Fatty Acid-Binding Proteins Aggravate Cerebral Ischemia-Reperfusion Injury in Mice.
Ontology highlight
ABSTRACT:
SUBMITTER: Guo Q
PROVIDER: S-EPMC8150391 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The glycolytic rate in neurons is low in order to allow glucose to be metabolized through the pentose-phosphate pathway (PPP), which regenerates NADPH to preserve the glutathione redox status and survival. This is controlled by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), the pro-glycolytic enzyme that forms fructose-2,6-bisphosphate, a powerful allosteric activator of 6-phosphofructo-1-kinase. In neurons, PFKFB3 protein is physiologically inactive due to its proteasomal degradation. However, upon an excitotoxic stimuli, PFKFB3 becomes stabilized to activate glycolysis, thus hampering PPP mediated protection of redox status leading to neurodegeneration. Here, we show that selective inhibition of PFKFB3 activity by the small molecule AZ67 prevents the NADPH oxidation, redox stress and apoptotic cell death caused by the activation of glycolysis triggered upon excitotoxic and oxygen-glucose deprivation/reoxygenation models in mouse primary neurons. Furthermore, in vivo administration of AZ67 to mice significantly alleviated the motor discoordination and brain infarct injury in the middle carotid artery occlusion ischemia/reperfusion model. These results show that pharmacological inhibition of PFKFB3 is a suitable neuroprotective therapeutic strategy in excitotoxic-related disorders such as stroke.
| S-EPMC6691133 | biostudies-literature
Project description:Fatty acid binding protein 4 (FABP4) has been known as a mediator of inflammatory response in the macrophages and adipose tissue, but its hepatic function is poorly understood. The goal of this study is to investigate the role of FABP4 in liver ischemia/reperfusion (I/R), a clinical condition that involves both hypoxia and inflammation.To examine the I/R regulation of FABP4, mice were subjected to I/R surgery before being measured for FABP4 gene expression. Both loss-of-function (by using a pharmacological FABP4 inhibitor) and gain-of-function (by adenoviral overexpression of FABP4) were used to determine the functional relevance of FABP4 expression and its regulation during I/R. To determine the hypoxia responsive regulation of FABP4, primary mouse hepatocytes were exposed to hypoxia. The FABP4 gene promoter was cloned and its regulation by hypoxia inducible factor 1? (HIF-1?) was characterized by luciferase reporter gene, electrophoretic mobility shift, and chromatin immunoprecipitation assays.We found that the hepatic expression of FABP4 was markedly induced by I/R. At the functional level, pharmacological inhibition of FABP4 alleviated the I/R injury, whereas adenoviral overexpression of FABP4 sensitized mice to I/R injury. We also showed that exposure of primary hepatocytes to hypoxia or transgenic overexpression of HIF-1? in the mouse liver was sufficient to induce the expression of FABP4. Our promoter analysis established FABP4 as a novel transcriptional target of HIF-1?.FABP4 is a hypoxia inducible gene that sensitizes mice to liver I/R injury. FABP4 may represent a novel therapeutic target, and FABP4 inhibitors may be used as therapeutic agents to manage hepatic I/R injury.
| S-EPMC4867094 | biostudies-literature
Project description:High mobility group box1 (HMGB1) promotes inflammatory injury, and accumulating evidence suggests that it plays a key role in brain ischemia reperfusion (I/R), as well as the development of diabetes mellitus (DM). The purpose of this study was to investigate whether HMGB1 plays a role in brain I/R in a DM mouse model. Diabetes mellitus was induced by a high-calorie diet and streptozotocin treatment, and cerebral ischemia was induced by middle cerebral artery occlusion. We examined HMGB1 levels following cerebral I/R injury in DM and non-DM mice and evaluated the influence of altered HMGB1 levels on the severity of cerebral injury. Serum HMGB1 levels and the inflammatory factors IL-1?, IL-6, and inflammation-related enzyme iNOS were significantly elevated in DM mice with brain I/R compared with non-DM mice with brain I/R. Blocking HMGB1 function by intraperitoneal injection of anti-HMGB1 neutralizing antibodies reversed the inflammatory response and the extent of brain damage, suggesting that HMGB1 plays an important role in cerebral ischemic stroke in diabetic mice.
| S-EPMC5112296 | biostudies-literature
Project description:Stroke is the third leading cause of death in the USA. Antithrombotic therapy targeting platelet activation is one of the treatments for ischemic stroke. Here we investigate the role of one of the thrombin receptors, protease-activated receptor 4 (PAR4), in a mouse transient middle cerebral artery occlusion (MCAO) model. After a 60 min MCAO and 23 h reperfusion, leukocyte and platelet rolling and adhesion on cerebral venules, blood-brain barrier (BBB) permeability, and cerebral edema were compared in PAR4-deficient mice and wild-type mice. Cerebral infarction volume and neuronal death were also measured. PAR4-/- mice had more than an 80% reduction of infarct volume and significantly improved neurologic and motor function compared with wild-type mice after MCAO. Furthermore, deficiency of PAR4 significantly inhibits the rolling and adhesion of both platelets and leukocytes after MCAO. BBB disruption and cerebral edema were also attenuated in PAR4-/- mice compared with wild-type animals. The results of this investigation indicate that deficiency of PAR4 protects mice from cerebral ischemia/reperfusion (I/R) injury, partially through inhibition of platelet activation and attenuation of microvascular inflammation.
| S-EPMC2949190 | biostudies-literature
Project description:Background and purposeThere is an urgent need to develop adjunct therapies that can be added onto reperfusion for acute ischemic stroke. Recently, mitochondrial transplantation has emerged as a promising therapeutic approach for boosting brain tissue protection. In this proof-of-concept study, we investigate the feasibility of using placenta as a source for mitochondrial transplantation in a mouse model of transient focal cerebral ischemia-reperfusion.MethodsMitochondria-enriched fractions were isolated from cryopreserved mouse placenta. Mitochondrial purity and JC1 membrane potentials were assessed by flow cytometry. Adenosine triphosphate and mitochondrial proteins were measured by luminescence intensity and western blot, respectively. Therapeutic efficacy of mitochondrial fractions was assessed in a mouse model of transient focal cerebral ischemia-reperfusion.ResultsFlow cytometry analysis demonstrated that about 87% of placental mitochondria were viable and maintained JC1 membrane potentials after isolation. Placental mitochondrial fractions contained adenosine triphosphate equivalent to mitochondrial fractions isolated from skeletal muscle and brown fat tissue. Normalized mitochondrial antioxidant enzymes (glutathione reductase, MnSOD [manganese superoxide dismutase]) and HSP70 (heat shock protein 70) were highly preserved in placental mitochondrial fractions. Treatment with placental mitochondrial fractions immediately after reperfusion significantly decreased infarction after focal cerebral ischemia in mice.ConclusionsCryopreserved placenta can be a feasible source for viable mitochondrial isolation. Transplantation with placental mitochondria may amplify beneficial effects of reperfusion in stroke.
| S-EPMC7530055 | biostudies-literature
Project description:Ischemic stroke is one of the most common causes of mortality worldwide and is a primary cause of disability and mortality in adults. There is an unmet need for drugs that can effectively treat ischemic stroke. Hence, the present study explored the neuroprotective effects of andrographolide (Andro) in a mouse model of bilateral common carotid artery occlusion, and systematically evaluated the potential mechanisms underlying its effects. The effects of Andro on mouse brain tissue following cerebral ischemia‑reperfusion injury (CIRI) were evaluated by histopathological (H&E and Nissl) and immunofluorescence [glial fibrillary acidic protein (GFAP) and neuronal nuclei (NeuN)] staining. A traditional Chinese medicine‑based network pharmacology method was performed to establish and analyze compound‑target‑disease and function‑pathway networks in order to elucidate the possible mechanisms responsible for the protective role of Andrographis paniculata in CIRI. In addition, western blot analysis and RT‑qPCR was performed to evaluate the expression and activation of signaling proteins predicted to be involved in this mechanism. The amelioration of histopathological alterations was observed in mice pre‑treated with Andro. Immunofluorescence staining revealed that Andro decreased the expression of GFAP and increased the expression of NeuN, and significantly decreased the levels of pro‑inflammatory cytokines (IL‑1β, IL‑6 and TNF‑α). Network pharmacology analysis revealed that neuroinflammatory response and apoptosis were associated with the effects of Andrographis paniculata on CIRI. Western blot analysis revealed that the mice pre‑treated with Andro exhibited an upregulated protein expression of tropomyosin receptor kinase B (TrkB), p‑PI3K and p‑Akt, as well as a decrease in the expression of GFAP and an increase in the expression of NeuN. In addition, the data of RT‑qPCR indicated that the mice pre‑treated with Andro exhibited a significantly decreased expression of encoding IL‑1β mRNA, IL‑6 mRNA and TNF‑α mRNA in the brain compared to the untreated mice following CIRI. On the whole, the findings of the present study suggest that pre‑treatment with Andro exerts a protective effect against CIRI, which may be partly related to its potential to reduce neuroinflammatory response and apoptosis in patients with stroke.
| S-EPMC8416143 | biostudies-literature
Project description:Oxidative stress and apoptosis contribute to the progression of cerebral ischemia/reperfusion (I/R) injury. Ubiquitin-specific protease 29 (USP29) is abundantly expressed in the brain and plays critical roles in regulating oxidative stress and cell apoptosis. The purpose of the present study is to investigate the role and underlying mechanisms of USP29 in cerebral I/R injury. Neuron-specific USP29 knockout mice were generated and subjected to cerebral I/R surgery. For USP29 overexpression, mice were stereotactically injected with the adenoassociated virus serotype 9 vectors carrying USP29 for 4 weeks before cerebral I/R. And primary cortical neurons were isolated and exposed to oxygen glucose deprivation/reperfusion (OGD/R) stimulation to imitate cerebral I/R injury in vitro. USP29 expression was elevated in the brain and primary cortical neurons upon I/R injury. Neuron-specific USP29 knockout significantly diminished, whereas USP29 overexpression aggravated cerebral I/R-induced oxidative stress, apoptosis, and neurological dysfunction in mice. In addition, OGD/R-induced oxidative stress and neuronal apoptosis were also attenuated by USP29 silence but exacerbated by USP29 overexpression in vitro. Mechanistically, neuronal USP29 enhanced p53/miR-34a-mediated silent information regulator 1 downregulation and then promoted the acetylation and suppression of brain and muscle ARNT-like protein, thereby aggravating oxidative stress and apoptosis upon cerebral I/R injury. Our findings for the first time identify that USP29 upregulation during cerebral I/R may contribute to oxidative stress, neuronal apoptosis, and the progression of cerebral I/R injury and that inhibition of USP29 may help to develop novel therapeutic strategies to treat cerebral I/R injury.
| S-EPMC8610700 | biostudies-literature
Project description:Ischemic stroke is one of the leading causes of death, and even timely treatment can result in severe disabilities. Reperfusion of the ischemic stroke region and restoration of the blood supply often lead to a series of cellular and biochemical consequences, including generation of reactive oxygen species (ROS), expression of inflammatory cytokines, inflammation, and cerebral cell damage, which is collectively called cerebral ischemia-reperfusion (IR) injury. Since ROS and inflammatory cytokines are involved in cerebral IR injury, injury could involve cellular senescence. Thus, we investigated whether senolytic therapy that eliminates senescent cells could be an effective treatment for cerebral IR injury. To determine whether IR induces neural cell senescence in vitro, astrocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). OGD/R induced astrocyte senescence and senescent cells in OGD/R-injured astrocytes were effectively eliminated in vitro by ABT263, a senolytic agent. IR in rats with intraluminal middle cerebral artery occlusion induced cellular senescence in the ischemic region. The senescent cells in IR-injured rats were effectively eliminated by intravenous injections of ABT263. Importantly, ABT263 treatment significantly reduced the infarct volume and improved neurological function in behavioral tests. This study demonstrated, for the first time, that senolytic therapy has therapeutic potential for cerebral IR injury.
| S-EPMC8584561 | biostudies-literature
Project description:Ischemic stroke (IS) is characterized by the sudden loss of blood circulation to an area of the brain, resulting in a corresponding loss of neurologic function. It has been a worldwide critical disease threatening to the health and life of human beings. Despite significant progresses achieved, effective treatment still remains a formidable challenge due to the complexity of the disease. Salvianolic acid B (Sal-B) and Puerarin (Pue) are two active neuroprotectants isolated from traditional Chinese herbs, Salvia miltiorrhiza and Kudzu root respectively, which have been used for the prevention and treatment of IS for thousands of years in China. The activities of two compounds against cerebral ischemia reperfusion injury have been confirmed via various pathways. However, the therapeutic efficacy of any of the two components is still unsatisfied. In the present study, the effect of the combination of Sal-B and Pue on IS was evaluated and validated in vitro and in vivo. The ratio of two compounds was firstly optimized based on the results of CoCl? damaged PC12 cells model. The co-administration exhibited significantly protective effect in CoCl? induced PC12 cells injury model by reducing ROS, inhibiting apoptosis and improving mitochondrial membrane potential in vitro. Moreover, Sal-B + Pue significantly relieved neurological deficit scores and infarct area than Sal-B or Pue alone in vivo. The results indicated that neuroprotection mechanism of Sal-B + Pue was related to TLR4/MyD88 and SIRT1 activation signaling pathway to achieve synergistic effect, due to the inhibition of NF-?B transcriptional activity and expression of pro-inflammatory cytokine (TNF-?, IL-1?, IL-6). In conclusion, the combination of Sal-B and Pue exerted much stronger neuroprotective effect than Sal-B or Pue alone, which provides a potential new drug and has great significance for the treatment of IS.
| S-EPMC6017479 | biostudies-literature
Project description:Ischemic stroke is among the leading causes of disability and death worldwide. In acute ischemic stroke, the rapid recanalization of occluded cranial vessels is the primary therapeutic aim. However, experimental data (obtained using mostly the transient middle cerebral artery occlusion model) indicates that progressive stroke can still develop despite successful recanalization, a process termed "reperfusion injury." Mounting experimental evidence suggests that platelets and T cells contribute to cerebral ischemia/reperfusion injury, and ischemic stroke is increasingly considered a thrombo-inflammatory disease. The interaction of von Willebrand factor and its receptor on the platelet surface, glycoprotein Ib, as well as many activatory platelet receptors and platelet degranulation contribute to secondary infarct growth in this setting. In contrast, interference with GPIIb/IIIa-dependent platelet aggregation and thrombus formation does not improve the outcome of acute brain ischemia but dramatically increases the susceptibility to intracranial hemorrhage. Here, we summarize the current understanding of the mechanisms and the potential translational impact of platelet contributions to cerebral ischemia/reperfusion injury.
| S-EPMC6838001 | biostudies-literature