with notable cardiovascular actions,has been used as a cardio-and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries.Preclinical studies have shown that ginkgolide B,a bioactive component in Ginkgo biloba,can ameliorate atherosclerosis in cultured vascular cells and disease models.Of clinical relevance,several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases,such as ischemia stroke.Here,we present a comprehensive review of the pharmacological activities,pharmacokinetic characteristics,and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy.We highlight new molecular targets of ginkgolide B,including nicotinamide adenine dinucleotide phosphate oxidases(NADPH oxidase),lectin-like oxidized LDL receptor-1(LOX-1),sirtuin 1(SIRT1),platelet-activating factor(PAF),proprotein convertase subtilisin/kexin type 9(PCSK9)and others.Finally,we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis.
基金supported by National Key Research and Development Program of China(No.2017ZX 09301005).
文摘Chang-Kang-Fang(CKF)formula,a Traditional Chinese Medicine(TCM)prescription,has been widely used for the treatment of irritable bowel syndrome(IBS).However,its potential material basis and underlying mechanism remain elusive.Therefore,this study employed an integrated approach that combined ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q/TOF-MS)with network pharmacology to systematically characterize the phytochemical components and metabolites of CKF,as well as elucidating its underlying mechanism.Through this comprehensive analysis,a total of 150 components were identified or tentatively characterized within the CKF formula.Notably,six N-acetyldopamine oligomers from Cicadae Periostracum and eight resin glycosides from Cuscutae Semen were characterized in this formula for the first time.Meanwhile,149 xenobiotics(58 prototypes and 91 metabolites)were detected in plasma,urine,feces,brain,and intestinal contents,and the in vivo metabolic pathways of resin glycosides were elaborated for the first time.Furthermore,network pharmacology and molecular docking analyses revealed that alkaloids,flavonoids,chromones,monoterpenes,N-acetyldopamine dimers,p-hydroxycinnamic acid,and Cus-3/isomer might be responsible for the beneficial effects of CKF in treating IBS,and CASP8,MARK14,PIK3C,PIK3R1,TLR4,and TNF may be its potential targets.These discoveries offer a comprehensive understanding of the potential material basis and clarify the underlying mechanism of the CKF formula in treating IBS,facilitating the broader application of CKF in the field of medicine.
文摘We deeply regret that the representative image of invaded 143B cells treated with Z-GP-DAVLBH + AXL-KD in the lower panel of Fig. 6C was incorrect due to inadvertent mistake of copying and pasting in the process of assembling figures with Adobe Illustrator software. The image has now been corrected, and the quantification of cell invasion in Fig. 6C remains correct. The corrected version of Fig. 6C has been provided below, and the change did not affect the results and conclusions of this study. We have provided the original data of this figure to Editorial Office, and the Editorial Office or the corresponding authors can be contacted for original data access.
基金This work was supported by National Science Foundation of China(90913020 and 30901847)Science and Technology Program of China(2012ZX09103-101-053)Science and Technology Star of Zhujiang of Guangzhou City(Dongmei Zhang).
文摘Heat shock protein 90(Hsp90)is a highly conserved molecular chaperone that plays a vital role in the signal transduction of cancers.Hsp90 inhibitors are able to inhibit Hsp90 or the complex of Hsp90 and co-chaperones resulting in the degradation of Hsp90-dependent client proteins through the ubiqui tina tion-proteasome pathway,thereby leading to the growth inhibition of tumor cells.This review will briefy discuss the molecular structure and biological function of Hsp90,and focus on a summary of recent progress in the development and testing of natural Hsp90 inhibitors and their different means by which they interact with Hsp90.
基金supported by the Fund of Guangxi Key Laboratory of Functional Phytochemicals Research and Utilization(Nos.FPRU2013-4,and ZRJJ2013-4)the National Natural Science Foundation of China(No.21072078)+1 种基金the Fundamental Research Funds for the Central Universities(No.11609202)the Guangdong High Level Talent Scheme to R.W.J
文摘Podophyllotoxone(1) was isolated from the roots of Dysosma versipellis. The structure was determined by spectroscopic analysis in combination with single-crystal X-ray analysis. The absolute configuration of compound 1 was assigned based on the Flack parameter. It showed significant inhibitory activities against human prostate cancer cells PC3 and DU145 with IC50 values being 14.7 and 20.6 μmol·L-1, respectively. It also arrested the cells at G2/M phase. Tubulin polymerization assay showed that it inhibited the tubulin polymerization in a dose-dependent manner, and molecular docking analysis revealed a different binding mode with tubulin as compared with those known tubulin inhibitors.
基金supported,in part,by National Natural Science Foundation of China(grant numbers 81673709,82004231,U1801284 and 81873209)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(grant number 2017BT01Y036,China)and GDUPS(2019,China)+5 种基金Guangdong Science and Technology Foundation for Distinguished Young Scholars(grant number 2017A030306004,China)Science and Technology Program of Guangzhou(grant numbers 201903010062 and 202102010116,China)Fellowship of China Postdoctoral Science Foundation(grant number 2020M683204,China)Guangdong Basic and Applied Basic Research Fund(grant number 2020A1515110388,China)Fundamental Research Funds for the Central Universities(grant number 21620448,China)support of K.C.Wong Education Foundation。
文摘The relationship between chronic psychological stress and tumorigenesis has been well defined in epidemiological studies;however, the underlying mechanism remains underexplored. In this study, we discovered that impaired macrophage phagocytosis contributed to the psychological stressevoked tumor susceptibility, and the stress hormone glucocorticoid(GC) was identified as a principal detrimental factor. Mechanistically, GC disturbed the balance of the "eat me" signal receptor(low-density lipoprotein receptor-related protein-1, LRP1) and the "don’t eat me" signal receptor(signal regulatory protein alpha, SIRPa). Further analysis revealed that GC led to a direct, glucocorticoid receptor(GR)-dependent trans-repression of LRP1 expression, and the repressed LRP1, in turn, resulted in the elevatedgene level of SIRPa by down-regulating mi RNA-4695-3 p. These data collectively demonstrate that stress induces the imbalance of the LRP1/SIRPa axis and entails the disturbance of tumor cell clearance by macrophages. Our findings provide the mechanistic insight into psychological stress-evoked tumor susceptibility and indicate that the balance of LRP1/SIRPa axis may serve as a potential therapeutic strategy for tumor treatment.
基金supported by the National Natural Science Foundation of China(81922026,82073821,81872842,91649115)the National Key Research and Development Program of China Stem Cell and Translational Research(2017YFA0105104)+2 种基金Guangdong Province Science and Technology Plan Project(2017A020211019,2020A1515011061)the Fundamental Research Funds for the Central Universities(21619104)Guangzhou Key Research Program on Brain Science(202007030008).
文摘Mitochondria are the energy center of cell operations and are involved in physiological functions and maintenance of metabolic balance and homeostasis in the body.Alterations of mitochondrial function are associated with a variety of degenerative and acute diseases.As mitochondria age in cells,they gradually become inefficient and potentially toxic Acute injury can trigger the permeability of mitochondrial membranes,which can lead to apoptosis or necrosis.Transactive response DNA-binding protein 43 kDa(TDP-43)is a protein widely present in cells.It can bind to RNA,regulate a variety of RNA processes,and play a role in the formation of multi-protein/RNA complexes.Thus,the normal physiological functions of TDP-43 are particularly important for cell survival.Normal TDP-43 is located in various subcellular structures including mitochondria,mitochondrial-associated membrane,RNA particles and stress granules to regulate the endoplasmic reticulum-mitochondrial binding,mitochondrial protein translation,and mRNA transport and translation.Importantly,TDP-43 is associated with a variety of neurodegenerative diseases,including amyotrophic lateral sclerosis,frontotemporal dementia and Alzheimer's disease,which are characterized by abnormal phosphorylation,ubiquitination,lysis or nuclear depletion of TDP-43 in neurons and glial cells.Although the pathogenesis of TDP-43 proteinopathy remains unknown,the presence of pathological TDP-43 inside or outside of mitochondria and the functional involvement of TDP-43 in the regulation of mitochondrial morphology,transport,and function suggest that mitochondria are associated with TDP-43-related diseases.Autophagy is a basic physiological process that maintains the homeostasis of cells,including targeted clearance of abnormally aggregated proteins and damaged organelles in the cytoplasm;therefore,it is considered protective against neurodegenerative diseases.However,the combination of abnormal TDP-43 aggregation,mitochondrial dysfunction,and insufficient autophagy can lead to a variety of aging-related pathologies.In this review,we describe the current knowledge on the associations of mitochondria with TDP-43 and the role of autophagy in the clearance of abnormally aggregated TDP-43 and dysfunctional mitochondria.Finally,we discuss a novel approach for neurodegenerative treatment based on the knowledge.
基金supported by National Natural Science Foundation of China(grant numbers:82003796,81803566,81973340 and 81630095)Local Innovative and Research Teams Project of the Guangdong Pearl River Talents Program(grant number:2017BT01Y036,China)+5 种基金National High-level Personnel of the Special Support Program(DM Zhang,China)National Science and Technology Major Project(grant number:2018ZX09711001008-008,China)Key-Area Research and Development Program of Guangdong Province(grant number:2020B1111110004,China)Natural Science Foundation of Guangdong Province(grant number:2019A1515010144,China)Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research,College of Pharmacy(grant number:2020B1212060076,China)Special Funds for the Cultivation of Guangdong College Students’Scientific and Technological Innovation(grant number:pdjh2021a0052,China)。
文摘Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties,a high incidence of pulmonary metastasis and a poor prognosis.Chemotherapy is the mainstay of treatment for osteosarcoma.Currently,there are no molecular targeted drugs approved for osteosarcoma treatment,particularly effective drugs for osteosarcoma with pulmonary metastases.It has been reported that fibroblast activation protein alpha(FAPa)is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis,demonstrating that FAPa-targeted agents might be a promising therapeutic strategy for osteosarcoma.In the present study,we reported that the FAPa-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPa-positive osteosarcoma cells in vitro and in vivo.Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells.Importantly,it also decreased the migration and invasion capacities and reversed epithelial-mesenchymal transition(EMT)of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo.Mechanistically,Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway,leading to inhibition of the growth and metastatic spread of osteosarcoma cells.These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPa-positive osteosarcoma,particularly osteosarcoma with pulmonary metastases.
基金supported by National Key R&D Program of China(2017YFC1703800)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y036)+3 种基金National Science Foundation of China(81630095,81973340,81903634 and 81803566)National Science and Technology Major Project(2018ZX09711001-008-008)National High-level Personnel of Special Support Program(Dongmei Zhang),Natural Science Foundation of Guangdong Province(2019A1515010144)China Postdoctoral Science Foundation-funded project(2019T120793).
文摘Epidermal growth factor receptor(EGFR)activation plays a pivotal role in EGFR-driven non-small cell lung cancer(NSCLC)and is considered as a key target of molecular targeted therapy.EGFR tyrosine kinase inhibitors(TKIs)have been canonically used in NSCLC treatment.However,prevalent innate and acquired resistances and EGFR kinase-independent pro-survival properties limit the clinical efficacy of EGFR TKIs.Therefore,the discovery of novel EGFR degraders is a promising approach towards improving therapeutic efficacy and overcoming drug resistance.Here,we identified a 23-hydroxybetulinic acid derivative,namely DPBA,as a novel EGFR small-molecule ligand.It exerted potent in vitro and in vivo anticancer activity in both EGFR wild type and mutant NSCLC by degrading EGFR.Mechanistic studies disclosed that DPBA binds to the EGFR extracellular domain at sites differing from those of EGF and EGFR.DPBA did not induce EGFR dimerization,phosphorylation,and ubiquitination,but it significantly promoted EGFR degradation and repressed downstream survival pathways.Further analyses showed that DPBA induced clathrin-independent EGFR endocytosis mediated by flotillin-dependent lipid rafts and unaffected by EGFR TKIs.Activation of the early and late endosome markers rab5 and rab7 but not the recycling endosome marker rab11 was involved in DPBA-induced EGFR lysosomal degradation.The present study offers a new EGFR ligand for EGFR pharmacological degradation and proposes it as a potential treatment for EGFR-positive NSCLC,particularly NSCLC with innate or acquired EGFR TKI resistance.DPBA can also serve as a chemical probe in the studies on EGFR trafficking and degradation.
基金Supported by the National Natural Science Foundation of China(No. 81573315), the Natural Science Foundation of Guangdong Province, China(No.2015A030313313), the Guangzhou Industry University Collaborative Innovation Major Projects, China (No.201508030016) and the Natural Science Foundation of Hainan Province, China(No. 817307).
文摘Oleandomycin glycosyltransferase variant P67T/S132F/A242V(ASP) was used to convert 10-hydroxycamptothecin into camptothecin-10-O-glucoside, which was confirmed by spectral analysis. Compared to the previously reported results, the present study reached the conversion rate up to 80% through the optimization of reaction conditions. In addition, compared with 10-hydroxycamptotheein(HCPT), camptothecin-10-O-glucoside inhibited the proliferation of Huh7 cells in a concentration-dependent manner and showed stronger antineoplastic effect but lower toxicity. Furthermore, camptothecin-10-O-glucoside induced more apoptotic cells as compared with the parent compound.
基金supported by Guangdong Key Scientific Project(2013A022100029)Guangdong Characteristic Innovation Projects of Universities(2018GKTSCX055)。
文摘The title compound maistemonine(1)was isolated from the total alkaloid fraction of the 95%ethanol extract of the roots of Stemona japonica,followed by preparative HPLC and recrystallization from a mixture of n-hexane and ethyl acetate.The crystal structure of 1,C23H29NO)6,was determined by single-crystal X-ray diffraction analysis.The crystal belongs to orthorhombic system,space group P212121 with a=8.5698(6),b=14.0460(11),c=17.8815(17)?,V=2152.4(3)?3,Z=4,Mr=415.47,Dc=1.282 g/cm3,λ=0.71079?,μ=0.092 cm^–1,F(000)=888,S=0.995,R=0.0535 and wR=0.1067.A total of 5136 unique reflections were collected,of which 3523 were observed(Ⅰ>2σ(Ⅰ)).The absolute configuration of 1 could be assigned by referring to the conserved configuration of the methyl groups at C(2).Compound 1 shows mild cytotoxic activity against the prostate cancer cells LNCaP and PC3 with the IC50 values of 29.4±2.3 and 46.6±3.1 mM,respectively.It is noteworthy that the natural maistemonine(1)is different from the synthetic compound which was a racemic with the triclinic space group P1.The lactone rings E from the natural and synthetic 1 are almost perpendicular to each other when overlapping the remaining parts of the molecules.
基金supported by the National Natural Science Foundation of China(82273941,81973340,82204427,81803566,82003796,81773758)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y036,China)+9 种基金Natural Science Foundation of Guangdong Province(2022A1515011813,2021A1515110242,2020A1515010071,2019A1515010144,2019A1515110543,2019A1515011934,China)Ministry of Science and Technology of China(2018ZX09711001-008-008)National high-level personnel of special support program(Zhang Dongmei),National Key R&D Program of China(2017YFC 1703800)Technology Key Project of Guangdong Province(2020B1111110004,China)Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research,College of Pharmacy(2020B1212060076,China)Special Funds for the Cultivation of Guangdong College Students’Scientifc and Technological Innovation(“Climbing Program”Special Funds)(pdjh2021a0052,China)Science and Technology Projects in Guangzhou(2023A03J0602,202201010173,202102070001,202002030010,China)Young S&T Talent Training Program of Guangdong Provincial Association for S&T,China(SKXRC202216)Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University(JNU1AF-CFTP-2022-a01227,China)China Postdoctoral Science Foundation(2022M 711345,China).
文摘Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer(LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha(FAPα) expression in LNM-CRC cells. Gain-or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis(CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.
基金supported by Guangdong Basic and Applied Basic Research Foundation(2021A1515011244,China)to Jinshan Tangthe National 111 Project of China(No.B13038,China)to Xinsheng Yao。
文摘DNA damage response(DDR)is a highly conserved genome surveillance mechanism that preserves cell viability in the presence of chemotherapeutic drugs.Hence,small molecules that inhibit DDR are expected to enhance the anti-cancer effect of chemotherapy.Through a recent chemical library screen,we identified shikonin as an inhibitor that strongly suppressed DDR activated by various chemotherapeutic drugs in cancer cell lines derived from different origins.Mechanistically,shikonin inhibited the activation of ataxia telangiectasia mutated(ATM),and to a lesser degree ATM and RAD3-related(ATR),two master upstream regulators of the DDR signal,through inducing degradation of ATM and ATR-interacting protein(ATRIP),an obligate associating protein of ATR,respectively.As a result of DDR inhibition,shikonin enhanced the anti-cancer effect of chemotherapeutic drugs in both cell cultures and in mouse models.While degradation of ATRIP is proteasome dependent,that of ATM depends on caspase-and lysosome-,but not proteasome.Overexpression of ATM significantly mitigated DDR inhibition and cell death induced by shikonin and chemotherapeutic drugs.These novel findings reveal shikonin as a pan DDR inhibitor and identify ATM as a primary factor in determining the chemo sensitizing effect of shikonin.Our data may facilitate the development of shikonin and its derivatives as potential chemotherapy sensitizers through inducing ATM degradation.