APX‑115A, a pan‑NADPH oxidase inhibitor, reduces the degree and incidence rate of dry eye in the STZ‑induced diabetic rat model

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Abstract

Dye eye disease (DED) is a common ocular disorder in patients with diabetes. It has been reported that APX-115A, a pan-nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase inhibitor, has an apoptosis-inducing effect on Epstein-Barr virus-infected retinal epithelial cells, but its effects in DED are poorly understood. Therefore, a rat model of diabetes was used in the present study to investigate whether APX-115A has an impact on DED in diabetic rats. A diabetic model was established in male Sprague Dawley rats via the intraperitoneal injection of streptozotocin. The eyeballs of the rats were treated with a solution containing APX-115A or a saline control. Tear secretion was measured with the phenol red thread tear test, and the morphology of the eyeball and lacrimal gland tissues was determined using hematoxylin and eosin staining. In addition, localization of NAPDH oxidase 2 (NOX2) in the eyeball and lacrimal gland tissues was detected by immunohistochemistry. The APX-115A treatment had no effect on body weight, blood glucose level or the size of the lacrimal glands. However, morphological changes, namely intracellular vacuoles and acinar atrophy, were observed in the lacrimal glands of the diabetic rats, and APX-115A treatment attenuated these changes. Immunohistochemistry revealed that NOX2 expression was decreased in the lacrimal glands of the diabetic rats, and APX-115A treatment did not attenuate the reduction in NOX2. The corneas of the diabetic rats treated with APX-115A exhibited no change in thickness but had lower NOX2 expression levels compared with those of the control diabetic rats. APX-115A also increased tear secretion and ameliorated the histological changes associated with diabetes. Furthermore, the NOX2 expression levels in the corneas of the diabetic rats treated with APX-115A were restored to the levels observed in normal rats. These findings suggest that APX-115A has potential as a therapeutic agent for DED.

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The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.

Karen Bedard, Karl-Heinz Krause (2007)

For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91(phox)), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). Activation mechanisms and tissue distribution of the different members of the family are markedly different. The physiological functions of NOX family enzymes include host defense, posttranlational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. NOX enzymes also contribute to a wide range of pathological processes. NOX deficiency may lead to immunosuppresion, lack of otoconogenesis, or hypothyroidism. Increased NOX activity also contributes to a large number or pathologies, in particular cardiovascular diseases and neurodegeneration. This review summarizes the current state of knowledge of the functions of NOX enzymes in physiology and pathology.

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Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities.

Miriam Cnop, Nils Welsh, Jean-Christophe Jonas … (2005)

Type 1 and type 2 diabetes are characterized by progressive beta-cell failure. Apoptosis is probably the main form of beta-cell death in both forms of the disease. It has been suggested that the mechanisms leading to nutrient- and cytokine-induced beta-cell death in type 2 and type 1 diabetes, respectively, share the activation of a final common pathway involving interleukin (IL)-1beta, nuclear factor (NF)-kappaB, and Fas. We review herein the similarities and differences between the mechanisms of beta-cell death in type 1 and type 2 diabetes. In the insulitis lesion in type 1 diabetes, invading immune cells produce cytokines, such as IL-1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. IL-1beta and/or TNF-alpha plus IFN-gamma induce beta-cell apoptosis via the activation of beta-cell gene networks under the control of the transcription factors NF-kappaB and STAT-1. NF-kappaB activation leads to production of nitric oxide (NO) and chemokines and depletion of endoplasmic reticulum (ER) calcium. The execution of beta-cell death occurs through activation of mitogen-activated protein kinases, via triggering of ER stress and by the release of mitochondrial death signals. Chronic exposure to elevated levels of glucose and free fatty acids (FFAs) causes beta-cell dysfunction and may induce beta-cell apoptosis in type 2 diabetes. Exposure to high glucose has dual effects, triggering initially "glucose hypersensitization" and later apoptosis, via different mechanisms. High glucose, however, does not induce or activate IL-1beta, NF-kappaB, or inducible nitric oxide synthase in rat or human beta-cells in vitro or in vivo in Psammomys obesus. FFAs may cause beta-cell apoptosis via ER stress, which is NF-kappaB and NO independent. Thus, cytokines and nutrients trigger beta-cell death by fundamentally different mechanisms, namely an NF-kappaB-dependent mechanism that culminates in caspase-3 activation for cytokines and an NF-kappaB-independent mechanism for nutrients. This argues against a unifying hypothesis for the mechanisms of beta-cell death in type 1 and type 2 diabetes and suggests that different approaches will be required to prevent beta-cell death in type 1 and type 2 diabetes.

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Streptozotocin-Induced Diabetic Models in Mice and Rats.

Brian L Furman (2015)

Streptozotocin (STZ) is an antibiotic that produces pancreatic islet β-cell destruction and is widely used experimentally to produce a model of type 1 diabetes mellitus (T1DM). Detailed in this unit are protocols for producing STZ-induced insulin deficiency and hyperglycemia in mice and rats. Also described are protocols for creating animal models for type 2 diabetes using STZ. These animals are employed for assessing the pathological consequences of diabetes and for screening potential therapies for the treatment of this condition.

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Author and article information

Journal

Journal ID (nlm-ta): Exp Ther Med

Journal ID (iso-abbrev): Exp Ther Med

Journal ID (publisher-id): ETM

Title: Experimental and Therapeutic Medicine

Publisher: D.A. Spandidos

ISSN (Print): 1792-0981

ISSN (Electronic): 1792-1015

Publication date Collection: May 2023

Publication date (Electronic): 17 March 2023

Publication date PMC-release: 17 March 2023

Volume: 25

Issue: 5

Electronic Location Identifier: 194

Affiliations

[1 ]Department of Anatomy and Tumor Immunology, Inje University College of Medicine, Busan 47392, Republic of Korea

[2 ]Department of Otolaryngology-Head and Neck Surgery, Dong-A University College of Medicine, Busan 49201, Republic of Korea

[3 ]AptaBio Therapeutics Incorporation, Yongin, Gyeonggi 16954, Republic of Korea

[4 ]Department of Internal Medicine, Inje University Ilsan-Paik Hospital, Goyang, Gyeonggi 10380, Republic of Korea

Author notes

Correspondence to: Professor Dae Young Hur, Department of Anatomy and Tumor Immunology, Inje University College of Medicine, 75 Bokji-ro, Busanjin, Busan 47392, Republic of Korea dyhurinje.ac.kr hansy@ 123456paik.ac.kr

Professor Sang Youb Han, Department of Internal Medicine, Inje University Ilsan-Paik Hospital, 170 Joowha-ro, IlsanSeo-gu, Goyang, Gyeonggi 10380, Republic of Korea hansy@ 123456paik.ac.kr

^*Contributed equally

Article

Publisher ID: ETM-25-5-11893

DOI: 10.3892/etm.2023.11893

PMC ID: 10119744

PubMed ID: 37090081

SO-VID: d7e9f0ae-f485-4896-94f6-d0109e1cfccf

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This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

History

Date received : 17 October 2022

Date accepted : 17 February 2023

Funding

Funding: The present study was supported by a 2019 Inje University research grant.

APX‑115A, a pan‑NADPH oxidase inhibitor, reduces the degree and incidence rate of dry eye in the STZ‑induced diabetic rat model

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Animal models of intrauterine growth restriction (IUGR)

Most cited references 72

The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.

Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities.

Streptozotocin-Induced Diabetic Models in Mice and Rats.

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