The manganese transporter SLC39A8 links alkaline ceramidase 1 to inflammatory bowel disease.

The metal ion transporter SLC39A8 is associated with physiological traits and diseases, including blood manganese (Mn) levels and inflammatory bowel diseases (IBD). The mechanisms by which SLC39A8 controls Mn homeostasis and epithelial integrity remain elusive. Here, we generate Slc39a8 intestinal epithelial cell-specific-knockout (Slc39a8-IEC KO) mice, which display markedly decreased Mn levels in blood and most organs.

Sex modulates the diet-induced changes to the plasma lipidome in a rat model of cardiorespiratory fitness.

Objective: Individuals with higher intrinsic cardiorespiratory fitness (CRF) experience decreased rates of cardiometabolic disease and mortality, and high CRF is associated with increased utilization of fatty acids (FAs) for energy. Studies suggest a complex relationship between CRF, diet, and sex with health outcomes, but this interaction is understudied. We hypothesized that FA utilization differences by fitness and sex could be detected in the plasma metabolome when rats or humans were fed a high carbohydrate (HC) or high fat (HF) diet.

Mapping regional funding for COVID-19 research in the Asia-Pacific region.

Introduction: The Global Research Collaboration for Infectious Disease Preparedness (GloPID-R) is a network of funders supporting research on infectious diseases of epidemic/pandemic potential. GloPID-R is establishing regional hubs to strengthen stakeholder engagement particularly among low-income and middle-income countries. The first pilot hub, led from Republic of Korea (South Korea), has been launched in the Asia-Pacific region, a region highly prone to outbreaks of emerging infectious diseases.

Cerebral Gray and White Matter Monogalactosyl Diglyceride Levels Rise with the Progression of Alzheimer's Disease.

Background: Multiple studies have reported brain lipidomic abnormalities in Alzheimer's disease (AD) that affect glycerophospholipids, sphingolipids, and fatty acids. However, there is no consensus regarding the nature of these abnormalities, and it is unclear if they relate to disease progression.

Objective: Monogalactosyl diglycerides (MGDGs) are a class of lipids which have been recently detected in the human brain.

Serum lipidomic determinants of human diabetic neuropathy in type 2 diabetes.

Objective: The serum lipidomic profile associated with neuropathy in type 2 diabetes is not well understood. Obesity and dyslipidemia are known neuropathy risk factors, suggesting lipid profiles early during type 2 diabetes may identify individuals who develop neuropathy later in the disease course. This retrospective cohort study examined lipidomic profiles 10 years prior to type 2 diabetic neuropathy assessment.

Lipid Alterations in African American Men with Prostate Cancer.

African-American (AA) men are more than twice as likely to die of prostate cancer (PCa) than European American (EA) men. Previous in silico analysis revealed enrichment of altered lipid metabolic pathways in pan-cancer AA tumors. Here, we performed global unbiased lipidomics profiling on 48 matched localized PCa and benign adjacent tissues (30 AA, 24 ancestry-verified, and 18 EA, 8 ancestry verified) and quantified 429 lipids belonging to 14 lipid classes.

Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer.

Multi-tyrosine kinase inhibitors (MTKIs) have thus far had limited success in the treatment of castration-resistant prostate cancer (CRPC). Here, we report a phase I-cleared orally bioavailable MTKI, ESK981, with a novel autophagy inhibitory property that decreased tumor growth in diverse preclinical models of CRPC. The anti-tumor activity of ESK981 was maximized in immunocompetent tumor environments where it upregulated expression through the interferon gamma pathway and promoted functional T cell infiltration, which resulted in enhanced therapeutic response to immune checkpoint blockade.

Comparing the Fasting and Random-Fed Metabolome Response to an Oral Glucose Tolerance Test in Children and Adolescents: Implications of Sex, Obesity, and Insulin Resistance.

As the incidence of obesity and type 2 diabetes (T2D) is occurring at a younger age, studying adolescent nutrient metabolism can provide insights on the development of T2D. Metabolic challenges, including an oral glucose tolerance test (OGTT) can assess the effects of perturbations in nutrient metabolism. Here, we present alterations in the global metabolome in response to an OGTT, classifying the influence of obesity and insulin resistance (IR) in adolescents that arrived at the clinic fasted and in a random-fed state.

Diminished retinal complex lipid synthesis and impaired fatty acid β-oxidation associated with human diabetic retinopathy.

BACKGROUNDThis study systematically investigated circulating and retinal tissue lipid determinants of human diabetic retinopathy (DR) to identify underlying lipid alterations associated with severity of DR.METHODSRetinal tissues were retrieved from postmortem human eyes, including 19 individuals without diabetes, 20 with diabetes but without DR, and 20 with diabetes and DR, for lipidomic study. In a parallel study, serum samples from 28 American Indians with type 2 diabetes from the Gila River Indian Community, including 12 without DR, 7 with mild nonproliferative DR (NPDR), and 9 with moderate NPDR, were selected.

Renin-angiotensin system inhibition reverses the altered triacylglycerol metabolic network in diabetic kidney disease.

Objective: Dyslipidemia is a significant risk factor for progression of diabetic kidney disease (DKD). Determining the changes in individual lipids and lipid networks across a spectrum of DKD severity may identify lipids that are pathogenic to DKD progression.

Methods: We performed untargeted lipidomic analysis of kidney cortex tissue from diabetic db/db and db/db eNOS mice along with non-diabetic littermate controls.

Plasma lipidomic profiling identifies a novel complex lipid signature associated with ischemic stroke in chronic kidney disease.

Rationale And Objective: Despite contribution of dyslipidemia to ischemic stroke, plasma lipidomic correlates of stroke in CKD is not studied. This study is aimed to identify plasma lipid alterations associated with stroke.

Study Design: Cross sectional.

Maternal lipid levels across pregnancy impact the umbilical cord blood lipidome and infant birth weight.

Major alterations in metabolism occur during pregnancy enabling the mother to provide adequate nutrients to support infant development, affecting birth weight (BW) and potentially long-term risk of obesity and cardiometabolic disease. We classified dynamic changes in the maternal lipidome during pregnancy and identified lipids associated with Fenton BW z-score and the umbilical cord blood (CB) lipidome. Lipidomics was performed on first trimester maternal plasma (M1), delivery maternal plasma (M3), and CB plasma in 106 mother-infant dyads.

Increased lipogenesis and impaired β-oxidation predict type 2 diabetic kidney disease progression in American Indians.

BACKGROUNDIn this study, we identified the lipidomic predictors of early type 2 diabetic kidney disease (DKD) progression, which are currently undefined.METHODSThis longitudinal study included 92 American Indians with type 2 diabetes. Serum lipids (406 from 18 classes) were quantified using mass spectrometry from baseline samples when iothalamate-based glomerular filtration rate (GFR) was at least 90 mL/min.

Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer.

Purpose: The bromodomain and extraterminal (BET)-containing proteins (BRD2/3/4) are essential epigenetic coregulators for prostate cancer growth. BRD inhibitors have shown promise for treatment of metastatic castration-resistant prostate cancer (mCRPC), and have been shown to function even in the context of resistance to next-generation AR-targeted therapies such as enzalutamide and abiraterone. Their clinical translation, however, has been limited by off-target effects, toxicity, and rapid resistance.

Lipidomics and Biomarker Discovery in Kidney Disease.

Technological advances in mass spectrometry-based lipidomic platforms have provided the opportunity for comprehensive profiling of lipids in biological samples and shown alterations in the lipidome that occur in metabolic disorders. A lipidomic approach serves as a powerful tool for biomarker discovery and gaining insight to molecular mechanisms of disease, especially when integrated with other -omics platforms (ie, transcriptomics, proteomics, and metabolomics) in the context of systems biology. In this review, we describe the workflow commonly applied to the conduct of lipidomic studies including important aspects of study design, sample preparation, biomarker identification and quantification, and data processing and analysis, as well as crucial considerations in clinical applications.

Shared and distinct lipid-lipid interactions in plasma and affected tissues in a diabetic mouse model.

Lipids are ubiquitous metabolites with diverse functions; abnormalities in lipid metabolism appear to be related to complications from multiple diseases, including type 2 diabetes. Through technological advances, the entire lipidome has been characterized and researchers now need computational approaches to better understand lipid network perturbations in different diseases. Using a mouse model of type 2 diabetes with microvascular complications, we examined lipid levels in plasma and in renal, neural, and retinal tissues to identify shared and distinct lipid abnormalities.

Impaired -Oxidation and Altered Complex Lipid Fatty Acid Partitioning with Advancing CKD.

Studies of lipids in CKD, including ESRD, have been limited to measures of conventional lipid profiles. We aimed to systematically identify 17 different lipid classes and associate the abundance thereof with alterations in acylcarnitines, a metric of -oxidation, across stages of CKD. From the Clinical Phenotyping Resource and Biobank Core (CPROBE) cohort of 1235 adults, we selected a panel of 214 participants: 36 with stage 1 or 2 CKD, 99 with stage 3 CKD, 61 with stage 4 CKD, and 18 with stage 5 CKD.

Evaluation of intensity drift correction strategies using MetaboDrift, a normalization tool for multi-batch metabolomics data.

In recent years, mass spectrometry-based metabolomics has increasingly been applied to large-scale epidemiological studies of human subjects. However, the successful use of metabolomics in this context is subject to the challenge of detecting biologically significant effects despite substantial intensity drift that often occurs when data are acquired over a long period or in multiple batches. Numerous computational strategies and software tools have been developed to aid in correcting for intensity drift in metabolomics data, but most of these techniques are implemented using command-line driven software and custom scripts which are not accessible to all end users of metabolomics data.

Distinct Lipidomic Landscapes Associated with Clinical Stages of Urothelial Cancer of the Bladder.

Background: The first global lipidomic profiles associated with urothelial cancer of the bladder (UCB) and its clinical stages associated with progression were identified.

Objective: To identify lipidomic signatures associated with survival and different clinical stages of UCB.

Design, Setting, And Participants: Pathologically confirmed 165 bladder-derived tissues (126 UCB, 39 benign adjacent or normal bladder tissues).

Fatty acid and lipidomic data in normal and tumor colon tissues of rats fed diets with and without fish oil.

Data is provided to show the detailed fatty acid and lipidomic composition of normal and tumor rat colon tissues. Rats were fed either a Western fat diet or a fish oil diet, and half the rats from each diet group were treated with chemical carcinogens that induce colon cancer (azoxymethane and dextran sodium sulfate). The data show total fatty acid profiles of sera and of all the colon tissues, namely normal tissue from control rats and both normal and tumor tissues from carcinogen-treated rats, as obtained by gas chromatography with mass spectral detection.

Effects of fish oil supplementation on prostaglandins in normal and tumor colon tissue: modulation by the lipogenic phenotype of colon tumors.

Dietary fish oils have potential for prevention of colon cancer, and yet the mechanisms of action in normal and tumor colon tissues are not well defined. Here we evaluated the impact of the colonic fatty acid milieu on the formation of prostaglandins and other eicosanoids. Distal tumors in rats were chemically induced to model inflammatory colonic carcinogenesis.

Lipidomic Signature of Progression of Chronic Kidney Disease in the Chronic Renal Insufficiency Cohort.

Introduction: Human studies report conflicting results on the predictive power of serum lipids on progression of chronic kidney disease (CKD). We aimed to systematically identify the lipids that predict progression to end-stage kidney disease.

Methods: From the Chronic Renal Insufficiency Cohort, 79 patients with CKD stage 2 to 3 who progressed to ESKD over 6 years of follow up were selected and frequency-matched by age, sex, race, and diabetes with 121 non-progressors with less than 25% decline in estimated glomerular filtration rate (eGFR) during the follow up.