1,721,290 research outputs found
Treatment based on Nutlin-3 combinations as innovative therapy for leucemia and pediatric malignancies
No full textStudies of combined treatment with Nutlins plus TRAIL as an innovative therapy for hematological malignancie
Circulating levels of TNF-related apoptosis inducing ligand (TRAIL)
No full textIn their interesting study published in this issue of Clinical Endocrinology, Xiang et al.[1]demonstrated that the circulating levels of TNF-related apoptosis inducing ligand (TRAIL) are significantly decreased in a cohort of 55 newly diagnosed type 2 diabetic (T2D) patients as compared to sex- and aged-matched normal controls, confirming and expanding the data reported in a previous study performed on a smaller group (n = 22) of T2D patients.[2] Of interest, another group of investigators has shown similar findings in an independent and larger cohort (n = 387) of paediatric patients with newly diagnosed with Type 1 diabetes (T1D).[3] In the study of Tornese et al.,[3] the lowest levels of TRAIL were observed in patients with ketoacidosis and those with higher insulin requirements. According to all these studies, both types of diabetes at diagnosis are characterized by low levels of circulating TRAIL, suggesting that metabolic compromise rather than immune-mediated mechanisms (characteristic of T1D but not of T2D) are responsible for the decrease in the circulating levels of TRAIL. The link between circulating levels of TRAIL and the metabolic situation is further suggested in the study of Xiang et al. by the fact that following 6 months therapy with insulin or metformin levels of circulating TRAIL increased significantly, although they still did not reach the values of the control group.[1] In addition, and perhaps more importantly, Xiang et al.[1] were able to demonstrate that circulating TRAIL levels showed a significant positive correlation with flow-mediated endothelium-dependent arterial dilation (FMD), an important clinical index of endothelial function. These findings are particularly relevant since endothelial dysfunction represents an early physiological event in atherosclerosis,[4] and thus the data of Xiang support the hypothesis that TRAIL might have a protective role in endothelial function, at least in the diabetic context. The current findings of Xiang et al.,[1] together with the previous works of Volpato et al. [5] and of Deftereos et al.,[6] strongly support experimental data obtained in animal models, showing that TRAIL is able to counteract the accelerated atherosclerosis observed in streptozotocin-treated apolipoprotein E−/− mice.[7, 8] Moreover, it was previously shown that recombinant TRAIL administration ameliorates the natural history of diabetes in streptozotocin-treated mice.[9] Finally, it has been shown that TRAIL −/− apolipoprotein E−/− mice on an high-fat diet gain more body weight and that they display higher fasting glucose and pro-inflammatory cytokines levels than apolipoprotein E−/− mice,[10] and that recombinant TRAIL delivery was able to reduce body weight, and lower fasting glucose and pro-inflammatory cytokine levels, overall ameliorating diabetes. In conclusion, this study of Xiang et al. [1] provides solid clinical support to the idea that there are significant changes in the circulating levels of TRAIL at the onset of T2D and in response to therapy. Future studies are needed to distinguish whether the decreased levels of circulating TRAIL in both types of diabetes represent simply a new biomarker of metabolic compromise, or whether such reduced levels might play a pathogenetic role in endothelial cell dysfuncion and the development of atherosclerosis
Effects of exogenous hydrogen sulfide on endothelial functions and potential interplay with TNF-members
No full textStudy of effects of exogenous hydrogen sulfide on endothelial functions and potential interplay with TNF-member
Editorial: Innovative therapeutical approaches for hematological malignancies based on molecular targeted therapies
No full text-
Combined treatment with Nutlins plus TRAIL as an innovative therapy for hematological malignancies
No full textStudy of combined treatment with Nutlins plus TRAIL as an innovative therapy for hematological malignancie
The puzzling role of TRAIL in endothelial cell biology
No full textIn their study published online in Arteriosclerosis, Thrombosis,
and Vascular Biology, O’Brien et al demonstrate that activated
protein C (APC) decreases tumor necrosis factor (TNF)-related
apoptosis-inducing ligand (TRAIL) expression in endothelial
cells.1 Although the molecular mechanism by which APC decreases the expression of TRAIL mRNA and protein via an
Egr-1/Erk-1/2 pathway appears convincing, much less clear is
whether the downregulation of TRAIL reflects a physiological
relevant decrease of surface TRAIL or TRAIL release by
endothelial cells. In fact, we have never detected surface TRAIL
by flow cytometry in human umbilical vein endothelial cells (HUVECs), cultured with or without TNF-alpha. On the
other hand, surface TRAIL was easily detectable in other cell
model systems, such as peripheral blood-derived adherent macrophages. Moreover, we were also unable to document
in ELISA detectable release of soluble TRAIL by HUVECs treated or not with TNF-alpha. Because in their study O Brien et al used an ELISA approach to detect the TRAIL protein in endothelial cell lysates, the reported modulation of TRAIL by TNF-alpha and APC likely involves an intracellular pool of TRAIL protein. Although this represents an interesting observation, the mechanisms involved in membrane expression/release of TRAIL in endothelial cells have not been defined yet, making unclear the physiopathological implications of this study. However, what raises some concern in the study of O’Brien et al is their interpretation on the putative role of TRAIL in endothelial cell biology in the context of the available scientific literature. In fact, although O’Brien and colleagues postulate a detrimental effect of TRAIL in vascular biology, in our opinion this hypothesis is not adequately supported. In spite of the observation that human endothelial cells obtained from different vascular districts express detectable levels of all transmembrane TRAIL receptors (TRAIL-R1–R4),2–4 most of the published studies have reported lack of toxicity in vitro when endothelial cells were exposed to recombinant TRAIL. Notwithstanding, different authors, including us, have shown that particular culture conditions, such as serum and extracellular matrix deprivation coupled to pharmacological inhibition of the PI-3 kinase/Akt prosurvival pathway were required to efficiently sensitize endothelial cells to TRAIL-mediated cytotoxicity. How these culture conditions reflect a physiopathological condition remains to be determined.
Contrary to the hypothesis of a detrimental effect of TRAIL in
vascular biology, in a series of in vitro studies we have documented that soluble recombinant TRAIL exhibits protective and antiinflammatory effects on endothelial cells. Moreover, we have recently reported that soluble TRAIL shows antiatherogenic effects in an in vivo model of Apo-E knockout mouse. Thus, the overall scenario emerging from these published studies is that the role of TRAIL in vascular biology deserves further investigation before any conclusion on the usefulness of drug decreasing its expression/release by endothelial cells can be drawn
Tumor necrosis factor-related apoptosis-inducing ligand and the regulation of hematopoiesis
No full textPURPOSE OF REVIEW: This review will focus on the emerging role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL-receptors in the pathophysiology of hematopoiesis and on the potential therapeutic applications of either recombinant TRAIL or anti-TRAIL-R1/-R2 agonistic antibodies for the treatment of hematological malignancies. RECENT FINDINGS: While CD34 stem/progenitor cells do not express TRAIL-receptors and are protected from TRAIL-induced apoptosis, accumulating evidence points to a role for elevated expression/release of TRAIL at the bone marrow level in the pathophysiology of aplastic anemia, Fanconi anemia, and myelodysplastic syndromes. In-vitro data show promising synergistic effects of recombinant TRAIL in association with proteasome or histone deacetylase inhibitors, natural compounds or small molecules in the therapy of myeloid and lymphoid malignancies. Moreover, although both recombinant TRAIL and anti-TRAIL-R1/-R2 antibodies are well tolerated in vivo, anti-TRAIL-R1/-R2 agonistic antibodies show the potential advantage of avoiding the neutralizing activity of the soluble receptor osteoprotegerin. SUMMARY: While a chronic pathological elevation of TRAIL at the bone marrow level might contribute to the impairment of normal hematopoiesis, the use of recombinant TRAIL and anti-TRAIL-R1/-R2 agonistic antibodies appears particularly promising for the treatment of hematological malignancies in particular, of multiple myeloma, especially if used in association with innovative therapeutic compounds
HIV-1-Related mechanisms of suppression of CD34+ hematopoietic progenitors
No full textPeripheral blood cytopenias and bone marrow abnormalities are frequently observed in HIV-1-seropositive subjects. Two major mechanisms have been proposed to explain the hematopoietic failure often observed in patients with advanced HIV-1 disease: (i) infection of cells composing the bone marrow microenvironment with a deranged production of hematopoietic growth factors; (ii) direct suppression of hematopoietic progenitor cells mediated by HIV-1 virions and/or viral proteins. In vivo and in vitro experimental evidence supports a combination of both mechanisms. In fact, it has been shown that: (i) infection with HIV-1 and/or exposure of bone marrow accessory cells to envelope glycoprotein 120 (env gp 120) increases the production of inhibitory cytokines such as tumor necrosis factor alpha; (ii) a subset of CD34+ hematopoietic progenitor cells co-expresses the CD4 antigen and may be infected in vivo with HIV-1; (iii) HIV-1 virions or immune complexes containing env gp 120 are able to induce apoptosis of uninfected CD34+ hematopoietic progenitors. This last inhibitory effect appears to be mediated by the upregulation of transforming growth factor beta 1, which is endogenously produced by hematopoietic progenitors. Both the load and the biological characteristics of the virus play an important role in causing these suppressive effects, since different HIV-1 isolates display varying abilities to suppress hematopoiesis, and some isolates are not cytopathic at all
- …
