Involvement of glucose transporter overexpression in the protection or damage after ischemic stroke.
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ABSTRACT:
SUBMITTER: Alquisiras-Burgos I
PROVIDER: S-EPMC8530140 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Although the innate immune response to induce postischemic inflammation is considered as an essential step in the progression of cerebral ischemia injury, the role of innate immunity mediator NLRP3 in the pathogenesis of ischemic stroke is unknown. In this study, focal ischemia was induced by middle cerebral artery occlusion in NLRP3(-/-), NOX2(-/-), or wild-type (WT) mice. By magnetic resonance imaging (MRI), Evans blue permeability, and electron microscopic analyses, we found that NLRP3 deficiency ameliorated cerebral injury in mice after ischemic stroke by reducing infarcts and blood-brain barrier (BBB) damage. We further showed that the contribution of NLRP3 to neurovascular damage was associated with an autocrine/paracrine pattern of NLRP3-mediated interleukin-1? (IL-1?) release as evidenced by increased brain microvessel endothelial cell permeability and microglia-mediated neurotoxicity. Finally, we found that NOX2 deficiency improved outcomes after ischemic stroke by mediating NLRP3 signaling. This study for the first time shows the contribution of NLRP3 to neurovascular damage and provides direct evidence that NLRP3 as an important target molecule links NOX2-mediated oxidative stress to neurovascular damage in ischemic stroke. Pharmacological targeting of NLRP3-mediated inflammatory response at multiple levels may help design a new approach to develop therapeutic strategies for prevention of deterioration of cerebral function and for the treatment of stroke.
| S-EPMC3982086 | biostudies-other
Project description:Stroke is a major cause of morbidity, mortality, and disability. During ischemic stroke, a marked and prolonged rise of glutamate concentration in the brain causes neuronal cell death. This study explores the protective effect of a bioconjugate form of glutamate oxaloacetate transaminase (hrGOT), which catalyzes the depletion of blood glutamate in the bloodstream for ~6 days following a single administration. When treated with this bioconjugate, a significant reduction of the infarct volume and a better retention of sensorimotor function was observed for ischemic rats compared to those treated with saline. Moreover, the equivalent dose of native hrGOT yielded similar results to the saline treated group for some tests. Targeting the bioconjugate to the blood-brain-barrier did not improve its performance. The data suggest that the bioconjugates draw glutamate out of the brain by displacing homeostasis between the different glutamate pools of the body.
| S-EPMC7713697 | biostudies-literature
Project description:Diabetes mellitus (DM) is a major risk factor for cardiovascular events, including ischemic stroke. Moreover, ischemic stroke appears to be more severe in these patients and to be associated with less favorable outcomes. However, strict glycemic control does not appear to reduce the risk of ischemic stroke. On the other hand, newer glucose-lowering agents (glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors) reduced the risk of cardiovascular events in recent randomized, placebo-controlled trials. Semaglutide also reduced the risk of ischemic stroke. These benefits are independent of glucose lowering and might be due to the favorable effects of these agents on body weight and blood pressure. Pioglitazone also reduced the risk of recurrent stroke in patients with insulin resistance or type 2 DM but the unfavorable safety profile limits its use. In contrast, sulfonylureas and dipeptidyl peptidase 4 inhibitors have a neutral effect on cardiovascular morbidity and might be less attractive options in this high-risk population.
| S-EPMC5483425 | biostudies-other
Project description:Background and purposeThis study aimed to explore the association between triglyceride-glucose (TyG) index and stroke recurrence in elderly patients with ischemic stroke in China.MethodsWe enrolled ischemic stroke patients aged ≥ 65 years from the Nanjing Stroke Registry Program. The primary endpoint was defined as recurrent stroke within one year after the index stroke. We used multivariable Cox proportional hazards regression models to investigate the association between TyG index and stroke recurrence. We assessed the discriminative ability of TyG index with the receiver operative characteristic and the area under the curve.ResultsA total of 955 patients (median age, 70.0 [67.0, 75.0]; male sex, 67.2%) from the Nanjing Stroke Registry Program were enrolled. During one year follow-up, 97 (10.2%) elderly patients experienced stroke recurrence. In multivariable analyses, the association between TyG index and stroke recurrence remained significant after adjusting for confounders (quartile 4 versus quartile 1; hazard ratio, 2.073, 95% confidence interval, 1.158-3.711; P = 0.014). The restricted cubic spline showed an increasing trend for TyG index and stroke recurrence (P for non-linearity = 0.072). The area under the curve to predict stroke recurrence with TyG index was 0.719 (95% confidence interval, 0.666-0.772). Besides, TyG index slightly improved the prediction for stroke recurrence.ConclusionElevated TyG index was associated with stroke recurrence in elderly patients with ischemic stroke. Further studies are warranted to assess the role of TyG index in the development of stroke recurrence in the elderly.
| S-EPMC9467280 | biostudies-literature
Project description:Hypoxia-induced miR-210 displays a pro-survival, cytoprotective and pro-angiogenic role in several in vitro systems. In vivo, we previously found that miR-210 inhibition increases ischemic damage. Here we describe the generation of a versatile transgenic mouse model allowing the evaluation of miR-210 therapeutic potential in ischemic cardiovascular diseases. We generated a Tet-On miR-210 transgenic mouse strain (TG-210) by targeted transgenesis in the ROSA26 locus. To functionally validate miR-210 transgenic mice, hindlimb ischemia was induced by femoral artery dissection. Blood perfusion was evaluated by power Doppler while tissue damage and inflammation were assessed by histological evaluation. We found that miR-210 levels were rapidly increased in TG-210 mice upon doxycycline administration. miR-210 overexpression was maintained over time and remained within physiological levels in multiple tissues. When hindlimb ischemia was induced, miR-210 overexpression protected from both muscular and vascular ischemic damage, decreased inflammatory cells density and allowed to maintain a better calf perfusion. In conclusion, we generated and functionally validated a miR-210 transgenic mouse model. Albeit validated in the context of a specific cardiovascular ischemic disease, miR-210 transgenic mice may also represent a useful model to assess the function of miR-210 in other physio-pathological conditions.
| S-EPMC5573334 | biostudies-literature
Project description:Axonal degeneration often leads to the death of neuronal cell bodies. Previous studies demonstrated the crucial role of nicotinamide mononucleotide adenylyltransferase (Nmnat) 1, 2, and 3 in axonal protection. In this study, Nmnat3 immunoreactivity was observed inside axons in the optic nerve. Overexpression of Nmnat3 exerts axonal protection against tumor necrosis factor-induced and intraocular pressure (IOP) elevation-induced optic nerve degeneration. Immunoblot analysis showed that both p62 and microtubule-associated protein light chain 3 (LC3)-II were upregulated in the optic nerve after IOP elevation. Nmnat3 transfection decreased p62 and increased LC3-II in the optic nerve both with and without experimental glaucoma. Electron microscopy showed the existence of autophagic vacuoles in optic nerve axons in the glaucoma, glaucoma+Nmnat3 transfection, and glaucoma+rapamycin groups, although preserved myelin and microtubule structures were noted in the glaucoma+Nmnat3 transfection and glaucoma+rapamycin groups. The axonal-protective effect of Nmnat3 was inhibited by 3-methyladenine, whereas rapamycin exerted axonal protection after IOP elevation. We found that p62 was present in the mitochondria and confirmed substantial colocalization of mitochondrial Nmnat3 and p62 in starved retinal ganglion cell (RGC)-5 cells. Nmnat3 transfection decreased p62 and increased autophagic flux in RGC-5 cells. These results suggest that the axonal-protective effect of Nmnat3 may be involved in autophagy machinery, and that modulation of Nmnat3 and autophagy may lead to potential strategies against degenerative optic nerve disease.
| S-EPMC3920931 | biostudies-literature
Project description:Background: The triglyceride glucose index (TyG index) has been proposed as a simple and credible surrogate marker of insulin resistance. However, it is unclear whether TyG index correlates with adverse clinical outcomes in patients with ischemic stroke. Accordingly, this study aimed to explore the relationship between baseline TyG index and clinical outcomes of ischemic stroke individuals. Methods: We included eligible subjects with ischemic stroke from the China National Stroke Registry II for the current analysis. TyG index was calculated and divided into quartiles to explore the relationship with the outcomes of ischemic stroke. Outcomes included stroke recurrence, all-cause mortality, poor functional outcome at 12 months, and neurologic worsening at discharge. Multivariable Cox regression and logistic regression models were performed to explore the correlation of baseline TyG index with the outcomes. Results: Among the 16,310 patients enrolled in the study, the average age was 64.83 ± 11.9 years, and 63.48% were men. The median TyG index was 8.73 (interquartile range, 8.33-9.21). After adjustment for multiple potential covariates, the fourth quartile of TyG index was associated with an increased risk of stroke recurrence (adjusted HR, 1.32; 95% CI, 1.11-1.57; P = 0.002), all-cause mortality (adjusted HR, 1.25; 95%CI, 1.06-1.47; P = 0.01) at 12-month follow-up, and neurological worsening (adjusted OR, 1.26; 95% CI, 1.02-1.55; P = 0.03) at discharge, but not poor functional outcome compared with the first quartile. Conclusion: TyG index representing insulin resistance was associated with an increased risk of stroke recurrence, all-cause mortality, and neurologic worsening in patients with ischemic stroke.
| S-EPMC7297915 | biostudies-literature
Project description:ObjectiveHyperglycemia is a common comorbidity for ischemic stroke and is associated with worsened neurological outcomes. Platelets are central mediators of ischemic stroke and hyperglycemia mediates platelet hyperactivity. In this study, we investigated the contribution of platelet glucose metabolism to ischemic stroke.MethodsMice lacking both Glut1 and Glut3 specifically in platelets (DKO) and their littermate controls (WT) were subjected to 1-hour transient middle cerebral artery occlusion under normoglycemic and streptozotocin-induced hyperglycemic conditions after which stroke outcomes, platelet activation, and platelet-neutrophil aggregate (PNA) formation were examined.ResultsUnder normoglycemic conditions, DKO mice were protected from ischemic stroke with smaller brain infarct volumes and improved cerebral blood flow. In addition, DKO mice had reduced platelet activation, PNA, and cerebral neutrophil recruitment after stroke. Hyperglycemia significantly increased infarct size and cerebral Evans blue extravasation and worsened neurological outcomes and cerebral blood flow in both WT and DKO mice, abolishing the protective effect witnessed under normoglycemic conditions. Flow cytometric analysis after stroke demonstrated increased platelet activation and neutrophil trafficking to the brain, independent of platelet glucose metabolism. Finally, platelets from healthy DKO mice were unable to become procoagulant upon dual agonist stimulation. Conversely, hyperglycemia increased platelet mitochondrial reactive oxygen species production which potentiated procoagulant platelet formation in WT mice and restored procoagulant platelet formation in DKO mice.ConclusionHyperglycemia aggravates ischemic stroke outcome independent of platelet glucose uptake. Furthermore, we demonstrated that hyperglycemia primes procoagulant platelet formation. This underlines the therapeutic potential for strategies targeting procoagulant platelet formation for the treatment of acute ischemic stroke.
| S-EPMC7902465 | biostudies-literature
Project description:Insulin resistance (IR) in skeletal muscle is a prerequisite for type 2 diabetes and is often associated with obesity. IR also develops alongside muscle atrophy in older individuals in sarcopenic obesity. The molecular defects that underpin this syndrome are not well characterized, and there is no licensed treatment. Deletion of the transforming growth factor-β family member myostatin, or sequestration of the active peptide by overexpression of the myostatin propeptide/latency-associated peptide (ProMyo) results in both muscle hypertrophy and reduced obesity and IR. We aimed to establish whether local myostatin inhibition would have a paracrine/autocrine effect to enhance glucose disposal beyond that simply generated by increased muscle mass, and the mechanisms involved. We directly injected adeno-associated virus expressing ProMyo in right tibialis cranialis/extensor digitorum longus muscles of rats and saline in left muscles and compared the effects after 17 days. Both test muscles were increased in size (by 7 and 11%) and showed increased radiolabeled 2-deoxyglucose uptake (26 and 47%) and glycogen storage (28 and 41%) per unit mass during an intraperitoneal glucose tolerance test. This was likely mediated through increased membrane protein levels of GLUT1 (19% higher) and GLUT4 (63% higher). Interestingly, phosphorylation of phosphoinositol 3-kinase signaling intermediates and AMP-activated kinase was slightly decreased, possibly because of reduced expression of insulin-like growth factor-I in these muscles. Thus, myostatin inhibition has direct effects to enhance glucose disposal in muscle beyond that expected of hypertrophy alone, and this approach may offer potential for the therapy of IR syndromes.
| S-EPMC3962614 | biostudies-literature
Project description:To evaluate whether topographical characteristics of insular involvement in ischemic stroke are associated with cardioembolism.A consecutive series of patients hospitalized for ischemic stroke within 7 days of symptom onset were identified. Based on diffusion-weighted imaging, we included those who had ischemic lesions in the middle cerebral artery (MCA) territory. Each patient was assigned to one of two groups based on the presence or absence of insular involvement. The primary outcome was the frequency of cardioembolism, which was compared based on insular involvement. Of 1,311 patients with ischemic stroke in the MCA territory, 112 had insular involvement (8.5%). The frequency of cardioembolism in patients with insular involvement (52.7%) was significantly higher than that in patients without insular involvement (30.4%, P < 0.001). Although insular involvement was associated with a severe baseline National Institutes of Health Stroke Scale score (13 vs. 4), it did not independently affect the 3-month functional outcome.In cases of stroke in the MCA territory, involvement of the insular cortex may be associated with a risk of cardioembolism.
| S-EPMC4619548 | biostudies-literature