Worldwide, colorectal cancer(CRC) is one of the most common malignant tumors, leading to immense social and economic burdens. Currently, the main treatments for CRC include surgery, chemotherapy,radiotherapy and immun...Worldwide, colorectal cancer(CRC) is one of the most common malignant tumors, leading to immense social and economic burdens. Currently, the main treatments for CRC include surgery, chemotherapy,radiotherapy and immunotherapy. Despite advances in the diagnosis and treatment of CRC, the prognosis for CRC patients remains poor. Furthermore, the occurrence of side effects and toxicities severely limits the clinical use of these therapies. Therefore, alternative medications with high efficacy but few side effects are needed. An increasing number of modern pharmacological studies and clinical trials have supported the effectiveness of Chinese herbal medicines(CHMs) for the prevention and treatment of CRC.CHMs may be able to effectively reduce the risk of CRC, alleviate the adverse reactions caused by chemotherapy, and prolong the survival time of patients with advanced CRC. Studies of molecular mechanisms have provided deeper insight into the roles of molecules from CHMs in treating CRC. This paper summarizes the current understanding of the use of CHMs for the prevention and treatment of CRC, the main molecular mechanisms involved in these processes, the role of CHMs in modulating chemotherapyinduced adverse reactions, and CHM's potential role in epigenetic regulation of CRC. The current study provides beneficial information on the use of CHMs for the prevention and treatment of CRC in the clinic,and suggests novel directions for new drug discovery against CRC.展开更多
Worldwide,cancer is a growing epidemic that results in large social and economic burdens.Despite advances in current diagnosis and treatment,most of the prognosis in cancer patients remains poor.It is urgent to find a...Worldwide,cancer is a growing epidemic that results in large social and economic burdens.Despite advances in current diagnosis and treatment,most of the prognosis in cancer patients remains poor.It is urgent to find alternative therapies with effective cancer prevention and treatment.Chinese herbal medicines(CHMs)have been increasingly used worldwide for cancer prevention and treatment due to their privileged properties.CHMs are useful in the suppression of various types of cancers through different mechanisms of action.Non-coding RNAs(ncRNAs),including microRNAs,long non-coding RNAs and circular RNAs,are closely involved in the cancer progression and development.Regulation of ncRNAs in tumor cells may be a useful pharmacological strategy for the cancer prevention and treatment.Substantial evidence exists that various phytochemicals from CHMs exert potent anticarcinogenic effects by regulating ncRNAs-related targets and signaling pathways.Herein,the purpose of this paper is to conclude the current understanding of phytochemicals from CHMs in ncRNAs-mediated cancer suppression and the molecular mechanisms.This review will help to provide beneficial clues related to the clinical use of CHMs in the cancer prevention and treatment and further promote new drug discovery against cancer.展开更多
Vitis amurensis is a wild Vitis plant that can withstand extreme cold temperatures.However,the accumulation of metabolites during cold acclimation(CA)in V.amurensis remains largely unknown.In this study,plantlets of V...Vitis amurensis is a wild Vitis plant that can withstand extreme cold temperatures.However,the accumulation of metabolites during cold acclimation(CA)in V.amurensis remains largely unknown.In this study,plantlets of V.amurensis and V.vinifera cv.Muscat of Hamburg were treated at 4℃ for 24 and 72 h,and changes of metabolites in leaves were detected by gas chromatography coupled with time-of-flight mass spectrometry.Most of the identified metabolites,including carbohydrates,amino acids,and organic acids,accumulated in the two types of grape after CA.Galactinol,raffinose,fructose,mannose,glycine,and ascorbate were continuously induced by cold in V.amurensis,but not in Muscat of Hamburg.Twelve metabolites,including isoleucine,valine,proline,2-oxoglutarate,and putrescine,increased in V.amurensis during CA.More galactinol,ascorbate,2-oxoglutarate,and putrescine,accumulated in V.amurensis,but not in Muscat of Hamburg,during CA,which may be responsible for the excellent cold tolerance in V.amurensis.The expression levels of the genes encodingβ-amylase(BAMY),galactinol synthase(GolS),and raffinose synthase(RafS)were evaluated by quantitative reverse transcription-PCR.The expression BAMY(VIT_02s0012 g00170)and RafS(VIT_05s0077 g00840)were primarily responsible for the accumulation of maltose and raffinose,respectively.The accumulation of galactinol was attributed to different members of GolS in the two grapes.In conclusion,these results show the inherent differences in metabolites between V.amurensis and V.vinifera under CA.展开更多
Blocking the MDM2/X-P53 protein-protein interaction has been widely recognized as an attractive therapeutic strategy for the treatment of cancers.Numerous small-molecule MDM2 inhibitors have been reported since the re...Blocking the MDM2/X-P53 protein-protein interaction has been widely recognized as an attractive therapeutic strategy for the treatment of cancers.Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2-P53 interaction in 1996,SAR405838,NVP-CGM097,MK-8242,RG7112,RG7388,DS-3032 b,and AMG232 currently undergo clinical evaluation for cancer therapy.This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera(PROTAC)degraders with a particular focus on how these inhibitors or degraders are identified from starting points,strategies employed,structure-activity relationship(SAR)studies,binding modes or co-crystal structures,biochemical data,mechanistic studies,and preclinical/clinical studies.Moreover,we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition,acquired resistance and toxicity of P53 activation as well as future directions.展开更多
Natural products generally fall into the biologically relevant chemical space and always possess novel biological activities, thus making them a rich source of lead compounds for new drug discovery. With the recent te...Natural products generally fall into the biologically relevant chemical space and always possess novel biological activities, thus making them a rich source of lead compounds for new drug discovery. With the recent technological advances, natural product-based drug discovery is now reaching a new era. Natural products have also shown promise in epigenetic drug discovery, some of them have advanced into clinical trials or are presently being used in clinic. The histone lysine specific demethylase1(LSD1), an important class of histone demethylases, has fundamental roles in the development of various pathological conditions. Targeting LSD1 has been recognized as a promising therapeutic option for cancer treatment. Notably, some natural products with different chemotypes including protoberberine alkaloids, flavones, polyphenols, and cyclic peptides have shown effectiveness against LSD1. These natural products provide novel scaffolds for developing new LSD1 inhibitors. In this review, we mainly discuss the identification of natural LSD1 inhibitors, analysis of the co-crystal structures of LSD1/natural product complex, antitumor activity and their modes of action. We also briefly discuss the challenges faced in this field. We believe this review will provide a landscape of natural LSD1 inhibitors.展开更多
Cibotium barometz(Linn.)J.Sm.,a tree fern in the Dicksoniaceae family,is an economically important industrial exported plant in China and widely used in Traditional Chinese Medicine.C.barometz produces a range of bioa...Cibotium barometz(Linn.)J.Sm.,a tree fern in the Dicksoniaceae family,is an economically important industrial exported plant in China and widely used in Traditional Chinese Medicine.C.barometz produces a range of bioactive triterpenes and their metabolites.However,the biosynthetic pathway of triterpenes in C.barometz remains unknown.To clarify the origin of diverse triterpenes in C.barometz,we conducted de novo transcriptome sequencing and analysis of C.barometz rhizomes and leaves to identify the candidate genes involved in C.barometz triterpene biosynthesis.Three C.barometz triterpene synthases(CbTSs)candidate genes were obtained.All of them were highly expressed in C.barometz rhizomes,consisting of the accumulation pattern of triterpenes in C.barometz.To characterize the function of these CbTSs,we constructed a squalene-and oxidosqualene-overproducing yeast chassis by overexpressing all the enzymes in the MVA pathway under the control of GAL-regulated promoter and disrupted the GAL80 gene in Saccharomyces cerevisiae simultaneously.Heterologous expressing CbTS1,CbTS2,and CbTS3 in engineering yeast strain produced cycloartenol,dammaradiene,and diploptene,respectively.Phylogenetic analysis revealed that CbTS1 belongs to oxidosqualene cyclase,while CbTS2 and CbTS3 belong to squalene cyclase.These results decipher enzymatic mechanisms underlying the origin of diverse triterpene in C.barometz.展开更多
Borneol is a traditional Chinese medicine that can promote drug absorption from the gastrointestinal tract and distribution to the brain.However,stomach irritation may occur when high doses of borneol are used.In the ...Borneol is a traditional Chinese medicine that can promote drug absorption from the gastrointestinal tract and distribution to the brain.However,stomach irritation may occur when high doses of borneol are used.In the present work,gastrodin,the main bioactive ingredient of the traditional Chinese drug“Tianma”(Rhizoma Gastrodiae)was used as a model drug to explore reasonable application of borneol.Sustained-release solid dispersions(SRSDs)for co-loading gastrodin and borneol were prepared using ethylcellulose as a sustained release matrix and hydroxy-propyl methylcellulose as a retarder.The dispersion state of drug within the SRSDs was analyzed by using scanning electron microscopy,differential scanning calorimetry,and powder X-ray diffractometry.The results indicated that both gastrodin and borneol were molecularly dispersed in an amorphous form.Assay of in vitro drug release demonstrated that the dissolution profiles of gastrodin and borneol from the SRSDs both fitted the Higuchi model.Subsequently,gastric mucosa irritation and the brain targeting of the SRSDs were evaluated.Compared with the free mixture of gastrodin and borneol,brain targeting of SRSDs was slightly weaker(brain targeting index:1.83 vs.2.09),but stomach irritation obviously reduced.Sustained-release technology can be used to reduce stomach irritation caused by borneol while preserving sufficient transport capacity for oral brain-targeting drug delivery.展开更多
Four new 3,4-seco-labdane diterpenoids,nudiflopenes J-M,were isolated from the leaves of Callicarpa nudiflora along with six known compounds.The structures of these diterpenoids were determined by comprehensive spectr...Four new 3,4-seco-labdane diterpenoids,nudiflopenes J-M,were isolated from the leaves of Callicarpa nudiflora along with six known compounds.The structures of these diterpenoids were determined by comprehensive spectroscopic analysis.All the isolated compounds were evaluated for their inhibitory effects on NO production in LPS-stimulated RPMs and RAW264.7 cells.The results suggest that nudiflopenes J-M and other four known compounds showed significant inhibitory effects against NO production comparable to the positive control dexamethasone.展开更多
Herein,we firstly developed a non-covalent glycosylated gold nanoparticles/peptides nanovaccine which is assembled byβ-cyclodextrin(β-CD)based host-guest recognitions.This nanovaccine can generate significant titers...Herein,we firstly developed a non-covalent glycosylated gold nanoparticles/peptides nanovaccine which is assembled byβ-cyclodextrin(β-CD)based host-guest recognitions.This nanovaccine can generate significant titers of antibodies and improve the therapeutic effect against melanoma,suggesting the immunogenicity of peptide antigens can be improved by loading with this carrier.The novel vaccine carrier provides a platform for the transport of various antigens especially T cell-independent antigens.展开更多
A facile and efficient strategy was established for the construction of RC-529 and its derivatives.Four conjugates of RC-529 derivatives with Tn antigen were synthesized and all elicited strong and T celldependent imm...A facile and efficient strategy was established for the construction of RC-529 and its derivatives.Four conjugates of RC-529 derivatives with Tn antigen were synthesized and all elicited strong and T celldependent immune responses in mice without requiring external adjuvants.In addition,all antisera induced by these conjugates could specifically recognize,bind to and kill Tn-overexpressing cancer cells.Thus,RC-529 shows promise as a useful platform for the development of new vaccine carriers with self-adjuvanting properties for the treatment of cancer.Moreover,preliminary structure-activity relationship analysis provides convincing support for further optimization of,and additional investigation into RC-529.展开更多
Inhibitor of nuclear factor kappa-B kinase subunit beta(IKKβ)is one of important kinases in inflammation to phosphorylate inhibitor of nuclear factor kappa-B(IκBα)and then activate nuclear factor kappa-B(NF-κB).In...Inhibitor of nuclear factor kappa-B kinase subunit beta(IKKβ)is one of important kinases in inflammation to phosphorylate inhibitor of nuclear factor kappa-B(IκBα)and then activate nuclear factor kappa-B(NF-κB).Inhibition of IKKβhas been a therapeutic strategy for inflammatory and autoimmune diseases.Here we report that IKKβis constitutively activated in healthy donors and healthy Ikkβ^(C46A)(cysteine 46 mutated to alanine)knock-in mice although they possess intensive IKKβ-IκBα-NF-κB signaling activation.These indicate that IKKβactivation probably plays homeostatic role instead of causing inflammation.Compared to IkkβWTlittermates,lipopolysaccharides(LPS)could induce high mortality rate in Ikkβ^(C46A) mice which is correlated to breaking the homeostasis by intensively activating p-IκBα-NF-κB signaling and inhibiting phosphorylation of 5’adenosine monophosphate-activated protein kinase(p-AMPK)expression.We then demonstrated that IKKβkinase domain(KD)phosphorylates AMPKa1 via interacting with residues Thr183,Ser184,and Thr388,while IKKβhelix-loop-helix motifs is essential to phosphorylate IκBαaccording to the previous reports.Kinase assay further demonstrated that IKKβsimultaneously catalyzes phosphorylation of AMPK and IκBαto mediate homeostasis.Accordingly,activation of AMPK rather than inhibition of IKKβcould substantially rescue LPS-induced mortality in Ikkβ^(C46A) mice by rebuilding the homeostasis.We conclude that IKKβactivates AMPK to restrict inflammation and IKKβmediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα.展开更多
Anemarrhena asphodeloides is an immensely popular medicinal herb in China,which contains an abundant of mangiferin.As an important bioactive xanthone C-glycoside,mangiferin possesses a variety of pharmacological activ...Anemarrhena asphodeloides is an immensely popular medicinal herb in China,which contains an abundant of mangiferin.As an important bioactive xanthone C-glycoside,mangiferin possesses a variety of pharmacological activities and is derived from the cyclization reaction of a benzophenone C-glycoside(maclurin).Biosyntheti-cally,C-glycosyltransferases are critical for the formation of benzophenone C-glycosides.However,the benzo-phenone C-glycosyltransferases from Anemarrhena asphodeloides have not been discovered.Herein,a promiscuous C-glycosyltransferase(AaCGT)was identified from Anemarrhena asphodeloides.It was able to catalyze efficiently mono-C-glycosylation of benzophenone,together with di-C-glycosylation of dihydrochalcone.It also exhibited the weak O-glycosylation or potent S-glycosylation capacities toward 12 other types of flavonoid scaffolds and a simple aromatic compound with–SH group.Homology modeling and mutagenesis experiments revealed that the glycosylation reaction of AaCGT was initiated by the conserved residue H23 as the catalytic base.Three critical residues H356,W359 and D380 were involved in the recognition of sugar donor through hydrogen-bonding interactions.In particular,the double mutant of F94W/L378M led to an unexpected enzy-matic conversion of mono-C-to di-C-glycosylation.This study highlights the important value of AaCGT as a potential biocatalyst for efficiently synthesizing high-value C-glycosides.展开更多
We present a new strategy for self-adjuvanting vaccine development that has different types of covalently-linked immunostimulants as the carrier molecule.Using Tn antigen as the model,a three-component vaccine(MPLA-Tn...We present a new strategy for self-adjuvanting vaccine development that has different types of covalently-linked immunostimulants as the carrier molecule.Using Tn antigen as the model,a three-component vaccine(MPLA-Tn-KRN7000)containing the TLR4 ligand MPLA and the iNKT cell agonist KRN7000 was designed and synthesized.This expands fully synthetic self-adjuvanting vaccine studies that use a single carrier to one with two different types of carriers.The corresponding two-component conjugate vaccines Tn-MPLA,Tn-KRN7000 and Tn-CRM197 were also synthesized,as controls.The immunological evaluation found that MPLA-Tn-KRN7000 elicits robust Tn-specific and T cell-dependent immunity.The antibodies specifically recognized,bound to and exhibited complement-dependent cytotoxicity against Tn-positive cancer cells.In addition,MPLA-Tn-KRN7000 increased the survival rate and survival time of tumor-challenged mice,and surviving mice reject further tumor attacks without any additional treatment.Compared to the glycoprotein vaccine Tn-CRM197,the two-component conjugate vaccines,Tn-MPLA and Tn-KRN7000,and the physical mixture of Tn-MPLA and Tn-KRN7000,MPLA-Tn-KRN7000 showed the most effect at combating tumor cells both in vitro and in vivo.The comparison of immunological studies in wild-type and TLR4 knockout mice,along with the test of binding affinity to CD1d protein suggests that the covalently linked MPLA-KRN7000 immunostimulant induces a synergistic activation of TLR4 and iNKT cell that improves the immunogenicity of Tn.This work demonstrates that MPLA-Tn-KRN7000 has the potential to be a vaccine candidate and provides a new direction for fully synthetic vaccine design.展开更多
Phosphorylated di-,tri-and tetra-saccharides ofβ-1,2-mannan antigen derived from Candida albicans(C.albicans)cell wall were synthesized and covalently conjugated with keyhole limpet hemocyanin(KLH)and human serum alb...Phosphorylated di-,tri-and tetra-saccharides ofβ-1,2-mannan antigen derived from Candida albicans(C.albicans)cell wall were synthesized and covalently conjugated with keyhole limpet hemocyanin(KLH)and human serum albumin(HSA)via a bifunctional linker under mild conditions.The semi-syntheticβ-1,2-mannoside–KLH conjugates were evaluated for the immunization of BALB/c mice.The ELISA results revealed that all three conjugates could elicit high levels of specific IgG antibodies and the acquired antisera could effectively identify theβ-1,2-mannan epitope.Furthermore,the immunofluorescence and flow cytometry assays also uncovered that the induced antibodies,especially that obtained from immunization withβ-1,2-mannotriose–KLH conjugate(1b),could bind well to fungi cell.Eventually,the structure–immunogenicity relationship analysis ofβ-mannan showed that the length of oligo-β-mannoses had a big impact on their immunogenicity andβ-1,2-mannotriose showed the strongest immunogenicity.The results suggested the great potential ofβ-1,2-mannotriose–KLH conjugate as an antifungal vaccine candidate.展开更多
We construct MUC1 vaccines usingβ-cyclodextrin grafted chitosan(CS-g-CD)as carrier via host-guest interaction.These vaccines based on non-covalent assembling can provoke robust immune responses,including high level o...We construct MUC1 vaccines usingβ-cyclodextrin grafted chitosan(CS-g-CD)as carrier via host-guest interaction.These vaccines based on non-covalent assembling can provoke robust immune responses,including high level of specific antibodies and cytokines.The induced antibodies can specifically recognize tumor cells and mediate cytotoxicity against tumor cells.These results indicate that CS-g-CD with strong immunostimulatory activities can be a straightforward platform for peptide-based vaccine construction.展开更多
基金supported by the grants of National Natural Science Foundation of China (No. 81703803 and 81720108033)Natural Science Foundation of Guangdong Province(No. 2017A030310464),which paid for planning and collection of literature+1 种基金by the Project of Guangzhou University of Chinese Medicine (No. QNYC20190103)Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine (No.2018B030322011),which paid for writing and submitting the article for publication。
文摘Worldwide, colorectal cancer(CRC) is one of the most common malignant tumors, leading to immense social and economic burdens. Currently, the main treatments for CRC include surgery, chemotherapy,radiotherapy and immunotherapy. Despite advances in the diagnosis and treatment of CRC, the prognosis for CRC patients remains poor. Furthermore, the occurrence of side effects and toxicities severely limits the clinical use of these therapies. Therefore, alternative medications with high efficacy but few side effects are needed. An increasing number of modern pharmacological studies and clinical trials have supported the effectiveness of Chinese herbal medicines(CHMs) for the prevention and treatment of CRC.CHMs may be able to effectively reduce the risk of CRC, alleviate the adverse reactions caused by chemotherapy, and prolong the survival time of patients with advanced CRC. Studies of molecular mechanisms have provided deeper insight into the roles of molecules from CHMs in treating CRC. This paper summarizes the current understanding of the use of CHMs for the prevention and treatment of CRC, the main molecular mechanisms involved in these processes, the role of CHMs in modulating chemotherapyinduced adverse reactions, and CHM's potential role in epigenetic regulation of CRC. The current study provides beneficial information on the use of CHMs for the prevention and treatment of CRC in the clinic,and suggests novel directions for new drug discovery against CRC.
基金the grants of National Natural Science Foundation of China(81720108033,81930114)Science and Technology Projects in Guangzhou(202201011393,202102021196)+2 种基金Project of Traditional Chinese Medicine Bureau of Guangdong Province(20211111,20231234)Key-Area Research and Development Program of Guangdong Province(2020B1111100004)Guangdong Basic and Applied Basic Reuter Foundation(2020B1515130005).
文摘Worldwide,cancer is a growing epidemic that results in large social and economic burdens.Despite advances in current diagnosis and treatment,most of the prognosis in cancer patients remains poor.It is urgent to find alternative therapies with effective cancer prevention and treatment.Chinese herbal medicines(CHMs)have been increasingly used worldwide for cancer prevention and treatment due to their privileged properties.CHMs are useful in the suppression of various types of cancers through different mechanisms of action.Non-coding RNAs(ncRNAs),including microRNAs,long non-coding RNAs and circular RNAs,are closely involved in the cancer progression and development.Regulation of ncRNAs in tumor cells may be a useful pharmacological strategy for the cancer prevention and treatment.Substantial evidence exists that various phytochemicals from CHMs exert potent anticarcinogenic effects by regulating ncRNAs-related targets and signaling pathways.Herein,the purpose of this paper is to conclude the current understanding of phytochemicals from CHMs in ncRNAs-mediated cancer suppression and the molecular mechanisms.This review will help to provide beneficial clues related to the clinical use of CHMs in the cancer prevention and treatment and further promote new drug discovery against cancer.
基金The Youth Innovation Promotion Association of CAS(2015281)National Natural Science Foundation of China(NSFC Accession No.31471857 and 31672132)+1 种基金Science and Technology Service Network Initiative of CAS(KFJ-STSZDTP-025)Grape Breeding Project of Ningxia(NXNYYZ201502)supported this work.
文摘Vitis amurensis is a wild Vitis plant that can withstand extreme cold temperatures.However,the accumulation of metabolites during cold acclimation(CA)in V.amurensis remains largely unknown.In this study,plantlets of V.amurensis and V.vinifera cv.Muscat of Hamburg were treated at 4℃ for 24 and 72 h,and changes of metabolites in leaves were detected by gas chromatography coupled with time-of-flight mass spectrometry.Most of the identified metabolites,including carbohydrates,amino acids,and organic acids,accumulated in the two types of grape after CA.Galactinol,raffinose,fructose,mannose,glycine,and ascorbate were continuously induced by cold in V.amurensis,but not in Muscat of Hamburg.Twelve metabolites,including isoleucine,valine,proline,2-oxoglutarate,and putrescine,increased in V.amurensis during CA.More galactinol,ascorbate,2-oxoglutarate,and putrescine,accumulated in V.amurensis,but not in Muscat of Hamburg,during CA,which may be responsible for the excellent cold tolerance in V.amurensis.The expression levels of the genes encodingβ-amylase(BAMY),galactinol synthase(GolS),and raffinose synthase(RafS)were evaluated by quantitative reverse transcription-PCR.The expression BAMY(VIT_02s0012 g00170)and RafS(VIT_05s0077 g00840)were primarily responsible for the accumulation of maltose and raffinose,respectively.The accumulation of galactinol was attributed to different members of GolS in the two grapes.In conclusion,these results show the inherent differences in metabolites between V.amurensis and V.vinifera under CA.
基金supported by the National Natural Science Foundation of China(Nos.81703326 and 81973177 for Bin Yu,and 81773580 for Guochao Liao)China Postdoctoral Science Foundation(Nos.2018M630840 and 2019T120641 for Bin Yu)+2 种基金the Open Fund of State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,China(No.KF-GN-201902 for Bin Yu)Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine(No.2018B030322011 for Guochao Liao,China)Guangdong Province Higher Vocational Colleges and Schools Pearl River Scholar Funded Scheme(No.Guochao Liao,2019,China)
文摘Blocking the MDM2/X-P53 protein-protein interaction has been widely recognized as an attractive therapeutic strategy for the treatment of cancers.Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2-P53 interaction in 1996,SAR405838,NVP-CGM097,MK-8242,RG7112,RG7388,DS-3032 b,and AMG232 currently undergo clinical evaluation for cancer therapy.This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera(PROTAC)degraders with a particular focus on how these inhibitors or degraders are identified from starting points,strategies employed,structure-activity relationship(SAR)studies,binding modes or co-crystal structures,biochemical data,mechanistic studies,and preclinical/clinical studies.Moreover,we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition,acquired resistance and toxicity of P53 activation as well as future directions.
基金the financial support from the National Natural Science Foundation of China (Nos. 81703326, 81973177,81773580 and 81802130)China Postdoctoral Science Foundation(Nos. 2018M630840 and 2019T120641)+1 种基金the Open Project of State Key Laboratory of Natural Medicines (No. SKLNMKF202005,China)Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine (No. 2018B030322011, China)。
文摘Natural products generally fall into the biologically relevant chemical space and always possess novel biological activities, thus making them a rich source of lead compounds for new drug discovery. With the recent technological advances, natural product-based drug discovery is now reaching a new era. Natural products have also shown promise in epigenetic drug discovery, some of them have advanced into clinical trials or are presently being used in clinic. The histone lysine specific demethylase1(LSD1), an important class of histone demethylases, has fundamental roles in the development of various pathological conditions. Targeting LSD1 has been recognized as a promising therapeutic option for cancer treatment. Notably, some natural products with different chemotypes including protoberberine alkaloids, flavones, polyphenols, and cyclic peptides have shown effectiveness against LSD1. These natural products provide novel scaffolds for developing new LSD1 inhibitors. In this review, we mainly discuss the identification of natural LSD1 inhibitors, analysis of the co-crystal structures of LSD1/natural product complex, antitumor activity and their modes of action. We also briefly discuss the challenges faced in this field. We believe this review will provide a landscape of natural LSD1 inhibitors.
基金the National Natural Science Foundation of China(No.81874333)the Key Laboratory of Guangdong Drug Administration(2021ZDB03)the Guangdong Basic and Applied Basic Research Foundation(No.2020B1515130005).
文摘Cibotium barometz(Linn.)J.Sm.,a tree fern in the Dicksoniaceae family,is an economically important industrial exported plant in China and widely used in Traditional Chinese Medicine.C.barometz produces a range of bioactive triterpenes and their metabolites.However,the biosynthetic pathway of triterpenes in C.barometz remains unknown.To clarify the origin of diverse triterpenes in C.barometz,we conducted de novo transcriptome sequencing and analysis of C.barometz rhizomes and leaves to identify the candidate genes involved in C.barometz triterpene biosynthesis.Three C.barometz triterpene synthases(CbTSs)candidate genes were obtained.All of them were highly expressed in C.barometz rhizomes,consisting of the accumulation pattern of triterpenes in C.barometz.To characterize the function of these CbTSs,we constructed a squalene-and oxidosqualene-overproducing yeast chassis by overexpressing all the enzymes in the MVA pathway under the control of GAL-regulated promoter and disrupted the GAL80 gene in Saccharomyces cerevisiae simultaneously.Heterologous expressing CbTS1,CbTS2,and CbTS3 in engineering yeast strain produced cycloartenol,dammaradiene,and diploptene,respectively.Phylogenetic analysis revealed that CbTS1 belongs to oxidosqualene cyclase,while CbTS2 and CbTS3 belong to squalene cyclase.These results decipher enzymatic mechanisms underlying the origin of diverse triterpene in C.barometz.
基金This study was supported by the grants of National Natural Science Foundation of China(30902009)the Key Scientific and Technological Innovation Programs of Higher Education Institutions in Guangdong(CXZD1121).
文摘Borneol is a traditional Chinese medicine that can promote drug absorption from the gastrointestinal tract and distribution to the brain.However,stomach irritation may occur when high doses of borneol are used.In the present work,gastrodin,the main bioactive ingredient of the traditional Chinese drug“Tianma”(Rhizoma Gastrodiae)was used as a model drug to explore reasonable application of borneol.Sustained-release solid dispersions(SRSDs)for co-loading gastrodin and borneol were prepared using ethylcellulose as a sustained release matrix and hydroxy-propyl methylcellulose as a retarder.The dispersion state of drug within the SRSDs was analyzed by using scanning electron microscopy,differential scanning calorimetry,and powder X-ray diffractometry.The results indicated that both gastrodin and borneol were molecularly dispersed in an amorphous form.Assay of in vitro drug release demonstrated that the dissolution profiles of gastrodin and borneol from the SRSDs both fitted the Higuchi model.Subsequently,gastric mucosa irritation and the brain targeting of the SRSDs were evaluated.Compared with the free mixture of gastrodin and borneol,brain targeting of SRSDs was slightly weaker(brain targeting index:1.83 vs.2.09),but stomach irritation obviously reduced.Sustained-release technology can be used to reduce stomach irritation caused by borneol while preserving sufficient transport capacity for oral brain-targeting drug delivery.
基金supported by the National Natural Science Foundation of China(No.81503224)Guangdong Key Laboratory for translational Cancer research of Chinese Medicine(No.2018B030322011)+1 种基金Department of education of Guangdong Province(No.2016KZD-XM031)Science and Technology Project of Guangzhou City(No.201707010467)
文摘Four new 3,4-seco-labdane diterpenoids,nudiflopenes J-M,were isolated from the leaves of Callicarpa nudiflora along with six known compounds.The structures of these diterpenoids were determined by comprehensive spectroscopic analysis.All the isolated compounds were evaluated for their inhibitory effects on NO production in LPS-stimulated RPMs and RAW264.7 cells.The results suggest that nudiflopenes J-M and other four known compounds showed significant inhibitory effects against NO production comparable to the positive control dexamethasone.
基金the Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine(No.20188030322011)the National Natural Science Foundation of China(No.81773580)。
文摘Herein,we firstly developed a non-covalent glycosylated gold nanoparticles/peptides nanovaccine which is assembled byβ-cyclodextrin(β-CD)based host-guest recognitions.This nanovaccine can generate significant titers of antibodies and improve the therapeutic effect against melanoma,suggesting the immunogenicity of peptide antigens can be improved by loading with this carrier.The novel vaccine carrier provides a platform for the transport of various antigens especially T cell-independent antigens.
基金supported by the National Natural Science Foundation of China(Nos.81773580,82003594)Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme to Guochao Liao(2019)+1 种基金the Department of education of Guangdong Province,China(No.2020KZDZX1057)the Science and Technology Planning Program of Guangzhou City,China(No.202008040004)。
文摘A facile and efficient strategy was established for the construction of RC-529 and its derivatives.Four conjugates of RC-529 derivatives with Tn antigen were synthesized and all elicited strong and T celldependent immune responses in mice without requiring external adjuvants.In addition,all antisera induced by these conjugates could specifically recognize,bind to and kill Tn-overexpressing cancer cells.Thus,RC-529 shows promise as a useful platform for the development of new vaccine carriers with self-adjuvanting properties for the treatment of cancer.Moreover,preliminary structure-activity relationship analysis provides convincing support for further optimization of,and additional investigation into RC-529.
基金Department of Science and Technology of Guangdong Province for financially supporting Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseasefunded by The Science and Technology Development Fund,Macao SAR(project code 0017/2018/A1,0002/2019/APDChina)。
文摘Inhibitor of nuclear factor kappa-B kinase subunit beta(IKKβ)is one of important kinases in inflammation to phosphorylate inhibitor of nuclear factor kappa-B(IκBα)and then activate nuclear factor kappa-B(NF-κB).Inhibition of IKKβhas been a therapeutic strategy for inflammatory and autoimmune diseases.Here we report that IKKβis constitutively activated in healthy donors and healthy Ikkβ^(C46A)(cysteine 46 mutated to alanine)knock-in mice although they possess intensive IKKβ-IκBα-NF-κB signaling activation.These indicate that IKKβactivation probably plays homeostatic role instead of causing inflammation.Compared to IkkβWTlittermates,lipopolysaccharides(LPS)could induce high mortality rate in Ikkβ^(C46A) mice which is correlated to breaking the homeostasis by intensively activating p-IκBα-NF-κB signaling and inhibiting phosphorylation of 5’adenosine monophosphate-activated protein kinase(p-AMPK)expression.We then demonstrated that IKKβkinase domain(KD)phosphorylates AMPKa1 via interacting with residues Thr183,Ser184,and Thr388,while IKKβhelix-loop-helix motifs is essential to phosphorylate IκBαaccording to the previous reports.Kinase assay further demonstrated that IKKβsimultaneously catalyzes phosphorylation of AMPK and IκBαto mediate homeostasis.Accordingly,activation of AMPK rather than inhibition of IKKβcould substantially rescue LPS-induced mortality in Ikkβ^(C46A) mice by rebuilding the homeostasis.We conclude that IKKβactivates AMPK to restrict inflammation and IKKβmediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα.
基金the National Natural Science Foundation of China No.81874333the Guangdong Foundation for Basic and Applied Basic Research No.2020A1515010926.
文摘Anemarrhena asphodeloides is an immensely popular medicinal herb in China,which contains an abundant of mangiferin.As an important bioactive xanthone C-glycoside,mangiferin possesses a variety of pharmacological activities and is derived from the cyclization reaction of a benzophenone C-glycoside(maclurin).Biosyntheti-cally,C-glycosyltransferases are critical for the formation of benzophenone C-glycosides.However,the benzo-phenone C-glycosyltransferases from Anemarrhena asphodeloides have not been discovered.Herein,a promiscuous C-glycosyltransferase(AaCGT)was identified from Anemarrhena asphodeloides.It was able to catalyze efficiently mono-C-glycosylation of benzophenone,together with di-C-glycosylation of dihydrochalcone.It also exhibited the weak O-glycosylation or potent S-glycosylation capacities toward 12 other types of flavonoid scaffolds and a simple aromatic compound with–SH group.Homology modeling and mutagenesis experiments revealed that the glycosylation reaction of AaCGT was initiated by the conserved residue H23 as the catalytic base.Three critical residues H356,W359 and D380 were involved in the recognition of sugar donor through hydrogen-bonding interactions.In particular,the double mutant of F94W/L378M led to an unexpected enzy-matic conversion of mono-C-to di-C-glycosylation.This study highlights the important value of AaCGT as a potential biocatalyst for efficiently synthesizing high-value C-glycosides.
基金Financial supports from the National Natural Science Foundation of China(Nos.81773580,82003594)Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme(No.Guochao Liao,2019,China)+4 种基金the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund(Guangdong-Hong Kong-Macao Joint La,No.2020B1212030006,China)the Department of Education of Guangdong Province,China(Nos.2020KZDZX1057,2020KQNCX016)The Department of Science and Technology of Guangdong Province,China(Grant No.2020A1111340003)Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine(No.2018B030322011,China)the postgraduate research and innovation project of Guangzhou University of Chinese Medicine.We thank Dr.Shikun Dai(the Equipment Public Service Center,SCSIO.CAS)for assistance in the MALDI-TOF mass spectrometric analyses.
文摘We present a new strategy for self-adjuvanting vaccine development that has different types of covalently-linked immunostimulants as the carrier molecule.Using Tn antigen as the model,a three-component vaccine(MPLA-Tn-KRN7000)containing the TLR4 ligand MPLA and the iNKT cell agonist KRN7000 was designed and synthesized.This expands fully synthetic self-adjuvanting vaccine studies that use a single carrier to one with two different types of carriers.The corresponding two-component conjugate vaccines Tn-MPLA,Tn-KRN7000 and Tn-CRM197 were also synthesized,as controls.The immunological evaluation found that MPLA-Tn-KRN7000 elicits robust Tn-specific and T cell-dependent immunity.The antibodies specifically recognized,bound to and exhibited complement-dependent cytotoxicity against Tn-positive cancer cells.In addition,MPLA-Tn-KRN7000 increased the survival rate and survival time of tumor-challenged mice,and surviving mice reject further tumor attacks without any additional treatment.Compared to the glycoprotein vaccine Tn-CRM197,the two-component conjugate vaccines,Tn-MPLA and Tn-KRN7000,and the physical mixture of Tn-MPLA and Tn-KRN7000,MPLA-Tn-KRN7000 showed the most effect at combating tumor cells both in vitro and in vivo.The comparison of immunological studies in wild-type and TLR4 knockout mice,along with the test of binding affinity to CD1d protein suggests that the covalently linked MPLA-KRN7000 immunostimulant induces a synergistic activation of TLR4 and iNKT cell that improves the immunogenicity of Tn.This work demonstrates that MPLA-Tn-KRN7000 has the potential to be a vaccine candidate and provides a new direction for fully synthetic vaccine design.
基金financially supported by the Natural Science Foundation of China (Nos. 21502223, 81773580)
文摘Phosphorylated di-,tri-and tetra-saccharides ofβ-1,2-mannan antigen derived from Candida albicans(C.albicans)cell wall were synthesized and covalently conjugated with keyhole limpet hemocyanin(KLH)and human serum albumin(HSA)via a bifunctional linker under mild conditions.The semi-syntheticβ-1,2-mannoside–KLH conjugates were evaluated for the immunization of BALB/c mice.The ELISA results revealed that all three conjugates could elicit high levels of specific IgG antibodies and the acquired antisera could effectively identify theβ-1,2-mannan epitope.Furthermore,the immunofluorescence and flow cytometry assays also uncovered that the induced antibodies,especially that obtained from immunization withβ-1,2-mannotriose–KLH conjugate(1b),could bind well to fungi cell.Eventually,the structure–immunogenicity relationship analysis ofβ-mannan showed that the length of oligo-β-mannoses had a big impact on their immunogenicity andβ-1,2-mannotriose showed the strongest immunogenicity.The results suggested the great potential ofβ-1,2-mannotriose–KLH conjugate as an antifungal vaccine candidate.
基金supported by the National Natural Science Foundation of China(Nos.21907038 and 32000904)Natural Science Foundation of Jiangsu Province(No.BK20200601)+5 种基金National Postdoctoral Program for Innovative Talents of China(No.BX20200153)China Postdoctoral Science Foundation(Nos.2018M632227 and2021M691293)the Social Development Key Project of Jiangsu Province(No.BE2019632)the Health and Family Planning Commission of Wuxi,China(No.Z202005)Suzhou People’s Livelihood Science and Technology Project,China(No.SYS2018100)supported by the 111 Project(No.111-2-06)。
文摘We construct MUC1 vaccines usingβ-cyclodextrin grafted chitosan(CS-g-CD)as carrier via host-guest interaction.These vaccines based on non-covalent assembling can provoke robust immune responses,including high level of specific antibodies and cytokines.The induced antibodies can specifically recognize tumor cells and mediate cytotoxicity against tumor cells.These results indicate that CS-g-CD with strong immunostimulatory activities can be a straightforward platform for peptide-based vaccine construction.