Absence of Depressive and Anxious Behavior with Genetic Dysregulation in Adult C57Bl/6J Mice after Prenatal Exposure to Ionizing Radiation.

The exposure of ionizing radiation during early gestation often leads to deleterious and even lethal effects; however, few extensive studies have been conducted on late gestational exposures. This research examined the behavior al effects of C57Bl/6J mouse offspring exposed to low dose ionizing gamma irradiation during the equivalent third trimester. Pregnant dams were randomly assigned to sham or exposed groups to either low dose or sublethal dose radiation (50, 300, or 1000 mGy) at gestational day 15. Adult offspring underwent a behavioral and genetic analysis after being raised under normal murine housing conditions. Our results indicate very little change in the behavioral tasks measuring general anxiety, social anxiety, and stress-management in animals exposed prenatally across the low dose radiation conditions. Quantitative real-time polymerase chain reactions were conducted on the cerebral cortex, hippocampus, and cerebellum of each animal; results indicate some dysregulation in markers of DNA damage, synaptic activity, reactive oxygen species (ROS) regulation, and methylation pathways in the offspring. Together, our results provide evidence in the C57Bl/6J strain, that exposure to sublethal dose radiation (<1000 mGy) during the last period of gestation leads to no observable changes in behaviour when assessed as adults, although some changes in gene expression were observed for specific brain regions. These results indicate that the level of oxidative stress occurring during late gestation for this mouse strain is not sufficient for a change in the assessed behavioral phenotype, but results in some modest dysregulation of the genetic profile of the brain.

Blueberry extract attenuates norepinephrine-induced oxidative stress and apoptosis in H9c2 cardiac cells.

Enhanced sympathetic system activation mediated by norepinephrine (NE) contributes to adverse cardiac remodeling leading to oxidative stress and cell death, progressing to heart failure. Natural antioxidants may help maintain redox balance, attenuating NE-mediated cardiac cell damage. In the present study, we evaluated the effect of a blueberry extract (BBE) on H9c2 cardiac cells exposed to NE on cell death, oxidative stress status and its major signaling pathways. H9c2 cells were pre-incubated with 50 µg/ml of BBE for 4 h and maintained in the presence of 100 µM NE for 24 h. NE exposure resulted in increased caspase 3/7 activity. This was associated with reduced protein expression of antioxidants catalase, superoxide dismutase and glutathione peroxidase and increase in 4-hydroxynonenal adduct formation. NE led to increased activity of Protein kinase B (Akt), Forkhead box O3a and AMP-activated protein kinase alpha and decreased activity of Signal transducer and activator of transcription 3. BBE prevented caspases activation and abrogated NE-induced increase in oxidative stress, as well as attenuated the increase in Akt. Based on these findings, it is concluded that BBE promoted cardioprotection of H9c2 cells in an in vitro model of NE-induced oxidative damage, suggesting a cardioprotective role for BBE in response to NE exposure.

Circadian mutant mice with obesity and metabolic syndrome are resilient to cardiovascular disease.

Obesity and metabolic syndrome commonly underlie cardiovascular disease. ClockΔ19/Δ19 mice fed a normal diet develop obesity and metabolic syndrome; however, it is not known whether they develop or are resilient to cardiovascular disease. We found that ClockΔ19/Δ19 mice do not develop cardiac dysfunction, despite their underlying conditions. Moreover, in contrast to wild-type controls fed a high-fat diet (HFD), ClockΔ19/Δ19 HFD mice still do not develop cardiovascular disease. Indeed, ClockΔ19/Δ19 HFD mice have preserved heart weight despite their obesity, no cardiomyocyte hypertrophy, and preserved heart structure and function, even after 24 wk of a HFD. To determine why ClockΔ19/Δ19 mice are resilient to cardiac dysfunction despite their underlying obesity and metabolic conditions, we examined global cardiac gene expression profiles by microarray and bioinformatics analyses, revealing that oxidative stress pathways were involved. We examined the pathways in further detail and found that 1) SIRT-dependent oxidative stress pathways were not directly involved in resilience; 2) 4-hydroxynonenal (4-HNE) increased in wild-type HFD but not ClockΔ19/Δ19 mice, suggesting less reactive oxygen species in ClockΔ19/Δ19 mice; 3) cardiac catalase (CAT) and glutathione peroxidase (GPx) increased, suggesting strong antioxidant defenses in the hearts of ClockΔ19/Δ19 mice; and 4) Pparγ was upregulated in the hearts of ClockΔ19/Δ19 mice; this circadian-regulated gene drives transcription of CAT and GPx, providing a molecular basis for resilience in the ClockΔ19/Δ19 mice. These findings shed new light on the circadian regulation of oxidative stress and demonstrate an important role for the circadian mechanism in resilience to cardiovascular disease.NEW & NOTEWORTHY We examined whether obesity and metabolic syndrome underlie the development of cardiac dysfunction in circadian mutant ClockΔ19/Δ19 mice. Surprisingly, we demonstrate that although ClockΔ19/Δ19 mice develop metabolic dysfunction, they are protected from cardiac hypertrophy, left ventricular remodeling, and diastolic dysfunction, in contrast to wild-type controls, even when challenged with a chronic high-fat diet. These findings shed new light on the circadian regulation of oxidative stress pathways, which can mediate resilience to cardiovascular disease.

Ascorbic acid diminishes bone morphogenetic protein 2-induced osteogenic differentiation of muscle precursor cells.

INTRODUCTION: Muscle precursor cells (MPC) are integral to the maintenance of skeletal muscle and have recently been implicated in playing a role in bone repair. The primary objective of this study was to understand better the role of oxidative stress during the osteogenic differentiation of MPCs. METHODS: Muscle precursor cells were treated with various combinations of ascorbic acid (AA), bone morphogenetic protein (BMP)-2, and either a superoxide dismutase analog (4-hydroxy-TEMPO [TEMPOL]) or polyethyleneglycol-conjugated catalase. Muscle precursor cell proliferation and differentiation were determined, and alkaline phosphatase activity was measured as an index of osteogenic differentiation. RESULTS: After treatment with 200 µM AA, superoxide was increased 1.5-fold, whereas AA in combination with 100 ng/ml BMP-2 did not increase alkaline phosphatase (ALP) activity. When cells were treated with TEMPOL in combination with 100 ng/ml BMP-2 and 200 µM AA, ALP activity significantly increased. DISCUSSION: These data suggest that increasing oxidative stress with AA induces sublethal oxidative stress that prevents BMP-2-induced osteogenic differentiation of MPCs. Muscle Nerve 59:501-508, 2019.

Blueberry extract attenuates doxorubicin-induced damage in H9c2 cardiac cells 1.

The objective of this study was to analyze the cardioprotective roles of 3 wild blueberry genotypes and one commercial blueberry genotype by measuring markers of oxidative stress and cell death in H9c2 cardiac cells exposed to doxorubicin. Ripe berries of the 3 wild blueberry genotypes were collected from a 10-year-old clearcut forest near Nipigon, Ontario, Canada (49°1'39″N, 87°52'21″W), whereas the commercial blueberries were purchased from a local grocery store. H9c2 cardiac cells were incubated with 15 µg gallic acid equivalent/mL blueberry extract for 4 h followed by 5 µM doxorubicin for 4 h, and oxidative stress and active caspase 3/7 were analyzed. The surface area as well as total phenolic content was significantly higher in all 3 wild blueberry genotypes compared with the commercial species. Increase in oxidative stress due to doxorubicin exposure was attenuated by pre-treatment with all 3 types of wild blueberries but not by commercial berries. Furthermore, increase in caspase 3/7 activity was also attenuated by all 3 wild genotypes as well. These data demonstrate that wild blueberry extracts can attenuate doxorubicin-induced damage to H9c2 cardiomyocytes through reduction in oxidative stress and apoptosis, whereas the commercial blueberry had little effect.

Sensitive Electrochemical Detection of Nitric Oxide Release from Cardiac and Cancer Cells via a Hierarchical Nanoporous Gold Microelectrode.

The importance of nitric oxide (NO) in many biological processes has garnered increasing research interest in the design and development of efficient technologies for the sensitive detection of NO. Here we report on a novel gold microelectrode with a unique three-dimensional (3D) hierarchical nanoporous structure for the electrochemical sensing of NO, which was fabricated via a facile electrochemical alloying/dealloying method. Following the treatment, the electrochemically active surface area (ECSA) of the gold microelectrode was significantly increased by 22.9 times. The hierarchical nanoporous gold (HNG) microelectrode exhibited excellent performance for the detection of NO with high stability. On the basis of differential pulse voltammetry (DPV) and amperometric techniques, the obtained sensitivities were 21.8 and 14.4 µA µM-1 cm-2, with detection limits of 18.1 ± 1.22 and 1.38 ± 0.139 nM, respectively. The optimized HNG microelectrode was further utilized to monitor the release of NO from different cells, realizing a significant differential amount of NO generated from the normal and stressed rat cardiac cells as well as from the untreated and treated breast cancer cells. The HNG microelectrode developed in the present study may provide an effective platform in monitoring NO in biological processes and would have a great potential in the medical diagnostics.

Secoisolariciresinol diglucoside attenuates cardiac hypertrophy and oxidative stress in monocrotaline-induced right heart dysfunction.

Pulmonary arterial hypertension (PAH) occurs when remodeling of pulmonary vessels leads to increased pulmonary vascular resistance resulting in increased pulmonary arterial pressure. Increased pulmonary arterial pressure results in right ventricle hypertrophy and eventually heart failure. Oxidative stress has been implicated in the pathogenesis of PAH and may play a role in the regulation of cellular signaling involved in cardiac response to pressure overload. Secoisolariciresinol diglucoside (SDG), a component from flaxseed, has been shown to reduce cardiac oxidative stress in various pathophysiological conditions. We investigated the potential protective effects of SDG in a monocrotaline-induced model of PAH. Five- to six-week-old male Wistar rats were given a single intraperitoneal injection of monocrotaline (60 mg/kg) and sacrificed 21 days later where heart, lung, and plasma were collected. SDG (25 mg/kg) was given via gavage as either a 21-day co-treatment or pre-treatment of 14 days before monocrotaline administration and continued for 21 days. Monocrotaline led to right ventricle hypertrophy, increased lipid peroxidation, and elevated plasma levels of alanine transaminase (ALT) and aspartate transaminase (AST). Co-treatment with SDG did not attenuate hypertrophy or ALT and AST levels but decreased reactive oxygen species (ROS) levels and catalase and superoxide dismutase activity compared to the monocrotaline-treated group. Pre-treatment with SDG decreased right ventricle hypertrophy, ROS levels, lipid peroxidation, catalase, superoxide dismutase, and glutathione peroxidase activity and plasma levels of ALT and AST when compared to the monocrotaline group. These findings indicate that pre-treatment with SDG provided better protection than co-treatment in this model of right heart dysfunction, suggesting an important role for SDG in PAH and right ventricular remodeling.

Sensitive electrochemical detection of nitric oxide based on AuPt and reduced graphene oxide nanocomposites.

Since nitric oxide (NO) plays a critical role in many biological processes, its precise detection is essential toward an understanding of its specific functions. Here we report on a facile and environmentally compatible strategy for the construction of an electrochemical sensor based on reduced graphene oxide (rGO) and AuPt bimetallic nanoparticles. The prepared nanocomposites were further employed for the electroanalysis of NO using differential pulse voltammetry (DPV) and amperometric methods. The dependence of AuPt molar ratios on the electrochemical performance was investigated. Through the combination of the advantages of the high conductivity from rGO and highly electrocatalytic activity from AuPt bimetallic nanoparticles, the AuPt-rGO based NO sensor exhibited a high sensitivity of 7.35 µA µM(-1) and a low detection limit of 2.88 nM. Additionally, negligible interference from common ions or organic molecules was observed, and the AuPt-rGO modified electrode demonstrated excellent stability. Moreover, this optimized electrochemical sensor was practicable for efficiently monitoring the NO released from rat cardiac cells, which were stimulated by l-arginine (l-arg), showing that stressed cells generated over 10 times more NO than normal cells. The novel sensor developed in this study may have significant medical diagnostic applications for the prevention and monitoring of disease.

Cardiac phenylethanolamine N-methyltransferase: localization and regulation of gene expression in the spontaneously hypertensive rat.

Phenylethanolamine N-methyltransferase (PNMT) is the terminal enzyme in the catecholamine biosynthetic pathway responsible for adrenaline biosynthesis. Adrenaline is involved in the sympathetic control of blood pressure; it augments cardiac function by increasing stroke volume and cardiac output. Genetic mapping studies have linked the PNMT gene to hypertension. This study examined the expression of cardiac PNMT and changes in its transcriptional regulators in the spontaneously hypertensive (SHR) and wild type Wistar-Kyoto (WKY) rats. SHR exhibit elevated levels of corticosterone, and lower levels of the cytokine IL-1ß, revealing systemic differences between SHR and WKY. PNMT mRNA was significantly increased in all chambers of the heart in the SHR, with the greatest increase in the right atrium. Transcriptional regulators of the PNMT promoter show elevated expression of Egr-1, Sp1, AP-2, and GR mRNA in all chambers of the SHR heart, while protein levels of Sp1, Egr-1, and GR were elevated only in the right atrium. Interestingly, only AP-2 protein-DNA binding was increased, suggesting it may be a key regulator of cardiac PNMT in SHR. This study provides the first insights into the molecular mechanisms involved in the dysregulation of cardiac PNMT in a genetic model of hypertension.

Modulation of apoptosis by sulforaphane is associated with PGC-1α stimulation and decreased oxidative stress in cardiac myoblasts.

Sulforaphane is a naturally occurring isothiocyanate capable of stimulating cellular antioxidant defenses and inducing phase 2 detoxifying enzymes, which can protect cells against oxidative damage. Oxidative stress and apoptosis are intimately involved in the pathophysiology of cardiac diseases. Although sulforaphane is known for its anticancer benefits, its role in cardiac cells is just emerging. The aim of the present study was to investigate whether sulforaphane can modulate oxidative stress, apoptosis, and correlate with PGC-1α, a transcriptional cofactor involved in energy metabolism. H9c2 cardiac myoblasts were incubated with R-sulforaphane 5 µmol/L for 24 h. Cell viability, ANP gene expression, oxidative stress and apoptosis markers, and protein expression of PGC-1α were studied. In cells treated with sulforaphane, cellular viability increased (12 %) and ANP gene expression decreased (46 %) compared to control cells. Moreover, sulforaphane induced a significant increase in superoxide dismutase (103 %), catalase (101 %), and glutathione S-transferase (72 %) activity, reduced reactive oxygen species levels (15 %) and lipid peroxidation (65 %), as well as stimulated the expression of the cytoprotective enzyme heme oxygenase-1 (4-fold). Sulforaphane also promoted an increase in the expression of the anti-apoptotic protein Bcl-2 (60 %), decreasing the Bax/Bcl-2 ratio. Active Caspase 3\7 and p-JNK/JNK were also reduced by sulforaphane, suggesting a reduction in apoptotic signaling. This was associated with an increased protein expression of PGC-1α (42 %). These results suggest that sulforaphane offers cytoprotection to cardiac cells by activating PGC1-α, reducing oxidative stress, and decreasing apoptosis signaling.

Melatonin improves nitric oxide bioavailability in isoproterenol induced myocardial injury.

Isoproterenol administration is associated with cardiac inflammation and decreased NO availability. Melatonin has been reported to have cardioprotective effect. The aim of this study was to investigate the effect of melatonin on NO bioavailability and inflammation in myocardial injury induced by isoproterenol. Isoproterenol was administrated in male Wistar rats for 7 days to induce cardiac injury. The animals were divided into 3 groups: Control, Isoproterenol, Isoproterenol + Melatonin. Animals received melatonin for 7 days. Echocardiographic analysis was performed and the hearts were collected for molecular analysis. Animals that received isoproterenol demonstrated a reduction in left ventricle systolic and diastolic diameter, indicating the presence of concentric hypertrophy. Melatonin was able to attenuate this alteration. Melatonin also improved NO bioavailability and decreased NF-κß, TNFα and IL-1ß expression. In conclusion, melatonin exhibited a cardioprotective effect which was associated with improving NO bioavailability and decreasing the pro-inflammatory proteins.

Redox-inflammatory synergy in the metabolic syndrome.

Metabolic syndrome (MetS) comprises interrelated disease states including obesity, insulin resistance and type 2 diabetes (T2DM), dyslipidemia, and hypertension. Essential to normal physiological function, and yet massively damaging in excess, oxidative stress and inflammation are pivotal common threads among the pathologies of MetS. Increasing evidence indicates that redox and inflammatory dysregulation parallels the syndrome's physiological, biochemical, and anthropometric features, leading many to consider the pro-oxidative, pro-inflammatory milieu an unofficial criterion in itself. Left unchecked, cross-promotion of oxidative stress and inflammation creates a feed-forward cycle that can initiate and advance disease progression. Such redox-inflammatory integration is evident in the pathogenesis of obesity, insulin resistance and T2DM, atherogenic dyslipidemia, and hypertension, and is thus hypothesized to be the "common soil" from which they develop. The present review highlights the synergistic contributions of redox-inflammatory processes to each of the components of the MetS.

The antioxidant resveratrol down-regulates inflammation in an in-vitro model of Pseudomonas aeruginosa infection of lung epithelial cells.

Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that can cause severe pulmonary infection in immunocompromized individuals. During the infectious process, P. aeruginosa provokes a potent inflammatory response and induces the release of reactive oxygen species (ROS). Cells undergo oxidative stress when cellular antioxidants are unable to effectively scavenge and detoxify ROS, resulting in lung damage. Resveratrol (3,5,4'-trihydroxystilbene) is a natural polyphenolic compound with recognized antioxidant effects. We hypothesized that owing to its antioxidant activities, resveratrol can attenuate an inflammatory response in P. aeruginosa-infected cells. Lung epithelial A549 cells were pre-treated with 100 µmol/L of resveratrol for 5 h, followed by infection with P. aeruginosa. Intracellular ROS generation was used as an indicator of P. aeruginosa-induced oxidative stress, and cell surface expression of Fas receptor and activation of caspases-3 and -7 as indicators of apoptosis. We also measured the surface expression of intercellular adhesion molecule (ICAM)-1 and enzymes related to inflammation and redox signaling. Resveratrol significantly reduced ROS generation, ICAM-1, and human beta-defensin-2 expression, as well as the markers of apoptosis in A549 cells infected with P. aeruginosa, and up-regulated glutathione peroxidase, suggesting its potential therapeutic role in protecting the lungs against the deleterious effects of P. aeruginosa infection.

Overexpression of FRA1 (FOSL1) Leads to Global Transcriptional Perturbations, Reduced Cellular Adhesion and Altered Cell Cycle Progression.

FRA1 (FOSL1) is a transcription factor and a member of the activator protein-1 superfamily. FRA1 is expressed in most tissues at low levels, and its expression is robustly induced in response to extracellular signals, leading to downstream cellular processes. However, abnormal FRA1 overexpression has been reported in various pathological states, including tumor progression and inflammation. To date, the molecular effects of FRA1 overexpression are still not understood. Therefore, the aim of this study was to investigate the transcriptional and functional effects of FRA1 overexpression using the CGL1 human hybrid cell line. FRA1-overexpressing CGL1 cells were generated using stably integrated CRISPR-mediated transcriptional activation, resulting in a 2-3 fold increase in FRA1 mRNA and protein levels. RNA-sequencing identified 298 differentially expressed genes with FRA1 overexpression. Gene ontology analysis showed numerous molecular networks enriched with FRA1 overexpression, including transcription-factor binding, regulation of the extracellular matrix and adhesion, and a variety of signaling processes, including protein kinase activity and chemokine signaling. In addition, cell functional assays demonstrated reduced cell adherence to fibronectin and collagen with FRA1 overexpression and altered cell cycle progression. Taken together, this study unravels the transcriptional response mediated by FRA1 overexpression and establishes the role of FRA1 in adhesion and cell cycle progression.

Lasiodiplodan, an exocellular (1→6)-ß-D: -glucan from Lasiodiplodia theobromae MMPI: production on glucose, fermentation kinetics, rheology and anti-proliferative activity.

Lasiodiplodan, an exopolysaccharide of the (1→6)-ß-D: -glucan type, is produced by Lasiodiplodia theobromae MMPI when grown under submerged culture on glucose. The objective of this study was to evaluate lasiodiplodan production by examining the effects of carbon (glucose, fructose, maltose, sucrose) and nitrogen sources (KNO(3), (NH(4))(2)SO(4), urea, yeast extract, peptone), its production in shake flasks compared to a stirred-tank bioreactor, and to study the rheology of lasiodiplodan, and lasiodiplodan's anti-proliferative effect on breast cancer MCF-7 cells. Although glucose (2.05 ± 0.05 g L(-1)), maltose (2.08 ± 0.04 g L(-1)) and yeast extract (2.46 ± 0.06 g L(-1)) produced the highest amounts of lasiodiplodan, urea as N source resulted in more lasiodiplodan per unit biomass than yeast extract (0.74 ± 0.006 vs. 0.22 ± 0.008 g g(-1)). A comparison of the fermentative parameters of L. theobromae MMPI in shake flasks and a stirred-tank bioreactor at 120 h on glucose as carbon source showed maximum lasiodiplodan production in agitated flasks (7.01 ± 0.07 g L(-1)) with a specific yield of 0.25 ± 0.57 g g(-1) and a volumetric productivity of 0.06 ± 0.001 g L(-1) h(-1). A factorial 2(2) statistical design developed to evaluate the effect of glucose concentration (20-60 g L(-1)) and impeller speed (100-200 rpm) on lasiodiplodan production in the bioreactor showed the highest production (6.32 g L(-1)) at 72 h. Lasiodiplodan presented pseudoplastic behaviour, and the apparent viscosity increased at 60°C in the presence of CaCl(2). Anti-proliferative activity of lasiodiplodan was demonstrated in MCF-7 cells, which was time- and dose-dependent with an IC(50) of 100 µg lasiodiplodan mL(-1).

Early loss of cardiac function in acute myocardial infarction is associated with redox imbalance.

BACKGROUND: The loss of viable myocardium subsequent to myocardial infarction (MI) impairs cardiac function, and oxidative stress is considered to be critical in this process. OBJECTIVES: To assess cardiac function and correlate it with oxidative stress and antioxidant levels in cardiac tissue at 48 h post-MI. METHODS: Adult male Wistar rats (n=6 per group) with a mean (± SD) weight of 229±24 g were randomly assigned to either an infarcted group or a control group. MI was induced by occlusion of the left coronary artery. Cardiac function was evaluated by measuring left ventricular (LV) ejection fraction, LV fractional shortening, cardiac output, myocardial performance index and the peak early diastolic velocity/peak atrial velocity ratio using echocardiography. The myocardial oxidative stress profile was assessed by measuring the reduced glutathione/oxidized glutathione ratio, H2O2 levels, peroxiredoxin-6 protein levels and activity levels of superoxide dismutase, catalase and glutathione peroxidase. Lipid peroxidation was quantified using chemiluminescence, and protein oxidation was determined by measuring protein carbonyl levels. RESULTS: LV ejection fraction and LV fractional shortening were lower in the infarcted group compared with the sham group, whereas the peak early diastolic velocity/peak atrial velocity ratio and myocardial performance index were significantly increased, indicating systolic dysfunction. Lipid peroxidation, protein carbonyls and superoxide dismutase and catalase activity levels did not differ between the groups. Peroxyredoxin-6 levels were increased in the infarcted group, while H2O2 levels were reduced. The reduced glutathione/oxidized glutathione ratio and the glutathione peroxidase activity were reduced in the infarcted group compared with control. DISCUSSION AND CONCLUSION: These data suggest that MI-induced cardiac dysfunction and impaired redox balance may be associated with the activation of counter-regulatory responses to maintain reduced H2O2 concentrations and, thereby, prevent further oxidative damage at this early time point.

Chronic glucocorticoid exposure causes brown adipose tissue whitening, alters whole-body glucose metabolism and increases tissue uncoupling protein-1.

Adipose tissue (AT) has been found to exist in two predominant forms, white and brown. White adipose tissue (WAT) is the body's conventional storage organ, and brown adipose tissue (BAT) is responsible for non-shivering thermogenesis which allows mammals to produce heat and regulate body temperature. Studies examining BAT and its role in whole-body metabolism have found that active BAT utilizes glucose and circulating fatty acids and is associated with improved metabolic outcomes. While the beiging of WAT is a growing area of interest, the possibility of the BAT depot to "whiten" and store more triglycerides also has metabolic and health implications. Currently, there are limited studies that examine the effects of chronic stress and its ability to induce a white-like phenotype in the BAT depot. This research examined how chronic exposure to the murine stress hormone, corticosterone, for 4 weeks can affect the whitening process of BAT in C57BL/6 male mice. Separate treatments with mirabegron, a known ß3-adrenergic receptor agonist, were used to directly compare the effects of corticosterone with a beiging phenotype. Corticosterone-treated mice had significantly higher body weight (p ≤ 0.05) and BAT mass (p ≤ 0.05), increased adipocyte area (p ≤ 0.05), were insulin resistant (p ≤ 0.05), and significantly elevated expressions of uncoupling protein 1 (UCP-1) in BAT (p ≤ 0.05) while mitochondrial content remained unchanged. This whitened phenotype has not been previously associated with increased uncoupling proteins under chronic stress and may represent a compensatory mechanism being initiated under these conditions. These findings have implications for the study of BAT in response to chronic glucocorticoid exposure potentially leading to BAT dysfunction and negative impacts on whole-body glucose metabolism.

Identification of Radiation-Induced miRNA Biomarkers Using the CGL1 Cell Model System.

MicroRNAs (miRNAs) have emerged as a potential class of biomolecules for diagnostic biomarker applications. miRNAs are small non-coding RNA molecules, produced and released by cells in response to various stimuli, that demonstrate remarkable stability in a wide range of biological fluids, in extreme pH fluctuations, and after multiple freeze-thaw cycles. Given these advantages, identification of miRNA-based biomarkers for radiation exposures can contribute to the development of reliable biological dosimetry methods, especially for low-dose radiation (LDR) exposures. In this study, an miRNAome next-generation sequencing (NGS) approach was utilized to identify novel radiation-induced miRNA gene changes within the CGL1 human cell line. Here, irradiations of 10, 100, and 1000 mGy were performed and the samples were collected 1, 6, and 24 h post-irradiation. Corroboration of the miRNAome results with RT-qPCR verification confirmed the identification of numerous radiation-induced miRNA expression changes at all doses assessed. Further evaluation of select radiation-induced miRNAs, including miR-1228-3p and miR-758-5p, as well as their downstream mRNA targets, Ube2d2, Ppp2r2d, and Id2, demonstrated significantly dysregulated reciprocal expression patterns. Further evaluation is needed to determine whether the candidate miRNA biomarkers identified in this study can serve as suitable targets for radiation biodosimetry applications.

Mirabegron: The most promising adipose tissue beiging agent.

Accumulation of white adipose tissue (WAT) underlies the obesity epidemic, leading to current therapeutic techniques that are being investigated for their ability to activate/"beige" this tissue. Adipose tissue (AT) beiging has been reported through intermittent cold exposure (CE), exercise, and ß3-Adrenergic Receptor (ß3AR) agonists. But how AT beiging can help in the treatment of metabolic disorders like obesity and type 2 diabetes (T2D) remains largely unexplored. This review summarizes recent research on the use of ß3AR agonist, mirabegron (Myrbetriq®), in stimulating beiging in AT. Researchers have only recently been able to determine the optimal therapeutic dose of mirabegron for inducing beiging in subcutaneous/ inguinal WAT, where the benefits of AT activation are evident without the undesired cardiovascular side effects. To determine whether the effects that mirabegron elicits are metabolically beneficial, a comparison of the undisputed findings resulting from intermittent CE-induced beiging and the disputed findings from exercise-induced beiging was conducted. Given the recent in vivo animal and clinical studies, the understanding of how mirabegron can be metabolically beneficial for both lean and obese individuals is more clearly understood. These studies have demonstrated that circulating adipokines, glucose metabolism, and lipid droplet (LD) size are all positively affected by mirabegron administration. Recent studies have also demonstrated that mirabegron has similar outcomes to intermittent CE and displays more direct evidence for beiging than those produced with exercise. With these current findings, mirabegron is considered the most promising and safest ß3AR agonist currently available that has the potential to be used in the therapeutic treatment of metabolic disorders, and future studies into its interaction with different conditions may prove to be useful as part of a treatment plan in combination with a healthy diet and exercise.

Oxidative Stress Mediates the Fetal Programming of Hypertension by Glucocorticoids.

The field of cardiovascular fetal programming has emphasized the importance of the uterine environment on postnatal cardiovascular health. Studies have linked increased fetal glucocorticoid exposure, either from exogenous sources (such as dexamethasone (Dex) injections), or from maternal stress, to the development of adult cardiovascular pathologies. Although the mechanisms are not fully understood, alterations in gene expression driven by altered oxidative stress and epigenetic pathways are implicated in glucocorticoid-mediated cardiovascular programming. Antioxidants, such as the naturally occurring polyphenol epigallocatechin gallate (EGCG), or the superoxide dismutase (SOD) 4-hydroxy-TEMPO (TEMPOL), have shown promise in the prevention of cardiovascular dysfunction and programming. This study investigated maternal antioxidant administration with EGCG or TEMPOL and their ability to attenuate the fetal programming of hypertension via Dex injections in WKY rats. Results from this study indicate that, while Dex-programming increased blood pressure in male and female adult offspring, administration of EGCG or TEMPOL via maternal drinking water attenuated Dex-programmed increases in blood pressure, as well as changes in adrenal mRNA and protein levels of catecholamine biosynthetic enzymes phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH), dopamine beta hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT), in a sex-specific manner. Furthermore, programmed male offspring displayed reduced antioxidant glutathione peroxidase 1 (Gpx1) expression, increased superoxide dismutase 1 (SOD1) and catalase (CAT) expression, and increased pro-oxidant NADPH oxidase activator 1 (Noxa1) expression in the adrenal glands. In addition, prenatal Dex exposure alters expression of epigenetic regulators histone deacetylase (HDAC) 1, 5, 6, 7, 11, in male and HDAC7 in female offspring. These results suggest that glucocorticoids may mediate the fetal programming of hypertension via alteration of epigenetic machinery and oxidative stress pathways.