Age-associated murine cardiac lesions are attenuated by the mitochondria-targeted antioxidant SkQ1

Age-related changes in mammalian hearts often result in cardiac hypertrophy and fibrosis that are preceded by inflammatory infiltration. In this paper, we show that lifelong treatment of BALB/c and C57BL/6 mice with the mitochondria-targeted antioxidant SkQ1 retards senescence-associated myocardial disease (cardiomyopathy), cardiac hypertrophy, and diffuse myocardial fibrosis. To investigate the molecular basis of the action of SkQ1, we have applied DNA microarray analysis. The global gene expression profile in heart tissues was not significantly affected by administration of SkQ1. However, we found some small but statistically significant modifications of the pathways related to cellto-cell contact, adhesion, and leukocyte infiltration. Probably, SkQ1-induced decrease in leukocyte and mesenchymal cell adhesion and/or infiltration lead to a reduction in age-related inflammation and subsequent fibrosis. The data indicate a causative role of mitochondrial reactive oxygen species in cardiovascular aging and imply that SkQ1 has poteential as a drug against age-related cardiac dysfunction

Inflammation in dry eye syndrome: Identification and targeting of oxylipin-mediated mechanisms

Dry eye syndrome (DES) is characterized by decreased tear production and stability, leading to desiccating stress, inflammation and corneal damage. DES treatment may involve targeting the contributing inflammatory pathways mediated by polyunsaturated fatty acids and their derivatives, oxylipins. Here, using an animal model of general anesthesia-induced DES, we addressed these pathways by characterizing inflammatory changes in tear lipidome, in correlation with pathophysiological and biochemical signs of the disease. The decline in tear production was associated with the infiltration of inflammatory cells in the corneal stroma, which manifested one to three days after anesthesia, accompanied by changes in tear antioxidants and cytokines, resulting in persistent damage to the corneal epithelium. The inflammatory response manifested in the tear fluid as a short-term increase in linoleic and alpha-linolenic acid-derived oxylipins, followed by elevation in arachidonic acid and its derivatives, leukotriene B4 (5-lipoxigenase product), 12-hydroxyeicosatetraenoic acid (12-lipoxigeanse product) and prostaglandins, D2, E2 and F2α (cyclooxygenase products) that was observed for up to 7 days. Given these data, DES was treated by a novel ophthalmic formulation containing a dimethyl sulfoxide-based solution of zileuton, an inhibitor of 5-lipoxigenase and arachidonic acid release. The therapy markedly improved the corneal state in DES by attenuating cytokine- and oxylipin-mediated inflammatory responses, without affecting tear production rates. Interestingly, the high efficacy of the proposed therapy resulted from the synergetic action of its components, namely, the general healing activity of dimethyl sulfoxide, suppressing prostaglandins and the more specific effect of zileuton, downregulating leukotriene B4 (inhibition of T-cell recruitment), as well as upregulating docosahexaenoic acid (activation of resolution pathways). © 2020 by the authors

Inflammatory Metabolites of Arachidonic Acid in Tear Fluid in UV-Induced Corneal Damage

Abstract—: The ultraviolet (UV) B-induced damage of the eye surface of experimental animals (rabbits) includes total loss of corneal epithelium, apoptosis of keratocytes and stromal edema. These changes are accompanied by clinically and histologically manifested corneal inflammation, neutrophil infiltration, and exudation of the anterior chamber of the eye. According to results of mass spectrometric analysis, the UV-induced corneal damage is associated with pronounced changes in the tear lipid composition, including a decrease in the amount of arachidonic acid and prostaglandin E2 and an increase in the concentrations of prostaglandin D2 and its derivative 15d-PGJ2. In addition, it is accompanied by changes in the levels of hydroxyeicosate tetraenic acids, including a decrease of 12-HETE and an increase of 5-HETE. These changes suggest activation of metabolic pathways involving 5-lipoxygenase, 12-lipoxygenase, cyclooxygenases 1 and 2, and prostaglandin D synthase. These findings contribute to understanding mechanisms of UV-induced keratitis and point to feasibility of selective anti-inflammatory therapy for improving corneal regeneration after iatrogenic UV damage. © 2019, Pleiades Publishing, Ltd

Воспалительные метаболиты арахидоновой кислоты в слёзной жидкости при индуцированном ультрафиолетовым излучением повреждении роговицы

The ultraviolet (UV) B-induced damage of the eye surface of experimental animals (rabbits) includes loss of corneal epithelium, apoptosis of keratocytes and stromal edema. These changes are accompanied by clinically and histologically manifested corneal inflammation, neutrophil infiltration, and exudation of the anterior chamber of the eye. According to mass spectrometric analysis, UV-induced corneal damage is associated with pronounced changes in the lipid composition of tears, including a decrease in the amount of arachidonic acid and prostaglandin E2 and an increase in the concentrations of prostaglandin D2 and its derivative 15d-PGJ2. In addition, it is accompanied by an alteration in the levels of hydroxyeicosate tetraenic acid derivatives, namely upregulation of 12-HETE and downregulation of 5-HETE. The revealed changes indicate the activation of metabolic pathways involving 5-lipoxygenase, 12-lipoxygenase, cyclooxygenase 1 and 2, and prostaglandin-D-synthase. These findings contribute to understanding mechanisms of UV-induced keratitis and point on feasibility of selective anti-inflammatory therapy for improving corneal regeneration after iatrogenic UV damage.Повреждения поверхности глаза экспериментальных животных (кроликов), индуцированные ультрафиолетовым (УФ) излучением (ультрафиолет В), включают полную деэпителизацию роговицы, апоптоз кератоцитов и отёк стромы этой ткани. Указанные изменения сопровождаются развитием клинически и гистологически детектируемой воспалительной реакции в роговице, а также нейтрофильной инфильтрацией и экссудацией передней камеры глаза. По данным масс-спектрометрического анализа, УФ-индуцированные повреждения роговицы ассоциированы с выраженными изменениями липидного состава слезы, включающими снижение количества арахидоновой кислоты и простагландина Е2, увеличение концентраций простагландина D2 и его производного 15d-PGJ2, а также изменение уровней гидроксиэйкозатетраеновых кислот 12-HETE (снижение) и 5-HETE (повышение). Это указывает на активацию метаболических путей с участием 5-липоксигеназы, 12-липоксигеназы, циклооксигеназ 1 и 2, и простагландин-D-синтазы. Результаты работы расширяют понимание механизмов развития УФ-индуцированного кератита, а также свидетельствуют о перспективности использования селективной противовоспалительной терапии для ускорения регенерации роговицы после ятрогенных повреждений, вызванных УФ-излучением

Tear Fluid Inflammatory Oxylipins in Perioperative Dry Eye Disease

Using the previously developed rabbit model of perioperative dry eye syndrome (PDES) and the method for quantitative mass spectrometric detection of oxylipins, it is shown that the development of corneal erosion under general anesthesia is associated with changes in tear fluid content of inflammatory metabolites including derivatives of linoleic (LA), alpha-linolenic (ALA), and arachidonic (AA) acids. The most significant growth is demonstrated for the metabolites of LA and ALA, while the content of AA derivatives (with the exception of 12-HETE) does not exhibit significant changes, indicating the key roles of the LA and ALA cascades in inflammatory response in PDES. An increase in oxylipins formed by nonenzymatic oxidation of LA (9-KODE) or its processing by cytochromes (12,13-EpOME) upon oxidative burst, indicates a significant contribution of oxidative stress to the PDES mechanism. The majority of metabolites of LA (13-HODE and 9-HODE), ALA (9-HOTrE and 13-HOTrE) and AK (12-HETE), the tear content of which is changed in PDES, are generated by the enzymes of the lipoxygenase family, while the concentration of cyclooxygenase products remains almost unchanged. These data suggest a low therapeutic potential of cyclooxygenase inhibitors (such as nonsteroidal anti-inflammatory drugs) and a high therapeutic potential of antioxidants and lipoxygenase inhibitors in respect to PDES, which should be taken into account when developing complex therapy for this widespread socially significant disease

Alterations in Tear Content of Inflammatory Oxylipines Associated with Perioperative Dry Eye Syndrome

Abstract: Using the previously developed rabbit model of perioperative dry eye syndrome (PDES) and quantitative mass spectrometric technique it is shown that the development of corneal erosion under conditions of general anesthesia is associated with changes in the content of inflammatory metabolites, namely, derivatives of linoleic (LA), alpha-linolenic (ALA), and arachidonic (AA) acids in tear fluid. The increase in the content of the metabolites of LA and ALA is found to be the most significant, while the content of AA derivatives (with the exception of 12-HETE) remains almost unchanged, indicating the key roles of the LA and ALA cascades in the inflammatory response in PDES. The increase in the concentration of oxylipins that can be formed by nonenzymatic oxidation of LA (9-KODE) or its processing by cytochromes (12,13-EpOME) under oxidative conditions indicates a significant contribution of oxidative stress to the development of PDES. The majority of metabolites of LA (13-HODE and 9-HODE), ALA (9-HOTrE and 13-HOTrE) and AA (12-HETE), the tear content of which was changed in PDES, are generated by the enzymes of lipoxygenase family. By contrast, the concentration of cyclooxygenase products does not exhibit any significant fluctuations. These data suggest a low therapeutic potential of cyclooxygenase inhibitors (such as nonsteroidal anti-inflammatory drugs) and a high therapeutic potential of antioxidants and lipoxygenase inhibitors in PDES, which should be taken into account upon developing a complex therapy for this disease. © 2020, Pleiades Publishing, Ltd

Mechanisms and treatment of light-induced retinal degeneration-associated inflammation: Insights from biochemical profiling of the aqueous humor

Ocular inflammation contributes to the pathogenesis of blind-causing retinal degenerative diseases, such as age-related macular degeneration (AMD) or photic maculopathy. Here, we report on inflammatory mechanisms that are associated with retinal degeneration induced by bright visible light, which were revealed while using a rabbit model. Histologically and electrophysiologically noticeable degeneration of the retina is preceded and accompanied by oxidative stress and inflammation, as evidenced by granulocyte infiltration and edema in this tissue, as well as the upregulation of total protein, pro-inflammatory cytokines, and oxidative stress markers in aqueous humor (AH). Consistently, quantitative lipidomic studies of AH elucidated increase in the concentration of arachidonic (AA) and docosahexaenoic (DHA) acids and lyso-platelet activating factor (lyso-PAF), together with pronounced oxidative and inflammatory alterations in content of lipid mediators oxylipins. These alterations include long-term elevation of prostaglandins, which are synthesized from AA via cyclooxygenase-dependent pathways, as well as a short burst of linoleic acid derivatives that can be produced by both enzymatic and non-enzymatic free radical-dependent mechanisms. The upregulation of all oxylipins is inhibited by the premedication of the eyes while using mitochondria-targeted antioxidant SkQ1, whereas the accumulation of prostaglandins and lyso-PAF can be specifically suppressed by topical treatment with cyclooxygenase inhibitor Nepafenac. Interestingly, the most prominent antioxidant and anti-inflammatory benefits and overall retinal protective effects are achieved by simultaneous administrating of both drugs indicating their synergistic action. Taken together, these findings provide a rationale for using a combination of mitochondria-targeted antioxidant and cyclooxygenase inhibitor for the treatment of inflammatory components of retinal degenerative diseases. © 2020 by the authors. Licensee MDPI, Basel, Switzerland