目的 探究驱动蛋白家族成员2A(kinesin family member 2A,KIF2A)对肝癌细胞5-FU耐药的作用及其作用机制。方法 采用浓度梯度递增联合大剂量间断冲击的方法诱导肝癌细胞BEL7402对5-FU耐药,以构建耐药株BEL7402/5-FU。采用慢病毒技术构建K...目的 探究驱动蛋白家族成员2A(kinesin family member 2A,KIF2A)对肝癌细胞5-FU耐药的作用及其作用机制。方法 采用浓度梯度递增联合大剂量间断冲击的方法诱导肝癌细胞BEL7402对5-FU耐药,以构建耐药株BEL7402/5-FU。采用慢病毒技术构建KIF2A沉默的BEL7402/5-FU细胞。用Notch1/Hes1信号通路激动剂丙戊酸(valproic acid,VPA)对KIF2A沉默的BEL7402/5-FU细胞进行干预。用CCK-8实验、蛋白印迹法、免疫荧光、流式细胞术检测细胞活性、细胞凋亡率、KIF2A、cleaved-caspase-3、Notch1和Hes1的蛋白表达。结果 BEL7402/5-FU细胞具有强5-FU耐药性,其IC_(50)为344.2μmol/L,是BEL7402细胞的92倍(IC_(50)=3.730μmol/L)。与BEL7402细胞比较,BEL7402/5-FU细胞中KIF2A蛋白表达明显增加(P<0.001);与si-NC组比较,si-KIF2A组BEL7402/5-FU细胞活性明显下降(P<0.001)、凋亡率和cleaved-caspase-3蛋白表达明显增加(P<0.001),另外Notch1和Hes1蛋白表达明显减少(P<0.001);与si-NC+5-FU组比较,si-KIF2A+5-FU组BEL7402/5-FU细胞活性显著下降(P<0.001)、凋亡率显著增加(P<0.001);与si-KIF2A+5-FU组比较,si-KIF2A+5-FU+VPA组BEL7402/5-FU细胞活性明显提高(P<0.001)、凋亡率显著降低(P<0.001)、Notch1和Hes1蛋白表达量显著增加(P<0.001)。结论 KIF2A的沉默通过抑制Notch1/Hes1信号通路活性减弱BEL7402/5-FU细胞对5-FU的化疗耐药性。展开更多
Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environme...Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.展开更多
Objective:Small cell lung cancer(SCLC)is commonly recognized as the most fatal lung cancer type.Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers,their benefits are limite...Objective:Small cell lung cancer(SCLC)is commonly recognized as the most fatal lung cancer type.Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers,their benefits are limited to a minority of patients with SCLC.In the present study,novel indicators for predicting the outcomes and molecular targets for SCLC treatment were elucidated.Methods:We conducted bioinformatics analysis to identify the key genes associated with tumor-infiltrating lymphocytes in SCLC.The functional role of the key gene identified in SCLC was determined both in vitro and in vivo.Results:A significant correlation was observed between patient survival and CD56dim natural killer(NK)cell proportion.Furthermore,we noted that the hub gene ubiquitin-specific protease 1(USP1)is closely correlated with both CD56dim NK cells and overall survival in SCLC.Bioinformatics analysis revealed that USP1 is upregulated in SCLC.In addition,gene set enrichment analysis revealed that USP1 overexpression hinders NK cell-mediated immune responses.By co-cultivating NK-92 cells with SCLC cells,we demonstrated that NK cell cytotoxicity against SCLC could be improved either via USP1 knock-down or pharmacological inhibition.Furthermore,using a nude-mice xenograft tumor model,we noted that USP1 inhibition effectively suppressed tumor proliferation and increased the expression of NK cell-associated markers.Conclusions:Our study findings highlight the importance of NK cells in regulating SCLC.USP1 overexpression can inhibit NK cell-mediated immunity;therefore,USP1 may serve not only as a prognostic biomarker but also as a potential molecular target of SCLC therapy.展开更多
BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly aggressive cancer with poor prognosis.When it metastasizes to the liver,treatment options become particularly limited and challenging.Current treatment opti...BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly aggressive cancer with poor prognosis.When it metastasizes to the liver,treatment options become particularly limited and challenging.Current treatment options for liver metastatic PDAC are limited,and chemotherapy alone often proves insufficient.Immunotherapy,particularly programmed cell death 1(PD-1)inhibitors like sintilimab,shows potential efficacy for various cancers but has limited reports on PDAC.This study compares the efficacy and safety of sintilimab plus S-1 and gemcitabine vs S-1 and gemcitabine alone in liver metastatic PDAC.AIM To explore the feasibility and effectiveness of combined PD-1 inhibitor sintilimab and S-1 and gemcitabine(combination group)vs S-1 and gemcitabine used alone(chemotherapy group)for treating liver metastatic pancreatic adenocarcinoma.METHODS Eligible patients were those with only liver metastatic PDAC,an Eastern Cooperative Oncology Group performance status of 0-1,adequate organ and marrow functions,and no prior anticancer therapy.Participants in the combination group received intravenous sintilimab 200 mg every 3 weeks,oral S-140 mg/m²twice daily on days 1-14 of a 21-day cycle,and intravenous gemcitabine 1000 mg/m²on days 1 and 8 of the same cycle for up to eight cycles or until disease progression,death,or unacceptable toxicity.Participants in the chemotherapy group received oral S-140 mg/m²twice daily on days 1-14 of a 21-day cycle and intravenous gemcitabine 1000 mg/m²on days 1 and 8 of the same cycle for up to eight cycles.Between June 2020 and December 2021,66 participants were enrolled,with 32 receiving the combination treatment and 34 receiving chemotherapy alone.RESULTS The group receiving the combined therapy exhibited a markedly prolonged median overall survival(18.8 months compared to 10.3 months,P<0.05)and progression-free survival(9.6 months vs 5.4 months,P<0.05).compared to the chemotherapy group.The incidence of severe adverse events did not differ significantly between the two groups(P>0.05).CONCLUSION The combination of PD-1 inhibitor sintilimab with S-1 and gemcitabine demonstrated effectiveness and safety for treating liver metastatic PDAC,meriting further investigation.展开更多
This editorial discusses the findings of Elbarky et al on the role of selenoprotein P1(SEPP1)in pediatric obesity and insulin resistance.Their study uncovered si-gnificantly lower SEPP1 Levels in children who were obe...This editorial discusses the findings of Elbarky et al on the role of selenoprotein P1(SEPP1)in pediatric obesity and insulin resistance.Their study uncovered si-gnificantly lower SEPP1 Levels in children who were obese compared with hea-lthy peers,demonstrating a negative correlation between SEPP1 levels and mea-sures of adiposity and insulin resistance.These findings suggest that SEPP1 is a biomarker useful in the early identification of insulin resistance in pediatric populations.This editorial emphasizes the clinical implications of the study and calls for further research to validate and explore the role of SEPP1 in metabolic health.展开更多
文摘目的 探究驱动蛋白家族成员2A(kinesin family member 2A,KIF2A)对肝癌细胞5-FU耐药的作用及其作用机制。方法 采用浓度梯度递增联合大剂量间断冲击的方法诱导肝癌细胞BEL7402对5-FU耐药,以构建耐药株BEL7402/5-FU。采用慢病毒技术构建KIF2A沉默的BEL7402/5-FU细胞。用Notch1/Hes1信号通路激动剂丙戊酸(valproic acid,VPA)对KIF2A沉默的BEL7402/5-FU细胞进行干预。用CCK-8实验、蛋白印迹法、免疫荧光、流式细胞术检测细胞活性、细胞凋亡率、KIF2A、cleaved-caspase-3、Notch1和Hes1的蛋白表达。结果 BEL7402/5-FU细胞具有强5-FU耐药性,其IC_(50)为344.2μmol/L,是BEL7402细胞的92倍(IC_(50)=3.730μmol/L)。与BEL7402细胞比较,BEL7402/5-FU细胞中KIF2A蛋白表达明显增加(P<0.001);与si-NC组比较,si-KIF2A组BEL7402/5-FU细胞活性明显下降(P<0.001)、凋亡率和cleaved-caspase-3蛋白表达明显增加(P<0.001),另外Notch1和Hes1蛋白表达明显减少(P<0.001);与si-NC+5-FU组比较,si-KIF2A+5-FU组BEL7402/5-FU细胞活性显著下降(P<0.001)、凋亡率显著增加(P<0.001);与si-KIF2A+5-FU组比较,si-KIF2A+5-FU+VPA组BEL7402/5-FU细胞活性明显提高(P<0.001)、凋亡率显著降低(P<0.001)、Notch1和Hes1蛋白表达量显著增加(P<0.001)。结论 KIF2A的沉默通过抑制Notch1/Hes1信号通路活性减弱BEL7402/5-FU细胞对5-FU的化疗耐药性。
基金supported by the National Natural Science Foundation of China,Nos.82271283(to XC),91854115(to JW),31970044(to JW)the Natural Science Foundation of Beijing,No.7202001(to XC)the Scientific Research Project of Beijing Educational Committee,No.KM202010005022(to XC)。
文摘Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.
基金supported by grants from the Dongguan Science and Technology of Social Development Program(No.20231800940192)the Talent Development Foundation of the First Dongguan Affiliated Hospital of Guangdong Medical University(No.PU2023002).
文摘Objective:Small cell lung cancer(SCLC)is commonly recognized as the most fatal lung cancer type.Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers,their benefits are limited to a minority of patients with SCLC.In the present study,novel indicators for predicting the outcomes and molecular targets for SCLC treatment were elucidated.Methods:We conducted bioinformatics analysis to identify the key genes associated with tumor-infiltrating lymphocytes in SCLC.The functional role of the key gene identified in SCLC was determined both in vitro and in vivo.Results:A significant correlation was observed between patient survival and CD56dim natural killer(NK)cell proportion.Furthermore,we noted that the hub gene ubiquitin-specific protease 1(USP1)is closely correlated with both CD56dim NK cells and overall survival in SCLC.Bioinformatics analysis revealed that USP1 is upregulated in SCLC.In addition,gene set enrichment analysis revealed that USP1 overexpression hinders NK cell-mediated immune responses.By co-cultivating NK-92 cells with SCLC cells,we demonstrated that NK cell cytotoxicity against SCLC could be improved either via USP1 knock-down or pharmacological inhibition.Furthermore,using a nude-mice xenograft tumor model,we noted that USP1 inhibition effectively suppressed tumor proliferation and increased the expression of NK cell-associated markers.Conclusions:Our study findings highlight the importance of NK cells in regulating SCLC.USP1 overexpression can inhibit NK cell-mediated immunity;therefore,USP1 may serve not only as a prognostic biomarker but also as a potential molecular target of SCLC therapy.
文摘BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly aggressive cancer with poor prognosis.When it metastasizes to the liver,treatment options become particularly limited and challenging.Current treatment options for liver metastatic PDAC are limited,and chemotherapy alone often proves insufficient.Immunotherapy,particularly programmed cell death 1(PD-1)inhibitors like sintilimab,shows potential efficacy for various cancers but has limited reports on PDAC.This study compares the efficacy and safety of sintilimab plus S-1 and gemcitabine vs S-1 and gemcitabine alone in liver metastatic PDAC.AIM To explore the feasibility and effectiveness of combined PD-1 inhibitor sintilimab and S-1 and gemcitabine(combination group)vs S-1 and gemcitabine used alone(chemotherapy group)for treating liver metastatic pancreatic adenocarcinoma.METHODS Eligible patients were those with only liver metastatic PDAC,an Eastern Cooperative Oncology Group performance status of 0-1,adequate organ and marrow functions,and no prior anticancer therapy.Participants in the combination group received intravenous sintilimab 200 mg every 3 weeks,oral S-140 mg/m²twice daily on days 1-14 of a 21-day cycle,and intravenous gemcitabine 1000 mg/m²on days 1 and 8 of the same cycle for up to eight cycles or until disease progression,death,or unacceptable toxicity.Participants in the chemotherapy group received oral S-140 mg/m²twice daily on days 1-14 of a 21-day cycle and intravenous gemcitabine 1000 mg/m²on days 1 and 8 of the same cycle for up to eight cycles.Between June 2020 and December 2021,66 participants were enrolled,with 32 receiving the combination treatment and 34 receiving chemotherapy alone.RESULTS The group receiving the combined therapy exhibited a markedly prolonged median overall survival(18.8 months compared to 10.3 months,P<0.05)and progression-free survival(9.6 months vs 5.4 months,P<0.05).compared to the chemotherapy group.The incidence of severe adverse events did not differ significantly between the two groups(P>0.05).CONCLUSION The combination of PD-1 inhibitor sintilimab with S-1 and gemcitabine demonstrated effectiveness and safety for treating liver metastatic PDAC,meriting further investigation.
文摘This editorial discusses the findings of Elbarky et al on the role of selenoprotein P1(SEPP1)in pediatric obesity and insulin resistance.Their study uncovered si-gnificantly lower SEPP1 Levels in children who were obese compared with hea-lthy peers,demonstrating a negative correlation between SEPP1 levels and mea-sures of adiposity and insulin resistance.These findings suggest that SEPP1 is a biomarker useful in the early identification of insulin resistance in pediatric populations.This editorial emphasizes the clinical implications of the study and calls for further research to validate and explore the role of SEPP1 in metabolic health.
