ABSTRACT
Fungal growth-dependent gene coregulation is strongly implicated in alteration of gene-encoding target proteases ruling with an antifungal resistance niche and biology of resistant mutants. On the basis of multi-alterative processes in this platform, the resistance-modifying strategy is designed in ketoconazole resistant Candida albicans and evaluated with less selective Momordica charantia protein and allosterically phosphorylated derivatives at the Thr102, Thr24 and Thr255 sites, respectively. We demonstrate absolutely chemo-sensitizing efficacy regarding stepwise-modifying resistance in sensitivity, by a load of only 26.23-40.00 µg/l agents in Sabouraud's dextrose broth. Five successive modifying-steps realize the decreasing of ketoconazole E-test MIC50 from 11.10 to a lower level than 0.10 mg/l. With the ketoconazole resistance-modifying, colony undergoes a high-frequency morphological switch between high ploidy (opaque) and small budding haploid (white). A cellular event in the first modifying-step associates with relatively slow exponential growth (ie, a 4-h delay)-dependent action, mediated by agents adsorption. Moreover, multiple molecular roles are coupled with intracellularly and extracellularly binding to ATP-dependent RNA helicase dbp6; the 0.08-2.45 fold upregulation of TATA-box-binding protein, rRNA-processing protein and translation initiation factor 5A; and the 7.52-55.33% decrease of cytochrome P450 lanosterol 14α-demethylase, glucan 1, 3-ß glucosidase, candidapepsin-1 and 1-acylglycerol-3-phosphate O-acyltransferase. Spatial and temporal gene coregulation, in the transcription and translation initiation stages with rRNA-processing, is a new coprocessing platform enabling target protease attenuations for resistance-impairing. An updated resistance-modifying measure of these agents in the low-dose antifungal strategic design may provide opportunities to a virtually safe therapy that is in high dose-dependency. LAY SUMMARY: A new platform to modify resistance is fungal growth-dependent gene coregulation. MAP30 and phosphorylated derivatives are candidate resistance-modifying agents. Low-dose stepwise treatment absolutely modifies azole resistance in model fungus.
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Objective To study the expression of nicotinic acetylcholine receptor α7 in CD4 + CD25 + T lymphocytes of peripheral blood in children with sepsis,and to analyze the role of α7nAChR in the development of sepsis.Methods Forty-nine hospitalized patients with sepsis from Nov.2011 to Dec.2012 in PICU of Nanjing Children's Hospital Affiliated to Nanjing Medical University were enrolled,and they were divided into the survival group (n =33)and the dead group (n =16) in accordance with the outcome.At the same time,the total of 40 cases including the children receiving inguinal hernia repair and the children receiving health examination were enrolled as control group.Peripheral venous blood was collected to detect the expression of CD4 +/CD25 +/α7nAChR by indirect flow cytometry.Simultaneously,the CD3 +,CD4 +,CD8 +,CD4 +/CD8 + ratio were detected,and Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) scores were calculated.Results The expressions of CD4 +/CD25 +/α7nAChR in sepsis group were much lower than those in the control group [(25.8 ± 3.1) ％ vs (34.9 ± 2.9) ％,P ＜ 0.05] ; and the expression of CD4 + CD25 +/α7nAChR in the dead group was also significantly lower than that in the survival group [(22.4 ± 2.5) ％ vs (28.1 ± 2.9) ％,P ＜ 0.05].The expressions of α7nAChR on CD4 +/CD25 + T lymphocytes of peripheral blood in children with sepsis was negatively correlated with the APACHE Ⅱ score (r =-0.512,P ＜ 0.05).The CD3 +,CD4 +,CD4 +/CD8 + ratios in the dead group were significantly lower than those in the control group (all P ＜ 0.05) ; in the survival group and the control group,the values of CD3 +,CD4 +,CD8 + were not significantly different,while the ratios of CD4 +/CD8 + between these 2 groups had a significant difference(P ＜ 0.05).Conclusions The expressions of α7nAChR on the CD4 + CD25 +T lymphocytes in the children with sepsis were reduced,and the expressions were lower,the outcome were worse;the children with sepsis have cell immune dysfunction.
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<p><b>OBJECTIVE</b>To review the characteristics of regulatory T cells (Tregs) and ex vivo expansion of Tregs for treatment of graft-versus-host disease (GVHD).</p><p><b>DATA SOURCES</b>The data used in this review were retrieved from PubMed (1970-2013). The terms "ex vivo expansion", "regulatory T cell", and "graft-versus-host disease" were used for literature search.</p><p><b>STUDY SELECTION</b>The publications about the characteristics of Tregs, ex vivo expansion of Tregs and clinical applications of Tregs against GVHD were identified, retrieved and reviewed.</p><p><b>RESULTS</b>Tregs can be classified as natural Tregs (nTregs) and induced Tregs (iTregs). Both subsets share most Treg features. Given their immunosuppressive property, Tregs have been tested for their capability of preventing GVHD. The bottleneck of Treg therapy is the limited numbers of naturally existing Tregs. To solve this problem, ex vivo expansion of nTregs or iTregs has been executed. The initial data indicate Treg therapy is effective in reducing GVHD without compromising graft-versus-leukemia (GVL).</p><p><b>CONCLUSION</b>Ex vivo expansion of Tregs is a reliable way to prepare sufficient number of Tregs for management of GVHD.</p>
Subject(s)
Humans , Graft vs Host Disease , Allergy and Immunology , Therapeutics , Hematopoietic Stem Cell Transplantation , T-Lymphocytes, Regulatory , Cell BiologyABSTRACT
<p><b>OBJECTIVE</b>Kawasaki disease (KD) is an acute and self-limited systemic vasculitis syndrome of unknown origin that mainly affects small and medium-sized arteries, particularly the coronary arteries, which is followed by aneurysm formation. Increased levels of matrix metalloproteinase-1 (MMP-1) have been detected in aortic aneurysms in adults, suggesting an important role of MMP-1 in arterial wall destruction and resultant aneurysm formation. The aim of this study was to investigate the potential role of MMP-1 in the pathogenesis of coronary artery lesions in patients with KD.</p><p><b>METHODS</b>Forty patients with KD, including 23 patients without coronary artery lesions (CAL) and 17 patients with CAL, as well as age-matched 10 febrile and 10 healthy afebrile controls were studied. The duration of KD was divided into three phases: the acute phase, the subacute phase and the convalescent phase. Enzyme-linked immunosorbent assay was used to detect the protein levels of MMP-1 in the sera. MMP-1 mRNA expression in the circulating leucocytes was studied using reverse transcription-polymerase chain reaction.</p><p><b>RESULTS</b>Levels of MMP-1 protein in serum and MMP-1 mRNA expression in the leucocytes were significantly elevated at the acute phase in the two groups of KD patients (CAL group: 14.91 +/- 3.88 ng/ml and 0.89 +/- 0.15 ng/ml; NO-CAL group: 11.27 +/- 3.28 ng/ml and 0.77 +/- 0.14, respectively), compared with febrile (7.05 +/- 1.98 ng/ml and 0.45 +/- 0.12 ng/ml, respectively) and afebrile (5.13 +/- 1.20 ng/ml and 0.29 +/- 0.12 ng/ml, respectively) controls (P < 0.01). Furthermore, MMP-1 protein and MMP-1 mRNA levels were significantly higher in KD patients with CAL than in KD patients without CAL (P < 0.05). There was a significantly positive correlation between the serum protein level of MMP-1 at the acute phase of KD and the circulating leucocytes counts (r = 0.750, P < 0.01). The MMP-1 serum protein level and mRNA expression in the leucocytes at the acute phase of the two KD groups decreased obviously from the subacute through the convalescent phases (P < 0.05 or P < 0.01).</p><p><b>CONCLUSION</b>The expression of MMP-1 at the acute phase of KD was significantly elevated, especially in KD patients with CAL. MMP-1 might be involved in the formation of coronary artery lesions and pathogenesis of KD.</p>
