Spata2 Knockdown Exacerbates Brain Inflammation via NF-κB/P38MAPK Signaling and NLRP3 Inflammasome Activation in Cerebral Ischemia/Reperfusion Rats

Ren, Yueping; Jiang, Jun; Jiang, Wenxia; Zhou, Xueling; Lu, Wenhao; Wang, Jingwen; Luo, Yong

doi:10.1007/s11064-021-03360-8

Cited by 12 publications

(7 citation statements)

References 75 publications

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“…When endogenous or exogenous NO is overproduced and released, it becomes a strong neurotoxic substance that can be involved in a variety of neurodegenerative and inflammatory pathological processes, leading to neuronal apoptosis and disease induction (8). A large volume of evidence has indicated excessive NO and its mediated apoptosis in organs and tissues to be associated with neurological diseases, such as epilepsy, AD, PD, amyotrophic lateral sclerosis and HD, as well as cerebral ischemia/reperfusion injury and Down's syndrome (18,(31)(32)(33)(34). This is of particular interest to neurodegenerative conditions, such as AD and PD, which increasingly are the focus of research on the pathogenesis and treatment of such diseases (3,35).…”

Section: Discussionmentioning

confidence: 99%

Hispidin inhibits LPS‑induced nitric oxide production in BV‑2 microglial cells via ROS‑dependent MAPK signaling

et al. 2021

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Neuroinflammation is associated with many neurodegenerative diseases. Abnormal activation of microglial cells in the central nervous system (CNS) is a major characteristic of neuroinflammation. Nitric oxide (NO) free radicals are produced by activated microglia and prolonged presence of large quantities of NO in the CNS can lead to neuroinflammation and disease. Hispidin is a polyphenol derived from Phellinus linteus (a valuable medicinal mushroom) with strong antioxidant, anticancer and antidiabetic properties. A previous study demonstrated that hispidin significantly inhibited NO production via lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Therefore, the present study used MTT assay was used to detect the effect of hispdin on cell viability. Griess reagent analysis was used to measure NO production. Reverse transcription-semi quantitative PCR and western blotting were used to evaluate the effects of hispdin on iNOS mRNA and MAPK/ERK/JNK protein levels. Fluorescence microscopy and flow cytometry were used to detect the effects of hispdin on the production of ROS and phagocytosis of cells. The present results indicated that hispidin could significantly inhibit the increase of NO production and iNOS expression in BV-2 microglial cells stimulated by LPS. The inhibitory effect of hispidin on NO production was similar to that of S-methylisothiourea sulfate, an iNOS inhibitor. Signaling studies demonstrated that hispidin markedly suppresses LPS-induced mitogen activated protein kinases and JAK1/STAT3 activation, although not the NF-κB signaling pathway. The present observations in LPS-stimulated BV-2 microglial cells indicated that hispidin might serve as a therapeutic candidate for the treatment of NO-induced neuroinflammation and, potentially, as a novel iNOS inhibitor.

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Section: Discussionmentioning

confidence: 99%

Hispidin inhibits LPS‑induced nitric oxide production in BV‑2 microglial cells via ROS‑dependent MAPK signaling

et al. 2021

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“…Down-regulation of Spata2 has led to increased microglia, up-regulation of Tnfa, Il-1β, and Il-18, and elevation of the infarct size. Moreover, Spata2 knockdown has enhanced activity of P38MAPK, NLRP3 inflammasome and NF-κB signals ( 26 ). Another study has shown prompt activation of NLRP3 inflammasome in microglia following cerebral I/R injury onset and subsequent expression of this protein in neurons and microvascular endothelial cells afterwards.…”

Section: Neurovascular I/r Injurymentioning

confidence: 99%

NLRP3: Role in ischemia/reperfusion injuries

et al. 2022

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NLR family pyrin domain containing 3 (NLRP3) is expressed in immune cells, especially in dendritic cells and macrophages and acts as a constituent of the inflammasome. This protein acts as a pattern recognition receptor identifying pathogen-associated molecular patterns. In addition to recognition of pathogen-associated molecular patterns, it recognizes damage-associated molecular patterns. Triggering of NLRP3 inflammasome by molecules ATP released from injured cells results in the activation of the inflammatory cytokines IL-1β and IL-18. Abnormal activation of NLRP3 inflammasome has been demonstrated to stimulate inflammatory or metabolic diseases. Thus, NLRP3 is regarded as a proper target for decreasing activity of NLRP3 inflammasome. Recent studies have also shown abnormal activity of NLRP3 in ischemia/reperfusion (I/R) injuries. In the current review, we have focused on the role of this protein in I/R injuries in the gastrointestinal, neurovascular and cardiovascular systems.

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“…Confirming this role and using a transient focal cerebral ischemia/reperfusion animal model, Ren et al showed that SPATA2 expression was reduced in rat brains after I/R and that Spata2 knockdown caused an increase in microglia cells with a consequent increase in the expression of TNF, IL -1β and IL-18. Furthermore, the silencing of Spata2 resulted in the activation of p38 MAPK and NLRP3 inflammasome with consequent activation of NF-κB signaling [ 14 ].…”

Section: Spata2 Tnf Receptor 1 Complex and Cell Deathmentioning

confidence: 99%

“…Since SPATA2 has been identified as a TNFR1 modulator required for TNF-induced inflammation and necroptosis [ 12 , 14 ], some authors have attempted to study the expression of SPATA2 and TNFA in the tissues of 171 patients with low-grade serous ovarian cancer (LGSOC), high-grade serous ovarian cancer (HGSOC), endometrioid and clear cell ovarian cancer (OC) compared to 28 non-malignant control tissues [ 32 ]. The expression of TNFA and SPATA2 was found to be significantly higher in OC than in control tissues.…”

Section: Spata2 Tnf Receptor 1 Complex and Cancermentioning

confidence: 99%

The role of SPATA2 in TNF signaling, cancer, and spermatogenesis

et al. 2022

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The activation of TNF receptors can lead to cell death with a mechanism of cell necrosis regulated genetically and distinct from apoptosis which is defined as necroptosis. Necroptosis has been one of the most studied emerging cell death/signaling pathways in recent years, especially in light of the role of this process in human disease. However, not all regulatory components of TNF signaling have been identified in relation to both physiological and pathological conditions. In 2008, Spata2 (Spermatogenesis-associated protein 2) was identified as one of the seven fundamental genes for the cellular signaling network that regulates necroptosis and apoptosis. This gene had been cloned by our group and named Spata2 as its expression was found to be elevated in the testis compared to other tissues, localized at the Sertoli cell level and FSH-dependent. More recently, it has been demonstrated that deletion of Spata2 gene causes increased inhibin α expression and attenuated fertility in male mice. However, more importantly, five recently published reports have highlighted that SPATA2 is crucial for recruiting CYLD to the TNFR1 signaling complex thus promoting its activation leading to TNF-induced cell death. Loss of SPATA2 increases transcriptional activation of NF-kB and limits TNF-induced necroptosis. Here we will discuss these important findings regarding SPATA2 and, in particular, focus attention on the evidence that suggests a role for this protein in the TNF signaling pathway.

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Spata2 Knockdown Exacerbates Brain Inflammation via NF-κB/P38MAPK Signaling and NLRP3 Inflammasome Activation in Cerebral Ischemia/Reperfusion Rats

Cited by 12 publications

References 75 publications

Hispidin inhibits LPS‑induced nitric oxide production in BV‑2 microglial cells via ROS‑dependent MAPK signaling

Hispidin inhibits LPS‑induced nitric oxide production in BV‑2 microglial cells via ROS‑dependent MAPK signaling

NLRP3: Role in ischemia/reperfusion injuries

The role of SPATA2 in TNF signaling, cancer, and spermatogenesis

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