Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone marrow-derived mesenchymal stem cells (MSCs) are being explored for clinical applications, and genetic engineering represents a useful strategy for boosting the therapeutic potency of MSCs. Vascular endothelial growth factor (VEGF)-based gene therapy protocols have been used to treat tissue ischemia, and a combined VEGF/MSC therapeutics is appealing due to their synergistic paracrine actions. However, multiple VEGF splice variants exhibit differences in their mitogenicity, chemotactic efficacy, receptor interaction, and tissue distribution, and the differential regulatory effects of multiple VEGF isoforms on the function of MSCs have not been characterized. We expressed three rat VEGF-A splice variants VEGF120, 164, and 188 in MSCs using adenoviral vectors, and analyzed their effects on MSC proliferation, differentiation, survival, and trophic factor production. The three VEGF splice variants exert common and differential effects on MSCs. All three expressed VEGFs are potent in promoting MSC proliferation. VEGF120 and 188 are more effective in amplifying expression of multiple growth factor and cytokine genes. VEGF164 on the other hand is more potent in promoting expression of genes associated with MSC remodeling and endothelial differentiation. The longer isoform VEGF188, which is preferentially retained by proteoglycans, facilitates bone morphogenetic protein-7 (BMP7)-mediated MSC osteogenesis. Under serum starvation condition, virally expressed VEGF188 preferentially enhances serum withdrawal-mediated cell death involving nitric oxide production. This work indicates that seeking the best possible match of an optimal VEGF isoform to a given disease setting can generate maximum therapeutic benefits and minimize unwanted side effects in combined stem cell and gene therapy.
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PMID:Adenoviral expression of vascular endothelial growth factor splice variants differentially regulate bone marrow-derived mesenchymal stem cells. 1828 39

Ketone bodies play a key role in mammalian energy metabolism during the suckling period. Normally ketone bodies' blood concentration during adulthood is very low, although it can rise during starvation, an exogenous infusion or a ketogenic diet. Whenever ketone bodies' levels increase, their oxidation in the brain rises. For this reason they have been used as protective molecules against refractory epilepsy and in experimental models of ischemia and excitotoxicity. The mechanisms underlying the protective effect of these compounds are not completely understood. Here, we studied a possible antioxidant capacity of ketone bodies and whether it contributes to the protection against oxidative damage induced during hypoglycemia. We report for the first time the scavenging capacity of the ketone bodies, acetoacetate (AcAc) and both the physiological and non-physiological isomers of beta-hydroxybutyrate (D- and L-BHB, respectively), for diverse reactive oxygen species (ROS). Hydroxyl radicals (.OH) were effectively scavenged by D- and L-BHB. In addition, the three ketone bodies were able to reduce cell death and ROS production induced by the glycolysis inhibitor, iodoacetate (IOA), while only D-BHB and AcAc prevented neuronal ATP decline. Finally, in an in vivo model of insulin-induced hypoglycemia, the administration of D- or L-BHB, but not of AcAc, was able to prevent the hypoglycemia-induced increase in lipid peroxidation in the rat hippocampus. Our data suggest that the antioxidant capacity contributes to protection of ketone bodies against oxidative damage in in vitro and in vivo models associated with free radical production and energy impairment.
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PMID:Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions. 1833 75

Autophagy is a highly conserved cellular process responsible for the degradation of long-lived proteins and organelles. Autophagy occurs at low levels under normal conditions, but is upregulated in response to stress such as nutrient deprivation, hypoxia, mitochondrial dysfunction, and infection. Upregulation of autophagy may be beneficial to the cell by recycling of proteins to generate free amino acids and fatty acids needed to maintain energy production, by removing damaged organelles, and by preventing accumulation of protein aggregates. In contrast, there is evidence that enhanced autophagy can contribute to cell death, possibly through excessive self-digestion. In the heart, autophagy has an essential role for maintaining cellular homeostasis under normal conditions and increased autophagy can be seen in conditions of starvation, ischemia/reperfusion, and heart failure. However, the functional significance of autophagy in heart disease is unclear and controversial. Here, we review the literature and discuss the evidence that autophagy can have both beneficial and detrimental roles in the myocardium depending on the level of autophagy, and discuss potential mechanisms by which autophagy provides protection in cells.
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PMID:Recycle or die: the role of autophagy in cardioprotection. 1835 58

Vascular cells provide a neural stem/progenitor cell (NSPC) niche that regulates expansion and differentiation of NSPCs within the germinal zones of the embryonic and adult brain under both physiologic and pathologic conditions. Here, we examined the NSPC-endothelial cell (NSPC/EC) interaction under conditions of ischemia, both in vitro and after intracerebral transplantation. In culture, embryonic mouse NSPCs supported capillary morphogenesis and protected ECs from cell death induced by serum starvation or by transient oxygen and glucose deprivation (OGD). Neural stem/progenitor cells constitutively expressed hypoxia-inducible factor 1alpha (HIF-1alpha) transcription factor and vascular endothelial growth factor (VEGF), both of which were increased approximately twofold after the exposure of NSPCs to OGD. The protective effects of NSPCs on ECs under conditions of serum starvation and hypoxia were blocked by pharmacological inhibitors of VEGF signaling, SU1498 and Flt-1-Fc. After intracerebral transplantation, NSPCs continued to express HIF-1alpha and VEGF, and promoted microvascular density after focal ischemia. These studies support a role for NSPCs in stabilization of vasculature during ischemia, mediated via HIF-1alpha-VEGF signaling pathways, and suggest therapeutic application of NSPCs to promote revascularization and repair after brain injury.
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PMID:Neural stem/progenitor cells promote endothelial cell morphogenesis and protect endothelial cells against ischemia via HIF-1alpha-regulated VEGF signaling. 1847 24

Clinical heart failure results from the cumulative loss of functioning myocardium from any cause. At the cellular level, cardiac myocytes die from three causes, individually or in combination: Necrosis occurs when external conditions are not sufficient to sustain minimal cellular functions, as with ischemia, and there is a general and unorganized breakdown of cell organelles, engendering an inflammatory response that may have harmful collateral tissue effects. Apoptosis, or cell suicide, occurs when specific external or internal conditions provoke a highly structured sequence of events to shut down cellular functions and remove the cell, with minimal consequences to surrounding tissue. Autophagy is a normal response to cell starvation that is induced under conditions of chronic metabolic or other stress. Current therapeutics, such as early myocardial revascularization after myocardial infarction, are focused exclusively upon minimizing cardiac myocyte necrosis and may even contribute to secondary apoptosis and autophagy. This review explores possible approaches to bring cardiac myocytes that are destined to die, back to life, i.e., cellular resuscitation. Two pro-apoptotic proteins in particular, Bnip3 and Nix, are transcriptionally upregulated specifically in response to myocardial ischemia and pathological hypertrophy and have been examined as therapeutic targets. In Bnip3 and Nix genetic mouse models, prevention of cardiac myocyte apoptosis in ischemic and hemodynamically overloaded hearts salvaged myocardium, minimized late ventricular remodeling, and enhanced ventricular performance. Cardiomyocyte resuscitation by preventing programmed cell death shows promise as an additive approach to minimizing necrosis for long-term prevention of heart failure.
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PMID:The rationale for cardiomyocyte resuscitation in myocardial salvage. 1856 79

During ischemia and heart failure, myocardial cells suffer for chronic energy starvation resulting in metabolic and contractile dysfunction. In normal conditions fatty acids, glucose, and lactate are the principal oxidative fuels in myocardium, while amino acids serve a minor role as an oxidative fuel. However, in pathological conditions, myocardial uptake of several amino acids increases significantly as a consequence of a metabolic remodelling. Amino acids are involved in a variety of key biochemical and physiological activities, that counteract the deleterious cellular effects of reduced oxygen availability. Several amino acids are a direct source of substrate for energy production, and they modulate the activity of some enzymes involved in the glucose metabolism. They increase contractile performance both in isolated animal and human myocardium. Furthermore, amino acids improve the oxidative stress counteracting the action of radical oxygen species, being either precursors of glutathione synthesis, or of substrate of nitric oxide biosynthesis; they act on endothelial function and increase protein synthetic efficiency of myocardial cells by regulating gene expression and modulating hormonal activity. An amount of studies have demonstrated that amino acids administration, on patients with ischemic heart disease and heart failure, can improve several clinical endpoints. Here, we present an overview of the principal effects of the most experienced amino acids and of amino acid derivatives on ischemia and heart failure.
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PMID:The role of amino acids in the modulation of cardiac metabolism during ischemia and heart failure. 1899 76

Autophagy, a highly conserved cellular mechanism wherein various cellular components are broken down and recycled through lysosomes, occurs constitutively in the heart and may serve as a cardioprotective mechanism in some situations. It has been implicated in the development of heart failure and is up-regulated following ischemia-reperfusion injury. Autophagic flux, a measure of autophagic vesicle formation and clearance, is an important measurement in evaluating the efficacy of the pathway, however, tools to measure flux in vivo have been limited. Here, we describe the use of monodansylcadaverine (MDC) and the lysosomotropic drug chloroquine to measure autophagic flux in in vivo model systems, specifically focusing on its use in the myocardium. This method allows determination of flux as a more precise measure of autophagic activity in vivo much in the same way that Bafilomycin A(1) is used to measure flux in cell culture. MDC injected 1 h before sacrifice, colocalizes with mCherry-LC3 puncta, validating its use as a marker of autophagosomes. This chapter provides a method to measure autophagic flux in vivo in both transgenic and nontransgenic animals, using MDC and chloroquine, and in addition describes the mCherry-LC3 mouse and the advantages of this animal model in the study of cardiac autophagy. Additionally, we review several methods for inducing autophagy in the myocardium under pathological conditions such as myocardial infarction, ischemia/ reperfusion, pressure overloading, and nutrient starvation.
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PMID:Novel methods for measuring cardiac autophagy in vivo. 1921 14

The ketogenic diet has been shown to have unique properties that make it a more suitable cerebral fuel under various neuropathological conditions (e.g., starvation, ischemia, and traumatic brain injury (TBI). Recently, age-dependent ketogenic neuroprotection was shown among postnatal day 35 (PND35) and PND45 rats after TBI, but not in PND17 and PND65 animals (Prins et al., 2005). The present study addresses the therapeutic potential of a ketogenic diet on motor and cognitive deficits after TBI. PND35 and PND75 rats received sham or controlled cortical impact (CCI) surgery and were placed on either standard (Std) or ketogenic (KG) diet for 7 days. Beam walking and the Morris water maze (MWM) were used to assess sensory motor function and cognition, respectively. PND35 CCI Std animals showed significantly longer traverse times than sham and CCI KG animals at the beginning of motor training. Footslip analysis revealed better performance among the sham and the CCI KG animals compared to the CCI Std group. In the MWM PND35 CCI KG animals showed significantly shorter escape latencies compared to CCI Std-fed animals. During the same time period there was no significant difference between sham animals and CCI KG animals. The therapeutic effect of the ketogenic diet on beam walking and cognitive performance was not observed in PND75 animals. This finding supports our theory about age-dependent utilization and effectiveness of ketones as an alternative fuel after TBI.
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PMID:The effects of a ketogenic diet on behavioral outcome after controlled cortical impact injury in the juvenile and adult rat. 1923 95

Autophagy is a critical cellular housekeeping process that is essential for removal of damaged or unwanted organelles and protein aggregates. Under conditions of starvation, it is also a mechanism to break down proteins to generate amino acids for synthesis of new and more urgently needed proteins. In the heart, autophagy is upregulated by starvation, reactive oxygen species, hypoxia, exercise, and ischemic preconditioning, the latter a well-known potent cardioprotective phenomenon. The observation that upregulation of autophagy confers protection against ischemia/reperfusion injury and inhibition of autophagy is associated with a loss of cardioprotection conferred by pharmacological conditioning suggests that the pathway plays a key role in enhancing the heart's tolerance to ischemia. While many of the antecedent signaling pathways of preconditioning are well-defined, the mechanisms by which preconditioning and autophagy converge to protect the heart are unknown. In this review we discuss mechanisms that potentially underlie the linkage between cardioprotection and autophagy in the heart.
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PMID:Cardioprotection requires taking out the trash. 1924 43

Autophagy is a catabolic process through which damaged or long-lived proteins, macromolecules, or organelles are recycled by using lysosomal degradation machinery. Although the occurrence of autophagy in several cardiac diseases including ischemic or dilated cardiomyopathy, heart failure, hypertrophy, and during ischemia/reperfusion injury have been reported, the exact role of autophagy in these diseases is not known. Emerging studies indicate that oxidative stress in cellular system could induce autophagy, and oxidatively modified macromolecules and organelles can be selectively removed by autophagy. Mild oxidative stress-induced autophagy could provide the first line of protection against major damage like apoptosis and necrosis. Cardiac-specific loss of Atg5, an autophagic gene involved in the formation of autophagosome, causes cardiac hypertrophy, left ventricular dilation, and contractile dysfunction. Recently, it was revealed that Atg4, another autophagic gene involved in the formation of autophagosomes, is controlled through redox regulation under the condition of starvation-induced autophagy. In this review, we discuss the function of autophagy in association with oxidative stress and redox signaling in the remodeling of cardiac myocardium. Further research is needed to explore the possibilities of redox regulation of other autophagic genes and the role of redox signaling-mediated autophagy in the heart.
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PMID:Autophagy, redox signaling, and ventricular remodeling. 1932 38


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