A5077144544- Dietary Effects on Health
- Immune Cell Function and Interaction
- Diet and metabolism studies
- Dermatological and Skeletal Disorders
- Immune cells in cancer
- Psoriasis: Treatment and Pathogenesis
- Connective tissue disorders research
- Cancer-related Molecular Pathways
- FOXO transcription factor regulation
- Tryptophan and brain disorders
- interferon and immune responses
- Cancer, Hypoxia, and Metabolism
- Cytomegalovirus and herpesvirus research
- Adipokines, Inflammation, and Metabolic Diseases
- Immune responses and vaccinations
- Enzyme Production and Characterization
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Adenosine and Purinergic Signaling
- Heterotopic Ossification and Related Conditions
- Mitochondrial Function and Pathology
- Parathyroid Disorders and Treatments
- Autophagy in Disease and Therapy
- Circadian rhythm and melatonin
- Atherosclerosis and Cardiovascular Diseases
- Peroxisome Proliferator-Activated Receptors
National Heart Lung and Blood Institute
2016-2024
National Institutes of Health
2018-2024
Activation of the NLRP3 inflammasome is associated with metabolic dysfunction, and intermittent fasting has been shown to improve clinical presentation inflammasome-linked diseases. As mitochondrial perturbations, which function as a damage-associated molecular pattern, exacerbate activation, we investigated whether blunts activation via sirtuin-mediated augmentation integrity.We performed study 19 healthy volunteers. Each subject underwent 24-hour fast then was fed fixed-calorie meal. Blood...
BACKGROUNDFasting and NAD+-boosting compounds, including NAD+ precursor nicotinamide riboside (NR), confer antiinflammatory effects. However, the underlying mechanisms therapeutic potential are incompletely defined.METHODSWe explored biology in myeloid cells from healthy volunteers following vivo placebo or NR administration subsequently tested findings vitro monocytes extracted patients with systemic lupus erythematosus (SLE).RESULTSRNA-Seq of unstimulated LPS-activated implicated...
Background: Arterial calcification due to deficiency of CD73 (ACDC; OMIM 211800) is a rare genetic disease resulting in calcium deposits arteries and small joints causing claudication, resting pain, severe joint deformities. Currently, there are no standard treatments for ACDC. Our previous work identified etidronate as potential targeted ACDC treatment, using vitro vivo models with patient-derived cells. In this study, we test the safety effectiveness attenuating progression lower-extremity...
Abstract Generally, fasting and refeeding confer anti- proinflammatory effects, respectively. In humans, these caloric-load interventions function, in part, via regulation of CD4+ T cell biology. However, mechanisms orchestrating this remain incomplete. We employed integrative bioinformatics RNA sequencing high-performance liquid chromatography–mass spectrometry data to measure serum metabolites gene expression peripheral blood mononuclear cells isolated from volunteers identify...
Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder caused by germline mutations in TP53 that can lead to increased mitochondrial metabolism patients. However, the implications of altered function for tumorigenesis LFS are unclear. Here, we have reported genetic or pharmacologic disruption respiration improves cancer-free survival mouse model expresses mutant p53. Mechanistically, inhibition autophagy and decreased aberrant proliferation signaling In pilot study, patients treated...
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and diagnosed in the absence of a specific cause, making its clinical management challenging. A better understanding molecular mechanism underlying this apparent bioenergetic deficiency state may reveal insights for developing targeted treatment strategies. We report that overexpression
To evaluate whether nicotinamide adenine dinucleotide-positive (NAD+) boosting modulates adaptive immunity, primary CD4+ T cells from healthy control and psoriasis subjects were exposed to vehicle or riboside (NR) supplementation. NR blunts interferon γ (IFNγ) interleukin (IL)-17 secretion with greater effects on helper (Th) 17 polarization. RNA sequencing (RNA-seq) analysis implicates blunting of sequestosome 1 (sqstm1/p62)-coupled oxidative stress. administration increases sqstm1 reduces...
A fasting mimetic diet blunts inflammation, and intermittent has shown ameliorative effects in obese asthmatics. To examine whether canonical inflammatory pathways linked with asthma are modulated by fasting, we designed a pilot study mild asthmatic subjects to assess the effect of on NLRP3 inflammasome, Th2 cell activation, airway epithelial cytokine production. Subjects documented reversible obstruction stable were recruited into this which pulmonary function testing (PFT) PBMCextraction...
Intermittent fasting and mimetic diets ameliorate inflammation. Similarly, serum extracted from fasted healthy asthmatic subjects' blunt inflammation in vitro, implicating components this immunomodulation. To identify the proteins orchestrating these effects, SOMAScan technology was employed to evaluate protein levels subjects following an overnight, 24-h fast 3 h after refeeding. Partial least square discriminant analysis identified several as potential candidates confer feeding status The...
Caloric deprivation interventions such as intermittent fasting and caloric restriction ameliorate metabolic inflammatory disease. As a human model of deprivation, 24-h fast blunts innate adaptive immune cell responsiveness relative to the refed state. Isolated serum at these time points confers same immunomodulatory effects on transformed lines. To identify mediators orchestrating this, metabolomic lipidomic analysis was performed extracted after re-feeding. Bioinformatic integration with...
Arterial calcification due to deficiency of CD73 (ACDC) is a hereditary autosomal recessive ectopic mineralization syndrome caused by loss-of-function mutations in the ecto-5'-nucleotidase gene. Periarticular has been reported but clinical characterization arthritis as well microstructure and chemical composition periarticular calcifications SF crystals not systematically investigated.Eight ACDC patients underwent extensive rheumatological radiological evaluation over period 11 years....
Abstract Background Li-Fraumeni syndrome (LFS) is a highly penetrant autosomal dominant cancer predisposition disorder caused by germline TP53 pathogenic variants. Patients with LFS have increased oxidative phosphorylation capacity in skeletal muscle and stress blood. Metformin inhibits phosphorylation, reducing available energy for cell proliferation decreasing production of reactive oxygen species that cause DNA damage. Thus, metformin may provide pharmacologic risk reduction patients LFS,...
ABSTRACT Lipid-derived acetyl-CoA is shown to be the major carbon source for histone acetylation. However, there no direct evidence demonstrating lipid metabolic pathway contribututions this process. Mitochondrial acetyltransferase 1 (ACAT1) catalyzes final step of ß-oxidation, aerobic process catabolizing fatty acids (FA) into acetyl-CoA. To investigate in context immunometabolism, we generated macrophage cell line lacking ACAT1. 13 C-carbon tracing combined with mass spectrometry confirmed...
NAD+ boosting via nicotinamide riboside (NR) confers anti-inflammatory effects. However, its underlying mechanisms and therapeutic potential remain incompletely defined. Here, we showed that NR increased the expression of CC-chemokine receptor 7 (CCR7) in human M1 macrophages by flow cytometric analysis cell surface receptors. Consequently, chemokine ligand 19 (CCL19, for CCR7)-induced macrophage migration was enhanced following administration. Metabolomics revealed prostaglandin E2 (PGE2)...
Abstract Intermittent fasting blunts inflammation in asthma and rheumatoid arthritis, suggesting that may be exploited as an immune-modulatory intervention. However, mechanisms underpinning anti-inflammatory effects of remain poorly characterized. Here, we show humans is sufficient to blunt CD4+ T helper cell responsiveness. RNA-seq flow cytometric immunophenotyping peripheral blood mononuclear cells (PBMCs) from volunteers subjected overnight or 24-hour fasting, 3-hours refeeding implicate...
Abstract Although NAD +levels modulate metabolism, how this regulates immunometabolism/inflammation remains unclear. Employing Nicotinamide Riboside (NR) to boost NAD, we explored T H17-linked inflammatory in Psoriasis. Primary Psoriasis CD4 +T cells exposed NR reduced IL-17 secretion and RNA-seq/pathway analysis implicated modulating sequestosome 1 (SQSTM1/p62)-coupled oxidative stress. In parallel, cell reactive oxygen species (ROS) levels activated the NRF2 transcription factor. Depletion...
Background/Purpose: CD73 is a ecto-5′-nucleotidase located on the plasma membrane that generates adenosine from AMP in extracellular space, and functions as checkpoint against immune vascular activation. inhibitors eliminate this blockade are being studied phase 2/3 cancer clinical trials. We recently identified lack of promotes thromboinflammation neutrophil trap (NET) formation mice. The role human NETosis, however, remains to be studied. Arterial calcification due deficiency (ACDC) rare,...