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![Sirius red-stained healing skin. Diminished collagen formation and maturation in diabetes are restored to normal by NTX treatment. These figures demonstrate remodeling of full-thickness wounds created in T1D and normal rats as measured by collagen formation in the reticular dermis 20 days after wounding and treatment with NTX dissolved in moisturizing cream or cream alone (vehicle). Wounds from normal and T1D rats were treated three times daily with either 10⁻⁵ M NTX or sterile saline (vehicle) dissolved in moisturizing cream. (a) Low magnification (4x) photomicrographs of Sirius red birefringence of skin sections encompassing the full-thickness wound and peripheral unwounded skin; bar = 100 mm. (b) High magnification of collagen maturation in Sirius red-stained sections described in (a); bar = 25 mm. (c) Histograms of the percent collagen maturation analyzed by ImageJ at 20 days. Values represent means ± SEM. Significantly∗ different from normal + vehicle values at P<0.05; significantly++ different between T1D + vehicle and T1D + NTX at P<0.01 (derived from [66]).](publication/308124827/figure/fig38/AS:1086768946380819@1636117316154/Sirius-red-stained-healing-skin-Diminished-collagen-formation-and-maturation-in-diabetes.jpg)
Sirius red-stained healing skin. Diminished collagen formation and maturation in diabetes are restored to normal by NTX treatment. These figures demonstrate remodeling of full-thickness wounds created in T1D and normal rats as measured by collagen formation in the reticular dermis 20 days after wounding and treatment with NTX dissolved in moisturizing cream or cream alone (vehicle). Wounds from normal and T1D rats were treated three times daily with either 10⁻⁵ M NTX or sterile saline (vehicle) dissolved in moisturizing cream. (a) Low magnification (4x) photomicrographs of Sirius red birefringence of skin sections encompassing the full-thickness wound and peripheral unwounded skin; bar = 100 mm. (b) High magnification of collagen maturation in Sirius red-stained sections described in (a); bar = 25 mm. (c) Histograms of the percent collagen maturation analyzed by ImageJ at 20 days. Values represent means ± SEM. Significantly∗ different from normal + vehicle values at P<0.05; significantly++ different between T1D + vehicle and T1D + NTX at P<0.01 (derived from [66]).
Source publication
The Opioid Growth Regulatory System consists of opioid growth factor (OGF), [Met 5 ]-enkephalin, and its unique receptor (OGFr). OGF inhibits cell division when bound to OGFr. Conversely, blockade of the interaction of OGF and OGFr, using the potent, long-acting opioid receptor antagonist, naltrexone (NTX), results in increased DNA synthesis and ce...
Citations
... The genes with altered expression in diabetic corneas [180,181] coded for HGF receptor, c-Met, cathepsin F, proteinases and MMP-10. HGF/c-Met signaling performs an essential position in wound healing-related methods of telephone migration, proliferation, and apoptosis in a number of organ systems, such as the cornea [182][183][184]. Gene microarray evaluation confirmed that HGF used to be upregulated in diabetic corneas with downregulation of c-Met [181]. ...
... Another increase thing that modulates corneal epithelial wound recuperation is the OGF that acts as a poor regulator of epithelial proliferation [184]. Transfection of OGFr antisense the usage of gene gun into rat corneas after central corneal abrasion resulted in fewer epithelial defects and accelerated wound healing, whereas the experience OGFr assemble delayed recovery [83,84]. ...
This literature offers complete information about the advances in gene treatment in the of the eye, inclusive of cornea, conjunctiva, lacrimal gland, and trabecular meshwork. We talked about gene transport systems, collectively with viral and non-viral vectors as exact as gene modifying techniques, generally CRISPR-Cas9, and epigenetic treatments, consisting of antisense and siRNA therapeutics. We moreover furnish a specific assessment of gene treatment has been examined with corresponding outcomes. Disease stipulations embody corneal and conjunctival fibrosis and scarring, corneal epithelial wound healing, corneal graft survival, corneal neovascularization, genetic corneal dystrophies, herpetic keratitis, glaucoma, dry eye disease, and specific ocular surface diseases. Although most of the analyzed consequences on the use and validity of gene treatment at the ocular surface have been offered in vitro or the utilization of animal models, we moreover talked about the on hand human studies. Gene treatment methods are nowadays viewed very promising as rising future remedies of a variety of diseases, and this area is unexpectedly expanding.
... The financial burden of diabetes and the treatment of its complications are estimated to approach $327 billion in the United States by 2045 [4]. Diabetic ocular surface complications include diminished tear production, abnormalities in corneal sensitivity, and delayed corneal epithelial wound healing are chronic and often more debilitating that the disease itself [5][6][7]. These complications may result from alterations in the limbus. ...
... Located adjacent to the cornea, the limbus plays a role in the healing of the corneal surface by providing limbal epithelial stem cells that undergo mitosis and ultimately provide terminally differentiated corneal epithelial cells [8,9]. Interactions between the Opioid Growth Factor (OGF) -OGF receptor (OGFr) pathway and the cornea have been reported in diabetic animal models [5][6][7], but little is known about the effects of Diabetes Clin Res. 2023;5(1): 1-10. ...
Ocular surface complications occur in more than 50% of individuals diagnosed with diabetes. The financial and health-related burden of diabetes is increasing annually. Several major ocular complications associated with diabetes involve the limbus. The vascular limbus, adjacent to the avascular cornea, is the source of circulating growth factors, elevated glucose, and cytokines for the cornea. The Opioid Growth Factor (OGF) - Opioid OGF Receptor (OGFr) axis is comprised of its effector peptide, OGF, [Met5]-enkephalin and the nuclear-associated receptor, OGFr, and has been demonstrated to be dysfunctional in diabetes with elevated serum and tissue levels of the inhibitory growth factor OGF recorded in corneal tissue. Little is known regarding the impact of OGF-OGFr axis dysregulation in diabetes on the functioning of the limbus constituents in support of corneal homeostasis. Adult male and female Sprague-Dawley rats were rendered hyperglycemic through intraperitoneal injections of streptozotocin (T1D); a subset of T1D rats received topical naltrexone (NTX) applied to the cornea and limbus daily for 8 weeks. At 4 and/or 8 weeks of hyperglycemia, different cohorts of animals were euthanized, eyes removed and processed for assessment of limbal morphology, expression of OGF, OGFr, cytokeratin 15, a marker for limbal cells, and Ki-67, a marker of proliferation. Limbal epithelial morphology (cell diameter, packing density) was altered in T1D male and female rats. OGF and OGFr were overexpressed in the limbus and CK15 expression was decreased, relative to normal control rats of the same sex. Blockade of the OGF- OGFr axis with NTX reversed limbal epithelial cell defects, and reduced OGF limbal tissue levels to those recorded in non-diabetic rats. In summary, OGF-OGFr axis dysregulation was observed in the limbus of T1D rats, contributing to the altered limbal morphology and delayed corneal surface healing observed in diabetic animals.
... MENK and its receptors have been shown to be present in the corneas of various species, including humans, mice, rats, and rabbits, and MENK is derived in an autocrine manner [158]. Studies using explant cultures and in vivo models of epithelial wound healing in rabbit corneas have demonstrated that MENK suppresses wound healing, and exposure to opioid antagonists, such as naloxone or naltrexone, blocks this effect [555,567,568]. Corneal wound healing is inhibited in the presence of MENK because it acts as a negative growth factor to repress cell division, DNA synthesis, and cell migration [567]. These effects are exerted via opioid receptor signaling as they can be blocked by disrupting opioid-receptor interactions using opioid antagonists [569]. ...
... Suppresses corneal wound healing. [549,555,[561][562][563][564][565][566][567][568][569] Neurotensin Pro-and anti-inflammatory effects. Enhances chemotaxis and may stimulate or inhibit cytokine synthesis. ...
The transparency of the cornea along with its dense sensory innervation and resident leukocyte populations make it an ideal tissue to study interactions between the nervous and immune systems. The cornea is the most densely innervated tissue of the body and possesses both immune and vascular privilege, in part due to its unique repertoire of resident immune cells. Corneal nerves produce various neuropeptides that have a wide range of functions on immune cells. As research in this area expands, further insights are made into the role of neuropeptides and their immunomodulatory functions in the healthy and diseased cornea. Much remains to be known regarding the details of neuropeptide signaling and how it contributes to pathophysiology, which is likely due to complex interactions among neuropeptides, receptor isoform-specific signaling events, and the inflammatory microenvironment in disease. However, progress in this area has led to an increase in studies that have begun modulating neuropeptide activity for the treatment of corneal diseases with promising results, necessitating the need for a comprehensive review of the literature. This review focuses on the role of neuropeptides in maintaining the homeostasis of the ocular surface, alterations in disease settings, and the possible therapeutic potential of targeting these systems.
... Other routes which have recently been studied include Serpine 1 [35], which, when compared to controls, is significantly diminished in corneal epithelium collected from diabetic rats. In addition, opioid growth factor (OGF) [45,46], which is elevated in the plasma of patients with diabetes, acts as a negative regulator of epithelial proliferation and wound healing. When OGF joins to its specific receptor, OGFr, they are able to inhibit cell replication [46]. ...
... In addition, opioid growth factor (OGF) [45,46], which is elevated in the plasma of patients with diabetes, acts as a negative regulator of epithelial proliferation and wound healing. When OGF joins to its specific receptor, OGFr, they are able to inhibit cell replication [46]. Moreover, it has been observed that opioids antagonists such as naltrexone, which block the axis OGF-OGFr, favor cell replication and therefore tissue remodeling [45]. ...
In the last decade, we have witnessed substantial progress in our understanding of corneal biomechanics and architecture. It is well known that diabetes is a systemic metabolic disease that causes chronic progressive damage in the main organs of the human body, including the eyeball. Although the main and most widely recognized ocular effect of diabetes is on the retina, the structure of the cornea (the outermost and transparent tissue of the eye) can also be affected by the poor glycemic control characterizing diabetes. The different corneal structures (epithelium, stroma, and endothelium) are affected by specific complications of diabetes. The development of new noninvasive diagnostic technologies has provided a better understanding of corneal tissue modifications. The objective of this review is to describe the advances in the knowledge of the corneal alterations that diabetes can induce.
... Naltrexone is a long-acting and potent opioid antagonist that can block the interaction of OGF and its receptor OGFr. In both in vitro and in vivo studies, treatment with naltrexone could significantly facilitate DNA synthesis, cell division, cell migration, corneal epithelial wound healing, and corneal epithelium proliferation and growth (Sassani et al., 2016). Interestingly, the combined topical use of naltrexone and insulin has no additive or synergistic effect on corneal epithelial regeneration in T1D rats (Klocek et al., 2009). ...
Diabetes mellitus (DM) is a major global public health problem that can cause complications such as diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy. Besides the reporting of reduction in corneal nerve density and decrease in corneal sensitivity in diabetic patients, there may be a subsequent result in delayed corneal wound healing and increased corneal infections. Despite being a potential cause of blindness, these corneal nerve changes have not gained enough attention. It has been proposed that corneal nerve changes may be an indicator for diabetic neuropathy, which can provide a window for early diagnosis and treatment. In this review, the authors aimed to give an overview of the relationship between corneal nerves and diabetic neuropathy as well as the underlying pathophysiological mechanisms of corneal nerve fiber changes caused by DM for improved prediction and prevention of diabetic neuropathy. In addition, the authors summarized current and novel therapeutic methods for delayed corneal wound healing, nerve protection and regeneration in the diabetic cornea.
... The Opioid Growth Factor (OGF)-OGF receptor (OGFr) pathway is active in corneal tissues, where it functions to maintain epithelial homeostasis of the cornea (7)(8)(9). Blockade of the OGF-OGFr pathway using naltrexone (NTX), an opioid antagonist, reverses numerous ocular epithelial complications in individuals with type 1 (T1D) or type 2 diabetes, including delayed epithelial wound healing, abnormal corneal sensitivity and low tear production (10)(11)(12). OGF, which is chemically termed [Met 5 ]-enkephalin, is an endogenous pentapeptide that reduces cell replication, and its levels are elevated in diabetic humans (13)(14)(15) and animals (16). ...
... For comparison, female rats in the T1D, T1D-INS and non-diabetic control groups not receiving NTX were included. The dose of NTX was based on previous studies which are reviewed elsewhere (8), and was considered an effective dosage to ensure prolonged blockade of the OGF-OGFr axis. ...
... These findings extend and corroborate those of a previous study, which used a male diabetic animal model (16), and suggest that both male and female rats with hyperglycemia are vulnerable to the effects of a dysregulated OGF-OGFr pathway. Moreover, topically administered NTX is a safe and effective treatment modality (8,23), and based on the results of the present study, may also be an effective means of preventing and/or treating ocular surface complications associated with diabetes in female rats. ...
Approximately 4.5 million women in the United States exhibit diabetes-associated ocular complications. The time course and magnitude of these complications, and their association with the dysregulation of the opioid growth factor (OGF)-OGF receptor (OGFr) signaling pathway are unknown. The present study investigated the onset and magnitude of ocular surface complications and the association with a dysregulated OGF-OGFr signaling pathway in diabetic female rats. Adult female Sprague-Dawley rats were injected with streptozotocin in order to establish a model of type 1 diabetes (T1D), and a subset received insulin (T1D-INS). Blood glucose, body weight, tear production and corneal sensitivity, as well as serum and tissue expression levels of OGF and OGFr, were assessed. Corneal epithelial wound healing was also evaluated. In a second study, female T1D rats were treated with topical naltrexone (NTX) to determine whether blockade of the OGF-OGFr signaling pathway by NTX altered development of corneal surface complications. Female T1D rats had elevated glucose levels and reduced body weight compared with control and T1D-INS rats. In both diabetic groups, tear production was decreased within 2 weeks and corneal sensitivity was decreased 2.5-fold within 5 weeks, while corneal epithelial wound healing was delayed only in T1D rats. Serum and tissue levels of OGF and OGFr were elevated in diabetes. Twice daily NTX treatment reversed most ocular surface complications in the diabetic female rats. The present data demonstrated a seminal discovery in female T1D rats, in which the onset and magnitude of diabetes-associated ocular surface complications were associated with dysregulation of the OGF-OGFr regulatory pathway. Blockade of the OGF-OGFr pathway with the opioid receptor antagonist NTX prevented the onset and/or decreased the magnitude of these deficits. The current data support the need for translational research on this therapeutic approach for diabetic human subjects.
... Opioid growth factor (OGF), or [Met 5 ]-enkephalin, acting through its ζ receptor (OGFR) negatively regulates corneal epithelial proliferation and wound healing (Sassani et al. 2016). Levels of OGF are elevated in plasma of diabetic patients (McLaughlin et al. 2010). ...
... Naltrexone, a potent inhibitor of the OGF-OGFR interaction, is FDA approved for clinical treatment of alcohol and opioid dependence. In T1D and T2D mice and rats, topical naltrexone can normalize corneal epithelial wound healing, tear secretion, and corneal sensitivity/nerve function (Zagon et al. 2014Sassani et al. 2016). Unlike many other agents mediating cell migration, naltrexone acts by stimulating cell proliferation inhibited by diabetes-elevated OGF . ...
There is a number of systemic diseases affecting the cornea. These include endocrine disorders (diabetes, Graves' disease, Addison's disease, hyperparathyroidism), infections with viruses (SARS-CoV-2, herpes simplex, varicella zoster, HTLV-1, Epstein-Barr virus) and bacteria (tuberculosis, syphilis and Pseudomonas aeruginosa), autoimmune and inflammatory diseases (rheumatoid arthritis, Sjögren's syndrome, lupus erythematosus, gout, atopic and vernal keratoconjunctivitis, multiple sclerosis, granulomatosis with polyangiitis, sarcoidosis, Cogan's syndrome, immunobullous diseases), corneal deposit disorders (Wilson's disease, cystinosis Fabry disease, Meretoja's syndrome, mucopolysaccharidosis, hyperlipoproteinemia), and genetic disorders (aniridia, Ehlers-Danlos syndromes, Marfan syndrome). Corneal manifestations often provide an insight to underlying systemic diseases and can act as the first indicator of an undiagnosed systemic condition. Routine eye exams can bring attention to potentially life-threatening illnesses. In this review, we provide a fairly detailed overview of the pathologic changes in the cornea described in various systemic diseases and also discuss underlying molecular mechanisms, as well as current and emerging treatments.
... The OGF-OGFr axis functions to maintain cellular homeostasis, and OGF acts to inhibit DNA synthesis in tissues such as the corneal epithelium and other tissues [21]. Studies involving this growth regulatory pathway have shown that in rats, rabbits, and mice with diabetes is associated with decreased corneal epithelial turnover, delayed corneal abrasion repair, reduced tear production, and decreased corneal sensitivity [22]. Treatment of diabetic mice and rats with naltrexone, at dosages known to invoke complete receptor blockade, normalized epithelialization [13][14][15][16]18,19] and reversed dry eye [17][18][19]. ...
Background:
Diabetes is a worldwide epidemic with more than 550 million individuals expected to be diagnosed with the disease by 2030. Complications associated with diabetes affect nearly all systems, but more than 54% of diabetic individuals have ocular surface disorders including keratopathy, dry eye or altered corneal surface sensitivity, and nearly 70% experience slow healing foot ulcers which if left untreated, can lead to amputation. There is new information regarding the underlying pathophysiology associated with these complications, as well as potential treatment.
Aim:
This commentary assembles data on preclinical studies showing that corneal surface complications such as dry eye and sensitivity, as well as delayed epithelial wound healing in the cornea and skin in diabetic rats and mice, correlate with a dysregulation of the opioid growth factor (OGF)-opioid growth factor receptor (OGFr) regulatory axis. The peptide in this pathway, OGF, chemically termed [Met5]-enkephalin, is elevated in the serum of humans and animals with either type 1 or type 2 diabetes. The cause for this finding is unknown. However, there are studies that demonstrate that blockade of the interactions between OGF (or elevated levels of OGF) and its receptor can reverse and, in some cases, prevent the onset of diabetic corneal complications. Clinicians and healthcare workers need to recognize this fundamental pathophysiology leading to diabetic complications.
Summary:
Dysfunction of the OGF-OGFr growth regulatory system plays a role in the development of ocular surface complications and delayed cutaneous wound healing complications in multiple animal models of both Type 1 and Type 2 diabetes. Modulation of this system may hold promise for reversing or even preventing these diabetic complications in humans. Moreover, monitoring serum levels of OGF should be investigated as an indicator of the development of these and other diabetic complications.
... The findings from several decades of research on the cornea are summarized by Sassani et al. [20] and demonstrate that blockade of the OGF-OGFr regulatory pathway with naltrexone provides an effective and safe treatment for some ocular surface complications of diabetes [21][22][23][24][25][26]. Based on our knowledge that naltrexone blockade of the OGF-OGFr axis accelerates diabetic corneal epithelial healing in rats and mice, and the knowledge that human diabetics experience dry eye [4], our laboratory began to investigate restoration of tear production in normal rats [27 and rodent models of diabetes [26,28]. ...
Diabetes is a widespread autoimmune disorder that affects nearly 10% of the adult population in the United States. In addition to the primary disease, there are numerous complications associated with inflammation including abnormalities of the heart, visual system, and peripheral nervous system. More than half of the individuals with diabetes will have one or more ocular related complications such as dry eye disease (DED), keratopathy, or retinopathy. Research over the last 3 decades has focused on the role of the opioid growth factor - opioid growth factor receptor (OGF-OGFr) axis as a regulatory system that maintains homeostasis in corneal epithelialization and tear secretion. In diabetes, OGF appears to be dysregulated resulting in decreased cell replication and increased corneal surface sensitivity. Utilization of naltrexone as a topical therapeutic to block the OGF-OGFr axis results in reversal of dry eye and restoration of corneal sensitivity and rates of corneal re-epithelialization. Naltrexone treatment at dosages that are substantially lower than systemically approved doses appear to be safe and effective therapy for corneal surface abnormalities associated with diabetes.
... Naltrexone, an opioid antagonist, was shown to facilitate corneal epithelial wound healing and seems to be ready for clinical use owing to its safety and efficacy. 34,35 Down-regulation of signaling through the axis PI3K/Akt by neuronal PTEN restrains axon outgrowth and nerve regeneration in peripheral and central nervous systems. Many studies support the negative role of PTEN in nerve growth and regeneration ,which makes PTEN inhibitor as a feasible approach to revert neurologic damage under pathologic conditions. ...
Purpose:
To investigate the contribution of phosphatase and tensin homologue (PTEN) on the delayed epithelial regeneration and impaired Akt activation in diabetic mice.
Methods:
The expression of PTEN on cornea was compared between normal and diabetic mice. The corneal epithelial and nerve regeneration rate was evaluated in diabetic mice after the treatment with PTEN small interfering RNA (siRNA), PTEN inhibitors, or Akt inhibitor. The reactivation of epithelial regeneration-related signaling, including phosphorylated (p)-Akt, p-Stat3, Sirt1, and Parkin, were assessed with Western blot and immunofluorescence staining. The effects of PTEN inhibition on cellular proliferation and migration were further evaluated in cultured mouse corneal epithelial cells.
Results:
PTEN messenger RNA and protein levels exhibited up-regulation in diabetic cornea. Upon central epithelial debridement, the epithelial regeneration rate was significantly promoted in diabetic mice with the treatment of PTEN inhibition than that of vehicle control (P < 0.05), which accompanied with the recovered levels of p-Akt, p-Stat3, Sirt1, and Parkin. However, the promotion of diabetic corneal epithelial regeneration rate and Akt reactivation was completed reversed by Akt inhibitor. In vitro, PTEN inhibition promoted their migration, but not the proliferation capacity. In addition, PTEN inhibitor treatment also improved the recovery of corneal nerve fiber density and sensitivity that was impaired in diabetic mice.
Conclusions:
Elevated PTEN expression contributes to the impaired corneal epithelial regeneration and Akt activation in diabetic mice, which can be improved with PTEN inhibition.
Translational relevance:
Our study suggests that PTEN inhibition may serve as a new strategy for restoring the impaired corneal epithelial regeneration ability in patients with diabetes.
