GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling. Transient ischemic attack before nonlacunar ischemic stroke in the elderly. At the onset of ischemic stroke, in order to maintain the energy demand, compensatory pathways are initiated, comprising a major metabolic reprogramming strategy including glycogen metabolism, lactate metabolism, amino acid metabolism, and lipid metabolism. Once ischemic stroke occurs, the PPP is boosted and more glycolytic intermediates are diverted into the PPP to sustain NADPH production [18]. These include: NADP+/NADPH. Irreversible injury to mitochondria is a cornerstone of pathogenesis of neurological diseases. In short, understanding the mechanism of metabolic reprogramming is expected to be greatly beneficial for our understanding of ischemic stroke treatment and for the standardized application of IPC. Recent research has shown that metabolic disorders have significant effects, both before and after the onset of ischemic stroke. The malateaspartate shuttle (MAS) is considered the most important NAD+/NADH shuttle in neurons, playing a prominent role in neuronal mitochondrial respiration. The ischemic penumbra is defined as the severely hypoperfused, functionally impaired, at-risk but not yet infarcted tissue that will be progressively recruited into the infarct core. If the ischemic penumbra is characterized by these approaches, then a reduction of CBF to levels between a lower threshold of 10-15 mL/100 g/min and an upper threshold of approximately 25 mL/100 g/min is likely to identify penumbral tissue. McIntosh V.J., Lasley R.D. Under high altitude or chronic kidney disease, hypoxia-responsive sphingosine-1-phosphate (S1P) promotes erythrocyte glycolysis, channeling glucose metabolism toward RapoportLuebering Shunt and inducing 2,3-bisphosphoglycerate (2,3-BPG) production for O2 delivery [71,72]. The pathophysiology of MetS seems to be largely attributable to the metabolic disorder caused by insulin resistance, with glucose intolerance and excessive flux of fatty acids also being implicated [57]. Patients underwent computer tomography . TCA cycle reactions yield metabolite intermediates and energetic precursors for oxidative phosphorylation. Here we provide a summary of metabolic mechanism of ischemic preconditioning when it is applied to ischemic stroke. Malpartida A.B., Williamson M., Narendra D.P., Wade M.R., Ryan B.J. Katsyuba E., Romani M., Hofer D., Auwerx J. NAD. Geng J.L., Aa J.Y., Feng S.Q., Wang S.Y., Wang P., Zhang Y., Ouyang B.C. Katayama H., Hama H., Nagasawa K., Kurokawa H., Sugiyama M., Ando R., Funata M., Yoshida N., Homma M., Nishimura T., et al. Ketones: Growing evidence has indicated that ketone bodies are beneficial in treating stroke [26], mainly -hydroxybutyrate (-HB) and acetoacetate, which can substitute for glucose under conditions of energy deficiency in the brain for cellular fuel [27]. Most ketones are generated in the liver, while the transport of ketone bodies across the blood-brain barrier (BBB) is the limiting step. Ischemic preconditioning triggers endogenous neuroprotection to defend against subsequent, more severe cerebral ischemia. Li M., Zhou Z.P., Sun M., Cao L., Chen J., Qin Y.Y., Gu J.H., Han F., Sheng R., Wu J.C., et al. This enhanced glycolysis drives the generation of energy-rich molecules (e.g., ATP, NADH, and NADPH) and the supply of carbon pool for the synthesis of amino acids, nucleotides, and lipids [64]. Furthermore, except for NADPH and GSH, whether there exist some other mechanisms induced by IPC to maintain the redox homeostasis under ischemia is not yet known; especially considering ferroptosis, which has been implicated in the pathological cell death associated with neurodegenerative diseases (i.e., Alzheimers, Huntingtons, and Parkinsons diseases). Betti et al. de Jonge R., de Jong J.W. Erythrocyte Metabolic Reprogramming by Sphingosine 1-Phosphate in Chronic Kidney Disease and Therapies. Ischemic preconditioning (IPC) is an endogenous protective strategy, which has been reported to exhibit a significant neuroprotective effect in reducing the incidence of ischemic stroke. Hess D.C., Blauenfeldt R.A., Andersen G., Hougaard K.D., Hoda M.N., Ding Y., Ji X. quences as drastically increase d metabolic demand cannot be satisfied in regions with critically reduced blood supply. However, due to the structural complexity and their specific physiological functions and metabolic patterns, the conclusive details on whether the dynamic metabolic reprogramming behavior accompanied with astrocyte-neuron interaction is induced by ischemia or IPC are still lacking. Effects of ischemic preconditioning on mitochondrial and metabolic neruoprotection: 5 adenosine monophosphate-activated protein kinase and sirtuins. Waves of depolarizations, the peri-infarct spreading depres- . Though glycolysis is advantageous for rapidly producing ATP to meet the high energy demands, hyperglycolysis can aggravate the brain damage caused by lactic acidosis and ROS overproduction [76]. Marchiq I., Pouyssgur J. Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H+ symporters. Preserving pools of NAD+ confers neuroprotection after ischemic stress. The metabolic characteristics of HBV-related ACLF patients revealed the inhibition of glycolysis, TCA and urea cycle, and the enhancement of fatty acid oxidation and glutamine anaplerosis [70]. All brain cell types are able to uptake ketones; the ketones are then metabolized to acetyl-CoA to support the cell energy [29]. As the storage form of glucose, the polymer glycogen is entirely located in astrocytes, and the glycogen metabolism rarely occurs in neurons [99]. Iron is essential for the accumulation of lipid peroxides and execution of ferroptosis. Intravenous thrombolysis and mechanical thrombectomy for selected . Numerous in vitro, in vivo, and clinical studies have indicated that influenza infection induces hyperglycolysis in infected cells, activated immune cells, foci, and lymph nodes [68]. Guan X., Li X., Yang X., Yan J., Shi P., Ba L., Cao Y., Wang P. The neuroprotective effects of carvacrol on ischemia/reperfusion-induced hippocampal neuronal impairment by ferroptosis mitigation. Sphingosine 1-phosphate (S1P) is a bioactive signaling lipid highly enriched in mature erythrocytes. Bouzat P., Sala N., Suys T., Zerlauth J.B. Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain. Brainin M., Feigin V.L., Norrving B., Martins S.C.O., Hankey G.J., Hachinski V. Global prevention of stroke and dementia: The WSO Declaration. Exogenous application of nicotinamide mononucleotide (NMN), an intermediate of NAD+ synthesis, mimics the protective effect of IPC under ischemia and reperfusion injury. As we showed in Section 1.2 and Section 1.3, under oxygen and glucose deprivation (OGD), the brain experiences a shift of the cerebral metabolism from glucose pathways to compensatory pathways, taking energy from other metabolic substrates, such as ketones, amino acids, endogenous carbohydrates, and lactate, in order to sustain energy and redox homeostasis. and increases energy demand and neurotransmitter effluxes, It should be noted that, due to different synaptic activities, loop connectivity, and functional domains, heterogeneity exists among the spatial distribution of endogenous metabolites; this distribution characteristic has only been noticed in recent years. As IPC is innocuous, cost-effective, and has fewer or no contraindications, and has exciting new prospects in the broader management of ischemic stroke (Figure 1). Current evidence-based . Meanwhile, the cerebellum is replete with amino acids, which are precursors for glucose regeneration through the pentosephosphate shunt or gluconeogenesis pathways. It was first discovered by Murry et al., in the canine heart, in 1986 [7]. However, the importance of PCr in energy homeostasis is underestimated by the fact that the total creatine pool (as creatine and PCr) in the brain is at least three-fold larger than the adenosine nucleotide pool (consisting of AMP, ADP, and ATP). Stroke is one of the leading causes of death and permanent disability worldwide. Banks M.A., Porter D.W., Martin W.G., Castranova V. Ozone-induced lipid-peroxidation and membrane leakage in isolated rat alveolar macrophages- protective effects of taurine. After ischaemic stroke, brain damage can be curtailed by rescuing the 'ischaemic penumbra' that is, the severely hypoperfused, at-risk but not yet infarcted tissue. Furthermore, metabolic reprogramming is a double-edged sword; for example, the enhancement of glucose uptake and glycolysis can provide ATP faster, but the ongoing delivery of large amounts of glucose to the ischemic tissue along with an anaerobic glycolysis shift can adversely promote lactic acidosis, thus leading to tissue necrosis. Hence, the abundance and localization of polyunsaturated fatty acids are crucial for the degree of lipid peroxidation that occurs in cells. Lactate: Studies in the past two decades have indicated that lactate is also an efficient energy substrate for maintaining neuronal integrity and functioning during cerebral ischemia [21]. In-depth research considering these open questions will be valuable for exploring the mechanisms of IPC. Morris-Blanco K.C., Cohan C.H., Neumann J.T., Sick T.J., Perez-Pinzon M.A. It has been implied that the neuroprotective ability of IPC may be related with the promotion of ANLS, where lactate serves as a potential agent to protect neurons against lethal ischemic injury. Lactate in cerebrospinal fluid (CSF) has also been found to be higher in stroke patients [17]. Upon ischemic stroke, cerebral glycolysis exhibits an increasing trend. Other metabolic-related genes in the pathogenesis of ischemic stroke include MTHFR, CBS, and MTR, which are involved in homocysteine metabolism, and apo E, LPL, CETP, ABCA1, apo AI, apo CIII, apo AIV, apo AV, apo B, apo H, apo(a), PON1/2/3, and LDLR/LOX-1, which are involved in lipid metabolism [36]. Metabolic syndrome (MetS) increases stroke incidence. Jackson C.W., Escobar I., Xu J., Perez-Pinzon M.A. However, continuing ischemic stress, or additional energy demanding episodes, or both, will exhaust this limited capacity and transform penumbra into necrotic tissue. Mounting evidence has shown that brain metabolic plasticity and IPC metabolic reprogramming are crucial for ischemic defense, typically through maintaining cellular energy and redox homeostasis. Therefore, it can be seen that mitochondrial mechanism is an important, but underutilized, target for improving CBF and decreasing brain injury in stroke patients [14]. Amino acids: To sustain fuel oxidation by the tricarboxylic acid (TCA) cycle, nerve cells upregulate glutaminolysis and use of fatty acids and branched chain amino acids. Accessibility You'll get a detailed solution from a subject matter expert that helps you learn core concepts. Wender R., Brown A.M., Fern R., Swanson R.A., Farrell K., Ransom B.R. It has been found that metabolic disorders are a determinant of the incidence and progression of stroke. An increased understanding of the pathogenic mechanisms of stroke and IPC serves to highlight the importance of metabolic reprogramming. Then, the accumulated free radicals damage cell membranes, mitochondria, and DNA, thus triggering caspase-mediated cell death. Therefore, a fastidious quality control system is important: as is well-known, mitochondrial dysfunction can initiate mitochondrial autophagy, which was first named mitophagy by Lemasters [54]. Accumulating evidence has suggested that IPC regulates the cerebral metabolism by providing alternative energy substrates, which partly reduce the dependence of the brain on a continuous supply of glucose, therefore improving the brains resistance to ischemia. NAMPT as a Therapeutic Target against Stroke. This refinement has potential therapeutic implications. Lemasters J. Sep 2011. Collaterals are demonstrated to be strong predictors of both response to endovascular therapy and functional outcomes [11]. To maintain the cerebral activity transiently, upon ischemia onset, brain tissues enhance their metabolic plasticity, mainly through energy metabolic reprogramming and antioxidant defense. ); nc.ude.aaub@9102gnorgnornah (R.H.), 2School of Engineering Medicine, Beihang University, Beijing 100191, China. However, research on metabolic reprogramming in the neuroscience field is still in its infancy. Second, polyunsaturated fatty acids are susceptible to lipid peroxidation and are necessary for ferroptosis [45]. The pathway mainly involves glycolysis, TCA cycle, PPP, and glutaminolysis to maintain the energy and redox homeostasis, which are the most primary demands for cells under the deprivation or limitation of nutrients and oxygen. Other significant changes in amino acid metabolic pathways have also been confirmed upon ischemia: the levels of some well-known energy-providing amino acids, such as leucine, isoleucine, valine, tyrosine, and lysine, increased significantly in brain tissues of mice treated by IPC, indicating that proteolysis was up-regulated [16]. Another critical concern is the proper time window for IPC metabolic reprogramming in sustaining the neuroprotection effects for the forthcoming ischemia stroke. Trial of 2860 patients and followed them for 3.5 years. Expanding fascinating horizons in metabolism of other cells under hypoxia or hypoglycemia may promote new inspirations. ROS is not elevated and, so, this region sustains little damage [89]. Elucidation of these endogenous defense mechanisms against ischemic injury is considered crucial for the development of novel stroke therapies. Regulation of glycogen metabolism: Physiological, pharmacological and pathological aspects. As the brain NADPH level decreases during ischemia, boosting the PPP activity may serve as a potential neuroprotective strategy for the regulation of the cellular redox environment [81]. Ferroptosis. Furthermore, such heterogeneous distribution of metabolic substrates may be exploited by different brain regions, in order to regulate their cellular metabolic homeostasis during mitochondrial dysfunction. There is also a beneficial role of erythrocyte S1P in hypertensive CKD, where S1P also induces 2,3-BPG production and oxygen delivery [72]. Mitochondrial Dysfunction and Mitophagy in Parkinsons Disease: From Mechanism to Therapy. The glucose taken up by astrocytes may have one of two primary fates: it may be converted to lactate through astrocytic glycolysis or converted via glycogenesis to glycogen storage. Yamamoto T., Byun J., Zhai P., Ikeda Y., Oka S., Sadoshima J. Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion. This necessitates that the brain has reliable mechanisms to adequately protect its metabolic homeostasis. However, the complex connection between the neuroprotective function of IPC and cerebral metabolic reprogramming is still an exciting area of investigation, especially with respect to their spatiotemporal variation in consideration of the brain metabolic compartmentalization and time dependence. Rink C., Gnyawali S., Peterson L., Khanna S. Oxygen-inducible glutamate oxaloacetate transaminase as protective switch transforming neurotoxic glutamate to metabolic fuel during acute ischemic stroke. In subsequent hours after IPC, the brain regresses to its nave state. Raf B., Rishi S., Annick W. Evaluation of lactate as a marker of metabolic stress and cause of secondary damage in acute ischemic stroke or TIA. Acute hyperglycemia adversely affects stroke outcome: A magnetic resonance imaging and spectroscopy study. Luo L.L., Li Y.F., Shan H.M., Wang L.P., Yuan F., Ma Y.Y., Li W.L., He T.T., Wang Y.Y., Qu M.J., et al. The ischemic core . Studies have shown that IPC upregulates NAMPT protein, and the protective effect of IPC against ischemia (30 min) and reperfusion (24 h) was attenuated in NAMPT knockdown mice, suggesting that NAMPT is essential in mediating the protective effect of IPC [80]. Previous evidence has revealed that IPC diverts excess glucose to oxPPP. Several studies also showed that transient ischemic attack (TIA) may produce IPC effect in people who have a subsequent stroke [101,102]. Lactate: Previous research has suggested that astrocytes play a pivotal role in the induction of ischemic tolerance [83], during which lactate is extremely crucial. Recently, Yang X. et al. For blood glucose and oxygen supply, IPC increases regional CBF and regulates the oxygen-delivery ability of erythrocytes through sphingosine 1-phosphate (S1P), in order to maintain glucose and oxygen metabolic consumption. Show abstract. Ischemic stroke occurs most frequently in individuals aged 65 years. Tang X., Fang M., Cheng R., Zhang Z., Wang Y., Shen C., Han Y., Lu Q., Du Y., Liu Y., et al. An increasing number of studies have shown the time-dependent metabolic changes during IPC or the acute-to-chronic post-stroke phase. In the ischemic penumbra, a further decrease in CBF leads to neuronal electrical silence and a synaptic activity decrease to preserve energy stores, while energy metabolism is partially preserved to transiently sustain tissue viability. Chen S.Y., Liu J.W., Wang Y.H., Huang J.Y., Chen S.C., Yang S.F., Wang P.H. official website and that any information you provide is encrypted Sato H., Nomura S., Maebara K., Sato K., Tamba M., Bannai S. Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute-On-Chronic Liver Failure. Furthermore, there exist some serious contraindications and complications; for example, thrombolytic agents have been associated with symptomatic intracerebral hemorrhage [6]. FOIA Berthet C., Castillo X., Magistretti P.J., Hirt L. New evidence of neuroprotection by lactate after transient focal cerebral ischaemia: Extended benefit after intracerebroventricular injection and efficacy of intravenous administration. Ketone. The clearance of damaged mitochondria through mitophagy is critical for cellular fitness, as dysfunctional mitochondria can impair ETC function and increase oxidative stress. Excessive glutamate release and impeded reuptake of excitatory amino acids result in the activation of NMDARs, AMPARs and KARs. investigated genomic DNA from 501 ischemic stroke patients and 1211 comparable controls, and identified significant genetic associations between premature ischemic stroke in BHMT, CBS, FOLH1, MTR, PON2, TCN2, and TYMS genes, which are involved in methionine metabolism [35]. The major function of mitochondria is ATP production, but they perform many other roles as well, including biosynthetic metabolism, generation of ROS, redox molecules and metabolites, and regulation of cell signaling and cell death. Long-term metabolic disorders, such as metabolic syndrome (MetS), increase the probability of occurrence of ischemic stroke. Laursen M.R., Hansen J., Elkjaer C., Stavnager N., Nielsen C.B., Pryds K., Johnsen J., Nielsen J.M., Botker H.E., Johannsen M. Untargeted metabolomics reveals a mild impact of remote ischemic conditioning on the plasma metabolome and alpha-hydroxybutyrate as a possible cardioprotective factor and biomarker of tissue ischemia. A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. A self-controlled interventional study measured dynamic cerebral autoregulation (dCA) and blood biomarkers at seven time points in healthy participants who had conducted IPC, and found that dCA was significantly increased at 6 h and was sustained for at least 24 h after IPC, while two neuroprotective factors and four inflammation-related biomarkers were significantly elevated, compared with their baseline levels. The https:// ensures that you are connecting to the Ischaemic conditioning and reperfusion injury. Magistretti P.J., Martin J.L. An untargeted metabolomics study has revealed that -hydroxybutyrate (-HB) stands out as highly significantly upregulated after IPC [78], while previous studies have shown that an elevation in the cytosolic NADH/NAD+ ratio would promote -HB formation. Further study focus on ischemic preconditioning metabolic reprogramming is needed, and it will be valuable for exploring the mechanisms of ischemic preconditioning, and will be greatly beneficial for the understanding of ischemic stroke treatment and standardized application of ischemic preconditioning. found that, after 60 min of glucose deprivation, astrocytes in the rat optic nerve (a CNS white matter tract) drove glycogen to be broken down to lactate, which was then transferred to fuel axons [19]. Creatine generally occurs as phosphocreatine (PCr), which is a storage form of high-energy phosphate and a shuttle for the transfer of high-energy phosphate from mitochondria to the cytosol. Such emerging evidence of the metabolic reprogramming involved in metabolic homeostasis on the progression of different diseases has revealed that metabolic reprogramming is an important stress-protective mechanism, which plays a key role in many biological activities. John P. Cooke, in Stem Cell and Gene Therapy for Cardiovascular Disease, 2016 Functional Response to Metabolic Demand Vascular response to metabolic demand involves a closely orchestrated set of hormonal, neuronal, endothelial, and metabolic mechanisms. 2011;42 . . IPC has also demonstrated neuroprotective activity through the activation of Nrf2 both in vivo and in vitro, which is a transcription factor that helps to maintain mitochondrial coupling and antioxidant protein expression [75]. found that ketone treatment in mice at 30 min after ischemia enhanced mitochondrial function, reduced oxidative stress and, therefore, reduced infarct volume [49]. (Stroke. It was shown that free and protein-bound NADH differs regarding lifetime. The primary definition of the ischemic penumbra is electrical. Coincidentally, a clinical study has implicated the effectiveness of IPC in preventing the progression of white matter hyperintensities (WMHs) and in ameliorating cognitive impairment of very elderly patients (83.5 2.3 year) with ICAS [94]. It has been demonstrated that mitochondria are a major target in ischemic injury. Metabolic Syndrome Is a Strong Risk Factor for Minor Ischemic Stroke and Subsequent Vascular Events. Research has found that brain ischemia-refusion (I/R) injury can activate AMPK, which is an adaptive response to stress that plays an essential role in maintaining energy homeostasis, while the overactivation of AMPK accentuates hyperglycolysis, which can lead to serious metabolic distress. 6-8 hours A patient presents to the emergency department with left leg weakness and numbness. The concept of the ischemic penumbra was initially proposed by Astrup et al. Additionally, GSH is synthesized from glutamate, cysteine, and glycine. Therefore, given the critical role of these organelles in disease onset and progression, strategies . . Dawson T.M., Dawson V.L. Though emerging studies have shown that metabolic reprogramming is especially critical in IPC, the study of metabolic reprogramming conducted by IPC is still in its infancy (Figure 4).
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