Postoperative cognitive dysfunction is a seve re complication of the central nervous system that occurs after anesthesia and surgery,and has received attention for its high incidence and effect on the quality of life ...Postoperative cognitive dysfunction is a seve re complication of the central nervous system that occurs after anesthesia and surgery,and has received attention for its high incidence and effect on the quality of life of patients.To date,there are no viable treatment options for postoperative cognitive dysfunction.The identification of postoperative cognitive dysfunction hub genes could provide new research directions and therapeutic targets for future research.To identify the signaling mechanisms contributing to postoperative cognitive dysfunction,we first conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the Gene Expression Omnibus GSE95426 dataset,which consists of mRNAs and long non-coding RNAs differentially expressed in mouse hippocampus3 days after tibial fracture.The dataset was enriched in genes associated with the biological process"regulation of immune cells,"of which Chill was identified as a hub gene.Therefore,we investigated the contribution of chitinase-3-like protein 1 protein expression changes to postoperative cognitive dysfunction in the mouse model of tibial fractu re surgery.Mice were intraperitoneally injected with vehicle or recombinant chitinase-3-like protein 124 hours post-surgery,and the injection groups were compared with untreated control mice for learning and memory capacities using the Y-maze and fear conditioning tests.In addition,protein expression levels of proinflammatory factors(interleukin-1βand inducible nitric oxide synthase),M2-type macrophage markers(CD206 and arginase-1),and cognition-related proteins(brain-derived neurotropic factor and phosphorylated NMDA receptor subunit NR2B)were measured in hippocampus by western blotting.Treatment with recombinant chitinase-3-like protein 1 prevented surgery-induced cognitive impairment,downregulated interleukin-1βand nducible nitric oxide synthase expression,and upregulated CD206,arginase-1,pNR2B,and brain-derived neurotropic factor expression compared with vehicle treatment.Intraperitoneal administration of the specific ERK inhibitor PD98059 diminished the effects of recombinant chitinase-3-like protein 1.Collectively,our findings suggest that recombinant chitinase-3-like protein 1 ameliorates surgery-induced cognitive decline by attenuating neuroinflammation via M2 microglial polarization in the hippocampus.Therefore,recombinant chitinase-3-like protein1 may have therapeutic potential fo r postoperative cognitive dysfunction.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact mo...BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact molecular mechanisms leading to the progression of HCC are still unclear.Research has shown that the microRNA-142-3p level decreases in HCC,whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues.In this paper,we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity,and the association between them.AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients.METHODS In this study,we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues,and retrospectively analyzed the prognosis of HCC patients.Furthermore,explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments,which involved the following experimental methods:Immunohistochemical staining,western blot,quantitative real-time-polymerase chain reaction,flow cytometric analysis,tumor xenografts in nude mice,etc.The statistical methods involved in this study contained t-test,one-way analysis of variance,theχ^(2)test,the Kaplan-Meier approach and the log-rank test.RESULTS In this study,we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate.ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3′untranslated region.Furthermore,microRNA-142-3p promotes apoptosis and inhibits proliferation,invasion,and migration of HCC cell lines in vitro via ASH1L.For the exploration mechanism,we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1,which is potentially relevant to the immune system.CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC.Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.展开更多
lin-12-like抑制/增强子(suppressor/enhancer of lin-12-like,SEL1L)分子可以参与调控多种肿瘤进展;同时,其作为内质网相关降解途径(endoplasmic reticulum-associated degradation,ERAD)的重要组成,还参与调控蛋白质合成,与内质网应激...lin-12-like抑制/增强子(suppressor/enhancer of lin-12-like,SEL1L)分子可以参与调控多种肿瘤进展;同时,其作为内质网相关降解途径(endoplasmic reticulum-associated degradation,ERAD)的重要组成,还参与调控蛋白质合成,与内质网应激(ER stress)及其引起的未折叠蛋白反应(unfolded protein response,UPR)密切相关。在肿瘤微环境中,ERAD不仅参与调控肿瘤细胞的生物学行为,对肿瘤进展发挥重要作用;其还参与对免疫细胞增殖分化、功能以及代谢途径的调节,影响免疫细胞发挥抗肿瘤免疫作用。因此,深入了解探索肿瘤微环境中SEL1L分子及ERAD的潜在机制,可为肿瘤发生、发展及免疫治疗提供新理论和新靶点。本文就SEL1L分子及其参与的内质网相关降解途径在肿瘤进展与免疫调节中的作用进行简要综述。展开更多
目的:总结MAB21L2基因的变异和临床特点,并与高度同源的MAB21L1基因进行比较。方法:对中山眼科中心临床基因数据库中MAB21L2基因变异患者进行基因型和表型分析,回顾性分析既往文献报道的MAB21L2基因和高度同源基因MAB21L1变异的表型-基...目的:总结MAB21L2基因的变异和临床特点,并与高度同源的MAB21L1基因进行比较。方法:对中山眼科中心临床基因数据库中MAB21L2基因变异患者进行基因型和表型分析,回顾性分析既往文献报道的MAB21L2基因和高度同源基因MAB21L1变异的表型-基因型的关系。结果:在2个小眼畸形家系中发现2个MAB21L2基因杂合变异:先证者1携带已知变异c.151C>G/p.(Arg51Gly),患者双眼小眼畸形伴虹膜脉络膜缺损,伴骨关节屈曲。母亲携带相同杂合变异但表型正常;先证者2携带未报道的变异c.1042G>T/p.(Glu348*),左眼小眼畸形,右眼正常且无全身异常。结合文献回顾发现,在显性遗传模式下,80%的MAB21L2杂合致病变异(20/25)和100%的MAB21L1杂合致病变异(25/25)发生在氨基酸49-52区域,导致小眼无眼或眼缺损异常(microphthalmia,anophthalmia or coloboma,MAC);携带该区域MAB21L2基因杂合突变的患者除MAC外,部分还伴骨骼关节发育异常(12/24,50%);杂合截短变异发生在MAB21L2基因可导致MAC(5/5,100%),而发生在MAB21L1则不致病。结论:在2个小眼畸形家系中发现了MAB21L2基因1个新致病变异和1个已知热点致病变异,通过文献综述比较和总结了MAB21L1和MAB21L2基因的突变频谱以及基因型-表型相互关系,为此类基因缺陷导致遗传病的诊断和鉴别诊断提供依据。展开更多
基金supported by the National Natural Science Foundation of China,Nos.81730033,82171193(to XG)the Key Talent Project for Strengthening Health during the 13^(th)Five-Year Plan Period,No.ZDRCA2016069(to XG)+1 种基金the National Key R&D Program of China,No.2018YFC2001901(to XG)Jiangsu Provincial Medical Key Discipline,No.ZDXK202232(to XG)。
文摘Postoperative cognitive dysfunction is a seve re complication of the central nervous system that occurs after anesthesia and surgery,and has received attention for its high incidence and effect on the quality of life of patients.To date,there are no viable treatment options for postoperative cognitive dysfunction.The identification of postoperative cognitive dysfunction hub genes could provide new research directions and therapeutic targets for future research.To identify the signaling mechanisms contributing to postoperative cognitive dysfunction,we first conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the Gene Expression Omnibus GSE95426 dataset,which consists of mRNAs and long non-coding RNAs differentially expressed in mouse hippocampus3 days after tibial fracture.The dataset was enriched in genes associated with the biological process"regulation of immune cells,"of which Chill was identified as a hub gene.Therefore,we investigated the contribution of chitinase-3-like protein 1 protein expression changes to postoperative cognitive dysfunction in the mouse model of tibial fractu re surgery.Mice were intraperitoneally injected with vehicle or recombinant chitinase-3-like protein 124 hours post-surgery,and the injection groups were compared with untreated control mice for learning and memory capacities using the Y-maze and fear conditioning tests.In addition,protein expression levels of proinflammatory factors(interleukin-1βand inducible nitric oxide synthase),M2-type macrophage markers(CD206 and arginase-1),and cognition-related proteins(brain-derived neurotropic factor and phosphorylated NMDA receptor subunit NR2B)were measured in hippocampus by western blotting.Treatment with recombinant chitinase-3-like protein 1 prevented surgery-induced cognitive impairment,downregulated interleukin-1βand nducible nitric oxide synthase expression,and upregulated CD206,arginase-1,pNR2B,and brain-derived neurotropic factor expression compared with vehicle treatment.Intraperitoneal administration of the specific ERK inhibitor PD98059 diminished the effects of recombinant chitinase-3-like protein 1.Collectively,our findings suggest that recombinant chitinase-3-like protein 1 ameliorates surgery-induced cognitive decline by attenuating neuroinflammation via M2 microglial polarization in the hippocampus.Therefore,recombinant chitinase-3-like protein1 may have therapeutic potential fo r postoperative cognitive dysfunction.
基金Supported by the Haihe Laboratory of Cell Ecosystem Innovation Fund,No.22HHXBJC00001the Key Discipline Special Project of Tianjin Municipal Health Commission,No.TJWJ2022XK016.
文摘BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact molecular mechanisms leading to the progression of HCC are still unclear.Research has shown that the microRNA-142-3p level decreases in HCC,whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues.In this paper,we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity,and the association between them.AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients.METHODS In this study,we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues,and retrospectively analyzed the prognosis of HCC patients.Furthermore,explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments,which involved the following experimental methods:Immunohistochemical staining,western blot,quantitative real-time-polymerase chain reaction,flow cytometric analysis,tumor xenografts in nude mice,etc.The statistical methods involved in this study contained t-test,one-way analysis of variance,theχ^(2)test,the Kaplan-Meier approach and the log-rank test.RESULTS In this study,we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate.ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3′untranslated region.Furthermore,microRNA-142-3p promotes apoptosis and inhibits proliferation,invasion,and migration of HCC cell lines in vitro via ASH1L.For the exploration mechanism,we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1,which is potentially relevant to the immune system.CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC.Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.
文摘lin-12-like抑制/增强子(suppressor/enhancer of lin-12-like,SEL1L)分子可以参与调控多种肿瘤进展;同时,其作为内质网相关降解途径(endoplasmic reticulum-associated degradation,ERAD)的重要组成,还参与调控蛋白质合成,与内质网应激(ER stress)及其引起的未折叠蛋白反应(unfolded protein response,UPR)密切相关。在肿瘤微环境中,ERAD不仅参与调控肿瘤细胞的生物学行为,对肿瘤进展发挥重要作用;其还参与对免疫细胞增殖分化、功能以及代谢途径的调节,影响免疫细胞发挥抗肿瘤免疫作用。因此,深入了解探索肿瘤微环境中SEL1L分子及ERAD的潜在机制,可为肿瘤发生、发展及免疫治疗提供新理论和新靶点。本文就SEL1L分子及其参与的内质网相关降解途径在肿瘤进展与免疫调节中的作用进行简要综述。
文摘目的:总结MAB21L2基因的变异和临床特点,并与高度同源的MAB21L1基因进行比较。方法:对中山眼科中心临床基因数据库中MAB21L2基因变异患者进行基因型和表型分析,回顾性分析既往文献报道的MAB21L2基因和高度同源基因MAB21L1变异的表型-基因型的关系。结果:在2个小眼畸形家系中发现2个MAB21L2基因杂合变异:先证者1携带已知变异c.151C>G/p.(Arg51Gly),患者双眼小眼畸形伴虹膜脉络膜缺损,伴骨关节屈曲。母亲携带相同杂合变异但表型正常;先证者2携带未报道的变异c.1042G>T/p.(Glu348*),左眼小眼畸形,右眼正常且无全身异常。结合文献回顾发现,在显性遗传模式下,80%的MAB21L2杂合致病变异(20/25)和100%的MAB21L1杂合致病变异(25/25)发生在氨基酸49-52区域,导致小眼无眼或眼缺损异常(microphthalmia,anophthalmia or coloboma,MAC);携带该区域MAB21L2基因杂合突变的患者除MAC外,部分还伴骨骼关节发育异常(12/24,50%);杂合截短变异发生在MAB21L2基因可导致MAC(5/5,100%),而发生在MAB21L1则不致病。结论:在2个小眼畸形家系中发现了MAB21L2基因1个新致病变异和1个已知热点致病变异,通过文献综述比较和总结了MAB21L1和MAB21L2基因的突变频谱以及基因型-表型相互关系,为此类基因缺陷导致遗传病的诊断和鉴别诊断提供依据。
