Antimicrobial Potential of Pomegranate and Lemon Extracts Alone or in Combination with Antibiotics against Pathogens.

Amidst the growing concern of antimicrobial resistance as a significant health challenge, research has emerged, focusing on elucidating the antimicrobial potential of polyphenol-rich extracts to reduce reliance on antibiotics. Previous studies explored the antifungal effects of extracts as potential alternatives to conventional therapeutic strategies. We aimed to assess the antibacterial and antifungal effects of standardised pomegranate extract (PE) and lemon extract (LE) using a range of Gram-negative and Gram-positive bacteria and two yeast species. Additionally, we assessed the antimicrobial activities of common antibiotics (Ciprofloxacin, Imipenem, Gentamicin, and Ceftazidime), either alone or in combination with extracts, against Staphylococcus aureus and Escherichia coli. PE displayed substantial antibacterial (primarily bactericidal) and antifungal effects against most pathogens, while LE exhibited antibacterial (mostly bacteriostatic) and antifungal properties to a lesser extent. When compared with antibiotics, PE showed a greater zone of inhibition (ZOI) than Ciprofloxacin and Ceftazidime (p < 0.01) and comparable ZOI to Gentamicin (p = 0.4) against Staphylococcus aureus. However, combinations of either PE or LE with antibiotics exhibited either neutral or antagonistic effects on antibiotic activity against Staphylococcus aureus and Escherichia coli. These findings contribute to the existing evidence regarding the antimicrobial effects of PE and LE. They add to the body of research suggesting that polyphenols exert both antagonistic and synergistic effects in antimicrobial activity. This highlights the importance of identifying optimal polyphenol concentrations that can enhance antibiotic activity and reduce antibiotic resistance. Further in vivo studies, starting with animal trials and progressing to human trials, may potentially lead to recommendation of these extracts for therapeutic use.

Effect of Polyphenol Supplementation on Memory Functioning in Overweight and Obese Adults: A Systematic Review and Meta-Analysis.

Negative health consequences of obesity include impaired neuronal functioning and cell death, thus bringing the risk of impaired cognitive functioning. Antioxidant properties of polyphenols offer a possible intervention for overweight people, but evidence for their effectiveness in supporting cognitive functioning is mixed. This review examined evidence from randomized controlled trials concerning the effect of polyphenols on tasks requiring either immediate or delayed retrieval of learned information, respectively, thus controlling for differences in cognitive processes and related neural substrates supporting respective task demands. Searches of the PubMed/Medline, PsycInfo, and Scopus databases identified 24 relevant primary studies with N = 2336 participants having a BMI ≥ 25.0 kg/m2. The participants' mean age for the 24 studies exceeded 60 years. Respective meta-analyses produced a significant summary effect for immediate retrieval but not for delayed retrieval. The present findings support a potential positive effect of chronic supplementation with polyphenols, most notably flavonoids, on immediate retrieval in participants aged over 60 years with obesity being a risk factor for cognitive impairment. We recommend further investigation of this potential positive effect in participants with such risk factors. Future research on all populations should report the phenolic content of the supplementation administered and be specific regarding the cognitive processes tested.

Synergistic Effects of AgNPs and Biochar: A Potential Combination for Combating Lung Cancer and Pathogenic Bacteria.

The synthesis of reliable biological nanomaterials is a crucial area of study in nanotechnology. In this study, Emericella dentata was employed for the biosynthesis of AgNPs, which were then combined with synthesized biochar, a porous structure created through biomass pyrolysis. The synergistic effects of AgNPs and biochar were evaluated through the assessment of pro-inflammatory cytokines, anti-apoptotic gene expression, and antibacterial activity. Solid biosynthesized AgNPs were evaluated by XRD and SEM, with SEM images revealing that most of the AgNPs ranged from 10 to 80 nm, with over 70% being less than 40 nm. FTIR analysis indicated the presence of stabilizing and reducing functional groups in the AgNPs. The nanoemulsion's zeta potential, hydrodynamic diameter, and particle distribution index were found to be -19.6 mV, 37.62 nm, and 0.231, respectively. Biochar, on the other hand, did not have any antibacterial effects on the tested bacterial species. However, when combined with AgNPs, its antibacterial efficacy against all bacterial species was significantly enhanced. Furthermore, the combined material significantly reduced the expression of anti-apoptotic genes and pro-inflammatory cytokines compared to individual treatments. This study suggests that low-dose AgNPs coupled with biochar could be a more effective method to combat lung cancer epithelial cells and pathogenic bacteria compared to either substance alone.

Rosmarinus officinalis and Mentha piperita Oils Supplementation Enhances Memory in a Rat Model of Scopolamine-Induced Alzheimer's Disease-like Condition.

Alzheimer's disease is regarded as a common neurodegenerative disease that may lead to dementia and the loss of memory. We report here the nootropic and anti-amnesic effects of both peppermint and rosemary oils using a rat model of scopolamine-induced amnesia-like AD. Rats were administered orally with two doses (50 and 100 mg/kg) of each single oil and combined oils. The positive group used donepezil (1 mg/kg). In the therapeutic phase, rats were administered scopolamine (1 mg/kg) through the oral administration of oils. During the nootropic phase, both oils showed a significant (p < 0.05) decrease in radial arm maze latency times, working memory, and reference memory errors compared with the normal group, along with significant (p < 0.05) enhancements of long-term memory during the passive avoidance test. Therapeutic phase results revealed significant enhancements of memory processing compared with the positive groups. In the hippocampus, oils exhibited an elevation of BDNF levels in a dose-dependent manner. Immunohistochemistry findings showed increased hippocampal neurogenesis suppressed by scopolamine in the sub-granular zone, and the anti-amnesic activity of single oil was enhanced when the two oils combined. Gas chromatography-mass spectrometry (GCMS) of the two oils revealed sufficient compounds (1,8-Cineole, α-Pinene, menthol and menthone) with potential efficacy in the memory process and cognitive defects. Our work suggests that both oils could enhance the performance of working and spatial memory, and when combined, more anti-amnesic activity was produced. A potential enhancement of hippocampal growth and neural plasticity was apparent with possible therapeutic activity to boost memory in AD patients.

Preparation, Characterization, Wound Healing, and Cytotoxicity Assay of PEGylated Nanophytosomes Loaded with 6-Gingerol.

BACKGROUND: Nutrients are widely used for treating illnesses in traditional medicine. Ginger has long been used in folk medicine to treat motion sickness and other minor health disorders. Chronic non-healing wounds might elicit an inflammation response and cancerous mutation. Few clinical studies have investigated 6-gingerol's wound-healing activity due to its poor pharmacokinetic properties. However, nanotechnology can deliver 6-gingerol while possibly enhancing these properties. Our study aimed to develop a nanophytosome system loaded with 6-gingerol molecules to investigate the delivery system's influence on wound healing and anti-cancer activities. METHODS: We adopted the thin-film hydration method to synthesize nanophytosomes. We used lipids in a ratio of 70:25:5 for DOPC(dioleoyl-sn-glycero-3-phosphocholine): cholesterol: DSPE/PEG2000, respectively. We loaded the 6-gingerol molecules in a concentration of 1.67 mg/mL and achieved size reduction via the extrusion technique. We determined cytotoxicity using lung, breast, and pancreatic cancer cell lines. We performed gene expression of inflammation markers and cytokines according to international protocols. RESULTS: The synthesized nanophytosome particle sizes were 150.16 ± 1.65, the total charge was -13.36 ± 1.266, and the polydispersity index was 0.060 ± 0.050. Transmission electron microscopy determined the synthesized particles' spherical shape and uniform size. The encapsulation efficiency was 34.54% ± 0.035. Our biological tests showed that 6-gingerol nanophytosomes displayed selective antiproliferative activity, considerable downregulation of inflammatory markers and cytokines, and an enhanced wound-healing process. CONCLUSIONS: Our results confirm the anti-cancer activity of PEGylated nanophytosome 6-gingerol, with superior activity exhibited in accelerating wound healing.

Antioxidant Properties and Beneficial Cardiovascular Effects of a Natural Extract of Pomegranate in Healthy Volunteers: A Randomized Preliminary Single-Blind Controlled Study.

Pomegranates are known to possess anti-hypertensive, anti-atherogenic and cardioprotective effects mainly due to their pleiotropic effects on various cellular pathways, especially those triggered by oxidative stress. The aim of this study was to investigate the effect of natural standardized pomegranate (PE) extract on cardiovascular risk factors in 24 healthy volunteers who participated in a randomized, single-blind placebo-controlled study. There were 12 subjects in the PE group and 12 in the placebo group. Variables were measured at baseline and after 14 and 28 days of supplementation are anthropometry, BP, pulse wave velocity, fat and lean body mass, salivary and urinary cortisol, and cortisone, total phenolics, antioxidant capacity and lipid peroxidation. Urinary total phenolics excretion and antioxidant capacity were significantly increased after 14 and 28 days of PE intake. At day 28, there were also statistically significant decreases in systolic and diastolic blood pressure (BP), pulse wave velocity, body fat and fat mass, as well as an increase in lean body mass. Significant changes in the placebo group were not found. Glucocorticoid levels showed a significant decrease in saliva cortisol at day 28 (morning) in the PE group, and cortisol/cortisone ratio was significantly decreased following 28 days of PE intake at morning, noon, and evening. Urine free cortisol was significantly reduced at day 14. These findings suggest that pomegranate extract intake may improve antioxidant and oxidative stress status and play a beneficial role in the attenuation of some cardiovascular risk factors. Future studies should concentrate on overweight and older people.

Effect of Pomegranate Extract Consumption on Satiety Parameters in Healthy Volunteers: A Preliminary Randomized Study.

There has been an increasing interest in nutraceuticals and functional foods in reducing appetite and to lose weight. We assessed the effect of oral pomegranate extract (PE) and PE juice (PJ) intake vs. placebo on satiety parameters in healthy volunteers. Twenty-eight subjects (mean age 34.5 ± 13.7 years, body mass index [BMI] 25.05 ± 3.91 kg/m2) were randomized to 3-week priming supplementation with PE (Pomanox®) or placebo. On week 3, satiety parameters were determined on 1 testing day after participants ingested a breakfast and a lunch meal with PJ juice, using 100-mm visual acuity scales (VAS) for hunger, desire to eat, fullness and satisfaction. Meal quality and palatability were also tested. The desire to eat was less at all time points in the PJ juice with PE priming group and participants were also less hungry (p = 0.044) than those who consumed placebo. There was an overall significant difference between the groups (p < 0.001). Participants in the PJ juice with PE priming group experienced significantly greater satisfaction (p = 0.036) and feeling of fullness (p = 0.02) than those in the placebo group. These findings suggest that consumption of PE could have the potential to modulate satiety indicators.

Antioxidant and Antihyperglycemic Effects of Ephedra foeminea Aqueous Extract in Streptozotocin-Induced Diabetic Rats.

BACKGROUND: Ephedra foeminea is known in Jordan as Alanda and traditionally. It is used to treat respiratory symptoms such as asthma and skin rashes as an infusion in boiling water. The purpose of this study was to determine the antidiabetic property of Ephedra foeminea aqueous extract in streptozotocin-induced diabetic rats. METHODS: The aqueous extract of Ephedra foeminea plant was used to determine the potential of its efficacy in the treatment of diabetes, and this extract was tested on diabetic rats as a model. The chemical composition of Ephedra foeminea aqueous extract was determined using liquid chromatography-mass spectrometry (LC-MS). Antioxidant activity was assessed using two classical assays (ABTS and DPPH). RESULTS: The most abundant compounds in the Ephedra foeminea extract were limonene (6.3%), kaempferol (6.2%), stearic acid (5.9%), ß-sitosterol (5.5%), thiamine (4.1%), riboflavin (3.1%), naringenin (2.8%), kaempferol-3-rhamnoside (2.3%), quercetin (2.2%), and ferulic acid (2.0%). The antioxidant activity of Ephedra foeminea aqueous extract was remarkable, as evidenced by radical scavenging capacities of 12.28 mg Trolox/g in ABTS and 72.8 mg GAE/g in DPPH. In comparison to control, induced diabetic rats treated with Ephedra foeminea extract showed significant improvement in blood glucose levels, lipid profile, liver, and kidney functions. Interleukin 1 and glutathione peroxidase levels in the spleen, pancreas, kidney, and liver of induced diabetic rats treated with Ephedra foeminea extract were significantly lower than in untreated diabetic rats. CONCLUSIONS: Ephedra foeminea aqueous extract appears to protect diabetic rats against oxidative stress and improve blood parameters. In addition, it has antioxidant properties that might be very beneficial medicinally.

The effect of endurance, resistance training, and supplements on mitochondria and bioenergetics of muscle cells.

Bioenergetics is the study of energy flow between biological systems and the surroundings and is measured quantitatively. Energy flow can be affected by many variables, including lifestyle and exercise, where exercise comes in different types; endurance and resistance training play significant roles in enhancing bioenergetics and promoting health. In addition, a supplementary diet supports recovery and energy production. This review aims to study the effect of endurance training, resistance training, and supplement intake on the muscle cell's bioenergetics. As a conclusion of the information presented in this mini-review, it was found that resistance, endurance training, and supplements can increase mitochondrial biogenesis, fat oxidation, myofibril synthesis, and increase VO2 max.

Preparation, Characterization, and Anticancer Effects of Capsaicin-Loaded Nanoliposomes.

BACKGROUND: Medicinal plants have proven their value as a source of molecules with therapeutic potential, and recent studies have shown that capsaicin has profound anticancer effects in several types of human cancers. However, its clinical use is handicapped due to its poor pharmacokinetics. This study aims to enhance capsaicin's pharmacokinetic properties by loading the molecule into nanoliposomes model and testing its anticancer activity. METHODS: Nanoliposomes were prepared using the thin-film method, and characteristics were examined followed by qualitative and quantitative analyses of encapsulation efficiency and drug loading using HPLC at different lipid/capsaicin ratios. Cell viability assay (MTT) was used to determine IC50. RESULTS: Capsaicin-loaded nanoliposomes showed optimum characteristics of morphology, particle size, zeta potential, and stability. In vitro anticancer activity of capsaicin and capsaicin-loaded nanoliposomes were compared against MCF7, MDA-MB-231, K562, PANC1, and A375 cell lines. Capsaicin-loaded nanoliposomes showed significant improvement in anticancer activity against cancers cell lines studied (p < 0.001), with increased selectivity against cancer cells compared to capsaicin. CONCLUSION: The encapsulated capsaicin nanoliposomes produced an improvement in pharmacokinetics properties, enhancing the anticancer activity and selectivity compared with capsaicin. This model seems to offer a potential for developing capsaicin formulations for the prevention and treatment of cancer.

Nano, micro particulate and cosmetic delivery systems of polylactic acid: A mini review.

BACKGROUND: Poly lactic acid and its copolymers are considered to be the preferred substrates for drug delivery devices. Poly lactic acid is a biocompatible, biodegradable and nontoxic polymer. It was approved by Food and Drug Administration and thought to be among the most attractive polymeric candidates intended for controlling drug delivery. It was utilized for the development of devices for the delivery of small molecules, proteins, genes, vaccines, anticancer drugs, and macromolecules. OBJECTIVES AND METHODS: This manuscript lists the different techniques for synthesizing poly lactic acid-based nano and microparticles such as emulsion-based methods, precipitation-based methods, direct compositing methods, in situ forming micro-particles, and microfluidic technique. CONCLUSIONS: In addition, it describes the application and use of poly lactic acid in biomedical and cosmetic delivery systems.

Effects of Ginseng Ingestion on Salivary Testosterone and DHEA Levels in Healthy Females: An Exploratory Study.

Ginseng is a traditional herbal adaptogen that has been historically used in China and the Far East. Ginsenosides are the active component of ginseng known to exert several actions by targeting "multi-receptor systems", both extracellular and intracellular. In humans, ginseng effects remain unclear. This study aimed to investigate whether ginseng can influence salivary androgen levels (testosterone and dehydroepiandrosterone (DHEA)) in females. The study followed a parallel partially controlled design. Healthy women (n = 24) were recruited and divided into two groups (A = 20-32 and B = 38-50 years). Volunteers were asked to maintain a food diary pre and post ginseng consumption and collected four salivary samples (7 a.m., 9 a.m., 12 p.m., and 5 p.m.) before and after ingesting 75 mg red Korean ginseng extract per day for seven days. Testosterone and DHEA were then assayed by ELISA methods. Group A's mean daily salivary testosterone pre ginseng ingestion increased from 76.3 ± 16.6 to 98.4 ± 21.1 pg/mL post ginseng (p < 0.01) with significant difference at all time points, and mean daily salivary DHEA increased from 1.53 ± 0.63 to 1.98 ± 0.89 ng/mL post ginseng (p = 0.02). Group B's mean daily salivary testosterone pre ginseng ingestion was 61.2 ± 16.9 and post ginseng 68.1 ± 11.5 pg/mL (p = 0.132), and daily salivary DHEA increased from 0.91 ± 0.32 to 1.62 ± 0.49 ng/mL post ginseng (p = 0.014) with significant difference at all time points. In conclusion, it appears that ginseng intake significantly increased salivary testosterone levels in the younger women group, but only slightly in the older group. However, DHEA levels in the older women showed a marked and significant increase. These results suggest a potential role for ginseng in modulating salivary androgen levels and that such effect may be more evident in older women where the levels of androgens (DHEA) start to decline. However, it has to be stressed that our results are preliminary and further properly controlled trials are justified.

Post-Prandial Changes in Salivary Glucocorticoids: Effects of Dietary Cholesterol and Associations with Bile Acid Excretion.

Mechanisms to explain post-prandial increases in circulating glucocorticoids are not well understood and may involve increased adrenal secretion and/or altered steroid metabolism. We have compared salivary levels of cortisol and cortisone levels in healthy male and female volunteers fed either a low or cholesterol-rich midday meal. Urinary levels of steroids, bile acids and markers of lipid peroxidation were also measured. Males and females showed expected circadian changes in salivary steroids and postprandial peaks within 1h of feeding. After a high-cholesterol meal, postprandial cortisol increases were higher in males whereas post-prandial cortisone levels were higher in females. Urinary cortisol but not cortisone levels were higher on the day when males and females ate a high-cholesterol meal. Urinary bile acid excretion and anti-oxidant markers of lipid peroxidation, thiobarbituric acid reactive substances (TBARS), and total phenol content were not affected by dietary cholesterol but tended to be higher in males. Cross-tabulation of correlation coefficients indicated positive associations between urinary markers of peroxidation, bile acids, and cortisol:cortisone ratios. We conclude that dietary cholesterol (a substrate for steroidogenesis) does not have an acute effect on adrenal glucocorticoid synthesis and that gender but not a high-cholesterol meal may influence the interconversion of cortisol and cortisone. Longer term studies of the effects of dietary cholesterol are needed to analyze the associations between bile acids, steroid metabolism, and secretion and lipid peroxidation.

A Short Study Exploring the Effect of the Glycaemic Index of the Diet on Energy intake and Salivary Steroid Hormones.

Background: The glycaemic index or load (GI or GL) is a concept for ranking carbohydrate-rich foods based on the postprandial blood glucose response compared with a reference food (glucose). Due to the limited research investigating the effect of the GI or GL of the diet on salivary steroidal hormones, this explorative short study was conducted. Methods: 12 female participants consumed a low GI and a high GI diet for three days each, followed by a washout period between each intervention. Saliva was collected at baseline, and following the low or high GI diets. Cortisol and testosterone concentrations were measured by enzyme-linked immuno-sorbent assay (ELISA). Results: GI and GL were significantly different between the low and high GI diets (p < 0.001). There was a small but significant increase in salivary cortisol after the high GI diet (7.38 to 10.93 ng/mL, p = 0.036). No effect was observed after the low GI diet. Higher levels of testosterone were produced after the low GI diet (83.7 to 125.9 pg/mL, p = 0.002), and no effect was found after the high GI diet. The total intake of calories consumed on the low GI diet was significantly lower compared to the high GI diet (p = 0.019). Conclusions: A low GI diet was associated with a small but significant increase in salivary testosterone, while a high GI diet increased cortisol levels. Altering the GI of the diet may influence overall energy intake and the health and wellbeing of female volunteers.

Renal and Blood Pressure Response to a High-Salt Diet in Mice With Reduced Global Expression of the Glucocorticoid Receptor.

Salt-sensitive hypertension is common in glucocorticoid excess. Glucocorticoid resistance also presents with hypercortisolemia and hypertension but the relationship between salt intake and blood pressure (BP) is not well defined. GRßgeo/+ mice have global glucocorticoid receptor (GR) haploinsufficiency and increased BP. Here we examined the effect of high salt diet on BP, salt excretion and renal blood flow in GRßgeo/+mice. Basal BP was ∼10 mmHg higher in male GRßgeo/+ mice than in GR+/+ littermates. This modest increase was amplified by ∼10 mmHg following a high-salt diet in GRßgeo/+ mice. High salt reduced urinary aldosterone excretion but increased renal mineralocorticoid receptor expression in both genotypes. Corticosterone, and to a lesser extent deoxycorticosterone, excretion was increased in GRßgeo/+ mice following a high-salt challenge, consistent with enhanced 24 h production. GR+/+ mice increased fractional sodium excretion and reduced renal vascular resistance during the high salt challenge, retaining neutral sodium balance. In contrast, sodium excretion and renal vascular resistance did not adapt to high salt in GRßgeo/+ mice, resulting in transient sodium retention and sustained hypertension. With high-salt diet, Slc12a3 and Scnn1a mRNAs were higher in GRßgeo/+ than controls, and this was reflected in an exaggerated natriuretic response to thiazide and benzamil, inhibitors of NCC and ENaC, respectively. Reduction in GR expression causes salt-sensitivity and an adaptive failure of the renal vasculature and tubule, most likely reflecting sustained mineralocorticoid receptor activation. This provides a mechanistic basis to understand the hypertension associated with loss-of-function polymorphisms in GR in the context of habitually high salt intake.

The utility of salivary testosterone and cortisol concentration measures for assessing the stress responses of junior athletes during a sporting competition.

BACKGROUND: This study examined the utility of salivary testosterone (T) and cortisol (C) concentration measures for assessing the acute stress responses of junior athletes during a sporting competition. METHODS: Paired capillary blood and saliva samples were taken from 71 junior athletes (45 males, 26 females) before and after a simulated Olympic weightlifting competition. The concentration measures of salivary T and C were referenced against blood total T (TT) and C (TC) concentrations. All hormones were tested by immunoassay. RESULTS: The competition promoted an increase in the blood TT concentrations of the male (10.1%±18.7%) and female (12.9%±19.9%) athletes (P<.05), with TC also rising in females (37.5%±69%) and tending to increase in males (23.2%±56.1%). No significant changes in salivary T or C were identified. Locally-weighted regression revealed that salivary T was strongly related to blood TT in males (r2 =.84), but not females (r2 =-.15), whereas salivary C was moderately related to blood TC in both sexes (r2 =.43, r2 =.48), respectively. CONCLUSIONS: A short, high-intensity competition promoted a predictable stress-induced rise in blood TT and TC concentrations. We observed no hormonal stress responses in saliva under the current format, which could be explained by individual variability and blood-saliva differences in hormone kinetics. Still, the salivary T and C measures did show a moderate to strong ability to track individual blood TT (males only) and TC (both sexes) concentrations in a young athletic cohort across a broad physiological range. Recommendations for researchers and practitioners are presented.

Polyphenols and Their Role in Obesity Management: A Systematic Review of Randomized Clinical Trials.

Polyphenols have been suggested to reduce body weight and modify body composition through different mechanisms. These effects have been extensively studied in animals and in vitro and to a lesser extent in humans. The aim of this review is to consider the association between polyphenols and body weight status by focusing on human intervention studies. We conducted a systematic literature search in MEDLINE (via EBSCOhost), ProQuest CENTRAL, and Cochrane CENTRAL without time restrictions. Randomized controlled trials assessing the effect of polyphenols on weight and/or body composition in the overweight and/or obese population were included. Nineteen studies met our inclusion criteria. Results suggest that further research is required before supporting a potential role of polyphenols in reducing weight in overweight and obese individuals (nine studies showed a significant decrease in weight by a mean of 1.47 ± 0.58 kg). Nevertheless, several studies indicated that polyphenols might be effective in preventing small increases in weight during periods of overfeeding rather than reducing weight as such. The outcomes noted do not yet support polyphenol supplementation as a complementary approach in weight loss diets. Further larger trials with a duration of 12 months or more are needed to elucidate the effect of polyphenols on body weight status. Copyright © 2017 John Wiley & Sons, Ltd.

Glucocorticoid receptor alters isovolumetric contraction and restrains cardiac fibrosis.

Corticosteroids directly affect the heart and vasculature and are implicated in the pathogenesis of heart failure. Attention is focussed upon the role of the mineralocorticoid receptor (MR) in mediating pro-fibrotic and other adverse effects of corticosteroids upon the heart. In contrast, the role of the glucocorticoid receptor (GR) in the heart and vasculature is less well understood. We addressed this in mice with cardiomyocyte and vascular smooth muscle deletion of GR (SMGRKO mice). Survival of SMGRKO mice to weaning was reduced compared with that of littermate controls. Doppler measurements of blood flow across the mitral valve showed an elongated isovolumetric contraction time in surviving adult SMGRKO mice, indicating impairment of the initial left ventricular contractile phase. Although heart weight was elevated in both genders, only male SMGRKO mice showed evidence of pathological cardiomyocyte hypertrophy, associated with increased myosin heavy chain-ß expression. Left ventricular fibrosis, evident in both genders, was associated with elevated levels of mRNA encoding MR as well as proteins involved in cardiac remodelling and fibrosis. However, MR antagonism with spironolactone from birth only modestly attenuated the increase in pro-fibrotic gene expression in SMGRKO mice, suggesting that elevated MR signalling is not the primary driver of cardiac fibrosis in SMGRKO mice, and cardiac fibrosis can be dissociated from MR activation. Thus, GR contributes to systolic function and restrains normal cardiac growth, the latter through gender-specific mechanisms. Our findings suggest the GR:MR balance is critical in corticosteroid signalling in specific cardiac cell types.

Effect of vitamin D supplementation on cardiovascular disease risk factors and exercise performance in healthy participants: a randomized placebo-controlled preliminary study.

BACKGROUND AND OBJECTIVES: Evidence suggests associations between vitamin D deficiency and cardiovascular disease (CVD) risk factors, including hypertension and excessive cortisol levels. Also, vitamin D levels may impact exercise performance. Thus, we aimed to investigate the effects of vitamin D intake on cardiovascular risk factors, free urinary cortisol and exercise performance. METHODS: A randomized placebo-controlled single-blinded parallel trial was conducted in healthy participants (n = 15). They received 2000 IU (50 µg) vitamin D3 per day (n = 9) or placebo (lactose) (n = 6) for 14 days. Body composition, systolic blood pressure (SBP), diastolic blood pressure (DBP) and arterial elasticity (as measured by pulse wave velocity, PWV) were recorded at baseline, day 7 and day 14 of intervention. A total of two 24-hour urine samples were collected to estimate free cortisol and cortisone levels. Exercise performance was assessed at the baseline and day 14 of the intervention using a bike ergometer in which BP and PWV were measured before and after exercise. The distance cycled in 20 minutes and the Borg Scale rate of perceived exertion (RPE) were recorded. RESULTS: In the intervention arm, at day 14, vitamin D supplementation significantly reduced SBP and DBP from 115.8 ± 17.1 and 75.4 ± 10.3 at baseline to 106.3 ± 10.9 (p = 0.022) and 68.5 ± 10.1 mmHg (p = 0.012) respectively. Also arterial stiffness was markedly reduced in the vitamin D group (from 7.45 ± 1.55 to 6.11 ± 1.89, p = 0.049). Urinary free cortisol levels and cortisol/cortisone ratio were significantly reduced from 162.65 ± 58.9 nmol/day and 2.22 ± 0.7 to 96.4 ± 37.2 (p = 0.029) and 1.04 ± 0.4 (p = 0.017) respectively. Exercise-induced SBP and DBP were significantly reduced post vitamin D intake from 130.7 ± 12.2 to 116.1 ± 8.1 (p = 0.012) and from 76.2 ± 8.4 to 70.5 ± 7.7 mmHg (p = 0.042) respectively. The distance cycled in 20 minutes significantly increased from 4.98 ± 2.65 to 6.51 ± 2.28km (p = 0.020), while the Borg Scale RPE reduced from 5.13 ± 1.36 to 4.25 ± 0.71 RPE (p = 0.021). In the placebo arm, no significant effects on CVD risk factors and exercise performance were observed. CONCLUSION: These results suggest that daily vitamin D supplementation may ameliorate CVD risk factors including a decrease in 11ß-HSD1 activity, as evidenced by the decrease in the cortisol/cortisone ratio, and improve exercise performance in healthy individuals. However, large scale studies are required to verify our findings.

Glucocorticoids Induce Nondipping Blood Pressure by Activating the Thiazide-Sensitive Cotransporter.

Blood pressure (BP) normally dips during sleep, and nondipping increases cardiovascular risk. Hydrochlorothiazide restores the dipping BP profile in nondipping patients, suggesting that the NaCl cotransporter, NCC, is an important determinant of daily BP variation. NCC activity in cells is regulated by the circadian transcription factor per1. In vivo, circadian genes are entrained via the hypothalamic-pituitary-adrenal axis. Here, we test whether abnormalities in the day:night variation of circulating glucocorticoid influence NCC activity and BP control. C57BL6/J mice were culled at the peak (1:00 AM) and trough (1:00 PM) of BP. We found no day:night variation in NCC mRNA or protein but NCC phosphorylation on threonine(53) (pNCC), required for NCC activation, was higher when mice were awake, as was excretion of NCC in urinary exosomes. Peak NCC activity correlated with peak expression of per2 and bmal1 (clock genes) and sgk1 and tsc22d3 (glucocorticoid-responsive kinases). Adrenalectomy reduced NCC abundance and blunted the daily variation in pNCC levels without affecting variation in clock gene transcription. Chronic corticosterone infusion increased bmal1, per1, sgk1, and tsc22d3 expression during the inactive phase. Inactive phase pNCC was also elevated by corticosterone, and a nondipping BP profile was induced. Hydrochlorothiazide restored rhythmicity of BP in corticosterone-treated mice without affecting BP in controls. Glucocorticoids influence the day:night variation in NCC activity via kinases that control phosphorylation. Abnormal glucocorticoid rhythms impair NCC and induce nondipping. Night-time dosing of thiazides may be particularly beneficial in patients with modest glucocorticoid excess.