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Nutrient Metabolites and Their Receptors in Human Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 30759

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Special Issue Editor

Dr. Anastasios Lymperopoulos

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Guest Editor

Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
Interests: cardiovascular G protein-coupled receptors (GPCRs); heart failure; autonomic control of the circulation; adrenal physiology and pharmacology; adrenergic receptors; angiotensin receptors; signal transduction; gene therapy; aldosterone pharmacology; GPCR-Kinases; arrestins; G protein signaling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The gut microbiota participate in food digestion, producing a variety of metabolites associated with health and disease risks. Metabolomics are becoming increasingly useful in nutrient metabolite identification and characterization for pathophysiological and therapeutic purposes. These nutrient- and diet-derived metabolites come in the form of short-, medium-, and long-chain fatty acids; secondary bile acids; microbial tryptophans; and other amino acid metabolites resulting from proteinolysis, branched-chain amino acids, phosphatidylcholine metabolites, choline, L-carnitine, and other metabolites derived from high-fat food digestion. There is great potential and ample opportunity to identify and characterize not only how all these matabolites are produced in the human body, but also their physiological actions in cells and tissues, as well as the receptors that mediate their cellular actions. Moreover, this exciting field remains unexplored. This Special Issue invites contributions that describe and report on the key advances, challenges, and limitations in the field of nutrient metabolite pathophysiology and their implications for therapies of various human diseases. Suggested disease areas/topics to be covered include (but are by no means limited to) the following:

cell biology;
signal transduction;
autonomic nervous system;
atherosclerosis/lipid disorders;
cancer;
hypertension;
cognitive dysfunction/neurodegeneration and other central nervous system (CNS) disorders;
heart failure and cardiac arrhythmias;
metabolic syndrome/diabetes mellitus;
stem cell biology/physiology;
inflammatory and/or autoimmune diseases and pain;
cardiovascular endocrinology (e.g., adrenal gland and neuronal control of the circulation);
end-organ damage and sepsis;
respiratory diseases;
kidney disorders;
vascular pathologies;
aging;
obesity/adipose tissue biology;
cellular energetics/mitochondria;
nuclear biology/DNA damage;
oxidative stress.

Dr. Anastasios Lymperopoulos
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

diabetes
metabolic disorders
cardiovascular disease
receptor
signal transduction
fatty acid
amino acid
metabolism
inflammation
human disease

Published Papers (10 papers)

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Research

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17 pages, 275 KiB

Open AccessArticle

Familial Partial Lipodystrophy: Clinical Features, Genetics and Treatment in a Greek Referral Center

by Aikaterini Kountouri, Emmanouil Korakas, Eirini Maratou, Ignatios Ikonomidis, Konstantinos Balampanis, Stavros Liatis, Nikolaos Tentolouris, Panagiotis Toulas, Foteini Kousathana, Christophoros Giatzakis, George D. Dimitriadis and Vaia Lambadiari

Int. J. Mol. Sci. 2023, 24(15), 12045; https://doi.org/10.3390/ijms241512045 - 27 Jul 2023

Viewed by 1010

Abstract

Familial partial lipodystrophy (FPLD) is a rare syndrome in which a patient’s phenotype is not merely dependent on the specific genetic mutation, but it is also defined by a combination of other demographic, environmental and genetic factors. In this prospective observational study in a Greek referral center, we enrolled 39 patients who fulfilled the clinical criteria of FPLD. A genetic analysis was conducted, which included sequence and deletion/duplication analyses of the LMNA and PPRARG genes, along with anthropometric and metabolic parameters. The treatment responses of patients who were eligible for treatment with metreleptin were evaluated at 3 and 12 months. In most of the patients, no significant changes were detected at the exon level, and any mutations that led to changes at the protein level were not associated with the lipodystrophic phenotype. On the contrary, various changes were detected at the intron level, especially in introns 7 and 10, whose clinical significance is considered unknown. In addition, treatment with metreleptin in specific FPLD patients significantly improved glycemic and lipidemic control, an effect which was sustained at the 12-month follow-up. More large-scale studies are necessary to clarify the genetic and allelic heterogeneity of the disease, along with other parameters which could predict treatment response. Full article

(This article belongs to the Special Issue Nutrient Metabolites and Their Receptors in Human Diseases)

24 pages, 8768 KiB

Open AccessArticle

Computational and Enzymatic Studies of Sartans in SARS-CoV-2 Spike RBD-ACE2 Binding: The Role of Tetrazole and Perspectives as Antihypertensive and COVID-19 Therapeutics

by Konstantinos Kelaidonis, Irene Ligielli, Spiros Letsios, Veroniki P. Vidali, Thomas Mavromoustakos, Niki Vassilaki, Graham J. Moore, Weronika Hoffmann, Katarzyna Węgrzyn, Harry Ridgway, Christos T. Chasapis and John M. Matsoukas

Int. J. Mol. Sci. 2023, 24(9), 8454; https://doi.org/10.3390/ijms24098454 - 8 May 2023

Cited by 1 | Viewed by 1916

Abstract

This study is an extension of current research into a novel class of synthetic antihypertensive drugs referred to as “bisartans”, which are bis-alkylated imidazole derivatives bearing two symmetric anionic biphenyltetrazoles. Research to date indicates that bisartans are superior to commercially available hypertension drugs, since the former undergo stronger docking to angiotensin-converting enzyme 2 (ACE2). ACE2 is the key receptor involved in SARS-CoV-2 entry, thus initiating COVID-19 infection and in regulating levels of vasoactive peptides such as angiotensin II and beneficial heptapeptides A(1-7) and Alamandine in the renin–angiotensin system (RAS). In previous studies using in vivo rabbit-iliac arterial models, we showed that Na⁺ or K⁺ salts of selected Bisartans initiate a potent dose–response inhibition of vasoconstriction. Furthermore, computational studies revealed that bisartans undergo stable binding to the vital interfacial region between ACE2 and the SARS-CoV-2 “receptor binding domain” (i.e., the viral RBD). Thus, bisartan homologs are expected to interfere with SARS-CoV-2 infection and/or suppress disease expression in humans. The primary goal of this study was to investigate the role of tetrazole in binding and the network of amino acids of SARS-CoV-2 Spike RBD-ACE2 complex involved in interactions with sartans. This study would, furthermore, allow the expansion of the synthetic space to create a diverse suite of new bisartans in conjunction with detailed computational and in vitro antiviral studies. A critical role for tetrazole was uncovered in this study, shedding light on the vital importance of this group in the binding of sartans and bisartans to the ACE2/Spike complex. The in silico data predicting an interaction of tetrazole-containing sartans with ACE2 were experimentally validated by the results of surface plasmon resonance (SPR) analyses performed with a recombinant human ACE2 protein. Full article

(This article belongs to the Special Issue Nutrient Metabolites and Their Receptors in Human Diseases)

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9 pages, 707 KiB

Open AccessArticle

Serum Starvation Accelerates Intracellular Metabolism in Endothelial Cells

by Mario Lorenz, Raphaela Fritsche-Guenther, Cornelia Bartsch, Angelika Vietzke, Alina Eisenberger, Karl Stangl, Verena Stangl and Jennifer A. Kirwan

Int. J. Mol. Sci. 2023, 24(2), 1189; https://doi.org/10.3390/ijms24021189 - 7 Jan 2023

Cited by 3 | Viewed by 1980

Abstract

Periods of low energy supply are challenging conditions for organisms and cells during fasting or famine. Although changes in nutrient levels in the blood are first sensed by endothelial cells, studies on their metabolic adaptations to diminished energy supply are lacking. We analyzed the dynamic metabolic activity of human umbilical vein endothelial cells (HUVECs) in basal conditions and after serum starvation. Metabolites of glycolysis, the tricarboxylic acid (TCA) cycle, and the glycerol pathway showed lower levels after serum starvation, whereas amino acids had increased levels. A metabolic flux analysis with ¹³C-glucose or ¹³C-glutamine labeling for different time points reached a plateau phase of incorporation after 30 h for ¹³C-glucose and after 8 h for ¹³C-glutamine under both experimental conditions. Notably, we observed a faster label incorporation for both ¹³C-glucose and ¹³C-glutamine after serum starvation. In the linear range of label incorporation after 3 h, we found a significantly faster incorporation of central carbon metabolites after serum starvation compared to the basal state. These findings may indicate that endothelial cells develop increased metabolic activity to cope with energy deficiency. Physiologically, it can be a prerequisite for endothelial cells to form new blood vessels under unfavorable conditions during the process of angiogenesis in vivo. Full article

(This article belongs to the Special Issue Nutrient Metabolites and Their Receptors in Human Diseases)

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15 pages, 8125 KiB

Open AccessArticle

Sirtuin 3 Deficiency Aggravates Kidney Disease in Response to High-Fat Diet through Lipotoxicity-Induced Mitochondrial Damage

by Monica Locatelli, Daniela Macconi, Daniela Corna, Domenico Cerullo, Daniela Rottoli, Giuseppe Remuzzi, Ariela Benigni and Carlamaria Zoja

Int. J. Mol. Sci. 2022, 23(15), 8345; https://doi.org/10.3390/ijms23158345 - 28 Jul 2022

Cited by 10 | Viewed by 2153

Abstract

Sirtuin 3 (SIRT3) is the primary mitochondrial deacetylase that controls the antioxidant pathway and energy metabolism. We previously found that renal Sirt3 expression and activity were reduced in mice with type 2 diabetic nephropathy associated with oxidative stress and mitochondrial abnormalities and that a specific SIRT3 activator improved renal damage. SIRT3 is modulated by diet, and to assess whether Sirt3 deficiency aggravates mitochondrial damage and accelerates kidney disease in response to nutrient overloads, wild-type (WT) and Sirt3^−/− mice were fed a high-fat-diet (HFD) or standard diet for 8 months. Sirt3^−/− mice on HFD exhibited earlier and more severe albuminuria compared to WT mice, accompanied by podocyte dysfunction and glomerular capillary rarefaction. Mesangial matrix expansion, tubular vacuolization and inflammation, associated with enhanced lipid accumulation, were more evident in Sirt3^−/− mice. After HFD, kidneys from Sirt3^−/− mice showed more oxidative stress than WT mice, mitochondria ultrastructural damage in tubular cells, and a reduction in mitochondrial mass and energy production. Our data demonstrate that Sirt3 deficiency renders mice more prone to developing oxidative stress and mitochondrial abnormalities in response to HFD, resulting in more severe kidney diseases, and this suggests that mitochondria protection may be a method to prevent HFD-induced renal injury. Full article

(This article belongs to the Special Issue Nutrient Metabolites and Their Receptors in Human Diseases)

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13 pages, 1377 KiB

Open AccessArticle

Regulator of G-Protein Signaling-4 Attenuates Cardiac Adverse Remodeling and Neuronal Norepinephrine Release-Promoting Free Fatty Acid Receptor FFAR3 Signaling

by Alexandra M. Carbone, Jordana I. Borges, Malka S. Suster, Anastasiya Sizova, Natalie Cora, Victoria L. Desimine and Anastasios Lymperopoulos

Int. J. Mol. Sci. 2022, 23(10), 5803; https://doi.org/10.3390/ijms23105803 - 22 May 2022

Cited by 12 | Viewed by 2138

Abstract

Propionic acid is a cell nutrient but also a stimulus for cellular signaling. Free fatty acid receptor (FFAR)-3, also known as GPR41, is a Gi/o protein-coupled receptor (GPCR) that mediates some of the propionate’s actions in cells, such as inflammation, fibrosis, and increased firing/norepinephrine release from peripheral sympathetic neurons. The regulator of G-protein Signaling (RGS)-4 inactivates (terminates) both Gi/o- and Gq-protein signaling and, in the heart, protects against atrial fibrillation via calcium signaling attenuation. RGS4 activity is stimulated by β-adrenergic receptors (ARs) via protein kinase A (PKA)-dependent phosphorylation. Herein, we examined whether RGS4 modulates cardiac FFAR3 signaling/function. We report that RGS4 is essential for dampening of FFAR3 signaling in H9c2 cardiomyocytes, since siRNA-mediated RGS4 depletion significantly enhanced propionate-dependent cAMP lowering, Gi/o activation, p38 MAPK activation, pro-inflammatory interleukin (IL)-1β and IL-6 production, and pro-fibrotic transforming growth factor (TGF)-β synthesis. Additionally, catecholamine pretreatment blocked propionic acid/FFAR3 signaling via PKA-dependent activation of RGS4 in H9c2 cardiomyocytes. Finally, RGS4 opposes FFAR3-dependent norepinephrine release from sympathetic-like neurons (differentiated Neuro-2a cells) co-cultured with H9c2 cardiomyocytes, thereby preserving the functional βAR number of the cardiomyocytes. In conclusion, RGS4 appears essential for propionate/FFAR3 signaling attenuation in both cardiomyocytes and sympathetic neurons, leading to cardioprotection against inflammation/adverse remodeling and to sympatholysis, respectively. Full article

(This article belongs to the Special Issue Nutrient Metabolites and Their Receptors in Human Diseases)

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Review

Jump to: Research

23 pages, 747 KiB

Open AccessReview

Ketone Bodies and Cardiovascular Disease: An Alternate Fuel Source to the Rescue

by Antonis S. Manolis, Theodora A. Manolis and Antonis A. Manolis

Int. J. Mol. Sci. 2023, 24(4), 3534; https://doi.org/10.3390/ijms24043534 - 10 Feb 2023

Cited by 9 | Viewed by 6241

Abstract

The increased metabolic activity of the heart as a pump involves a high demand of mitochondrial adenosine triphosphate (ATP) production for its mechanical and electrical activities accomplished mainly via oxidative phosphorylation, supplying up to 95% of the necessary ATP production, with the rest attained by substrate-level phosphorylation in glycolysis. In the normal human heart, fatty acids provide the principal fuel (40–70%) for ATP generation, followed mainly by glucose (20–30%), and to a lesser degree (<5%) by other substrates (lactate, ketones, pyruvate and amino acids). Although ketones contribute 4–15% under normal situations, the rate of glucose use is drastically diminished in the hypertrophied and failing heart which switches to ketone bodies as an alternate fuel which are oxidized in lieu of glucose, and if adequately abundant, they reduce myocardial fat delivery and usage. Increasing cardiac ketone body oxidation appears beneficial in the context of heart failure (HF) and other pathological cardiovascular (CV) conditions. Also, an enhanced expression of genes crucial for ketone break down facilitates fat or ketone usage which averts or slows down HF, potentially by avoiding the use of glucose-derived carbon needed for anabolic processes. These issues of ketone body utilization in HF and other CV diseases are herein reviewed and pictorially illustrated. Full article

(This article belongs to the Special Issue Nutrient Metabolites and Their Receptors in Human Diseases)

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15 pages, 1254 KiB

Open AccessReview

Dihomo-γ-Linolenic Acid (20:3n-6)—Metabolism, Derivatives, and Potential Significance in Chronic Inflammation

by Anne-Mari Mustonen and Petteri Nieminen

Int. J. Mol. Sci. 2023, 24(3), 2116; https://doi.org/10.3390/ijms24032116 - 20 Jan 2023

Cited by 13 | Viewed by 2784

Abstract

Dihomo-γ-linolenic acid (DGLA) has emerged as a significant molecule differentiating healthy and inflamed tissues. Its position at a pivotal point of metabolic pathways leading to anti-inflammatory derivatives or via arachidonic acid (ARA) to pro-inflammatory lipid mediators makes this n-6 polyunsaturated fatty acid (PUFA) an intriguing research subject. The balance of ARA to DGLA is probably a critical factor affecting inflammatory processes in the body. The aim of this narrative review was to examine the potential roles of DGLA and related n-6 PUFAs in inflammatory conditions, such as obesity-associated disorders, rheumatoid arthritis, atopic dermatitis, asthma, cancers, and diseases of the gastrointestinal tract. DGLA can be produced by cultured fungi or be obtained via endogenous conversion from γ-linolenic acid (GLA)-rich vegetable oils. Several disease states are characterized by abnormally low DGLA levels in the body, while others can feature elevated levels. A defect in the activity of ∆6-desaturase and/or ∆5-desaturase may be one factor in the initiation and progression of these conditions. The potential of GLA and DGLA administrations as curative or ameliorating therapies in inflammatory conditions and malignancies appears modest at best. Manipulations with ∆6- and ∆5-desaturase inhibitors or combinations of long-chain PUFA supplements with n-3 PUFAs could provide a way to modify the body’s DGLA and ARA production and the concentrations of their pro- and anti-inflammatory mediators. However, clinical data remain scarce and further well-designed studies should be actively promoted. Full article

(This article belongs to the Special Issue Nutrient Metabolites and Their Receptors in Human Diseases)

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33 pages, 1187 KiB

Open AccessReview

Role of Micronutrients and Gut Microbiota-Derived Metabolites in COVID-19 Recovery

by Teresita de Jesús Hernández-Flores, Eliza Julia Pedraza-Brindis, Jhonathan Cárdenas-Bedoya, José Daniel Ruíz-Carrillo, Anibal Samael Méndez-Clemente, Marco Alonso Martínez-Guzmán and Liliana Iñiguez-Gutiérrez

Int. J. Mol. Sci. 2022, 23(20), 12324; https://doi.org/10.3390/ijms232012324 - 14 Oct 2022

Cited by 4 | Viewed by 3689

Abstract

A balanced and varied diet provides diverse beneficial effects on health, such as adequate micronutrient availability and a gut microbiome in homeostasis. Besides their participation in biochemical processes as cofactors and coenzymes, vitamins and minerals have an immunoregulatory function; meanwhile, gut microbiota and its metabolites coordinate directly and indirectly the cell response through the interaction with the host receptors. Malnourishment is a crucial risk factor for several pathologies, and its involvement during the Coronavirus Disease 2019 pandemic has been reported. This pandemic has caused a significant decline in the worldwide population, especially those with chronic diseases, reduced physical activity, and elder age. Diet and gut microbiota composition are probable causes for this susceptibility, and its supplementation can play a role in reestablishing microbial homeostasis and improving immunity response against Coronavirus Disease 2019 infection and recovery. This study reviews the role of micronutrients and microbiomes in the risk of infection, the severity of disease, and the Coronavirus Disease 2019 sequelae. Full article

(This article belongs to the Special Issue Nutrient Metabolites and Their Receptors in Human Diseases)

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13 pages, 754 KiB

Open AccessReview

EVOO’s Effects on Incretin Production: Is There a Rationale for a Combination in T2DM Therapy?

by Simona Amodeo, Luigi Mirarchi, Aurelio Seidita, Roberto Citarrella, Anna Licata, Maurizio Soresi, Juan Lucio Iovanna and Lydia Giannitrapani

Int. J. Mol. Sci. 2022, 23(17), 10120; https://doi.org/10.3390/ijms231710120 - 4 Sep 2022

Cited by 2 | Viewed by 1920

Abstract

Type 2 diabetes mellitus (T2DM) is a serious public health concern as it is one of the most common chronic diseases worldwide due to social and economic developments that have led to unhealthy lifestyles, with a considerable impact both in terms of morbidity and mortality. The management of T2DM, before starting specific therapies, includes cornerstones such as healthy eating, regular exercise and weight loss. Strict adherence to the Mediterranean diet (MedDiet) has been related to an inverse association with the risk of T2DM onset, as well as an improvement in glycaemic control; in particular, thanks to the consumption of extra virgin olive oil (EVOO). Agonists of gut-derived glucagon-like peptide-1 (GLP-1), gastrointestinal hormones able to increase insulin secretion in response to hyperglycaemia (incretins), have been recently introduced in T2DM therapy, quickly entering the international guidelines. Recent studies have linked the action of EVOO in reducing postprandial glycaemia to the increase in GLP-1 and the reduction of its inactivating protease, dipeptidyl peptidase-4 (DPP-4). In this review, we explore observations regarding the pathophysiological basis of the existence of an enhanced effect between the action of EVOO and incretins and, consequently, try to understand whether there is a rationale for their use in combination for T2DM therapy. Full article

(This article belongs to the Special Issue Nutrient Metabolites and Their Receptors in Human Diseases)

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12 pages, 1438 KiB

Open AccessReview

Short-Chain Fatty Acid Receptors and Cardiovascular Function

by Anastasios Lymperopoulos, Malka S. Suster and Jordana I. Borges

Int. J. Mol. Sci. 2022, 23(6), 3303; https://doi.org/10.3390/ijms23063303 - 18 Mar 2022

Cited by 44 | Viewed by 6024

Abstract

Increasing experimental and clinical evidence points toward a very important role for the gut microbiome and its associated metabolism in human health and disease, including in cardiovascular disorders. Free fatty acids (FFAs) are metabolically produced and utilized as energy substrates during almost every biological process in the human body. Contrary to long- and medium-chain FFAs, which are mainly synthesized from dietary triglycerides, short-chain FFAs (SCFAs) derive from the gut microbiota-mediated fermentation of indigestible dietary fiber. Originally thought to serve only as energy sources, FFAs are now known to act as ligands for a specific group of cell surface receptors called FFA receptors (FFARs), thereby inducing intracellular signaling to exert a variety of cellular and tissue effects. All FFARs are G protein-coupled receptors (GPCRs) that play integral roles in the regulation of metabolism, immunity, inflammation, hormone/neurotransmitter secretion, etc. Four different FFAR types are known to date, with FFAR1 (formerly known as GPR40) and FFAR4 (formerly known as GPR120) mediating long- and medium-chain FFA actions, while FFAR3 (formerly GPR41) and FFAR2 (formerly GPR43) are essentially the SCFA receptors (SCFARs), responding to all SCFAs, including acetic acid, propionic acid, and butyric acid. As with various other organ systems/tissues, the important roles the SCFARs (FFAR2 and FFAR3) play in physiology and in various disorders of the cardiovascular system have been revealed over the last fifteen years. In this review, we discuss the cardiovascular implications of some key (patho)physiological functions of SCFAR signaling pathways, particularly those regulating the neurohormonal control of circulation and adipose tissue homeostasis. Wherever appropriate, we also highlight the potential of these receptors as therapeutic targets for cardiovascular disorders. Full article

(This article belongs to the Special Issue Nutrient Metabolites and Their Receptors in Human Diseases)

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