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Role of the lipoperoxidation product 4-hydroxynonenal in the pathogenesis of severe malaria anemia and malaria immunodepression.

Schwarzer E, Arese P, Skorokhod OA - Oxid Med Cell Longev (2015)

Bottom Line: Complications are associated with oxidative stress and lipoperoxidation.Its final product 4-hydroxynonenal (4-HNE), a stable yet very reactive and diffusible molecule, forms covalent conjugates with proteins, DNA, and phospholipids and modulates important cell functions at very low concentrations.Data from other diseases qualify 4-HNE both as oxidative stress marker and as pathomechanistically important molecule.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, University of Torino, Via Santena 5 Bis, 10126 Torino, Italy.

ABSTRACT
Oxidative stress plays an important role in the pathogenesis of falciparum malaria, a disease still claiming close to 1 million deaths and 200 million new cases per year. Most frequent complications are severe anemia, cerebral malaria, and immunodepression, the latter being constantly present in all forms of malaria. Complications are associated with oxidative stress and lipoperoxidation. Its final product 4-hydroxynonenal (4-HNE), a stable yet very reactive and diffusible molecule, forms covalent conjugates with proteins, DNA, and phospholipids and modulates important cell functions at very low concentrations. Since oxidative stress plays important roles in the pathogenesis of severe malaria, it appears important to explore the role of 4-HNE in two important malaria complications such as malaria anemia and malaria immunodepression where oxidative stress is considered to be involved. In this review we will summarize data about 4-HNE chemistry, its biologically relevant chemical properties, and its role as regulator of physiologic processes and as pathogenic factor. We will review studies documenting the role of 4-HNE in severe malaria with emphasis on malaria anemia and immunodepression. Data from other diseases qualify 4-HNE both as oxidative stress marker and as pathomechanistically important molecule. Further studies are needed to establish 4-HNE as accepted pathogenic factor in severe malaria.

No MeSH data available.


Related in: MedlinePlus

The formation of 4-HNE from arachidonic acid by lipid peroxidation, chain break, and hydroxylation. In malaria, it was shown that the heme core of hemozoin (HZ, malaria pigment) could catalyze the lipoperoxidation of PUFAs. Resulting hydroperoxides are chemically unstable: they (i) are reduced to the hydroxy-fatty acid such as hydroxyeicosatetraenoic acid (HETE) from arachidonic (note, HETEs are bioactive PPAR-γ (peroxisome proliferator-activated receptor gamma) ligands) or (ii) are decomposed to 4-HNE. C1 and C3 are 4-HNE reactive sites. Biologically relevant properties of 4-HNE are listed in blue.
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fig2: The formation of 4-HNE from arachidonic acid by lipid peroxidation, chain break, and hydroxylation. In malaria, it was shown that the heme core of hemozoin (HZ, malaria pigment) could catalyze the lipoperoxidation of PUFAs. Resulting hydroperoxides are chemically unstable: they (i) are reduced to the hydroxy-fatty acid such as hydroxyeicosatetraenoic acid (HETE) from arachidonic (note, HETEs are bioactive PPAR-γ (peroxisome proliferator-activated receptor gamma) ligands) or (ii) are decomposed to 4-HNE. C1 and C3 are 4-HNE reactive sites. Biologically relevant properties of 4-HNE are listed in blue.

Mentions: Thanks to their unpaired electron, free radicals are highly reactive compounds. One of the most reactive representatives of oxygen radicals is the hydroxyl radical (•OH) that is able to initiate the peroxidation process by hydrogen abstraction from a C-atom positioned between two conjugated double bonds in PUFAs (Figure 2). Similarly, iron (Fe2+/Fe3+) can act as a catalyst for this step and produce additional hydroxyl radicals. The result of hydrogen abstraction is a PUFA radical which binds molecular oxygen, becoming highly reactive peroxide that propagates the peroxidation chain reaction by “stealing” hydrogen from a further PUFA to become a PUFA hydroperoxide (PUFA-OOH). The newly formed PUFA radical may continue the peroxidation chain reaction. Similar to free iron, iron-containing heme is a highly efficient catalyst and accelerates substantially the lipoperoxidation process. The peroxidized PUFA rearranges the hydroperoxy group within the molecule (Hock rearrangement [13]), and the bond between carbons 9 and 10 of the fatty acid chain is destabilized and breaks up. The so-called Hock cleavage splits the peroxidized PUFA molecule between the C11 and C12 carbon atoms (in case of arachidonic acid) and the rearranged peroxy-group and releases the aldehyde nonenal and the oxidized residual 11-C fatty acid. Nonenal consists of the last 9 carbons of the omega-6 fatty acid. A further peroxidation with hydrogen abstraction and oxygen binding occurs at position 4 and the resulting 4-hydroperoxynonenal is finally reduced to 4-HNE. All reactions may run efficiently without enzyme catalysis and are enhanced by heme.


Role of the lipoperoxidation product 4-hydroxynonenal in the pathogenesis of severe malaria anemia and malaria immunodepression.

Schwarzer E, Arese P, Skorokhod OA - Oxid Med Cell Longev (2015)

The formation of 4-HNE from arachidonic acid by lipid peroxidation, chain break, and hydroxylation. In malaria, it was shown that the heme core of hemozoin (HZ, malaria pigment) could catalyze the lipoperoxidation of PUFAs. Resulting hydroperoxides are chemically unstable: they (i) are reduced to the hydroxy-fatty acid such as hydroxyeicosatetraenoic acid (HETE) from arachidonic (note, HETEs are bioactive PPAR-γ (peroxisome proliferator-activated receptor gamma) ligands) or (ii) are decomposed to 4-HNE. C1 and C3 are 4-HNE reactive sites. Biologically relevant properties of 4-HNE are listed in blue.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4417603&req=5

fig2: The formation of 4-HNE from arachidonic acid by lipid peroxidation, chain break, and hydroxylation. In malaria, it was shown that the heme core of hemozoin (HZ, malaria pigment) could catalyze the lipoperoxidation of PUFAs. Resulting hydroperoxides are chemically unstable: they (i) are reduced to the hydroxy-fatty acid such as hydroxyeicosatetraenoic acid (HETE) from arachidonic (note, HETEs are bioactive PPAR-γ (peroxisome proliferator-activated receptor gamma) ligands) or (ii) are decomposed to 4-HNE. C1 and C3 are 4-HNE reactive sites. Biologically relevant properties of 4-HNE are listed in blue.
Mentions: Thanks to their unpaired electron, free radicals are highly reactive compounds. One of the most reactive representatives of oxygen radicals is the hydroxyl radical (•OH) that is able to initiate the peroxidation process by hydrogen abstraction from a C-atom positioned between two conjugated double bonds in PUFAs (Figure 2). Similarly, iron (Fe2+/Fe3+) can act as a catalyst for this step and produce additional hydroxyl radicals. The result of hydrogen abstraction is a PUFA radical which binds molecular oxygen, becoming highly reactive peroxide that propagates the peroxidation chain reaction by “stealing” hydrogen from a further PUFA to become a PUFA hydroperoxide (PUFA-OOH). The newly formed PUFA radical may continue the peroxidation chain reaction. Similar to free iron, iron-containing heme is a highly efficient catalyst and accelerates substantially the lipoperoxidation process. The peroxidized PUFA rearranges the hydroperoxy group within the molecule (Hock rearrangement [13]), and the bond between carbons 9 and 10 of the fatty acid chain is destabilized and breaks up. The so-called Hock cleavage splits the peroxidized PUFA molecule between the C11 and C12 carbon atoms (in case of arachidonic acid) and the rearranged peroxy-group and releases the aldehyde nonenal and the oxidized residual 11-C fatty acid. Nonenal consists of the last 9 carbons of the omega-6 fatty acid. A further peroxidation with hydrogen abstraction and oxygen binding occurs at position 4 and the resulting 4-hydroperoxynonenal is finally reduced to 4-HNE. All reactions may run efficiently without enzyme catalysis and are enhanced by heme.

Bottom Line: Complications are associated with oxidative stress and lipoperoxidation.Its final product 4-hydroxynonenal (4-HNE), a stable yet very reactive and diffusible molecule, forms covalent conjugates with proteins, DNA, and phospholipids and modulates important cell functions at very low concentrations.Data from other diseases qualify 4-HNE both as oxidative stress marker and as pathomechanistically important molecule.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, University of Torino, Via Santena 5 Bis, 10126 Torino, Italy.

ABSTRACT
Oxidative stress plays an important role in the pathogenesis of falciparum malaria, a disease still claiming close to 1 million deaths and 200 million new cases per year. Most frequent complications are severe anemia, cerebral malaria, and immunodepression, the latter being constantly present in all forms of malaria. Complications are associated with oxidative stress and lipoperoxidation. Its final product 4-hydroxynonenal (4-HNE), a stable yet very reactive and diffusible molecule, forms covalent conjugates with proteins, DNA, and phospholipids and modulates important cell functions at very low concentrations. Since oxidative stress plays important roles in the pathogenesis of severe malaria, it appears important to explore the role of 4-HNE in two important malaria complications such as malaria anemia and malaria immunodepression where oxidative stress is considered to be involved. In this review we will summarize data about 4-HNE chemistry, its biologically relevant chemical properties, and its role as regulator of physiologic processes and as pathogenic factor. We will review studies documenting the role of 4-HNE in severe malaria with emphasis on malaria anemia and immunodepression. Data from other diseases qualify 4-HNE both as oxidative stress marker and as pathomechanistically important molecule. Further studies are needed to establish 4-HNE as accepted pathogenic factor in severe malaria.

No MeSH data available.


Related in: MedlinePlus