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1.
Cell Adh Migr ; 18(1): 1-11, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38357988

ABSTRACT

The intensive study and investigation of neuroprotective therapy for central nervous system (CNS) diseases is ongoing. Due to shared mechanisms of neurodegeneration, a neuroprotective approach might offer benefits across multiple neurological disorders, despite variations in symptoms or injuries. C-Jun N-terminal Kinase 3 (JNK3) is found primarily in the CNS and is involved in physiological processes such as brain development, synapse formation, and memory formation. The potential of JNK3 as a target for pharmacological development holds promise for advancing neuroprotective therapies. Developing small molecule JNK3 inhibitors into drugs with neuroprotective qualities could facilitate neuronal restoration and self-repair. This review focuses on elucidating key neuroprotective mechanisms, exploring the interplay between neurodegenerative diseases and neuroprotection, and discussing advancements in JNK3 inhibitor drug development.


Subject(s)
Mitogen-Activated Protein Kinase 10 , Neuroprotection , Mitogen-Activated Protein Kinase 10/physiology , Protein Kinase Inhibitors/pharmacology
2.
Angew Chem Int Ed Engl ; 62(49): e202315249, 2023 Dec 04.
Article in English | MEDLINE | ID: mdl-37877345

ABSTRACT

Discovering new bonding scenarios and subsequently exploring the reactivity contribute substantially to advance the main group element chemistry. Herein, we report on the isolation and characterization of an intriguing class of the hydrido-benzosiloles 2-4. These compounds exhibit a side arm of the amidinatosilylenyl group, featuring unidirectional silicon(II)/silicon(IV) donor-acceptor interaction on account of the geometric constraint. Furthermore, the reactions involving 2-4 with nitriles yield the tricyclic compounds that edge-fused of the Si-heteroimidazolidine-CN2 Si2 , silole-C4 Si, and phenyl-C6 -rings (5-13). These compounds are manifesting a unique reaction that the silicon(II)/silicon(IV) interaction enables the enamination of the α-H-bearing nitriles. The reaction mechanism involved in H-shift under oxidative addition at silylene followed by hydrosilylation of a ketenimine intermediate was revealed by density function theory (DFT) calculations.

3.
Nat Commun ; 14(1): 3864, 2023 06 30.
Article in English | MEDLINE | ID: mdl-37391417

ABSTRACT

The eukaryotic single-stranded DNA (ssDNA)-binding protein Replication Protein A (RPA) plays a crucial role in various DNA metabolic pathways, including DNA replication and repair, by dynamically associating with ssDNA. While the binding of a single RPA molecule to ssDNA has been thoroughly studied, the accessibility of ssDNA is largely governed by the bimolecular behavior of RPA, the biophysical nature of which remains unclear. In this study, we develop a three-step low-complexity ssDNA Curtains method, which, when combined with biochemical assays and a Markov chain model in non-equilibrium physics, allow us to decipher the dynamics of multiple RPA binding to long ssDNA. Interestingly, our results suggest that Rad52, the mediator protein, can modulate the ssDNA accessibility of Rad51, which is nucleated on RPA coated ssDNA through dynamic ssDNA exposure between neighboring RPA molecules. We find that this process is controlled by the shifting between the protection mode and action mode of RPA ssDNA binding, where tighter RPA spacing and lower ssDNA accessibility are favored under RPA protection mode, which can be facilitated by the Rfa2 WH domain and inhibited by Rad52 RPA interaction.


Subject(s)
DNA, Single-Stranded , Rad51 Recombinase , Replication Protein A , DNA, Single-Stranded/genetics , DNA-Binding Proteins/genetics , Replication Protein A/genetics , Rad51 Recombinase/genetics
4.
BMC Cancer ; 23(1): 479, 2023 May 26.
Article in English | MEDLINE | ID: mdl-37237269

ABSTRACT

BACKGROUND: B-cell lymphoma 2 (Bcl-2) family proteins are key regulators of apoptosis, which possess four conserved Bcl-2 homologies (BH) domains. Among the BH domains, the BH3 domain is considered as a potent 'death domain' while the BH4 domain is required for anti-apoptotic activity. Bcl-2 can be converted to a pro-apoptotic molecule through the removal or mutation of the BH4 domain. Bcl-2 is considered as an inducer of angiogenesis, which can promote tumor vascular network formation and further afford nutrients and oxygen to promote tumor progression. However, whether disrupting the function of the BH4 domain to convert Bcl-2 into a pro-apoptotic molecule could make Bcl-2 possess the potential for anti-angiogenic therapy remains to be defined. METHODS: CYD0281 was designed and synthesized according to the lead structure of BDA-366, and its function on inducing a conformational change of Bcl-2 was further evaluated via immunoprecipitation (IP) and immunofluorescence (IF) assays. Moreover, the function of CYD0281 on apoptosis of endothelial cells was analyzed via cell viability, flow cytometry, and western blotting assays. Additionally, the role of CYD0281 on angiogenesis in vitro was determined via endothelial cell migration and tube formation assays and rat aortic ring assay. Chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models, breast cancer cell xenograft tumor on CAM and in mouse models as well as the Matrigel plug angiogenesis assay were used to explore the effects of CYD0281 on angiogenesis in vivo. RESULTS: We identified a novel potent small-molecule Bcl-2-BH4 domain antagonist, CYD0281, which exhibited significant anti-angiogenic effects both in vitro and in vivo, and further inhibited breast cancer tumor growth. CYD0281 was found to induce conformational changes in Bcl-2 through the exposure of the BH3 domain and convert Bcl-2 from an anti-apoptotic molecule into a cell death inducer, thereby resulting in the apoptosis of vascular endothelial cells. CONCLUSIONS: This study has revealed CYD0281 as a novel Bcl-2-BH4 antagonist that induces conformational changes of Bcl-2 to convert to a pro-apoptotic molecule. Our findings indicate that CYD0281 plays a crucial role in anti-angiogenesis and may be further developed as a potential anti-tumor drug candidate for breast cancer. This work also provides a potential anti-angiogenic strategy for breast cancer treatment.


Subject(s)
Antineoplastic Agents , Breast Neoplasms , Chick Embryo , Mice , Humans , Rats , Animals , Female , Proto-Oncogene Proteins c-bcl-2/metabolism , Endothelial Cells/metabolism , Protein Domains , Breast Neoplasms/drug therapy , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Apoptosis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use
5.
Front Psychol ; 13: 967568, 2022.
Article in English | MEDLINE | ID: mdl-36160564

ABSTRACT

An increasing number of college students have taken out campus loans. This trend has had a negative impact on their learning and development. Using survey data about Chinese college students, this study explores the influence of a conspicuous identity and conformity on campus loan behavior and usage intention. Identify economics posits that identity is a key factor affecting individual behavior and decision-making. Differentiated identify is linked to differentiated social groups and constituted through specific value orientations, social norms and codes of conduct. This study shows that college students with a conspicuous identity are more likely to take out campus loans and more willing to take out such loans in the following year. The discussion on heterogeneity shows that a conspicuous identity has significantly positive effects on campus loan behavior for students in groups with higher consumption and grade, while conformity has significantly positive effects on campus loan behavior when students are in lower-grade groups. Compared with students who have never used campus loans, students who have taken out are more willing to take them out again in the future. Finally, avoidance strategies of campus loan debt are provided from two perspectives, namely, identity construction and the classification of education.

6.
Inorg Chem ; 61(13): 5215-5223, 2022 Apr 04.
Article in English | MEDLINE | ID: mdl-35312318

ABSTRACT

Two borylaminoamidinatosilylenes (L)[(1,5-C8H14)B(Ar)N]Si (L = PhC(NtBu)2, Ar = 2,6-iPr2C6H3 (1)) and (L)[(1,5-C8H14)B(Ar')N]Si (Ar' = 2,4,6-Me3C6H2 (2)) have been prepared and utilized to investigate the reaction toward isocyanide. Reactions of 1 with the respective CN-2,6-Me2C6H3 and CNCy (Cy = cyclo-C6H11) produced compounds (L)Si(NAr)C(N-2,6-Me2C6H3)B(1,5-C8H14)(CN-2,6-Me2C6H3) (3) and (L)Si(NAr)C(NCy)C(NCy)B(1,5-C8H14)(CNCy) (4). Reactions of 2 with the respective CNCy and CN-2,6-Me2C6H3 yielded compounds cyclo-(L)SiN(Ar')C(NCy)B(1,5-C8H14)C(NCy) (5) and cyclo-(L)[(1,5-C8H14)B(Ar')N]SiC(CN-2,6-Me2C6H3)N(2,6-Me2C6H3)C(N-2,6-Me2C6H3) (6). Compounds 3-6 have different compositions and structures from each other. Density functional theory (DFT) calculations suggest initial formation of (L)[(1,5-C8H14)B(←:CN-2,6-Me2C6H3)(Ar)N]Si (A), (L)[(1,5-C8H14)B(←:CNCy)(Ar)N]Si (A'), (L)[(1,5-C8H14)B(←:CNCy)-(Ar')N]Si (A″), and (L)[(1,5-C8H14)B(←:CN-2,6-Me2C6H3)(Ar')N]Si (A‴) as the respective intermediates. The as-followed transition states TS, TS1', TS1″, and TS‴ all feature probable Si:→C(═N):→B bonding with different Gibbs energies of 7.24, 2.46, 3.86, and 6.59 kcal/mol, respectively, due to variation among the Ar, Ar', 2,6-Me2C6H3, and Cy groups in these species, and reacted in different ways.

7.
EMBO J ; 41(4): e108290, 2022 02 15.
Article in English | MEDLINE | ID: mdl-35028974

ABSTRACT

Nucleotide metabolism fuels normal DNA replication and is also primarily targeted by the DNA replication checkpoint when replication stalls. To reveal a comprehensive interconnection between genome maintenance and metabolism, we analyzed the metabolomic changes upon replication stress in the budding yeast S. cerevisiae. We found that upon treatment of cells with hydroxyurea, glucose is rapidly diverted to the oxidative pentose phosphate pathway (PPP). This effect is mediated by the AMP-dependent kinase, SNF1, which phosphorylates the transcription factor Mig1, thereby relieving repression of the gene encoding the rate-limiting enzyme of the PPP. Surprisingly, NADPH produced by the PPP is required for efficient recruitment of replication protein A (RPA) to single-stranded DNA, providing the signal for the activation of the Mec1/ATR-Rad53/CHK1 checkpoint signaling kinase cascade. Thus, SNF1, best known as a central energy controller, determines a fast mode of replication checkpoint activation through a redox mechanism. These findings establish that SNF1 provides a hub with direct links to cellular metabolism, redox, and surveillance of DNA replication in eukaryotes.


Subject(s)
DNA Replication , Protein Serine-Threonine Kinases/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Checkpoint Kinase 2/genetics , Checkpoint Kinase 2/metabolism , DNA Replication/drug effects , DNA, Single-Stranded/metabolism , Glucose/genetics , Glucose/metabolism , Glycolysis/physiology , Hydroxyurea , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , NADP/metabolism , Pentose Phosphate Pathway , Phosphorylation , Protein Serine-Threonine Kinases/genetics , Replication Protein A/genetics , Replication Protein A/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism
8.
Nat Commun ; 13(1): 359, 2022 01 18.
Article in English | MEDLINE | ID: mdl-35042867

ABSTRACT

Single-stranded DNA (ssDNA) commonly occurs as intermediates in DNA metabolic pathways. The ssDNA binding protein, RPA, not only protects the integrity of ssDNA, but also directs the downstream factor that signals or repairs the ssDNA intermediate. However, it remains unclear how these enzymes/factors outcompete RPA to access ssDNA. Using the budding yeast Saccharomyces cerevisiae as a model system, we find that Dna2 - a key nuclease in DNA replication and repair - employs a bimodal interface to act with RPA both in cis and in trans. The cis-activity makes RPA a processive unit for Dna2-catalyzed ssDNA digestion, where RPA delivers its bound ssDNA to Dna2. On the other hand, activity in trans is mediated by an acidic patch on Dna2, which enables it to function with a sub-optimal amount of RPA, or to overcome DNA secondary structures. The trans-activity mode is not required for cell viability, but is necessary for effective double strand break (DSB) repair.


Subject(s)
DNA Helicases/metabolism , DNA, Fungal/metabolism , DNA, Single-Stranded/metabolism , Replication Protein A/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/metabolism , Biocatalysis , Cell Survival/drug effects , DNA Breaks, Double-Stranded , DNA Repair , Models, Biological , Mutation/genetics , Peptides/metabolism , Phleomycins/pharmacology , Protein Binding , Protein Domains , Saccharomyces cerevisiae Proteins/chemistry , Tyrosine/metabolism
9.
Chemistry ; 28(5): e202103715, 2022 Jan 24.
Article in English | MEDLINE | ID: mdl-34837718

ABSTRACT

Electron-transferable oxidants such as B(C6 F5 )3 /nBuLi, B(C6 F5 )3 /LiB(C6 F5 )4 , B(C6 F5 )3 /LiHBEt3 , Al(C6 F5 )3 /(o-RC6 H4 )AlH2 (R=N(CMe2 CH2 )2 CH2 ), B(C6 F5 )3 /AlEt3 , Al(C6 F5 )3 , Al(C6 F5 )3 /nBuLi, Al(C6 F5 )3 /AlMe3 , (CuC6 F5 )4 , and Ag2 SO4 , respectively were employed for reactions with (L)2 Si2 C4 (SiMe3 )2 (C2 SiMe3 )2 (L=PhC(NtBu)2 , 1). The stable radical cation [1]+. was formed and paired with the anions [nBuB(C6 F5 )3 ]- (in 2), [B(C6 F5 )4 ]- (in 3), [HB(C6 F5 )3 ]- (in 4), [EtB(C6 F5 )3 ]- (in 5), {[(C6 F5 )3 Al]2 (µ-F)]- (in 6), [nBuAl(C6 F5 )3 ]- (in 7), and [Cu(C6 F5 )2 ]- (in 8), respectively. The stable dication [1]2+ was also generated with the anions [EtB(C6 F5 )3 ]- (9) and [MeAl(C6 F5 )3 ]- (10), respectively. In addition, the neutral compound [(L)2 Si2 C4 (SiMe3 )2 (C2 SiMe3 )2 ][µ-O2 S(O)2 ] (11) was obtained. Compounds 2-11 are characterized by UV-vis absorption spectroscopy, X-ray crystallography, and elemental analysis. Compounds 2-8 are analyzed by EPR spectroscopy and compounds 9-11 by NMR spectroscopy. The structure features are discussed on the central Si2 C4 -rings of 1, [1]+. , [1]2+ , and 11, respectively.

10.
Food Funct ; 12(23): 11862-11871, 2021 Nov 29.
Article in English | MEDLINE | ID: mdl-34734615

ABSTRACT

In this study, the mechanisms of the delay of starch digestion by luteolin were revealed by studying the luteolin-PPA (porcine pancreatic α-amylase) interaction and luteolin-starch interaction. The luteolin-PPA interaction was investigated by inhibitory kinetics analysis, fluorescence quenching, circular dichroism (CD), Fourier transform infrared (FT-IR) spectroscopy and molecular docking. The results of the inhibitory kinetics revealed that luteolin was a mixed-type inhibitor of PPA and that the inhibitory action was reversible. Fluorescence spectroscopy (including fluorescence quenching and thermodynamics) and molecular docking analyses indicated that hydrogen bonds and hydrophobic forces were the main forces between PPA and luteolin. CD and FT-IR spectroscopy analyses showed that the interaction between luteolin and PPA changed the secondary structure of PPA and induced a decline in its activity. In addition, the luteolin-starch interaction was also studied using UV-visible absorption and X-ray diffraction analyses. These indicated that luteolin could bind with PPA, and that hydrogen bonds and van der Waals forces may be present. Overall, luteolin delayed starch digestion not only by binding with PPA but also by binding with starch. Thus, luteolin has the potential to prevent and control diabetes by being added into starch-based food to delay starch digestion.


Subject(s)
Digestion/drug effects , Luteolin , Starch/metabolism , Animals , Luteolin/chemistry , Luteolin/metabolism , Luteolin/pharmacology , Models, Biological , Molecular Docking Simulation , Pancreatic alpha-Amylases/antagonists & inhibitors , Protein Binding , Starch/chemistry , Swine
11.
J Am Chem Soc ; 143(5): 2212-2216, 2021 Feb 10.
Article in English | MEDLINE | ID: mdl-33507736

ABSTRACT

The reaction of (LSi:)2 (1; L = PhC(NtBu)2) with 2 equiv of Me3SiC2C2SiMe3 resulted in the formation of (Me3SiC2)2(Me3Si)2C4Si2(L)2 (2). 2 exhibited a one-electron transfer when treated with 1 equiv of [Ph3C]+[B(C6F5)4]- to yield [(Me3SiC2)2(Me3Si)2C4Si2(L)2]·+[B(C6F5)4]- (3) and Ph3CCPh3, respectively. When compound 2 was treated with 2 equiv of AgOSO2CF3 a transfer of two electrons occurred to produce [(Me3SiC2)2(Me3Si)2C4Si2(L)2]2+·2[OSO2CF3]- (4) and elemental silver. The 1,4-disilabenzene 2 is disclosed of an open-shell singlet diradical character, and 3 and 4 are, respectively, the elusive stable radical cation and dication species of the 1,4-disilabenzene (2). Furthermore, 2 reacted with group 16 elements of O, S, and Se by oxidative addition to form (Me3SiC2)2(Me3Si)2C4Si2(L)2(µ-O2) (5) and (Me3SiC2)2(Me3Si)2C4Si2(L)2(µ-E) (E = S (6) and Se (7)), respectively.

12.
Genome Announc ; 5(19)2017 May 11.
Article in English | MEDLINE | ID: mdl-28495768

ABSTRACT

The complete genome sequence of the enterovirus 71 strain CSF15/YN/CHN/2013, first isolated from cerebrospinal fluid of a child in Yunnan, China, in 2013, was determined. According to the phylogenetic and homogeneity analyses, the isolate was assigned to subgenotype C4a.

13.
Tumour Biol ; 39(2): 1010428317692264, 2017 Feb.
Article in English | MEDLINE | ID: mdl-28222663

ABSTRACT

Tumor necrosis factor receptor 1 is the main receptor mediating many tumor necrosis factor-alpha-induced cellular events. Some studies have shown that tumor necrosis factor receptor 1 promotes tumorigenesis by activating nuclear factor-kappa B signaling pathway, while other studies have confirmed that tumor necrosis factor receptor 1 plays an inhibitory role in tumors growth by inducing apoptosis in breast cancer. Therefore, the function of tumor necrosis factor receptor 1 in breast cancer requires clarification. In this study, we first found that tumor necrosis factor receptor 1 was significantly increased in human breast cancer tissues and cell lines, and knockdown of tumor necrosis factor receptor 1 by small interfering RNA inhibited cell proliferation by arresting the cell cycle and inducing apoptosis. In addition, miR-29a was predicted as a regulator of tumor necrosis factor receptor 1 by TargetScan and was shown to be inversely correlated with tumor necrosis factor receptor 1 expression in human breast cancer tissues and cell lines. Luciferase reporter assay further confirmed that miR-29a negatively regulated tumor necrosis factor receptor 1 expression by binding to the 3' untranslated region. In our functional study, miR-29a overexpression remarkably suppressed cell proliferation and colony formation, arrested the cell cycle, and induced apoptosis in MCF-7 cell. Furthermore, in combination with tumor necrosis factor receptor 1 transfection, miR-29a significantly reversed the oncogenic role caused by tumor necrosis factor receptor 1 in MCF-7 cell. In addition, we demonstrated that miR-29a suppressed MCF-7 cell growth by inactivating the nuclear factor-kappa B signaling pathway and by decreasing cyclinD1 and Bcl-2/Bax protein levels. Taken together, our results suggest that miR-29a is an important regulator of tumor necrosis factor receptor 1 expression in breast cancer and functions as a tumor suppressor by targeting tumor necrosis factor receptor 1 to influence the growth of MCF-7 cell.


Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/pathology , MicroRNAs/metabolism , Receptors, Tumor Necrosis Factor, Type I/metabolism , 3' Untranslated Regions , Apoptosis/genetics , Breast Neoplasms/metabolism , Cell Proliferation/genetics , Down-Regulation , Female , Gene Knockdown Techniques , Humans , MCF-7 Cells , MicroRNAs/genetics , NF-kappa B/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering , Receptors, Tumor Necrosis Factor, Type I/genetics , Signal Transduction , Up-Regulation
14.
Int J Oncol ; 48(3): 1085-94, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26782945

ABSTRACT

The formation of EMT and EMT-induced CSC-like phenotype is crucial for the metastasis of tumor cells. The stromal cell-derived factor-1 (SDF-1) is upregulated in various human carcinomas, which is closely associated with proliferation, migration, invasion and prognosis of malignancies. However, limited attention has been directed towards the effect of SDF-1 on epithelial to mesenchymal transition (EMT) or cancer stem cell (CSC)-like phenotype formation in breast cancer cells and the related mechanism. In the present study, we screened MCF-7 cells with low SDF-1 expression level for the purpose of evaluating whether SDF-1 is involved in EMT and CSC-like phenotype formation in MCF-7 cells. The pEGFP-N1-SDF-1 plasmid was transfected into MCF-7 cells, and the stably overexpressed SDF-1 in MCF-7 cells was confirmed by real-time PCR and western blot analysis. Colony formation assay, MTT, wound healing assay and Transwell invasion assay demonstrated that overexpression of SDF-1 significantly boosted the proliferation, migration and invasion of MCF-7 cells compared with parental (P<0.05). Flow cytometry analysis revealed a notable increase of CD44+/CD24- subpopulation in SDF-1 overexpressing MCF-7 cells (P<0.001), accompanied by the apparently elevated ALDH activity and the upregulation of the stem cell markers OCT-4, Nanog, and SOX2 compared with parental (P<0.01). Besides, western blot analysis and immunofluorescence assay observed the significant decreased expression of E-cadherin and enhanced expression of slug, fibronectin and vimentin in SDF-1 overexpressed MCF-7 cells in comparison with parental (P<0.01). Further study found that overexpression of SDF-1 induced the activation of NF-κB pathway in MCF-7 cells. Conversely, suppressing or silencing p65 expression by antagonist or RNA interference could remarkably increase the expression of E-cadherin in SDF-1 overexpressed MCF-7 cells (P<0.001). Overall, the above results indicated that overexpression of SDF-1 enhanced EMT by activating the NF-κB pathway of MCF-7 cells and further induced the formation of CSC-like phenotypes, ultimately promoting the proliferation and metastasis of MCF-7 cells. Therefore, SDF-1 may further be assessed as a potential target for gene therapy of breast cancer.


Subject(s)
Breast Neoplasms/metabolism , Chemokine CXCL12/metabolism , Gene Expression Regulation, Neoplastic , NF-kappa B/metabolism , Neoplastic Stem Cells/cytology , Aldehyde Dehydrogenase/metabolism , Antigens, CD , Cadherins/metabolism , Cell Movement , Cell Proliferation , Epithelial-Mesenchymal Transition , Female , Gene Silencing , Genetic Therapy/methods , Humans , MCF-7 Cells , Microscopy, Fluorescence , Neoplasm Invasiveness , Neoplasm Metastasis , Phenotype , Real-Time Polymerase Chain Reaction , Vimentin/metabolism , Wound Healing
15.
Oncol Lett ; 9(3): 1266-1272, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25663895

ABSTRACT

The aim of the present study was to retrospectively assess the correlation between the expression levels of proteins involved in G2/M arrest signaling pathways in non-small cell lung cancer (NSCLC) tissue, as determined by immunohistochemical (IHC) methods, and the overall survival of patients with advanced stage NSCLC. IHC analysis of advanced NSCLC specimens was used to determine the expression levels of proteins involved in G2/M arrest signaling pathways, including ataxia telangiectasia mutated (ATM) kinase, ataxia telangiectasia and Rad3-related (ATR) kinase, checkpoint kinase (Chk) 1, Chk2, cell division cycle 25C (Cdc25C), total cyclin-dependent kinase 1 (Cdk1) and active Cdk1 signaling pathways, the latter of which refers to dephospho-Cdk1 (Tyr15) and phospho-Cdk1 (Thr161). Patients were enrolled continuously and followed up for ≥2 years. Univariate analysis demonstrated that the protein expression levels of dephospho-Cdk1 (P=0.015) and phospho-Cdk1 (P=0.012) exhibited prognostic significance, while the expression of the other proteins was not significantly associated with patient survival (ATM, P=0.843; ATR, P=0.245; Chk1, P=0.341; Chk2, P=0.559; Cdc25C, P=0.649; total Cdk1, P=0.093). Furthermore, the patients with tumors exhibiting low expression levels of active Cdk1 survived significantly longer than those with tumors exhibiting high active Cdk1 expression levels (P<0.05). In addition, Cox regression analysis demonstrated that the expression of active Cdk1 [odds ratio (OR), 0.624; 95% confidence ratio (CI), 0.400-0.973; P=0.038] and the pathological tumor-node-metastasis stage (OR, 0.515; 95% CI, 0.297-0.894; P=0.018) were significant independent prognostic factors for NSCLC. Therefore, the results of the present study indicated that active Cdk1 protein is an independent prognostic factor for advanced NSCLC and may validate Cdk1 as a therapeutic target for advanced NSCLC patients.

16.
Int J Clin Exp Pathol ; 8(10): 12357-67, 2015.
Article in English | MEDLINE | ID: mdl-26722422

ABSTRACT

CXCL12 is positively associated with the metastasis and prognosis of various human malignancies. Cancer-associated fibroblasts (CAFs), the main cells secreting CXCL12, are capable of inducing epithelial to mesenchymal transition (EMT) of breast cancer cells. However, it has not been completely understood whether CXCL12 is involved in EMT of breast cancer cells and the underlying mechanisms. The present study aimed to investigate the effects of CXCL12 on the EMT and cancer stem cell (CSC)-like phenotypes formation by transfecting pEGFP-N1-CXCL12 plasmid into MCF-7 cells. Real time-PCR and Western blot analysis demonstrated the successful over expression of CXCL12 in MCF-7 cells. Cell counting kit-8 assay, wound healing assay and Transwell invasion analysis confirmed that over expression of CXCL12 significantly promoted the proliferation, migration and invasion in MCF-7 cells (P<0.05). In addition, ALDH activity was dramatically enhanced compared with parental (P<0.001), accompanied by the notably elevated mRNA and protein levels of OCT-4, Nanog, and SOX2 in CXCL12 overexpressed-MCF-7 cells (P<0.001). Furthermore, we observed the down regulation of E-cadherin and up regulation of vimentin, N-cadherin, and α-SMA in CXCL12 overexpressed-MCF-7 cells (P<0.01). Meanwhile, western blot and immunofluorescence assay showed that over expression of CXCL12 activated Wnt/ß-catenin pathway to induce EMT of MCF-7 cells, as evidenced by the increased expression of E-cadherin after silencing ß-catenin by siRNA interference (P<0.001). Collectively, our findings suggested that over expression of CXCL12 could trigger EMT by activating Wnt/ß-catenin pathway and induce CSC-like phenotypes formation to promote the proliferation and metastasis in MCF-7. Hence, CXCL12 may become a promising candidate for breast cancer therapy.


Subject(s)
Breast Neoplasms/pathology , Chemokine CXCL12/metabolism , Epithelial-Mesenchymal Transition/physiology , Neoplastic Stem Cells/metabolism , Wnt Signaling Pathway/physiology , Blotting, Western , Breast Neoplasms/metabolism , Female , Fluorescent Antibody Technique , Gene Knockdown Techniques , Humans , MCF-7 Cells , Neoplastic Stem Cells/pathology , RNA, Small Interfering , Real-Time Polymerase Chain Reaction , Transfection
17.
Shock ; 40(4): 312-9, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23807248

ABSTRACT

Notch signaling, a critical pathway in cell fate determination, is well known to be involved in immune and inflammatory reactions, whereas its role in acute lung injury (ALI) remains unclear. Here, we report that notch signal activity is upregulated in lung tissue harvested from an ALI mouse model (induced by zymosan). We showed that notch signal activity in lung tissue was increased 6 h after zymosan injection and peaked at 24 h. Inhibition of notch signaling by either pre- or post-zymosan treatment with N-[N-(3,5-difluorophenacetyl)-l-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) significantly reduced lung injury, characterized by improvement in lung histopathology, lung permeability (protein concentration in bronchoalveolar lavage fluid and lung wet-to-dry weight ratio), lung inflammation (bronchoalveolar lavage fluid cell count, lung myeloperoxidase, and tumor necrosis factor α), and also alleviated systemic inflammation and tissue damage, thus increasing the 7-day survival rate in zymosan-challenged mice. In conclusion, the role of notch signaling is functionally significant in the development of ALI. Inhibition of notch signaling by pretreatment or posttreatment with DAPT likely exerts its effects in part by mediating the expression of proinflammatory and anti-inflammatory cytokines and influencing tissue neutrophil recruitment. These results also imply that notch inhibitors may help attenuate local inflammatory lung damage.


Subject(s)
Acute Lung Injury/prevention & control , Lung/immunology , Receptors, Notch/physiology , Signal Transduction/physiology , Acute Lung Injury/chemically induced , Acute Lung Injury/pathology , Animals , Dipeptides/pharmacology , Lung/pathology , Male , Mice , Receptors, Notch/antagonists & inhibitors , Signal Transduction/drug effects , Zymosan
18.
J Surg Res ; 174(2): e75-83, 2012 May 15.
Article in English | MEDLINE | ID: mdl-22261596

ABSTRACT

BACKGROUND: The 100% oxygen inhalation has been demonstrated to have a protective effect on mice with zymosan-induced generalized inflammation. However, the underlying mechanism is largely unknown. The present study was designed to explore the role of the cholinergic anti-inflammatory pathway in this animal model. METHODS: Oxygen inhalation was given to mice at 4 and 12 h after zymosan injection. One group of mice underwent vagotomy 7 d before zymosan injection. The other two groups of mice either received nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine, or α7 nicotinic acetylcholine receptor (α7nAChR) antagonist methyllycaconitine 30 min before oxygen was given. RESULTS: The 100% oxygen treatment significantly decreased the serum level of TNF-α and increased the serum level of IL-10. The pathologic changes of the heart, lung, liver, and kidney were attenuated, as well as the dysfunction of liver and kidney. The 7-d survival rate of zymosan-challenged mice was also improved. Conversely, all these protective effects caused by pure oxygen treatment were abolished in those animals that received anti-cholinergic treatments. CONCLUSIONS: The cholinergic anti-inflammatory pathway may be involved in the 100% oxygen protective mechanism against zymosan-induced generalized inflammation in mice.


Subject(s)
Nicotinic Antagonists , Oxygen/therapeutic use , Receptors, Nicotinic/physiology , Systemic Inflammatory Response Syndrome/therapy , Vagotomy , Aconitine/analogs & derivatives , Animals , Cytokines/blood , Kidney/pathology , Kidney Function Tests , Liver/pathology , Liver Function Tests , Lung/pathology , Male , Mecamylamine , Mice , Mice, Inbred ICR , Myocardium/pathology , Respiratory Insufficiency/prevention & control , Zymosan
19.
Zhongguo Zhong Yao Za Zhi ; 33(14): 1732-5, 2008 Jul.
Article in Chinese | MEDLINE | ID: mdl-18841780

ABSTRACT

OBJECTIVE: To investigate effect of total anthraquinone in rheum on aquaporin 2 expression in rat distal colon. METHOD: SD rats were randomly divided into control group, low dose group, middle dose group and high dose group. Gavaged to control group, and treated group were administered saline and total anthraquinone in rheum with dosage of 0.14, 2.5, 4.5 g x kg(-1) x d(-1), respectively. All rats were put sacrificed after 5 days and stool in full length colon was gently collected to detect water content stool. Distal colon was removed to detect AQP2 expression with immunohistochemistry, western blot and RT-PCR. RESULT: No diarrhea was found in low dose group and control group, there were not significant difference water content of stool and AQP2 expression between low dose group and control group. However, soft feces and loose stools occurred in diarrheic dose group, loose stools and watery stool appeared in high dose group. Stool water content increased in diarrheic dose group and High dose group, expression of AQP2 decreased evidently in these two groups (P < 0.01). CONCLUSION: Total anthraquinone in rheum can reduce the transcription and translation of AQP2 in rats' distal colon, increase fecal water content, which probably is one of the mechanisms of diarrhea caused by total anthraquinone in rheum.


Subject(s)
Anthraquinones/chemistry , Anthraquinones/pharmacology , Aquaporin 2/genetics , Aquaporin 2/metabolism , Colon/drug effects , Colon/metabolism , Gene Expression Regulation/drug effects , Rheum/chemistry , Animals , Immunohistochemistry , In Vitro Techniques , Male , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction
20.
Zhonghua Zhong Liu Za Zhi ; 27(8): 489-91, 2005 Aug.
Article in Chinese | MEDLINE | ID: mdl-16188149

ABSTRACT

OBJECTIVE: To study the histochemical staining in the diagnosis of osteosarcoma. METHODS: To compare the effectiveness of picrosirius red, improved Ponceau trichrome and Masson trichrome staining methods on bone formation tissues in conventional osteosarcoma, paraosteal osteosarcoma, periosteal osteosarcoma, extraskeletal osteosarcoma, inflammatory myofibroblastic tumour, malignant fibrohistiocytoma, chondrosarcoma, fibrosis with ossification and calcification. RESULTS: With modified Ponceau trichrome staining, bone formation tissues showed a homogenous, orange-red interblended with blue in color. From osteoid to mature bone the color changed from orange-red, light blue to dark blue. Fibrotic tissue was stained blue in color with striated appearance. Cartilage was not stained. Picrosirius red method gave bone formation tissues homogenous staining. Along with bone maturation, from osteoid tissue to mineralized bones, the color showed changes from light red, yellow, orange-red, red to dark purple. The cartilage demonstrated homogenous light red in color. Fibrous tissue stained red interblended with yellow in color, striated in shape. With Masson trichrome staining osteoid displayed pale blue and mineralized bone showed dark blue in color. Fibrotic tissue showed a striated blue staining. CONCLUSION: The modified Ponceau trichrome and Picrosirius red staining methods are better than Masson trichrome to demonstrate bone formation tissue in osteosarcoma. The former two methods could be also used in study on bone formation.


Subject(s)
Bone Neoplasms/pathology , Osteosarcoma/pathology , Staining and Labeling/methods , Histocytochemistry , Humans
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