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Repurposed benzydamine targeting CDK2 suppresses the growth of esophageal squamous cell carcinoma

《医学前沿（英文）》 2023年 第17卷 第2期   页码 290-303 doi: 10.1007/s11684-022-0956-8

摘要： Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer death worldwide. It is urgent to develop new drugs to improve the prognosis of ESCC patients. Here, we found benzydamine, a locally acting non-steroidal anti-inflammatory drug, had potent cytotoxic effect on ESCC cells. Benzydamine could suppress ESCC proliferation in vivo and in vitro. In terms of mechanism, CDK2 was identified as a target of benzydamine by molecular docking, pull-down assay and in vitro kinase assay. Specifically, benzydamine inhibited the growth of ESCC cells by inhibiting CDK2 activity and affecting downstream phosphorylation of MCM2, c-Myc and Rb, resulting in cell cycle arrest. Our study illustrates that benzydamine inhibits the growth of ESCC cells by downregulating the CDK2 pathway.

关键词： benzydamine     cyclin-dependent kinase 2     patient-derived xenograft     esophageal squamous cell carcinoma    

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Lentivector-mediated RNAi efficiently downregulates expression of murine cdk4 gene

Feng JIANG PhD , Xuezhen WANG PhD , Zheng XUE MD , Suming ZHANG PhD , Siyu FANG BM , Min ZHANG MD, PhD ,

《医学前沿（英文）》 2009年 第3卷 第3期   页码 287-291 doi: 10.1007/s11684-009-0050-5

摘要： In order to explore the role of cyclin-dependent kinase 4 (cdk4) in neurodegenerative diseases, lentiviral-delivered RNA interference (RNAi) was used to silence the expression of the murine cdk4 gene . Three cdk4-shRNAs of mouse and a negative sequence were designed. After synthesis and annealing, double strand oligonucleotides were cloned into a linearized pSIH1-H1-copGFP shRNA vector. It was confirmed by polymerase chain reaction (PCR) and sequencing that three pairs of cdk4-shRNAs and a negative shRNA were correctly inserted into the pSIH1-H1-copGFP vector. The above recombinants were transfected by lipofectamine into BV-2 cells. The gene silencing efficacy rates of the 3 targets were compared by Western blotting. The cdk4-siRNA2 was the most effective in silencing cdk4. The optimized pSIH1-cdk4-siRNA2 and pSIH-negative-siRNA were co-transfected into 293T cells with the lentiviral packaging plasmids respectively. The culture supernatant was harvested and condensed at the 24th and 48thh after transfection. Interference efficiency of the lentivirus expressing cdk4-siRNA was determined by reverse transcriptase-PCR (RT-PCR) and Western blotting in BV-2 cells. Lentivector-mediated RNAi could efficiently down-regulate the expression of the murine cdk4 gene , which provides a potential tool for studying and treating cdk4-related diseases.

关键词： cyclin-dependent kinase 4     RNA interference     plasmid     lentiviral vector    

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The role of CDK1 siRNA interference in cell cycle and cell apoptosis

Hui XIAO PhD, Ming TIAN MM, Junna GE MM, Xin Wei MD, Zhaoming LI MM, Xiaolan LI MS, Deding TAO PhD, Junbo HU MD, Jianping GONG MD,

《医学前沿（英文）》 2009年 第3卷 第4期   页码 384-389 doi: 10.1007/s11684-009-0070-1

摘要： In the present report, cyclin-dependent kinase1 (CDK1) siRNA was transfected into cells to silence the CDK1 gene expression and study its role in the cell cycle and cell apoptosis. The siRNA targeting CDK1 gene was chemically synthesized and transfected into Hela cells by lipofectamine 2000. The expression levels of CDK1 gene and protein were examined by real-time quantitative polymerase chain reaction (PCR) and Western blot, respectively. The cell cycle was analyzed by using DNA content analysis by flow cytometry. Cell apoptosis was detected by the Annexin V/PI method. The morphological changes of transfected cells were examined under the microscopy by Wright-Giemsa stain. CDK1 gene was successfully silenced by its siRNA, and the CDK1 protein expression level was decreased significantly, especially from 48thh to 60thh after transfection. The DNA content analysis showed that transfection of CDK1 siRNA led to cells accumulating in G/M phase. There was no significant difference in the apoptotic rate between transfected cells and the control cells after transfection of CDK1 siRNA for 48 or 60h. More double nucleus or multinucleus cells could be seen under the microscopy among the transfected cells. The decreased CDK1 expression by siRNA silencing gave rise to cell cycle arrest in G/M phase but did not induce apoptosis.

关键词： cyclin-dependent kinase1     siRNA interference     cell cycle     apoptosis    

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Effect of inhibiting tyrosine kinase Src expression on protein phosphatase 2A and tau phosphorylation

LIU Rong, ZENG Ji, ZHOU Xinwen, WANG Jianzhi, PEI Jinjing

《医学前沿（英文）》 2008年 第2卷 第3期   页码 235-238 doi: 10.1007/s11684-008-0044-8

摘要： The aim of this study is to investigate the effect of tyrosine kinase Src on Tyrosine 307(Y307) phosphorylation, protein phosphatase 2A (PP2A) activity, and on tau phosphorylation. Specific Src siRNA was transfected into cultured mouse neuroblastoma N2a cells to inhibit the expression of Src protein, and the phosphorylation levels of PP2A Y307 and tau at different sites, as well as PP2A activity were detected at different time points after siRNA transfection. Twelve hours after siRNA transfection, the protein level of Src was dramatically decreased, with decreased PP2A Y307 phosphorylation. However, the total PP2A protein level was also decreased, together with a decreased PP2A activity. Tau was hyperphosphorylated at the Ser198/199/202 sites. Multiple factors may be involved in the cellular regulation of PP2A activity. Inhibiting Src expression could induce inactivation of PP2A and tau hyperphosphorylation.

关键词： hyperphosphorylation     PP2A activity     cellular regulation     siRNA     siRNA transfection    

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GDF15 negatively regulates chemosensitivity via TGFBR2-AKT pathway-dependent metabolism in esophageal

《医学前沿（英文）》 2023年 第17卷 第1期   页码 119-131 doi: 10.1007/s11684-022-0949-7

摘要： Treating patients with esophageal squamous cell carcinoma (ESCC) is challenging due to the high chemoresistance. Growth differentiation factor 15 (GDF15) is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research. In this study, the link between GDF15 and chemotherapy resistance in ESCC was further explored. The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies. ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response. GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2. Through an in vivo study, we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin. Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A. AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A, indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin. The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy, resulting in beneficial therapeutic outcomes.

关键词： GDF15     esophageal squamous cell carcinoma     chemoresistance     cellular metabolism     TGFBR2     AKT    

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Inhibition of protein kinase B by Palmitate in the insulin signaling of HepG2 cells and the preventive

XIA Yanzhi, WAN Xuedong, DUAN Qiuhong, HE Shansu, WANG Ximing

《医学前沿（英文）》 2007年 第1卷 第2期   页码 200-206 doi: 10.1007/s11684-007-0038-y

摘要： Elevated plasma levels of free fatty acids (FFAs) may contribute to insulin resistance (IR) that is characteristic of type 2 diabetes mellitus. In this study, we investigated the effects of two fatty acids, palmitate (PA) and arach

关键词： palmitate     characteristic     study     plasma     resistance    

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China’s carbon neutrality: an extensive and profound systemic reform

《环境科学与工程前沿（英文）》 2023年 第17卷 第2期 doi: 10.1007/s11783-023-1614-3

摘要：

● China has pledged ambitious carbon peak and neutrality goals for mitigating global climate change.

关键词： Carbon neutrality     Energy structure     Technology-dependent society     Coordinated mitigation for air pollutants and CO2    

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Mechanisms of insulin resistance in obesity

null

《医学前沿（英文）》 2013年 第7卷 第1期   页码 14-24 doi: 10.1007/s11684-013-0262-6

摘要：

Obesity increases the risk for type 2 diabetes through induction of insulin resistance. Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance. In those hypotheses, inflammation, mitochondrial dysfunction, hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention. Oxidative stress, endoplasmic reticulum (ER) stress, genetic background, aging, fatty liver, hypoxia and lipodystrophy are active subjects in the study of these concepts. However, none of those concepts or views has led to an effective therapy for type 2 diabetes. The reason is that, there has been no consensus for a unifying mechanism of insulin resistance. In this review article, literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance, in which insulin resistance is a result of energy surplus in cells. The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance. In support, many of existing insulin sensitizing medicines inhibit ATP production in mitochondria. The effective therapies such as weight loss, exercise, and caloric restriction all reduce ATP in insulin sensitive cells. This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity, which may apply to insulin resistance in aging and lipodystrophy.

关键词： type 2 diabetes     energy expenditure     inflammation     lipotoxicity     mitochondria     hyperinsulinemia     adenosine monophosphate-activated protein kinase (AMPK)    

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Annexin A2-S100A10 heterotetramer is upregulated by PML/RARα fusion protein and promotes plasminogen-dependent

null

《医学前沿（英文）》 2017年 第11卷 第3期   页码 410-422 doi: 10.1007/s11684-017-0527-6

摘要：

Aberrant expression of annexin A2-S100A10 heterotetramer (AIIt) associated with PML/RARα fusion protein causes lethal hyperfibrinolysis in acute promyelocytic leukemia (APL), but the mechanism is unclear. To facilitate the investigation of regulatory association between ANXA2 and promyelocytic leukemia/retinoic acid receptor a (PML/RARα) fusion protein, this work was performed to determine the transcription start site of ANXA2 promoter with rapid amplification of 5′-cDNA ends analysis. Zinc-induced U937/PR9 cells expressed PML/RARα fusion protein, and resultant increases in ANXA2 transcripts and translational expressions of both ANXA2 and S100A10, while S100A10 transcripts remained constitutive. The transactivation of ANXA2 promoter by PML/RARα fusion protein was 3.29±0.13 fold higher than that by control pSG5 vector or wild-type RARα. The overexpression of ANXA2 in U937 transfected with full-length ANXA2 cDNA was associated with increased S100A10 subunit, although S100A10 transcripts remained constitutive. The tPA-dependent initial rate of plasmin generation (IRPG) in zinc-treated U937/PR9 increased by 2.13-fold, and cell invasiveness increased by 27.6%. Antibodies against ANXA2, S100A10, or combination of both all remarkably inhibited the IRPG and invasiveness in U937/PR9 and NB4. Treatment of zinc-induced U937/PR9 or circulating APL blasts with all-trans retinoic acid (ATRA) significantly reduced cell surface ANXA2 and S100A10 and associated reductions in IRPG and invasiveness. Thus, PML/RARα fusion protein transactivated the ANXA2 promoter to upregulate ANXA2 and accumulate S100A10. Increased AIIt promoted IRPG and invasiveness, both of which were partly abolished by antibodies against ANXA2 and S100A10 or by ATRA.

关键词： annexin A2-S100A10 heterotetramer     PML/RARα fusion protein     plasmin     cell invasion     acute promyelocytic leukemia    

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Transformer2 proteins protect breast cancer cells from accumulating replication stress by ensuring productivesplicing of checkpoint kinase 1

Andrew Best,Katherine James,Gerald Hysenaj,Alison Tyson-Capper,David J. Elliott

《化学科学与工程前沿（英文）》 2016年 第10卷 第2期   页码 186-195 doi: 10.1007/s11705-015-1540-4

摘要： Increased expression levels of the RNA splicing regulator Transformer2 (abbreviated Tra2 ) have been reported in several types of cancer. Recent work has revealed an intimate cross-regulation between Tra2 and the highly similar Tra2 protein in human breast cancer cells, though these two proteins are encoded by separate genes created by a gene duplication that occurred over 500 million years ago. This cross-regulation involves splicing control of a special class of exons, called poison exons. Down-regulation of Tra2 reduces splicing inclusion of a poison exon in the mRNA encoding Tra2 , thereby up-regulating Tra2 protein expression. This buffers any splicing changes that might be caused by individual depletion of Tra2 alone. Discovery of this cross-regulation pathway, and its by-pass by joint depletion of both human Tra2 proteins, revealed Tra2 proteins are essential for breast cancer cell viability, and led to the identification of important targets for splicing control. These exons include a critical exon within the checkpoint kinase 1 (CHK1) gene that plays a crucial function in the protection of cancer cells from replication stress. Breast cancer cells depleted for Tra2 proteins have reduced CHK1 protein levels and accumulate DNA damage. These data suggest Tra2 proteins and/or their splicing targets as possible cancer drug targets.

关键词： RNA splicing     gene expression     breast cancer     DNA damage     CHK1    

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Discovery of small molecule degraders for modulating cell cycle

《医学前沿（英文）》   页码 823-854 doi: 10.1007/s11684-023-1027-5

摘要： The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.

关键词： PROTAC     molecular glue     degrader     cell cycle     CDK     cyclin    

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The role of protein kinase C epsilon in neural signal transduction and neurogenic diseases

null

《医学前沿（英文）》 2011年 第5卷 第1期   页码 70-76 doi: 10.1007/s11684-011-0119-9

摘要：

Protein kinase C epsilon (PKC ?) is one of major isoforms in novel PKC family. Although it has been extensively characterized in the past decade, the role of PKC ? in neuron is still not well understood. Advances in molecular biology have now removed significant barriers to the direct investigation of PKC ? functions in vivo, and PKC ? has been increasingly implicated in the neural biological functions and associated neurogenic diseases. Recent studies have provided important insights into the influence of PKC ? on cortical processing at both the single cell level and network level. These studies provide compelling evidence that PKC ? could regulate distinct aspects of neural signal transduction and suggest that the coordinated actions of a number of molecular signals contribute to the specification and differentiation of PKC ? signal pathway in the developing brain.

关键词： protein kinase C ?     signal transduction     neurogenic disease    

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Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors

null

《医学前沿（英文）》 2016年 第10卷 第4期   页码 383-388 doi: 10.1007/s11684-016-0488-1

摘要：

The tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are becoming the first line of therapy for advanced non-small cell lung cancer (NSCLC). Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 (osimertinib; Tagrisso) is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9–13 months of therapy. The mechanisms of resistance to third-generation inhibitors reported to date include the EGFR C797S mutation, EGFR L718Q mutation, and amplifications of HER-2, MET, or ERBB2. To overcome the acquired resistance to AZD9291, EAI045 was discovered and recently reported to be an allosteric EGFR inhibitor that overcomes T790M- and C797S-mediated resistance. This review summarizes recent investigations on the mechanisms of resistance to the EGFR TKIs, as well as the latest development of EAI045 as a fourth-generation EGFR inhibitor.

关键词： EGFR     tyrosine kinase inhibitor     AZD9291     EAI045    

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Data-driven approach to solve vertical drain under time-dependent loading

《结构与土木工程前沿（英文）》 2021年 第15卷 第3期   页码 696-711 doi: 10.1007/s11709-021-0727-7

摘要： Currently, the vertical drain consolidation problem is solved by numerous analytical solutions, such as time-dependent solutions and linear or parabolic radial drainage in the smear zone, and no artificial intelligence (AI) approach has been applied. Thus, in this study, a new hybrid model based on deep neural networks (DNNs), particle swarm optimization (PSO), and genetic algorithms (GAs) is proposed to solve this problem. The DNN can effectively simulate any sophisticated equation, and the PSO and GA can optimize the selected DNN and improve the performance of the prediction model. In the present study, analytical solutions to vertical drains in the literature are incorporated into the DNN–PSO and DNN–GA prediction models with three different radial drainage patterns in the smear zone under time-dependent loading. The verification performed with analytical solutions and measurements from three full-scale embankment tests revealed promising applications of the proposed approach.

关键词： vertical drain     artificial neural network     time-dependent loading     deep learning network     genetic algorithm     particle swarm optimization    

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Chloride binding and time-dependent surface chloride content models for fly ash concrete

S. MUTHULINGAM,B. N. RAO

《结构与土木工程前沿（英文）》 2016年 第10卷 第1期   页码 112-120 doi: 10.1007/s11709-015-0322-x

摘要： Corrosion of embedded rebars is a classical deterioration mechanism of reinforced concrete structures exposed to chloride environments. Such environments can be attributed to the presence of seawater, deicing or sea-salts, which have high concentrations of chloride ion. Chloride ingress into concrete, essential for inducing rebar corrosion, is a complex interaction between many physical and chemical processes. The current study proposes two chloride ingress parameter models for fly ash concrete, namely: 1) surface chloride content under tidal exposure condition; and 2) chloride binding. First, inconsistencies in surface chloride content and chloride binding models reported in literature, due to them not being in line with past research studies, are pointed out. Secondly, to avoid such inconsistencies, surface chloride content and chloride binding models for fly ash concrete are proposed based upon the experimental work done by other researchers. It is observed that, proposed models are simple, consistent and in line with past research studies reported in literature.

关键词： binding isotherms     chloride ingress     concrete     fly ash     surface chloride content    

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标题 作者 时间 类型 操作

Repurposed benzydamine targeting CDK2 suppresses the growth of esophageal squamous cell carcinoma

期刊论文

Lentivector-mediated RNAi efficiently downregulates expression of murine cdk4 gene

Feng JIANG PhD , Xuezhen WANG PhD , Zheng XUE MD , Suming ZHANG PhD , Siyu FANG BM , Min ZHANG MD, PhD ,

期刊论文

The role of CDK1 siRNA interference in cell cycle and cell apoptosis

Hui XIAO PhD, Ming TIAN MM, Junna GE MM, Xin Wei MD, Zhaoming LI MM, Xiaolan LI MS, Deding TAO PhD, Junbo HU MD, Jianping GONG MD,

期刊论文

Effect of inhibiting tyrosine kinase Src expression on protein phosphatase 2A and tau phosphorylation

LIU Rong, ZENG Ji, ZHOU Xinwen, WANG Jianzhi, PEI Jinjing

期刊论文

GDF15 negatively regulates chemosensitivity via TGFBR2-AKT pathway-dependent metabolism in esophageal

期刊论文

Inhibition of protein kinase B by Palmitate in the insulin signaling of HepG2 cells and the preventive

XIA Yanzhi, WAN Xuedong, DUAN Qiuhong, HE Shansu, WANG Ximing

期刊论文

China’s carbon neutrality: an extensive and profound systemic reform

期刊论文

Mechanisms of insulin resistance in obesity

null

期刊论文

Annexin A2-S100A10 heterotetramer is upregulated by PML/RARα fusion protein and promotes plasminogen-dependent

null

期刊论文

Transformer2 proteins protect breast cancer cells from accumulating replication stress by ensuring productivesplicing of checkpoint kinase 1

Andrew Best,Katherine James,Gerald Hysenaj,Alison Tyson-Capper,David J. Elliott

期刊论文

Discovery of small molecule degraders for modulating cell cycle

期刊论文

The role of protein kinase C epsilon in neural signal transduction and neurogenic diseases

null

期刊论文

Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors

null

期刊论文

Data-driven approach to solve vertical drain under time-dependent loading

期刊论文

Chloride binding and time-dependent surface chloride content models for fly ash concrete

S. MUTHULINGAM,B. N. RAO

期刊论文