Vitamin D, immune function, and atherosclerosis. Where are we now?

The role of vitamin D in regulating calcium metabolism and skeletal growth and disease is widely recognized. Indeed, current recommendations for serum vitamin D concentrations are based on these parameters. A serum vitamin D <20 ng/mL is considered deficient, concentrations between 20 and 30 ng/mL are insufficient, and >30 ng/mL is adequate.

Cardiomodulatory Effects of Cardiometabolic and Antihyperglycemic Medications: The Roles of Oxidative and Endoplasmic Reticulum Stress.

Uncontrolled hyperglycemia in people with diabetes is an established risk of premature cardiovascular disease. Repeated hypoglycemic events are also associated with increased cardiovascular mortality. Both hyperglycemia and hypoglycemia induce cellular stress, notably endoplasmic reticulum (ER) stress, a known promoter of cardiovascular disease.

Sugar or Sweetener?

Human beings have a natural craving for sweets. The intensity of this craving varies with genetic and environmental factors; however, excessive use of table sugar has been associated with adverse health outcomes, including increased risk of obesity, diabetes mellitus, and cardiovascular disease. As such, the World Health Organization has called for restricting sugar consumption to less than 5% of total energy intake.

Sex- and Age-Associated Differences in Genomic Alterations among Patients with Advanced Non-Small Cell Lung Cancer (NSCLC).

Genomic mutations impact non-small cell lung cancer (NSCLC) biology. The influence of sex and age on the distribution of these alterations is unclear. We analyzed circulating-tumor DNA from individuals with advanced NSCLC from March 2018 to October 2020.

Cardioprotective antihyperglycemic drugs ameliorate endoplasmic reticulum stress.

Cellular stress, notably oxidative, inflammatory, and endoplasmic reticulum (ER) stress, is implicated in the pathogenesis of cardiovascular disease. Modifiable risk factors for cardiovascular disease such as diabetes, hypercholesterolemia, saturated fat consumption, hypertension, and cigarette smoking cause ER stress whereas currently known cardioprotective drugs with diverse pharmacodynamics share a common pleiotropic effect of reducing ER stress. Selective targeting of oxidative stress with known antioxidative vitamins has been ineffective in reducing cardiovascular risk.

Diabetes-related perturbations in the integrity of physiologic barriers.

One of the hallmarks of health is the integrity of barriers at the cellular and tissue levels. The two cardinal functions of barriers include preventing access of deleterious elements of the environment (barrier function) while facilitating the transport of essential ions, signaling molecules and nutrients needed to maintain the internal milieu (transport function). There are several cellular and subcellular barriers and some of these barriers can be interrelated.

Transcription factor EB protects against endoplasmic reticulum stress in human coronary artery endothelial cells.

Oxidative stress and endoplasmic reticulum (ER) stress promote atherogenesis while transcription factor EB (TFEB) inhibits atherosclerosis. Since reducing oxidative stress with antioxidants have failed to reduce atherosclerosis possibly because of aggravation of ER stress, we studied the effect of TFEB on ER stress in human coronary artery endothelial cells. ER stress was measured using the secreted alkaline phosphatase assay.

Endoplasmic reticulum stress: A common pharmacologic target of cardioprotective drugs.

Despite the advances made in cardiovascular disease prevention, there is still substantial residual risk of adverse cardiovascular events. Contemporary evidence suggests that additional reduction in cardiovascular disease risk can be achieved through amelioration of cellular stresses, notably inflammatory stress and endoplasmic reticulum (ER) stress. Only two clinical trials with anti-inflammatory agents have supported the role of inflammatory stress in cardiovascular risk.

Potential Therapeutic Agents That Target ATP Binding Cassette A1 (ABCA1) Gene Expression.

The cholesterol efflux protein ATP binding cassette protein A1 (ABCA) and apolipoprotein A1 (apo A1) are key constituents in the process of reverse-cholesterol transport (RCT), whereby excess cholesterol in the periphery is transported to the liver where it can be converted primarily to bile acids for either use in digestion or excreted. Due to their essential roles in RCT, numerous studies have been conducted in cells, mice, and humans to more thoroughly understand the pathways that regulate their expression and activity with the goal of developing therapeutics that enhance RCT to reduce the risk of cardiovascular disease. Many of the drugs and natural compounds examined target several transcription factors critical for ABCA1 expression in both macrophages and the liver.

Automating Assignment, Quantitation, and Biological Annotation of Redox Proteomics Datasets with ProteoSushi.

Redox proteomics plays an increasingly important role characterizing the cellular redox state and redox signaling networks. As these datasets grow larger and identify more redox regulated sites in proteins, they provide a systems-wide characterization of redox regulation across cellular organelles and regulatory networks. However, these large proteomic datasets require substantial data processing and analysis in order to fully interpret and comprehend the biological impact of oxidative posttranslational modifications.

The effect of black seed (Nigella sativa) extract on lipid metabolism in HepG2 cells.

Black seed extract stimulates apolipoprotein A-I (apo A-I) gene expression in hepatocytes and intestinal cells in part by elevating peroxisome proliferator-activated receptor α (PPARα) and retinoid X receptor α (RXRα) levels. To explore potential ramifications of these observations, we examined the effects of black seed extract on hepatocyte lipid content and expression of key transcriptional regulators of fatty acid β-oxidation and lipogenesis in HepG2 cells. PPARα, peroxisome proliferator-activated receptor γ (PPARγ), RXRα, thyroid hormone receptor β (TRβ), sterol-responsive element binding protein 1 (SREBP1), and sterol-responsive element binding protein 2 (SREBP2) levels were measured in black seed extract treated liver-derived HepG2 cells.

Pathophysiology and Clinical Features of Neuropsychiatric Manifestations of Thyroid Disease.

Thyroid hormones (TH) have a cardinal role in the development of the central nervous system during embryogenesis and early infancy. However, the TH-responsive genes in the developing brain cease to respond to TH in adulthood. Nevertheless, thyroid dysfunction in adults is commonly associated with a host of cognitive and psychiatric problems.

Insulin mimetic effect of D-allulose on apolipoprotein A-I gene.

Several nutrients modulate the transcriptional activity of the apolipoprotein A-I (apo A-I) gene. To determine the influence of rare sugars on apo A-I expression in hepatic (HepG2) and intestinal derived (Caco-2) cell lines, apo A-I, albumin, and SP1 were quantified with enzyme immunoassay and Western blots while mRNA levels were quantified with real-time polymerase chain reaction. The promoter activity was measured using transient transfection assays with plasmids containing various segments and mutations in the promoter.

Management of Hyperglycemia in Older Adults with Type 2 Diabetes.

The increasing incidence of type 2 diabetes in the general population as well as enhanced life expectancy has resulted in a rapid rise in the prevalence of diabetes in the older population. Diabetes causes significant morbidity and impairs quality of life. Managing diabetes in older adults is a daunting task due to unique health and psychosocial challenges.

Differential effects of cyclooxygenase-2 (COX-2) inhibitors on endoplasmic reticulum (ER) stress in human coronary artery endothelial cells.

Selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib was pulled off the market because of its association with increased risk of adverse cardiovascular effects. The precise underlying mechanism for the differential effects of COX-2 inhibitors on cardiovascular risk is not known. Since endoplasmic reticulum (ER) stress is implicated in atherogenesis, we examined the effects of COX-2 inhibitors on ER stress in primary human coronary artery endothelial cells (HCAEC), human umbilical vein endothelial cells (HUVEC), and human pulmonary artery endothelial cells (HPAEC).

Clinical Considerations for Insulin Therapy in Older Adults with Type 1 Diabetes.

Type 1 diabetes represents an autoimmune condition with a strong inherited background, and its incidence is increasing worldwide. About 25% of such cases are diagnosed in adulthood, some even as late as the ninth decade of life. The number of older adults with type 1 diabetes is increasing due to improvements in care and decreased mortality rate.

Effect of anti-hyperglycemic drugs on endoplasmic reticulum (ER) stress in human coronary artery endothelial cells.

Endoplasmic reticulum (ER) stress plays a critical role in progression of diabetes and development of complications, notably cardiovascular disease. Some of the contemporary anti-hyperglycemic drugs have been shown to inhibit ER stress. To extend these observations, the effects of various anti-hyperglycemic agents were screened for their effects on ER stress.

ProteoSushi: A Software Tool to Biologically Annotate and Quantify Modification-Specific, Peptide-Centric Proteomics Data Sets.

Large-scale proteomic profiling of protein post-translational modifications has provided important insights into the regulation of cell signaling and disease. These modification-specific proteomics workflows nearly universally enrich modified peptides prior to mass spectrometry analysis, but protein-centric proteomic software tools have many limitations evaluating and interpreting these peptide-centric data sets. We, therefore, developed ProteoSushi, a software tool tailored to analysis of each modified site in peptide-centric proteomic data sets that is compatible with any post-translational modification or chemical label.

The effect of nicotine and dextrose on endoplasmic reticulum stress in human coronary artery endothelial cells.

Cigarette smoking is one of the major causes of coronary artery disease (CAD) as is diabetes. However, nicotine has been generally regarded as safe and is used in smoking cessation programs. This presumption of nicotine safety was examined in human coronary artery endothelial cells (HCAEC).

Reduced cellular glucose transport confers natural protection against dextrose-induced superoxide generation and endoplasmic reticulum stress in domestic hen.

Normal blood glucose levels in avian species are two to fourfold higher than that in humans and the higher blood glucose levels in birds do not cause adverse effects. Endothelial cells isolated from the aorta of the domestic hen (Gallus gallus domesticus) and chicken aortic smooth muscle cells (CAOSMC) were compared to human coronary artery endothelial cells (HCAEC) and human primary aortic smooth muscle cells (HASMC). Superoxide (SO) generation was measured using a superoxide-reactive probe.

Effects of D-allulose on glucose tolerance and insulin response to a standard oral sucrose load: results of a prospective, randomized, crossover study.

Introduction: Current dietary guidelines recommend limiting sugar intake for the prevention of diabetes mellitus (DM). Reduction in sugar intake may require sugar substitutes. Among these, D-allulose is a non-calorie rare monosaccharide with 70% sweetness of sucrose, which has shown anti-DM effects in Asian populations.

Cancer-associated exportin-6 upregulation inhibits the transcriptionally repressive and anticancer effects of nuclear profilin-1.

Aberrant expression of nuclear transporters and deregulated subcellular localization of their cargo proteins are emerging as drivers and therapeutic targets of cancer. Here, we present evidence that the nuclear exporter exportin-6 and its cargo profilin-1 constitute a functionally important and frequently deregulated axis in cancer. Exportin-6 upregulation occurs in numerous cancer types and is associated with poor patient survival.

An Evaluation of Faculty Development Programs for Clinician-Educators: A Scoping Review.

Purpose: Faculty development (FD) has become increasingly important for clinician-educators. An array of FD programs has been developed, but the impact of these programs on clinician-educators and their learners and workplace is less known. The authors conducted a scoping review to explore the status of program evaluation in FD for clinician-educators to inform future planning and research.

Demystifying Oxidative Stress.

The hypothesis that reactive oxygen species (ROS) can be not just associated with but causally implicated in disease was first made in 1956, but so far, the oxidative stress theory of disease has not led to major therapeutic breakthrough, and the use of antioxidant is now confined to the field of complementary medicine. This chapter reviews the lack of high-level clinical evidence for the effectiveness of antioxidants in preventing disease and the epistemological problems of the oxidative stress theory of disease. We conclude on possible ways forward to test this hypothesis with approaches that take into account personalized medicine.