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International Journal of Molecular... Jul 2023When tissues are under physiological stresses, such as vigorous exercise and cold exposure, skeletal muscle cells secrete succinate into the extracellular space for... (Review)
Review
When tissues are under physiological stresses, such as vigorous exercise and cold exposure, skeletal muscle cells secrete succinate into the extracellular space for adaptation and survival. By contrast, environmental toxins and injurious agents induce cellular secretion of succinate to damage tissues, trigger inflammation, and induce tissue fibrosis. Extracellular succinate induces cellular changes and tissue adaptation or damage by ligating cell surface succinate receptor-1 (SUCNR-1) and activating downstream signaling pathways and transcriptional programs. Since SUCNR-1 mediates not only pathological processes but also physiological functions, targeting it for drug development is hampered by incomplete knowledge about the characteristics of its physiological vs. pathological actions. This review summarizes the current status of extracellular succinate in health and disease and discusses the underlying mechanisms and therapeutic implications.
Topics: Humans; Succinic Acid; Succinates; Signal Transduction; Cell Membrane; Fibrosis
PubMed: 37446354
DOI: 10.3390/ijms241311165 -
Atherosclerosis Nov 2023Sex-specific differences in the response to lipid-lowering therapies have been reported. Here, we assessed the effect of bempedoic acid in women and men using pooled,...
BACKGROUND AND AIMS
Sex-specific differences in the response to lipid-lowering therapies have been reported. Here, we assessed the effect of bempedoic acid in women and men using pooled, patient-level data from four phase 3 clinical trials of bempedoic acid.
METHODS
Patients were grouped into two pools: 1) atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) "on statins" and 2) "low-dose or no statin". Percent changes from baseline to at least week 12 in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (Apo B), and high-sensitivity C-reactive protein (hsCRP), as well as safety, were analyzed by statin pool and sex.
RESULTS
Overall, 3623 patients were included (bempedoic acid, 2425; placebo, 1198). Significant reductions in lipid parameters and hsCRP were observed with bempedoic acid vs. placebo in both sexes in the ASCVD and/or HeFH on statins (n = 3009) and the low-dose or no statin (n = 614) pools (p ≤ 0.002). Compared with men, women had significantly greater placebo-corrected reductions in LDL-C (-21.2% vs. -17.4%; p = 0.044), non-HDL-C (-17.3% vs. -12.1%; p = 0.003), TC (-13.8% vs. -10.5%; p = 0.012), and Apo B (-16.0% vs. -11.3%; p = 0.004) in the ASCVD and/or HeFH on statins pool. Women had similar reductions to men in lipid parameters in the low-dose or no statin pool and hsCRP in both pools. The safety of bempedoic acid was comparable between sexes.
CONCLUSIONS
In this pooled analysis, women experienced significant improvements in levels of LDL-C and other lipid parameters with bempedoic acid.
Topics: Male; Humans; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; C-Reactive Protein; Hypercholesterolemia; Fatty Acids; Dicarboxylic Acids; Cholesterol; Atherosclerosis; Apolipoproteins B; Anticholesteremic Agents; Treatment Outcome
PubMed: 37648637
DOI: 10.1016/j.atherosclerosis.2023.117192 -
Genes Aug 2023Oxalate is a metabolic end-product whose systemic concentrations are highly variable among individuals. Genetic (primary hyperoxaluria) and non-genetic (e.g., diet,... (Review)
Review
Oxalate is a metabolic end-product whose systemic concentrations are highly variable among individuals. Genetic (primary hyperoxaluria) and non-genetic (e.g., diet, microbiota, renal and metabolic disease) reasons underlie elevated plasma concentrations and tissue accumulation of oxalate, which is toxic to the body. A classic example is the triad of primary hyperoxaluria, nephrolithiasis, and kidney injury. Lessons learned from this example suggest further investigation of other putative factors associated with oxalate dysmetabolism, namely the identification of precursors (glyoxylate, aromatic amino acids, glyoxal and vitamin C), the regulation of the endogenous pathways that produce oxalate, or the microbiota's contribution to oxalate systemic availability. The association between secondary nephrolithiasis and cardiovascular and metabolic diseases (hypertension, type 2 diabetes, and obesity) inspired the authors to perform this comprehensive review about oxalate dysmetabolism and its relation to cardiometabolic toxicity. This perspective may offer something substantial that helps advance understanding of effective management and draws attention to the novel class of treatments available in clinical practice.
Topics: Humans; Oxalates; Diabetes Mellitus, Type 2; Hyperoxaluria, Primary; Kidney; Nephrolithiasis; Hypertension
PubMed: 37761859
DOI: 10.3390/genes14091719 -
Atherosclerosis Aug 2023Bempedoic acid significantly lowers low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia but its effects in patients with metabolic syndrome...
BACKGROUND AND AIMS
Bempedoic acid significantly lowers low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia but its effects in patients with metabolic syndrome (MetS) have not been well characterized. We sought to determine the efficacy and safety of bempedoic acid in patients with hypercholesterolemia by baseline MetS status.
METHODS
This study used pooled data from four phase 3 studies. Using modified International Atherosclerosis Society guidelines, patients were grouped into two pools: those with and those without MetS. Patients with diabetes were excluded. Endpoints assessed change from baseline to week 12 in lipid and glycemic parameters and high-sensitivity C-reactive protein (hsCRP), and safety.
RESULTS
The study included 936 patients with MetS (bempedoic acid, 648; placebo, 288) and 1573 without MetS (bempedoic acid, 1037; placebo, 536). Significant placebo-corrected reductions in LDL-C were observed with bempedoic acid (p < 0.0001), with a slightly larger decrease in patients with vs. without MetS (-22.3% vs. -18.4%; interaction p = 0.0472). Compared with placebo, bempedoic acid significantly (p < 0.0001) lowered total cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and hsCRP, with a similar magnitude of benefit observed between MetS categories. Triglycerides increased with bempedoic acid but only to a lesser extent than with placebo in patients without MetS (placebo-corrected difference, -4.4%; p = 0.02). Only patients with MetS experienced decreases in glycated hemoglobin (-0.07%; p < 0.0001) and fasting plasma glucose (-2.4 mg/dL; p = 0.002). Safety was comparable between MetS categories and treatment groups.
CONCLUSIONS
These data suggest that bempedoic acid is a suitable therapy for patients with and without MetS who require additional lipid lowering.
Topics: Humans; Hypercholesterolemia; Cholesterol, LDL; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Metabolic Syndrome; C-Reactive Protein; Fatty Acids; Dicarboxylic Acids; Cholesterol; Treatment Outcome; Anticholesteremic Agents
PubMed: 37517922
DOI: 10.1016/j.atherosclerosis.2023.06.973 -
Advanced Science (Weinheim,... Sep 2023The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell...
The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation-induced immunoevasion as a crucial contributor. In this study, a significant decrease is found in the abundance of alpha-ketoglutarate (αKG), a crucial intermediate metabolite in the TCA cycle, which is correlated with higher grades and a worse prognosis in clinical RCC samples. Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of β2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti-tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC.
Topics: Animals; Mice; Carcinoma, Renal Cell; Programmed Cell Death 1 Receptor; Ketoglutaric Acids; Kidney Neoplasms; Immunotherapy
PubMed: 37526345
DOI: 10.1002/advs.202301975 -
Metabolism: Clinical and Experimental Aug 2023Gluconeogenesis, a pathway for glucose synthesis from non-carbohydrate substances, begins with the synthesis of oxaloacetate (OA) from pyruvate and intermediates of... (Review)
Review
Gluconeogenesis, a pathway for glucose synthesis from non-carbohydrate substances, begins with the synthesis of oxaloacetate (OA) from pyruvate and intermediates of citric acid cycle in hepatocyte mitochondria. The traditional view is that OA does not cross the mitochondrial membrane and must be shuttled to the cytosol, where most enzymes involved in gluconeogenesis are compartmentalized, in the form of malate. Thus, the possibility of transporting OA in the form of aspartate has been ignored. In the article is shown that malate supply to the cytosol increases only when fatty acid oxidation in the liver is activated, such as during starvation or untreated diabetes. Alternatively, aspartate synthesized from OA by mitochondrial aspartate aminotransferase (AST) is transported to the cytosol in exchange for glutamate via the aspartate-glutamate carrier 2 (AGC2). If the main substrate for gluconeogenesis is an amino acid, aspartate is converted to OA via urea cycle, therefore, ammonia detoxification and gluconeogenesis are simultaneously activated. If the main substrate is lactate, OA is synthesized by cytosolic AST, glutamate is transported to the mitochondria through AGC2, and nitrogen is not lost. It is concluded that, compared to malate, aspartate is a more suitable form of OA transport from the mitochondria for gluconeogenesis.
Topics: Gluconeogenesis; Aspartic Acid; Malates; Glutamates; Pyruvic Acid; Lactic Acid
PubMed: 37286128
DOI: 10.1016/j.metabol.2023.155614 -
Redox Biology Nov 2023Oxalate is a small compound found in certain plant-derived foods and is a major component of calcium oxalate (CaOx) kidney stones. Individuals that consume oxalate...
Oxalate is a small compound found in certain plant-derived foods and is a major component of calcium oxalate (CaOx) kidney stones. Individuals that consume oxalate enriched meals have an increased risk of forming urinary crystals, which are precursors to CaOx kidney stones. We previously reported that a single dietary oxalate load induces nanocrystalluria and reduces monocyte cellular bioenergetics in healthy adults. The purpose of this study was to extend these investigations to identify specific oxalate-mediated mechanisms in monocytes and macrophages. We performed RNA-Sequencing analysis on monocytes isolated from healthy subjects exposed to a high oxalate (8 mmol) dietary load. RNA-sequencing revealed 1,198 genes were altered and Ingenuity Pathway Analysis demonstrated modifications in several pathways including Interleukin-10 (IL-10) anti-inflammatory cytokine signaling, mitochondrial metabolism and function, oxalic acid downstream signaling, and autophagy. Based on these findings, we hypothesized that oxalate induces mitochondrial and lysosomal dysfunction in monocytes and macrophages via IL-10 and reactive oxygen species (ROS) signaling which can be reversed with exogenous IL-10 or Mitoquinone (MitoQ; a mitochondrial targeted antioxidant). We exposed monocytes and macrophages to oxalate in an in-vitro setting which caused oxidative stress, a decline in IL-10 cytokine levels, mitochondrial and lysosomal dysfunction, and impaired autophagy in both cell types. Administration of exogenous IL-10 and MitoQ attenuated these responses. These findings suggest that oxalate impairs metabolism and immune response via IL-10 signaling and mitochondrial ROS generation in both monocytes and macrophages which can be potentially limited or reversed. Future studies will examine the benefits of these therapies on CaOx crystal formation and growth in vivo.
Topics: Adult; Humans; Monocytes; Oxalates; Reactive Oxygen Species; Interleukin-10; Calcium Oxalate; Macrophages; Cytokines; Kidney Calculi; RNA
PubMed: 37806112
DOI: 10.1016/j.redox.2023.102919 -
GeroScience Oct 2023Targeting molecular processes of aging will enable people to live healthier and longer lives by preventing age-related diseases. Geroprotectors are compounds with the...
Targeting molecular processes of aging will enable people to live healthier and longer lives by preventing age-related diseases. Geroprotectors are compounds with the potential to increase healthspan and lifespan. Even though many of them have been tested in animal models, the translation to humans is limited. Alpha-Ketoglutarate (AKG) has been studied widely in model animals, but there are few studies testing its geroprotective properties in humans. ABLE is a double blinded placebo-controlled randomized trial (RCT) of 1 g sustained release Ca-AKG versus placebo for 6 months of intervention and 3 months follow up including 120 40-60-year-old healthy individuals with a higher DNA methylation age compared to their chronological age. The primary outcome is the decrease in DNA methylation age from baseline to the end of the intervention. A total of 120 participants will be randomized to receive either sustained release Ca-AKG or placebo. Secondary outcomes include changes in the inflammatory and metabolic parameters in blood, handgrip strength and leg extension strength, arterial stiffness, skin autofluorescence, and aerobic capacity from baseline to 3 months, 6 months, and 9 months. This study will recruit middle-aged participants with an older DNA methylation age compared to their chronological age, and test whether supplementation with Ca-AKG can reduce DNA methylation age. This study is unique in its inclusion of biologically older participants.
Topics: Animals; Humans; Middle Aged; Ketoglutaric Acids; Hand Strength; Delayed-Action Preparations; Aging; Dietary Supplements; Randomized Controlled Trials as Topic
PubMed: 37217632
DOI: 10.1007/s11357-023-00813-6 -
Cell Reports Sep 20232-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and is readily detected in the tissues of healthy individuals. 2HG is found in two...
2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in cluster of differentiation (CD)8 T cell biology, where we find they have highly divergent effects on proliferation, differentiation, and T cell function. We show here an analysis of structural determinants that likely underlie these differential effects on specific α-ketoglutarate (αKG)-dependent enzymes. Treatment of CD8 T cells with exogenous S-2HG, but not R-2HG, increased CD8 T cell fitness in vivo and enhanced anti-tumor activity. These data show that S-2HG and R-2HG should be considered as two distinct and important actors in the regulation of T cell function.
Topics: Humans; T-Lymphocytes, Cytotoxic; CD8-Positive T-Lymphocytes; Glutarates; Neoplasms; Isocitrate Dehydrogenase
PubMed: 37632752
DOI: 10.1016/j.celrep.2023.113013 -
Biomedicine & Pharmacotherapy =... Aug 2023Calcium oxalate (CaOx) stones are among the most common types of kidney stones and are associated with renal tubular damage, interstitial fibrosis, and chronic kidney...
Calcium oxalate (CaOx) stones are among the most common types of kidney stones and are associated with renal tubular damage, interstitial fibrosis, and chronic kidney disease. The mechanism of CaOx crystal-induced renal fibrosis remains unknown. Ferroptosis, a type of regulated cell death, is characterised by iron-dependent lipid peroxidation, and the tumour suppressor p53 is a key regulator of ferroptosis. In the present study, our results demonstrated that ferroptosis was significantly activated in patients with nephrolithiasis and hyperoxaluric mice as well as verified the protective effects of ferroptosis inhibition on CaOx crystal-induced renal fibrosis. Moreover, the single-cell sequencing database, RNA-sequencing, and western blot analysis revealed that the expression of p53 was increased in patients with chronic kidney disease and the oxalate-stimulated human renal tubular epithelial cell line, HK-2. Additionally, the acetylation of p53 was enhanced by oxalate stimulation in HK-2 cells. Mechanistically, we found that the induction of p53 deacetylation, owing to either the SRT1720-induced activation of deacetylase sirtuin 1 or the triple mutation of p53, inhibited ferroptosis and alleviated renal fibrosis caused by CaOx crystals. We conclude that ferroptosis is one of the critical mechanisms contributing to CaOx crystal-induced renal fibrosis, and the pharmacological induction of ferroptosis via sirtuin 1-mediated p53 deacetylation may be a potential target for preventing renal fibrosis in patients with nephrolithiasis.
Topics: Animals; Humans; Mice; Calcinosis; Calcium Oxalate; Ferroptosis; Fibrosis; Kidney; Kidney Calculi; Oxalates; Renal Insufficiency, Chronic; Sirtuin 1; Tumor Suppressor Protein p53
PubMed: 37236026
DOI: 10.1016/j.biopha.2023.114925