We have investigated the serum proteome of Han-nationality Chinese by using shotgun strategy. A complete proteomics analysis was performed on two reference specimens from a total of 20 healthy donors, in which each sample was made from ten-pooled male or female serum, respectively. The methodology used encompassed (1) removal of six high-abundant proteins; (2) tryptic digestion of low- and high-abundant proteins of serum; (3) separation of peptide mixture by RP-HPLC followed by ESI-MS/MS identification. A total of 944 nonredundant proteins were identified under a stringent filter condition (X(corr) > or = 1.9, > or = 2.2, and > or = 3.75, < or = C(n) > or = 0.1, and R(sp) > or = 4.0) in both pooled male and female samples, in which 594 and 622 entire proteins were found, respectively. Compared with the total 3020 protein identifications confirmed by more than one laboratory or more than one specimen in HUPO Plasma Proteome Project (PPP) participating laboratories recently, 206 proteins were identified with at least two distinct peptides per protein and 185 proteins were considered as high-confidence identification. Moreover, some lower abundance serum proteins (ng/mL range) were detected, such as complement C5 and CA125, routinely used as an ovarian cancer marker in plasma and serum. The resulting nonredundant list of serum proteins would add significant information to the knowledge base of human plasma proteome and facilitate disease markers discovery.
AbstractBackground and AimsInterleukin 6 [IL-6] or its receptor is currently a candidate for targeted biological therapy of inflammatory bowel disease [IBD]. Thus, a comprehensive understanding of the consequences of blocking IL-6 is imperative. We investigated this by evaluating the effects of IL-6 deletion on the spontaneous colitis of IL-10-deficient mice [IL-10−/−].MethodsIL-6/IL-10 double-deficient mice [IL-6−/−/IL-10−/−] were generated and analysed for intestinal inflammation, general phenotypes and molecular/biochemical changes in the colonic mucosa compared with wild-type and IL-10−/− mice.ResultsUnexpectedly, the IL-6−/−/IL-10−/− mice showed more pronounced gut inflammation and earlier disease onset than IL-10−/− mice, both locally [colon and small bowel] and systemically [splenomegaly, ulcerative dermatitis, leukocytosis, neutrophilia and monocytosis]. IL-6−/−/IL-10−/− mice exhibited elevations of multiple cytokines [IL-1β, IL-4, IL-12, TNFα] and chemokines [MCP-1 and MIG], but not IFN-γ [Th1], IL-17A and IL-17G [Th17], or IL-22 [Th22]. FOXP3 and TGF-β, two key factors for regulatory T [Treg] cell differentiation, were significantly down-regulated in the colonic mucosa, but not in the thymus or mesenteric lymph nodes, of IL-6−/−/IL-10−/− mice. CTLA-4 was diminished while iNOS was up-regulated in the colonic mucosa of IL-6−/−/IL-10−/− mice.ConclusionIn IL-10−/− mice, complete IL-6 blockade significantly aggravates gut inflammation, at least in part by suppressing Treg/CTLA-4 and promoting the IL-1β/Th2 pathway. In addition, the double mutant exhibits signs of severe systemic inflammation. Our data define a new function of IL-6 and suggest that caution should be exercised when targeting IL-6 in IBD patients, particularly those with defects in IL-10 signalling.
Colorectal cancer ranks within the top three cancers both in terms of incidence as well as deaths. Metastasis is often the major cause of mortality and liver is the primary and most common site to which colorectal cancers metastasize. We tested the prognostic ability of a long non-coding RNA (lncRNA) signature in liver metastatic colorectal cancers. We first evaluated expression levels of several lncRNAs in eight excised liver metastases from primary colorectal cancers and found significantly upregulated lncRNAs HOTAIR and MALAT1 along with significantly downregulated LOC285194. We further compared the expression levels of HOTAIR, MALAT1 and LOC285194 in primary colorectal tumors at the time of initial diagnosis and correlated them with disease progression and liver metastasis. HOTAIR and MALAT1 were significantly upregulated and LOC285194 was significantly downregulated in twelve patients who were diagnosed with liver metastasis within 5 years of initial diagnosis, compared to the five patients with no metastasis. A positive signature comprising of high HOTAIR/MALAT1 and low LOC285194 also correlated with progression to higher grade tumors. Thus, the lncRNA signature comprising of high HOTAIR/MALAT1 and low LOC285194 could be a prognostic signature for liver metastasis as well as overall poor survival.
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