TABLE 1 - uploaded by Rafael Deminice
Content may be subject to copyright.
Source publication
Anti-oxidation and exocytosis are important for maintaining exocrine tissue homeostasis. During aging, functional and structural alterations occur in the lacrimal gland (LG), including oxidative damage to proteins, lipids, and DNA. The aims of the present study were to determine in the aging LG: a) the effects of aging on LG structure and secretory...
Context in source publication
Context 1
... amplification of cDNA was performed with a GeneAmp PCR System 9700 (Applied Biosystems, Foster City, CA) using 1.5 units of Taq DNA polymerase (Gibco/ BRL), 0.3 mM each of dATP, dCTP, dGTP, and dTTP (Invitrogen), PCR buffer (Tris-Hcl 60 mM, MgCl2 1.5 mM,NH4 15 mM SO4, pH 10; Invitrogen), and 10 mM of 5′ and 3′ primers (Life Technologies, Gaithersburg, MD) corresponding to rat Rab3d, Rab 27b, Vamp-2, and Actb cDNA (Table 1). Positive (pancreatic islets) and negative (without reverse transcriptase or cDNAs) controls were run in parallel. ...
Citations
... Возникшая воспалительная реакция в комплексе роговица ↔ слезная железа, в свою очередь, обладает потенцирующим влиянием и постепенно переходит в хроническую фазу [29][30][31]. Развивающееся с возрастом хроническое воспаление, а также оксидативный стресс в слезной железе и являются основной причиной ее деградации и сопряженного с ней синдрома сухого глаза [32][33][34]. Обнаруженное нами развитие хронического воспаления в ткани ЭСЖ параллельно с выявленной ее деструкцией подтверждает эти наблюдения. Особенностью данных процессов у крыс Wistar являются их раннее проявление и развитие. ...
Purpose . Wistar rats are often used in ophthalmological studies and in testing substances having therapeutic effects. The condition of the eyes of these animals, as well as other mammals, including humans, in the normal state, pathology, and aging, depends on the work of the lacrimal glands. The aim of this study was to develop convenient approaches for determining age-dependent histopathological changes in the exorbital lacrimal glands (ELGs) of aging rats.
Material and methods . Isolated ELGs obtained from Wistar rats aged of 8 and 11 months served as a material of the study. Changes in the structure of ELGs were evaluated using methods of computer analysis of morphological patterns and quantitative data processing.
Results . The functioning and state of the ELGs are reflected in their dramatic structural changes and progressive inflammation. Our study proposes a simple way to assess the state of ELGs in aging rats using methods of morphology and computer programs. Using the proposed approach, it was shown that in the period from 8 to 11 months of postnatal development, significant age-related changes occur in aging rats. Changes manifest in the progress of parenchymal degeneration and progressive infiltration of the tissue by inflammatory cells.
Conclusions . The proposed method of ELG state’s evaluation can be used in ophthalmological studies, and in particular, when studying the development of “dry eye” syndrome and testing the means of its therapy.
... In an aging group of rats, the lacrimal gland shows increased accumulation of lipofuscin-like substances, indicating age-related oxidative damage, while the levels of vitamin E, which has antioxidant capacity, are lower. Furthermore, there is a decrease in the expression of Rab3d and Rab27b proteins involved in vesicular transport and cytosolic uptake [90]. Aging alters the expression of cytokinesis-related proteins and oxidative stress biomarkers in the lacrimal gland, which controls the expression of its downstream signaling partners, affects tear secretion, and increases susceptibility to DED. ...
Dry eye disease (DED) is a multifactorial condition affecting the ocular surface. It is characterized by loss of tear film homeostasis and accompanied by ocular symptoms that may potentially result in damage to the ocular surface and even vision loss. Unmodifiable risk factors for DED mainly include aging, hormonal changes, and lifestyle issues such as reduced sleep duration, increased screen exposure, smoking, and ethanol consumption. As its prevalence continues to rise, DED has garnered considerable attention, prompting the exploration of potential new therapeutic targets. Recent studies have found that when the production of ROS exceeds the capacity of the antioxidant defense system on the ocular surface, oxidative stress ensues, leading to cellular apoptosis and further oxidative damage. These events can exacerbate inflammation and cellular stress responses, further increasing ROS levels and promoting a vicious cycle of oxidative stress in DED. Therefore, given the central role of reactive oxygen species in the vicious cycle of inflammation in DED, strategies involving antioxidants have emerged as a novel approach for its treatment. This review aims to enhance our understanding of the intricate relationship between oxidative stress and DED, thereby providing directions to explore innovative therapeutic approaches for this complex ocular disorder.
... These changes make the ocular surface microenvironment more irritable, with increases in a series of oxidative stress markers, such as 8-OHdG, nitrotyrosine, 4-HNE and lipofuscin-like inclusions.71 The data showed that the accumulation of lipofuscin-like material in lacrimal acini and corneal epithelial metaplasia are higher among aged rats, accompanied by a decrease in the level of the antioxidant marker vitamin E.72 Under conditions of desiccating stress, additional oxidative stress is produced, which is accompanied by a decrease in the antioxidant capacity of the corneal epithelium.31 Hence, maintaining the cellular redox balance on the ocular surface could serve as a strategic approach for dry eye prevention and treatment. ...
Oxidative stress is an important mechanism of aging, and in turn, aging can also aggravate oxidative stress, which leads to a vicious cycle. In the process of the brain converting light into visual signals, the eye is stimulated by harmful blue‐light radiation directly. Thus, the eye is especially vulnerable to oxidative stress and becomes one of the organs most seriously involved during the aging process. Cataracts, age‐related macular degeneration (AMD), glaucoma, diabetic retinopathy (DR), and dry eye are inextricably linked to the aging process and oxidative stress. Chlorogenic acid (CGA) has been demonstrated to have antioxidant and anti‐inflammatory activities, and its validity has been established experimentally in numerous fields, including cardiovascular disease, metabolic disorders, cancers, and other chronic diseases. There has previously been evidence of CGA's therapeutic effect in the field of ophthalmopathy. Considering that many ophthalmic drugs lead to systemic side effects, CGA may act as a natural exogenous antioxidant for patients to take regularly, controlling their condition while minimizing side effects. In this paper, in vitro and in vivo studies of CGA in the treatment of age‐related eye diseases are reviewed, and the prospects of CGA's antioxidant application for the eye are discussed. The aim of this review is to summarize the relevant knowledge and provide theoretical support for future research.
... Firstly, the elevation of chronic oxidative stress is a substantial and widely acclaimed cause of aging [16,17]. Oxidative stress is also implicated in dry eye pathogenesis in the aged population [18]. MDA has been used as a marker for lipid peroxidation in the LGs [19,20], while 8-OHdG often represents the extent of DNA damage during aging [1,10,16]. ...
Simple Summary
The Klotho gene null mutation has been shown to cause accelerated senescence in many organs. Nevertheless, whether the mutation may cause lacrimal gland dysfunction and degeneration has not been elucidated. This study shows that the Klotho null mutation leads to reduced tear volume with characteristics of lacrimal gland degeneration, including glandular and acinar atrophy, thickened capsules, and collagen deposition. The mechanism analysis showed a multi-fold pathogenesis process, including chronic elevated oxidative stress, constant extracellular matrix remodeling, and epithelial−mesenchymal transition. The results support the concept that Klotho null mutant mice may be a study model for age-related dry eye disease.
Abstract
The Klotho null mutation is known to lead to accelerated aging in many organs, but its effects on tear secretion and lacrimal gland (LG) senescence have not been addressed. This study investigated whether the Klotho null mutation would lead to a dry eye status and the outcome of LG without Klotho function. The Klotho (−/−) mutant mice showed reduced LG size and tear volume on the 8th week, as compared to their littermates (+/+, +/−). Hematoxylin–Eosin and Masson’s trichrome staining were performed to determine morphological changes and collagen deposition. Traits of LG aging, including acinar atrophy, thickened capsules, and more collagen depositions, were observed. Immunohistochemical detections for Klotho, α-SMA, MDA, 8-OHdG, vasoactive intestinal polypeptide (VIP), tyrosine hydroxylase (TH), MMP-2, MMP-9, and FGF-23 were performed and compared among the three genotypes (+/+, +/−, −/−) at 6 and 8 weeks of age for mechanism analyses. Unexpectedly, the Klotho protein was not detected in the LG of all the three genotypes, indicating indirect effects from the Klotho null mutation. Further analyses showed abundant MDA and 8-OHdG detected in the Klotho (−/−) LG on the 8th week, indicating elevated oxidative stress. In addition, both sympathetic and parasympathetic neural transducing activities, as represented by TH and VIP expression, respectively, and α-SMA were increased in LGs with Klotho mutations. Furthermore, MMP-2 and MMP-9 expression were elevated, with FGF-23 expression being decreased on the 8th week in the Klotho (−/−) LG. In conclusion, characteristics of age-related LG degeneration were found in the Klotho null mutant mice. These traits support the use of Klotho mutant mice as a model of age-related dry eye disease.
... Consequently, the ocular surface is no longer protected in the eye's anterior segment. Animal studies provide invaluable information about the role of oxidative stress in the cornea in various forms of dry eye disease [34]. For instance, Nakamura et al. demonstrated the relationship between the deposition of oxidative stress and corneal epithelial changes in the blink-suppressed dry eye mice model. ...
The eye is a metabolically active structure, constantly exposed to solar radiations making its structure vulnerable to the high burden of reactive oxygen species (ROS), presenting many molecular interactions. The biomolecular cascade modification is caused especially in diseases of the ocular surface, cornea, conjunctiva, uvea, and lens. In fact, the injury in the anterior segment of the eye takes its origin from the perturbation of the pro-oxidant/antioxidant balance and leads to increased oxidative damage, especially when the first line of antioxidant defence weakens with age. Furthermore, oxidative stress is related to mitochondrial dysfunction, DNA damage, lipid peroxidation, protein modification, apoptosis, and inflammation, which are involved in anterior ocular disease progression such as dry eye, keratoconus, uveitis, and cataract. The different pathologies are interconnected through various mechanisms such as inflammation, oxidative stress making the diagnostics more relevant in early stages. The end point of the molecular pathway is the release of different antioxidant biomarkers offering the potential of predictive diagnostics of the pathology. In this review, we have analysed the oxidative stress and inflammatory processes in the front of the eye to provide a better understanding of the pathomechanism, the importance of biomarkers for the diagnosis of eye diseases, and the recent treatment of anterior ocular diseases.
... 74,75 The mechanism by which insulin resistance leads to dry eye may be associated with increased oxidative stress, degeneration of lacrimal glands, decreased secretion of tear fluid, and increased expression of pro-inflammatory cytokines. [76][77][78] Adrenocorticotropic hormones (ACTH) and cortisol (CORT) may play a role in the development of dry eye. The hypothalamic-pituitary-adrenal axis (HPA axis) is associated with various stress physiological responses, and its main physiological functions are: the hypothalamus releases corticotropin-releasing hormone (CRH), CRH acts on the pituitary gland to release adrenocorticotropic hormone (ACTH), after which ACTH acts on the adrenal cortex to release cortisol (CORT), 79 dysfunction of the HPA axis can cause sleep disorders. ...
Dry eye is a disease that severely affects patients’ quality of life, increasing the global burden on public health and finance. There is growing evidence that a poor lifestyle is a significant risk factor for dry eye. Along with the development of society, sleep, as a way of life, is also constantly changing. The main manifestations of sleep disorders are reduced sleep time, circadian rhythm disturbances, and sleep breathing disturbances. Sleep disorders and their secondary systemic diseases have attracted wide attention in recent years. This review mainly explored the correlation between sleep disorders and dry eye, and found that sleep-related problems and other factors potentially leading from sleep disorders could be critical factors for dry eye. These results suggest that ophthalmologists should pay attention to the sleep health problems in patients with dry eye, and we hope that this paper can provide help for future research in this field.
... First, we identified 43 driving genes. For example, vesicle-associated membrane protein-2 (Vamp2) is associated with exocytosis of lacrimal gland antioxidants and visual stabilization protein 1, which may cause dry eye disease, photoreceptor synapse damage, and various eye diseases such as diabetic retinopathy leading to the occurrence and development of myopia [35][36][37]. The epidermal growth factor receptor (EGFR) is thought to regulate adhesion dynamics and corneal epithelial homeostasis during eye development [38,39]. ...
Myopia is recognized as a multifactor, multicascade complex disease. However, people still know little about the pathogenesis of myopia. Therefore, we aim to guide the personalized treatment, drug research, and development of myopia. Here, based on the interaction network of myopia-related genes, this study constructed a multifactor-driven myopia disease module map. We first identified differentially expressed (DE) miRNAs in myopia. Then, we constructed a myopia-related protein interaction network targeted by these DE miRNAs. Further, we clustered the network into modules and identified module-driven factors, including ncRNAs and transcription factors. Especially, miR-16-5p and miR-34b-5p significantly differentially expressed drive the pathogenic module to influence the progression of myopia. At the same time, transcription factors were involved in myopia-related functions and pathways by regulating the expression of genes in modules, such as Ctnnb1, Myc, and Notch1. In addition, we identified 43 genes in modules that played key roles in the development and progression of myopia such as Vamp2, Egfr, and Wasl. Finally, we constructed a comprehensive multifactor-driven myopia pathogenic module landscape and predicted potential drug and drug targets for myopia. In general, our work not only provided candidates for biological experiments which laid the foundation for the in-depth study of myopia but also has a high reference value for the personalized treatment of myopia and drug development.
... Under physiological conditions, oxidant-antioxidant balance or redox homeostasis is equalized with minimum rest (Droge 2002). Signs of waste can be observed when comparing biologic markers of oxidative stress in aged versus young organisms, as well as on the ocular surface (Batista et al., 2012;Cejka and Cejkova 2015;Forman 2016). 1 | Genetic source and comparison of antioxidants and free radical scavengers identified in the lacrimal gland and ocular surface cells or tear secretion of human, mouse, rabbit or rat (Flicek 2020 Limitations in tracking the events associated with healthy and pathologic OS using biologic and chemical in vitro and in vivo assays are rarely mentioned. Approximately 0.1% of the O 2 reduced during normal cell metabolism generates free radicals. ...
... The LG of old mice and rats present lower peroxidase activity and lower stimulated peroxidase secretion than their younger counterparts (8 weeks old) (Bromberg et al., 1989;Alves et al., 2005b;Rios et al., 2005). These observations are also in agreement with functional impairment of secretion, reduction of molecules associated with secretory control such as Rab3d, accumulation of degenerative and oxidative stress markers such as lipofuscin, and reduction of vitamin E (an antioxidant) in the LG of aged rats (Batista et al., 2012). Functional changes were prevented in aging rats with 35% calorie restriction (CR), which also preserved the tissue structure, reduced inflammatory cell infiltration, and attenuated the markers of oxidative damage to the LG . ...
Oxidative stress (OS) is a major disruption in the physiology of the lacrimal functional unit (LFU). Antioxidant enzymes have dual protective activities: antioxidant and antimicrobial activities. Peroxidases have been indistinctly used as markers of the secretory activity of the LFU and implicated in the pathophysiology, diagnosis and treatment of dry eye disease (DED), even though they comprise a large family of enzymes that includes lactoperoxidase (LPO) and glutathione peroxidase (GPO), among others. Assays to measure and correlate OS with other local LFU phenomena have methodological limitations. Studies implicate molecules and reactions involved in OS as markers of homeostasis, and other studies identify them as part of the physiopathology of diseases. Despite these conflicting concepts and observations, it is clear that OS is influential in the development of DED. Moreover, many antioxidant strategies have been proposed for its treatment, including calorie restriction to nutritional supplementation. This review offers a critical analysis of the biological mechanisms, diagnostic outcomes, drug use, dietary supplements, and life habits that implicate the influence of OS on DED.
... Therefore, tear film dysfunction can lead to infection and inflammation on the ocular surface and cause an increase in oxidative pressure, leading to epidermal and glandular cell oxidative damage, which in turn leads to nonautoimmune dry eye syndrome [53]. In a murine model, aging changed the LG structure and tear secretion, resulting in an increase in oxidative stress markers [54]. The number of 8-OHdG-positive cells in LGs and MGs increases with aging, indicating that oxidative damage is one of the factors that causes gland degeneration seen in aging [55]. ...
Oxidative stress is an important pathomechanism found in numerous ocular degenerative diseases. To provide a better understanding of the mechanism and treatment of oxidant/antioxidant imbalance-induced ocular diseases, this article summarizes and provides updates on the relevant research. We review the oxidative damage (e.g., lipid peroxidation, DNA lesions, autophagy, and apoptosis) that occurs in different areas of the eye (e.g., cornea, anterior chamber, lens, retina, and optic nerve). We then introduce the antioxidant mechanisms present in the eye, as well as the ocular diseases that occur as a result of antioxidant imbalances (e.g., keratoconus, cataracts, age-related macular degeneration, and glaucoma), the relevant antioxidant biomarkers, and the potential of predictive diagnostics. Finally, we discuss natural antioxidant therapies for oxidative stress-related ocular diseases.
... Histopathological alterations of the human and murine lacrimal glands have been described with aging; some of these anatomical changes are similar to the ones observed in Sjögren Syndrome (Batista et al., 2012;Bian et al., 2019;Coursey et al., 2015;Damato et al., 1984;Draper et al., 1999;Rocha et al., 2008;Yoon et al., 2020). Inhibition of cathepsin S reduces lacrimal gland inflammation and increases tear flow in a mouse model of Sjögren Syndrome (Klinngam et al., 2019), suggesting that modulation of cathepsin S might be a novel approach to improve dry eye-related changes. ...
Cathepsin S (Ctss) is a protease that is proinflammatory on epithelial cells. The purpose of this study was to investigate the role of Ctss in age-related dry eye disease. Ctss−/- mice [in a C57BL/6 (B6) background] of different ages were compared to B6 mice. Ctss activity in tears and lacrimal gland (LG) lysates was measured. The corneal barrier function was investigated in naïve mice or after topical administration of Ctss eye drops 5X/day for two days. Eyes were collected, and conjunctival goblet cell density was measured in PAS-stained sections. Immunoreactivity of the tight junction proteins, ZO-1 and occludin, was investigated in primary human cultured corneal epithelial cells (HCEC) without or with Ctss, with or without a Ctss inhibitor. A significant increase in Ctss activity was observed in the tears and LG lysates in aged B6 compared to young mice. This was accompanied by higher Ctss transcripts and protein expression in LG and spleen. Compared to B6, 12 and 24-month-old Ctss−/- mice did not display age-related corneal barrier disruption and goblet cell loss. Treatment of HCEC with Ctss for 48 hours disrupted occludin and ZO-1 immunoreactivity compared to control cells. This was prevented by the Ctss inhibitor LY3000328 or Ctss-heat inactivation. Topical reconstitution of Ctss in Ctss−/- mice for two days disrupted corneal barrier function. Aging on the ocular surface is accompanied by increased expression and activity of the protease Ctss. Our results suggest that cathepsin S modulation might be a novel target for age-related dry eye disease.
