Alterations in Energy Metabolism, Mitochondrial Function and Redox Homeostasis in GK Diabetic Rat Tissues Treated with Aspirin

Our recent studies have demonstrated that aspirin treatment prevents inflammatory and oxidative stress-induced alterations in mitochondrial function, improves glucose tolerance and pancreatic endocrine function and preserves tissue-specific glutathione (GSH)-dependent redox homeostasis in Goto-Kakizaki (GK) diabetic rats. In the current study, we have investigated the mechanism of action of aspirin in maintaining mitochondrial bioenergetics and redox metabolism in the liver and kidneys of GK rats. Aspirin reduced the production of reactive oxygen species (ROS) and oxidative stress-induced changes in GSH metabolism. Aspirin treatment also improved mitochondrial respiratory function and energy metabolism, in addition to regulating the expression of cell signaling proteins that were altered in diabetic animals. Ultrastructural electron microscopy studies revealed decreased accumulation of glycogen in the liver of aspirin-treated diabetic rats. Hypertrophic podocytes with irregular fusion of foot processes in the renal glomerulus and detached microvilli, condensed nuclei and degenerated mitochondria observed in the proximal convoluted tubules of GK rats were partially restored by aspirin. These results provide additional evidence to support our previous observation of moderation of diabetic complications by aspirin treatment in GK rats and may have implications for cautious use of aspirin in the therapeutic management of diabetes.

Bisphenol S Impairs Invasion and Proliferation of Extravillous Trophoblasts Cells by Interfering with Epidermal Growth Factor Receptor Signaling

The placenta supports fetal growth and is vulnerable to exogenous chemical exposures. We have previously demonstrated that exposure to the emerging chemical bisphenol S (BPS) can alter placental endocrine function. Mechanistically, we have demonstrated that BPS interferes with epidermal growth factor receptor (EGFR) signaling, reducing placenta cell fusion. Extravillous trophoblasts (EVTs), a placenta cell type that aids with vascular remodeling, require EGF to invade into the maternal endometrium. We hypothesized that BPS would impair EGF-mediated invasion and proliferation in EVTs. Using human EVTs (HTR-8/SVneo cells), we tested whether BPS could inhibit the EGF response by blocking EGFR activation. We also evaluated functional endpoints of EGFR signaling, including EGF endocytosis, cell invasion and proliferation, and endovascular differentiation. We demonstrated that BPS blocked EGF-induced phosphorylation of EGFR by acting as a competitive antagonist to EGFR. Transwell assay and a three-dimensional microfluidic chip invasion assay revealed that BPS exposure can block EGF-mediated cell invasion. BPS also blocked EGF-mediated proliferation and endovascular differentiation. In conclusion, BPS can prevent EGF-mediated EVT proliferation and invasion through EGFR antagonism. Given the role of EGFR in trophoblast proliferation and differentiation during placental development, our findings suggest that maternal exposure to BPS may contribute to placental dysfunction via EGFR-mediated mechanisms.

The peculiarities of hormonal background in boars under correction of reproductive capacity by gadolinium orthovanadate nanoparticles

Determination of the influence of redox nanomaterials on the body of males is of great interest to researchers, because the basis of the pathogenesis of male infertility is oxidative stress. A necessary condition in the development of such drugs is the absence of toxic effects on sexual function. It has been proved that nanomaterials based on oxides of rare earth elements have a positive effect on reproductive capacity and, at the same time, they are not gonadotoxic. A comprehensive approach is of particular importance in order to justify their use as a means of reproductive capacity correction. Taking into account the toxicity parameters the mechanisms of their action need to be studied at the biochemical, morphological and clinical levels. The positive effect of gadolinium orthovanadate nanoparticles on the quality of boar sperm (especially in terms of motility and the number of motile sperm in the ejaculate) with an effective reduction of the oxidative load on the body have been shown. The aim of this study was to determine the effect of these nanoparticles on the hormonal background of males with a decreased reproductive capacity under oxidative stress. Thus, the administration of hydrosol of gadolinium orthovanadate nanoparticles for 14 days revealed a normalization of sex hormones – an increase in total testosterone, in particular, on the 15th day of the study – by 22.6 % (P ˂ 0.01), and on the 30th day – by 77.4 % (P ˂ 0.001) compared with the group of animals before the administration. There was a decrease in the level of 17β-estradiol on the 30th day – by 25.0 % (P ˂ 0.01), which almost reached the values of the control group. A decrease in the content of globulin testosterone-estradiol-binding in boars of the experimental group, in particular, on the 15th day of the experiment – by 13.0 % (P ˂ 0.05), and on the 30th day – by 26.8 % (P ˂ 0.001) was determined, which, in turn, led to an increase in androgen saturation of the animal body – the index of free androgens at the end of the study was 43.2 %. The results are explained by the properties of the nanoparticles. Correcting oxidative stress, they increase the antioxidant potential, thereby normalizing the activity of endocrine glands and ways of regulating the germ-endocrine function of the gonads. The prospect of further research is to elucidate the effect of the correction of decreased reproductive capacity in boars under oxidative stress by nanoparticles of oxides of rare earth elements on the morphological state of the gonads.

The Impact of Trace Elements on Osteoarthritis

Osteoarthritis (OA) is a progressive degenerative disease characterized by cartilage degradation, synovial inflammation, subchondral sclerosis and osteophyte formation. It has a multifactorial etiology with potential contributions from heredity, endocrine function, abnormal mechanical load and nutrition. Of particular considerations are trace element status. Several trace elements, such as boron and magnesium are essential for normal development of the bone and joint in human. While cadmium correlates with the severity of OA. The present review focuses on the roles of trace elements (boron, cadmium, copper, iron, magnesium, manganese, selenium, zinc) in OA and explores the mechanisms by which they act.

Fatquant: An automated image analysis tool for identification of fat cells in heterogeneous hematoxylin and eosin tissue sections.

Hematoxylin and eosin (H and E) is one of the common histological staining techniques that provides information on the tissue cytoarchitecture. Adipose (fat) cells accumulation in pancreas has been shown to impact beta cell survival and its endocrine function. The current automated tools available for fat analysis are suited for white adipose tissue which is homogeneous and easier to segment unlike heterogeneous tissues such as pancreas where fat cells continue to play critical physiopathological functions. In the current study, we present an automated fat analysis tool, Fatquant, where mathematical formula to calculate diagonal of a square drawn inside circle is utilized for identification and analysis of fat cells in heterogeneous H and E tissue sections. Using histological images of pancreas from a publicly available database, we show an area accuracy overlap of 89-93% between manual versus automated algorithm based fat cell detection.

miR-208a in Cardiac Hypertrophy and Remodeling

Various stresses, including pressure overload and myocardial stretch, can trigger cardiac remodeling and result in heart diseases. The disorders are associated with high risk of morbidity and mortality and are among the major health problems in the world. MicroRNAs, a class of ~22nt-long small non-coding RNAs, have been found to participate in regulating heart development and function. One of them, miR-208a, a cardiac-specific microRNA, plays key role(s) in modulating gene expression in the heart, and is involved in a broad array of processes in cardiac pathogenesis. Genetic deletion or pharmacological inhibition of miR-208a in rodents attenuated stress-induced cardiac hypertrophy and remodeling. Transgenic expression of miR-208a in the heart was sufficient to cause hypertrophic growth of cardiomyocytes. miR-208a is also a key regulator of cardiac conduction system, either deletion or transgenic expression of miR-208a disturbed heart electrophysiology and could induce arrhythmias. In addition, miR-208a appeared to assist in regulating the expression of fast- and slow-twitch myofiber genes in the heart. Notably, this heart-specific miRNA could also modulate the “endocrine” function of cardiac muscle and govern the systemic energy homeostasis in the whole body. Despite of the critical roles, the underlying regulatory networks involving miR-208a are still elusive. Here, we summarize the progress made in understanding the function and mechanisms of this important miRNA in the heart, and propose several topics to be resolved as well as the hypothetical answers. We speculate that miR-208a may play diverse and even opposite roles by being involved in distinct molecular networks depending on the contexts. A deeper understanding of the precise mechanisms of its action under the conditions of cardiac homeostasis and diseases is needed. The clinical implications of miR-208a are also discussed.

Attenuation Value in Adrenal Incidentalomas: A Longitudinal Study

ContextA tendency to grow has been reported in adrenal incidentalomas. However, long-term data regarding attenuation value, a measure of lipid content, are not available.AimThis study aims to collect radiological data (diameter in mm and attenuation value in Hounsfield units, HU) with computed tomography (CT) in adrenal incidentalomas, in order to compare baseline characteristics with the last follow-up imaging.DesignThis is a longitudinal study which included patients with a new diagnosis of adrenal incidentaloma, evaluated from January 2002 to June 2020.SettingReferral University-Hospital center.PatientsTwo hundred seventy-seven patients with 355 different cortical adenomas (baseline group) were evaluated at the first outpatient visit; the follow-up cohort consists of 181 patients with 234 adenomas (12–175 months after baseline). Inclusion criteria were conservative management and radiological features able to minimize malignancy or risk of progression.Main Outcome MeasureCT modification according to endocrine function: autonomous cortisol secretion (ACS) if cortisol >50 nmol/L after 1-mg dexamethasone test (DST).ResultsAt baseline CT, mean diameter was 18.7 mm and attenuation value was 0.8 HU (higher in ACS, 66 cases >10 HU), without modification in early imaging (12–36 months). The size increased over time (r = 0.289), achieving the largest differences after at least 60 months of follow-up (mean diameter, +2 mm; attenuation value, −4 HU), combined with a reduction in the attenuation value (r = −0.195, especially in patients with ACS). Lipid-poor adenomas (>10 HU) presented a reduced cortisol suppression after 1-mg DST, an increase in size and the largest decrease in attenuation value during follow-up. Univariate analysis confirmed that larger adenomas presented reduced suppression after DST and increase in size during follow-up.ConclusionsGrowth is clinically modest in adrenal incidentaloma: the first follow-up CT 5 years after baseline is a reasonable choice, especially in ACS. Mean density is increased in patients with ACS and overt hypercortisolism. Mean density reduces during follow-up in all adrenal adenomas, suggesting an increase in lipid content, especially in those with ACS.