Dear Editor,Ferroptosis,an iron-dependent form of cell death driven by overwhelming lipid peroxidation,represents a vulnerability in cancers,and therapeutic strategies to further potentiate ferroptosis hold great pote...Dear Editor,Ferroptosis,an iron-dependent form of cell death driven by overwhelming lipid peroxidation,represents a vulnerability in cancers,and therapeutic strategies to further potentiate ferroptosis hold great potential for melanoma treatment.展开更多
BACKGROUND The overexpression of the MYC gene plays an important role in the occurrence,development and evolution of colorectal cancer(CRC).Bromodomain and extraterminal domain(BET)inhibitors can decrease the function...BACKGROUND The overexpression of the MYC gene plays an important role in the occurrence,development and evolution of colorectal cancer(CRC).Bromodomain and extraterminal domain(BET)inhibitors can decrease the function BET by recognizing acetylated lysine residues,thereby downregulating the expression of MYC.AIM To investigate the inhibitory effect and mechanism of a BET inhibitor on CRC cells.METHODS The effect of the BET inhibitor JAB-8263 on the proliferation of various CRC cell lines was studied by CellTiter-Glo method and colony formation assay.The effect of JAB-8263 on the cell cycle and apoptosis of CRC cells was studied by propidium iodide staining and Annexin V/propidium iodide flow assay,respectively.The effect of JAB-8263 on the expression of c-MYC,p21 and p16 in CRC cells was detected by western blotting assay.The anti-tumor effect of JAB-8263 on CRC cells in vivo and evaluation of the safety of the compound was predicted by constructing a CRC cell animal tumor model.RESULTS JAB-8263 dose-dependently suppressed CRC cell proliferation and colony formation in vitro.The MYC signaling pathway was dose-dependently inhibited by JAB-8263 in human CRC cell lines.JAB-8263 dose-dependently induced cell cycle arrest and apoptosis in the MC38 cell line.SW837 xenograft model was treated with JAB-8263(0.3 mg/kg for 29 d),and the average tumor volume was significantly decreased compared to the vehicle control group(P<0.001).The MC38 syngeneic murine model was treated with JAB-8263(0.2 mg/kg for 29 d),and the average tumor volume was significantly decreased compared to the vehicle control group(P=0.003).CONCLUSION BET could be a potential effective drug target for suppressing CRC growth,and the BET inhibitor JAB-8263 can effectively suppress c-MYC expression and exert anti-tumor activity in CRC models.展开更多
组蛋白赖氨酸乙酰化的识别是组蛋白乙酰化参与表观遗传调控的关键步骤,乙酰化的组蛋白赖氨酸可以被bromodomains(BRDs)结构域所特异性的识别,从而招募染色质调控因子到特定区域,协同完成基因表达调控。其中作用于bromodomain and extra-...组蛋白赖氨酸乙酰化的识别是组蛋白乙酰化参与表观遗传调控的关键步骤,乙酰化的组蛋白赖氨酸可以被bromodomains(BRDs)结构域所特异性的识别,从而招募染色质调控因子到特定区域,协同完成基因表达调控。其中作用于bromodomain and extra-terminal(BET)蛋白家族的BRD结构域的小分子抑制剂在抗炎和抗肿瘤方面显示出巨大的潜力。本文通过对与BET bromodomain靶点相关的疾病、BET bromodomain结构、BET bromodomain小分子抑制剂的化学结构分类及其构效关系等多方面进行总结,为设计和开发高活性的BET bromodomain小分子抑制剂提供参考依据。展开更多
Periodontitis is a frequent chronic inflammatory disorder destroying periodontium.Recent studies have revealed the role of bromodomain and extraterminal domain inhibitor(BETi)and microRNA(miR)-130a in regulating macro...Periodontitis is a frequent chronic inflammatory disorder destroying periodontium.Recent studies have revealed the role of bromodomain and extraterminal domain inhibitor(BETi)and microRNA(miR)-130a in regulating macrophage polarization and pro-inflammatory response.However,little is known about whether apabetalone(a novel BETi)and miR-130a are correlated with chronic inflammatory state in periodontitis by regulating macrophage polarization.Here murine RAW264.7 macrophages were applied as an in vitro inflammatory model.After treatment with Porphyromonas gingivalis-derived lipopolysaccharide(Pg LPS)and apabetalone,the expression of macrophage M1 polarization markers and inflammatory cytokines was assessed using real-time PCR,western blot,and enzyme-linked immuno sorbent assay(ELISA).MiR-130a level was assessed using real-time PCR,and the target gene was identified using dual luciferase reporter assay.We demonstrated that apabetalone repressed Pg LPS-induced macrophage M1 polarization in a dose-dependent manner,as evidenced by decreased expression of inducible nitric oxide synthase(iNOS),CD86,and pro-inflammatory cytokines,and increased expression of Arg-1 and CD206.Mechanistically,Pg LPS increased miR-130a expression in macrophages,whereas apabetalone treatment repressed the effect.Functionally,forced expression of miR-130a promoted macrophage M1 polarization,and signal transducer and activator of transcription(STAT)-3 was the direct target gene of miR-130a in the process.Taken together,apabetalone decreases Pg LPS-induced macrophage M1 polarization via regulating miR-130a-3p/STAT3 axis,and may be a promising target for the clinical management of periodontitis.展开更多
The N-terminal domain of heat shock protein 90(Hsp90~N) is responsible for the catalytic activity of Hsp90.The reported inhibitors of Hsp90 bind to this domain and would inhibit tumor growth and progression. Here,we s...The N-terminal domain of heat shock protein 90(Hsp90~N) is responsible for the catalytic activity of Hsp90.The reported inhibitors of Hsp90 bind to this domain and would inhibit tumor growth and progression. Here,we synthesized FS23, a small molecule inhibitor of hsp90 and collected X-ray diffraction data of the complex crystal of Hsp90-FS23. High resolution X-ray crystallography shows that FS23 interacted with Hsp90 Nat the nucleotide binding cleft, and this suggests that FS23 may complete with nucleotides to bind to Hsp90~N. The crystal structure and the interaction between Hsp90 Nand FS23 suggest a rational basis for the design of novel antitumor drugs.展开更多
Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibi...Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.展开更多
大豆疫霉根腐病是由大豆疫霉菌(Phytophthora sojae)引起的危害大豆生长的严重病害。课题组前期研究表明具有P-loop结构域的GmPR10(Gene Bank accession no.FJ960440)和具有P-loop、Bet v1结构域的Gly m 4l(Gene Bank accession no.HQ91...大豆疫霉根腐病是由大豆疫霉菌(Phytophthora sojae)引起的危害大豆生长的严重病害。课题组前期研究表明具有P-loop结构域的GmPR10(Gene Bank accession no.FJ960440)和具有P-loop、Bet v1结构域的Gly m 4l(Gene Bank accession no.HQ913577.1)抑制大豆疫霉菌生长,并且过表达GmPR10和Gly m 4l的转基因大豆植株可以提高对大豆疫霉根腐病的抗性。为研究GmPR10和Gly m 4l抑菌机理,本研究利用点突变技术,获得了GmPR10的P-loop结构域突变体(Gly48/Thr48和Gly^51/Arg^51)、Gly m 4l的P-loop结构域突变体(Gly^49/Ile^49和Lys^55/Pro^55)、GmPR10和Gly m 4l的P-loop结构域以及Gly m 4l的Bet v1结构域缺失突变体,并纯化回收相应突变体蛋白,进行体外抑制大豆疫霉菌试验。结果表明,突变或缺失P-loop,Bet v1结构域的GmPR10和Gly m 4l失去了抑制大豆疫霉菌(Race 1)生长的能力,说明P-loop、Bet v 1结构域对GmPR10和Gly m 4l行使抑菌功能至关重要。展开更多
FMS-like tyrosine kinase 3(FLT3) is classified as a type Ⅲ receptor tyrosine kinase, which exerts a key role in regulation of normal hematopoiesis. FLT3 mutation is the most common genetic mutation in acute myeloid l...FMS-like tyrosine kinase 3(FLT3) is classified as a type Ⅲ receptor tyrosine kinase, which exerts a key role in regulation of normal hematopoiesis. FLT3 mutation is the most common genetic mutation in acute myeloid leukemia(AML) and represents an attractive therapeutic target. Targeted therapy with FLT3 inhibitors in AML shows modest promising results in current ongoing clinical trials suggesting the complexity of FLT3 targeting in therapeutics. Importantly, resistance to FLT3 inhibitors may explain the lack of overwhelming response and could obstruct the successful treatment for AML. Here, we summarize the molecular mechanisms of primary resistance and acquired resistance to FLT3 inhibitors and discuss the strategies to circumvent the emergency of drug resistance and to develop novel treatment intervention.展开更多
基金This work was supported by grants from the National Natural Science Foundation of China(82103183,82102803,82272849)the Natural Science Foundation of Hunan Province(2022JJ40767,2021JJ40976)+1 种基金the Natural Science Fund for Outstanding Youths in Hunan Province(2023JJ20093)the National Key Research and Development Program(2022YFC2504700).
文摘Dear Editor,Ferroptosis,an iron-dependent form of cell death driven by overwhelming lipid peroxidation,represents a vulnerability in cancers,and therapeutic strategies to further potentiate ferroptosis hold great potential for melanoma treatment.
基金Supported by the National Natural Science Foundation of China,No.81871317.
文摘BACKGROUND The overexpression of the MYC gene plays an important role in the occurrence,development and evolution of colorectal cancer(CRC).Bromodomain and extraterminal domain(BET)inhibitors can decrease the function BET by recognizing acetylated lysine residues,thereby downregulating the expression of MYC.AIM To investigate the inhibitory effect and mechanism of a BET inhibitor on CRC cells.METHODS The effect of the BET inhibitor JAB-8263 on the proliferation of various CRC cell lines was studied by CellTiter-Glo method and colony formation assay.The effect of JAB-8263 on the cell cycle and apoptosis of CRC cells was studied by propidium iodide staining and Annexin V/propidium iodide flow assay,respectively.The effect of JAB-8263 on the expression of c-MYC,p21 and p16 in CRC cells was detected by western blotting assay.The anti-tumor effect of JAB-8263 on CRC cells in vivo and evaluation of the safety of the compound was predicted by constructing a CRC cell animal tumor model.RESULTS JAB-8263 dose-dependently suppressed CRC cell proliferation and colony formation in vitro.The MYC signaling pathway was dose-dependently inhibited by JAB-8263 in human CRC cell lines.JAB-8263 dose-dependently induced cell cycle arrest and apoptosis in the MC38 cell line.SW837 xenograft model was treated with JAB-8263(0.3 mg/kg for 29 d),and the average tumor volume was significantly decreased compared to the vehicle control group(P<0.001).The MC38 syngeneic murine model was treated with JAB-8263(0.2 mg/kg for 29 d),and the average tumor volume was significantly decreased compared to the vehicle control group(P=0.003).CONCLUSION BET could be a potential effective drug target for suppressing CRC growth,and the BET inhibitor JAB-8263 can effectively suppress c-MYC expression and exert anti-tumor activity in CRC models.
基金This work was supported by the National Natural Science Foundation for Young Scientists of China(Grant No.81901004)the Youth Program Shanghai Municipal Health and Family Planning Commission grant(Grant No.20194Y0227)Shanghai Stomatological Hospital Science Foundation(Grant No.SSDC-2018-02).
文摘Periodontitis is a frequent chronic inflammatory disorder destroying periodontium.Recent studies have revealed the role of bromodomain and extraterminal domain inhibitor(BETi)and microRNA(miR)-130a in regulating macrophage polarization and pro-inflammatory response.However,little is known about whether apabetalone(a novel BETi)and miR-130a are correlated with chronic inflammatory state in periodontitis by regulating macrophage polarization.Here murine RAW264.7 macrophages were applied as an in vitro inflammatory model.After treatment with Porphyromonas gingivalis-derived lipopolysaccharide(Pg LPS)and apabetalone,the expression of macrophage M1 polarization markers and inflammatory cytokines was assessed using real-time PCR,western blot,and enzyme-linked immuno sorbent assay(ELISA).MiR-130a level was assessed using real-time PCR,and the target gene was identified using dual luciferase reporter assay.We demonstrated that apabetalone repressed Pg LPS-induced macrophage M1 polarization in a dose-dependent manner,as evidenced by decreased expression of inducible nitric oxide synthase(iNOS),CD86,and pro-inflammatory cytokines,and increased expression of Arg-1 and CD206.Mechanistically,Pg LPS increased miR-130a expression in macrophages,whereas apabetalone treatment repressed the effect.Functionally,forced expression of miR-130a promoted macrophage M1 polarization,and signal transducer and activator of transcription(STAT)-3 was the direct target gene of miR-130a in the process.Taken together,apabetalone decreases Pg LPS-induced macrophage M1 polarization via regulating miR-130a-3p/STAT3 axis,and may be a promising target for the clinical management of periodontitis.
基金Supported by National Natural Science Foundation of China(No.81402850)the Natural Science Basic Research Plan in Shaanxi Province of China(No.2015JM3114)+1 种基金the Introduced talents Foundation of Xi’an Medical University(No.2015 RCYJ01)the Doctorate Foundation of Xi’an Medical University(No.2015 DOC23)
文摘The N-terminal domain of heat shock protein 90(Hsp90~N) is responsible for the catalytic activity of Hsp90.The reported inhibitors of Hsp90 bind to this domain and would inhibit tumor growth and progression. Here,we synthesized FS23, a small molecule inhibitor of hsp90 and collected X-ray diffraction data of the complex crystal of Hsp90-FS23. High resolution X-ray crystallography shows that FS23 interacted with Hsp90 Nat the nucleotide binding cleft, and this suggests that FS23 may complete with nucleotides to bind to Hsp90~N. The crystal structure and the interaction between Hsp90 Nand FS23 suggest a rational basis for the design of novel antitumor drugs.
基金a Ph D fellowship by FCT-Fundacao para a Ciência Tecnologia (SFRH/BD/135868/2018)(to SSC)。
文摘Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.
文摘大豆疫霉根腐病是由大豆疫霉菌(Phytophthora sojae)引起的危害大豆生长的严重病害。课题组前期研究表明具有P-loop结构域的GmPR10(Gene Bank accession no.FJ960440)和具有P-loop、Bet v1结构域的Gly m 4l(Gene Bank accession no.HQ913577.1)抑制大豆疫霉菌生长,并且过表达GmPR10和Gly m 4l的转基因大豆植株可以提高对大豆疫霉根腐病的抗性。为研究GmPR10和Gly m 4l抑菌机理,本研究利用点突变技术,获得了GmPR10的P-loop结构域突变体(Gly48/Thr48和Gly^51/Arg^51)、Gly m 4l的P-loop结构域突变体(Gly^49/Ile^49和Lys^55/Pro^55)、GmPR10和Gly m 4l的P-loop结构域以及Gly m 4l的Bet v1结构域缺失突变体,并纯化回收相应突变体蛋白,进行体外抑制大豆疫霉菌试验。结果表明,突变或缺失P-loop,Bet v1结构域的GmPR10和Gly m 4l失去了抑制大豆疫霉菌(Race 1)生长的能力,说明P-loop、Bet v 1结构域对GmPR10和Gly m 4l行使抑菌功能至关重要。
基金Supported by the Singapore National Research Foundation and the Ministry of Education under the Research Center of Excellence Program(to Chng WJ)NMRC Clinician-Scientist IRG Grant,No.CNIG11nov38(to Zhou J)+1 种基金supported by NMRC Clinician Scientist Investigator awardsupported by the RNA Biology Center at CSI Singapore,NUS,from funding by the Singapore Ministry of Education’s Tier 3 grants,No.MOE2014-T3-1-006
文摘FMS-like tyrosine kinase 3(FLT3) is classified as a type Ⅲ receptor tyrosine kinase, which exerts a key role in regulation of normal hematopoiesis. FLT3 mutation is the most common genetic mutation in acute myeloid leukemia(AML) and represents an attractive therapeutic target. Targeted therapy with FLT3 inhibitors in AML shows modest promising results in current ongoing clinical trials suggesting the complexity of FLT3 targeting in therapeutics. Importantly, resistance to FLT3 inhibitors may explain the lack of overwhelming response and could obstruct the successful treatment for AML. Here, we summarize the molecular mechanisms of primary resistance and acquired resistance to FLT3 inhibitors and discuss the strategies to circumvent the emergency of drug resistance and to develop novel treatment intervention.
