Evaluation of macular choroidal and microvascular network changes by activity scores and serum antibodies in thyroid eye patients and healthy subjects

AIM: To investigate the choroidal thickness and the microvascular network changes around the macula in thyroid eye disease (TED) patients at different stages and the relationship of those changes with risk factors, serum antibodies and the severity of TED. METHODS: A total of 85 participants were enrolled. All participants underwent ophthalmology and endocrinology examinations. Subfoveal choroidal thickness (SFCT), superficial (s) and deep (d) foveal avascular zone (FAZ) area, mean (m) and central (c) superficial vascular density (SVD), deep vascular density (DVD) measurements of the enrolled cases were performed with Topcon swept source optical coherence tomography (OCT)/OCT angiography (OCTA) DRI OCT Triton. Multiple linear regression analysis was used to explore the associations between SFCT, FAZ area, SVD, DVD and the relevant factors of TED. RESULTS: Those with active TED patients had higher c-DVD and m-DVD levels (P<0.05), however there is no statistically significant difference in SFCT between active and stable TED patients. Among the serum antibodies, it was observed that s-FAZ and d-FAZ increased, c-SVD and m-SVD decreased in patients with high thyroid stimulating hormone-receptor autoantibodies (TRAB) level, whereas SFCT thickened in patients with high levels of both TRAB and human thyroglobulin (hTG). There was no significant difference in SFCT, FAZ, SVD and DVD measurement at gender, between hyperthyroid and euthyroid patients and among those with or without thyroid papillary carcinoma. CONCLUSION: The results show that both disease activation and serum antibodies differentially affect both superficial and deep retinal vascular density. It has also been shown that high serum antibody levels affect choroidal thickness independent of clinical activity

Altered mitochondrial metabolism in the insulin-resistant heart.

Obesity-induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA-induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.COST Action MitoEAGL

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondria-Targeting Antioxidant Provides Cardioprotection through Regulation of Cytosolic and Mitochondrial Zn2+ Levels with Re-Distribution of Zn2+-Transporters in Aged Rat Cardiomyocytes

Aging is an important risk factor for cardiac dysfunction. Heart during aging exhibits a depressed mechanical activity, at least, through mitochondria-originated increases in ROS. Previously, we also have shown a close relationship between increased ROS and cellular intracellular free Zn2+ ([Zn2+]i) in cardiomyocytes under pathological conditions as well as the contribution of some re-expressed levels of Zn2+-transporters for redistribution of [Zn2+]i among suborganelles. Therefore, we first examined the cellular (total) [Zn2+] and then determined the protein expression levels of Zn2+-transporters in freshly isolated ventricular cardiomyocytes from 24-month rat heart compared to those of 6-month rats. The [Zn2+]i in the aged-cardiomyocytes was increased, at most, due to increased ZIP7 and ZnT8 with decreased levels of ZIP8 and ZnT7. To examine redistribution of the cellular [Zn2+]i among suborganelles, such as Sarco/endoplasmic reticulum, S(E)R, and mitochondria ([Zn2+]SER and [Zn2+]Mit), a cell model (with galactose) to mimic the aged-cell in rat ventricular cell line H9c2 was used and demonstrated that there were significant increases in [Zn2+]Mit with decreases in [Zn2+]SER. In addition, the re-distribution of these Zn2+-transporters were markedly changed in mitochondria (increases in ZnT7 and ZnT8 with no changes in ZIP7 and ZIP8) and S(E)R (increase in ZIP7 and decrease in ZnT7 with no changes in both ZIP8 and ZnT8) both of them isolated from freshly isolated ventricular cardiomyocytes from aged-rats. Furthermore, we demonstrated that cellular levels of ROS, both total and mitochondrial lysine acetylation (K-Acetylation), and protein-thiol oxidation were significantly high in aged-cardiomyocytes from 24-month old rats. Using a mitochondrial-targeting antioxidant, MitoTEMPO (1 &micro;M, 5-h incubation), we provided an important data associated with the role of mitochondrial-ROS production in the [Zn2+]i-dyshomeostasis of the ventricular cardiomyocytes from 24-month old rats. Overall, our present data, for the first time, demonstrated that a direct mitochondria-targeting antioxidant treatment can be a new therapeutic strategy during aging in the heart through a well-controlled [Zn2+] distribution among cytosol and suborganelles with altered expression levels of the Zn2+-transporters

A SGLT2 inhibitor dapagliflozin comparison with insulin exerts important effects on Zn2+-transporters in cardiomyocytes from insulin-resistant metabolic syndrome rats through inhibition of oxidative stress

Sodium-glucose cotransporter 2 (SGLT2)-inhibitors showed signiďŹ cant effect in patients with diabetes or metabolic syndrome, MetS with high cardiovascular-risk. Although the increased intracellular Zn2+ level ([Zn2+]i), oxidative stress and alterated cardiac matrix metalloproteinases (MMPs) in diabetic cardiomyopathy can intersect with different signaling pathways, the exact mechanisms are not known yet. Since either MMPs or SGLT2 have important role in cardiac-fibrosis under hyperglycemia, we aimed to examine the role of SGLT2-inhibitor dapagliflozin (DAP) on cardiac Zn2+-transporters responsible from [Zn2+]i-regulation, comparison to insulin (INS), together with MMP levels and systemic oxidative-stress-status in MetS-rats. High-carbohydrated diet-induced MetS-rats received DAP or INS for two weeks. DAP but not INS in MetS-rats significantly decreased high blood-glucose level, while both treatments exerted benefits on increased total-oxidative-status and decreased total-antioxidant-status in MetS-rat plasma as well as in heart tissue. Protein levels of Zn2+-transporters, responsible from Zn2+-influx into cytosol, ZIP7 and ZIP14 were decreased with no change in ZIP8 of MetS-rat cardiomyoctes, while Zn2+-transporters, responsible from cytosolic Zn2+-efflux, ZnT7 was decreased. Both treatments induced significant beneficial effects on altered ZIP14, ZIP8 and ZnT7 levels. Furthermore, both treatments exerted also benefits on depressed gelatin-zymography and protein expression levels of MMP-2 and MMP-9 in MetS-rat ventricular cardiomyocytes. The direct effect of DAP on heart was also confirmed with measurement of left ventricular developed pressure. Overall, we showed that DAP has important antioxidant-like cardio-protective effect in MetS-rats, similar to INS-effect, affecting Zn2+-regulation via Zn2+-transporters, MMPs and oxidative-stress. Therefore one can suggest that SGLT2-inhibitors can be new therapeutic agents for cardio-protection not only in hyperglycemia but also in failing heartThe accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Swimming exercise reverses aging-related contractile abnormalities of female heart by improving structural alterations

Background: The objective of this study was to examine the effect of swimming exercise on aging-related Ca2+ handling alterations and structural abnormalities of female rat heart. Methods: For this purpose, 4-month and 24-month old female rats were used and divided into three following groups: sedentary young (SY), sedentary old (SO), and exercised old (Ex-O). Swimming exercise was performed for 8 weeks (60 min/day, 5 days/week). Myocyte shortening, L-type Ca2+ currents and associated Ca2+ transients were measured from ventricular myocytes at 36 ± 1°C. NOX-4 levels, aconitase activity, glutathione measurements and ultrastructural examination by electron microscopy were conducted in heart tissue. Results: Swimming exercise reversed the reduced shortening and slowed kinetics of aged cardiomyocytes. Although the current density was similar for all groups, Ca2+ transients were higher in SO and Ex-O myocytes with respect to the SY group. Caffeine-induced Ca2+ transients and the integrated NCX current were lower in cardiomyocytes of SY rats compared with other groups, suggesting an increased sarcoplasmic reticulum Ca2+ content in an aged heart. Aging led to upregulated cardiac NOX-4 along with declined aconitase activity. Although it did not reverse these oxidative parameters, swimming exercise achieved a significant increase in glutathione levels and improved structural alterations of old rats’ hearts. Conclusions: We conclude that swimming exercise upregulates antioxidant defense capacity and improves structural abnormalities of senescent female rat heart, although it does not change Ca2+ handling alterations further. Thereby, it improves contractile function of aged myocardium by mitigating detrimental effects of oxidative stress

Interrelated In Vitro Mechanisms of Sibutramine-Induced Cardiotoxicity.

Consumption of illicit pharmaceutical products containing sibutramine has been reported to cause cardiovascular toxicity problems. This study aimed to demonstrate the toxicity profile of sibutramine, and thereby provide important implications for the development of more effective strategies in both clinical approaches and drug design studies. Action potentials (APs) were determined from freshly isolated ventricular cardiomyocytes with whole-cell configuration of current clamp as online. The maximum amplitude of APs (MAPs), the resting membrane potential (RMP), and AP duration from the repolarization phases were calculated from original records. The voltage-dependent K-channel currents (I) were recorded in the presence of external Cd and both inward and outward parts of the current were calculated, while their expression levels were determined with qPCR. The levels of intracellular free Ca and H (pH) as well as reactive oxygen species (ROS) were measured using either a ratiometric micro-spectrofluorometer or confocal microscope. The mechanical activity of isolated hearts was observed with Langendorff-perfusion system. Acute sibutramine applications (10-10 M) induced significant alterations in both MAPs and RMP as well as the repolarization phases of APs and I in a concentration-dependent manner. Sibutramine (10 μM) induced Ca-release from the sarcoplasmic reticulum under either electrical or caffeine stimulation, whereas it depressed left ventricular developed pressure with a marked decrease in the end-diastolic pressure. pH inhibition by sibutramine supports the observed negative alterations in contractility. Changes in mRNA levels of different I subunits are consistent with the acute inhibition of the repolarizing I, affecting AP parameters, and provoke the cardiotoxicity