Role of Fetuin-A in Injury and Infection

Wang, Haichao; Li, Wei; Zhu, Shu; Wang, Ping; Sama, Andrew E.

doi:10.5772/18073

Cited by 5 publications

(5 citation statements)

References 99 publications

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“…In SH-SY5Y cells we found that Alexa-488 labeled fetuin-A is internalized within cytoplasmic vesicles (Fig. 8A), similarly to the endocytosis of fluorescently labeled fetuin-A already described for other cells such as vascular smooth muscle cells (Reynolds et al, 2005;Chen et al, 2007), or murine macrophages (Wang et al, 2011). We investigated the hypothesis whether uranium could be colocalized with vesicles containing fetuin-A in SH-SY5Y cells.…”

Section: Uranium Organelles and Fetuin-a Imagingsupporting

confidence: 78%

Cytoplasmic aggregation of uranium in human dopaminergic cells after continuous exposure to soluble uranyl at non-cytotoxic concentrations

et al. 2021

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Uranium exposure can lead to neurobehavioral alterations in particular of the monoaminergic system, even at non-cytotoxic concentrations. However, the mechanisms of uranium neurotoxicity after noncytotoxic exposure are still poorly understood. In particular, imaging uranium in neurons at low intracellular concentration is still very challenging. We investigated uranium intracellular localization by means of synchrotron X-ray fluorescence imaging with high spatial resolution (< 300 nm) and high analytical sensitivity (< 1 µg.g-1 per 300 nm pixel). Neuron-like SH-SY5Y human cells differentiated into a dopaminergic phenotype were continuously exposed, for seven days, to a non-cytotoxic concentration (10 μM) of soluble natural uranyl. Cytoplasmic submicron uranium aggregates were observed accounting on average for 62% of the intracellular uranium content. In some aggregates, uranium and iron were co-localized suggesting common metabolic pathways between uranium and iron storage. Uranium aggregates contained no calcium or phosphorous indicating that detoxification mechanisms in neuron-like cells are different from those described in bone or kidney cells. Uranium intracellular distribution was compared to fluorescently labeled organelles (lysosomes, early and late endosomes) and to fetuin-A, a high affinity uranium-binding protein. A strict correlation could not be evidenced between uranium and the labelled organelles, or with vesicles containing fetuin-A. Our results indicate a new mechanism of uranium cytoplasmic aggregation after non-cytotoxic uranyl exposure that could be involved in neuronal defense through uranium sequestration into less reactive species. The remaining soluble fraction of uranium would be responsible for protein binding and the resulting neurotoxic effects.

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Section: Uranium Organelles and Fetuin-a Imagingsupporting

confidence: 78%

Cytoplasmic aggregation of uranium in human dopaminergic cells after continuous exposure to soluble uranyl at non-cytotoxic concentrations

et al. 2021

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“…Fetuin-A is expressed in the mature brain and may have a neuroprotective function in mature inflamed and ischemic human brains (Heinen et In SH-SY5Y cells we found that Alexa-488 labeled fetuin-A is internalized within cytoplasmic vesicles (Fig. 8A), similarly to the endocytosis of fluorescently labeled fetuin-A already described for other cells such as vascular smooth muscle cells (Reynolds et al, 2005;Chen et al, 2007), or murine macrophages (Wang et al, 2011). We investigated the hypothesis whether uranium could be colocalized with vesicles containing fetuin-A in SH-SY5Y cells.…”

Section: Uranium Organelles and Fetuin-a Imagingsupporting

confidence: 77%

Cytoplasmic aggregation of uranium in human dopaminergic cells after continuous exposure to soluble uranyl at non-cytotoxic concentrations

Carmona

Porcaro

Somogyì

et al. 2020

Preprint

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Uranium exposure can lead to neurobehavioral alterations in particular of the monoaminergic system, even at non-cytotoxic concentrations. However, the mechanisms of uranium neurotoxicity after non-cytotoxic exposure are still poorly understood. In particular, imaging uranium in neurons at low intracellular concentration is still very challenging. We investigated uranium intracellular localization by means of synchrotron X-ray fluorescence imaging with high spatial resolution (< 300 nm) and high analytical sensitivity (< 1 μg.g-1 per 300 nm pixel). Neuron-like SH-SY5Y human cells differentiated into a dopaminergic phenotype were continuously exposed, for seven days, to a non-cytotoxic concentration (10 μM) of soluble natural uranyl. Cytoplasmic submicron uranium aggregates were observed accounting on average for 62% of the intracellular uranium content. In some aggregates, uranium and iron were co-localized suggesting common metabolic pathways between uranium and iron storage. Uranium aggregates contained no calcium or phosphorous indicating that detoxification mechanisms in neuron-like cells are different from those described in bone or kidney cells. Uranium intracellular distribution was compared to fluorescently labeled organelles (lysosomes, early and late endosomes) and to fetuin-A, a high affinity uranium-binding protein. A strict correlation could not be evidenced between uranium and the labelled organelles, or with vesicles containing fetuin-A. Our results indicate a new mechanism of uranium cytoplasmic aggregation after non-cytotoxic uranyl exposure that could be involved in neuronal defense through uranium sequestration into less reactive species. The remaining soluble fraction of uranium would be responsible for protein binding and the resulting neurotoxic effects.

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“…Indeed, levels of fetuin-A in macrophage cultures was decreased by 40% after stimulation with LPS (100 ng/ml, 2 h). Supplementation of LPS-stimulated macrophages with fetuin-A (100 μg/ml) conversely elevated cellular fetuin-A levels by 30–50% [116], confirming the notion that macrophages can ‘adopt” fetuin-A from the environment [81]. Intriguingly, exogenously administered fetuin-A was predominantly localized in LC3-containing cytoplasmic vesicles - possibly autophagosomes or amphisomes - in LPS-stimulated macrophages [116].…”

Section: Fetuin-a As An Anti-inflammatory Proteinmentioning

confidence: 78%

“…Supplementation of LPS-stimulated macrophages with fetuin-A (100 μg/ml) conversely elevated cellular fetuin-A levels by 30–50% [116], confirming the notion that macrophages can ‘adopt” fetuin-A from the environment [81]. Intriguingly, exogenously administered fetuin-A was predominantly localized in LC3-containing cytoplasmic vesicles - possibly autophagosomes or amphisomes - in LPS-stimulated macrophages [116]. At higher concentrations (e.g., 3.5 mg/ml), even crude fetuin-A (> 98%) can almost completely abrogated endotoxin-induced release of IL-1 and nitric oxide in macrophage cultures [117].…”

Section: Fetuin-a As An Anti-inflammatory Proteinmentioning

confidence: 99%

Anti-Inflammatory Role of Fetuin-A in Injury and Infection

Wang

Sama²

2012

CMM

141

119

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Infection and injury are two seemingly unrelated processes that often converge on common innate inflammatory responses mediated by pathogen- or damage-associated molecular patterns (PAMPs or DAMPs). If dysregulated, an excessive inflammation manifested by the overproduction and release of proinflammatory mediators (e.g., TNF, IFN-γ, and HMGB1) may adversely lead to many pathogenic consequences. As a counter-regulatory mechanism, the liver strategically re-prioritizes the synthesis and systemic release of acute phase proteins (APP) including the fetuin-A (also termed alpha-2-HS-glycoprotein for the human homologue). Fetuin-A is divergently regulated by different proinflammatory mediators, and functions as a positive or negative APP in injury and infection. It not only facilitates anti-inflammatory actions of cationic polyamines (e.g., spermine), but also directly inhibits PAMP-induced HMGB1 release by innate immune cells. Peripheral administration of fetuin-A promotes a short-term reduction of cerebral ischemic injury, but confers a long-lasting protection against lethal endotoxemia. Furthermore, delayed administration of fetuin-A rescues mice from lethal sepsis even when the first dose is given 24 hours post the onset of disease. Collectively, these findings have reinforced an essential role for fetuin-A in counter-regulating injury- or infection-elicited inflammatory responses.

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Role of Fetuin-A in Injury and Infection

Cited by 5 publications

References 99 publications

Cytoplasmic aggregation of uranium in human dopaminergic cells after continuous exposure to soluble uranyl at non-cytotoxic concentrations

Cytoplasmic aggregation of uranium in human dopaminergic cells after continuous exposure to soluble uranyl at non-cytotoxic concentrations

Cytoplasmic aggregation of uranium in human dopaminergic cells after continuous exposure to soluble uranyl at non-cytotoxic concentrations

Anti-Inflammatory Role of Fetuin-A in Injury and Infection

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