Overexpressed FOXO3 improves inflammatory status in mice by affecting NLRP3-mediated cell coronation in necrotizing colitis mice

Yin, Yiyu; Wang, Jian; Zhao, Xiaodong; Wu, Xiling; Zou, Huaxin; Qin, Zhenfang; Cao, Junhua

doi:10.1016/j.biopha.2020.109867

Cited by 24 publications

(16 citation statements)

References 27 publications

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“…Meanwhile, knockdown of foxo3 led to significant elevating of these mRNA levels, while the foxo3 overexpression significantly decreased these levels. This is consistent with the previous study, in which foxo3 overexpression in intestinal epithelial cells caused a significant decrease in the gene expressions of il-1 and il-6 ( 13 ). In mice, silence of foxo3 increased the gene expressions of il-1β , il-6 and tnfα , but overexpressing of foxo3 attenuated liver failure by decreasing the mRNA levels of those genes ( 16 ).…”

Section: Discussionsupporting

confidence: 94%

“…In mammals, FoxO3 has been found to be a multifunctional transcription factor involved in regulating gene expression in the cell cycle, DNA repair, hypoxia and apoptosis (7)(8)(9)(10)(11)(12). In mice, overexpression of FoxO3 improves inflammatory status in by decreasing the levels il-1b, il-6, caspase-3 and other genes (13). Interleukin-1b (il-1b), interleukin-6 (il-6) and tumor necrosis factor-a (tnf-a) are pro-inflammatory cytokines that are the major markers of inflammation (14).…”

Section: Introductionmentioning

confidence: 99%

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FoxO3 Modulates LPS-Activated Hepatic Inflammation in Turbot (Scophthalmus maximus L.)

et al. 2021

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In mammals, forkhead box O3 (foxo3) plays important roles in liver immune system. The foxo3 can regulate cell cycle, DNA repair, hypoxia, apoptosis and so on. However, as such an important transcription factor, few studies on foxo3 in fish have been reported. The present study characterized the foxo3 in turbot (Scophthalmus maximus L.). Lipopolysaccharide (LPS) incubated in vitro (hepatocytes) and injected in vivo (turbot liver) were used to construct inflammatory models. The foxo3 was interfered and overexpressed to investigate its functions in liver inflammation. The open reading frame (ORF) of foxo3 was 1998 bp (base pair), encoding 665 amino acids. Sequence analysis showed that foxo3 of turbot was highly homologous to other fishes. Tissue distribution analysis revealed that the highest expression of foxo3 was in muscle. Immunofluorescence result showed that foxo3 was expressed in cytoplasm and nucleus. Knockdown of foxo3 significantly increased mRNA levels of tumor necrosis factor-α (tnf-α), interleukin-1β (il-1β), interleukin-6 (il-6), myeloid-differentiation factor 88 (myd88), cd83, toll-like receptor 2 (tlr-2) and protein level of c-Jun N-terminal kinase (JNK) in sifoxo3 + LPS (siRNA of foxo3+ LPS) group compared with NC + LPS (negative control + LPS) group in turbot hepatocytes. Overexpressed foxo3 significantly decreased mRNA levels of tnf-α, il-6, nuclear transcription factor-kappa B (nf-κb), cd83, tlr-2 and the protein level of JNK in vitro. In vivo analysis, foxo3 knockdown significantly increased levels of GOT in serum after LPS injection compared with NC+LPS group. Overexpressed foxo3 significantly decreased levels of GPT and GOT in pcDNA3.1-foxo3+LPS group compared with pcDNA3.1+LPS group in vivo. Foxo3 knockdown significantly increased mRNA levels of tnf-α, il-1β, il-6, nf-κb, myd88 and protein level of JNK in vivo in sifoxo3+LPS group compared with NC+LPS group in turbot liver. Overexpressed foxo3 significantly decreased mRNA levels of il-1β, il-6, myd88, cd83, jnk and protein level of JNK in pcDNA3.1-foxo3+LPS group compared with pcDNA3.1+LPS group in turbot liver. The results indicated that foxo3 might modulate LPS-activated hepatic inflammation in turbot by decreasing the proinflammatory cytokines, the levels of GOT and GPT as well as activating JNK/caspase-3 and tlr-2/myd88/nf-κb pathways. Taken together, these findings indicated that FoxO3 may play important roles in liver immune responses to LPS in turbot and the research of FoxO3 in liver immunity enriches the studies on immune regulation, and provides theoretical basis and molecular targets for solving liver inflammation and liver injury in fish.

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Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

FoxO3 Modulates LPS-Activated Hepatic Inflammation in Turbot (Scophthalmus maximus L.)

et al. 2021

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“…In the current study, FOXO3 was confirmed to be a downstream target of miR-27a-3p. FOXO3 was previously reported to regulate pulmonary fibrosis (33) and inflammation in mice with necrotizing colitis (34). The present results indicated that FOXO3 expression was negatively regulated by miR-27a-3p and was positively regulated by XIST.…”

Section: Discussionsupporting

confidence: 65%

Long non‑coding RNA XIST promotes cerebral ischemia/reperfusion injury by modulating miR‑27a‑3p/FOXO3 signaling

Zhang

Xia

et al. 2021

Mol Med Rep

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Cerebral ischemia/reperfusion (I/R) injury leads to neuronal damage, which may cause disability and even mortality. Multiple studies have revealed that long non-coding RNAs (lncRNAs) serve pivotal roles in the pathogenesis of cerebral I/R injury. Therefore, the present study aimed to investigate whether the lncRNA X inactivate-specific transcript (XIST) protects neuronal cells from cerebral I/R injury. In the present study, reverse transcription-quantitative PCR demonstrated that XIST expression was upregulated in the brain tissues of an I/R mouse model and in oxygen and glucose deprivation/reperfusion (OGD/R)-treated Neuro-2a (N2a) cells. Knockdown of XIST alleviated cerebral injury, as well as reduced N2a cell apoptosis and reactive oxygen species (ROS) production. Additionally, luciferase reporter and RNA immunoprecipitation assays identified that XIST could bind with microRNA (miR)-27a-3p. It was found that miR-27a-3p expression was downregulated in the brain tissues of an I/R mouse model and in OGD/R-induced N2a cells. In addition, miR-27a-3p overexpression attenuated I/R-induced cerebral injury, and inhibited the apoptosis and ROS production of N2a cells. miR-27a-3p was found to target FOXO3. Silencing of FOXO3 alleviated cerebral injury, as well as inhibited N2a cell apoptosis and ROS production. Collectively, these findings indicated that XIST aggravated cerebral I/R injury by regulating miR-27a-3p/FOXO3 signaling, which may provide a novel insight into the treatment of cerebral I/R injury.

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“…FOXO3a, a transcription factor of the O subclass of the forkhead family, has been shown to promote the activation of mitophagy by regulating the expression levels of key proteins associated with mitophagy, such as Parkin and BNIP3 [ 31 , 32 ]. FOXO3a has also been reported to inhibit pyroptosis by regulating the inflammatory response [ 33 , 34 ]. Recently, FOXO3a was demonstrated to be an important downstream target of MSC-exos [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Human Umbilical Cord Mesenchymal Stem Cell‐Derived Exosomes Attenuate Oxygen‐Glucose Deprivation/Reperfusion‐Induced Microglial Pyroptosis by Promoting FOXO3a‐Dependent Mitophagy

Yuan

Zhang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Background. Mesenchymal stem cell-derived exosomes (MSC-exos) have been recognized as a promising therapeutic strategy for neonatal hypoxic-ischemic brain damage (HIBD). Recently, microglial pyroptosis was shown to play a vital role in the progression of neonatal HIBD. However, whether MSC-exos improve HIBD by regulating microglial pyroptosis remains unknown. Methods. Exosomes were isolated from human umbilical cord mesenchymal stem cells (huMSCs) and identified by transmission electron microscopy (TEM), western blot, and nanoparticle tracking analysis (NTA). BV-2 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to induce microglial ischemia/reperfusion (I/R) in vitro. CCK-8, ELISA, western blot, and Hoechst 33342/PI double staining were performed to detect the pyroptosis of BV-2 cells. Conditioned medium (CM) from BV-2 cells exposed to different treatments was used to investigate its effect on neuronal injury. Moreover, 3-methyladenine (3-MA) and mitochondrial division inhibitor-1 (mdi-1) were used to verify the involvement of mitophagy in the protection of MSC-exos against OGD/R-induced pyroptosis in BV-2 cells. Finally, FOXO3a siRNA was used to investigate the involvement of FOXO3a in MSC-exo-induced mitophagy and pyroptosis inhibition. Results. Exosomes from huMSCs were successfully extracted. In OGD/R-exposed BV-2 cells, MSC-exos increased cell viability and decreased the expression of NLRP3, cleaved caspase-1, and GSDMD-N as well as the release of IL-1β and IL-18. Compared with CM from OGD/R-exposed BV-2 cells treated with PBS, CM from OGD/R-exposed BV-2 cells treated with MSC-exos significantly increased the viability of SH-SY5Y cells and decreased LDH release. MSC-exos also increased the expression of TOM20 and COX IV in OGD/R-exposed BV-2 cells. Additionally, 3-MA and mdi-1 attenuated the inhibition of pyroptosis with MSC-exo treatment. Furthermore, FOXO3a siRNA partially abolished the neuroprotective effect of MSC-exos and attenuated mitophagy and pyroptosis inhibition induced by MSC-exo treatment. Conclusions. Our findings demonstrated that MSC-exos increased FOXO3a expression to enhance mitophagy, therefore protecting microglia from I/R-induced pyroptosis and alleviating subsequent neuronal injury.

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Overexpressed FOXO3 improves inflammatory status in mice by affecting NLRP3-mediated cell coronation in necrotizing colitis mice

Cited by 24 publications

References 27 publications

FoxO3 Modulates LPS-Activated Hepatic Inflammation in Turbot (Scophthalmus maximus L.)

FoxO3 Modulates LPS-Activated Hepatic Inflammation in Turbot (Scophthalmus maximus L.)

Long non‑coding RNA XIST promotes cerebral ischemia/reperfusion injury by modulating miR‑27a‑3p/FOXO3 signaling

Human Umbilical Cord Mesenchymal Stem Cell‐Derived Exosomes Attenuate Oxygen‐Glucose Deprivation/Reperfusion‐Induced Microglial Pyroptosis by Promoting FOXO3a‐Dependent Mitophagy

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