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Ca2+/calmodulin-dependent protein kinase II regulates colon cancer proliferation and migration via ERK1/2 and p38 pathways 被引量:7
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作者 Wei Chen Ping An +4 位作者 Xiao-Jing Quan Jun Zhang Zhong-Yin Zhou Li-Ping Zou He-Sheng Luo 《World Journal of Gastroenterology》 SCIE CAS 2017年第33期6111-6118,共8页
AIM To investigate the role of calmodulin-dependent protein kinase Ⅱ(Ca MKⅡ) in colon cancer growth,migration and invasion.METHODS Ca MKⅡ expression in colon cancer and paracancerous tissues was evaluated via immun... AIM To investigate the role of calmodulin-dependent protein kinase Ⅱ(Ca MKⅡ) in colon cancer growth,migration and invasion.METHODS Ca MKⅡ expression in colon cancer and paracancerous tissues was evaluated via immunochemistry. Transcriptional and posttranscriptional levels of Ca MKⅡin tissue samples and MMP2,MMP9 and TIMP-1 expression in the human colon cancer cell line HCT116 were assessed by q RTPCR and western blot. Cell proliferation was detected with the MTT assay. Cancer cell migration and invasion were investigated with the Transwell culture system and woundhealing assay.RESULTS We first demonstrated that CaMK Ⅱ was ove rexpressed in human colon cancers and was associated with cancer differentiation. In the human colon cancer cell line HCT116,the Ca MKII-specific inhibitor KN93,but not its inactive analogue KN92,decreased cancer cell proliferation. Furthermore,KN93 also significantly prohibited HCT116 cell migration and invasion. The specific inhibition of ERK1/2 or p38 decreased the proliferation and migration of colon cancer cells.CONCLUSION Our findings highlight Ca MKⅡ as a potential critical mediator in human colon tumor development and metastasis. 展开更多
关键词 Ca2+/calmodulin-dependent protein kinase II Colon cancer PROLIFERATION MIGRATION
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Role of Protein Kinase C in the Activation of Store-operated Ca^(2+) Entry in Airway Smooth Muscle Cells 被引量:1
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作者 高亚东 邹进晶 +2 位作者 耿爽 郑君文 杨炯 《Journal of Huazhong University of Science and Technology(Medical Sciences)》 SCIE CAS 2012年第3期303-310,共8页
Store-operated Ca2+ channels (SOCs) are plasma membrane Ca2+ permeable channels activated by depletion of intracellular Ca2+ store. Ca2+ entry through SOCs is known as store-operated Ca2+ entry (SOCE), which ... Store-operated Ca2+ channels (SOCs) are plasma membrane Ca2+ permeable channels activated by depletion of intracellular Ca2+ store. Ca2+ entry through SOCs is known as store-operated Ca2+ entry (SOCE), which plays an important role in the functional regulation of airway smooth muscle cells (ASMCs). Protein kinase C (PKC) has been shown to have an activating or inhibiting effect on SOCE, depending on cell types and PKC isoforms that are involved. In ASMCs, the effect of PKC on SOCE has not been elucidated so far. In this study, the role of PKC in the activation of SOCE in rat ASMCs was examined by using Ca2+ fluorescence imaging technique. The results showed that acute application of PKC activators PMA and PDBu did not affect SOCE induced by the sarcoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor thapsigargin. The non-selective PKC inhibitor chelerythrine significantly inhibited thapsigargin- and bradykinin-induced SOCE. RT-PCR assay identified PKCα, δ and ε isoforms in rat ASMCs. PKCα-selective inhibitor G6976 and PKCε-inhibiting peptide Epsilon-V1-2 had no effect on SOCE; by contrast, PKCδ-selective inhibitor rottlerin attenuated SOCE dramatically, suggesting that PKCδ was the major PKC isoform involved in the activation of SOCE in ASMCs. Moreover, PKC down-regulation by extended exposure to high doses of PMA or PDBu also reduced SOCE, confirming the essential role of PKC in the activation of SOCE in ASMCs. In addition, PKC down-regulation did not influence the expression of stromal interaction molecule 1 (STIM1) and Orai1, two elementary molecules in the regulation and activation of SOCs. These results identified PKCδ as an essential PKC isoform involved in the activation of SOCE, and confirmed that PKC regulates the function of ASMCs in a SOCE-dependent manner. 展开更多
关键词 airway smooth muscle cells protein kinase C store-operated Ca2+ entry
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Amelioration of mitochondrial dysfunction in heart failure through S-sulfhydration of Ca^2+/calmodulin-dependent protein kinase Ⅱ
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作者 Dan WU Qing-xun HU +1 位作者 De-qiu ZHU Yi-zhun ZHU 《中国药理学与毒理学杂志》 CSCD 北大核心 2017年第10期976-976,共1页
OBJECTIVE To determine the functional role of hydrogen sulfide(H_2S) in protecting against mitochondrial dysfunction in heart failure through the inhibition of Ca^(2+)/calmodulin-dependent protein kinaseⅡ(Ca MKⅡ) us... OBJECTIVE To determine the functional role of hydrogen sulfide(H_2S) in protecting against mitochondrial dysfunction in heart failure through the inhibition of Ca^(2+)/calmodulin-dependent protein kinaseⅡ(Ca MKⅡ) using wild type and CSE knockout mouse models.METHODS Continuous subcutaneous injection isoprenaline(7.5 mg·kg^(-1) per day),once a day for 4 weeks to induce heart failure in male C57BL/6(6-8 weeks old) mice and CSE-/-mice.150 μmol·L^(-1) H_2O_2 was used to induce oxidative stress in H9c2 cells.Echocardiograph was used to detect cardiac parameters.H&E stain and Masson stain was to observation histopathological changes.Western blot was used to detect protein expression and activity.The si RNA was used to silence protein expression.HPLC was used to detect H_2S level.Biotin assay was used to detect the level of S-sulfhydration protein.RESULTS Treatment with S-propyl-L-cysteine(SPRC) or sodium hydrosulfide(Na HS),modulators of blood H_2S levels,attenuated the development of heart failure in animals,reduced lipid peroxidation,and preserved mitochondrial function.The inhibition Ca MKⅡ phosphorylation by SPRC and Na HS as demonstrated using both in vivo and in vitro models corresponded with the cardioprotective effects of these compounds.Interestingly,Ca MKⅡ activity was found to be elevated in CSE-/-mice as compared to wild type animals and the phosphorylation status of Ca MK Ⅱ appeared to relate to the severity of heart failure.Importantly,in wild type mice SPRC was found to promote S-sulfhydration of Ca MKⅡ leading to reduced activity of this protein however,in CSE-/-mice S-sulfhydration was abolished following SPRC treatment.CONCLUSION A novel mechanism depicting a role of S-sulfhydration in the regulation of Ca MKⅡ is presented.SPRC mediated S-sulfhydration of Ca MKⅡ was found to inhibit Ca MKⅡ activity and to preserve cardiovascular homeostasis. 展开更多
关键词 hydrogen sulfide MITOCHONDRIA heart failure Ca2+/calmodulin-dependent protein kinase S sulfhydration
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Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer's disease 被引量:11
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作者 Isaac G. Onyango 《Neural Regeneration Research》 SCIE CAS CSCD 2018年第1期19-25,共7页
Alzheimer’s disease (AD) is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved... Alzheimer’s disease (AD) is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria. 展开更多
关键词 Alzheimer's disease mitochondria BIOENERGETICS mitochondrial DNA neuroinflammation mitohormesis caloric restriction HYPOMETABOLISM MITOPHAGY mitochondrial biogenesis recombinant-human mitochondrial transcription factor A antioxidants PROTEASOME mitochondrial transcription activator-like effector nucleases clustered regularly interspaced short palindromic repeats/associated protein 9 (CRISPR/cas9) caloric restriction stem cells
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CRISPR/Cas: a Nobel Prize award-winning precise genome editing technology for gene therapy and crop improvement 被引量:7
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作者 Chao LI Eleanor BRANT +1 位作者 Hikmet BUDAK Baohong ZHANG 《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》 SCIE CAS CSCD 2021年第4期253-284,共32页
Since it was first recognized in bacteria and archaea as a mechanism for innate viral immunity in the early 2010 s,clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein(Cas)has ra... Since it was first recognized in bacteria and archaea as a mechanism for innate viral immunity in the early 2010 s,clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein(Cas)has rapidly been developed into a robust,multifunctional genome editing tool with many uses.Following the discovery of the initial CRISPR/Cas-based system,the technology has been advanced to facilitate a multitude of different functions.These include development as a base editor,prime editor,epigenetic editor,and CRISPR interference(CRISPRi)and CRISPR activator(CRISPRa)gene regulators.It can also be used for chromatin and RNA targeting and imaging.Its applications have proved revolutionary across numerous biological fields,especially in biomedical and agricultural improvement.As a diagnostic tool,CRISPR has been developed to aid the detection and screening of both human and plant diseases,and has even been applied during the current coronavirus disease 2019(COVID-19)pandemic.CRISPR/Cas is also being trialed as a new form of gene therapy for treating various human diseases,including cancers,and has aided drug development.In terms of agricultural breeding,precise targeting of biological pathways via CRISPR/Cas has been key to regulating molecular biosynthesis and allowing modification of proteins,starch,oil,and other functional components for crop improvement.Adding to this,CRISPR/Cas has been shown capable of significantly enhancing both plant tolerance to environmental stresses and overall crop yield via the targeting of various agronomically important gene regulators.Looking to the future,increasing the efficiency and precision of CRISPR/Cas delivery systems and limiting off-target activity are two major challenges for wider application of the technology.This review provides an in-depth overview of current CRISPR development,including the advantages and disadvantages of the technology,recent applications,and future considerations. 展开更多
关键词 Genome editing Clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein(cas) Coronavirus disease 2019(COVID-19) Cancer Precision breeding Crop improvement Gene knock-out/in Gene repair/replacement
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OsDMI3-mediated OsUXS3 phosphorylation improves oxidative stress tolerance by modulating OsCATB protein abundance in rice
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作者 Lan Ni Qingwen Wang +7 位作者 Chao Chen Shuang Wang Tao Shen Jingjing Jiang Zhenzhen Cui Kaiyue Li Qiqing Yang Mingyi Jiang 《Journal of Integrative Plant Biology》 SCIE CAS CSCD 2022年第5期1087-1101,共15页
Calcium(Ca^(2+))/calmodulin(CaM)-dependent protein kinase(CCaMK)is an important positive regulator of antioxidant defenses and tolerance against oxidative stress.However,the underlying molecular mechanisms are largely... Calcium(Ca^(2+))/calmodulin(CaM)-dependent protein kinase(CCaMK)is an important positive regulator of antioxidant defenses and tolerance against oxidative stress.However,the underlying molecular mechanisms are largely unknown.Here,we report that the rice(Oryza sativa)CCa MK(OsDMI3)physically interacts with and phosphorylates OsUXS3,a cytosol-localized UDP-xylose synthase.Genetic and biochemical evidence demonstrated that OsUXS3 acts downstream of OsDMI3 to enhance the oxidative stress tolerance conferred by higher catalase(CAT)activity.Indeed,OsUXS3 interacted with CAT isozyme B(OsCATB),and this interaction was required to increase OsCATB protein abundance under oxidative stress conditions.Furthermore,we showed that OsDMI3 phosphorylates OsUXS3 on residue Ser-245,thereby further promoting the interaction between OsUXS3 and OsCATB.Our results indicate that OsDMI3 promotes the association of OsUXS3 with OsCATB to enhance CAT activity under oxidative stress.These findings reveal OsUXS3 as a direct target of OsDMI3 and demonstrate its involvement in antioxidant defense. 展开更多
关键词 Ca2+/calmodulin-dependent protein kinase CATALASE oxidative stress RICE UDP-xylose synthase
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Role of oxygen free radicals in the proliferation of myofibroblasts induced by AngII
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作者 Liying Wang Hong Li Shijie Yang 《Acta Pharmaceutica Sinica B》 SCIE CAS 2013年第1期32-37,共6页
Previous studies have demonstrated the important role of angiotension II(AngII)in promoting proliferation of myofibroblasts(myoFbs)and myocardial fibrosis.However,the underlying mechanisms and the role of oxygen free ... Previous studies have demonstrated the important role of angiotension II(AngII)in promoting proliferation of myofibroblasts(myoFbs)and myocardial fibrosis.However,the underlying mechanisms and the role of oxygen free radicals in the proliferation of myofibroblasts induced by AngII are unclear.The present study was designed to shed light on this issue through exploration of AngII signaling pathways via in vitro experiments.Primary cultures of neonatal rat myoFbs were divided into five groups which were treated with AngII(10^(-8) to 10^(-6) M),AngII with the antioxidant N-acetyl-L-cysteine(NAC),or normal culture medium.We observed the proliferation of myoFbs as induced by AngII at different concentrations with MTT.Reactive oxygen species(ROS)levels in myoFbs were detected by monitoring the fluorescence of 2',7'-dichlorofluorescein.The contents and levels of oxygen free radicals(OH·)in the three groups were detected by spectrophotometer,immunocytochemical staining,and confocal fluorescence.Western blot and image analysis were used to measure membrane translocation and expression of phospho-protein kinase Ca.MyoFbs incubated with AngII(10^(-8) to 10^(-6) M)for 24 h increased their rate of proliferation,the content of OH·,and expression of ROS(P<0.01 vs.control group),whereas these parameters decreased in the presence of NAC.Immunocytochemistry,confocal fluorescence staining and image analysis showed that AngII could promote the translocation and expression of p-PKCα in membrane,and the antioxidant NAC blocked this increase(P<0.01).Western blot results also showed that NAC could inhibit the expression of p-PKCα. 展开更多
关键词 N-ACETYL-L-CYSTEINE ANGII Oxygen free radical MYOFIBROBLASTS protein kinase Ca
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