BACKGROUND Radiotherapy stands as a promising therapeutic modality for colorectal cancer(CRC);yet,the formidable challenge posed by radio-resistance significantly undermines its efficacy in achieving CRC remission.AIM...BACKGROUND Radiotherapy stands as a promising therapeutic modality for colorectal cancer(CRC);yet,the formidable challenge posed by radio-resistance significantly undermines its efficacy in achieving CRC remission.AIM To elucidate the role played by microRNA-298(miR-298)in CRC radio-resistance.METHODS To establish a radio-resistant CRC cell line,HT-29 cells underwent exposure to 5 gray ionizing radiation that was followed by a 7-d recovery period.The quantification of miR-298 levels within CRC cells was conducted through quantitative RT-PCR,and protein expression determination was realized through Western blotting.Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and proliferation by clonogenic assay.Radio-induced apoptosis was discerned through flow cytometry analysis.RESULTS We observed a marked upregulation of miR-298 in radio-resistant CRC cells.MiR-298 emerged as a key determinant of cell survival following radiation exposure,as its overexpression led to a notable reduction in radiation-induced apoptosis.Intriguingly,miR-298 expression exhibited a strong correlation with CRC cell viability.Further investigation unveiled human dual-specificity tyrosine(Y)-regulated kinase 1A(DYRK1A)as miR-298’s direct target.CONCLUSION Taken together,our findings underline the role played by miR-298 in bolstering radio-resistance in CRC cells by means of DYRK1A downregulation,thereby positioning miR-298 as a promising candidate for mitigating radioresistance in CRC.展开更多
Background: Preeclampsia (PE) is still one of the leading causes of maternal/perinatal morbidity/mortality in Nigeria. Imbalance between placenta growth factor (PLGF) and soluble fms-like tyrosine kinase 1 (sFlt1) has...Background: Preeclampsia (PE) is still one of the leading causes of maternal/perinatal morbidity/mortality in Nigeria. Imbalance between placenta growth factor (PLGF) and soluble fms-like tyrosine kinase 1 (sFlt1) has been reportedly present both before and after the manifestation <span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">of </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">PE;however, Nigerian data regarding these angiogenesis-related substances are lacking. We here attempted to determine the maternal serum level of PLGF and sFlt1 and sFlt1/PLGF ratio in PE vs. non-PE women in Lagos State University Teaching Hospital, Nigeria.</span></span></span><span><span><span style="font-family:;" "=""> </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">Methods: An observational cross-sectional study was made on 75 women with PE and 75 age-gestational-age matched women without PE, as case and control, respectively. Levels of sFlt-1, PIGF and the sFlt-1: PIGF ratio was compared between the two. Results: Serum levels of Flt-1 and sFlt1/PIGF ratio were significantly higher in PE patients (6581.86 ± 865.75, and 146.42 ± 92.43) than in the normotensive control (4584.52 ± 1479.6 and 11.60 ± 6.42). PIGF was significantly lower in PE patients (70.14 ± 51.03) than the normotensives (494.06 ± 475.8). There were positive and negative correlation</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">s</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;"> between the sFlt-1 and PLGF respectively and mean arterial blood pressure. Conclusion: Serum sFlt-1, sFlt1/PIGF ratio was significantly higher and PIGF levels </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">were </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">significantly lower in PE than normotensive control in Nigerian population</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">.</span></span></span>展开更多
Objective：To investigate the effects of E7080 and N5-（1-iminoethyl）-L-ornithine dihydrochloride （L-NIO）on colorectal cancer alone and in combination.Methods：HT29 colorectal cancer cell line from Sap Institute wa...Objective：To investigate the effects of E7080 and N5-（1-iminoethyl）-L-ornithine dihydrochloride （L-NIO）on colorectal cancer alone and in combination.Methods：HT29 colorectal cancer cell line from Sap Institute was used.Real-time cell analysis （xCELLigence system） was performed to determine the effects of E7080 and L-NIO on colorectal cell proliferation.While apoptosis was determined with Annexin V staining,and the effect of agents on angiogenesis was determined with chorioallantoic membrane （CAM） model.Results：We found that E7080 has a strong antiproliferative effect with an half maximum inhibition of concentration （IC50） value of 5.60×10-8 mol/L.Also it has been observed that E7080 showed antiangiogenic and apoptotic effects on HT29 colorectal cancer cells.Antiangiogenic scores of E7080 were 1.2,t.0 and 0.6 for 100,10 and 1 nmol/L E7080 concentrations,respectively.Furthermore,apoptosis has been detected in 71％ of HT29 colorectal cancer cells after administration of 100 nmol/L E7080 which may indicate strong apoptotic effect.Meanwhile administration of L-NIO alone did not show any effect,but the combination of E7080 with L-NIO increased the antiproliferative,antiangiogenic and apoptotic effects of E7080.Conclusions：Results of this study indicate that E7080 may be a good choice in treatment of colorectal tumors.Furthermore the increased effects of E7080 when combined with L-NIO raise the possibility to use a lower dose of E7080 and therefore avoid/minimize the side effects observed with E7080.展开更多
Since in most tumors multiple signaling pathways are involved,many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases.The most important tyrosine kinase families in the d...Since in most tumors multiple signaling pathways are involved,many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases.The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL,SCR,platelet derived growth factor,vascular endothelial growth factor receptor and epidermal growth factor receptor families.Both multi-kinase inhibitors and singlekinase inhibitors have advantages and disadvantages,which are related to potential resistance mechanisms,pharmacokinetics,selectivity and tumor environment.In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist.Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor.Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity,while differences in gene expression exist between tumor and stromal cells.Considering these aspects,one type of inhibitor can generally not be preferred above the other,but will depend on the specific genetic constitution of the patient and the tumor,allowing personalized therapy.The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered(epi)genetics of the tumor.This strategy might result in treatment by a single multi kinase inhibitor for one patient,but in treatment by a couple of single kinase inhibitors for other patients.展开更多
AIMTo evaluate whether protein tyrosine phosphatase 1B (PTP1B) contributed to initiate human retinal pigment epithelium cells (A)-19 migration and investigate the signaling pathways involved in this process.METHODSARP...AIMTo evaluate whether protein tyrosine phosphatase 1B (PTP1B) contributed to initiate human retinal pigment epithelium cells (A)-19 migration and investigate the signaling pathways involved in this process.METHODSARPE-19 cells were cultured and treated with the siRNA-PTP1B. Expression of PTP1B was confirmed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). AG1478 [a selective inhibitor of epidermal growth factor receptor (EGFR)] and PD98059 (a specific inhibitor of the activation of mitogen-activated protein kinase) were used to help to determine the PTP1B signaling mechanism. Western blot analysis verified expression of EGFR and extracellular signal-regulated kinase (ERK) in ARPE-19 cells. The effect of siRNA-PTP1B on cell differentiation was confirmed by immunostaining for α-smooth muscle actin (α-SMA) and qRT-PCR. Cell migration ability was analyzed by transwell chamber assay.RESULTSThe mRNA levels of PTP1B were reduced by siRNA-PTP1B as determined by qRT-PCR assay. SiRNA-PTP1B activated EGFR and ERK phosphorylation. α-SMA staining and qRT-PCR assay demonstrated that siRNA-PTP1B induced retinal pigment epithelium (RPE) cells to differentiate toward better contractility and motility. Transwell chamber assay proved that PTP1B inhibition improved migration activity of RPE cells. Treatment with AG1478 and PD98059 abolished siRNA-PTP1B-induced activation of EGFR and ERK, α-SMA expression and cell migration.CONCLUSIONPTP1B inhibition promoted myofibroblast differentiation and migration of ARPE-19 cells, and EGFR/ERK signaling pathway played important role in migration process.展开更多
基金This study was reviewed and approved by the Experimental Animal Ethics Committee of the First Affiliated Hospital of Guangxi Medical University(Approval No.2023-E386-01).
文摘BACKGROUND Radiotherapy stands as a promising therapeutic modality for colorectal cancer(CRC);yet,the formidable challenge posed by radio-resistance significantly undermines its efficacy in achieving CRC remission.AIM To elucidate the role played by microRNA-298(miR-298)in CRC radio-resistance.METHODS To establish a radio-resistant CRC cell line,HT-29 cells underwent exposure to 5 gray ionizing radiation that was followed by a 7-d recovery period.The quantification of miR-298 levels within CRC cells was conducted through quantitative RT-PCR,and protein expression determination was realized through Western blotting.Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and proliferation by clonogenic assay.Radio-induced apoptosis was discerned through flow cytometry analysis.RESULTS We observed a marked upregulation of miR-298 in radio-resistant CRC cells.MiR-298 emerged as a key determinant of cell survival following radiation exposure,as its overexpression led to a notable reduction in radiation-induced apoptosis.Intriguingly,miR-298 expression exhibited a strong correlation with CRC cell viability.Further investigation unveiled human dual-specificity tyrosine(Y)-regulated kinase 1A(DYRK1A)as miR-298’s direct target.CONCLUSION Taken together,our findings underline the role played by miR-298 in bolstering radio-resistance in CRC cells by means of DYRK1A downregulation,thereby positioning miR-298 as a promising candidate for mitigating radioresistance in CRC.
文摘Background: Preeclampsia (PE) is still one of the leading causes of maternal/perinatal morbidity/mortality in Nigeria. Imbalance between placenta growth factor (PLGF) and soluble fms-like tyrosine kinase 1 (sFlt1) has been reportedly present both before and after the manifestation <span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">of </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">PE;however, Nigerian data regarding these angiogenesis-related substances are lacking. We here attempted to determine the maternal serum level of PLGF and sFlt1 and sFlt1/PLGF ratio in PE vs. non-PE women in Lagos State University Teaching Hospital, Nigeria.</span></span></span><span><span><span style="font-family:;" "=""> </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">Methods: An observational cross-sectional study was made on 75 women with PE and 75 age-gestational-age matched women without PE, as case and control, respectively. Levels of sFlt-1, PIGF and the sFlt-1: PIGF ratio was compared between the two. Results: Serum levels of Flt-1 and sFlt1/PIGF ratio were significantly higher in PE patients (6581.86 ± 865.75, and 146.42 ± 92.43) than in the normotensive control (4584.52 ± 1479.6 and 11.60 ± 6.42). PIGF was significantly lower in PE patients (70.14 ± 51.03) than the normotensives (494.06 ± 475.8). There were positive and negative correlation</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">s</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;"> between the sFlt-1 and PLGF respectively and mean arterial blood pressure. Conclusion: Serum sFlt-1, sFlt1/PIGF ratio was significantly higher and PIGF levels </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">were </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">significantly lower in PE than normotensive control in Nigerian population</span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">.</span></span></span>
文摘Objective：To investigate the effects of E7080 and N5-（1-iminoethyl）-L-ornithine dihydrochloride （L-NIO）on colorectal cancer alone and in combination.Methods：HT29 colorectal cancer cell line from Sap Institute was used.Real-time cell analysis （xCELLigence system） was performed to determine the effects of E7080 and L-NIO on colorectal cell proliferation.While apoptosis was determined with Annexin V staining,and the effect of agents on angiogenesis was determined with chorioallantoic membrane （CAM） model.Results：We found that E7080 has a strong antiproliferative effect with an half maximum inhibition of concentration （IC50） value of 5.60×10-8 mol/L.Also it has been observed that E7080 showed antiangiogenic and apoptotic effects on HT29 colorectal cancer cells.Antiangiogenic scores of E7080 were 1.2,t.0 and 0.6 for 100,10 and 1 nmol/L E7080 concentrations,respectively.Furthermore,apoptosis has been detected in 71％ of HT29 colorectal cancer cells after administration of 100 nmol/L E7080 which may indicate strong apoptotic effect.Meanwhile administration of L-NIO alone did not show any effect,but the combination of E7080 with L-NIO increased the antiproliferative,antiangiogenic and apoptotic effects of E7080.Conclusions：Results of this study indicate that E7080 may be a good choice in treatment of colorectal tumors.Furthermore the increased effects of E7080 when combined with L-NIO raise the possibility to use a lower dose of E7080 and therefore avoid/minimize the side effects observed with E7080.
文摘Since in most tumors multiple signaling pathways are involved,many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases.The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL,SCR,platelet derived growth factor,vascular endothelial growth factor receptor and epidermal growth factor receptor families.Both multi-kinase inhibitors and singlekinase inhibitors have advantages and disadvantages,which are related to potential resistance mechanisms,pharmacokinetics,selectivity and tumor environment.In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist.Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor.Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity,while differences in gene expression exist between tumor and stromal cells.Considering these aspects,one type of inhibitor can generally not be preferred above the other,but will depend on the specific genetic constitution of the patient and the tumor,allowing personalized therapy.The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered(epi)genetics of the tumor.This strategy might result in treatment by a single multi kinase inhibitor for one patient,but in treatment by a couple of single kinase inhibitors for other patients.
文摘目的:探讨胎盘生长因子(placental growth factor,PLGF)、可溶性fms样酪氨酸激酶-1(soluble fms-like tyrosine kinase-1,SFLT-1)和糖基化纤连蛋白(glycosylated fibronectin,GLYFN)检测对子痫前期的预测价值。方法:选择在无锡市妇幼保健院就诊的188例孕妇,分154例正常孕妇(对照组)和34例子痫前期患者(子痫组),应用免疫荧光法分别检测其在孕16~18周血清中PLGF、SFLT-1和GLYFN的浓度,比较子痫前期组和对照组各标志物的水平,并使用受试者操作特征曲线(receiver operating characteristic,ROC)对3种标志物的预测价值进行效能评估。结果:在妊娠中期,子痫前期组血清PLGF浓度低于对照组,SFLT-1及GLYFN浓度均高于对照组,3种标志物的差异均有统计学意义(3指标P=0.000)。95%置信区间的ROC曲线下面积(areas under the ROC curve,AUC)为,PLGF为0.941(0.907~0.974),SFLT-1为0.881(0.800~0.962),GLYFN为0.951(0.918~0.985),联合指标SFLT-1和GLYFN、3项指标联合检测在ROC曲线下面积(areas under the ROC curve,AUC)分别为0.968、0.986。结论:PLGF、SFLT-1、GLYFN 3种标志物水平在对照组和子痫前期组均存在明显差异,对子痫前期的发病具有一定的预测价值,SFLT-1联合PLGF、SFLT-1联合GLYFN、3项指标联合检测对子痫前期的预测价值高于任一单项指标。
基金Supported by Shandong Provincial Natural Science Foundation,China(No.ZR2012HQ004)the Research Fund for Fundamental Research Project of Qingdao(No.13-1-4-180-jch)+1 种基金the Scientific Research Fund of Huangdao District of Qingdao City(No.2014-1-74)the Young People Scientific Research Fund of Affiliated Hospital,Qingdao University(No.QDFY134)
文摘AIMTo evaluate whether protein tyrosine phosphatase 1B (PTP1B) contributed to initiate human retinal pigment epithelium cells (A)-19 migration and investigate the signaling pathways involved in this process.METHODSARPE-19 cells were cultured and treated with the siRNA-PTP1B. Expression of PTP1B was confirmed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). AG1478 [a selective inhibitor of epidermal growth factor receptor (EGFR)] and PD98059 (a specific inhibitor of the activation of mitogen-activated protein kinase) were used to help to determine the PTP1B signaling mechanism. Western blot analysis verified expression of EGFR and extracellular signal-regulated kinase (ERK) in ARPE-19 cells. The effect of siRNA-PTP1B on cell differentiation was confirmed by immunostaining for α-smooth muscle actin (α-SMA) and qRT-PCR. Cell migration ability was analyzed by transwell chamber assay.RESULTSThe mRNA levels of PTP1B were reduced by siRNA-PTP1B as determined by qRT-PCR assay. SiRNA-PTP1B activated EGFR and ERK phosphorylation. α-SMA staining and qRT-PCR assay demonstrated that siRNA-PTP1B induced retinal pigment epithelium (RPE) cells to differentiate toward better contractility and motility. Transwell chamber assay proved that PTP1B inhibition improved migration activity of RPE cells. Treatment with AG1478 and PD98059 abolished siRNA-PTP1B-induced activation of EGFR and ERK, α-SMA expression and cell migration.CONCLUSIONPTP1B inhibition promoted myofibroblast differentiation and migration of ARPE-19 cells, and EGFR/ERK signaling pathway played important role in migration process.
