Recovery of Corneal Sensitivity and Increase in Nerve Density and Wound Healing in Diabetic Mice After PEDF Plus DHA Treatment

He, Jiucheng; Pham, Thang Luong; Kakazu, Azucena H; Bazán, Haydee E. P.

doi:10.2337/db17-0249

Cited by 59 publications

(76 citation statements)

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“…Identification of novel RvD6si in mouse tears. The biological activities of PEDF + DHA have been revealed previously by our laboratory [20][21][22][23][24] . A mechanistic link of PEDF + DHA action on corneal nerve regeneration has been uncovered with the activation of the iPLA2ζ and the increased expression of the neurotrophic factors, brain-derived growth factor (BDNF) and nerve growth factor (NGF), and the axon growth guidance semaphorin 7a (Sema7A) released in tears 25 .…”

Section: Resultsmentioning

confidence: 79%

“…Previous studies have shown that PEDF + DHA promotes corneal wound healing in rabbit 20,21 , and in normal and diabetic mice 24,25 after experimental surgery. We tested the ability of RvD6s (either RvD6 or RvD6si) in stimulating corneal wound healing.…”

Section: Rvd6si Enhances Corneal Wound Healing and Recovery Of Corneamentioning

confidence: 94%

“…Topical treatment of the neurotrophin pigment epithelium-derived factor (PEDF) plus the ω−3 fatty acid family member docosahexaenoic acid (DHA) enhances nerve regeneration and stimulates nerve regrowth in rabbit and mouse corneas after experimental surgery, as well as in pathologies like diabetes and herpes virus simplex (HSV1) infection [20][21][22][23][24] . Moreover, PEDF activates the Ca 2+ -independent phospholipase A2 (iPLA2ζ) activity of the PEDF receptor (PEDF-R) and releases DHA from membrane phospholipids that can be converted into bioactive docosanoids 25 , including neuroprotectin D1 (NPD1) that induces corneal nerve regeneration in a rabbit RvD6si is derived from DHA.…”

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confidence: 99%

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Novel RvD6 stereoisomer induces corneal nerve regeneration and wound healing post-injury by modulating trigeminal transcriptomic signature

Pham

Kakazu

et al. 2020

Sci Rep

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The high-density corneal innervation plays a pivotal role in sustaining the integrity of the ocular surface. We have previously demonstrated that pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA) promotes corneal nerve regeneration; here, we report the mechanism involved and the discovery of a stereospecific Resolvin D6-isomer (RvD6si) that drives the process. RvD6si promotes corneal wound healing and functional recovery by restoring corneal innervation after injury. RvD6si applied to the eye surface elicits a specific transcriptome signature in the trigeminal ganglion (TG) that includes Rictor, the rapamycin-insensitive complex-2 of mTOR (mTORC2), and genes involved in axon growth, whereas genes related to neuropathic pain are decreased. As a result, attenuation of ocular neuropathic pain and dry eye will take place. Thus, RvD6si opens up new therapeutic avenues for pathologies that affect corneal innervation.model of refractive surgery 20 . Herein, we report the discovery of a novel lipid mediator that is part of the signaling mechanism exerted by PEDF + DHA on the ocular surface. Furthermore, we uncovered that the TG genes sense corneal injury and respond to corneal stereospecific Resolvin D6-isomer (RvD6si) treatment with a specific transcriptomic signature. We demonstrate that the topical application of RvD6si is cornea protective, revealing novel mechanisms and potential therapeutic avenues for dry eye and ocular neuropathic pain. ResultsIdentification of novel RvD6si in mouse tears. The biological activities of PEDF + DHA have been revealed previously by our laboratory [20][21][22][23][24] . A mechanistic link of PEDF + DHA action on corneal nerve regeneration has been uncovered with the activation of the iPLA2ζ and the increased expression of the neurotrophic factors, brain-derived growth factor (BDNF) and nerve growth factor (NGF), and the axon growth guidance semaphorin 7a (Sema7A) released in tears 25 . To define which docosanoids are produced after the release of DHA by PEDF activation, mouse corneas were injured and treated, tears collected, and lipids extracted and analyzed by LC-MS/MS (Fig. 1A). The total ion chromatogram (TIC) of 359 m/z represented all di-hydroxy DHA isomers in tears after 4 h of treatment, and three peaks were well defined with retention times (RT) 8.20, 8.74, and 9.20 min (Fig. 1B). The internal standard LTB 4 -d4 (green) eluted at 8.25 min. We focused on the peak eluted at 8.20 min (Peak 1) that displays a parent ion 359 m/z upon full fragmentation, showing at least 6 matched product ions (daughter ions) compared to the RvD6 standard (Fig. 1C) with two hydroxy-groups at Carbon number 4 and 17 (Fig. 1D). When Peak 1 was co-injected with RvD6 at the same concentration, Peak 1 eluted 0.27 min earlier than RvD6 at 6 major multiple reaction monitoring (MRM) channels 359 −> 297, 279, 239, 199, 159, and 101 (Fig. 1E). The UV spectra for Peak 1 and RvD6 showed maxima absorbance (λ max ) at 238 nm, revealing that both compounds have a conjugated diene structure (...

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Section: Resultsmentioning

confidence: 79%

Section: Rvd6si Enhances Corneal Wound Healing and Recovery Of Corneamentioning

confidence: 94%

mentioning

confidence: 99%

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Novel RvD6 stereoisomer induces corneal nerve regeneration and wound healing post-injury by modulating trigeminal transcriptomic signature

Pham

Kakazu

et al. 2020

Sci Rep

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“…Cats often suffer from herpetic keratitis, an ocular surface disease known to damage corneal nerves . Our previous studies have shown in rabbits and mice that topical treatment with a combination of the neurotrophic factor pigment epithelium‐derived factor (PEDF) and the omega‐3 fatty acid docosahexaenoic acid (DHA) stimulates the nerve regeneration after refractive surgery, diabetes, and herpesvirus‐1 infection . Recent studies to uncover the mechanism show an activation of the PEDF receptor that enhances the synthesis of docosanoids and neurotrophins .…”

Section: Discussionmentioning

confidence: 99%

“…19,33,34 Our previous studies have shown in rabbits and mice that topical treatment with a combination of the neurotrophic factor pigment epithelium-derived factor (PEDF) and the omega-3 fatty acid docosahexaenoic acid (DHA) stimulates the nerve regeneration after refractive surgery, diabetes, and herpesvirus-1 infection. [35][36][37] Recent studies to uncover the mechanism show an activation of the PEDF receptor that enhances the synthesis of docosanoids and neurotrophins. 38 While there are no studies on cat herpetic keratitis, this could represent an important future treatment to improve regeneration of nerves damaged by this disease.…”

Section: Discussionmentioning

confidence: 99%

Mapping the entire nerve architecture of the cat cornea

Pham

Bazán

2019

Veterinary Ophthalmology

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Objective To provide a complete nerve architecture and neuropeptide distribution in the cat cornea. Animals studied Two adult domestic cats. Procedure The cat corneas were stained with protein gene product (PGP) 9.5 antibody—a pan marker for nerve fibers—and then divided into four quarters and double labeled with calcitonin gene‐related peptide (CGRP) or substance P (SP) antibodies. Relative corneal nerve fiber densities and nerve terminals were evaluated in whole mount images by computer‐assisted analysis. Results An average of 21.5 ± 2.1 thick stromal nerves enters the cornea around the limbus where they split into many branches going up to the anterior stroma. Some branches link to each other, but most of them penetrate the basement membrane in the periphery to give origin to subbasal bundles, which run centripetally and merge to form a whirl‐like structure (vortex) at the center. These nerve bundles send out many fine terminals that innervate the epithelial cells. Subbasal nerve density and nerve terminals were greater in the center than in the periphery of the cornea. Additionally, CGRP‐positive central epithelial nerve fibers and terminals were more abundant than SP‐positive nerves and terminals. Conclusion The architecture of cat corneal nerves shows similarities to human and mouse cornea innervation. This study provides useful data for researchers who use the cat model to assess corneal nerve pathological alterations, as well as in the veterinary field where corneal opacities, ulcerations, and infections damage the nerves and decrease sensitivity.

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Docosahexaenoic acid (DHA) alleviates inflammation and damage induced by experimental colitis

Ariturk,

Cilingir,

Kolgazi

et al. 2024

Eur J Nutr

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Purpose Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic gastrointestinal disorders associated with significant morbidity and complications. This study investigates the therapeutic potential of docosahexaenoic acid (DHA) in a trinitrobenzene sulfonic acid (TNBS) induced colitis model, focusing on inflammation, oxidative stress, and intestinal membrane permeability. Methods Wistar albino rats were divided into Control, Colitis, and Colitis + DHA groups (n = 8–10/group). The Colitis and Colitis + DHA groups received TNBS intrarectally, while the Control group received saline. DHA (600 mg/kg/day) or saline was administered via gavage for six weeks. Macroscopic and microscopic evaluations of colon tissues were conducted. Parameters including occludin and ZO-1 expressions, myeloperoxidase (MPO) activity, malondialdehyde (MDA), glutathione (GSH), total antioxidant status (TAS), total oxidant status (TOS), Interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) levels were measured in colon tissues. Results Colitis induction led to significantly higher macroscopic and microscopic damage scores, elevated TOS levels, reduced occludin and ZO-1 intensity, decreased mucosal thickness, and TAS levels compared to the Control group (p < 0.001). DHA administration significantly ameliorated these parameters (p < 0.001). MPO, MDA, TNF-α, and IL-6 levels were elevated in the Colitis group but significantly reduced in the DHA-treated group (p < 0.001 for MPO, MDA; p < 0.05 for TNF-α and IL-6). Conclusion DHA demonstrated antioxidant and anti-inflammatory effects by reducing reactive oxygen species production, enhancing TAS capacity, preserving GSH content, decreasing proinflammatory cytokine levels, preventing neutrophil infiltration, reducing shedding in colon epithelium, and improving gland structure and mucosal membrane integrity. DHA also upregulated the expressions of occludin and ZO-1, critical for barrier function. Thus, DHA administration may offer a therapeutic strategy or supplement to mitigate colitis-induced adverse effects.

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Recovery of Corneal Sensitivity and Increase in Nerve Density and Wound Healing in Diabetic Mice After PEDF Plus DHA Treatment

Cited by 59 publications

References 53 publications

Novel RvD6 stereoisomer induces corneal nerve regeneration and wound healing post-injury by modulating trigeminal transcriptomic signature

Novel RvD6 stereoisomer induces corneal nerve regeneration and wound healing post-injury by modulating trigeminal transcriptomic signature

Mapping the entire nerve architecture of the cat cornea

Docosahexaenoic acid (DHA) alleviates inflammation and damage induced by experimental colitis

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