scholarly journals Dietary exposure of deoxynivalenol affected cytochrome P450 and growth related-gene expression via DNA methylation in piglet liver

2020 ◽  
Author(s):  
Aimei Liu ◽  
Siyi Hu ◽  
Xiaohui Zhu ◽  
Awais Ihsan ◽  
Qinghua Wu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cytochrome P450 ◽  
Liver Injury ◽  
Growth Inhibition ◽  
Molecular Mechanisms ◽  
Animal Feed ◽  
Metabolic Enzyme ◽  
Control Group ◽  
Dependent Manner ◽  
Aminotransferase Activity

Abstract Background Deoxynivalenol (DON) is an inevitable contaminant in animal feed and human food and can lead to decreased appetite and growth retardation in children and piglets, which are often used as models for children. Hepatotoxicity induced by DON is closely related to growth inhibition. Although many molecular mechanisms are related to the liver damage caused by DON, few studies have been done on cytochrome P450 (CYP450s) and DNA methylation, and the role of DNA methylation in growth inhibition of piglets was also unclear. Results In the present study, piglets were randomly assigned to the following three different dietary treatments for 4 weeks: control diet, diet containing 1 mg DON/kg feed, and diet containing 3 mg DON/kg feed. Compared to the control group, elevated alanine aminotransferase activity and globulin level were observed in DON groups; however, aspartate aminotransferase activity was decreased in 3 mg/kg DON group. DON exposure increased the mRNA expression of CYP450s including CYP1A1, CYP1A2, CYP2B22, CYP2C33, CYP2D25, CYP2E1, CYP3A22 and CYP3A39, in which DNA methylation was involved in the regulation of the expression of these enzymes. By estimating the benchmark dose value of the metabolic enzymes, CYP1A1 was found to be the most sensitive metabolic enzyme to evaluate the clinical liver injury caused by DON. DON upregulated the expression of DNA methyltransferases (DNMT1 and DNMT3B) in a dose-dependent manner, thus increasing the level of 5-mC in the whole genome. Notably, DON downregulated the expression of nicotinamide n-methyltransferase, possibly reducing the weight of the piglets. Additionally, 1 mg/kg DON decreased the expression of galanin-like peptide (GALP), while 3 mg/kg DON significantly increased the level of GALP through DNA methylation, thus affecting the appetite of the piglets. DON can significantly reduce the methylation level of insulin-like growth factor 1 (IGF-1) promoter and thus increase its expression. Conclusions Taken together, increased CYP450 expression and DNA methylation are important mechanisms of liver injury and growth inhibition induced by DON, which provide future reference values determination of antagonistic toxicity.

scholarly journals Knock-Down of Gossypol-Inducing Cytochrome P450 Genes Reduced Deltamethrin Sensitivity in Spodoptera exigua (Hübner)

2019 ◽  
Vol 20 (9) ◽  
pp. 2248 ◽  
Author(s):  
Muhammad Hafeez ◽  
Sisi Liu ◽  
Saad Jan ◽  
Le Shi ◽  
G. Mandela Fernández-Grandon ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Secondary Metabolites ◽  
Molecular Mechanisms ◽  
Spodoptera Exigua ◽  
Plant Secondary Metabolites ◽  
Detoxification Enzymes ◽  
Beet Armyworm ◽  
Cytochrome P450 Monooxygenases ◽  
Control Group ◽  
P450 Monooxygenases

Plants employ an intricate and dynamic defense system that includes physiological, biochemical, and molecular mechanisms to counteract the effects of herbivorous attacks. In addition to their tolerance to phytotoxins, beet armyworm has quickly developed resistance to deltamethrin; a widely used pyrethroid insecticide in cotton fields. The lethal concentration (LC50) required to kill 50% of the population of deltamethrin to gossypol-fed Spodoptera exigua larvae was 2.34-fold higher than the control group, suggesting a reduced sensitivity as a consequence of the gossypol diet. Piperonyl butoxide (PBO) treatment was found to synergize with deltamethrin in gossypol-fed S. exigua larvae. To counteract these defensive plant secondary metabolites, beet armyworm elevates their production of detoxification enzymes, including cytochrome P450 monooxygenases (P450s). Gossypol-fed beet armyworm larvae showed higher 7-ethoxycoumarin-O-deethylase (ECOD) activities and exhibited enhanced tolerance to deltamethrin after 48 and 72 h when compared to the control. Moreover, gossypol pretreated S. exigua larvae showed faster weight gain than the control group after transferring to a deltamethrin-supplemented diet. Meanwhile, gossypol-induced P450s exhibited high divergence in the expression level of two P450 genes: CYP6AB14 and CYP9A98 in the midgut and fat bodies contributed to beet armyworm tolerance to deltamethrin. Knocking down of CYP6AB14 and CYP9A98, via double-stranded RNAs (dsRNA) in a controlled diet, rendered the larvae more sensitive to the insecticide. These data demonstrate that generalist insects can exploit secondary metabolites from host plants to enhance their defense systems against other toxic chemicals. Impairing this defense pathway by RNA interference (RNAi) holds a potential to eliminate the pest’s tolerance to insecticides and, therefore, reduce the required dosages of agrochemicals in pest control.

scholarly journals Maltol Improves APAP-Induced Hepatotoxicity by Inhibiting Oxidative Stress and Inflammation Response via NF-κB and PI3K/Akt Signal Pathways

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 395 ◽  
Author(s):  
Zi Wang ◽  
Weinan Hao ◽  
Junnan Hu ◽  
Xiaojie Mi ◽  
Ye Han ◽  
...  
Keyword(s):  
Liver Injury ◽  
Protective Effect ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
B Cell Lymphoma ◽  
Inflammatory Factors ◽  
Signal Pathways ◽  
Dependent Manner ◽  
Beneficial Effects

Maltol, a food-flavoring agent and Maillard reaction product formed during the processing of red ginseng (Panax ginseng, C.A. Meyer), has been confirmed to exert a hepatoprotective effect in alcohol-induced oxidative damage in mice. However, its beneficial effects on acetaminophen (APAP)-induced hepatotoxicity and the related molecular mechanisms remain unclear. The purpose of this article was to investigate the protective effect and elucidate the mechanisms of action of maltol on APAP-induced liver injury in vivo. Maltol was administered orally at 50 and 100 mg/kg daily for seven consecutive days, then a single intraperitoneal injection of APAP (250 mg/kg) was performed after the final maltol administration. Liver function, oxidative indices, inflammatory factors—including serum alanine and aspartate aminotransferases (ALT and AST), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), liver glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) were measured. Results demonstrated that maltol possessed a protective effect on APAP-induced liver injury. Liver histological changes and Hoechst 33258 staining also provided strong evidence for the protective effect of maltol. Furthermore, a maltol supplement mitigated APAP-induced inflammatory responses by increasing phosphorylated nuclear factor-kappa B (NF-κB), inhibitor kappa B kinase α/β (IKKα/β), and NF-kappa-B inhibitor alpha (IκBα) in NF-κB signal pathways. Immunoblotting results showed that maltol pretreatment downregulated the protein expression levels of the B-cell-lymphoma-2 (Bcl-2) family and caspase and altered the phosphorylation of phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) in a dose-dependent manner. In conclusion, our findings clearly demonstrate that maltol exerts a significant liver protection effect, which may partly be ascribed to its anti-inflammatory and anti-apoptotic action via regulation of the PI3K/Akt signaling pathway.

scholarly journals Comparative Transcriptome Analysis Reveals the Protective Mechanism of Glycyrrhinic Acid for Deoxynivalenol-Induced Inflammation and Apoptosis in IPEC-J2 Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Xiaoxiang Xu ◽  
Guorong Yan ◽  
Juan Chang ◽  
Ping Wang ◽  
Qingqiang Yin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathway ◽  
Transcriptome Analysis ◽  
Animal Feed ◽  
Control Group ◽  
Protective Mechanism ◽  
Dependent Manner ◽  
Gene Expressions ◽  
Lactate Dehydrogenase Release ◽  
Tnf Α

Deoxynivalenol (DON) is the most common mycotoxin that frequently contaminates human food and animal feed, resulting in intestinal diseases and systemic immunosuppression. Glycyrrhinic acid (GA) exhibits various pharmacological activities. To investigate the protective mechanism of GA for DON-induced inflammation and apoptosis in IPEC-J2 cells, RNA-seq analysis was used in the current study. The IPEC-J2 cells were treated with the control group (CON), 0.5 μg/mL DON, 400 μg/mL GA, and 400 μg/mL GA+0.5 μg/mL DON (GAD) for 6 h. Results showed that 0.5 μg/mL DON exposure for 6 h could induce oxidative stress, inflammation, and apoptosis in IPEC-J2 cells. GA addition could specifically promote the proliferation of DON-induced IPEC-J2 cells in a dose- and time-dependent manner. In addition, GA addition significantly increased Bcl-2 gene expression ( P < 0.05 ) and superoxide dismutase and catalase activities ( P < 0.01 ) and decreased lactate dehydrogenase release, the contents of malonaldehyde, IL-8, and NF-κB ( P < 0.05 ), the relative mRNA abundances of IL-6, IL-8, TNF-α, COX-2, NF-κB, Bax, and caspase 3 ( P < 0.01 ), and the protein expressions of Bax and TNF-α. Moreover, a total of 1576, 289, 1398, and 154 differentially expressed genes were identified in CON vs. DON, CON vs. GA, CON vs. GAD, and DON vs. GAD, respectively. Transcriptome analysis revealed that MAPK, TNF, and NF-κB signaling pathways and some chemokines played significant roles in the regulation of inflammation and apoptosis induced by DON. GA may alleviate DON cytotoxicity via the TNF signaling pathway by downregulating IL-15, CCL5, and other gene expressions. These results indicated that GA could alleviate DON-induced oxidative stress, inflammation, and apoptosis via the TNF signaling pathway in IPEC-J2 cells.

scholarly journals Lactobacillus reuteri ZJ617 Culture Supernatant Attenuates Acute Liver Injury Induced in Mice by Lipopolysaccharide

2019 ◽  
Vol 149 (11) ◽  
pp. 2046-2055 ◽  
Author(s):  
Yanjun Cui ◽  
Sirui Qi ◽  
Wenming Zhang ◽  
Jiangdi Mao ◽  
Renlong Tang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Intraperitoneal Injection ◽  
Molecular Mechanisms ◽  
Culture Supernatant ◽  
Lactobacillus Reuteri ◽  
Acute Liver Injury ◽  
Saline Control ◽  
Control Group ◽  
Intestinal Integrity ◽  
Oral Inoculation

ABSTRACT Background Lactobacillus rhamnosus GG culture supernatant (LGGs) promotes intestinal integrity and ameliorates acute liver injury induced by alcohol in mice. Objectives The aim of this study was to investigate the protective effects and molecular mechanisms of Lactobacillus reuteri ZJ617 culture supernatant (ZJ617s) on acute liver injury induced by lipopolysaccharide (LPS) in mice. Methods Male C57BL/6 mice (20 ± 2 g, 8 wk old) were randomly divided into 4 groups (6 mice/group): oral inoculation with phosphate-buffered saline (control), intraperitoneal injection of LPS (10 mg/kg body weight) (LPS), oral inoculation with ZJ617s 2 wk before intraperitoneal injection of LPS (ZJ617s + LPS), or oral inoculation with LGGs 2 wk before intraperitoneal injection of LPS (LGGs + LPS). Systemic inflammation, intestinal integrity, biomarkers of hepatic function, autophagy, and apoptosis signals in the liver were determined. Results Twenty-four hours after LPS injection, the activities of serum alanine transaminase and aspartate transaminase were 32.2% and 30.3% lower in the ZJ617s + LPS group compared with the LPS group, respectively (P < 0.05). The ZJ617s + LPS group exhibited higher intestinal expression of claudin 3 (62.5%), occludin (60.1%), and zonula occludens 1 (60.5%) compared with the LPS group (P < 0.05). The concentrations of hepatic interleukin-6 and tumor necrosis factor-α were 21.4% and 27.3% lower in the ZJ617s + LPS group compared with the LPS group, respectively (P < 0.05). However, the concentration of interleukin-10 was 22.2% higher in the ZJ617s + LPS group. LPS increased the expression of Toll-like receptor 4 (TLR4; by 50.5%), phosphorylation p38 mitogen-activated protein kinase (p38MAPK; by 57.1%), extracellular signal-regulated kinase (by 77.8%), c-Jun N-terminal kinase (by 42.9%), and nuclear factor-κB (NF-κB; by 36.0%) compared with the control group. Supplementation with ZJ617s or LGGs ameliorated these effects (P < 0.05). Moreover, the hepatic expression of active caspase-3 and microtubule-associated protein 1 light chain 3 II was 23.8% and 28.6% lower in the ZJ617s + LPS group compared with the LPS group, respectively (P < 0.05). Conclusions ZJ617s exerts beneficial effects on the mouse liver through suppression of hepatic TLR4/MAPK/NF-κB activation, apoptosis, and autophagy. This trial was registered at Zhejiang University (http://www.lac.zju.edu.cn) as NO.ZJU20170529.

scholarly journals Acetaminophen-Induced Liver Injury Alters Expression and Activities of Cytochrome P450 Enzymes in an Age-Dependent Manner in Mouse Liver

2020 ◽  
Vol 48 (5) ◽  
pp. 326-336 ◽  
Author(s):  
Yifan Bao ◽  
Pei Wang ◽  
Xueyan Shao ◽  
Junjie Zhu ◽  
Jingcheng Xiao ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Liver Injury ◽  
Mouse Liver ◽  
Dependent Manner ◽  
Cytochrome P450 Enzymes ◽  
Age Dependent

Evaluation of selected serum biochemical and haematological parameters in gilts exposed per os to 100 ppb of zearalenone

2015 ◽  
Vol 18 (4) ◽  
pp. 865-872 ◽  
Author(s):  
E. Jakimiuk ◽  
J. Radwińska ◽  
A. Pomianowski ◽  
M. Woźny ◽  
K. Obremski ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Animal Feed ◽  
White Blood Cells ◽  
Cell System ◽  
Biologically Active ◽  
Haematological Parameters ◽  
Control Group ◽  
Cholesterol Levels ◽  
Serum Biochemical ◽  
Experimental Group

Abstract Zearalenone (ZEN) widely contaminates animal feed of plant origin. The recommended safe concentrations of ZEN in feeds for various animal species are set mainly based on the mycotoxin’s hormonal properties (NOEL). Our growing knowledge about biologically active concentrations of ZEN, molecular mechanisms and cells/tissues targeted by ZEN indicates that the harmful effects exerted by this mycotoxin on animals may be far greater than previously believed. This experiment was performed on pre-pubertal gilts divided into a control group (n=9) and an experimental group (ZEN, n=9). The control group received placebo, whereas the experimental group was administered ZEN at a dose of 0.1 mg/kg feed (equivalent to 5 μg/kg BW/day) for 42 days. On days 14, 28 and 42 blood samples were collected from the animals to determine the concentrations of selected zearalenols, serum biochemical and haematological parameters. Conjugated ZEN was found in the blood serum of the experimental gilts. Changes in the analysed biochemical parameters included a transient increase in albumin and cholesterol levels. A statistically significant increase in the concentrations of neutrophilic and acidophilic granulocytes was observed in the white blood cell system. The results indicate that long-term per os exposure of pre-pubertal gilts to low doses of ZEN (below NOEL) has a modulatory effect on liver function and white blood cells.

Sufentanil Affects High Glucose-Induced Oxidative Stress in and Apoptosis of Cardiomyocytes by Regulation of miR-142-3p Expression

2021 ◽  
Vol 11 (3) ◽  
pp. 466-470
Author(s):  
Zhiyong Liu ◽  
Cuiqing Ding ◽  
Changqing Yao ◽  
Jinhui Chen
Keyword(s):  
Oxidative Stress ◽  
High Glucose ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Sod Activity ◽  
Apoptosis Rate ◽  
Mda Content

To explore the effects and molecular mechanisms of sufentanil on high glucose-induced oxidative stress in and apoptosis of cardiomyocytes, cardiomyocytes H9c2 cells were classified into groups based on different treatments as high-glucose (HG), HG with low, medium, or high-dose sufentanil, HG with high-dose sufentanil and anti-miR-NC, HG with high-dose sufentanil and anti-miR-142-3p, and control. The cells’ superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were detected using respective kits. The apoptosis rate in each group was detected by flow cytometry. The expressions of cleaved caspase-3 and pro-caspase3 were determined using western blotting. The expression of miR-142-3p in cardiomyocytes was detected using real-time fluorescent quantitative PCR. Compared with the control group, the HG group had decreased SOD activity, pro-caspase-3 expression, and miR-142-3p expression and increased MDA content, apoptosis, and cleaved caspase-3 expression (P < 0.05). Compared with the HG group, the SOD activity and pro-caspase-3 expression increased and the MDA content, apoptosis rate, and cleaved caspase-3 expression decreased in HG cells treated with low, medium, or high-dose sufentanil. The expression of miR-142-3p was increased in a dose-dependent manner (P < 0.05). The interference of miR-142-3p reversed the effect of sufentanil on high glucose-induced oxidative stress in and apoptosis of cardiomyocytes. Sufentanil may inhibit high glucose-induced oxidative stress in and apoptosis of cardiomyocytes by upregulating miR-142-3p expression.

Sfrps Family Invovled in Growth Inhibition of K562 Cells Induced by Artesunate

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5015-5015
Author(s):  
Wang Ying ◽  
Guo xiao Nan ◽  
Zhang xue Jun ◽  
Ren jin Hai ◽  
Qiao shu Kai ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Research Funding ◽  
Wnt Pathway ◽  
K562 Cells ◽  
Hebei Province ◽  
Control Group ◽  
Dependent Manner ◽  
Inhibition Rate ◽  
Concentration Dependent Manner ◽  
Expression Levels

Abstract Abstract 5015 Introduction: Studies have shown that abnormal activation of wnt signaling pathway is closely related to tumor genesis. Cell surface coil protein (frizzled, fzd) is a specific receptor for wnt pathway to activate its downstream signaling through β-catenin to stimulate the growth of a range of tumor cells. Secreted frizzled related proteins (sfrps) are the main antagonists of wnt pathway. sfrps can inhibit the function of wnt pathway via competing with fzd receptor. Recent studies have found that sfrps family memberes expressed at very low levels in a variety of tumor cells,which was closely related to the methylation of sfrps gene promoters. DNA methyltransferase (dnmts) are the key enzymes involved in DNA methylation, which can promote the methylation of tumor suppressor genes' promoters and inhibit transcription of these genes, and induce tumor genesis. Artesunate, a semi-synthetic derivative of artemisinin, is very effective in antimalaria. Recent studies have shown that artesunate has anti-tumor functions. However, the effect of artesunate on the expression of sfrps- and dnmts- mRNAs and β-catenin protein are not clear. To evaluate the growth inhibition effect of Artesunate (at final concentrations of 0μg/ml, 4μg/ml, 10μg/ml, 20μg/ml and 40μg/ml) on K562 cells and to investigate its potential mechanism by detecting the expression levels of sfrps- and dnmts- mRNAs and β-catenin protein in K562 cells treated with artesunate. Methods: Cell growth inhibition rate and cell cycle distribution of K562 cells induced by artesunate treatment were measured by MTT assay and flow cytometry, respectively. The mRNA expression levels of sfrp1, sfrp2, sfrp4 and dnmt1, dnmt3a, dnmt3b in K562 cells which had been treated with or without artesunate for 48 hours were evaluated with reverse transcription-polymerase chain reaction (RT-PCR). Protein expression level of β-catenin in K562 cells were detected by Western blot. Results: Artesunate treatment significantly induced growth inhibition of K562 cells in a concentration-dependent manner after the cells were treated with artesunate for 48 hours(p < 0.05). The inhibition rate of 4,10,20 and 40(μg/ml)artesunate exposure were 54.29%, 58.03%, 69.33% and 77.98% respectively. Flow cytometry analysis showed that K562 cells were arrested at G0/Gl and G2/M phase in concentration-dependent manner after 48 hours exposure of artesunate (p < 0.05). After treated with artesunate at the final concentrations of 0, 4, 10, 20 and 40μg/ml, the relative expression levels of sfrp1, sfrp2 and sfrp4 mRNA in K562 cells increased, while the expression levels of dnmtl, dnmt3a, dnmt3b mRNA decreased significantly compared with the control group. Results from Western blot showed that β-catenin protein levels decreased in a concentration-dependent manner, when compared with that of the control group (P<0.05). Conclusion: Results from the present study indicated that artesunate could inhibite the mRNA expression of dnmts family and minimize the methylation of sfrps gene promoter. Therefore, sfrps could inhibit the function of wnt pathway through competing with fzd receptors. Meanwhile, artesunate could decrease the expression of β-catenin protein in K562 cells, and could further inhibit the function of wnt pathway. Therefore, data from the present experiment provides a new theoretical basis for clinical application of artesunate in leukemia treatment. Disclosures: Ying: Nature science foundation of Hebei Province: Research Funding. Nan:Nature science foundation of Hebei Province: Research Funding. Jun:Nature science foundation of Hebei Province: Research Funding. Hai:Nature science foundation of Hebei Province: Research Funding. Kai:Nature science foundation of Hebei Province: Research Funding. Xu:Nature science foundation of Hebei Province: Research Funding. Pan:Nature science foundation of Hebei Province: Research Funding.

scholarly journals Toxicity of DON on GPx1-Overexpressed or Knockdown Porcine Splenic Lymphocytes In Vitro and Protective Effects of Sodium Selenite

2019 ◽  
Vol 2019 ◽  
pp. 1-24 ◽  
Author(s):  
Zhihua Ren ◽  
Changhao Chen ◽  
Yu Fan ◽  
Chaoxi Chen ◽  
Hongyi He ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Antioxidant Capacity ◽  
Sodium Selenite ◽  
Animal Feed ◽  
Cell Damage ◽  
The Body ◽  
Dependent Manner ◽  
Protective Effects ◽  
Splenic Lymphocytes ◽  
Apoptosis Rate

Deoxynivalenol (DON) is a common contaminant of grain worldwide and is often detected in the human diet and animal feed. Selenium is an essential trace element in animals. It has many biological functions. The role of selenium in the body is mainly orchestrated by selenoprotein. Glutathione peroxidase (GPx) also exists widely in the body and has attracted much attention due to its high antioxidant capacity. In order to explore the effect of the GPx1 gene on toxicity of DON, in this study, we overexpressed or knockdown GPx1 in porcine splenic lymphocytes, then added different concentrations of DON (0.1025, 0.205, 0.41, and 0.82 μg/mL) and sodium selenite (2 μmol/L) to the culture system. Using various techniques, we detected antioxidant function, free radical content, cell apoptosis, and methylation-related gene expression to explore the effect of GPx1 expression on DON-induced cell damage. We also explored whether selenium can antagonize the toxicity of DON in these two cell models and revealed the protective effect of sodium selenite on DON-induced cell damage in GPx1-overexpressing or knockdown splenic lymphocytes. Finally, our findings revealed the following: (1) GPx1 can regulate the antioxidant capacity, apoptosis rate, and expression of DNA methylation-related genes in pig splenic lymphocytes. (2) Na2SeO3 (2 μmol/L) can regulate the antioxidant capacity, apoptosis rate, and expression of DNA methylation-related genes in pig splenic lymphocytes, and this effect is more significant in GPx1-overexpressing cells than in GPx1-knockdown cells. (3) DON can cause oxidative damage, apoptosis, and methylation injury in GPx1-overexpressing or knockdown pig splenic lymphocytes in a concentration-dependent manner. (4) Na2SeO3 (2 μmol/L) can antagonize the toxic effect of DON on GPx1-overexpressing or knockdown pig splenic lymphocytes. Our findings may have important implications for food/feed safety, human health, and environmental protection.

Cyclin A transcriptional suppression is the major mechanism mediating homocysteine-induced endothelial cell growth inhibition

Blood ◽  
2002 ◽  
Vol 99 (3) ◽  
pp. 939-945 ◽  
Author(s):  
Hong Wang ◽  
XiaoHua Jiang ◽  
Fan Yang ◽  
Gary B. Chapman ◽  
William Durante ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Endothelial Cells ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Cyclin D1 ◽  
Messenger Rna ◽  
Molecular Mechanisms ◽  
Kinase Activity ◽  
Cyclin A ◽  
Dependent Manner

Abstract Previously, it was reported that homocysteine (Hcy) specifically inhibits the growth of endothelial cells (ECs), suppresses Ras/mitogen-activated protein (MAP) signaling, and arrests cell growth at the G1/S transition of the cell cycle. The present study investigated the molecular mechanisms underlying this cell-cycle effect. Results showed that clinically relevant concentrations (50 μM) of Hcy significantly inhibited the expression of cyclin A messenger RNA (mRNA) in ECs in a dose- and time-dependent manner. G1/S-associated molecules that might account for this block were not changed, because Hcy did not affect mRNA and protein expression of cyclin D1 and cyclin E. Cyclin D1- and E-associated kinase activities were unchanged. In contrast, cyclin A–associated kinase activity and CDK2 kinase activity were markedly suppressed. Nuclear run-on assay demonstrated that Hcy decreased the transcription rate of the cyclin A gene but had no effect on the half-life of cyclin A mRNA. In transient transfection experiments, Hcy significantly inhibited cyclin A promoter activity in endothelial cells, but not in vascular smooth muscle cells. Finally, adenovirus-transduced cyclin A expression restored EC growth inhibition and overcame the S phase block imposed by Hcy. Taken together, these findings indicate that cyclin A is a critical functional target of Hcy-mediated EC growth inhibition.

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