Harperkaas2274

In fact, early multifactorial therapy, particularly with newer antihyperglycemic agents, has shown that the burden of micro- and macrovascular complications can be favorably modified despite the rising pressure imposed by protracted obesity.Macrovascular complications such as atherosclerosis, myocardial infarction and stroke, and microvascular complications such as nephropathy, retinopathy, and neuropathy are the major causes of increased morbidity and mortality in both type 1 and type 2 diabetes. Increased inflammation, oxidative stress, and fibrosis are common features in most diabetes complications. Although extensive studies have examined the biochemical pathways leading to the expression of inflammatory, profibrotic, and other pathological genes, as well as genetic factors related to diabetes and associated complications, much less is known about the contribution of epigenetic changes that occur without alterations in the DNA sequence. Environmental factors, lifestyles, and improper diet implicated in diabetes can affect epigenetic states. Epigenetic modifications, including DNA methylation and histone modifications, can alter gene transcription in response to environmental stimuli and cooperate with noncoding RNAs. These epigenetic modifications have been observed in various target cells under diabetic conditions. Moreover, epigenetics has also been implicated in the phenomenon of metabolic memory observed in clinic trials and animal studies, in which prior episodes of poor glycemic control can confer continued risk of complications despite subsequent glucose normalization. Epigenome-wide association studies in cohorts with diabetes are uncovering epigenotype variations that provide new insights into diabetic vascular complications. CDK activation Here, I discuss the role of epigenetics and noncoding RNAs in diabetes complications and metabolic memory, and their translation potential to serve as biomarkers and drug targets to improve clinical management of diabetic vascular complications.Type 1 diabetes (T1D) is characterized by insulin deficiency resulting from the selective destruction of pancreatic β-cells by self-reactive T cells. Recent evidence demonstrates that innate immune responses substantially contribute to the pathogenesis of T1D, as they represent a first line of response to danger/damage signals. Here we discuss evidence on how, in a relapsing-remitting pattern, pancreas remodeling, diet, microbiota, gut permeability, and viral/bacterial infections induce the accumulation of leukocytes of the innate arm of the immune system throughout the pancreas. The subsequent acquisition and presentation of endocrine and exocrine antigens to the adaptive arm of the immune system results in a chronic progression of pancreatic damage. This process provides for the generation of self-reactive T-cell responses; however, the relative weight that genetic and environmental factors have on the etiopathogenesis of T1D is endotype imprinted and patient specific. With this Perspectives in Diabetes, our goal is to encourage the scientific community to rethink mechanisms underlying T1D pathogenesis and to consider therapeutic approaches that focus on these processes in intervention trials within new-onset disease as well as in efforts seeking the disorder's prevention in individuals at high risk.Bone morphogenetic proteins (BMPs) are a group of signaling molecules that belong to the TGF-β superfamily. Initially discovered for their ability to induce bone formation, BMPs are known to play a diverse and critical array of biological roles. We here focus on recent evidence showing that BMP4 is an important regulator of white/beige adipogenic differentiation with important consequences for thermogenesis, energy homeostasis, and development of obesity in vivo. BMP4 is highly expressed in, and released by, human adipose tissue, and serum levels are increased in obesity. Recent studies have now shown BMP4 to play an important role not only for white/beige/brown adipocyte differentiation and thermogenesis but also in regulating systemic glucose homeostasis and insulin sensitivity. It also has important suppressive effects on hepatic glucose production and lipid metabolism. Cellular BMP4 signaling/action is regulated by both ambient cell/systemic levels and several endogenous and systemic BMP antagonists. Reduced BMP4 signaling/action can contribute to the development of obesity, insulin resistance, and associated metabolic disorders. In this article, we summarize the pleiotropic functions of BMP4 in the pathophysiology of these diseases and also consider the therapeutic implications of targeting BMP4 in the prevention/treatment of obesity and its associated complications.Respiratory virus challenge studies involve administration of the challenge virus and sampling to assess for protection from the same anatomical locations. It can therefore be difficult to differentiate actively replicating virus from input challenge virus. For SARS-CoV-2, specific monitoring of actively replicating virus is critical to investigate the protective and therapeutic efficacy of vaccines, monoclonal antibodies, and antiviral drugs. We developed a SARS-CoV-2 subgenomic RNA (sgRNA) RT-PCR assay to differentiate productive infection from inactivated or neutralized virus. Subgenomic RNAs are generated after cell entry and are poorly incorporate into mature virions, and thus may provide a marker for actively replicating virus. We show envelope (E) sgRNA was degraded by RNase in infected cell lysates, while genomic RNA (gRNA) was protected, presumably due to packaging into virions. To investigate the capacity of the sgRNA assay to distinguish input challenge virus from actively replicating virus in vivowe assess SARS-CoV-2 subgenomic RNA as a potential measure of replicating virus in rhesus macaques.HSV-1 employs cellular motor proteins and modulates kinase pathways to facilitate intracellular virion capsid transport. Previously, we and others have shown that the Akt inhibitor miltefosine inhibited virus entry. Herein, we show that the protein kinase C inhibitors staurosporine (STS) and gouml inhibited HSV-1 entry into Vero cells, and that miltefosine prevents HSV-1 capsid transport toward the nucleus. We have reported that the HSV-1 UL37 tegument protein interacts with the dynein motor complex during virus entry and virion egress, while others have shown that the UL37/UL36 protein complex binds dynein and kinesin causing a saltatory movement of capsids in neuronal axons. Co-immoprecipitation experiments confirmed previous findings from our laboratory that the UL37 protein interacted with the dynein intermediate chain (DIC) at early times post infection. This UL37-DIC interaction was concurrent with DIC phosphorylation in infected, but not mock-infected cells. Miltefosine inhibited dynein phosphorylation when added before, but not after virus entry.