Malformations of cortical development(MCD)are a group of developmental disorders characterized by abnormal cortical structures caused by genetic or harmful environmental factors.Many kinds of MCD are caused by genetic...Malformations of cortical development(MCD)are a group of developmental disorders characterized by abnormal cortical structures caused by genetic or harmful environmental factors.Many kinds of MCD are caused by genetic variation.MCD is the common cause of intellectual disability and intractable epilepsy.With rapid advances in imaging and sequencing technologies,the diagnostic rate of MCD has been increasing,and many potential genes causing MCD have been successively identified.However,the high genetic heterogeneity of MCD makes it challenging to understand the molecular pathogenesis of MCD and to identify effective targeted drugs.Thus,in this review,we outline important events of cortical development.Then we illustrate the progress of molecular genetic studies about MCD focusing on the PI3K/PTEN/AKT/mTOR pathway.Finally,we briefly discuss the diagnostic methods,disease models,and therapeutic strategies for MCD.The information will facilitate further research on MCD.Understanding the role of the PI3K/PTEN/AKT/mTOR pathway in MCD could lead to a novel strategy for treating MCD-related diseases.展开更多
Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage.The E26 transformation-specific sequence-related t...Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage.The E26 transformation-specific sequence-related transcription factor Spi1 regulates microglial/macrophage commitment and maturation.However,the effect of Spi1 on intracerebral hemorrhage remains unclear.In this study,we found that Spi1 may regulate recovery from the neuroinflammation and neurofunctional damage caused by intracerebral hemorrhage by modulating the microglial/macrophage transcriptome.We showed that high Spi1expression in microglia/macrophages after intracerebral hemorrhage is associated with the activation of many pathways that promote phagocytosis,glycolysis,and autophagy,as well as debris clearance and sustained remyelination.Notably,microglia with higher levels of Soil expression were chara cterized by activation of pathways associated with a variety of hemorrhage-related cellular processes,such as complement activation,angiogenesis,and coagulation.In conclusion,our results suggest that Spi1 plays a vital role in the microglial/macrophage inflammatory response following intracerebral hemorrhage.This new insight into the regulation of Spi1 and its target genes may advance our understanding of neuroinflammation in intracerebral hemorrhage and provide therapeutic targets for patients with intracerebral hemorrhage.展开更多
Objective This study investigated the impact of occupational mercury(Hg) exposure on human gene transcription and expression, and its potential biological mechanisms.Methods Differentially expressed genes related to H...Objective This study investigated the impact of occupational mercury(Hg) exposure on human gene transcription and expression, and its potential biological mechanisms.Methods Differentially expressed genes related to Hg exposure were identified and validated using gene expression microarray analysis and extended validation. Hg-exposed cell models and PTEN lowexpression models were established in vitro using 293T cells. PTEN gene expression was assessed using qRT-PCR, and Western blotting was used to measure PTEN, AKT, and PI3K protein levels. IL-6 expression was determined by ELISA.Results Combined findings from gene expression microarray analysis, bioinformatics, and population expansion validation indicated significant downregulation of the PTEN gene in the high-concentration Hg exposure group. In the Hg-exposed cell model(25 and 10 μmol/L), a significant decrease in PTEN expression was observed, accompanied by a significant increase in PI3K, AKT, and IL-6 expression.Similarly, a low-expression cell model demonstrated that PTEN gene knockdown led to a significant decrease in PTEN protein expression and a substantial increase in PI3K, AKT, and IL-6 levels.Conclusion This is the first study to report that Hg exposure downregulates the PTEN gene, activates the PI3K/AKT regulatory pathway, and increases the expression of inflammatory factors, ultimately resulting in kidney inflammation.展开更多
We evaluated the effect of isoquercetin(quercetin-O-3-glucoside-quercetin,IQ)as a functional component of Abeliophyllum disistichum Nakai ethanol extract(ADLE)on prostate cell proliferation and apoptosis and its effec...We evaluated the effect of isoquercetin(quercetin-O-3-glucoside-quercetin,IQ)as a functional component of Abeliophyllum disistichum Nakai ethanol extract(ADLE)on prostate cell proliferation and apoptosis and its effects on the IGF-1/PI3K/Akt/mTOR pathway in benign prostatic hyperplasia(BPH).Metabolites in ADLE were analyzed using UHPLC-qTOF-MS and HPLC.IQ was orally administered(1 or 10 mg/kg)to a testosterone propionate-induced BPH rat model,and its effects on the prostate weight were evaluated.The effect of IQ on androgen receptor(AR)signaling was analyzed in LNCaP cells.Whether IGF-1 and IQ affect the IGF-1/PI3K/Akt/mTOR pathway in BPH-1 cells was also examined.The metabolites in ADLE were identified and quantified,which confirmed that ADLE contained abundant IQ(20.88 mg/g).IQ significantly reduced the prostate size in a concentration-dependent manner in a BPH rat model,and significantly decreased the expression of AR signaling factors in the rat prostate tissue and LNCaP cells in a concentration-dependent manner.IQ also inhibited the PI3K/AKT/mTOR pathway activated by IGF-1 treatment in BPH-1 cells.In BPH-1 cells,IQ led to G0/G1 arrest and suppressed the expression of proliferation factors while inducing apoptosis.Thus,IQ shows potential for use as a pharmaceutical and nutraceutical for BPH.展开更多
Background:Oral squamous cell carcinoma(OSCC)is a common malignant tumor.Recently,Laminin Gamma 2(LAMC2)has been shown to be abnormally expressed in OSCC;however,how LAMC2 signaling contributes to the occurrence and d...Background:Oral squamous cell carcinoma(OSCC)is a common malignant tumor.Recently,Laminin Gamma 2(LAMC2)has been shown to be abnormally expressed in OSCC;however,how LAMC2 signaling contributes to the occurrence and development of OSCC and the role of autophagy in OSCC has not been fully explored.This study aimed to analyze the role and mechanism of LAMC2 signaling in OSCC and the involvement of autophagy in OSCC.Methods:To explore the mechanism by which LAMC2 is highly expressed in OSCC,we used small interfering RNA(siRNA)to knock down LAMC2 to further observe the changes in the signaling pathway.Furthermore,we used cell proliferation assays,Transwell invasion assays,and wound-healing assays to observe the changes in OSCC proliferation,invasion,and metastasis.RFP-LC3 was used to detect the level of autophagy intensity.A cell line-derived xenograft(CDX)model was used to detect the effect of LAMC2 on tumor growth in vivo.Results:This study found that the level of autophagy was correlated with the biological behavior of OSCC.The downregulation of LAMC2 activated autophagy and inhibited OSCC proliferation,invasion,and metastasis via inhibiting the PI3K/AKT/mTOR pathway.Moreover,autophagy has a dual effect on OSCC,and the synergistic downregulation of LAMC2 and autophagy can inhibit OSCC metastasis,invasion,and proliferation via the PI3K/AKT/mTOR pathway.Conclusions:LAMC2 interacts with autophagy to regulate OSCC metastasis,invasion,and proliferation via the PI3K/AKT/mTOR pathway.LAMC2 down-regulation can synergistically modulate autophagy to inhibit OSCC migration,invasion,and proliferation.展开更多
A kind of triterpene glycosides echinoside A(EA)was extracted from sea cucumber Pearsonothuria graeffei,and its yield was about 0.78%.The purity of EA was 99.0%,and its molecular weight was 1206 Da.EA was a linear tet...A kind of triterpene glycosides echinoside A(EA)was extracted from sea cucumber Pearsonothuria graeffei,and its yield was about 0.78%.The purity of EA was 99.0%,and its molecular weight was 1206 Da.EA was a linear tetrasaccharide attached to a pentacyclic triterpene aglycon.It inhibited the growth of MDA-MB-231 cells in vitro.The antitumor effect was related to elevate ROS level,decrease mitochondrial membrane potential,enhance caspase-3 expression,induce cells apoptosis and arrest cell cycle at G2/M phase.EA also dose-dependently suppressed the expressions of phophorylation proteins p-PI3K,p-Akt,and p-mTOR as analyzed by western blotting.These results suggested that EA caused MDA-MB-231 cells apoptosis via intrinsic mitochondrial and PI3K/Akt/mTOR pathway.EA can be a potential anti-breast cancer agent to enhance the clinical efficacy.展开更多
As a pathway that plays a role in nutrient absorption,anabolic response,cell growth and survival,the important role of AKT/mTOR in tumorigenesis has also come to light.For cancer patients,most deaths are caused by the...As a pathway that plays a role in nutrient absorption,anabolic response,cell growth and survival,the important role of AKT/mTOR in tumorigenesis has also come to light.For cancer patients,most deaths are caused by the growth of metastatic tumors outside the primary focus.Therefore,migration and invasion in the late stage of tumor progression are the main unresolved issues in the study of tumor pathogenesis,and AKT/mTOR has been found to participate in the migration and invasion of cancer cells,which means that the study of this pathway may contribute to a solution for the problem.Because of its extensive and complex functions in the organism,this pathway can be regulated by a variety of different signals in the body,and then realize its function through different downstream signal molecules.This article reviews the proteins that can indirectly affect this pathway by regulating the common upstream signaling molecules of this pathway,and the proteins that can directly affect the level of phosphorylation of AKT/mTOR in cancer cells.We also review the proteins that can co-regulate this pathway and its downstream pathways.Through this study,we hope to gain a deeper understanding of the regulatory mechanism of the AKT/mTOR pathway in cancer cells,in hopes of finding effective and harmless cancer treatment targets in the future.展开更多
目的:探讨氧化苦参碱能否通过第10号染色体缺失的磷酸酶及张力蛋白同源的基因/3-磷酸肌醇激酶/蛋白激酶B/哺乳动物雷帕霉素靶向基因(Phosphatase and tension homolog deleted on chromosome ten/phosphoinositide 3-kinase/protein kin...目的:探讨氧化苦参碱能否通过第10号染色体缺失的磷酸酶及张力蛋白同源的基因/3-磷酸肌醇激酶/蛋白激酶B/哺乳动物雷帕霉素靶向基因(Phosphatase and tension homolog deleted on chromosome ten/phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin,PTEN/PI3K/Akt/mTOR)通路对人膀胱癌T24细胞的增殖、凋亡产生影响。方法:T24细胞复苏传代后与不同剂量氧化苦参碱共培养,MTT法检测不同剂量氧化苦参碱对T24细胞增殖的影响,流式细胞仪检测氧化苦参碱对T24细胞凋亡的影响,Hoechst光镜观察氧化苦参碱对T24细胞核形态的影响,Western blot检测氧化苦参碱对T24细胞PI3K、Akt、mTOR、PTEN蛋白表达的影响。结果:与0μmol/L组比较,氧化苦参碱各剂量组T24细胞的增殖率下降,凋亡率升高,PI3K、Akt、mTOR蛋白表达下降,PTEN蛋白表达上升,且在一定范围内存在剂量依赖性(P<0.05)。结论:氧化苦参碱可能通过PTEN/PI3K/Akt/mTOR通路抑制T24细胞的增殖,促进其凋亡。展开更多
基金the Tou-Yan Innovation Team Program of the Heilongjiang Province,China(No.2019-15).
文摘Malformations of cortical development(MCD)are a group of developmental disorders characterized by abnormal cortical structures caused by genetic or harmful environmental factors.Many kinds of MCD are caused by genetic variation.MCD is the common cause of intellectual disability and intractable epilepsy.With rapid advances in imaging and sequencing technologies,the diagnostic rate of MCD has been increasing,and many potential genes causing MCD have been successively identified.However,the high genetic heterogeneity of MCD makes it challenging to understand the molecular pathogenesis of MCD and to identify effective targeted drugs.Thus,in this review,we outline important events of cortical development.Then we illustrate the progress of molecular genetic studies about MCD focusing on the PI3K/PTEN/AKT/mTOR pathway.Finally,we briefly discuss the diagnostic methods,disease models,and therapeutic strategies for MCD.The information will facilitate further research on MCD.Understanding the role of the PI3K/PTEN/AKT/mTOR pathway in MCD could lead to a novel strategy for treating MCD-related diseases.
基金supported by the National Natural Science Foundation of China,No.81971097(to JY)。
文摘Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage.The E26 transformation-specific sequence-related transcription factor Spi1 regulates microglial/macrophage commitment and maturation.However,the effect of Spi1 on intracerebral hemorrhage remains unclear.In this study,we found that Spi1 may regulate recovery from the neuroinflammation and neurofunctional damage caused by intracerebral hemorrhage by modulating the microglial/macrophage transcriptome.We showed that high Spi1expression in microglia/macrophages after intracerebral hemorrhage is associated with the activation of many pathways that promote phagocytosis,glycolysis,and autophagy,as well as debris clearance and sustained remyelination.Notably,microglia with higher levels of Soil expression were chara cterized by activation of pathways associated with a variety of hemorrhage-related cellular processes,such as complement activation,angiogenesis,and coagulation.In conclusion,our results suggest that Spi1 plays a vital role in the microglial/macrophage inflammatory response following intracerebral hemorrhage.This new insight into the regulation of Spi1 and its target genes may advance our understanding of neuroinflammation in intracerebral hemorrhage and provide therapeutic targets for patients with intracerebral hemorrhage.
基金supported by the Jiangsu Province’s Outstanding Medical Academic Leader Program [CXTDA2017029]the Jiangsu Provincial Key Medical Discipline [ZDXK202249].
文摘Objective This study investigated the impact of occupational mercury(Hg) exposure on human gene transcription and expression, and its potential biological mechanisms.Methods Differentially expressed genes related to Hg exposure were identified and validated using gene expression microarray analysis and extended validation. Hg-exposed cell models and PTEN lowexpression models were established in vitro using 293T cells. PTEN gene expression was assessed using qRT-PCR, and Western blotting was used to measure PTEN, AKT, and PI3K protein levels. IL-6 expression was determined by ELISA.Results Combined findings from gene expression microarray analysis, bioinformatics, and population expansion validation indicated significant downregulation of the PTEN gene in the high-concentration Hg exposure group. In the Hg-exposed cell model(25 and 10 μmol/L), a significant decrease in PTEN expression was observed, accompanied by a significant increase in PI3K, AKT, and IL-6 expression.Similarly, a low-expression cell model demonstrated that PTEN gene knockdown led to a significant decrease in PTEN protein expression and a substantial increase in PI3K, AKT, and IL-6 levels.Conclusion This is the first study to report that Hg exposure downregulates the PTEN gene, activates the PI3K/AKT regulatory pathway, and increases the expression of inflammatory factors, ultimately resulting in kidney inflammation.
基金supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF)funded by the Ministry of Education,Science and Technology (NRF2020R1A2C1014798 to E-K Kim)。
文摘We evaluated the effect of isoquercetin(quercetin-O-3-glucoside-quercetin,IQ)as a functional component of Abeliophyllum disistichum Nakai ethanol extract(ADLE)on prostate cell proliferation and apoptosis and its effects on the IGF-1/PI3K/Akt/mTOR pathway in benign prostatic hyperplasia(BPH).Metabolites in ADLE were analyzed using UHPLC-qTOF-MS and HPLC.IQ was orally administered(1 or 10 mg/kg)to a testosterone propionate-induced BPH rat model,and its effects on the prostate weight were evaluated.The effect of IQ on androgen receptor(AR)signaling was analyzed in LNCaP cells.Whether IGF-1 and IQ affect the IGF-1/PI3K/Akt/mTOR pathway in BPH-1 cells was also examined.The metabolites in ADLE were identified and quantified,which confirmed that ADLE contained abundant IQ(20.88 mg/g).IQ significantly reduced the prostate size in a concentration-dependent manner in a BPH rat model,and significantly decreased the expression of AR signaling factors in the rat prostate tissue and LNCaP cells in a concentration-dependent manner.IQ also inhibited the PI3K/AKT/mTOR pathway activated by IGF-1 treatment in BPH-1 cells.In BPH-1 cells,IQ led to G0/G1 arrest and suppressed the expression of proliferation factors while inducing apoptosis.Thus,IQ shows potential for use as a pharmaceutical and nutraceutical for BPH.
基金This work was supported by the National Natural Science Foundation of China(Grant Numbers 31971106,BWS21L013,21WS09002,JK20211A010213).
文摘Background:Oral squamous cell carcinoma(OSCC)is a common malignant tumor.Recently,Laminin Gamma 2(LAMC2)has been shown to be abnormally expressed in OSCC;however,how LAMC2 signaling contributes to the occurrence and development of OSCC and the role of autophagy in OSCC has not been fully explored.This study aimed to analyze the role and mechanism of LAMC2 signaling in OSCC and the involvement of autophagy in OSCC.Methods:To explore the mechanism by which LAMC2 is highly expressed in OSCC,we used small interfering RNA(siRNA)to knock down LAMC2 to further observe the changes in the signaling pathway.Furthermore,we used cell proliferation assays,Transwell invasion assays,and wound-healing assays to observe the changes in OSCC proliferation,invasion,and metastasis.RFP-LC3 was used to detect the level of autophagy intensity.A cell line-derived xenograft(CDX)model was used to detect the effect of LAMC2 on tumor growth in vivo.Results:This study found that the level of autophagy was correlated with the biological behavior of OSCC.The downregulation of LAMC2 activated autophagy and inhibited OSCC proliferation,invasion,and metastasis via inhibiting the PI3K/AKT/mTOR pathway.Moreover,autophagy has a dual effect on OSCC,and the synergistic downregulation of LAMC2 and autophagy can inhibit OSCC metastasis,invasion,and proliferation via the PI3K/AKT/mTOR pathway.Conclusions:LAMC2 interacts with autophagy to regulate OSCC metastasis,invasion,and proliferation via the PI3K/AKT/mTOR pathway.LAMC2 down-regulation can synergistically modulate autophagy to inhibit OSCC migration,invasion,and proliferation.
基金supported by the National Key R&D Program of China(No.2018YFC0311206)the China Postdoctoral Science Foundation(No.2018M642706)the Postdoctoral Innovation Program of Shandong Province.
文摘A kind of triterpene glycosides echinoside A(EA)was extracted from sea cucumber Pearsonothuria graeffei,and its yield was about 0.78%.The purity of EA was 99.0%,and its molecular weight was 1206 Da.EA was a linear tetrasaccharide attached to a pentacyclic triterpene aglycon.It inhibited the growth of MDA-MB-231 cells in vitro.The antitumor effect was related to elevate ROS level,decrease mitochondrial membrane potential,enhance caspase-3 expression,induce cells apoptosis and arrest cell cycle at G2/M phase.EA also dose-dependently suppressed the expressions of phophorylation proteins p-PI3K,p-Akt,and p-mTOR as analyzed by western blotting.These results suggested that EA caused MDA-MB-231 cells apoptosis via intrinsic mitochondrial and PI3K/Akt/mTOR pathway.EA can be a potential anti-breast cancer agent to enhance the clinical efficacy.
基金supported by the National Natural Science Foundation of China(Nos.32102786,32270555).
文摘As a pathway that plays a role in nutrient absorption,anabolic response,cell growth and survival,the important role of AKT/mTOR in tumorigenesis has also come to light.For cancer patients,most deaths are caused by the growth of metastatic tumors outside the primary focus.Therefore,migration and invasion in the late stage of tumor progression are the main unresolved issues in the study of tumor pathogenesis,and AKT/mTOR has been found to participate in the migration and invasion of cancer cells,which means that the study of this pathway may contribute to a solution for the problem.Because of its extensive and complex functions in the organism,this pathway can be regulated by a variety of different signals in the body,and then realize its function through different downstream signal molecules.This article reviews the proteins that can indirectly affect this pathway by regulating the common upstream signaling molecules of this pathway,and the proteins that can directly affect the level of phosphorylation of AKT/mTOR in cancer cells.We also review the proteins that can co-regulate this pathway and its downstream pathways.Through this study,we hope to gain a deeper understanding of the regulatory mechanism of the AKT/mTOR pathway in cancer cells,in hopes of finding effective and harmless cancer treatment targets in the future.
文摘目的:探讨氧化苦参碱能否通过第10号染色体缺失的磷酸酶及张力蛋白同源的基因/3-磷酸肌醇激酶/蛋白激酶B/哺乳动物雷帕霉素靶向基因(Phosphatase and tension homolog deleted on chromosome ten/phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin,PTEN/PI3K/Akt/mTOR)通路对人膀胱癌T24细胞的增殖、凋亡产生影响。方法:T24细胞复苏传代后与不同剂量氧化苦参碱共培养,MTT法检测不同剂量氧化苦参碱对T24细胞增殖的影响,流式细胞仪检测氧化苦参碱对T24细胞凋亡的影响,Hoechst光镜观察氧化苦参碱对T24细胞核形态的影响,Western blot检测氧化苦参碱对T24细胞PI3K、Akt、mTOR、PTEN蛋白表达的影响。结果:与0μmol/L组比较,氧化苦参碱各剂量组T24细胞的增殖率下降,凋亡率升高,PI3K、Akt、mTOR蛋白表达下降,PTEN蛋白表达上升,且在一定范围内存在剂量依赖性(P<0.05)。结论:氧化苦参碱可能通过PTEN/PI3K/Akt/mTOR通路抑制T24细胞的增殖,促进其凋亡。
