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Connecting Cholesterol Efflux Factors to Lung Cancer Biology and Therapeutics
Cholesterol is a foundational molecule of biology. There is a long-standing interest in understanding how cholesterol metabolism is intertwined with cancer biology. In this review, we focus on the known connections between lung cancer and molecules mediating cholesterol efflux. A major take-home lesson is that the roles of many cholesterol efflux factors remain underexplored. It is our hope that this article would motivate others to investigate how cholesterol efflux factors contribute to lung cancer biology.
Journal Article
Women Have Greater Endothelin-B Receptor Function and Lower Mitochondrial Capacity Compared to Men With Type 1 Diabetes
Abstract
Context
Type 1 diabetes (T1D) negatively affects both the endothelin system and muscle oxidative capacity. The endothelin pathway is a critical regulator of microcirculatory function and may exhibit sexual dichotomy by which healthy premenopausal women have greater endothelin-B receptor (ETBR) function compared to men. Moreover, T1D may differentially alter muscle oxidative capacity in men and women; however, whether ETBR function is impaired in women compared to men with T1D and its relationship with muscle oxidative capacity has yet to be explored.
Objective
The purpose of this investigation was to determine if ETBR-mediated dilation is impaired in women compared to men with T1D and if this is related to their skeletal muscle oxidative capacity.
Methods
Men (n = 9; glycated hemoglobin A1c [HbA1c] = 7.8 ± 1.0%) and women (N = 10 women; HbA1c = 8.4 ± 1.3%) with uncomplicated T1D were recruited for this investigation. Near-infrared spectroscopy (NIRS) and intradermal microdialysis (750 nM BQ-123 + ET-1 [10−20–10−8 mol/L]) were used to evaluate skeletal muscle oxidative capacity and assess ETBR-mediated vasodilation, respectively.
Results
Skeletal muscle oxidative capacity was significantly lower (P = .031) in women compared with men with T1D. However, ETBR-mediated dilation induced a significantly greater (P = .012) vasodilatory response in women compared to men with T1D, and the area under the curve was negatively associated with skeletal muscle oxidative capacity (r = −.620; P = .042).
Conclusion
Compared to men with uncomplicated T1D, muscle oxidative capacity was lower and ETBR-mediated vasodilation was higher in women with uncomplicated T1D. ETBR-induced vasodilatory capacity was inversely related to skeletal muscle oxidative capacity, suggesting there may be compensatory mechanisms occurring to preserve microvascular blood flow in women with T1D.
Journal Article
The decorin and myostatin response to acute whole body vibration: impact of adiposity, sex, and race
Background
Traditional forms of exercise affect immune, metabolic, and myokine responses and contribute to a multitude of health benefits. Whole body vibration (WBV) has recently emerged as an exercise mimetic that may be more tolerable for those individuals that cannot perform traditional exercise. However, the myokines response to acute WBV in humans has yet to be fully elucidated.
Objective
To characterize the decorin and myostatin response to acute whole body vibration (WBV) and determine the impact of adiposity, sex, and race.
Subjects
One hundred twenty-nine adults (32.8 ± 0.4 years, 66.7% female, 53.5% non-Hispanic Black) were recruited as part of an ongoing, longitudinal twin cohort parent study. Participants were classified into three groups: those with obesity (OB: ≥30 kg/m
2
), those who are overweight (OW: ≥25 and <30 kg/m
2
), or those with normal weight (NW: <25 kg/m
2
) based on BMI.
Methods
Blood was collected at baseline (PRE), immediately post (POST), and 1 h (1H), 3 h (3H), and 24 h (24H) post WBV. The acute WBV protocol consisted of 10 cycles of 1 min of vibration exercise followed by 30 s of standing rest.
Results
The response was similar between NW and OW, so these groups were combined for analysis (NW/OW: BMI < 30 kg/m
2
). Overall, circulating concentrations of decorin were higher (
p
< 0.001) POST (8.80 ± 0.19 pg/mL) and significantly lower (
p
’s ≤ 0.005) at 1H (8.66 ± 0.19 pg/mL) and 3H (8.68 ± 0.19 pg/mL), compared to PRE (8.71 ± 0.19 pg/mL). Decorin POST was greater (
p
= 0.016) in the OB group (8.82 ± 0.18 pg/mL) compared to the NW/OW group (8.77 ± 0.20 pg/mL). Overall, myostatin was higher (
p
= 0.002) POST (54.93 ± 1.04 pg/mL) and lower (
p
< 0.001) at 24H (49.13 ± 1.04 pg/mL) compared to PRE (53.49 ± 1.04 pg/mL). The myostatin response was lower (
p
’s ≤ 0.001) in female and non-Hispanic White individuals compared to male and non-Hispanic Black individuals, respectively.
Conclusions
A single bout of WBV can facilitate the release of decorin and myostatin into circulation, a similar response to traditional exercise. Additionally, adiposity, sex and race should be considered when evaluating the myokines response to WBV.
Journal Article
Smoking cessation reduces systemic inflammation and circulating endothelin-1
Smoking increases systemic inflammation and circulating endothelin-1 (ET-1), both of which contribute to an elevated risk of cardiovascular disease (CVD). The present study sought to test the hypothesis that a 12-week smoking cessation intervention would contribute to a long-term reduction in circulating ET-1, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). 30 individuals participated in a 12-week evidence-based smoking cessation program at Augusta University. Serum cotinine, plasma inflammatory cytokines, and plasma ET-1 were determined at baseline, immediately after the 12-week cessation program (end of treatment, EOT), and 12-months (12M) following the cessation program. Serum cotinine was significantly reduced (
p
< 0.001) at EOT and 12M following the smoking cessation program. Compared to BL (7.0 ± 1.6 pg/mL), TNF-α was significantly reduced at EOT (6.3 ± 1.5 pg/mL,
p
= 0.001) and 12M (5.2 ± 2.7 pg/mL,
p
< 0.001). ET-1 was significantly lower at EOT (1.9 ± 0.6 pg/mL,
p
= 0.013) and at 12M (2.0 ± 0.8 pg/mL,
p
= 0.091) following smoking cessation compared with BL (2.3 ± 0.6 pg/mL). BL concentrations of cotinine were significantly associated with basal ET-1 (r = 0.449,
p
= 0.013) and the change in cotinine at 12M following smoking cessation was significantly associated with the change in plasma ET-1 at 12M (r = 0.457,
p
= 0.011). Findings from the present pilot investigation demonstrate that a 12-week smoking cessation program reduces circulating concentrations of ET-1 and TNF-α for at least a year. The reduction in serum cotinine was associated with the decrease in circulating ET-1. The attenuation in ET-1 and inflammation may in part, contribute to the lower risk of CVD that is observed with smoking cessation.
Journal Article
Daily Physical Activity Does Not Contribute to Differences in Muscle Oxidative Capacity Between Overweight and Obesity
ABSTRACT
Background
The interaction between physical activity, skeletal muscle health, and adiposity has been explored in normal weight and overweight/obesity grouped together; however, the overall risks associated with being overweight are less than those observed with obesity and can be confounded by disparities in both sex and race. Thus, the present study sought to investigate the intricate interplay of daily physical activity and skeletal muscle oxidative capacity (SMOC) in overweight and obesity, while exploring how sex and race impact this dynamic relationship.
Methods
One hundred and forty participants were grouped by body mass index (BMI) as overweight (n = 73; BMI >25–<30 kg/m2) or obese (n = 67; BMI ≥30 kg/m2). SMOC was assessed using near‐infrared spectroscopy and daily physical activity was assessed for 7 days using accelerometry.
Results
Overweight individuals exhibited a higher (p = 0.004) SMOC and engaged in more (p = 0.007) vigorous physical activity compared to obese individuals. In addition, SMOC was lower (p = 0.005) in obese non‐Hispanic Black (NHB) men compared to overweight NHB men. No relationships between physical activity and SMOC were observed.
Conclusion
Physical activity is not associated with differences in SMOC in overweight and obesity. Obese individuals engage in less vigorous physical activity and exhibit lower SMOC compared to overweight individuals and these differences are emphasised in NHB men.
Overweight individuals exhibit higher skeletal muscle oxidative capacity and engage in more vigorous physical activity compared to their obese counterparts. No correlation between physical activity and muscle oxidative capacity were observed and suggest that factors beyond increased activity contribute to greater muscle oxidative capacity in overweight versus obese individuals.
Journal Article
Retinoic Acid-Mediated Inhibition of Mouse Coronavirus Replication Is Dependent on IRF3 and CaMKK
The ongoing COVID-19 pandemic has revealed the shortfalls in our understanding of how to treat coronavirus infections. With almost 7 million case fatalities of COVID-19 globally, the catalog of FDA-approved antiviral therapeutics is limited compared to other medications, such as antibiotics. All-trans retinoic acid (RA), or activated vitamin A, has been studied as a potential therapeutic against coronavirus infection because of its antiviral properties. Due to its impact on different signaling pathways, RA’s mechanism of action during coronavirus infection has not been thoroughly described. To determine RA’s mechanism of action, we examined its effect against a mouse coronavirus, mouse hepatitis virus strain A59 (MHV). We demonstrated that RA significantly decreased viral titers in infected mouse L929 fibroblasts and RAW 264.7 macrophages. The reduced viral titers were associated with a corresponding decrease in MHV nucleocapsid protein expression. Using interferon regulatory factor 3 (IRF3) knockout RAW 264.7 cells, we demonstrated that RA-induced suppression of MHV required IRF3 activity. RNA-seq analysis of wildtype and IRF3 knockout RAW cells showed that RA upregulated calcium/calmodulin (CaM) signaling proteins, such as CaM kinase kinase 1 (CaMKK1). When treated with a CaMKK inhibitor, RA was unable to upregulate IRF activation during MHV infection. In conclusion, our results demonstrate that RA-induced protection against coronavirus infection depends on IRF3 and CaMKK.
Journal Article
The Clinical Utility of Whole Body Vibration: A Review of the Different Types and Dosing for Application in Metabolic Diseases
Whole body vibration (WBV) is an innovative exercise mimetic that utilizes a vibrating platform to transmit mechanical vibrations throughout the body. WBV has been a popular area of research in recent years due to its potential physiological and therapeutic benefits in both health and disease. The utility of WBV is rooted in the various parameters (i.e., frequency, amplitude, duration) that affect the overall dose of vibration delivered to the body. Each type of WBV, coupled with these aforementioned parameters, should be considered when evaluating the use of WBV in the clinical setting. Thus, the purpose of this review is to provide an overview of recent literature detailing the different types of WBV, the various parameters that contribute to WBV efficacy, and the evidence of WBV in metabolic disease. A systematic search was conducted using Medline, Embase, Cochrane, CINAHL, and PubMed. All types of study designs were considered, with exclusions made for animal studies, duplicates, and study protocols without data. Thirty-four studies were included. In conclusion, as a modern exercise mimetic with therapeutic potential for metabolic diseases, understanding the interplay between the types and dosing of WBV is critical for determining its utility and efficacy. Further studies are certainly needed to elucidate the full therapeutic potential of WBV in metabolic diseases.
Journal Article
Endogenous estradiol contributes to vascular endothelial dysfunction in premenopausal women with type 1 diabetes
Background
Endogenous estrogen is cardio-protective in healthy premenopausal women. Despite this favorable action of estrogen, animal models depict a detrimental effect of estradiol on vascular function in the presence of diabetes. The present study sought to determine the role of endogenous estradiol on endothelial function in women with type 1 diabetes.
Method
32 women with type 1 diabetes (HbA
1c
= 8.6 ± 1.7%) and 25 apparently healthy women (HbA
1c
= 5.2 ± 0.3%) participated. Flow-mediated dilation (FMD), a bioassay of nitric-oxide bioavailability and endothelial function was performed during menses (M) and the late follicular (LF) phase of the menstrual cycle to represent low and high concentrations of estrogen, respectively. In addition, a venous blood sample was collected at each visit to determine circulating concentrations of estradiol, thiobarbituric acid reactive substances (TBARS), and nitrate/nitrite (NOx), biomarkers of oxidative stress and nitric oxide, respectively. Data were collected in (1) 9 additional women with type 1 diabetes using oral hormonal birth control (HBC) (HbA
1c
= 8.3 ± 2.1%) during the placebo pill week and second active pill week, and (2) a subgroup of 9 demographically matched women with type 1 diabetes not using HBC (HbA
1c
= 8.9 ± 2.1%).
Results
Overall, estradiol was significantly increased during the LF phase compared to M in both type 1 diabetes (Δestradiol = 75 ± 86 pg/mL) and controls (Δestradiol = 71 ± 76 pg/mL); however, an increase in TBARS was only observed in patients with type 1 diabetes (ΔTBARS = 3 ± 13 µM) compared to controls (ΔTBARS = 0 ± 4 µM). FMD was similar (
p
= 0.406) between groups at M. In addition, FMD increased significantly from M to the LF phase in controls (
p
= 0.024), whereas a decrease was observed in type 1 diabetes. FMD was greater (
p
= 0.015) in patients using HBC compared to those not on HBC, independent of menstrual cycle phase.
Conclusion
Endogenous estradiol increases oxidative stress and contributes to endothelial dysfunction in women with diabetes. Additionally, HBC use appears to be beneficial to endothelial function in type 1 diabetes.
Journal Article