Arginine is neuroprotective through suppressing HIF-1α/LDHA-mediated inflammatory response after cerebral ischemia/reperfusion injury

Chen, Songfeng; Pan, Meng‐Xian; Tang, Jia; Cheng, Jing; Zhao, Dan; Zhang, Ya; Liao, Hua‐Bao; Liu, Rui; Yang, Zhuang; Zhang, Zhifeng; Chen, Juan; Lei, Ruixue; Li, Shifang; Li, Huanting; Wang, Xinghuan; Wan, Qi

doi:10.1186/s13041-020-00601-9

Cited by 46 publications

(28 citation statements)

References 50 publications

(58 reference statements)

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“…During ischemia, there is a buildup of xanthine dehydrogenase, which interacts with oxygen when blood flow returns that subsequently leads to production of superoxide, hydrogen peroxide, and hydroxyl radical OH, all leading to endothelial activation and release of proinflammatory cytokines [ 226 ]. This can lead to a secondary injury caused by inflammation, oxidative stress, and/or BBB breakdown [ 227 ], which can in turn cause exacerbation of tissue damage, neurological deficits, and cognitive impairment. Thus, stroke injury can present itself with an acute phase (within 24 h), subacute phase (1–5 days), and chronic phase (weeks to months).…”

Section: Strokementioning

confidence: 99%

The good, the bad, and the opportunities of the complement system in neurodegenerative disease

Schartz

Tenner

2020

J Neuroinflammation

152

180

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The complement cascade is a critical effector mechanism of the innate immune system that contributes to the rapid clearance of pathogens and dead or dying cells, as well as contributing to the extent and limit of the inflammatory immune response. In addition, some of the early components of this cascade have been clearly shown to play a beneficial role in synapse elimination during the development of the nervous system, although excessive complement-mediated synaptic pruning in the adult or injured brain may be detrimental in multiple neurogenerative disorders. While many of these later studies have been in mouse models, observations consistent with this notion have been reported in human postmortem examination of brain tissue. Increasing awareness of distinct roles of C1q, the initial recognition component of the classical complement pathway, that are independent of the rest of the complement cascade, as well as the relationship with other signaling pathways of inflammation (in the periphery as well as the central nervous system), highlights the need for a thorough understanding of these molecular entities and pathways to facilitate successful therapeutic design, including target identification, disease stage for treatment, and delivery in specific neurologic disorders. Here, we review the evidence for both beneficial and detrimental effects of complement components and activation products in multiple neurodegenerative disorders. Evidence for requisite co-factors for the diverse consequences are reviewed, as well as the recent studies that support the possibility of successful pharmacological approaches to suppress excessive and detrimental complement-mediated chronic inflammation, while preserving beneficial effects of complement components, to slow the progression of neurodegenerative disease.

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Section: Strokementioning

confidence: 99%

The good, the bad, and the opportunities of the complement system in neurodegenerative disease

Schartz

Tenner

2020

J Neuroinflammation

152

180

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“…SRC can also phosphorylate LDHA and promote conversion enzyme activity. HIF-1α is the upstream regulator of LDHA, and both HIF-1α and LDHA stimulate the inflammatory response ( 77 ).…”

Section: Glycolysismentioning

confidence: 99%

Mechanism overview and target mining of atherosclerosis: Endothelial cell injury in atherosclerosis is regulated by glycolysis (Review)

Wang

et al. 2020

Int J Mol Med

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Atherosclerosis (AS) is a chronic disease with a complex pathology that may lead to several cardiovascular and cerebrovascular diseases; however, further research is necessary to fully elucidate its pathogenesis. The main risk factors for AS include lipid metabolism disorders, endothelial cell injury, inflammation and immune dysfunction, among which vascular endothelial cell damage is considered as the main trigger for AS occurrence and development. Endothelial cell damage leads to enhanced intimal permeability and leukocyte adhesion, promoting thrombus formation and accelerating disease progression. The function of endothelial cells is affected by glycolysis regulation, since 80% of ATP in these cells is produced via this pathway. Genes associated with AS and endothelial cell glycolysis, including AKT1, interleukin-6, vascular endothelial growth factor A, TP53, signal transducer and activator of transcription 3, SRc and mitogen-activated protein kinase 1, were screened. Through integrated analysis, these genes were found to play a key role in AS by regulating multiple signaling pathways associated with cell signal transduction, energy metabolism, immune function and thrombosis. In conclusion, endothelial cell injury in AS may be alleviated by glycolysis and is a potential clinical treatment strategy for AS.

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“…When cells are exposed to hypoxia, there is an increase in hypoxia-induced factor-1α (HIF-1α) expression [52]. There is also an elevated expression of HIF-1α during periods of ischemia/reperfusion in neurons [25]. HIF-1α mediates in ammatory response after cerebral ischemia/reperfusion injury [25].…”

Section: Discussionmentioning

confidence: 99%

“…p38 is activated after cerebral ischemia and induces a series of pathological processes such as in ammation and NLRP3 in ammasome activation [22][23][24]. Hypoxia-inducible factor 1 alpha (HIF-1 alpha) and Forkhead box transcription factor O1 (FoxO1) are also related to the in ammatory response and in ammasome activation [25,18,26].…”

Section: Introductionmentioning

confidence: 99%

Phenothiazine Inhibits Neuroinflammation and Inflammasome Activation Independent of Hypothermia After Ischemic Stroke

Guo

Lee

et al. 2021

Mol Neurobiol

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A depressive or hibernation-like effect of chlorpromazine and promethazine (C + P) on brain activity was reported to induce neuroprotection, with or without induced-hypothermia. However, the underlying mechanisms remain unclear. The current study evaluated the pharmacological function of C + P on the inhibition of neuroin ammatory response and in ammasome activation after ischemia/reperfusion. A total of 72 adult male Sprague-Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 6 or 24 h reperfusion. At the onset of reperfusion, rats received C + P (8 mg/kg) with temperature control. Brain cell death was detected by measuring CD68 and myeloperoxidase (MPO) levels. In ammasome activation was measured by mRNA levels of NLRP3, IL-1β, and TXNIP, and protein quantities of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Activation of JAK2/STAT3 pathway was detected by the phosphorylation of STAT3 (p-STAT3) and JAK2 (p-JAK2), and the co-localization of p-STAT3 and NLRP3. Activation of the p38 pathway was assessed with the protein levels of p-p38/p38.The mRNA and protein levels of HIF-1α, FoxO1, and p-FoxO1, and the co-localization of p-STAT3 with HIF-1α or FoxO1 were quantitated. As expected, C + P signi cantly reduced cell death and attenuated the neuroin ammatory response as determined by reduced CD68 and MPO. C + P decreased ischemiainduced in ammasome activation, shown by reduced mRNA and protein expressions of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Phosphorylation of JAK2/STAT3 and p38 pathways and the colocalization of p-STAT3 with NLRP3 were also inhibited by C + P. Furthermore, mRNA levels of HIF-1α and FoxO1 were decreased in the C + P group. While C + P inhibited HIF-1α protein expression, it increased FoxO1 phosphorylation, which promoted the exclusion of FoxO1 from the nucleus and inhibited FoxO1 activity. At the same time, C + P reduced the co-localization of p-STAT3 with HIF-1α or FoxO1. In conclusion, C + P treatment conferred neuroprotection in stroke by suppressing neuroin ammation and NLRP3 in ammasome activation. The present study suggests that JAK2/STAT3/p38/HIF-1α/FoxO1 are vital regulators and potential targets for e cacious therapy following ischemic stroke.

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Arginine is neuroprotective through suppressing HIF-1α/LDHA-mediated inflammatory response after cerebral ischemia/reperfusion injury

Cited by 46 publications

References 50 publications

The good, the bad, and the opportunities of the complement system in neurodegenerative disease

The good, the bad, and the opportunities of the complement system in neurodegenerative disease

Mechanism overview and target mining of atherosclerosis: Endothelial cell injury in atherosclerosis is regulated by glycolysis (Review)

Phenothiazine Inhibits Neuroinflammation and Inflammasome Activation Independent of Hypothermia After Ischemic Stroke

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