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ABSTRACT: Both prokaryotes and eukaryotes have pyramid-shaped hierarchical regulatory networks that control gene transcription, enabling the cell to respond to natural environmental changes. In recent years, manipulation and engineering of transcriptional regulatory proteins and networks have been used to elicit microbial tolerance to industrially relevant stresses. We review the current research on the engineering of regulators that include specific, "middle level", and global regulators, and native, artificial, and exogenous regulators. With an increasing number of transcriptional regulators identified and characterized, this methodology should prove promising for the improvement of microbial stress tolerance.
Biotechnology advances 03/2013; · 8.25 Impact Factor
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ABSTRACT: Lipid disorder causes vascular endothelial cell damage and contributes to the early development of dyslipidaemia-induced atherosclerosis. In vivo and in vitro, it has been found that increasing shear stress can improve endothelial function. Clinically, enhanced external counterpulsation (EECP) plays important roles in the treatment of coronary artery disease by promoting arterial shear stress. The present study aims to evaluate the effect of EECP on vascular endothelial function in porcine hypercholesterolaemic model.
Twenty-six hypercholesterolaemic pigs were equally divided into EECP group (HC-EECP group) and control group (HC group). Shear stress of a right forearm superficial artery was measured during EECP in comparison with the basal physiological status in the HC-EECP group. Endothelial-dependent flow-mediated vasodilation (FMD) was applied to assess endothelial function. Serum high-sensitivity C-reactive protein (hs-CRP) levels were measured at indicated time points.
Endothelial shear stress was increased significantly during EECP treatment (P<0.001). Compared to HC group, hs-CRP decreased significantly by EECP at 18- and 36-h, respectively (P<0.05). FMD was improved significantly by EECP compared to that of HC group at 18 h (11.09 ± 5.63%) and at 36 h (11.42 ± 2.75%) post-EECP, P<0.05. Meanwhile, in animals of HC group, FMD was decreased from baseline 7.76 ± 3.70% to 6.75 ± 3.57% at 18 h and 5.07 ± 1.97% at 36 h, P<0.05.
Long-term EECP can improve endothelial function partially by an increased endothelial shear stress in hypercholesterolaemic porcine model. This implies that long-term EECP can be used as a complementary therapeutic strategy to prevent atherosclerosis in hypercholesterolaemic patients.
Clinical Physiology and Functional Imaging 07/2012; 32(4):262-7. · 1.33 Impact Factor
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ABSTRACT: Lignocellulosic biomass is regarded as the most viable source of feedstock for industrial biorefinery, but the harmful inhibitors generated from the indispensable pretreatments prior to fermentation remain a daunting technical hurdle. Using an exogenous regulator, irrE, from the radiation-resistant Deinococcus radiodurans, we previously showed that a novel global regulator engineering (GRE) approach significantly enhanced tolerances of Escherichia coli to alcohol and acetate stresses. In this work, an irrE library was subjected to selection under various stresses of furfural, a typical hydrolysate inhibitor. Three furfural tolerant irrE mutants including F1-37 and F2-1 were successfully obtained. The cells containing these mutants reached OD(600) levels of 4- to 16-fold of that for the pMD18T cells in growth assay under 0.2% (v/v) furfural stress. The cells containing irrE F1-37 and F2-1 also showed considerably reduced intracellular oxygen species (ROS) levels under furfural stress. Moreover, these two irrE mutants were subsequently found to confer significant cross tolerances to two other most common inhibitors, 5-hydroxymethyl-2-furaldehyde (HMF), vanillin, as well as real lignocellulosic hydrolysates. When evaluated in Luria-Bertani (LB) medium supplemented with corn stover cellulosic hydrolysate (prepared with a solid loading of 30%), the cells containing the mutants exhibited lag phases markedly shortened by 24-44 h in comparison with the control cells. This work thus presents a promising step forward to resolve the inhibitor problem for E. coli. From the view of synthetic biology, irrE can be considered as an evolvable "part" for various stresses. Furthermore, this GRE approach can be extended to exploit other exogenous global regulators from extremophiles, and the native counterparts in E. coli, for eliciting industrially useful phenotypes. Biotechnol. Bioeng. © 2012 Wiley Periodicals, Inc.
Biotechnology and Bioengineering 06/2012; · 3.95 Impact Factor
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ABSTRACT: Progesterone has been proven to have limited effects on endometrial cancers (ECs), mainly owing to the down-regulation of progesterone receptor (PR). Here, we explored whether 5-aza-2'-deoxycytidine (5-aza-CdR), a demethylating agent, could enhance the susceptibility of EC cells to medroxyprogesterone acetate (MPA).
Ishikawa and KLE cell lines were treated with 5-aza-CdR and/or MPA. The expression of PR, PR target genes, and matrix metalloproteinase (MMP) was investigated by real-time polymerase chain reaction and Western blot. Promoter methylation was detected by methylation-specific polymerase chain reaction. The effects of 5-aza-CdR and/or MPA on cell proliferation, apoptosis, and invasion of EC cells were evaluated by 2-(4-Iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium assay, flow cytometry, invasion assay, and gelatin zymography, respectively.
5-Aza-2'-deoxycytidine significantly increased the expression of PR and its downstream targets by demethylating PR promoter in both Ishikawa and KLE cells. 5-Aza-2'-deoxycytidine combined with MPA synergistically suppressed the EC cell growth by inducing cell cycle arrest at G2/M phase and apoptosis. Furthermore, 5-aza-CdR synergized with MPA to inhibit the invasion of EC cells, perhaps owing to the down-regulation of MMP-2 and MMP-9 expression and activity.
5-Aza-2'-deoxycytidine and MPA synergistically inhibit EC cell growth and invasion. Their combined use may provide a new effective therapeutic opportunity for endometrial carcinoma.
International Journal of Gynecological Cancer 06/2012; 22(6):951-9. · 1.65 Impact Factor
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ABSTRACT: A 6β-N-heterocyclic substituted naltrexamine derivative, NAP, was proposed as a peripheral mu opioid receptor (MOR) selective antagonist based on the in vitro and in vivo pharmacological and pharmacokinetic studies. To further validate this notion, several functional assays were carried out to fully characterize this compound. In the charcoal gavage and intestinal motility assay in morphine-pelleted mice, when administered 0.3 mg/kg or higher doses up to 3 mg/kg subcutaneously, NAP significantly increased the intestinal motility compared to the saline treatment. The comparative opioid withdrawal precipitation study and the lower locomotor assay demonstrated that NAP showed only marginal intrinsic effect in the central nervous system either given subcutaneously or intravenously: no jumps were witnessed for the tested animals even given up to a dose of 50 mg/kg, while similar noticeable wet-dog shakes only occurred at the dose 50 times of those for naloxone or naltrexone, and significant reduction of the hyper-locomotion only happened at the dose as high as 32 mg/kg. Collectively, these results suggested that NAP may serve as a novel lead to develop peripheral MOR selective antagonist which might possess therapeutic potential for opioid-induced bowel dysfunction (OBD), such as opioid-induced constipation (OIC).
Bioorganic & medicinal chemistry letters 05/2012; 22(14):4731-4. · 2.65 Impact Factor
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ABSTRACT: To assess the clinical effects and safety of Shencao Tongmai Granule (STG) in treatment of patients with chronic heart failure (CHF) (NYHA functional class II - III) of qi deficiency blood stasis and water retention syndrome (QDBSWRS).
This was a multi-centered, double blinded, randomized, and placebo parallel controlled study. A total of 280 CHF patients of QDBSWRS were randomly assigned to the trial group and the control group in the ratio of 1:1. All patients received Western medicine (WM) treatment such as ACEI, diuretics, Digoxin Elixirs, and so on. Additionally, patients in the trial group took STG while those in the control group took the placebo. The therapeutic course for all was twelve weeks. The NYHA functional classification, Chinese medicine (CM) syndrome integral, and left ventricular ejection fraction (LVEF) were compared between the two groups. The safety assessment was also carried out.
Totally 265 patients completed this trial (138 cases in the trial group and 127 cases in the control group). The effective rate of NYHA functional classification and CM syndrome integral were obviously higher in the trial group than in the control group (94.20% vs 55.90%, 97.83% vs 70.08% respectively), showing statistical difference (P < 0.01). There was no statistical difference in LVEF between the two groups before treatment (P > 0.05). The LVEF both increased in the two groups when compared with before treatment (P < 0.05). The post-treatment increment of LVEF was obviously higher in the trial group than in the control group (6.55% +/- 6.23% vs 3.14% +/- 4.99%, P < 0.05). The rate of adverse reaction was 0.71% in the two groups (1/140).
n STG showed good therapeutic effectiveness and safety in treating CHF patients of QDBSWRS.
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine / Zhongguo Zhong xi yi jie he xue hui, Zhongguo Zhong yi yan jiu yuan zhu ban 05/2012; 32(5):612-5.
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ABSTRACT: Mouse Trmt112, the homologous gene of yeast Trm112 (tRNA methyltransferase 11-2), was initially cloned from RIKEN with uncertain function. The yeast TRM112 is now known to play important roles in RNA methylation. Here, we studied the expression of Trmt112 by in situ hybridization and quantitative real-time RT-PCR (QRT-PCR). A higher expression level of Trmt112 was observed in the brain and nervous system by whole mount in situ hybridization from embryonic day 10.5 (E10.5) to E11.5. At later developmental stages E13.5 and E16.5, abundant expression was prominently found in various organs and tissues including developing brain, nervous system, thymus, lung, liver, intestine, kidney, and cartilage. Furthermore, Trmt112 was persistently expressed from E9.5 to E18.5 on whole embryos and highly expressed in multiple organs at E12.5, E15.5 and E18.5 by QRT-PCR. These results showed that Trmt112 gene was highly and ubiquitously expressed during mouse embryonic development, implying that it might be involved in the morphogenesis of diverse organs and tissues and numerous physiological functions.
ACTA HISTOCHEMICA ET CYTOCHEMICA 04/2012; 45(2):113-9. · 1.68 Impact Factor
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ABSTRACT: Rhesus macaques infected with lymphocytic choriomeningitis virus (LCMV) provide a model for human Lassa fever. Disease begins with flu-like symptoms and progresses rapidly with fatal consequences. Previously, we profiled the blood transcriptome of LCMV-infected monkeys (M. Djavani et al J. Virol. 2007) showing distinct pre-viremic and viremic stages that discriminated virulent from benign infections. In the present study, changes in liver gene expression from macaques infected with virulent LCMV-WE were compared to gene expression in uninfected monkeys as well as to monkeys that were infected but not diseased.
Based on a functional pathway analysis of differentially expressed genes, virulent LCMV-WE had a broader effect on liver cell function than did infection with non-virulent LCMV-Armstrong. During the first few days after infection, LCMV altered expression of genes associated with energy production, including fatty acid and glucose metabolism. The transcriptome profile resembled that of an organism in starvation: mRNA for acetyl-CoA carboxylase, a key enzyme of fatty acid synthesis was reduced while genes for enzymes in gluconeogenesis were up-regulated. Expression was also altered for genes associated with complement and coagulation cascades, and with signaling pathways involving STAT1 and TGF-beta.
Most of the 4500 differentially expressed transcripts represented a general response to both virulent and mild infections. However, approximately 250 of these transcripts had significantly different expression in virulent infections as compared to mild infections, with approximately 30 of these being differentially regulated during the pre-viremic stage of infection. The genes that are expressed early and differently in mild and virulent disease are potential biomarkers for prognosis and triage of acute viral disease.
Virology Journal 03/2009; 6:20. · 2.34 Impact Factor
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ABSTRACT: Abstract
Background
Rhesus macaques infected with lymphocytic choriomeningitis virus (LCMV) provide a model for human Lassa fever. Disease begins with flu-like symptoms and progresses rapidly with fatal consequences. Previously, we profiled the blood transcriptome of LCMV-infected monkeys (M. Djavani et al J. Virol. 2007) showing distinct pre-viremic and viremic stages that discriminated virulent from benign infections. In the present study, changes in liver gene expression from macaques infected with virulent LCMV-WE were compared to gene expression in uninfected monkeys as well as to monkeys that were infected but not diseased.
Results
Based on a functional pathway analysis of differentially expressed genes, virulent LCMV-WE had a broader effect on liver cell function than did infection with non-virulent LCMV-Armstrong. During the first few days after infection, LCMV altered expression of genes associated with energy production, including fatty acid and glucose metabolism. The transcriptome profile resembled that of an organism in starvation: mRNA for acetyl-CoA carboxylase, a key enzyme of fatty acid synthesis was reduced while genes for enzymes in gluconeogenesis were up-regulated. Expression was also altered for genes associated with complement and coagulation cascades, and with signaling pathways involving STAT1 and TGF-β.
Conclusion
Most of the 4500 differentially expressed transcripts represented a general response to both virulent and mild infections. However, approximately 250 of these transcripts had significantly different expression in virulent infections as compared to mild infections, with approximately 30 of these being differentially regulated during the pre-viremic stage of infection. The genes that are expressed early and differently in mild and virulent disease are potential biomarkers for prognosis and triage of acute viral disease.
Virology Journal. 01/2009;
