Inhalation Exposure to Airborne PM Attenuates Hepatic Metabolic Pathways through S-Nitrosylation of the Primary ER Stress Sensor.

Inhalation exposure to airborne fine particulate matter (aerodynamic diameter < 2.5 µm, PM) is known to cause metabolic dysfunction-associated steatohepatitis (MASH) and the associated metabolic syndrome. Hepatic lipid accumulation and inflammation are the key characteristics of MASH.

Alterations in Skeletal Muscle Insulin Signaling DNA Methylation: A Pilot Randomized Controlled Trial of Olanzapine in Healthy Volunteers.

Antipsychotics are associated with severe metabolic side effects including insulin resistance; however, the mechanisms underlying this side effect are not fully understood. The skeletal muscle plays a critical role in insulin-stimulated glucose uptake, and changes in skeletal muscle DNA methylation by antipsychotics may play a role in the development of insulin resistance. A double-blind, placebo-controlled trial of olanzapine was performed in healthy volunteers.

Identification of PP1c-PPP1R12A Substrates Using Kinase-Catalyzed Biotinylation to Identify Phosphatase Substrates.

Protein phosphatase 1 regulatory subunit 12A (PPP1R12A) interacts with the catalytic subunit of protein phosphatase 1 (PP1c) to form the myosin phosphatase complex. In addition to a well-documented role in muscle contraction, the PP1c-PPP1R12A complex is associated with cytoskeleton organization, cell migration and adhesion, and insulin signaling. Despite the variety of biological functions, only a few substrates of the PP1c-PPP1R12A complex are characterized, which limit a full understanding of PP1c-PPP1R12A activities in muscle contraction and cytoskeleton regulation.

Quantitative Proteomics Reveals Transforming Growth Factor β Receptor Targeted by Resveratrol and Hesperetin Coformulation in Endothelial Cells.

The endothelium is the frontline target of multiple metabolic stressors and pharmacological agents. As a consequence, endothelial cells (ECs) display highly dynamic and diverse proteome profiles. We describe here the culture of human aortic ECs from healthy and type 2 diabetic donors, the treatment with a small molecular coformulation of trans-resveratrol and hesperetin (tRES+HESP), followed by proteomic analysis of whole-cell lysate.

Effect of Insulin and Pioglitazone on Protein Phosphatase 2A Interaction Partners in Primary Human Skeletal Muscle Cells Derived from Obese Insulin-Resistant Participants.

Skeletal muscle insulin resistance is a major contributor to type-2 diabetes (T2D). Pioglitazone is a potent insulin sensitizer of peripheral tissues by targeting peroxisome proliferator-activated receptor gamma. Pioglitazone has been reported to protect skeletal muscle cells from lipotoxicity by promoting fatty acid mobilization and insulin signaling.

The effect of antipsychotic treatment on hormonal, inflammatory, and metabolic biomarkers in healthy volunteers: A systematic review and meta-analysis.

Antipsychotic medications demonstrate a variable range of efficacy and side effects in patients with mental illness. Research has attempted to identify biomarkers associated with antipsychotic effects in various populations. Research designs utilizing healthy volunteers may have the added benefit of measuring the effect of antipsychotics on a given biomarker (s) independent of the varied environmental and clinical factors that often accompany patient populations.

Profiling the Skeletal Muscle Proteome in Patients on Atypical Antipsychotics and Mood Stabilizers.

Atypical antipsychotics (AAP) are used in the treatment of severe mental illness. They are associated with several metabolic side effects including insulin resistance. The skeletal muscle is the primary tissue responsible for insulin-stimulated glucose uptake.

Metformin Increases Protein Phosphatase 2A Activity in Primary Human Skeletal Muscle Cells Derived from Lean Healthy Participants.

Objective: To investigate if PP2A plays a role in metformin-induced insulin sensitivity improvement in human skeletal muscle cells. . Eight lean insulin-sensitive nondiabetic participants (4 females and 4 males; age: 21.

Antipsychotic Medications and DNA Methylation in Schizophrenia and Bipolar Disorder: A Systematic Review.

The pharmacoepigenetics of antipsychotic treatment in severe mental illness is a growing area of research that aims to understand the interface between antipsychotic treatment and genetic regulation. Pharmacoepigenetics may some day assist in identifying treatment response mechanisms or become one of the components in the implementation of precision medicine. To understand the current evidence regarding the effects of antipsychotics on DNA methylation a systematic review with qualitative synthesis was performed through Pubmed, Embase and Psychinfo from earliest data to June 2019.

Kinome Profiling Reveals Abnormal Activity of Kinases in Skeletal Muscle From Adults With Obesity and Insulin Resistance.

Context: Obesity-related insulin resistance (OIR) is one of the main contributors to type 2 diabetes and other metabolic diseases. Protein kinases are implicated in insulin signaling and glucose metabolism. Molecular mechanisms underlying OIR involving global kinase activities remain incompletely understood.

Skeletal muscle DNA methylation modifications and psychopharmacologic treatment in bipolar disorder.

Both severe mental illness and atypical antipsychotics have been independently associated with insulin resistance and weight gain. Altered regulation of skeletal muscle DNA methylation may play a role. We aimed to evaluate DNA methylation modifications in human skeletal muscle samples to further understand its potential role in the metabolic burden observed in psychiatric patients and psychopharmacologic treatment.

Quantitative proteomics reveals novel interaction partners of Rac1 in pancreatic β-cells: Evidence for increased interaction with Rac1 under hyperglycemic conditions.

Rac1, a small G protein, regulates physiological insulin secretion from the pancreatic β-cell. Interestingly, Rac1 has also been implicated in the onset of metabolic dysfunction of the β-cell under the duress of hyperglycemia (HG). This study is aimed at the identification of interaction partners of Rac1 in β-cells under basal and HG conditions.

Ameliorating Methylglyoxal-Induced Progenitor Cell Dysfunction for Tissue Repair in Diabetes.

Patient-derived progenitor cell (PC) dysfunction is severely impaired in diabetes, but the molecular triggers that contribute to mechanisms of PC dysfunction are not fully understood. Methylglyoxal (MGO) is one of the highly reactive dicarbonyl species formed during hyperglycemia. We hypothesized that the MGO scavenger glyoxalase 1 (GLO1) reverses bone marrow-derived PC (BMPC) dysfunction through augmenting the activity of an important endoplasmic reticulum stress sensor, inositol-requiring enzyme 1α (IRE1α), resulting in improved diabetic wound healing.

Atypical Antipsychotics and the Human Skeletal Muscle Lipidome.

Atypical antipsychotics (AAPs) are a class of medications associated with significant metabolic side effects, including insulin resistance. The aim of this study was to analyze the skeletal muscle lipidome of patients on AAPs, compared to mood stabilizers, to further understand the molecular changes underlying AAP treatment and side effects. Bipolar patients on AAPs or mood stabilizers underwent a fasting muscle biopsy and assessment of insulin sensitivity.

Association of Protein Kinase B (AKT) DNA Hypermethylation with Maintenance Atypical Antipsychotic Treatment in Patients with Bipolar Disorder.

Study Objective: Atypical antipsychotics cause insulin resistance that leads to an increased risk of diabetes mellitus and cardiovascular disease. Skeletal muscle is the primary tissue for uptake of glucose, and its dysfunction is considered one of the primary defects in the development of insulin resistance. Protein kinase B (AKT) plays an important role in overall skeletal muscle health and glucose uptake into the muscle.

Atypical antipsychotics, insulin resistance and weight; a meta-analysis of healthy volunteer studies.

Atypical antipsychotics increase the risk of diabetes and cardiovascular disease through their side effects of insulin resistance and weight gain. The populations for which atypical antipsychotics are used carry a baseline risk of metabolic dysregulation prior to medication which has made it difficult to fully understand whether atypical antipsychotics cause insulin resistance and weight gain directly. The purpose of this work was to conduct a systematic review and meta-analysis of atypical antipsychotic trials in healthy volunteers to better understand their effects on insulin sensitivity and weight gain.

Successful metformin treatment of insulin resistance is associated with down-regulation of the kynurenine pathway.

Context: An extensive body of literature indicates a relationship between insulin resistance and the up-regulation of the kynurenine pathway, i.e. the preferential conversion of tryptophan to kynurenine, with subsequent overproduction of diabetogenic downstream metabolites, such as kynurenic acid.

Proteomic Characterization of the World Trade Center dust-activated mdig and c-myc signaling circuit linked to multiple myeloma.

Several epidemiological studies suggested an increased incidence rate of multiple myeloma (MM) among first responders and other individuals who exposed to World Trade Center (WTC) dust. In this report, we provided evidence showing that WTC dust is potent in inducing mdig protein and/or mRNA in bronchial epithelial cells, B cells and MM cell lines. An increased mdig expression in MM bone marrow was observed, which is associated with the disease progression and prognosis of the MM patients.

Proteomics analyses of subcutaneous adipocytes reveal novel abnormalities in human insulin resistance.

Objective: To provide a more global view of adipocyte changes in human insulin resistance by proteomics analyses.

Methods: Baseline biopsies of abdominal subcutaneous adipose tissue were obtained from 23 subjects without diabetes. Euglycemic clamps were used to divide subjects into an insulin-resistant group (IR, N = 10) and an insulin-sensitive (IS, N = 13) group, which were of similar age and gender but unequal adiposity (greater in IR).

Quantitative proteomics reveals novel protein interaction partners of PP2A catalytic subunit in pancreatic β-cells.

Protein phosphatase 2A (PP2A) is one of the major serine/threonine phosphatases. We hypothesize that PP2A regulates signaling cascades in pancreatic β-cells in the context of glucose-stimulated insulin secretion (GSIS). Using co-immunoprecipitation (co-IP) and tandem mass spectrometry, we globally identified the protein interaction partners of the PP2A catalytic subunit (PP2Ac) in insulin-secreting pancreatic β-cells.

Novel Endogenous, Insulin-Stimulated Akt2 Protein Interaction Partners in L6 Myoblasts.

Insulin resistance and Type 2 diabetes are marked by an aberrant response in the insulin signaling network. The phosphoinositide-dependent serine/threonine kinase, Akt2, plays a key role in insulin signaling and glucose uptake, most notably within skeletal muscle. Protein-protein interaction regulates the functional consequence of Akt2 and in turn, Akt2's role in glucose uptake.

Optimization of Search Engines and Postprocessing Approaches to Maximize Peptide and Protein Identification for High-Resolution Mass Data.

The two key steps for analyzing proteomic data generated by high-resolution MS are database searching and postprocessing. While the two steps are interrelated, studies on their combinatory effects and the optimization of these procedures have not been adequately conducted. Here, we investigated the performance of three popular search engines (SEQUEST, Mascot, and MS Amanda) in conjunction with five filtering approaches, including respective score-based filtering, a group-based approach, local false discovery rate (LFDR), PeptideProphet, and Percolator.

The proteomic investigation reveals interaction of mdig protein with the machinery of DNA double-strand break repair.

To investigate how mineral dust-induced gene (mdig, also named as mina53, MINA, or NO52) promotes carcinogenesis through inducing active chromatin, we performed proteomics analyses for the interacting proteins that were co-immunoprecipitated by anti-mdig antibody from either the lung cancer cell line A549 cells or the human bronchial epithelial cell line BEAS-2B cells. On SDS-PAGE gels, three to five unique protein bands were consistently observed in the complexes pulled-down by mdig antibody, but not the control IgG. In addition to the mdig protein, several DNA repair or chromatin binding proteins, including XRCC5, XRCC6, RBBP4, CBX8, PRMT5, and TDRD, were identified in the complexes by the proteomics analyses using both Orbitrap Fusion and Orbitrap XL nanoESI-MS/MS in four independent experiments.

Plasma Lactate Levels Increase during Hyperinsulinemic Euglycemic Clamp and Oral Glucose Tolerance Test.

Insulin resistance, which plays a central role in the pathogenesis of type 2 diabetes (T2D), is an early indicator that heralds the occurrence of T2D. It is imperative to understand the metabolic changes that occur at the cellular level in the early stages of insulin resistance. The objective of this study was to determine the pattern of circulating lactate levels during oral glucose tolerance test (OGTT) and hyperinsulinemic euglycemic clamp (HIEC) study in normal nondiabetic subjects.

Quantitative phosphoproteomics reveals novel phosphorylation events in insulin signaling regulated by protein phosphatase 1 regulatory subunit 12A.

Unlabelled: Serine/threonine protein phosphatase 1 regulatory subunit 12A (PPP1R12A) modulates the activity and specificity of the catalytic subunit of protein phosphatase 1, regulating various cellular processes via dephosphorylation. Nonetheless, little is known about phosphorylation events controlled by PPP1R12A in skeletal muscle insulin signaling. Here, we used quantitative phosphoproteomics to generate a global picture of phosphorylation events regulated by PPP1R12A in a L6 skeletal muscle cell line, which were engineered for inducible PPP1R12A knockdown.