The Structure and Biological Function of CREG

The cellular repressor of E1A-stimulated genes (CREG) is a 220 amino acid glycoprotein structurally similar to oxidoreductases. However, CREG does not have enzymatic activities because it cannot bind to the cofactor flavin mononucleotide. Although CREG can be secreted, it is mainly an intracellular protein localized in the endocytic-lysosomal compartment. It undergoes proteolytic maturation mediated by lysosomal cysteine proteases. Biochemical studies have demonstrated that CREG interacts with mannose-6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF2R) and exocyst Sec8. CREG inhibits proliferation and induces differentiation and senescence when overexpressed in cultured cells. In Drosophila, RNAi-mediated knockdown of CREG causes developmental lethality at the pupal stage. In mice, global deletion of the CREG1 gene leads to early embryonic death. These findings establish an essential role for CREG in development. CREG1 haploinsufficient and liver-specific knockout mice are susceptible to high fat diet-induced obesity, hepatic steatosis and insulin resistance. The purpose of this review is to provide an overview of what we know about the biochemistry and biology of CREG and to discuss the important questions that remain to be addressed in the future

Bevacizumab specifically decreases elevated levels of circulating KIT+CD11b+ cells and IL-10 in metastatic breast cancer patients.

Whether bevacizumab exerts its anti-tumor properties through systemic effects beyond local inhibition of angiogenesis and how these effects can be monitored in patients, remain largely elusive. To address these questions, we investigated bone marrow-derived cells and cytokines in the peripheral blood of metastatic breast cancer patients undergoing therapy with bevacizumab. Circulating endothelial cells (CEC), circulating endothelial progenitor (CEP) and circulating CD11b+ cells in metastatic breast cancer patients before and during therapy with paclitaxel alone (n = 11) or in combination with bevacizumab (n = 10) were characterized using flow cytometry, real time PCR and RNASeq. Circulating factors were measured by ELISA. Aged-matched healthy donors were used as baseline controls (n = 12). Breast cancer patients had elevated frequencies of CEC, CEP, TIE2+CD11b+ and KIT+CD11b+ cell subsets. CEC decreased during therapy, irrespective of bevacizumab, while TIE2+CD11b+ remained unchanged. KIT+CD11b+ cells decreased in response to paclitaxel with bevacizumab, but not paclitaxel alone. Cancer patients expressed higher mRNA levels of the M2 polarization markers CD163, ARG1 and IL-10 in CD11b+ cells and increased levels of the M2 cytokines IL-10 and CCL20 in plasma. M1 activation markers and cytokines were low or equally expressed in cancer patients compared to healthy donors. Chemotherapy with paclitaxel and bevacizumab, but not with paclitaxel alone, significantly decreased IL-10 mRNA in CD11b+ cells and IL-10 protein in plasma. This pilot study provides evidence of systemic immunomodulatory effects of bevacizumab and identified circulating KIT+CD11b+ cells and IL-10 as candidate biomarkers of bevacizumab activity in metastatic breast cancer patients

Modulation of apoptosis in human hepatocellular carcinoma (HepG2 cells) by a standardized herbal decoction of Nigella sativa seeds, Hemidesmus indicus roots and Smilax glabra rhizomes with anti- hepatocarcinogenic effects

<p>Abstract</p> <p>Background</p> <p>A standardized poly-herbal decoction of <it>Nigella sativa </it>seeds, <it>Hemidesmus indicus </it>roots and <it>Smilax glabra </it>rhizomes used traditionally in Sri Lanka for cancer therapy has been demonstrated previously, to have anti-hepatocarcinogenic potential. Cytotoxicity, antioxidant activity, anti-inflammatory activity, and up regulation of p53 and p21 activities are considered to be some of the possible mechanisms through which the above decoction may mediate its anti-hepatocarcinogenic action. The main aim of the present study was to determine whether apoptosis is also a major mechanism by which the decoction mediates its anti-hepatocarcinogenic action.</p> <p>Methods</p> <p>Evaluation of apoptosis in HepG2 cells was carried out by (a) microscopic observations of cell morphology, (b) DNA fragmentation analysis, (c) activities of caspase 3 and 9, as well as by (d) analysis of the expression of pro-apoptotic (Bax) and anti-apoptotic (Bcl-2) proteins associated with cell death.</p> <p>Results</p> <p>The results demonstrated that in HepG2 cells, the decoction can induce (a) DNA fragmentation and (b) characteristic morphological changes associated with apoptosis (nuclear condensation, membrane blebbing, nuclear fragmentation and apoptotic bodies). The decoction could also, in a time and dose dependent manner, up regulate the expression of the pro-apoptotic gene <it>Bax </it>and down regulate expression of anti-apoptotic <it>Bcl-2 </it>gene (as evident from RT-PCR analysis, immunohistochemistry and western blotting). Further, the decoction significantly (<it>p </it>< .001) enhanced the activities of caspase-3 and caspase-9 in a time and dose dependent manner.</p> <p>Conclusions</p> <p>Overall findings provide confirmatory evidence to demonstrate that the decoction may mediate its reported anti-hepatocarcinogenic effect, at least in part, through modulation of apoptosis.</p

Transplant Acceptance Following Anti-CD4 Versus Anti-CD40L Therapy: Evidence for Differential Maintenance of Graft-Reactive T Cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73145/1/j.1600-6143.2008.02372.x.pd

Effects of IL-8 up-regulation on cell survival and osteoclastogenesis in multiple myeloma

[EN]IL-8 promotes cancer cell growth, survival, angiogenesis, and metastasis in several tumors. Herein, we investigated the sources of IL-8 production in multiple myeloma (MM) and its potential roles in MM pathogenesis. We found that bone marrow cells from patients with MM secreted higher amounts of IL-8 than healthy donors. IL-8 production was detected in cultures of CD138+ plasma cells and CD138(-) cells isolated from bone marrows of MM patients, and in three of seven human myeloma cell lines (HMCLs) analyzed. Interactions between MM and stromal cells increased IL-8 secretion by stromal cells through cell-cell adhesion and soluble factors. Interestingly, 1L8 expression also increased in HMCLs, stromal cells, and osteoclasts after treatment with the antimyeloma drugs melphalan and bortezomib. In fact, the effect of bortezomib on IL-8 production was higher than that exerted by stromal-MM cell interactions. Addition of exogenous IL-8 did not affect growth of HMCLs, although it protected cells from death induced by serum starvation through a caspase-independent mechanism. Furthermore, IL-8 induced by stromal-MM cell interactions strongly contributed to osteoclast formation in vitro, because osteoclastogenesis was markedly reduced by IL-8 specific neutralizing antibodies. In conclusion, our results implicate IL-8 in myeloma bone disease and point to the potential utility of an anti IL-8 therapy to prevent unwanted effects of IL-8 up-regulation on survival, angiogenesis, and osteolysis in MM.Spanish RTICC, Spanish Association against Cancer (AECC), the INNOCAMPUS Program , Spanish ISCIII-FIS (PI12/02591) and FEDER, Regional Council from Castilla y León (Consejería de Educación) and the Network of Centers for Regenerative Medicine and Cellular Therapy from Castilla y León

Pretransplant Prediction of Posttransplant Survival for Liver Recipients with Benign End-Stage Liver Diseases: A Nonlinear Model

Background: The scarcity of grafts available necessitates a system that considers expected posttransplant survival, in addition to pretransplant mortality as estimated by the MELD. So far, however, conventional linear techniques have failed to achieve sufficient accuracy in posttransplant outcome prediction. In this study, we aim to develop a pretransplant predictive model for liver recipients ’ survival with benign end-stage liver diseases (BESLD) by a nonlinear method based on pretransplant characteristics, and compare its performance with a BESLD-specific prognostic model (MELD) and a generalillness severity model (the sequential organ failure assessment score, or SOFA score). Methodology/Principal Findings: With retrospectively collected data on 360 recipients receiving deceased-donor transplantation for BESLD between February 1999 and August 2009 in the west China hospital of Sichuan university, we developed a multi-layer perceptron (MLP) network to predict one-year and two-year survival probability after transplantation. The performances of the MLP, SOFA, and MELD were assessed by measuring both calibration ability and discriminative power, with Hosmer-Lemeshow test and receiver operating characteristic analysis, respectively. By the forward stepwise selection, donor age and BMI; serum concentration of HB, Crea, ALB, TB, ALT, INR, Na +; presence of pretransplant diabetes; dialysis prior to transplantation, and microbiologically proven sepsis were identified to be the optimal input features. The MLP, employing 18 input neurons and 12 hidden neurons, yielded high predictive accuracy, wit

Effects of Imatinib Mesylate (Gleevec) on Human Islet NF-kappaB Activation and Chemokine Production In Vitro

Imatinib Mesylate (Gleevec) is a drug that potently counteracts diabetes both in humans and in animal models for human diabetes. We have previously reported that this compound in human pancreatic islets stimulates NF-κB signaling and islet cell survival. The aim of this study was to investigate control of NF-κB post-translational modifications exerted by Imatinib and whether any such effects are associated with altered islet gene expression and chemokine production in vitro.Human islets were either left untreated or treated with Imatinib for different timepoints. IκB-α and NF-κB p65 phosphorylation and methylation were assessed by immunoblot analysis. Islet gene expression was assessed using a commercial Pathway Finder microarray kit and RT-PCR. Islet chemokine production was determined by flow cytometric bead array analysis.Human islet IκB-α and Ser276-p65 phosphorylation were increased by a 20 minute Imatinib exposure. Methylation of p65 at position Lys221 was increased after 60 min of Imatinib exposure and persisted for 3 hours. Microarray analysis of islets exposed to Imatinib for 4 hours revealed increased expression of the inflammatory genes IL-4R, TCF5, DR5, I-TRAF, I-CAM, HSP27 and IL-8. The islet release of IL-8 was augmented in islets cultured over night in the presence of Imatinib. Following 30 hours of Imatinib exposure, the cytokine-induced IκB-α and STAT1 phosphorylation was abolished and diminished, respectively. The cytokine-induced release of the chemokines MIG and IP10 was lower in islets exposed to Imatinib for 30 hours.Imatinib by itself promotes a modest activation of NF-κB. However, a prolonged exposure of human islets to Imatinib is associated with a dampened response to cytokines. It is possible that Imatinib induces NF-κB preconditioning of islet cells leading to lowered cytokine sensitivity and a mitigated islet inflammation

Antitumor Peptides from Marine Organisms

The biodiversity of the marine environment and the associated chemical diversity constitute a practically unlimited resource of new antitumor agents in the field of the development of marine bioactive substances. In this review, the progress on studies of antitumor peptides from marine sources is provided. The biological properties and mechanisms of action of different marine peptides are described; information about their molecular diversity is also presented. Novel peptides that induce apoptosis signal pathway, affect the tubulin-microtubule equilibrium and inhibit angiogenesis are presented in association with their pharmacological properties. It is intended to provide useful information for further research in the fields of marine antitumor peptides