Melatonin Ameliorates Axonal Hypomyelination of Periventricular White Matter by Transforming A1 to A2 Astrocyte via JAK2/STAT3 Pathway in Septic Neonatal Rats

Jiang, Shuqi; Wang, Hong; Zhang, Qiuping; Li, Qian; Liu, Nan; Li, Zhenggong; Chen, Chunbo; Deng, Yiyu

doi:10.2147/jir.s337499

Cited by 30 publications

(22 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Melatonin is extensively reviewed and documented for its potent antiviral properties [ 140 , 141 , 142 , 143 , 144 , 145 ] that can activate type I IFN-⍺ responsible for promoting JAK1/2 signaling and phosphorylation of STAT3 [ 146 , 147 , 148 , 149 ]. Leukocytes, including neutrophils, are largely responsible for the production of IFN-⍺ [ 150 , 151 ], and melatonin can increase the production of leukocytes.…”

Section: Sars-cov-2 Proteins Phase Separation Disrupt Host Biomolecul...mentioning

confidence: 99%

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Loh¹,

Reíter

2022

IJMS

View full text Add to dashboard Cite

The relentless, protracted evolution of the SARS-CoV-2 virus imposes tremendous pressure on herd immunity and demands versatile adaptations by the human host genome to counter transcriptomic and epitranscriptomic alterations associated with a wide range of short- and long-term manifestations during acute infection and post-acute recovery, respectively. To promote viral replication during active infection and viral persistence, the SARS-CoV-2 envelope protein regulates host cell microenvironment including pH and ion concentrations to maintain a high oxidative environment that supports template switching, causing extensive mitochondrial damage and activation of pro-inflammatory cytokine signaling cascades. Oxidative stress and mitochondrial distress induce dynamic changes to both the host and viral RNA m6A methylome, and can trigger the derepression of long interspersed nuclear element 1 (LINE1), resulting in global hypomethylation, epigenetic changes, and genomic instability. The timely application of melatonin during early infection enhances host innate antiviral immune responses by preventing the formation of “viral factories” by nucleocapsid liquid-liquid phase separation that effectively blockades viral genome transcription and packaging, the disassembly of stress granules, and the sequestration of DEAD-box RNA helicases, including DDX3X, vital to immune signaling. Melatonin prevents membrane depolarization and protects cristae morphology to suppress glycolysis via antioxidant-dependent and -independent mechanisms. By restraining the derepression of LINE1 via multifaceted strategies, and maintaining the balance in m6A RNA modifications, melatonin could be the quintessential ancient molecule that significantly influences the outcome of the constant struggle between virus and host to gain transcriptomic and epitranscriptomic dominance over the host genome during acute infection and PASC.

show abstract

Section: Sars-cov-2 Proteins Phase Separation Disrupt Host Biomolecul...mentioning

confidence: 99%

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Loh¹,

Reíter

2022

IJMS

View full text Add to dashboard Cite

show abstract

“…Similar to the two adaptive states M1 and M2 of macrophages, two phenotypes, A1 and A2, are also present in astrocytes [ 6 – 8 ]. During inflammation, bacterial lipopolysaccharide induces astrocytes to be converted to the deleterious A1 phenotype [ 9 ], releasing neurotoxic factors such as complement components and inflammatory cytokines to mediate neuronal and oligodendrocyte cell death [ 6 , 10 – 12 ]. Hypoxia induces A2 astrocytes, which exert neuroprotective functions by producing anti-inflammatory cytokines and neurotrophic factors [ 6 , 12 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

Homer1 promotes the conversion of A1 astrocytes to A2 astrocytes and improves the recovery of transgenic mice after intracerebral hemorrhage

Fei

Dou

Wang

et al. 2022

J Neuroinflammation

View full text Add to dashboard Cite

Background Inflammation induced by intracerebral hemorrhage (ICH) is one of the main causes of the high mortality and poor prognosis of patients with ICH. A1 astrocytes are closely associated with neuroinflammation and neurotoxicity, whereas A2 astrocytes are neuroprotective. Homer scaffolding protein 1 (Homer1) plays a protective role in ischemic encephalopathy and neurodegenerative diseases. However, the role of Homer1 in ICH-induced inflammation and the effect of Homer1 on the phenotypic conversion of astrocytes remain unknown. Methods Femoral artery autologous blood from C57BL/6 mice was used to create an ICH model. We use the A1 phenotype marker C3 and A2 phenotype marker S100A10 to detect astrocyte conversion after ICH. Homer1 overexpression/knock-down mice were constructed by adeno-associated virus (AAV) infection to explore the role of Homer1 and its mechanism of action after ICH. Finally, Homer1 protein and selumetinib were injected into in situ hemorrhage sites in the brains of Homer1flox/flox/Nestin-Cre+/− mice to study the efficacy of Homer1 in the treatment of ICH by using a mouse cytokine array to explore the potential mechanism. Results The expression of Homer1 peaked on the third day after ICH and colocalized with astrocytes. Homer1 promotes A1 phenotypic conversion in astrocytes in vivo and in vitro. Overexpression of Homer1 inhibits the activation of MAPK signaling, whereas Homer1 knock-down increases the expression of pathway-related proteins. The Homer1 protein and selumetinib, a non-ATP competitive MEK1/2 inhibitor, improved the outcome in ICH in Homer1flox/flox/Nestin-Cre+/− mice. The efficacy of Homer1 in the treatment of ICH is associated with reduced expression of the inflammatory factor TNFSF10 and increased expression of the anti-inflammatory factors activin A, persephin, and TWEAK. Conclusions Homer1 plays an important role in inhibiting inflammation after ICH by suppressing the A1 phenotype conversion in astrocytes. In situ injection of Homer1 protein may be a novel and effective method for the treatment of inflammation after ICH.

show abstract

“…Separately, Guo et al [41] showed that glycogen mobilization in cerebral ischemia/reperfusion (I/R) injury reduced ROS levels during reperfusion, inhibited NF-κB signaling and activated STAT3 signaling, thereby inducing the transformation of astrocytes from A1-like (toxic) to A2-like (protective) subtypes. Jiang et al [42] showed that melatonin (MEL) signi cantly down-regulated the expression of A1 astrocyte markers and upregulated the expression of A2 astrocyte markers through MT1/JAK2/STAT3 signaling pathway, thus alleviating the periventricular white matter (PWM) damage of septic neonatal rats. In the same disease context, MEL signi cantly reduced the LPS activated microglia in the expression of proin ammatory cytokines, and increased the expression of anti-in ammatory cytokines via MT1/JAK2/STAT3/telomerase signal pathway, convert activated microglia from M1 to M2 phenotypes [43] .…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology to explore the mechanism of scutellarin in the treatment of brain ischemia and experimental verification of JAK2/STAT3 signaling pathway

Jia

Chen

et al. 2022

Preprint

View full text Add to dashboard Cite

Objective This study elucidated the neuroprotective mechanisms of scutellarin in microglia and astrocytes during the progression of neuropathology in cerebral ischemia. Methods Network pharmacology was first used to filtrate the core targets and pathways. Arising from this, JAK2/STAT3 signaling pathway was specifically identified and experimentally verified. Expression of JAK2/STAT3 signaling related proteins in TNC-1 astrocytes subjected to different treatments with BV-2 microglia conditioned medium (CM) was then analyzed by western blot and immunofluorescence staining. Along with the above, expression of the various biomarkers was also evaluated in astrocytes given pretreatment with AG490, the JAK2/STAT3 signaling inhibitor. In tandem, middle cerebral artery occlusion (MCAO) in rats was performed in different experimental groups to detect the expression of the above biomarkers in the cerebral astrocytes. Results Network pharmacology suggests that JAK2/STAT3 signaling pathway is one of the mechanisms by which scutellarin can mitigate the cerebral ischemia damage. In TNC-1 astrocytes, p-JAK2 and p-STAT3 expression was significantly up-regulated in microglia CM group. Scutellarin promoted the up-regulation of various markers, and of note, AG490 neutralized the effect of scutellarin. In vivo at 1, 3, and 7d after MCAO, p-JAK2 and p-STAT3 expression was significantly increased. Consistent with in vitro results, the rise in expression was augmented by scutellarin. Conclusion It is concluded from this study that scutellarin exerts its neuroprotective effects via activated microglia by activating the astrocyte JAK2/STAT3 signaling pathway. This has given the herbal compound a firm experimental basis for its clinical application.

show abstract

Melatonin Ameliorates Axonal Hypomyelination of Periventricular White Matter by Transforming A1 to A2 Astrocyte via JAK2/STAT3 Pathway in Septic Neonatal Rats

Cited by 30 publications

References 59 publications

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Homer1 promotes the conversion of A1 astrocytes to A2 astrocytes and improves the recovery of transgenic mice after intracerebral hemorrhage

Network pharmacology to explore the mechanism of scutellarin in the treatment of brain ischemia and experimental verification of JAK2/STAT3 signaling pathway

Contact Info

Product

Resources

About