Inhibition of Voltage-Gated Hv1 Alleviates LPS-Induced Neuroinflammation via Regulation of Microglial Metabolic Reprogramming

2022 ◽  
Author(s):  
Lingbin Sun ◽  
Xihua Wang ◽  
Shuyuan Guan ◽  
TAO LUO
Keyword(s):  
Cell Death ◽  
Microglial Activation ◽  
Therapeutic Potential ◽  
Aerobic Glycolysis ◽  
Neuronal Cell ◽  
Metabolic Reprogramming ◽  
Proinflammatory Response ◽  
Voltage Gated

Abstract Background Neuroinflammation plays an important role in the onset and advancement of cognitive loss and neurodegenerative disorders. The voltage-gated H channel (Hv1) has been reported to be involved in microglial activation and act as key drivers of neuroinflammation. This study aims at evaluating the mechanism of Hv1 involvement in neuroinflammation and the therapeutic potential of Hv1 inhibitor, 2-guanidinobenzimidazole (2-GBI), in a model of lipopolysaccharide (LPS)-induced neuroinflammation. Methods We investigated the influence of Hv1 inhibitor (2-GBI) on the generation of reactive oxidative species (ROS), metabolic reprogramming, and inflammatory mediators in vitro and examined the therapeutic potential of 2-GBI on microglial activation and hippocampal neuroinflammation in vivo. Novel object recognition and Y-maze were employed to assess cognitive function. Results 2-GBI reduced the LPS-induced proinflammatory response and aerobic glycolysis in microglia. HIF1α overexpression mediated aerobic glycolysis reprogramming alleviated by 2-GBI. We reported that Hv1 inhibitor exerted a protective effect on LPS-induced neuroinflammation through the ROS/HIF1α and PI3K/AKT/HIF1α pathways -mediated aerobic glycolysis. The cell death of PC12 induced by microglia-mediated neuroinflammation was reversed in a transwell co-culture system by 2-GBI. Furthermore, in vivo results suggested that 2-GBI mitigated the neuroinflammatory processes and recognition injury through regulation of microglial metabolic reprogramming. Conclusion 2-GBI protects LPS-induced neuroinflammation, neuronal cell death, and subsequently reverses the hippocampus-dependent cognitive deficits through regulation of microglial metabolic reprogramming. Taken together, these results demonstrate a key role for Hv1 in driving a pro-inflammatory microglia phenotype in neuroinflammation.

scholarly journals miR-214 Alleviates Ischemic Stroke-Induced Neuronal Death by Targeting DAPK1 in Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Yan Shi ◽  
Tian Tian ◽  
Er-Li Cai ◽  
Can Yang ◽  
Xin Yang
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Neuronal Death ◽  
Therapeutic Potential ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neurological Deficits ◽  
Tunel Staining

BackgroundIschemic stroke induces neuronal cell death and causes brain dysfunction. Preventing neuronal cell death after stroke is key to protecting the brain from stroke damage. Nevertheless, preventative measures and treatment strategies for stroke damage are scarce. Emerging evidence suggests that microRNAs (miRNAs) play critical roles in the pathogenesis of central nervous system (CNS) disorders and may serve as potential therapeutic targets.MethodsA photochemically induced thrombosis (PIT) mouse model was used as an ischemic stroke model. qRT-PCR was employed to assess changes in miRNAs in ischemic lesions of PIT-stroke mice and primary cultured neurons subjected to oxygen-glucose deprivation (OGD). 2,3,5-triphenyltetrazolium chloride (TTC) staining was performed to evaluate brain infarction tissues in vivo. TUNEL staining was employed to assess neuronal death in vitro. Neurological scores and motor coordination were investigated to evaluate stroke damage, including neurological deficits and motor function.ResultsIn vivo and in vitro results demonstrated that levels of miR-124 were significantly decreased following stroke, whereas changes in death-associated protein kinase 1 (DAPK1) levels exhibited the converse pattern. DAPK1 was identified as a direct target of miR-124. N-methyl-D-aspartate (NMDA) and OGD-induced neuronal death was rescued by miR-124 overexpression. Upregulation of miR-124 levels significantly improved PIT-stroke damage, including the overall neurological function in mice.ConclusionWe demonstrate the involvement of the miR-124/DAPK1 pathway in ischemic neuronal death. Our results highlight the therapeutic potential of targeting this pathway for ischemic stroke.

scholarly journals Antitumor effects of the small molecule DMAMCL in neuroblastoma via suppressing aerobic glycolysis and targeting PFKL

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Simeng Zhang ◽  
Zhongyan Hua ◽  
Gen Ba ◽  
Ning Xu ◽  
Jianing Miao ◽  
...  
Keyword(s):  
Cell Death ◽  
Synergistic Effects ◽  
Aerobic Glycolysis ◽  
Single Agent ◽  
Molecular Compound ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Atp Production

Abstract Background Neuroblastoma (NB) is a common solid malignancy in children that is associated with a poor prognosis. Although the novel small molecular compound Dimethylaminomicheliolide (DMAMCL) has been shown to induce cell death in some tumors, little is known about its role in NB. Methods We examined the effect of DMAMCL on four NB cell lines (NPG, AS, KCNR, BE2). Cellular confluence, survival, apoptosis, and glycolysis were detected using Incucyte ZOOM, CCK-8 assays, Annexin V-PE/7-AAD flow cytometry, and Seahorse XFe96, respectively. Synergistic effects between agents were evaluated using CompuSyn and the effect of DMAMCL in vivo was evaluated using a xenograft mouse model. Phosphofructokinase-1, liver type (PFKL) expression was up- and down-regulated using overexpression plasmids or siRNA. Results When administered as a single agent, DMAMCL decreased cell proliferation in a time- and dose-dependent manner, increased the percentage of cells in SubG1 phase, and induced apoptosis in vitro, as well as inhibiting tumor growth and prolonging survival in tumor-bearing mice (NGP, BE2) in vivo. In addition, DMAMCL exerted synergistic effects when combined with etoposide or cisplatin in vitro and displayed increased antitumor effects when combined with etoposide in vivo compared to either agent alone. Mechanistically, DMAMCL suppressed aerobic glycolysis by decreasing glucose consumption, lactate excretion, and ATP production, as well as reducing the expression of PFKL, a key glycolysis enzyme, in vitro and in vivo. Furthermore, PFKL overexpression attenuated DMAMCL-induced cell death, whereas PFKL silencing promoted NB cell death. Conclusions The results of this study suggest that DMAMCL exerts antitumor effects on NB both in vitro and in vivo by suppressing aerobic glycolysis and that PFKL could be a potential target of DMAMCL in NB.

Selective Release of Calpain Produced αII-Spectrin (α-Fodrin) Breakdown Products by Acute Neuronal Cell Death

2002 ◽  
Vol 383 (5) ◽  
pp. 785-791 ◽  
Author(s):  
Satavisha Dutta ◽  
Yuk Chun Chiu ◽  
Albert W. Probert ◽  
Kevin K.W. Wang
Keyword(s):  
Cell Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neuronal Injury ◽  
Nmda Receptor Antagonist ◽  
Breakdown Product ◽  
Calpain Inhibitor ◽  
Neural Cells

Abstract Activation of calpain results in the breakdown of α II spectrin (αfodrin), a neuronal cytoskeleton protein, which has previously been detected in various in vitro and in vivo neuronal injury models. In this study, a 150 kDa spectrin breakdown product (SBDP150) was found to be released into the cellconditioned media from SHSY5Y cells treated with the calcium channel opener maitotoxin (MTX). SBDP150 release can be readily quantified on immunoblot using an SBDP150- specific polyclonal antibody. Increase of SBDP150 also correlated with cell death in a timedependent manner. MDL28170, a selective calpain inhibitor, was the only protease inhibitor tested that significantly reduced MTXinduced SBDP150 release. The cellconditioned media of cerebellar granule neurons challenged with excitotoxins (NMDA and kainate) also exhibited a significant increase of SBDP150 that was attenuated by pretreatment with an NMDA receptor antagonist, R()-3-(2-carbopiperazine-4-yl)propyl-1- phosphonic acid (CPP), and MDL28170. In addition, hypoxic/hypoglycemic challenge of cerebrocortical cultures also resulted in SBDP150 liberation into the media. These results support the theory that an antibody based detection of SBDP150 in the cellconditioned media can be utilized to quantify injury to neural cells. Furthermore, SBDP150 may potentially be used as a surrogate biomarker for acute neuronal injury in clinical settings.

scholarly journals Cylindromatosis mediates neuronal cell death in vitro and in vivo

2018 ◽  
Vol 25 (8) ◽  
pp. 1394-1407 ◽  
Author(s):  
Goutham K. Ganjam ◽  
Nicole Angela Terpolilli ◽  
Sebastian Diemert ◽  
Ina Eisenbach ◽  
Lena Hoffmann ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell

Degradation of mutant huntingtin via the ubiquitin/proteasome system is modulated by FE65

2012 ◽  
Vol 443 (3) ◽  
pp. 681-689 ◽  
Author(s):  
Wan Ning Vanessa Chow ◽  
Hon Wing Luk ◽  
Ho Yin Edwin Chan ◽  
Kwok-Fai Lau
Keyword(s):  
Cell Death ◽  
Degradation Mechanism ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Adaptor Protein ◽  
Ubiquitin Proteasome System ◽  
Exon 1 ◽  
Ubiquitin Proteasome

An unstable expansion of the polyglutamine repeat within exon 1 of the protein Htt (huntingtin) causes HD (Huntington's disease). Mounting evidence shows that accumulation of N-terminal mutant Htt fragments is the source of disruption of normal cellular processes which ultimately leads to neuronal cell death. Understanding the degradation mechanism of mutant Htt and improving its clearance has emerged as a new direction in developing therapeutic approaches to treat HD. In the present study we show that the brain-enriched adaptor protein FE65 is a novel interacting partner of Htt. The binding is mediated through WW–polyproline interaction and is dependent on the length of the polyglutamine tract. Interestingly, a reduction in mutant Htt protein level was observed in FE65-knockdown cells, and the process requires the UPS (ubiquitin/proteasome system). Moreover, the ubiquitination level of mutant Htt was found to be enhanced when FE65 is knocked down. Immunofluroescence staining revealed that FE65 associates with mutant Htt aggregates. Additionally, we demonstrated that overexpression of FE65 increases mutant Htt-induced cell death both in vitro and in vivo. These results suggest that FE65 facilitates the accumulation of mutant Htt in cells by preventing its degradation via the UPS, and thereby enhances the toxicity of mutant Htt.

scholarly journals The Therapeutic Potential of Rosemary (Rosmarinus officinalis) Diterpenes for Alzheimer’s Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Solomon Habtemariam
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Rosmarinus Officinalis ◽  
Brain Inflammation ◽  
Important Species

Rosemary (Rosmarinus officinalisL.) is one of the most economically important species of the family Lamiaceae. Native to the Mediterranean region, the plant is now widely distributed all over the world mainly due to its culinary, medicinal, and commercial uses including in the fragrance and food industries. Among the most important group of compounds isolated from the plant are the abietane-type phenolic diterpenes that account for most of the antioxidant and many pharmacological activities of the plant. Rosemary diterpenes have also been shown in recent years to inhibit neuronal cell death induced by a variety of agents bothin vitroandin vivo. The therapeutic potential of these compounds for Alzheimer’s disease (AD) is reviewed in this communication by giving special attention to the chemistry of the compounds along with the various pharmacological targets of the disease. The multifunctional nature of the compounds from the general antioxidant-mediated neuronal protection to other specific mechanisms including brain inflammation and amyloid beta (Aβ) formation, polymerisation, and pathologies is discussed.

Effects of PACAP on in vitro and in vivo neuronal cell death, platelet aggregation, and production of reactive oxygen radicals

2004 ◽  
Vol 123 (1-3) ◽  
pp. 51-59 ◽  
Author(s):  
Dóra Reglödi ◽  
Zsolt Fábián ◽  
Andrea Tamás ◽  
Andrea Lubics ◽  
József Szeberényi ◽  
...  
Keyword(s):  
Cell Death ◽  
Platelet Aggregation ◽  
Oxygen Radicals ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Reactive Oxygen

scholarly journals AL355338 acts as an oncogenic lncRNA by interacting with protein ENO1 to regulate EGFR/AKT pathway in NSCLC

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qian Hua ◽  
Dongliang Wang ◽  
Lin Zhao ◽  
Zhihui Hong ◽  
Kairu Ni ◽  
...  
Keyword(s):  
Aerobic Glycolysis ◽  
Transcript Abundance ◽  
Metabolic Reprogramming ◽  
Clinical Samples ◽  
Abnormal Metabolism ◽  
Considerable Morbidity

Abstract Background Non-small cell lung cancer (NSCLC) is a malignancy with considerable morbidity and mortality. Abnormal metabolism is a hallmark of cancer; however, the mechanism of glycolysis regulation in NSCLC progression is not completely understood. Recent studies suggest that some dysregulated long non-coding RNAs (lncRNAs) play important roles in tumor metabolic reprogramming. Methods To identify glycolysis-associated-lncRNAs in NSCLC, we compared RNA-sequencing results between high 18F-fluorodeoxyglucose (FDG)-uptake NSCLC tissues and paired paratumor tissues. The transcript abundance of AL355338 in 80 pairs of clinical samples was evaluated by quantitative real-time PCR assay and fluorescence in situ hybridization. The biological role of AL355338 on NSCLC cells were evaluated by functional experiments in vitro and in vivo. Moreover, RNA pull-down, mass spectrometry and RNA immunoprecipitation (RIP) assays were used to identify the protein interacted with AL355338. Co-immunoprecipitation, in situ proximity ligation assays and western blotting were applied to define the potential downstream pathways of AL355338. Results AL355338 was an upregulated glycolysis-associated lncRNA in NSCLC. Functional assays revealed that AL355338 was critical for promoting aerobic glycolysis and NSCLC progression. Mechanistic investigations showed that AL355338 directly bound with alpha-enolase (ENO1) and enhanced the protein’s stability by modulating its degradation and ubiquitination. A positive correlation was observed between AL355338 and ENO1 in NSCLC, and ENO1 was subsequently confirmed to be responsible for the oncogenic role of AL355338. Furthermore, AL355338 was capable of modulating ENO1/EGFR complex interaction and further activating EGFR-AKT signaling. Conclusions This study indicates that AL355338 confers an aggressive phenotype to NSCLC, and targeting it might be an effective therapeutic strategy.

scholarly journals Voltage-Gated Potassium Channel Kv1.3 as a Therapeutic Target for Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Weiwei Li ◽  
Gregory C. Wilson ◽  
Magdalena Bachmann ◽  
Jiang Wang ◽  
Andrea Mattarei ◽  
...  
Keyword(s):  
Cell Death ◽  
Potassium Channel ◽  
Mapk Pathway ◽  
Tissue Expression ◽  
Ductal Adenocarcinoma ◽  
Voltage Gated ◽  
Pancreas Tumor ◽  
Anti Oxidant

AbstractThe mitochondrial voltage-gated potassium channel, Kv1.3, has been emerged as an attractive oncologic target but its function in pancreas cancer (PDAC) is unknown. In this study we evaluated tissue expression of Kv1.3 in resected PDAC from 55 patients and tumor inhibition in orthotopic mouse models using the recently developed Kv1.3 inhibitors PCARBTP and PAPTP. Immunohistochemistry of 55 human PDAC specimens showed that all tumors expressed Kv1.3 with 60% of tumor specimens having high Kv1.3 expression. In pancreas tumor models (Pan02 cells injected into C57BL/6 mice), PCARBTP and PAPTP treatment resulted in tumor reductions of 87% and 70%, respectively. When combined with gemcitabine/abraxane, this increased to 95% and 80% without resultant organ toxicity. In vivo models indicated PCARBTP-mediated cell death occurred through the p38-MAPK pathway. In vitro-generated resistant clones to PCARBTP escaped cell death through upregulation of the anti-oxidant system as determined using SWATH-MS analysis. These data show Kv1.3 is highly expressed in resected human PDAC and the use of novel mitochondrial Kv1.3 inhibitors combined with cytotoxic chemotherapies might be novel, effective treatment for PDAC.

scholarly journals Gout and pseudo-gout-related crystals promote GLUT1-mediated glycolysis that governs NLRP3 and interleukin-1β activation on macrophages

2020 ◽  
Vol 79 (11) ◽  
pp. 1506-1514
Author(s):  
Felix Renaudin ◽  
Lucie Orliaguet ◽  
Florence Castelli ◽  
François Fenaille ◽  
Aurelie Prignon ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Glucose Uptake ◽  
Aerobic Glycolysis ◽  
Metabolic Reprogramming ◽  
Metabolic Phenotype ◽  
Glucose Transporter 1 ◽  
Gout Flare

ObjectiveMacrophage activation by monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals mediates an interleukin (IL)-1β-dependent inflammation during gout and pseudo-gout flare, respectively. Since metabolic reprogramming of macrophages goes along with inflammatory responses dependently on stimuli and tissue environment, we aimed to decipher the role of glycolysis and oxidative phosphorylation in the IL-1β-induced microcrystal response.MethodsBriefly, an in vitro study (metabolomics and real-time extracellular flux analysis) on MSU and CPP crystal-stimulated macrophages was performed to demonstrate the metabolic phenotype of macrophages. Then, the role of aerobic glycolysis in IL-1β production was evaluated, as well in vitro as in vivo using 18F-fluorodeoxyglucose positron emission tomography imaging and glucose uptake assay, and molecular approach of glucose transporter 1 (GLUT1) inhibition.ResultsWe observed that MSU and CPP crystals led to a metabolic rewiring toward the aerobic glycolysis pathway explained by an increase in GLUT1 plasma membrane expression and glucose uptake on macrophages. Also, neutrophils isolated from human synovial fluid during gout flare expressed GLUT1 at their plasma membrane more frequently than neutrophils isolated from bloodstream. Both glucose deprivation and treatment with either 2-deoxyglucose or GLUT1 inhibitor suppressed crystal-induced NLRP3 activation and IL-1β production, and microcrystal inflammation in vivo.ConclusionIn conclusion, we demonstrated that GLUT1-mediated glucose uptake is instrumental during the inflammatory IL-1β response induced by MSU and CPP crystals. These findings open new therapeutic paths to modulate crystal-related inflammation.

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