LRG1 is an adipokine that mediates obesity-induced hepatosteatosis and insulin resistance

Dysregulation in adipokine biosynthesis and function contributes to obesity-induced metabolic diseases. However, the identities and functions of many of the obesity-induced secretory molecules remain unknown. Here, we report the identification of leucine-rich alpha-2-glycoprotein 1 (LRG1) as an obesity-associated adipokine that exacerbates high fat diet–induced hepatosteatosis and insulin resistance. Serum levels of LRG1 were markedly elevated in obese humans and mice compared with their respective controls. LRG1 deficiency in mice greatly alleviated diet-induced hepatosteatosis, obesity, and insulin resistance. Mechanistically, LRG1 bound with high selectivity to the liver and promoted hepatosteatosis by increasing de novo lipogenesis and suppressing fatty acid β-oxidation. LRG1 also inhibited hepatic insulin signaling by downregulating insulin receptor substrates 1 and 2. Our study identified LRG1 as a key molecule that mediates the crosstalk between adipocytes and hepatocytes in diet-induced hepatosteatosis and insulin resistance. Suppressing LRG1 expression and function may be a promising strategy for the treatment of obesity-related metabolic diseases.     

T cell recognition motifs of an immunodominant peptide of myelin basic protein in patients with multiple sclerosis: structural requirements and clinical implications

Myelin basic protein (MBP)-reactive T cells may play an important role in the pathogenesis of multiple sclerosis (MS). The T cell response to the 83 – 99 region of MBP represents a dominant autoreactive response to MBP in MS patients of DR2 haplotype. In this study, a large panel of DR2- and DR4-restricted T cell clones specific for the MBP83 – 99 peptide were examined for the recognition motifs and structural requirements for antigen recognition using alanine-substituted peptides. Our study revealed that although the recognition motifs of the T cell clones were diverse, the TCR contact residues within the 83 – 99 region of MBP were highly conserved. Two central residues (Phe90 and Lys91) served as the critical TCR contact points for both DR2- and DR4-restricted T cell clones. Single alanine substitution at residue 90 or residue 91 abolished the responses of 81 – 95 % of the T cell clones while a double alanine substitution rendered all T cell clones unresponsive. It was also demonstrated in this study that the substituted peptides altered the cytokine profile of some, but not all, T cell clones. Some MBP83 – 99-specific T cell clones were able to sustain alanine substitutions and were susceptible to activation by microbial antigens. The study has an important implication in designing a peptide-based therapy for MS.     

Early proliferation enhancement by monosomy 10 and intratumor heterogeneity in malignant human gliomas as revealed by smear preparations from biopsies

We performed simultaneous fluorescence in situ hybridization (FISH) with centromere-specific DNA probes for chromosomes 7 and 10 and Ki-67 proliferation labelling on smear preparations of 17 differentiated and anaplastic human astrocytomas and glioblastomas. In 15 of the 17 cases studied, Ki-67-positive clones differed from Ki-67-negative clones mainly by the loss of one copy of chromosome 10, either combined with or Independent of trisomy 7. The findings suggest that monosomy 10 is an earlier event than generally supposed in the development of human gliomas and that it is directly related to cellular hyper-proliferation. Genes Chromosom Cancer 16:180–184 (1996). © 1996 Wiley-Liss, Inc.     

急性白血病患者血浆Hcy、AT-III及vWF的检测及其临床意义

目的:检测急性白血病(acuteleukemia,AL)患者不同发展阶段血浆同型半胱氨酸(homocysteine,Hcy)、抗凝血酶Ⅲ(antithrombinIII)、血管性血友病因子(vonwillebrandfactor,vWF)水平,探讨这些活性物质在AL的诊断、治疗及预后判断中的临床意义。方法:选择初诊AL患者40例,正常对照30例。测定其血浆Hcy、AT-III及vWF水平,并对AL患者进行治疗前、后不同阶段的动态检测。骨髓涂片在显微镜下按常规分类计数200个有核细胞,计算原始加幼稚细胞比例。结果:AL组初诊时血浆vWF含量明显升高,与正常对照组比较有显著性差异(P<0.01)。AL组初诊时血浆AT-III含量明显减低,与正常对照组比较差异有统计学意义(P<0.05)。AL组初诊时血浆Hcy含量明显升高,与正常对照组比较有显著性差异(P<0.01)。经过2-3个疗程的治疗后,达到完全缓解(CR)时,血浆Hcy、AT-Ⅲ及vWF含量恢复正常,与正常对照组比较无显著差异(P>0.05)。经过2-3个疗程的治疗后,未达到缓解[包括部分缓解(PR)和未缓解(NR)]时,上述因子与治疗前比较差异无统计学意义(P>0.05);AL初诊患者治疗前血浆vWF及Hcy水平与骨髓原始加幼稚细胞数呈正相关(P<0.001和P<0.01),而AT-Ⅲ水平与骨髓原始加幼稚细胞数呈负相关(P<0.05,r=-0.622)。结论:动态监测AL患者血浆Hcy、AT-III及vWF水平,可作为白血病病情进展、疗效过程及判断预后的重要参考指标。     

The polymorphism interleukin-8 -251A/T is associated with a significantly increased risk of cancers from a meta-analysis

Emerging evidences show that interleukin-8 (IL-8) has important regulatory functions in tumorigenesis. IL-8 -251A/T is a single nucleotide polymorphism in the promoter region of the IL-8 gene and affects IL-8 production. Analysis of previous studies on the association of -251A/T polymorphism with different cancer types remained to be illustrated. To further assess the effect of -251A/T polymorphism on cancer risks, we performed this meta-analysis, up to November 2013, of 12,917 cases with different cancer types and 17,689 controls from 47 published case-control designed studies. Statistical analyses were performed using STATA 11.0 software. Crude odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of associations. ORs with 95 % CIs for IL-8 -251A/T polymorphism and cancer were estimated using fixed- and random-effects models when appropriate. Significantly increased risks were found in overall under the models of A allele vs. T allele, AA vs. TT, and AA vs. AT/TT. Significantly elevated risks were observed in breast cancer under the models of A allele vs. T allele, AT vs. TT, AA/AT vs. TT, and AA vs. AT/TT, and in nasopharyngeal carcinoma under the models of AT vs. TT, AA/AT vs. TT, and AA vs. AT/TT. We found that significantly elevated risks were observed in the Asian population and hospital-based studies in all comparison models. Thus, this meta-analysis indicates that IL-8 -251A/T polymorphism is associated with a significantly increased risk of cancers and may provide evidence-based medical certificate to study the cancer susceptibility.     

Erythropoietin stimulates a rise in intracellular-free calcium concentration in single BFU-E derived erythroblasts at specific stages of differentiation

Human cord blood progenitor-derived erythroblasts have recently been shown to respond to erythropoietin (Epo) or granulocyte-macrophage colony-stimulating factor (GM-CSF) with a transient increase in intracellular free calcium concentration [Cac]. However, the importance of [Cac] changes in mediating cell proliferation and/or differentiation is undefined. In the present study, the response of erythroid precursors at different stages of differentiation to Epo was examined. Erythroblasts were derived from adult blood erythroid progenitors (BFU- E) at day 7 or day 10 of culture. [Cac] was measured in individual Fura- 2 loaded cells with fluorescence microscopy coupled digital video imaging. The dynamic range (Rmax/Rmin) of intracellular Fura-2 was similar to that measured in free solution, suggesting insignificant amounts of intracellular Ca insensitive forms of Fura-2. Baseline [Cac] of erythroid cells calculated with an in vitro calibration method was 44 +/- 4 nmol/L and with an in vivo method was 46 +/- 4 nmol/L. Treatment of day 7 BFU-E derived erythroblasts with Epo resulted in no significant increase in [Cac]. In contrast, in more mature erythroblasts (day 10 of culture), Epo stimulated a large increase in [Cac] from 49 +/- 11 nmol/L at baseline to 279 +/- 47 nmol/L. This [Cac] increase occurred in phosphate buffered saline (PBS) containing no added calcium. The increase in [Cac] persisted for 18 minutes and was dose dependent. Day 7 and day 10 control cells treated with either insulin or media showed no significant change in [Cac] during 18 minutes of observation. Our data demonstrate that early (day 7) and late (day 10) erythroblasts display different responses to Epo, at least in terms of intracellular Ca++ fluxes. The differential [Cac] response observed in early and late erythroid precursors to growth factor stimulation suggests that [Cac] may be an important signal in cell differentiation.     

Individual immunosuppressive protocol after liver transplantation in benign end-stage liver disease:a single-center experience of 645 cases

<正>Objective To analyze individual immunosuppressive protocol ( IP) after liver transplantation ( LT) in benign end - stage liver disease. Methods The clinical data of 645 patients with benign end - stage liver disease undergoing LT in our institute from April 2002 to Aug 2010 were analyzed retrospectively. 146 cases from Apr.