1,721,128 research outputs found
Stem cells for the cell and molecular therapy of type 1 diabetes mellitus (T1D): the gap between dream and reality.
No full textIn spite of intense research, over the past 2-3 decades, targeted to validating methods for the cure of T1D, based on cell substitution therapy in the place of exogenously administered insulin injections, achievement of the final goal continues to remain out of reach. In fact, aside of very limited clinical success of the few clinical trials of pancreatic islet cell transplantation in totally immunosuppressed patients with T1D, the vast majority of these diabetic patients invariably is insulin-dependent. New advances for cell and molecular therapy for T1D, including use of stem cells, are reviewed and discussed in an attempt to clearly establish where we are and where are we may go for the final cure for T1DM
Advanced glycosylation end-products and the pathogenesis of accelerated atherosclerosis in diabetes
No full textAdvanced glycosylation end-products and the pathogenesis of accelerated atherosclerosis in diabetes
No full textIn Vitro Cultured Human Islet Cell Monolayers : Stemness Markers and Insulin Recovery upon Streptozotocin exposure.
No full textWe have investigated long-term in vitro–cultured human islet-derived cell monolayers (CM) to determine their
suitability as source of newly generated b-cells. Initial loss of the islet three-dimensional architecture resulted in
rearrangement of pancreatic hormone and key transcriptional factor expression, or decreased insulin secretion,
or declined glucose-stimulated insulin release, reflecting reversal to an immature precursor stage. However,
upon exposure to several streptozotocin (STZ) concentrations, CM showed glucose-stimulated insulin release
recovery and an increased synthesis of insulin mRNA. Possibly, this outcome could derive from eventual
‘‘stemness’’ properties of such cell populations, unfolded by subtoxic STZ-induced CM damage. To test this
hypothesis, we have examined messenger and protein expression of embryonic stem cell markers (Nanog, Sox-2,
Oct-4A), which varied in CM versus control whole human islets. Moreover, different STZ concentrations were
shown to modulate marker expression in CM. All together our data preliminarily seem to indicate that CM
may generate reconstituted insulin-producing cells likely due to their intrinsic, preexisting stemness properties
Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes
No full textAbstract
The formation of advanced glycation end products (AGEs) is an important biochemical abnormality that accompanies diabetes mellitus
and, likely, inflammation in general. Here we summarize and discuss recent studies indicating that the effects of AGEs on vessel wall
homeostasis may account for the rapidly progressive atherosclerosis associated with diabetes mellitus. Driven by hyperglycemia and oxidant
stress, AGEs form to a greatly accelerated degree in diabetes. Within the vessel wall, collagen-linked AGEs may ‘‘trap’’ plasma proteins,
quench nitric oxide (NO) activity and interact with specific receptors to modulate a large number of cellular properties. On plasma low
density lipoproteins (LDL), AGEs initiate oxidative reactions that promote the formation of oxidized LDL. Interaction of AGEs with
endothelial cells as well as with other cells accumulating within the atherosclerotic plaque, such as mononuclear phagocytes and smooth
muscle cells (SMCs), provides a mechanism to augment vascular dysfunction. Specifically, the interaction of AGEs with vessel wall
components increases vascular permeability, the expression of procoagulant activity and the generation of reactive oxygen species (ROS),
resulting in increased endothelial expression of endothelial leukocyte adhesion molecules. AGEs potently modulate initiating steps in
atherogenesis involving blood-vessel wall interactions, triggering an inflammatory-proliferative process and, furthermore, critically
contribute to propagation of inflammation and vascular perturbation in established disease. Thus, a better understanding of the biochemical
mechanisms by which AGEs contribute to such processes in the vessel wall could be relevant to devise preventive and therapeutic strategies
for diabetic atherosclerosis
Microencapsulation of cells and molecular therapy of type 1 diabetes mellitus: The actual state and future perspectives between promise and progress
No full textThe history of microencapsulation of live cells started with an idea of Thomas MS Chang in 1964, thereafter applied to isolated pancreatic islets by Anthony M Sun in 1980. The original aim was to provide isolated cells with an immune-protective shield, to prevent physical contact between the transplanted cells and the host’s immune system, with retention of the microcapsules’ biocompatibility and physical–chemical properties over time. In particular, this revolutionary approach essentially applied to islet grafts, in diabetic recipients who are not immunosuppressed, at a preclinical (rodents) and, subsequently, clinical level. Among the different chemistries potentially suitable for microencapsulation of live cells, alginic acid-based polymers, originally proposed by Sun, proved to be superior to all others in the following decades. In fact, only alginic acid-based microcapsules, containing allogeneic islets, ultimately entered pilot human clinical trials in patients with type 1 diabetes mellitus, as immuno-selectiveness and biocompatibility of alginic acid-hydrogels were never matched by other biopolymers. With problems related to human islet procurement coming into a sharper focus, in conjunction with technical limits of the encapsulated islet grafting procedures, new challenges are actually being pursued, with special regard to developing both new cellular systems – able to release immunomodulatory molecules and insulin itself – and new microencapsulation methods, with the use of novel polymeric formulations, under actual scrutiny. The use of embryonic and adult stem cells, within microcapsules, should address the restricted availability of cadaveric human donor-derived islets, whereas a new generation of newly-engineered microcapsules could better fulfill issues with graft site and long-term retention of biopolymer properties
Islet transplantation versus stem cells for the cell therapy of type 1 diabetes mellitus
No full textPancreatic islet cell transplantation has represented the mainstay of cell therapy for the potential, final cure of type 1 diabetes mellitus (T1D), along the past two decades. Unfortunately, the restricted availability of cadaveric human donor pancreases coupled with heavy side effects of the recipient's general immunosuppression, have severely crippled progress of this approach into clinical trials. Only a few excellence centers, worldwide, have thus far accrued still quite marginal clinical success. In an attempt to overcome the limits of islet transplantation new technologies for use of several stem cell lineages are being under investigation, with initial experimental evidence of success. Essentially, the actual lines of research involve attempts to either activate native endogenous stem cells that replace diseased/dead cells, by a cell regeneration process, or condition other stem cells to acquire the functional properties of the targeted cells to be substituted (i.e., beta-cell-like elements associated with insulin secretory competence). A wide array of stem cells may fulfill this task, from embryonic (whose use still faces strong ethical barriers), to adult, to induced pluripotent stem cells. Mesenchymal adult stem cells, retrievable from many different sites, including adipose tissue, bone marrow and post-partum umbilical cord Wharton Jelly, seem to couple plastic to immunoregulatory properties that might greatly help progress for the disease cure
Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes
No full textAbstract
The formation of advanced glycation end products (AGEs) is an important biochemical abnormality that accompanies diabetes mellitus
and, likely, inflammation in general. Here we summarize and discuss recent studies indicating that the effects of AGEs on vessel wall
homeostasis may account for the rapidly progressive atherosclerosis associated with diabetes mellitus. Driven by hyperglycemia and oxidant
stress, AGEs form to a greatly accelerated degree in diabetes. Within the vessel wall, collagen-linked AGEs may ‘‘trap’’ plasma proteins,
quench nitric oxide (NO) activity and interact with specific receptors to modulate a large number of cellular properties. On plasma low
density lipoproteins (LDL), AGEs initiate oxidative reactions that promote the formation of oxidized LDL. Interaction of AGEs with
endothelial cells as well as with other cells accumulating within the atherosclerotic plaque, such as mononuclear phagocytes and smooth
muscle cells (SMCs), provides a mechanism to augment vascular dysfunction. Specifically, the interaction of AGEs with vessel wall
components increases vascular permeability, the expression of procoagulant activity and the generation of reactive oxygen species (ROS),
resulting in increased endothelial expression of endothelial leukocyte adhesion molecules. AGEs potently modulate initiating steps in
atherogenesis involving blood-vessel wall interactions, triggering an inflammatory-proliferative process and, furthermore, critically
contribute to propagation of inflammation and vascular perturbation in established disease. Thus, a better understanding of the biochemical
mechanisms by which AGEs contribute to such processes in the vessel wall could be relevant to devise preventive and therapeutic strategies
for diabetic atherosclerosis
- …
