Blockade of OGFr delays the onset and reduces the severity of diabetic ocular surface complications

The opioid growth factor (OGF)–OGF receptor (OGFr) pathway is present in the ocular surface and functions to maintain homeostasis of the epithelium. The OGF–OGFr pathway has been reported to be dysregulated in diabetic individuals and animal models, and is reflected in elevations of the inhibitory growth factor, OGF, chemically termed [Met5]-enkephalin. Recently, our laboratory reported elevated levels of OGF and OGFr in the serum and corneal epithelium of type 1 diabetic rats, suggesting that dysregulation of the OGF–OGFr axis may lead to dry eye, abnormal corneal surface sensitivity, and delayed re-epithelialization. Blockade of OGF–OGFr pathway using naltrexone, a potent opioid receptor antagonist, reverses dry eye symptoms and restores corneal surface sensitivity in diabetic rats when used as a therapy. Based on the evidence that both OGF and OGFr are elevated in type 1 diabetic rats, this study examined whether systemic or topical naltrexone treatment initiated at the time of induction of hyperglycemia could protect against the development of diabetic ocular surface complications. Diabetic male Sprague-Dawley rats treated systemically or topically with naltrexone had a delayed onset of dry eye and altered corneal surface sensitivity, and an improved healing rate for corneal wounds, that were comparable to non-diabetic rats. Serum levels of OGF were normal for rats receiving systemic naltrexone, and OGF tissue levels were normal for type 1 diabetic rats receiving twice daily naltrexone drops. OGFr levels remained elevated. These data support the role of the OGF–OGFr axis in regulation of ocular surface complications, and suggest that naltrexone therapy may be beneficial for pre-diabetic and early diabetic individuals.

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Dysregulation of the OGF–OGFr pathway correlates with elevated serum OGF and ocular surface complications in the diabetic rat

Experimental Biology and Medicine ◽

10.1177/1535370220940273 ◽

2020 ◽

Vol 245 (15) ◽

pp. 1414-1421 ◽

Cited By ~ 1

Author(s):

Ian S Zagon ◽

Joseph W Sassani ◽

Indira Purushothaman ◽

Patricia J McLaughlin

Keyword(s):

Type 1 Diabetes ◽

Growth Factor ◽

Dry Eye ◽

Ocular Surface ◽

Surface Defects ◽

Serum Levels ◽

Male Rats ◽

Corneal Surface ◽

Surface Sensitivity

Diabetes often presents with ocular surface complications including dry eye, keratopathy, and altered sensitivity, along with systemic disorders. A common theme associated with corneal surface defects is decreased cellular proliferation. The opioid growth factor (OGF)–OGF receptor (OGFr) regulatory axis maintains epithelial homeostasis and can be modulated by naltrexone, an opioid receptor antagonist, to block OGF–OGFr interaction and increase cellular replication. Complete blockade using naltrexone accelerates cell proliferation, increases the rate of re-epithelialization in corneal surface abrasions, reverses dry eye, and restores corneal surface sensitivity in animal models of type 1 and type 2 diabetes. Data on the efficacy of naltrexone in these models suggest that the OGF–OGFr axis is dysregulated in diabetes. In the present study, we investigated the OGF–OGFr axis by assessing serum and tissue levels of OGF and OGFr during the development of streptozotocin-induced hyperglycemia and postulated a mechanism of action. We correlated the dysregulation of the OGF–OGFr axis with the onset and magnitude of corneal surface complications (e.g. tear fluid production, corneal surface sensitivity) in type 1 diabetes (T1D). Serum levels of OGF increased in both uncontrolled T1D and insulin-controlled (T1D-INS) male rats within four weeks of streptozotocin injection. Serum OGFr levels were significantly reduced in diabetic rats on weeks 3 and 8 post streptozotocin. Tear production was significantly reduced, and corneal sensitivity measurements were abnormal in both T1D and T1D-INS animals within four weeks of streptozotocin. Corneal re-epithelialization was delayed in T1D rats, but not in T1D-INS animals; however, expression levels of the inhibitory growth factor OGF and its receptor, OGFr, were elevated in the corneal epithelium more than 2-fold in both diabetic groups. These data demonstrate for the first time that dysregulation of the OGF–OGFr axis in the diabetic cornea is associated with the onset and magnitude of ocular surface complications. Impact statement This research extends our knowledge about the presence and role of the OGF–OGFr regulatory axis in type 1 diabetes (T1D) and demonstrates specific targets within the pathway that are dysregulated. Serum levels of OGF, an inhibitory growth factor, are significantly elevated in male T1D rats, and OGFr serum values are increased in T1D. The onset of elevated OGF corresponds to the onset of ocular surface complications including dry eye, delayed corneal epithelial repair, and abnormal corneal surface sensitivity in T1D. Systemic insulin does not protect against elevated OGF levels or the onset of dry eye and sensitivity. These data are the first to associate some ocular surface defects in T1D with alterations in the OGF–OGFr pathway.

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Nicotine Exposure Exacerbates Development of Cataracts in a Type 1 Diabetic Rat Model

Experimental Diabetes Research ◽

10.1155/2012/349320 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Nima Tirgan ◽

Gabriela A. Kulp ◽

Praveena Gupta ◽

Adam Boretsky ◽

Tomasz A. Wiraszka ◽

...

Keyword(s):

Rat Model ◽

Serum Levels ◽

Diabetic Rats ◽

Diabetic Rat ◽

Positive Trend ◽

Sprague Dawley ◽

Nicotine Treatment ◽

Sprague Dawley Rats ◽

Diabetic Rat Model

Diabetes and smoking are known risk factors for cataract development. In this study, we evaluated the effect of nicotine on the progression of cataracts in a type 1 diabetic rat model. Diabetes was induced in Sprague-Dawley rats by a single injection of 65 mg/kg streptozotocin. Daily nicotine injections were administered subcutaneously. Forty-five rats were divided into groups of diabetics with and without nicotine treatment and controls with and without nicotine treatment. Progression of lens opacity was monitored using a slit lamp biomicroscope and scores were assigned. To assess whether systemic inflammation played a role in mediating cataractogenesis, we studied serum levels of eotaxin, IL-6, and IL-4. The levels of the measured cytokines increased significantly in nicotine-treated and untreated diabetic animals versus controls and demonstrated a positive trend in the nicotine-treated diabetic rats. Our data suggest the presence of a synergistic relationship between nicotine and diabetes that accelerated cataract formation via inflammatory mediators.

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CLINICAL AND HISTOPATHOLOGICAL FEATURES OF SCOPOLAMINE HYDROBROMIDE INDUCED DRY EYE SYNDROME IN SPRAGUE-DAWLEY RATS

Taiwan Veterinary Journal ◽

10.1142/s1682648520500134 ◽

2021 ◽

pp. 1-8

Author(s):

Sze-Min Chan ◽

Hui-Wen Chang ◽

Pei-Shiue Tsai ◽

Chian-Ren Jeng ◽

Hao Lee ◽

...

Keyword(s):

Dry Eye ◽

Histopathological Examination ◽

Tear Film ◽

Dry Eye Syndrome ◽

Therapeutic Interventions ◽

Sprague Dawley ◽

Corneal Surface ◽

Fluorescein Staining ◽

Scopolamine Hydrobromide ◽

Volume Assessment

Dry eye syndrome (DES), is one of the most common and irritating ocular diseases in humans and animals due to deficits in quantities or/and quality of tear film. In this study, a rat model of experimental DES has been developed using the cholinergic inhibitor, scopolamine hydrobromide (SCOP), at the dose of 25[Formula: see text]mg/rat/day via subcutaneous injection, for a consecutive 21 days without low humidity environment. Clinical ophthalmic evaluations were performed by tear volume assessment using endodontic paper point, slit-lamp biomicroscope, and fluorescein staining at day 0, 7, 14, and 21 post-inductions. The results of ophthalmic examination showed that rats with SCOP treatment reduced about 40% of tear secretion. Half of the SCOP-treated rats exhibited diffuse corneal fluorescein staining involving 80% of the corneal surface, minimal keratoconjunctivitis, roughened corneal surface and thin corneal epithelium under histopathological examination. About 30% of the rats showed variable infiltration of lymphocytes in between the tubular acinar glands. This animal model with significant reduction of tear production and diffuse corneal fluorescein staining in rats could be used for the preclinical assessment of therapeutic interventions.

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Des(1–3)IGF-1 Treatment Normalizes Type 1 IGF Receptor and Phospho-Akt (Thr 308) Immunoreactivity in Predegenerative Retina of Diabetic Rats

Experimental Diabesity Research ◽

10.1080/15438600303729 ◽

2003 ◽

Vol 4 (1) ◽

pp. 45-57 ◽

Cited By ~ 8

Author(s):

A. Kummer ◽

B. E. Pulford ◽

D. N. Ishii ◽

G. M. Seigel

Keyword(s):

Growth Factor ◽

Ganglion Cell Layer ◽

Systemic Treatment ◽

Diabetic Rats ◽

Vascular Endothelial ◽

Diabetic Retina ◽

Igf Receptor ◽

Endothelial Growth Factor ◽

Biochemical Abnormalities

Little is known about interventions that may prevent predegenerative changes in the diabetic retina. This study tested the hypothesis that immediate, systemic treatment with an insulin-like growth factor (IGF)-1 analog can prevent abnormal accumulations of type 1 IGF receptor, and phospho-Akt (Thr 308) immunoreactivity in predegenerative retinas of streptozotocin (STZ) diabetic rats. Type 1 IGF receptor immunoreactivity increased approximately 3-fold in both inner nuclear layer (INL) and ganglion cell layer (GCL) in retinas from STZ rats versus nondiabetic controls. Phospho-Akt (Thr 308) immunoreactivity increased 5-fold in GCL and 8-fold in INL of STZ rat retinas. In all cases, immunoreactive cells were significantly reduced in STZ des(1–3)IGF-1–treated versus STZ rats. Preliminary results suggested that vascular endothelial growth factor (VEGF) levels may also be reduced. Hyperglycemia/ failure of weight gain in diabetic rats continued despite systemic des(1–3)IGF-1. These data show that an IGF-1 analog can prevent early retinal biochemical abnormalities implicated in the progression of diabetic retinopathy, despite ongoing hyperglycemia.

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Berberine in Combination with Insulin Has Additive Effects on Titanium Implants Osseointegration in Diabetes Mellitus Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2015/824259 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 8

Author(s):

Li Lu ◽

Huang Zhijian ◽

Li Lei ◽

Chen Wenchuan ◽

Zhu Zhimin

Keyword(s):

Combined Treatment ◽

Insulin Injection ◽

Serum Levels ◽

Diabetic Rats ◽

Titanium Implants ◽

Sprague Dawley ◽

Machined Surface ◽

Double Labeling ◽

The Right ◽

Cp Ti

This study evaluated the effects of berberine in combination with insulin on early osseointegration of implants in diabetic rats. Fifty male Sprague-Dawley rats were randomly divided into 5 groups: healthy rats were used as control (HC), and streptozotocin-induced diabetic rats were treated with insulin, berberine, berberine + insulin (IB), or no treatment. Each rat received one machined-surface cp-Ti implant into the right tibia and was given insulin injection and/or gavage feeding with berberine daily for 8 weeks until being sacrificed. Serum levels of alkaline phosphatase (ALP) and bone gamma-carboxyglutamic acid-containing protein (BGP) were analyzed in each group. Peri-implant mineral apposition was marked by fluorochrome double-labeling and osseointegration was histomorphologically examined. The ALP and BGP levels decreased in diabetic rats but were successfully corrected by insulin and berberine combined treatment. Moreover, untreated diabetic rats had less labeled mineral apposition and impaired osseointegration. In contrast, Groups I, B, and IB were observed with increased peri-implant bone formation. The combination treatment of insulin and berberine was more effective than each administrated as a monotherapy. These results suggest that berberine combined with insulin could promote osseointegration in diabetic rats, thereby highlighting its potential application to patients, though further studies are needed.

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C-Reactive protein and insulin growth factor 1 serum levels during the menstrual cycle in adolescents with Type 1 diabetes

Diabetic Medicine ◽

10.1111/dme.12829 ◽

2015 ◽

Vol 33 (1) ◽

pp. 70-76 ◽

Cited By ~ 1

Author(s):

E. Codner ◽

P. M. Merino ◽

D. Martínez ◽

P. Lopez ◽

C. Godoy ◽

...

Keyword(s):

Type 1 Diabetes ◽

Growth Factor ◽

Menstrual Cycle ◽

Serum Levels ◽

C Reactive Protein ◽

Insulin Growth Factor ◽

Reactive Protein

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Clinical value of selected markers of angiogenesis, inflammation, insulin resistance and obesity in type 1 endometrial cancer

10.21203/rs.2.15416/v2 ◽

2020 ◽

Author(s):

Katarzyna M. Terlikowska ◽

Bozena Dobrzycka ◽

Robert Terlikowski ◽

Anna Sienkiewicz ◽

Maciej Kinalski ◽

...

Keyword(s):

Insulin Resistance ◽

Endometrial Cancer ◽

Growth Factor ◽

Myometrial Invasion ◽

Serum Levels ◽

Figo Stage ◽

Cancer Type ◽

Cox Regression Analysis ◽

Angiopoietin 2

Abstract Background: It is a well-known fact show that the risk of developing endometrial cancer (type 1 EC) is strongly associated with obesity. In this study, selected markers, such as obesity, insulin resistance, angiogenesis and inflammation markers related to EC type 1 progression and patients’ survival data were analyzed.Methods: To measure levels of adiponectin, C-reactive protein (CRP), vascular endothelial growth factor-A (VEGF-A), angiopoietin-2 (Ang-2), insulin-like growth factor-1 (IGF-1), insulin and C-peptide in 176 preoperative serum samples, the immunoassay technique (EMIT) has been applied.Results: Angiopoietin-2 levels increase with age (P=0.005), FIGO stage (p=0.042), myometrial invasion (P=0.009) and LVSI (P<0.001). The CRP levels increase with age (P=0.01), as well as the advancement of the FIGO stage (P<0.001), higher tumor grade (P=0.012), and myometrial invasion (P<0.001). A positive correlation between serum Ang-2 and CRP levels was demonstrated (r=0.44; p<0.001). Kaplan-Meier survival analysis showed that patients with high CRP levels in serum and Ang-2 presented a worse outcome (P=0.03 and P=0.015, respectively). Cox regression analysis of individual predictors revealed that high serum levels of Ang-2, CRP, advanced clinical FIGO stage (P<0.001, respectively), old age (P=0.013) were all significant overall survival predictors. By means of multivariate analysis, their predictive significance was confirmed.Conclusion: Our study provides evidence that serum levels of Ang-2 and CRP may serve as predictors for assessment of the clinical stage of type 1 EC and are significantly associated with poor prognosis. It is likely that angiogenesis and inflammation associated with obesity have a significant impact on EC type 1 progression and survival rate of patients.

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Impaired Proliferation, Apoptosis, and Angiogenesis of Adipose-Derived Stem Cells Isolated from Rats during the Course of Diabetes

Coatings ◽

10.3390/coatings11121549 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1549

Author(s):

Lixia Wen ◽

Peng Liu ◽

Qi Chen ◽

Jiayuan Ge ◽

Bo Jia ◽

...

Keyword(s):

Growth Factor ◽

Diabetic Rats ◽

Vascular Endothelial ◽

Disease Course ◽

Adipose Tissues ◽

Angiogenic Activity ◽

Morphological Variations ◽

Endothelial Growth Factor ◽

Oil Red O Staining

Background: To characterize the impaired of proliferation, apoptosis, and angiogenic activity in ASCs isolated at different stages of the disease course from rats with type 1 diabetes mellitus (T1DM) rats induced by streptozotocin (STZ). Methods: Adipose tissues of the epididymis were harvested at 0, 4, 8, 12, and 16 weeks after the induction of T1DM in rats and from normal rats at the same time points and the morphological variations were detected by Oil red O staining. ASCs were collected from adipose tissues. Cell proliferation, apoptosis, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) expression were assessed. Results: With the prolongation of the disease course, the size and the morphology of adipocytes were distorted, and intracellular lipid droplets became smaller. After 4 weeks, the proliferation of ASCs was decreased, while apoptosis in ASCs was increased. Furthermore, as the disease proceeded, proliferation decreased and apoptosis increased. VEGF and bFGF expression in ASCs from diabetic rats was downregulated at 8 weeks. Conclusion: At 4 weeks after T1DM induction, the proliferation of ASCs decreased and apoptosis increased. The expression of angiogenic factors in ASCs declined at 8 weeks after T1DM induction. The changes in the proliferation, apoptosis, and angiogenic activity are related to the prolongation of disease course.

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Neurotrophic keratitis in autoimmune polyglandular syndrome type 1: a case report

BMC Ophthalmology ◽

10.1186/s12886-020-01770-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Po-Ying Wu ◽

Huai-Wen Chang ◽

Wei-Li Chen

Keyword(s):

Dry Eye ◽

Ocular Surface ◽

Hypogonadotropic Hypogonadism ◽

Ocular Surface Disease ◽

Syndrome Type ◽

Autoimmune Polyglandular Syndrome ◽

Corneal Nerves ◽

Neurotrophic Keratitis ◽

Autoimmune Polyglandular Syndrome Type

Abstract Background Autoimmune polyglandular syndrome type 1 (APS-1) is a rare autosomal recessive disease. In patients with APS-1, the most frequently reported ocular manifestations are keratoconjunctivitis with dry eye and retinal degeneration. However, to our knowledge, no research studies have reported the relationship between APS-1 and neurotrophic keratitis (NK). Possible explanations such as limbus cell deficiency being the primary cause of APS-1 keratopathy are not applicable to our unusual case of the patient with APS-1 presenting as ocular surface disease with NK. Our case findings suggest a new explanation for the observed corneal pathology and a potential treatment for these patients. Case presentation A 27-year-old woman was referred to our hospital because of intermittent blurred vision and recalcitrant ocular surface problems in both eyes for many years. She has a history of autoimmune polyglandular syndrome type 1 (APS-1), which includes hypothyroidism, hypoparathyroidism, hypoadrenalism, and hypogonadotropic hypogonadism. In vivo confocal microscopy clearly demonstrated significant degeneration of the sub-basal nerve plexus and stromal nerve bundles in her corneas bilaterally. She was diagnosed with severe NK and ocular surface disease caused by dry eye. Treatment included the application of therapeutic soft contact lenses and punctual occlusion; however, both treatments had a limited effect. Conclusion Patients with APS-1 may have ocular surface disease and severe damage to corneal nerves. Regular follow-up and treatment focusing on the regeneration of corneal nerves is particularly important in these patients.

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Effect of recombinant human nerve growth factor eye drops in patients with dry eye: a phase IIa, open label, multiple-dose study

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2018-312470 ◽

2019 ◽

pp. bjophthalmol-2018-312470 ◽

Cited By ~ 5

Author(s):

Marta Sacchetti ◽

Alessandro Lambiase ◽

Doreen Schmidl ◽

Leopold Schmetterer ◽

Mauro Ferrari ◽

...

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Dry Eye ◽

Ocular Surface ◽

Multiple Dose ◽

Eye Drops ◽

Open Label ◽

Nerve Growth ◽

Link Type ◽

Human Nerve

BackgroundDry eye disease (DED) affects more than 14% of the elderly population causing decrease of quality of life, high costs and vision impairment. Current treatments for DED aim at lubricating and controlling inflammation of the ocular surface. Development of novel therapies targeting different pathogenic mechanisms is sought-after. The aim of this study is to evaluate safety and efficacy of recombinant human nerve growth factor (rhNGF) eye drops in patients with DED.MethodsForty consecutive patients with moderate to severe DED were included in a phase IIa, prospective, open label, multiple-dose, clinical trial to receive rhNGF eye drops at 20 µg/mL (Group 1: G1) or at 4 µg/mL (Group 2: G2) concentrations, two times a day in both eyes for 28 days (NCT02101281). The primary outcomes measures were treatment-emerged adverse events (AE), Symptoms Assessment in Dry Eye (SANDE) scale, ocular surface staining and Schirmer test.ResultsOf 40 included patients, 39 completed the trial. Both tested rhNGF eye drop concentrations were safe and well tolerated. Twenty-nine patients experienced at least one AE (14 in G1 and 15 in G2), of which 11 had at least 1 related AE (8 in G1 and 3 in G2). Both frequency and severity of DED symptoms and ocular surface damage showed significant improvement in both groups, while tear function improved only in G1.ConclusionsThe data of this study indicate that rhNGF eye drops in both doses is safe and effective in improving symptoms and signs of DED. Randomised clinical trials are ongoing to confirm the therapeutic benefit of rhNGF in DED.Trial registration numberNCT02101281.

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