Exercise and vascular function in sedentary lifestyles in humans.

People with sedentary lifestyles engage in minimal or no physical activity. A sedentary lifestyle promotes dysregulation of cellular redox balance, diminishes mitochondrial function, and increases NADPH oxidase activity. These changes collectively increase cellular oxidative stress, which alters endothelial function by oxidizing LDL-C, reducing NO production, and causing eNOS uncoupling. Reduced levels of nitric oxide (NO) leads to vasoconstriction, vascular remodeling, and vascular inflammation. Exercise modulates reactive oxygen species (ROS) to modify NRF2-KEAP signaling, leading to the activation of NRF2 to alleviate oxidative stress. While regular moderate exercise activates NRF2 through ROS production, high-intensity intermittent exercise stimulates NRF2 activation to a greater degree by reducing KEAP levels, which can be more beneficial for sedentary individuals. We review the damaging effects of a sedentary lifestyle on the vascular system and the health benefits of regular and intermittent exercise.

Potential for Novel Therapeutic Uses of Alpha Lipoic Acid.

Alpha-lipoic acid (ALA) is a potent antioxidant used in the management of diabetic neuropathy due to its ability to prevent neuronal lipid peroxidation. ALA also chelates transition metals, which can be beneficial in some diseases related to metal overload. Due to its unique antioxidant properties, ALA has potential novel applications in other diseases related to oxidative stress and inflammation. This review summarizes aspects of recent clinical trials and describes the uses of ALA in managing neuropathies. The unique pharmacological actions of ALA, coupled with relatively low toxicity, have led to several trials on the potential therapeutic uses of ALA in the management of diseases associated with increased oxidative stress, inflammation, and metal overload.

Nrf2 modulates the benefits of evening exercise in type 2 diabetes.

Exercise has well-characterized therapeutic benefits in the management of type 2 diabetes mellitus (T2DM). Most of the beneficial effects of exercise arise from the impact of nuclear factor erythroid 2 related factor-2 (Nrf2) activation of glucose metabolism. Nrf2 is an essential controller of cellular anti-oxidative capacity and circadian rhythms. The circadian rhythm of Nrf2 is influenced by circadian genes on its expression, where the timing of exercise effects the activation of Nrf2 and the rhythmicity of Nrf2 and signaling, such that the timing of exercise has differential physiological effects. Exercise in the evening has beneficial effects on diabetes management, such as lowering of blood glucose and weight. The mechanisms responsible for these effects have not yet been associated with the influence of exercise on the circadian rhythm of Nrf2 activity. A better understanding of exercise-induced Nrf2 activation on Nrf2 rhythm and signaling can improve our appreciation of the distinct effects of morning and evening exercise. This review hypothesizes that activation of Nrf2 by exercise in the morning, when Nrf2 level is already at high levels, leads to hyperactivation and decrease in Nrf2 signaling, while activation of Nrf2 in the evening, when Nrf2 levels are at nadir levels, improves Nrf2 signaling and lowers blood glucose levels and increases fatty acid oxidation. Exploring the effects of Nrf2 activators on rhythmic signaling could also provide valuable insights into the optimal timing of their application, while also holding promise for timed treatment of type 2 diabetes.

Potential harms of supplementation with high doses of antioxidants in athletes.

Vigorous exercise generates large amounts of reactive oxygen species (ROS) as a result of the consumption of large volumes of O2 in athletes, causing some athletes to consume antioxidants in the erroneous belief that this will counteract the damaging effects of ROS. There is currently no convincing evidence to support the benefits of antioxidant supplementation in acute physical exercise and exercise training. On the contrary, exogenous antioxidants prevent some physiological functions of free radicals that are needed for cell signaling, causing higher dosages of antioxidants to hamper or prevent performance-enhancing and health-promoting training adaptation such as mitochondrial biogenesis, skeletal and cardiac muscle hypertrophy, and improved insulin sensitivity. However, there remains the perception that antioxidants can counterbalance oxidative stress and benefit exercise adaptation and performance in athletes. It is likely that the negative effects of high doses of antioxidant supplementation exceed their potential benefits. We discuss some proposed pathways of potential side effects of exogenous antioxidant supplementation in athletes.

Impact of Obstructive Sleep Apnea and Current Treatments on the Development and Progression of Type 2 Diabetes.

Type 2 diabetes mellitus remains a growing health concern, affecting more than 420 million people globally. Preventing and treating diabetes require a better understanding of the associated risk factors. Sleep-disordered breathing, especially obstructive sleep apnea (OSA), is likely a contributor to the pathogenesis and aggravation of poor glycemic control. We review key epidemiological data that address the link between OSA and type 2 diabetes and present the current proposed pathophysiological mechanisms underlying this association. Several biological pathways are linking OSA and an increased propensity to diabetes. We review the impact of current treatment strategies for OSA based on the association between diabetes and sleep apnea.

Harnessing the cardiovascular benefits of exercise: Are Nrf2 activators useful?

The ability of physical activity to ameliorate cardiovascular disease and improve cardiovascular health is well accepted, but many aspects of the molecular mechanisms underlying these benefits are incompletely understood. Exercise increases the levels of reactive oxygen species (ROS) through various mechanisms. This triggers the activation of Nrf2, a redox-sensitive transcription factor activated by increases in oxidative stress. Activation of Nrf2 mitigates oxidative stress by increasing the nuclear transcription of many antioxidant genes while also mediating additional beneficial effects through the cytoprotective nature of Nrf2 signaling. Understanding the transcriptional patterns of Nrf2 caused by exercise can help in the design of pharmacological mimicry of the process in patients who are unable to exercise for various reasons.

Oral and subcutaneous absorption of insulin poly(isobutylcyanoacrylate) nanoparticles.

Dispersions of insulin poly(isobutylcyanoacrylate) nanoparticles were obtained by anionic in situ polymerization using aqueous pluronic acid solution. Results showed a decrease in particle size diameter by increasing the pluronic acid concentration. Nanoparticles prepared in the presence of 2.5% pluronic acid resulted in particles of 85 nm average diameter and 59% intra-particular insulin load without the use of the oily core [Damge, C., Michel, M., Aprahamian, M., Couveur, P., 1988. New approach for oral administration with polycyanoacrylate nanocapsules as drug carrier. Diabetes 37, 246-251]. In vivo testing was performed on streptozocin induced diabetic rats. The subcutaneous injection of insulin nanoparticles was able to prolong its duration of hypoglycemic effect from 6 to 72 h. Effective oral absorption of the entrapped insulin was significantly better (p<0.01) when compared with non-encapsulated insulin or the control experiments.