Novel 14,21-dihydroxy-docosahexaenoic acids: structures, formation pathways, and enhancement of wound healing

Lü, Yan; Tian, Haibin; Hong, Song

doi:10.1194/jlr.m000059

Cited by 62 publications

(98 citation statements)

References 40 publications

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“…Under the same conditions, 14R,21R-diHDHA and 14R,21S-diHDHA were generated from 14R-HDHA by h-P450. 8 14S-HDHA or 14S-HDHA-d 5 were prepared by incubating DHA or DHA-d 5 (50 g each), respectively, with porcine L-12-LOX (1000 U) in buffer containing 0.1 mol/L Tris at pH 7.4 for 20 minutes at 37°C. At the end of the incubation, 3 mg of NaBH 4 was added.…”

Section: Cell Culturesmentioning

confidence: 99%

“…Docosahexaenoic acid (DHA), an essential -3 fatty acid, is a relatively abun- dant, endogenous lipid component in blood and in wounded full-thickness skin. 8 Previous studies showed that DHA can ameliorate diabetes complications, such as cardiovascular disease, by improving endothelial function through anti-inflammatory mechanisms and reduced platelet aggregation, as well as by reducing blood triglyceride levels and increasing high-density lipoprotein cholesterol. 9 -11 DHA can also significantly promote wound healing by enhancing angiogenesis.…”

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confidence: 99%

“…The DHA-derived lipid mediator neuroprotectin D1 (NPD1; 10R,17S-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid) enhances corneal wound healing, 15 and 14S,21R-dihydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (14S,21R-diHDHA), a novel endogenous DHA-derived lipid mediator, is generated by macrophages and in wounded skin. 8,16 14S,21R-diHDHA is produced by sequential enzymatic actions of 14S-hydroperoxylation-specific leukocyte-12-lipoxygenase (L-12-LOX) and -1-hydroxylation-specific P450. 8 When applied to wounds, 14S,21R-diHDHA potently promotes healing and angiogenesis in wounds.…”

mentioning

confidence: 99%

“…8,16 14S,21R-diHDHA is produced by sequential enzymatic actions of 14S-hydroperoxylation-specific leukocyte-12-lipoxygenase (L-12-LOX) and -1-hydroxylation-specific P450. 8 When applied to wounds, 14S,21R-diHDHA potently promotes healing and angiogenesis in wounds. 8,16 Diabetes and the accompanying hyperglycemia and oxidative stress damage DNA, proteins, and lipids in various tissues.…”

mentioning

confidence: 99%

“…8 When applied to wounds, 14S,21R-diHDHA potently promotes healing and angiogenesis in wounds. 8,16 Diabetes and the accompanying hyperglycemia and oxidative stress damage DNA, proteins, and lipids in various tissues. These conditions cause cellular and enzymatic dysfunction during the formation of cytokines and eicosanoids associated with cell growth, angiogenesis, and/or inflammation, 4,7,[17][18][19] all of which are at least in part responsible for impairment of macrophage functions in diabetes.…”

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confidence: 99%

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Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

Tian

Lü

Shah

et al. 2011

The American Journal of Pathology

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Impaired macrophage functions imposed by diabetic complications and the suppressed formation of 14S, 2 1 R -d i h y d r o x y d o c o s a -4 Z , 7Z , 1 0 Z , 1 2 E , 1 6 Z , 19Z-hexaenoic acid (14S,21R-diHDHA) in wounds contribute significantly to deficient wound healing in diabetics, but how are macrophage functions and 14S,21R-diHDHA formation associated? We studied 14S,21R-diHDHA generation from macrophages using liquid chromatography/mass spectrometry. The role in macrophage-mediated wound healing functions was determined using a murine splinted excisional wound healing model and in vitro assays. 14S,21R-diHDHA acts as a macrophage-generated autacoid, and its attenuated formation in macrophages of diabetic db/db mice was accompanied by impairment of macrophage prohealing functions. 14S,21R-diHDHA restored db/db macrophage-impaired prohealing functions by promoting wound re-epithelialization, formulation of granulation tissue, and vascularization. Additionally, 12/15-lipoxygenase-deficient macrophages, which are unable to produce 14S,21R-diHDHA, exhibited impaired prohealing functions, which also were restored by 14S,21R-diHDHA treatment. The molecular mechanism for 14S,21R-diHDHA-induced recovery of impaired prohealing functions of db/db macrophages involves enhancing their secretion of vascular endothelial growth factor and platelet-derived growth factor BB, decreasing hyperglycemia-induced generation of reactive oxygen species, and increasing IL-10 expression under inflammatory stimulation. Taken together, these results indicate that deficiency of 14S,21R-diHDHA formation by diabetic macrophages contributes to their impaired prohealing functions. Our findings provide mechanistic insights into wound healing in diabetics and suggest the possibility of using autologous macrophages/monocytes, treated with 14S,21R-diHDHA, or related compounds, to promote diabetes-impaired wound healing. (Am J Pathol

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Section: Cell Culturesmentioning

confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

Tian

Lü

Shah

et al. 2011

The American Journal of Pathology

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Diets and Nutrition

Groetch

2013

Food Allergy

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Novel 14S,21‐dihydroxy‐docosahexaenoic acid rescues wound healing and associated angiogenesis impaired by acute ethanol intoxication/exposure

Tian

Lü

Shah

et al. 2010

J of Cellular Biochemistry

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Acute ethanol intoxication and exposure (AE) has been known to impair wound healing and associated angiogenesis. Here we found that AE diminished the formation of novel reparative lipid mediator 14S,21-dihydroxy-docosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (14S,21-diHDHA) and its biosynthetic intermediate 14S-hydroxy-DHA (14S-HDHA) from docosahexaenoic acid (DHA) in murine wounds. However, AE did not reduce the formation of DHA and the intermediate 21-HDHA. These results indicate that in the biosynthetic pathways of 14S,21-diHDHA in wounds, AE suppresses the 14S-hydroxy-generating activity of 12-lipoxygenase-like (LOX-like), but does not suppress the 21-hydroxy-generating activity of cytochrome P450 and DHA-generating activities. The AE-suppression of 12-LOX-like activity was further confirmed by the diminished formation of 12-hydroxy-eicosatetraenoic acid in wounds under AE. Supplementing 14S,21-diHDHA to wounds rescued the AE-impaired healing and vascularization. 14S,21-diHDHA restored AE-impaired processes of angiogenesis in vitro: endothelial cell migration, tubulogenesis, and phosphorylation of p38 mitogen-activated protein kinase (MAPK). Taken together, the suppression of 14S,21-diHDHA formation is responsible, at least partially, for the AE-impairment of cutaneous wound healing and angiogenesis. Supplementing 14S,21-diHDHA to compensate its deficit in AE-impaired wounds rescues the healing and angiogenesis. These results provide a novel mechanistic insight for AE-impaired wound healing that involves the necessary roles of 14S,21-diHDHA. They also offer leads for developing 14S,21-diHDHA-related therapeutics to ameliorate AE-impairment of wound healing.

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Novel 14,21-dihydroxy-docosahexaenoic acids: structures, formation pathways, and enhancement of wound healing

Cited by 62 publications

References 40 publications

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

Diets and Nutrition

Novel 14S,21‐dihydroxy‐docosahexaenoic acid rescues wound healing and associated angiogenesis impaired by acute ethanol intoxication/exposure

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