Alpha-ketoglutarate

Alpha-ketoglutarate (αKG) emerged as a key regulator of energetic and redox metabolism in cells, affecting the immune response in various conditions. However, it remained unclear how the exogenous αKG modulates the functions of dendritic cells (DCs), key cells regulating T-cell response. Here we found that non-toxic doses of αKG display anti-inflammatory properties in human APC-T cell interaction models. In a model of monocyte-derived (mo)DCs, αKG impaired the differentiation, and the maturation of moDCs induced with lipopolysaccharide (LPS)/interferon (IFN)-γ, and decreased their capacity to induce Th1 cells...

Osteoporosis is a chronic skeletal disease and the major source of risk for fractures in aged people. It is urgent to investigate the mechanism regulating osteoporosis for developing potential treatment and prevention strategies. Osteogenic differentiation of preosteoblast enhances bone formation, which might be a promising strategy for treatment and prevention of osteoporosis. Protein disulfide isomerase family A, member 3 (PDIA3) could induce bone formation, yet the role of PDIA3 in osteogenic differentiation of preosteoblast remains unknown...

SCOPE: Premature ovarian insufficiency (POI) is a common female infertility problem, with its pathogenesis remains unknown. The NOD-like receptor family pyrin domain-containing 3 (NLRP3)-mediated pyroptosis has been proposed as a possible mechanism in POI. This study investigates the therapeutic effect of α-ketoglutarate (AKG) on ovarian reserve function in POI rats and further explores the potential molecular mechanisms. METHODS AND RESULTS: POI rats are caused by administration of cyclophosphamide (CTX) to determine whether AKG has a protective effect...

Evidence from diverse areas of research including chronobiology, metabolomics and magnetic resonance spectroscopy indicate that energy dysregulation is a central feature of bipolar disorder pathophysiology. In this paper, we propose that mania represents a condition of heightened cerebral energy metabolism facilitated by hyperglycolysis and glutaminolysis. When oxidative glucose metabolism becomes impaired in the brain, neurons can utilize glutamate as an alternative substrate to generate energy through oxidative phosphorylation...

BACKGROUND: T cell immunoglobulin and mucin-domain containing-3 (TIM-3) is a cell surface molecule that was first discovered on T cells. However, recent studies revealed that it is also highly expressed in acute myeloid leukemia (AML) cells and it is related to AML progression. As, Glutamine appears to play a prominent role in malignant tumor progression, especially in their myeloid group, therefore, in this study we aimed to evaluate the relation between TIM-3/Galectin-9 axis and glutamine metabolism in two types of AML cell lines, HL-60 and THP-1...

Eradication of acute myeloid leukemia (AML) is therapeutically challenging; many patients succumb to AML despite initially responding to conventional treatments. Here, we showed that the imipridone ONC213 elicits potent antileukemia activity in a subset of AML cell lines and primary patient samples, particularly in leukemia stem cells, while producing negligible toxicity in normal hematopoietic cells. ONC213 suppressed mitochondrial respiration and elevated alpha-ketoglutarate by suppressing alpha-ketoglutarate dehydrogenase (α-KGDH) activity...

OBJECTIVES: Acute reversible leukoencephalopathy with increased urinary alpha-ketoglutarate (ARLIAK) is a recently described autosomal recessive leukoencephalopathy caused by pathogenic variants in the SLC13A3 gene. ARLIAK is characterized by acute neurologic involvement, often precipitated by febrile illness, with largely reversible clinical symptoms and imaging findings. Three patients have been reported in the literature to date. Our objective is to report newly identified patients and their genetic variants and phenotypes and review published literature on ARLIAK...

N-6 methyladenosine is the most abundant nucleic acid modification in eukaryotes and plays a crucial role in gene regulation. The AlkB family of alpha-ketoglutarate-dependent dioxygenases is responsible for nucleic acid demethylation. Recent studies have discovered that a chemical demethylation system using hydrogen peroxide and ammonium bicarbonate can effectively demethylate nucleic acids. The addition of ferrous ammonium sulfate boosts the oxidation rate by forming a Fenton reagent with hydrogen peroxide...

India experiences a significant amount of morbidity and mortality due to gliomas particularly glioblastoma multiforme (GBM), which ranks among the worst cancers. Oxaloacetate (OAA) is a human keto acid that is central to cellular metabolism; it has been recognized by the US FDA for use in GBM patients, triggering a review to revisit the cellular mechanism of its therapeutic action. Various cellular and molecular studies have proposed that instead of fueling the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), gliomas prefer to use glycolysis (the Warburg effect) to fuel macromolecules for the synthesis of nucleotides, fatty acids, and amino acids for the accelerated mitosis...

Recently, it has been reported that oral probiotics improve the apparent digestibility of nitrogen in weaned piglets; however, the underlying mechanism is unclear. A total of 12 crossbred piglets (Yorkshire × Landrace; 28 days old) were randomly divided into two groups. The control (Con) group was fed with a basic diet + Luria-Bertani (LB; sterile; 10 mL), whereas the subject (Sub) group was fed with a basic diet + B. subtilis JATP-3 (1 × 109  CFU/mL; 10 mL)...

Platelets from patients with myeloproliferative neoplasms (MPNs) exhibit a hyperreactive phenotype. Here, we found elevated P-selectin exposure and platelet-leukocyte aggregates indicating activation of platelets from essential thrombocythemia (ET) patients. Single cell RNA-seq analysis of primary samples revealed significant enrichment of transcripts related to platelet activation, mTOR and oxidative phosphorylation (OXPHOS) in ET patient platelets. These observations were validated via proteomic profiling...

Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate to alpha-ketoglutarate. IDH1/2 mutations preferentially convert αKG to R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and S-2-hydroxyglutarate (S2HG) levels in blood and tumor tissues were analyzed in a discovery cohort of IDHmt glioma and CCA patients...

2-Hydroxyglutarate (2-HG) is an oncometabolite that accumulates in certain cancers. Gain-of-function mutations in isocitrate dehydrogenase lead to 2-HG accumulation at the expense of alpha-ketoglutarate. Elevated 2-HG levels inhibit histone and DNA demethylases, causing chromatin structure and gene regulation changes with tumorigenic consequences. We investigated the effects of elevated 2-HG levels in Saccharomyces cerevisiae , a yeast devoid of DNA methylation and heterochromatin-associated histone methylation...

Idiosyncratic drug-induced liver injury (DILI) is an unpredictable reaction of individuals exposed to a certain drug, and drug-induced autoimmune hepatitis (DIAIH) presents a DILI phenotype that mimics idiopathic autoimmune hepatitis (AIH) when considering the clinical, biochemical, serological and histological parameters. We present a case report of a 48-year-old male who was hospitalized due to severe hepatocellular liver injury two months after self-treatment with a muscle-building dietary supplement based on arginine-alpha-ketoglutarate, L-citrulline, L tyrosine, creatine malate and beet extract...

Osteoporosis (OP), which largely increases the risk of fractures, is the most common chronic degenerative orthopedic disease in the elderly due to the imbalance of bone homeostasis. Alpha-ketoglutaric acid (AKG), an endogenous metabolic intermediate involved in osteogenesis, plays critical roles in osteogenic differentiation and mineralization and the inhibition of osteoclastogenic differentiation. However, the low bioavailability and poor bone-targeting efficiency of AKG seriously limit its efficacy in OP treatment...

BACKGROUND: High caloric diets with high amounts of fats and sweeteners such as fructose may predispose organisms to neurodegenerative diseases. METHODS: This study aimed to examine the effects of a high-fat high-fructose diet (HFFD) on the behavior of mice, energy metabolism, and markers of oxidative stress in murine cerebral cortex. Dietary α-ketoglutarate (AKG) was chosen as a treatment which could modulate the putative effects of HFFD. RESULTS: We found that HFFD stimulated locomotion and defecation in mice, whereas an AKG-supplemented diet had a proclivity to promote anxiety-like behavior...

OBJECTIVE: To explore whether fat mass and obesity associated proteins (FTO) is an important target of Qiteng Xiaozhuo granules (QTXZG,) medicated serum in regulating proliferation and apoptosis of glomerular mesangial cells. METHODS: Medicated serum was obtained from Sprague-Dawley (SD) rats administered intragastrically with QTXZG decoction. The optimal concentration and intervention time of medicated serum were selected with the cell counting kit 8 assay. Cell proliferation was assessed by 5-ethynyl-2'-deoxyuridine (EdU) and cell apoptosis was investigated using flow cytometry...

Increased utilization of glucose is a hallmark of cancer. Sodium-glucose transporter 2 (SGLT2) is a critical player in glucose uptake in early-stage and well-differentiated lung adenocarcinoma (LUAD). SGLT2 inhibitors, which are FDA-approved for diabetes, heart failure, and kidney disease, have been shown to significantly delay LUAD development and prolong survival in murine models and in retrospective studies in diabetic patients, suggesting that they may be re-purposed for lung cancer. Despite the anti-tumor effects of SGLT2 inhibition, tumors eventually escape treatment...

Halomonas elongata 1H9T is a moderate halophilic strain able to produce poly(3-hydroxybutyrate) (P(3HB)), a biodegradable plastic, and gluconic acid, a valuable organic acid with wide industrial applications. In this work, the green alga Ulva rigida was used as platform to produce cultivation substrates for microbial conversion as well as functional ingredients, targeting its full valorization. The liquor obtained by autohydrolysis presented the highest concentration of oligosaccharides and protein, being an interesting feedstock to produce functional ingredients...

BACKGROUND: Branched-chain aminotransferase 1 (BCAT1) has been proposed to drive proliferation and invasion of isocitrate dehydrogenase ( IDH ) wild-type glioblastoma cells. However, the Cancer Genome Atlas (TCGA) dataset shows considerable variation in the expression of this enzyme in glioblastoma. The aim of this study was to determine the role of BCAT1 in driving the proliferation and invasion of glioblastoma cells and xenografts that have widely differing levels of BCAT1 expression and the mechanism responsible...