Showing papers in "Journal of Cellular and Molecular Medicine in 2004"
TL;DR: A model for the regulation of MSC differentiation is proposed, and recent findings regarding theregulation of M SC differentiation are discussed.
Abstract: A considerable amount of retrospective data is available that describes putative mesenchymal stem cells (MSCs). However, there is still very little knowledge available that documents the properties of a MSC in its native environment. Although the precise identity of MSCs remains a challenge, further understanding of their biological properties will be greatly advanced by analyzing the mechanisms that govern their self-renewal and differentiation potential. This review begins with the current state of knowledge on the biology of MSCs, specifically with respect to their existence in the adult organism and postulation of their biological niche. While MSCs are considered suitable candidates for cell-based strategies owing to their intrinsic capacity to self-renew and differentiate, there is currently little information available regarding the molecular mechanisms that govern their stem cell potential. We propose here a model for the regulation of MSC differentiation, and recent findings regarding the regulation of MSC differentiation are discussed. Current research efforts focused on elucidating the mechanisms regulating MSC differentiation should facilitate the design of optimal in vitro culture conditions to enhance their clinical utility cell and gene therapy.
1,093 citations
TL;DR: Recent clinical studies employing endothelial progenitor cells for neo‐vascularization of ischemic organs have just been published, however, the specificity of the observed positive clinical effects, the mechanisms regulating the differentiation of EPCs and their homing to sites of injured tissue remain partially unknown at present.
Abstract: Bone marrow and peripheral blood of adults contain a special sub-type of progenitor cells which are able to differentiate into mature endothelial cells, thus contributing to re-endothelialization and neo-vascularization. These angiogenic cells have properties of embryonal angioblasts and were termed endothelial progenitor cells (EPCs). In general, three surface markers (CD133, CD34 and the vascular endothelial growth factor receptor-2) characterize the early functional angioblast, located predominantly in the bone marrow. Later, when migrating to the systemic circulation EPCs gradually lose their progenitor properties and start to express endothelial marker like VE-cadherin, endothelial nitric oxide synthase and von Willebrand factor. The number of circulating EPCs in healthy subjects is rather low and a variety of conditions or factors may further influence this number. In the context of possible therapeutic application of EPCs recent clinical studies employing these cells for neo-vascularization of ischemic organs have just been published. However, the specificity of the observed positive clinical effects, the mechanisms regulating the differentiation of EPCs and their homing to sites of injured tissue remain partially unknown at present.
485 citations
TL;DR: increasing evidence of functional changes resulting from this modification, and the growing number of proteins shown to be S‐glutathionylated both in vitro and in vivo support this contention, and confirm this as an attractive area of research.
Abstract: Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play an integral role in the modulation of several physiological functions but can also be potentially destructive if produced in excessive amounts. Protein cysteinyl thiols appear especially sensitive to ROS/RNS attack. Experimental evidence started to accumulate recently, documenting that S-glutathionylation occurs in a number of physiologically relevant situations, where it can produce discrete modulatory effects on protein function. The increasing evidence of functional changes resulting from this modification, and the growing number of proteins shown to be S-glutathionylated both in vitro and in vivo support this contention, and confirm this as an attractive area of research. S-glutathionylated proteins are now actively investigated with reference to problems of biological interest and as possible biomarkers of human diseases associated with oxidative/nitrosative stress.
283 citations
TL;DR: Some of the recent findings resulting from tissue engineering science related to the attempt of creation and regeneration of functional skeletal muscle tissue are reviewed.
Abstract: The reconstruction of skeletal muscle tissue either lost by traumatic injury or tumor ablation or functional damage due to myopathies is hampered by the lack of availability of functional substitution of this native tissue. Until now, only few alternatives exist to provide functional restoration of damaged muscle tissues. Loss of muscle mass and their function can surgically managed in part using a variety of muscle transplantation or transposition techniques. These techniques represent a limited degree of success in attempts to restore the normal functioning, however they are not perfect solutions. A new alternative approach to addresssing difficult tissue reconstruction is to engineer new tissues. Although those tissue engineering techniques attempting regeneration of human tissues and organs have recently entered into clinical practice, the engineering of skletal muscle tissue ist still a scientific challenge. This article reviews some of the recent findings resulting from tissue engineering science related to the attempt of creation and regeneration of functional skeletal muscle tissue.
282 citations
TL;DR: How the recent progress in the molecular mechanisms of TNF‐α‐induced apoptosis in hepatocytes are shaping the understanding of the pathogenesis of liver diseases and the strategy to develop novel therapeutics is discussed.
Abstract: Tumor necrosis factor (TNF)-alpha-induced hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion liver injury, and fulminant hepatic failure. TNF-alpha exerts a variety of effects that are mediated mainly by TNF-receptor 1 (TNF-R1) in cell death. The activation of TNF-R1 leads to the activation of multiple apoptotic pathways involving the activation of the pro-death Bcl-2 family proteins, reactive oxygen species, C-Jun NH2-terminal kinase, cathepsin B, acidic sphingomyelinase and neutral sphingomyelinase. These pathways are closely interlinked and mainly act on mitochondria, which release the apoptogenic factors and other events, resulting in apoptosis. This article reviews the recent progress in the molecular mechanisms of TNF-alpha-induced apoptosis in hepatocytes, and discusses how these molecular findings are shaping our understanding of the pathogenesis of liver diseases and our strategy to develop novel therapeutics.
267 citations
TL;DR: Two broad categories of caspase‐directed compounds are focused on: highly specific caspases inhibitors that distinctly block the progress of apoptosis and casp enzyme activators that selectively induce cell death in a variety of in vitro and in vivo systems.
Abstract: While in multicellular organisms all cells inexorably die, there are several different ways provided for the realization of cell death. One of them, apoptosis, represents a universal energy-dependent and tightly regulated physiologic process of cell death in both normal and pathologic tissues. The execution of apoptosis appears to be uniformly mediated through consecutive activation of the members of a caspase family. This review briefly summarizes current knowledge on the molecular mechanisms of caspase activation and the inhibitory components of caspase cascades. The suitability of caspases as a new potential therapeutic target is discussed next. Particular attention is focused on two broad categories of caspase-directed compounds: highly specific caspase inhibitors that distinctly block the progress of apoptosis and caspase activators that selectively induce cell death in a variety of in vitro and in vivo systems. These agents promise to be useful clinically, either alone or in combination with more conventional therapeutics.
240 citations
TL;DR: The correlation of chromo‐somal DNA fragmentation and apoptosis or necrosis induced by GSH depletion, and the possible mechanisms of oxidative stress‐induced cell death are referred to.
Abstract: Chromosomal DNA and mitochondrial dysfunctions play a role on mammalian cell death induced by oxidative stress. The major biochemical dysfunction of chromosome is the presence of an ordered cleavage of the DNA backborn, which is separated and visualized as an electrophoretic pattern of fragments. Oxidative stress provides chromatin dysfunction such as single strand and double strand DNA fragmentation leading to cell death. More than 1 Mb of giant DNA, 200-800 kb or 50-300 kb high molecular weight (HMW) DNA and internucleosomal DNA fragments are produced during apoptosis or necrosis induced by oxidative stress such as glutathione (GSH) depletion in several types of mammalian cells. Reactive oxygen species (ROS)-mediated DNA fragmentation is enhanced by polyunsaturated fatty acids including arachidonic acid or their hydroperoxides, leading to necrosis. Mitochondrial dysfunction on decrease of trans membrane potential, accumulation of ROS, membrane permeability transition and release of apoptotic factors during apoptosis or necrosis has been implicated. This review refers to the correlation of chromosomal DNA fragmentation and apoptosis or necrosis induced by GSH depletion, and the possible mechanisms of oxidative stress-induced cell death.
210 citations
TL;DR: A model is provided to explain the communication between HIF‐1 and p53 under (patho)physiological conditions and it is shown that cell death pathways are associated with stabilization of the tumor suppressor p53, a response also seen under hypoxic conditions.
Abstract: Oxygen sensing and reactivity to changes in the concentration of oxygen is a fundamental property of cell physiology. The lack of O(2) (hypoxia) is transmitted into many adaptive responses, a process that is largely controlled by a transcription factor known as hypoxia inducible factor-1 (HIF-1). More recent reports suggest that besides its traditional regulation via proteasomal degradation other signaling pathways contribute to stability regulation of the HIF-1alpha subunit and/or HIF-1 transactivation. These regulatory circuits allow for the integration of HIF-1 into scenarios of cell-survival vs. cell-death with the rule of the thumb that short-term mild hypoxia maintains cell viability while prolonged and severe hypoxia provokes cell demise. Cell death pathways are associated with stabilization of the tumor suppressor p53, a response also seen under hypoxic conditions. Here we summarize recent information on accumulation of HIF-1alpha and p53 under hypoxia and provide a model to explain the communication between HIF-1 and p53 under (patho)physiological conditions.
174 citations
TL;DR: A review article will summarize the literature data concerning this new role played by EPCs in tumor angiogenesis and show emerging evidence indicate that bone marrow‐derived circulating E PCs can contribute to tumor ang iogenesis and growth of certain tumors.
Abstract: Endothelial progenitor cells (EPCs) have been isolated from peripheral blood CD34, VEGFR-2, or AC 133 (CD133) antigen-positive cells, which may home to site of neovascularization and differentiate into endothelial cells in situ. Endothelial cells contribute to tumor angiogenesis, and can originate from sprouting or co-option of neighbouring pre-existing vessels. Emerging evidence indicate that bone marrow-derived circulating EPCs can contribute to tumor angiogenesis and growth of certain tumors. This review article will summarize the literature data concerning this new role played by EPCs in tumor angiogenesis.
144 citations
TL;DR: Recent research revealed that at the cellular level, vitamin E acts by inhibition of smooth muscle cell proliferation, platelet aggregation, monocyte adhesion, oxLDL uptake and cytokine production, all reactions implied in the progression of atherosclerosis.
Abstract: Atherosclerosis and its complications such as coronary heart disease, myocardial infarction and stroke are the leading causes of death in the developed world. High blood pressure, diabetes, smoking and a diet high in cholesterol and lipids clearly increase the likelihood of premature atherosclerosis, albeit other factors, such as the individual genetic makeup, may play an additional role. Several epidemiological studies and intervention trials have been performed with vitamin E, and some of them showed that it prevents atherosclerosis. For a long time, vitamin E was assumed to act by decreasing the oxidation of LDL, a key step in atherosclerosis initiation. However, at the cellular level, vitamin E acts by inhibition of smooth muscle cell proliferation, platelet aggregation, monocyte adhesion, oxLDL uptake and cytokine production, all reactions implied in the progression of atherosclerosis. Recent research revealed that these effects are not the result of the antioxidant activity of vitamin E, but rather of precise molecular actions of this compound. It is assumed that specific interactions of vitamin E with enzymes and proteins are at the basis of its non-antioxidant effects. Vitamin E influences the activity of several enzymes (e.g. PKC, PP2A, COX-2, 5-lipooxygenase, nitric oxide synthase, NADPH-oxidase, superoxide dismutase, phopholipase A2) and modulates the expression of genes that are involved in atherosclerosis (e.g. scavenger receptors, integrins, selectins, cytokines, cyclins). These interactions promise to reveal the biological properties of vitamin E and allow designing better strategies for the protection against atherosclerosis progression.
142 citations
TL;DR: It is demonstrated that FK506 modulates hypertrophic/proliferative responses and proinflammatory cytokine expression in astrocytes and microglia in vitro and in focal transient brain ischemia, and the findings suggest that astroCytes andmicroglia are direct targets of FK505 and modulation of glial response and inflammation is a possible mechanism of Fk506‐mediated neuroprotection in ischemIA.
Abstract: Cyclosporin A (CsA) and FK506 (Tacrolimus) are short polypeptides which block the activation of lymphocytes and other immune system cells. Immunosuppressants exert neuroprotective and neurotrophic action in traumatic brain injury, sciatic nerve injury, focal and global ischemia in animals. Their neuroprotective actions are not understood and many hypotheses have been formed to explain such effects. We discuss a role of drug target - calcineurin in neuroprotective action of immunosuppressants. Protein dephosphorylation by calcineurin plays an important role in neuronal signal transduction due to its ability to regulate the activity of ion channels, glutamate release, and synaptic plasticity. In vitro FK506 protects cortex neurons from NMDA-induced death, augments NOS phosphorylation inhibiting its activity and NO synthesis. However, in vivo experiments demonstrated that FK506 in neuroprotective doses did not block excitotoxic cell death nor did it alter NO production during ischemia/reperfusion. Tissue damage in ischemia is the result of a complex pathophysiological cascade, which comprises a variety of distinct pathological events. Resident non-neuronal brain cells respond rapidly to neuronal cell death and may have both deleterious and useful role in neuronal damage. There is increasing evidence that reactive gliosis and post-ischemic inflammation involving microglia contribute to ischemic damage. We have demonstrated that FK506 modulates hypertrophic/proliferative responses and proinflammatory cytokine expression in astrocytes and microglia in vitro and in focal transient brain ischemia. Our findings suggest that astrocytes and microglia are direct targets of FK506 and modulation of glial response and inflammation is a possible mechanism of FK506-mediated neuroprotection in ischemia.
TL;DR: This review updates the progress of ES cell research in CRT, discusses about the problems encountered in the practical utility of ES cells inCRT and evaluates how far this approach is successful experimentally.
Abstract: Embryonic stem (ES) cells are revolutionizing the field of developmental biology as a potential tool to understand the molecular mechanisms occurring during the process of differentiation from the embryonic stage to the adult phenotype. ES cells harvested from the inner cell mass (ICM) of the early embryo can proliferate indefinitely in vitro while retaining the ability to differentiate into all somatic cells. Emerging results from mice models with ES cells are promising and raising tremendous hope among the scientific community for the ES-cell based cell replacement therapy (CRT) of various severe diseases. ES cells could potentially revolutionize medicine by providing an unlimited renewable source of cells capable of replacing or repairing tissues that have been damaged in almost all degenerative diseases such as diabetes, myocardial infarction and Parkinson's disease. This review updates the progress of ES cell research in CRT, discusses about the problems encountered in the practical utility of ES cells in CRT and evaluates how far this approach is successful experimentally.
TL;DR: Evidence is presented demonstrating that highly purified MS IgGs (but not Igs from the sera of healthy individuals) catalyze specifically hydrolysis of human myelin basic protein (hMBP).
Abstract: Various catalytic antibodies or abzymes have been detected recently in the sera of patients with several autoimmune pathologies, where their presence is most probably associated with autoimmunization. Recently we have shown that DNase, RNase, and polysaccharide-hydrolyzing activities are associated with IgGs from the sera of patients with multiple sclerosis (MS). Here we present evidence demonstrating that highly purified MS IgGs (but not Igs from the sera of healthy individuals) catalyze specifically hydrolysis of human myelin basic protein (hMBP). In contrast to many known proteases, IgGs do not hydrolyze many other different proteins. Specific inhibitors of acidic and thiol proteases have no remarkable effect on proteolytic activity of IgGs. However, specific inhibitor of serine (PMSF, AEBSF, and benzamidin) and metal-dependent (EDTA) proteases significantly inhibit activity of proteolytic abzymes. Interestingly, the ratio of serine-like and metal-dependent activities of MS IgGs varied very much from patient to patient. The findings speak in favor of the generation by the immune systems of individual MS patients of a variety of polyclonal anti-MBP IgGs with different catalytic properties.
TL;DR: The finding that STAT‐1 and STAT‐3 can modulate the apoptotic programme both by direct DNA binding or via a co‐activator mechanism and despite their very similar structures, suggests that these related factors may be therapeutic targets against the damage myocardium following I/R injury.
Abstract: Ischaemia/reperfusion (I/R) injury results in the death of irreplaceable cardiac myocytes by a programme cell death or apoptosis. The signal transducers and activators of transcription (STAT) factors function as modulators of cytokine signaling and sensors responding to cellular stress. Interestingly, many studies have demonstrated that although they have a similar structural organization, STAT-1 and STAT-3 have apposing effects on processes such as differentiation or apoptosis. For example, STAT-1 has been shown to induced apoptosis, whilst STAT3 is able protect cardiac myocytes following ischaemia/reperfusion (I/R) injury. Many of the effects of STAT-1 and STAT-3 involve the direct binding to DNA and transcriptional activation of target genes. However, recent studies have shown that for STAT-1 some of its effects appear not to require DNA binding. For example, induction of apoptosis by STAT-1 can be produced by the C-terminal activation domain in the absence of the DNA binding domain. This therefore, appears to involve a co-activator effect in which STAT-1 is recruited to DNA via a DNA-bound transcription factor. In this regard, it is of interest that STAT-1 but not STAT-3 has been shown to interact with p53 and enhance its growth arrest and apoptosis- inducing properties. Hence, the finding that STAT-1 and STAT-3 can modulate the apoptotic programme both by direct DNA binding or via a co-activator mechanism and despite their very similar structures, suggests that these related factors may be therapeutic targets against the damage myocardium following I/R injury. Recently, we reported that the polyphenolic agent epigallocatechin-3-gallate (EGCG), a major constituent of green tea and a potent inhibitor of STAT-1 activation, protects the myocardium against I/R injury.
TL;DR: The role of calcium influx from the extracellular medium in the control of proliferative processes is centers on, and the current understanding of the pathways responsible for this influx and of the second messengers involved in their activation are reviewed.
Abstract: The progression through the cell cycle in non-transformed cells is under the strict control of extracellular signals called mitogens, that act by eliciting complex cascades of intracellular messengers. Among them, increases in cytosolic free calcium concentration have been long realized to play a crucial role; however, the mechanisms coupling membrane receptor activation to calcium signals are still only partially understood, as are the pathways of calcium entry in the cytosol. This article centers on the role of calcium influx from the extracellular medium in the control of proliferative processes, and reviews the current understanding of the pathways responsible for this influx and of the second messengers involved in their activation.
TL;DR: The PHEX gene, which is mutated in XLH, encodes an endopeptidase, predominantly expressed in bone and teeth, but not in kidney, and FGF‐23 may be a substrate of this endopePTidase and may therefore accumulate in patients with XLH and TIO, which exhibit similar biochemical and clinical features.
Abstract: Inorganic phosphate (Pi) is required for cellular function and skeletal mineralization. Serum Pi level is maintained within a narrow range through a complex interplay between intestinal absorption, exchange with intracellular and bone storage pools, and renal tubular reabsorption. The crucial regulated step in Pi homeostasis is the transport of Pi across the renal proximal tubule. Type II sodium-dependent phosphate (Na/Pi) cotransporter (NPT2) is the major molecule in the renal proximal tubule and is regulated by Pi, parathyroid hormone and by 1,25-dihydroxyvitamin D. Recent studies of inherited and acquired hypophosphatemia [X-linked hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and tumor-induced rickets/osteomalacia (TIO)], which exhibit similar biochemical and clinical features, have led to the identification of novel genes, PHEX and FGF23, that play a role in the regulation of Pi homeostasis. The PHEX gene, which is mutated in XLH, encodes an endopeptidase, predominantly expressed in bone and teeth, but not in kidney. FGF-23 may be a substrate of this endopeptidase and may therefore accumulate in patients with XLH. In the case of ADHR mutations in the furin cleavage site, which prevent the processing of FGF-23 into fragments, lead to the accumulation of a "stable" circulating form of the peptide which also inhibits renal Pi reabsorption. In the case of TIO, ectopic overproduction of FGF-23 overwhelms its processing and degradation by PHEX, leading to the accumulation of FGF-23 in the circulation and inhibition of renal Pi reabsorption. Mice homozygous for severely hypomorphic alleles of the Klotho gene exhibit a syndrome resembling human aging, including atherosclerosis, osteoporosis, emphysema, and infertility. The KLOTHO locus is associated with human survival, defined as postnatal life expectancy, and longevity, defined as life expectancy after 75. In considering the relationship of klotho expression to the dietary Pi level, the klotho protein seemed to be negatively controlled by dietary Pi.
TL;DR: Biological features of EPCs are discussed and the clinical potential of E PCs for therapeutic neovascularization is speculated and translational research aiming at the devices to acquire the optimized quality and quantity is speculated.
Abstract: Recent evidences suggest that endothelial progenitor cells (EPCs) derived from bone marrow (BM) contribute to de novo vessel formation in adults occurring as physiological and pathological responses. Emerging preclinical trials have shown that EPCs home to sites of neovascularization after ischemic events in limb and myocardium. On the basis of these aspects, EPCs are expected to develop as a key strategy of therapeutic applications for the ischemic organs. Such clinical requirements of EPCs will tentatively accelerate the translational research aiming at the devices to acquire the optimized quality and quantity of EPCs. In this review, we attempt to discuss about biological features of EPCs and speculate on the clinical potential of EPCs for therapeutic neovascularization.
TL;DR: The changes of NMDA receptors in the hippocampus support the concept that estrogen‐enhancing effect on spatial reference memory could be through the enhancing ofNMDA function.
Abstract: Estrogen modulates NMDA receptors function in the brain It increases both dendritic spine density and synapse number in the hippocampus, an effect that can be blocked by NMDA antagonist In this study, we investigated the effect of 17beta-estradiol and progesterone treatment on NMDA receptors in ovariectomized rats Two different doses were used for 10 weeks Receptor autoradiography was done on brain sections using [(3)H] MK-801 as a ligand Our results showed a significant increase in [(3)H] MK-801 binding in the dentate gyrus, CA3 and CA4 areas of the hippocampus of ovariectomized compared to sham operated rats In addition, we observed similar changes in CA1 17beta-estradiol treatment in both doses reduced the binding back to the normal level while progesterone treatment did not show any effect Spatial reference memory was tested on Morris water maze task Ovariectomy severely impaired spatial reference memory Estradiol but not progesterone treatment significantly improved the memory performance of the ovariectomized rats Low dose treatment showed better learning than high dose estrogen treatment The decrease in the antagonist sites by estradiol treatment could result in an increase in the sensitivity of the hippocampus to the excitatory stimulation by glutamate system and hence the effect of estradiol on learning and memory The changes of NMDA receptors in the hippocampus support the concept that estrogen-enhancing effect on spatial reference memory could be through the enhancing of NMDA function
TL;DR: The hypothesis is that apoptosis might be a favorable response to acinar cell and that interventions which favor induction of apoptotic, as opposed to necrotic, acinarcell death might reduce the severity of an attack of acute pancreatitis.
Abstract: Acute pancreatitis is a disease of variable severity in which some patients experience mild, self-limited attacks while others manifest a severe, highly morbid, and frequently lethal attack. The events that regulate the severity of acute pancreatitis are, for the most part, unknown. Several recent studies have suggested that the acinar cell response to injury may be an important determinant of disease severity. In these studies, mild acute pancreatitis was found to be associated with extensive apoptotic acinar cell death while severe acute pancreatitis was found to involve extensive acinar cell necrosis but very little acinar cell apoptosis. These observations have led to the hypothesis that apoptosis might be a favorable response to acinar cell and that interventions which favor induction of apoptotic, as opposed to necrotic, acinar cell death might reduce the severity of an attack of acute pancreatitis. This review aims to discuss our current understanding of the contribution of acinar cell apoptosis to the severity of acute pancreatitis.
TL;DR: Time‐lapse imagery revealed that filopodia rapidly move at a rate of microns per minute to contact neighboring cells and intercellular bridges are conduits for transport of membrane vesicles between adjacent cells.
Abstract: We detected cell-to-cell communication via intercellular bridges in DU 145 human prostate cancer cells by fluorescence microscopy. Since DU 145 cells have deficient gap junctions, intercellular bridges may have a prominent role in the transfer of chemical signals between these cells. In culture, DU 145 cells are contiguous over several cell diameters through filopodial extensions, and directly communicate with adjacent cells across intercellular bridges. These structures range from 100 nm to 5 microm in diameter, and from a few microns to at least 50-100 microm in length. Time-lapse imagery revealed that (1) filopodia rapidly move at a rate of microns per minute to contact neighboring cells and (2) intercellular bridges are conduits for transport of membrane vesicles (1-3 microm in diameter) between adjacent cells. Immunofluorescence detected alpha-tubulin in intercellular bridges and filopodia, indicative of microtubule bundles, greater than a micron in diameter. The functional meaning, interrelationship of these membrane extensions are discussed, along with the significance of these findings for other culture systems such as stem cells. Potential applications of this work include the development of anti-cancer therapies that target intercellular communication and controlling formation of cancer spheroids for drug testing.
TL;DR: In the primate Papio ursinus, the induction of bone formation has been extended to the TGF‐β isoforms per se and of particular interest is that biomimetic matrices with intrinsic osteoinductivity would be an affordable option in the local context.
Abstract: Bone morphogenetic and osteogenic proteins (BMPs/OPs), members of the transforming growth factor-beta (TGF-beta) superfamily, are soluble mediators of tissue morphogenesis and induce de novo endochondral bone formation in heterotopic extraskeletal sites as a recapitulation of embryonic development. In the primate Papio ursinus, the induction of bone formation has been extended to the TGF-beta isoforms per se. In the primate and in the primate only, the TGF-beta isoforms are initiators of endochondral bone formation by induction and act in a species-, site- and tissue-specific mode with robust endochondral bone induction in heterotopic sites but with limited new bone formation in orthotopic bone defects. The limited inductive capacity orthotopically of TGF-beta isoforms is associated with expression of the inhibitory Smads, Smad6 and Smad7. In primates, bone formation can also be induced using biomimetic crystalline hydroxyapatite matrices with a specific surface geometry and without the exogenous application of osteogenic proteins of the TGF-beta superfamily, even when the biomimetic matrices are implanted heterotopically in the rectus abdominis muscle. The sequence of events that directs new bone formation upon the implantation of highly crystalline biomimetic matrices initiates with vascular invasion, mesenchymal cell migration, attachment and differentiation of osteoblast-like cells attached to the substratum, expression and synthesis of osteogenic proteins of the TGF-beta superfamily resulting in the induction of bone as a secondary response. The above findings in the primate indicate enormous potential for the bioengineering industry. Of particular interest is that biomimetic matrices with intrinsic osteoinductivity would be an affordable option in the local context.
TL;DR: The presence of erg currents in smooth muscle fibres of the gastrointestinal tract, neuroblastoma cells or neuroendocrine cells and in many other excitable cells suggests that changes in the resting potential are related to cell‐specific functions like increase in hormone secretion, frequency adaptation or increase in contractility.
Abstract: Ether-a-go-go-related gene (erg) channels are voltage-dependent K+ channels mediating inward-rectifying K+ currents because of their peculiar gating kinetics. These characteristics are essential for repolarization of the cardiac action potential. Inherited and acquired malfunctioning of erg channels may lead to the long QT-syndrome. However, erg currents have also been recorded in many other excitable cells, like smooth muscle fibres of the gastrointestinal tract, neuroblastoma cells or neuroendocrine cells. In these cells erg currents contribute to the maintenance of the resting potential. Changes in the resting potential are related to cell-specific functions like increase in hormone secretion, frequency adaptation or increase in contractility.
TL;DR: Fibrosis following breast radiotherapy for mammary cancer is a frequent undesired effect with objective (esthetic) and subjective (pain) consequences and the local antifibrosis effect of copper zinc superoxide dismutase [SOD(Cu/Zn] was found to be effective in reducing radiation induced fibrosis.
Abstract: Fibrosis following breast radiotherapy for mammary cancer is a frequent undesired effect with objective (esthetic) and subjective (pain) consequences. Forty-four patients with clinical radiofibrosis following conservative treatment of breast cancer were evaluated for the local antifibrosis effect of copper zinc superoxide dismutase [SOD(Cu/Zn)]. Extracted SOD(Cu/Zn) in a concentration of 3,600 units/mg was applied as ointment to the fibrotic affected area, b.i.d. for 90 days, in a total dose of 40 mg. The radiofibrosis intensity was scored on the basis of clinical criteria (pain and the fibrosis area) before and after SOD(Cu/Zn) treatment. SOD(Cu/Zn) was found to be effective in reducing radiation induced fibrosis by a lowering pain score in 36/39 patients and a decrease of the fibrotic area size in half cases, after 6 months. The intensity and changes of breast fibrosis were assessed also by mammography and, for the topographical distribution of subcutaneous temperature, by infrared thermography. Mammography density suggested decreased fibrosis in one third of patients. Thermography showed that fibrosis was accompanied by two zones clinically indistinctive: a central area with maximum thermal activity, called "Maximal Thermic zone" (MTZ) and a peripheral area with less thermal activity but higher than in the surrounding normal tissue, "Transitional Thermic Zone" (TTZ). Both MTZ and TTZ were significantly decreased in 36/44 patients after SOD(Cu/Zn) treatment. Clinical changes persisted all along the study. Treatment was well tolerated except for one case of local allergic reaction, and no important side effects. Molecular mechanisms involved are discussed. Further studies are running to confirm and explain these results.
TL;DR: This review provides an overview of cellular‐based therapeutic concepts and the therapeutic potential of ex vivo generated endothelial progenitor cells (EPC) and their role in vasculogenesis and tumor targeting.
Abstract: Angiogenesis has been defined as sprouting of blood vessels from pre-existing vascular structures. Risau and coworkers defined the term vasculogenesis while studying the formation of new blood vessels in embryoid bodies. This process is characterized by the recruitment of endothelial progenitor cells (EPC) to sites of new vessel formation with subsequent differentiation of EPC into mature endothelial cells, extensively proliferating in situ. Data from recent years provided evidence that EPC also exist in the adult and contribute to new vessel formation, a process called postnatal vasculogenesis. The existence of EPC has been convincingly shown in both, animals and humans. They represent a perfect cellular progenitor cell population for the ex vivo generation of EC, which in turn serve as cellular source for therapeutic vasculogenesis or tumor targeting. This review provides an overview on this hot topic of cellular-based therapeutic concepts and the therapeutic potential of ex vivo generated EPC.
TL;DR: This review provides an explanation for why during the earlier phase, the heart attempts to adapt itself against the detrimental effects of angiotensin II by upregulating several cardioprotective genes and proteins.
Abstract: A large number of studies have demonstrated the role of angiotensin II in cardiac preconditioning against ischemic reperfusion injury. Generally, angiotensin II is a detrimental factor for the heart, and its inhibition with an ACE inhibitor provides cardioprotection. This review provides an explanation for such paradoxical behavior of angiotensin II. Angiotensin II can potentiate the induction of the expression of a variety of redox-sensitive factors including p38 MAPK, JNK and Akt, IGF-IR, EGF-R, and HO-1 as well as redox-regulated genes and transcription factors such as NFkappaB. It becomes increasingly apparent that during the earlier phase, the heart attempts to adapt itself against the detrimental effects of angiotensin II by upregulating several cardioprotective genes and proteins. These genes and proteins are redox-regulated and the antioxidants or ROS scavengers block their expressions. Interestingly, an identical pattern of cardioprotective proteins and genes are expressed in the preconditioned heart, which are also inhibited with ROS scavengers. It is tempting to speculate that the induction of the expression of the redox-sensitive cardioprotective proteins is the results of adaptation of the heart against the oxidative stress resulting from angiotensin II; and preconditioning is the net result of harnessing its own protection during ischemic and/or oxidative stress through its ability to trigger redox signaling.
TL;DR: The proposal that the age‐induced changes in synaptic plasticity are, ultimately, determined by changes in the metabolic state of the aged neurones, that are manifest particularly after neuronal stimulation is assessed.
Abstract: Normal brain ageing is associated with a degree of functional impairment of neuronal activity that results in a reduction in memory and cognitive functions. One mechanism proposed to explain the age-dependent changes was the "Ca(2+) hypothesis of ageing" but data accumulated in the last decade revealed a number of inconsistencies. Two important questions were raised: (a) which are, if any, the most reliable age-associated change in neuronal Ca(2+) homeostasis and (b) are these changes primary, and thus determinant of the ageing phenotype, or are they secondary to other changes in the physiology of the aged neurones. After a brief review of the evidence accumulated for the age-induced changes in synaptic plasticity, we assess the proposal that these changes are, ultimately, determined by changes in the metabolic state of the aged neurones, that are manifest particularly after neuronal stimulation. In this context, it appears that the changes in mitochondrial status and function are of primary importance.
TL;DR: In this article, the role of diabetic conditions such as high glucose, AGE-Lysine, and angiotensin II in modulation of antioxidant enzymes activities, glutathione level and reactive oxygen species (ROS) production in pericytes was investigated.
Abstract: Recent data indicate that the oxidative stress plays an important role in the pathogenesis of diabetes and its complications such as retinopathy, nephropathy and accelerated atherosclerosis. In diabetic retinopathy, it was demonstrated a selective loss of pericytes accompanied by capillary basement membrane thickening, increased permeability and neovascularization. This study was designed to investigate the role of diabetic conditions such as high glucose, AGE-Lysine, and angiotensin II in the modulation of antioxidant enzymes activities, glutathione level and reactive oxygen species (ROS) production in pericytes. The activity of antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and total glutathione (GSH) was measured spectrophotometrically. The production of ROS was detected by spectrofluorimetry and fluorescence microscopy after loading the cells with 2'-7' dichlorofluoresceine diacetate; as positive control H2O2 was used. Intracellular calcium was determined using Fura 2 AM assay. The results showed that the cells cultured in high glucose alone, do not exhibit major changes in the antioxidant enzyme activities. The presence of AGE-Lys or Ang II induced the increase of SOD activity. Their combination decreased significantly GPx activity and GSH level. A three times increase in ROS production and a significant impairment of intracellular calcium homeostasis was detected in cells cultured in the presence of the three pro-diabetic agents used. In conclusion, our data indicate that diabetic conditions induce in pericytes: (i) an increase of ROS and SOD activity, (ii) a decrease in GPx activity and GSH level, (iii) a major perturbation of the intracellular calcium homeostasis. The data may explain the structural and functional abnormalities of pericytes characteristic for diabetic retinopathy.
TL;DR: By displaying their plasticity during kidney maintenance and repair, terminally differentiated cells may well function as multipotent stem cells despite being at a later stage of maturation than adult stem cells.
Abstract: The therapeutic potential of adult stem cells in the treatment of chronic degenerative diseases has becoming increasingly evident over the last few years. Significant attention is currently being paid to the development of novel treatments for acute and chronic kidney diseases too. To date, promising sources of stem cells for renal therapies include adult bone marrow stem cells and the kidney precursors present in the early embryo. Both cells have clearly demonstrated their ability to differentiate into the kidney's specialized structures. Adult renal stem cells have yet to be identified, but the papilla is where the stem cell niche is probably located. Now we need to isolate and characterize the fraction of papillary cells that constitute the putative renal stem cells. Our growing understanding of the cellular and molecular mechanisms behind kidney regeneration and repair processes - together with a knowledge of the embryonic origin of renal cells - should induce us, however, to bear in mind that in the kidney, as in other mesenchymal tissues, the need for a real stem cell compartment might be less important than the phenotypic flexibility of tubular cells. Thus, by displaying their plasticity during kidney maintenance and repair, terminally differentiated cells may well function as multipotent stem cells despite being at a later stage of maturation than adult stem cells. One of the major tasks of Regenerative Medicine will be to disclose the molecular mechanisms underlying renal tubular plasticity and to exploit its biological and therapeutic potential.
TL;DR: Evidence that proapoptotic Fas‐Fas ligand (FasL) signaling plays a central role in pulmonary inflammation, injury and fibrosis and Identification of the pathogenic role of FasL could facilitate the discovery of more effective treatments for currently untreatable inflammatory lung diseases.
Abstract: Following inflammation and injury in the lung, loss of epithelial cell precursors could determine the balance between tissue regeneration and fibrosis. This review discusses evidence that proapoptotic Fas-Fas ligand (FasL) signaling plays a central role in pulmonary inflammation, injury and fibrosis. FasL signaling induces inflammatory apoptosis in epithelial cells and alveolar macrophages, with concomitant IL-1β and chemokine release, leading to neutrophil infiltration. FasL signaling plays a critical role in models of acute lung injury, idiopathic pulmonary fibrosis and silicosis; blockade of Fas-FasL interactions either prevents or attenuates pulmonary inflammation and fibrosis. Serologic and immunohistochemical studies in patients support a major pathogenic role of Fas and FasL molecules in inflammatory lung diseases. Identification of the pathogenic role of FasL could facilitate the discovery of more effective treatments for currently untreatable inflammatory lung diseases.
TL;DR: The molecular mechanism of secretory vesicles fusion at the base of porosomes, and vesicle swelling, have been resolved and a new understanding of cell secretion has emerged and confirmed by a number of laboratories.
Abstract: Secretion and membrane fusion are fundamental cellular processes involved in the physiology of health and disease. Studies within the past decade reveal the molecular mechanism of secretion and membrane fusion in cells. Studies reveal that membrane-bound secretory vesicles dock and fuse at porosomes, which are specialized plasma membrane structures. Swelling of secretory vesicles result in a build-up of intravesicular pressure, which allows expulsion of vesicular contents. The discovery of the porosome, its isolation, its structure and dynamics at nm resolution and in real time, its biochemical composition and functional reconstitution, are discussed. The molecular mechanism of secretory vesicle fusion at the base of porosomes, and vesicle swelling, have been resolved. With these findings a new understanding of cell secretion has emerged and confirmed by a number of laboratories.