Manganese (II) induces chemical hypoxia by inhibiting HIF-prolyl hydroxylase: Implication in manganese-induced pulmonary inflammation

Han, Jeongoh; Lee, Jong-Suk; Choi, Daekyu; Lee, You-Na; Hong, Sungchae; Choi, Jungyun; Han, Sang-oh; Ko, Young Jin; Kim, Jung-Ae; Kim, Young Mi

doi:10.1016/j.taap.2009.01.003

Cited by 29 publications

(23 citation statements)

References 33 publications

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“…However, the hypoxia-independent induction of HIF-1α expression has also been reported. For example, it has previously been shown that interleukin-1β (IL-1β), transforming growth factor-β1 (TGF-β1), insulin-like growth factor-1 (IGF-1) or certain heavy metals like manganese can induce the expression of HIF-1α under normoxic conditions (12)(13)(14)(15)(16)(17) and that the HIF-1α inducibility by these factors is largely dependent of activities of multiple intracellular signaling proteins, including protein kinase B (PKB), extracellular-regulated protein kinase-1/2 (ERK-1/2), p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase-1/2 (JNK-1/2), and/or nuclear factor-κB (NF-κB) (14)(15)(16)(17)(18). Little is known about the relationship between NFJ and HIF-1α expression.…”

Section: Introductionmentioning

confidence: 99%

The fruit juice of Morinda citrifolia (noni) downregulates HIF-1α protein expression through inhibition of PKB, ERK-1/2, JNK-1 and S6 in manganese-stimulated A549 human lung cancer cells

Jang

2011

Int J Mol Med

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Abstract. High exposure of manganese is suggested to be a risk factor for many lung diseases. Evidence suggests anticancerous and antiangiogenic effects by products derived from Morinda citrifolia (noni) fruit. In this study, we investigated the effect of noni fruit juice (NFJ) on the expression of HIF-1α, a tumor angiogenic transcription factor in manganese-chloride (manganese)-stimulated A549 human lung carcinoma cells. Treatment with manganese largely induced expression of HIF-1α protein but did not affect HIF-1α mRNA expression in A549 cells, suggesting the metal-mediated co-and/or post-translational HIF-1α upregulation. Manganese treatment also led to increased phosphorylation of extracellular-regulated protein kinase-1/2 (ERK-1/2), c-Jun N-terminal kinase-1 (JNK-1), protein kinase B (PKB), S6 and eukaryotic translation initiation factor-2α (eIF-2α) in A549 cells. Of note, the exposure of NFJ inhibited the manganese-induced HIF-1α protein upregulation in a concentration-dependent manner. Importantly, as assessed by results of pharmacological inhibition and siRNA transfection studies, the effect of NFJ on HIF-1α protein downregulation seemed to be largely associated with the ability of NFJ to interfere with the metal's signaling to activate PKB, ERK-1/2, JNK-1 and S6 in A549 cells. It was further shown that NFJ could repress the induction of HIF-1α protein by desferoxamine or interleukin-1β (IL-1β), another HIF-1α inducer in A549 cells. Thus, the present study provides the first evidence that NFJ has the ability to strongly downregulate manganese-induced HIF-1α protein expression in A549 human lung cancer cells, which may suggest the NFJ-mediated beneficial effects on lung pathologies in which manganese and HIF-1α overexpression play pathogenic roles.

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Section: Introductionmentioning

confidence: 99%

The fruit juice of Morinda citrifolia (noni) downregulates HIF-1α protein expression through inhibition of PKB, ERK-1/2, JNK-1 and S6 in manganese-stimulated A549 human lung cancer cells

Jang

2011

Int J Mol Med

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“…They further demonstrated that MnCl 2 treatment activated hypoxia-response element (HRE) reporter gene expression and increased the protein levels of Cap43, an HIF-1a responsive protein. Along the same lines, Han et al 94 showed that manganese inhibited HIF prolyl hydroxylase, an enzyme that leads to HIF inactivation, resulting in elevated expression of VEGF by an HIF-dependent manner. Manganese-mediated HIF induction was attenuated by iron supplementation, indicating a deleterious effect of manganese on iron homeostasis during pulmonary inflammation.…”

Section: Toxic Effects Of Manganese On Lung Epithelial Cellsmentioning

confidence: 92%

“…90 Nonetheless, several lines of evidence have revealed that manganese inhalation is associated with pulmonary inflammation 91 and its inflammatory potential is comparable to or greater than other transition metals. 92 Recent investigations have demonstrated that manganese promotes pulmonary toxicity by several mechanisms, including upregulation of hypoxia inducible factor (HIF) and vascular endothelial growth factor (VEGF), 93,94 inflammatory response in the small airway, 95 and induction of apoptosis. 96 Cyclooxygenase 2 (Cox-2), an inducible inflammatory enzyme, is involved in pathogenesis of lung inflammation mediated by manganese.…”

Section: Toxic Effects Of Manganese On Lung Epithelial Cellsmentioning

confidence: 99%

“…Manganese also transactivates HIF-1a, 94 which senses cellular oxygen availability and promotes erythropoiesis and angiogenesis. 100 While HIF-1a is induced by many stimuli, such as IL-1b, TGF-1b and IGF-1, Shin et al 101 demonstrated that its protein level was post-transcriptionally elevated upon MnCl 2 exposure in Hep2 laryngeal cells, but not in H292 bronchial or A549 lung cells.…”

Section: Toxic Effects Of Manganese On Lung Epithelial Cellsmentioning

confidence: 99%

“…Manganese-mediated HIF induction was attenuated by iron supplementation, indicating a deleterious effect of manganese on iron homeostasis during pulmonary inflammation. 94 In addition, manganese can induce VEGF expression independent of HIF activation based on the finding that deletion of the HRE from the VEGF promoter did not diminish manganese-induced promoter activity. 93 The concentration of manganese exposure may determine the degree of HIF dependency on VEGF induction.…”

Section: Toxic Effects Of Manganese On Lung Epithelial Cellsmentioning

confidence: 99%

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Manganese Transport Across the Pulmonary Epithelium

Thompson¹,

Kim²,

Wessling‐Resnick³

2014

Manganese in Health and Disease

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Our lungs represent a significant exposure site to airborne metals. Manganese and other metals enter the bloodstream from a variety of airborne sources across the pulmonary epithelium. Once absorbed, manganese can be taken up by other organ systems like the brain, where it is known to exert neurotoxic effects. Models of pulmonary manganese absorption have been developed based on known pathways of uptake across the intestinal epithelium, which are regulated by iron status. The sum of evidence suggests that additional and perhaps unique transport pathways are available to manganese in order to transit the pulmonary epithelium. Both in vitro and in vivo models have been established to characterize not only the transport but also toxicity of manganese on pulmonary epithelial cells. Handling of manganese by the lungs plays an important role in the inflammatory response, and has a strong influence on lung infection. These issues and emerging new questions are discussed in this chapter.

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The impact of environmental and occupational exposures of manganese on pulmonary, hepatic, and renal functions

Gandhi¹,

Rudrashetti

Rajasekaran³

2021

J of Applied Toxicology

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Manganese (Mn) is an essential trace element for humans, but long‐term environmental or occupational exposures can lead to numerous health problems. Although many studies have identified an association between Mn exposures and neurological abnormalities, emerging data suggest that occupationally and environmentally relevant levels of Mn may also be linked to multiple organ dysfunction in the general population. In this regard, many experimental and clinical studies provide support for a causal link between Mn exposure and structural and functional changes that are responsible for organ dysfunction in major organs like lung, liver, and kidney. The underlying mechanisms suggested to Mn toxicity include altered activities of the components of intracellular signaling cascades, oxidative stress, apoptosis, affected cell cycle regulation, autophagy, angiogenesis, and an inflammatory response. We further discussed the sources and possible mechanisms of Mn absorption and distribution in different organs. Finally, treatment strategies available for treating Mn toxicity as well as directions for future studies were discussed.

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Manganese (II) induces chemical hypoxia by inhibiting HIF-prolyl hydroxylase: Implication in manganese-induced pulmonary inflammation

Cited by 29 publications

References 33 publications

The fruit juice of Morinda citrifolia (noni) downregulates HIF-1α protein expression through inhibition of PKB, ERK-1/2, JNK-1 and S6 in manganese-stimulated A549 human lung cancer cells

The fruit juice of Morinda citrifolia (noni) downregulates HIF-1α protein expression through inhibition of PKB, ERK-1/2, JNK-1 and S6 in manganese-stimulated A549 human lung cancer cells

Manganese Transport Across the Pulmonary Epithelium

The impact of environmental and occupational exposures of manganese on pulmonary, hepatic, and renal functions

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