Fetuin-A exerts a protective effect against experimentally induced intestinal ischemia/reperfusion by suppressing autophagic cell death

El-Malkey, Nanees F.; Alsemeh, Amira Ebrahim; Ashour, Wesam M. R.; Hassan, Nancy Husseiny; Edrees, Husam M.

doi:10.1177/1535370221995207

Cited by 14 publications

(10 citation statements)

References 49 publications

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“…Previous studies have revealed that Fetuin-A attenuates the inflammatory response and protects against injury in cerebral ischemia, intestinal ischemia/reperfusion and hereditary angioedema [ 38 , 48 , 49 ]. And according to our GO analysis, Fetuin-A is predicted to be involved in the biological processes of “acute phase response” and “inflammation”.…”

Section: Discussionmentioning

confidence: 99%

Fetuin-A alleviates neuroinflammation against traumatic brain injury-induced microglial necroptosis by regulating Nrf-2/HO-1 pathway

Zhao

Wei

Sun

et al. 2022

J Neuroinflammation

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Background The microglia-mediated inflammatory response is a vital mechanism of secondary damage following traumatic brain injury (TBI), but the underlying mechanism of microglial activation is unclear. Methods Controlled cortical impact (CCI) was induced in adult male C57BL/6J mice, and glutamate was used to construct a classical in vitro injury model in the primary microglia. Microglial activation was determined by western blot and immunostaining. The inflammatory factors were measured by enzyme-linked immunosorbent assay. The oxidative stress marker and mitochondrial reactive oxygen species (ROS) were measured by immunoblotting and MitoSox Red staining. Transmission electron microscopy was used to observe the typical morphology of necroptotic cells. Results Our quantitative proteomics identified 2499 proteins; 157 were significantly differentially expressed in brain tissue between the 6 h after CCI (CCI6h) group and sham group, and 109 were significantly differentially expressed between the CCI24h and sham groups. Moreover, compared with the sham group, the terms “acute-phase response”, “inflammation”, and “protein binding” were significantly enriched in CCI groups. Fetuin-A, a liver-secreted acute-phase glycoprotein, was involved in these biological processes. Using an experimental TBI model, we found that the Fetuin-A level peaked at 6 h and then decreased gradually. Importantly, we showed that administration of Fetuin-A reduced the cortical lesion volume and edema area and inhibited the inflammatory response, which was associated with suppressing microglial necroptosis, thus decreasing microglial activation. Furthermore, administration of Fetuin-A attenuated mitochondrial oxidative stress in glutamate-treated microglial cells, which is a critical mechanism of necroptosis suppression. In addition, we demonstrated that Fetuin-A treatment promoted translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus in vivo; however, the Nrf-2 inhibitor ML385 and si-heme oxygenase-1 (si-HO-1) disrupted the regulation of oxidative stress by Fetuin-A and induced increased ROS levels and necroptosis in glutamate-treated microglial cells. Fetuin-A also protected neurons from adverse factors in vivo and in vitro. Conclusions Our results demonstrated that Fetuin-A activated Nrf-2/HO-1, suppressed oxidative stress and necroptosis levels, and thereby attenuates the abnormal inflammatory response following TBI. The findings suggest a potential therapeutic strategy for TBI treatment.

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Section: Discussionmentioning

confidence: 99%

Fetuin-A alleviates neuroinflammation against traumatic brain injury-induced microglial necroptosis by regulating Nrf-2/HO-1 pathway

Zhao

Wei

Sun

et al. 2022

J Neuroinflammation

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“…The intestinal epithelium is most sensitive to IRI ( 9 , 10 ) and thus its integrity is decisive for the fate of the patient. As the barrier between the gut lumen and the rest of the organism, it is a critical factor for the systemic health of the whole organism and thus the outcome of intestinal IRI.…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies proposed that the grade of autophagy might be crucial for the cellular survival in the course of IRI ( 31 – 35 ). However, there are controversial results whether autophagy is beneficial or detrimental in IRI ( 9 , 36 – 40 ). Due to the complete lack of nutrients, an activation of AMPK and thus autophagy is more likely to happen (faster) in no flow ischemia, whereas in low flow conditions the activation of AMPK may be postponed or completely abolished, possibly causing differing rates of autophagy under the different conditions.…”

Section: Introductionmentioning

confidence: 99%

Adaptive mechanisms in no flow vs. low flow ischemia in equine jejunum epithelium: Different paths to the same destination

et al. 2022

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Intestinal ischemia reperfusion injury (IRI) is a frequent complication of equine colic. Several mechanisms may be involved in adaptation of the intestinal epithelium to IRI and might infer therapeutic potential, including hypoxia-inducible factor (HIF) 1α, AMP-activated protein kinase (AMPK), nuclear factor-erythroid 2-related factor 2 (NRF2), and induction of autophagy. However, the mechanisms supporting adaptation and thus cellular survival are not completely understood yet. We investigated the activation of specific adaptation mechanisms in both no and low flow ischemia and reperfusion simulated in equine jejunum epithelium in vivo. We found an activation of HIF1α in no and low flow ischemia as indicated by increased levels of HIF1α target genes and phosphorylation of AMPKα tended to increase during ischemia. Furthermore, the protein expression of the autophagy marker LC3B in combination with decreased expression of nuclear-encoded mitochondrial genes indicates an increased rate of mitophagy in equine intestinal IRI, possibly preventing damage by mitochondria-derived reactive oxygen species (ROS). Interestingly, ROS levels were increased only shortly after the onset of low flow ischemia, which may be explained by an increased antioxidative defense, although NFR2 was not activated in this setup. In conclusion, we could demonstrate that a variety of adaptation mechanisms manipulating different aspects of cellular homeostasis are activated in IRI irrespective of the ischemia model, and that mitophagy might be an important factor for epithelial survival following small intestinal ischemia in horses that should be investigated further.

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“…Previous studies have revealed that fetuin-A attenuates the in ammatory response and protects against injury in cerebral ischemia, intestinal ischemia/reperfusion and hereditary angioedema [35,43,44]. And fetuin-A is involved in the biological processes of "acute-phase response" and "in ammation" according to our GO analysis.…”

Section: Discussionmentioning

confidence: 71%

Fetuin-A Alleviates Neuroinflammation Against Traumatic Brain Injury-Induced Microglial Necroptosis By Regulating Nrf-2/HO-1 Pathway

Zhao

Bao

Sun

et al. 2021

Preprint

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Background: The microglia-mediated inflammatory response is a vital mechanism of secondary damage following traumatic brain injury (TBI), but its underlying mechanism of microglial activation is unclear. Methods: Controlled cortical impact (CCI) was induced in adult male C57BL/6J mice, and we also used glutamate to construct a classical in vitro injury model in BV2 cell line. The activation of microglia was determined by western blot assessments and immunostaining. The inflammatory factors were determined by ELLSA. The oxidative stress marker and mitochondrial ROS were determined by immunoblotting and MitoSox Red staining. Transmission electron microscopy (TEM) was used to observe a typical morphology of necroptotic cells. Results: Our quantitative proteomics identified 2499 proteins, 157 were significantly differentially expressed between brain tissues at 6 hours after CCI (CCI6h) and sham groups, and 109 were significantly differentially expressed between CCI24h and sham brain tissues. Moreover, compared with sham groups, the terms “acute-phase response”, “inflammation”, and “protein binding” were significantly enriched in CCI groups. Interestingly, fetuin-A, a liver-secreted acute-phase glycoprotein, was involved in these biological processes. Using experimental TBI models, we found that the fetuin-A level peaked at 6 h and then decreased gradually. Importantly, we showed that fetuin-A reduced the cortical lesion volume and edema area and inhibited the inflammatory response, which was associated with suppressing microglial necroptosis, thus decreasing microglial polarization to the M1 phenotype. Furthermore, administration of fetuin-A attenuated mitochondrial oxidative stress in glutamate-treated BV2 cells, which is a critical mechanism of necroptosis suppression. In addition, we demonstrated that fetuin-A treatment promoted translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus in vivo; however, the Nrf-2 inhibitor ML385 and si-heme oxygenase-1 (HO-1) disrupted the regulation of oxidative stress by fetuin-A and induced increased ROS levels and necroptosis in glutamate-treated BV2 cells. Interestingly, the mechanism of fetuin-A in BV2 cells also protects neurons from adverse factors in co-culture assays.Conclusions: Our results demonstrate that fetuin-A activates Nrf-2/HO-1, suppresses oxidative stress and necroptosis levels, and thereby attenuates the abnormal inflammatory response following TBI, providing a potential therapeutic strategy for TBI treatment.

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Fetuin-A exerts a protective effect against experimentally induced intestinal ischemia/reperfusion by suppressing autophagic cell death

Cited by 14 publications

References 49 publications

Fetuin-A alleviates neuroinflammation against traumatic brain injury-induced microglial necroptosis by regulating Nrf-2/HO-1 pathway

Fetuin-A alleviates neuroinflammation against traumatic brain injury-induced microglial necroptosis by regulating Nrf-2/HO-1 pathway

Adaptive mechanisms in no flow vs. low flow ischemia in equine jejunum epithelium: Different paths to the same destination

Fetuin-A Alleviates Neuroinflammation Against Traumatic Brain Injury-Induced Microglial Necroptosis By Regulating Nrf-2/HO-1 Pathway

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