International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

Amino Acids in Health and Disease: The Good, the Bad, and the Ugly

by Isao Ishii and Madhav Bhatia

Int. J. Mol. Sci. 2023, 24(5), 4931; https://doi.org/10.3390/ijms24054931 - 3 Mar 2023

Cited by 2 | Viewed by 2870

Abstract

The Special Issue “Amino Acid Metabolism and Regulation in Health and Disease 2 [...] Full article

(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease 2.0)

Research

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19 pages, 2026 KiB

Open AccessArticle

Effect of Isoleucine and Added Valine on Performance, Nutrients Digestibility and Gut Microbiota Composition of Pigs Fed with Very Low Protein Diets

by Parniyan Goodarzi, Caitlyn Marie Wileman, Mohammad Habibi, Katherine Walsh, Julia Sutton, Cedrick Ndhumba Shili, Jianmin Chai, Jiangchao Zhao and Adel Pezeshki

Int. J. Mol. Sci. 2022, 23(23), 14886; https://doi.org/10.3390/ijms232314886 - 28 Nov 2022

Cited by 11 | Viewed by 2146

Abstract

Little is known whether a combination Ile and added Val improves the growth of pigs offered very low protein (VLP) diets through changes in nutrients digestibility and gut microbiota. The objective of this study was to investigate the effect of a mixture of [...] Read more.

Little is known whether a combination Ile and added Val improves the growth of pigs offered very low protein (VLP) diets through changes in nutrients digestibility and gut microbiota. The objective of this study was to investigate the effect of a mixture of Val above and Ile at NRC levels on growth, nutrient digestibility and gut microbiota in pigs fed with VLP diets. Forty, weaned piglets were assigned to: positive control: normal-protein-diet; negative control (NC): VLP diet supplemented with first four limiting amino acids; VA: NC with Val above NRC; IL: NC with Ile at NRC level; VAIL: NC with Val above and Ile at NRC levels. While both VAIL and VA groups completely recovered the inhibitory effects of VLP diets on feed intake, only VAIL partially recovered the negative effects of VLP diets on growth performance. VAIL and VA increased the thermal radiation and decreased the digestibility of nitrogen. NC increased the relative abundance of Pasteurellaceae and Enterobacteriaceae in the colon. VAIL had a higher abundance of colonic Actinobacteria, Enterococcus, and Brevibacillus and the colon content of VA was more enriched with Mogibacterium. Overall, VAIL partially improved the growth performance which is likely linked with alterations in gut microbiota composition. Full article

(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease 2.0)

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20 pages, 4280 KiB

Open AccessArticle

Short-Term Supplementation of Sodium Nitrate vs. Sodium Chloride Increases Homoarginine Synthesis in Young Men Independent of Exercise

by Dimitrios Tsikas, Norbert Maassen, Antonie Thorns, Armin Finkel, Moritz Lützow, Magdalena Aleksandra Röhrig, Larissa Sarah Blau, Laurianne Dimina, François Mariotti, Bibiana Beckmann, Vladimir Shushakov and Mirja Jantz

Int. J. Mol. Sci. 2022, 23(18), 10649; https://doi.org/10.3390/ijms231810649 - 13 Sep 2022

Cited by 9 | Viewed by 2157

Abstract

The aim of the study was to investigate the effects of short-term oral administration of inorganic nitrate (NaNO₃; n = 8) or placebo (NaCl; n = 9) (each 0.1 mmol/kg body weight/d for 9 days) on plasma amino acids, creatinine, and [...] Read more.

The aim of the study was to investigate the effects of short-term oral administration of inorganic nitrate (NaNO₃; n = 8) or placebo (NaCl; n = 9) (each 0.1 mmol/kg body weight/d for 9 days) on plasma amino acids, creatinine, and oxidative stress in healthy young men. At baseline, the plasma concentrations of amino acids did not differ between the groups. At the end of the study, the plasma concentrations of homoarginine (hArg; by 24%, p = 0.0001), citrulline and ornithine (Cit/Orn; by 16%, p = 0.015), and glutamine/glutamate (Gln/Glu; by 6%, p = 0.0003) were higher in the NaNO₃ group compared to the NaCl group. The plasma concentrations of sarcosine (Sarc; by 28%, p < 0.0001), tyrosine (by 14%, p = 0.0051), phenylalanine (by 8%, p = 0.0026), and tryptophan (by 8%, p = 0.0047) were lower in the NaNO₃ group compared to the NaCl group. These results suggest that nitrate administration affects amino-acid metabolism. The arginine/glycine amidinotransferase (AGAT) catalyzes two reactions: (1) the formation of l-homoarginine (hArg) and l-ornithine (Orn) from l-arginine (Arg) and l-lysine (Lys): Arg + Lys <−> hArg + Orn, with equilibrium constant K_harg; (2) the formation of guanidinoacetate (GAA) and Orn from Arg and glycine (Gly): Arg + Gly <−> GAA + Orn, with equilibrium constant K_gaa. The plasma K_gaa/K_hArg ratio was lower in the NaNO₃ group compared to the NaCl group (1.57 vs. 2.02, p = 0.0034). Our study suggests that supplementation of inorganic nitrate increases the AGAT-catalyzed synthesis of hArg and decreases the N-methyltransferase-catalyzed synthesis of GAA, the precursor of creatine. To our knowledge, this is the first study to demonstrate elevation of hArg synthesis by inorganic nitrate supplementation. Remarkably, an increase of 24% corresponds to the synthesis capacity of one kidney in healthy humans. Differences in the association between plasma concentrations of amino acids in the NaNO₃ and NaCl groups suggest changes in amino-acid homeostasis. Plasma concentrations of the oxidative stress marker malondialdehyde (MDA) did not change after supplementation of NaNO₃ or NaCl over the whole exercise time range. Plasma nitrite concentration turned out to be a more discriminant marker of NaNO₃ ingestion than plasma nitrate (area under the receiver operating characteristic curve: 0.951 vs. 0.866, p < 0.0001 each). Full article

(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease 2.0)

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17 pages, 3097 KiB

Open AccessArticle

Balanced Free Essential Amino Acids and Resistance Exercise Training Synergistically Improve Dexamethasone-Induced Impairments in Muscle Strength, Endurance, and Insulin Sensitivity in Mice

by Jiwoong Jang, Jin-Ho Koh, Yeongmin Kim, Hee-Joo Kim, Sanghee Park, Yewon Chang, Jiyeon Jung, Robert R. Wolfe and Il-Young Kim

Int. J. Mol. Sci. 2022, 23(17), 9735; https://doi.org/10.3390/ijms23179735 - 27 Aug 2022

Cited by 7 | Viewed by 3455

Abstract

Our previous study shows that an essential amino acid (EAA)-enriched diet attenuates dexamethasone (DEX)-induced declines in muscle mass and strength, as well as insulin sensitivity, but does not affect endurance. In the present study, we hypothesized that the beneficial effects will be synergized [...] Read more.

Our previous study shows that an essential amino acid (EAA)-enriched diet attenuates dexamethasone (DEX)-induced declines in muscle mass and strength, as well as insulin sensitivity, but does not affect endurance. In the present study, we hypothesized that the beneficial effects will be synergized by adding resistance exercise training (RET) to EAA, and diet-free EAA would improve endurance. To test hypotheses, mice were randomized into the following four groups: control, EAA, RET, and EAA+RET. All mice except the control were subjected to DEX treatment. We evaluated the cumulative rate of myofibrillar protein synthesis (MPS) using ²H₂O labeling and mass spectrometry. Neuromuscular junction (NMJ) stability, mitochondrial contents, and molecular signaling were demonstrated in skeletal muscle. Insulin sensitivity and glucose metabolism using ¹³C₆-glucose tracing during oral glucose tolerance tests were analyzed. We found that EAA and RET synergistically improve muscle mass and/or strength, and endurance capacity, as well as insulin sensitivity, and glucose metabolism in DEX-treated muscle. These improvements are accomplished, in part, through improvements in myofibrillar protein synthesis, NMJ, fiber type preservation, and/or mitochondrial biogenesis. In conclusion, free EAA supplementation, particularly when combined with RET, can serve as an effective means that counteracts the adverse effects on muscle of DEX that are found frequently in clinical settings. Full article

(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease 2.0)

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22 pages, 10184 KiB

Open AccessArticle

Pilot Study on Acute Effects of Pharmacological Intraperitoneal L-Homoarginine on Homeostasis of Lysine and Other Amino Acids in a Rat Model of Isoprenaline-Induced Takotsubo Cardiomyopathy

by Dimitrios Tsikas and Björn Redfors

Int. J. Mol. Sci. 2022, 23(9), 4734; https://doi.org/10.3390/ijms23094734 - 25 Apr 2022

Cited by 7 | Viewed by 2082

Abstract

L-Arginine:glycine amidinotransferase (AGAT) catalyzes the formation of L-homoarginine (hArg) and L-ornithine (Orn) from L-arginine (Arg) and L-lysine (Lys): Arg + Lys ↔ hArg + Orn; equilibrium constant K_hArg. AGAT also catalyzes the formation of guanidinoacetate (GAA) and Orn from Arg and [...] Read more.

L-Arginine:glycine amidinotransferase (AGAT) catalyzes the formation of L-homoarginine (hArg) and L-ornithine (Orn) from L-arginine (Arg) and L-lysine (Lys): Arg + Lys ↔ hArg + Orn; equilibrium constant K_hArg. AGAT also catalyzes the formation of guanidinoacetate (GAA) and Orn from Arg and glycine (Gly): Arg + Gly ↔ GAA + Orn; equilibrium constant K_GAA. In humans, pharmacological hArg is metabolized to Lys. Low circulating and low excretory concentrations of hArg are associated with worse outcomes and mortality in the renal and cardiovascular systems. The metabolism and pharmacology of hArg have been little investigated. In the present study, we investigated the effects of pharmacological hArg (i.p., 0, 20, 220, 440 mg/kg at time point 0 min) on amino acids homeostasis in a rat model of isoprenaline-induced takotsubo cardiomyopathy (i.p., 50 mg/kg at time point 15 min). We measured by gas chromatography-mass spectrometry free and proteinic amino acids, as well as the polyamines putrescine and spermidine in the heart, lung, kidney, and liver of ten rats sacrificed at various time points (range, 0 to 126 min). hArg administration resulted in multiple changes in the tissue contents of several free and proteinic amino acids, as well as in the putrescine-spermidine molar ratio, an indicator of polyamines catabolism. Our results suggest that Lys and Arg are major metabolites of pharmacological hArg. Kidneys and heart seem to play a major metabolic role for hArg. Circulating Lys does not change over time, yet there is a considerable interchange of free Lys between organs, notably kidney and heart, during the presence of isoprenaline in the rats (time range, 15 to 90 min). Antidromic changes were observed for K_hArg and K_GAA, notably in the heart in this time window. Our study shows for the first time that free hArg and sarcosine (N-methylglycine) are positively associated with each other. The acute effects of high-dosed hArg administration and isoprenaline on various amino acids and on AGAT-catalyzed reaction in the heart, lung, kidney, and liver are detailed and discussed. Full article

(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease 2.0)

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28 pages, 39684 KiB

Open AccessArticle

A Mixture of Valine and Isoleucine Restores the Growth of Protein-Restricted Pigs Likely through Improved Gut Development, Hepatic IGF-1 Pathway, and Plasma Metabolomic Profile

by Mohammad Habibi, Parniyan Goodarzi, Cedrick Ndhumba Shili, Julia Sutton, Caitlyn Marie Wileman, Dohyung Markus Kim, Dingbo Lin and Adel Pezeshki

Int. J. Mol. Sci. 2022, 23(6), 3300; https://doi.org/10.3390/ijms23063300 - 18 Mar 2022

Cited by 16 | Viewed by 3174

Abstract

Valine (Val) alone or in combination with isoleucine (Ile) improves the growth under severe protein restriction; however, the underlying mechanisms remain unknown. In this study, we assessed whether Val/Ile-induced growth in protein-restricted pigs is associated with changes in gut development, hepatic insulin-like growth [...] Read more.

Valine (Val) alone or in combination with isoleucine (Ile) improves the growth under severe protein restriction; however, the underlying mechanisms remain unknown. In this study, we assessed whether Val/Ile-induced growth in protein-restricted pigs is associated with changes in gut development, hepatic insulin-like growth factor 1 (IGF-1) production, and blood metabolomics. Forty piglets were assigned to five dietary groups: positive control (PC) with standard protein content; low protein (LP) with very low protein content; and LP supplemented with Val (LPV), Ile (LPI), and Val and Ile (LPVI). LPVI reversed the negative effects of VLP diets on growth and gut morphology. Both LPV and LPVI restored the reduced transcript of IGF-1 while decreasing the transcript of insulin-like growth factor binding protein 1 (IGFBP1) in the liver. LPV and LPVI recovered the reduced plasma Val, glycine, and leucine concentrations, which were positively correlated with improved gut morphology and the hepatic IGF-1 gene expression and negatively correlated with hepatic IGFBP1 mRNA abundance. In conclusion, supplementation with a combination of Val and Ile into the VLP diets restored the decreased growth performance of pigs fed with these diets likely through improved gut development, hepatic IGF-1 expression and bioavailability, and plasma metabolomics profile. Full article

(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease 2.0)

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15 pages, 734 KiB

Open AccessArticle

Characterization of the L-Arginine/Nitric Oxide Pathway and Oxidative Stress in Pediatric Patients with Atopic Diseases

by Beatrice Hanusch, Kathrin Sinningen, Folke Brinkmann, Stefanie Dillenhöfer, Mirjam Frank, Karl-Heinz Jöckel, Cordula Koerner-Rettberg, Martin Holtmann, Tanja Legenbauer, Christian Langrock, Thomas Reinehr, Patricia Maasjosthusmann, Bibiana Beckmann, Eckard Hamelmann, Dimitrios Tsikas and Thomas Lücke

Int. J. Mol. Sci. 2022, 23(4), 2136; https://doi.org/10.3390/ijms23042136 - 15 Feb 2022

Cited by 12 | Viewed by 5166

Abstract

Introduction: L-Arginine (Arg) is a semi-essential amino acid. Constitutive and inducible nitric oxide synthase (NOS) isoforms convert Arg to nitric oxide (NO), a potent vaso- and bronchodilator with multiple biological functions. Atopic dermatitis (AD) and bronchial asthma (BA) are atopic diseases affecting many [...] Read more.

Introduction: L-Arginine (Arg) is a semi-essential amino acid. Constitutive and inducible nitric oxide synthase (NOS) isoforms convert Arg to nitric oxide (NO), a potent vaso- and bronchodilator with multiple biological functions. Atopic dermatitis (AD) and bronchial asthma (BA) are atopic diseases affecting many children globally. Several studies analyzed NO in airways, yet the systemic synthesis of NO in AD and BA in children with BA, AD or both is elusive. Methods: In a multicenter study, blood and urine were obtained from 130 of 302 participating children for the measurement of metabolites of the Arg/NO pathway (BA 31.5%; AD 5.4%; AD + BA 36.1%; attention deficit hyperactivity disorder (ADHD) 12.3%). In plasma and urine amino acids Arg and homoarginine (hArg), both substrates of NOS, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), both inhibitors of NOS, dimethylamine (DMA), and nitrite and nitrate, were measured by gas chromatography–mass spectrometry. Malondialdehyde (MDA) was measured in plasma and urine samples to evaluate possible effects of oxidative stress. Results: There were no differences in the Arg/NO pathway between the groups of children with different atopic diseases. In comparison to children with ADHD, children with AD, BA or AD and BA had higher plasma nitrite (p < 0.001) and nitrate (p < 0.001) concentrations, suggesting higher systemic NO synthesis in AD and BA. Urinary excretion of DMA was also higher (p = 0.028) in AD and BA compared to patients with ADHD, suggesting elevated ADMA metabolization. Discussion/Conclusion: The Arg/NO pathway is activated in atopic diseases independent of severity. Systemic NO synthesis is increased in children with an atopic disease. Plasma and urinary MDA levels did not differ between the groups, suggesting no effect of oxidative stress on the Arg/NO pathway in atopic diseases. Full article

(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease 2.0)

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17 pages, 1983 KiB

Open AccessArticle

Advanced Glycation End-Products (AGEs) of Lysine and Effects of Anti-TCR/Anti-TNF-α Antibody-Based Therapy in the LEW.1AR1-iddm Rat, an Animal Model of Human Type 1 Diabetes

by Svetlana Baskal, Stefanos A. Tsikas, Olga Begou, Alexander Bollenbach, Sigurd Lenzen, Anne Jörns and Dimitrios Tsikas

Int. J. Mol. Sci. 2022, 23(3), 1541; https://doi.org/10.3390/ijms23031541 - 28 Jan 2022

Cited by 4 | Viewed by 2894

Abstract

The LEW.1AR1-iddm rat is an animal model of human type 1 diabetes (T1D). Previously, we have shown that combination with anti-TCR/anti-TNF-α antibody-based therapy re-established normoglycemia and increased proteinic arginine-dimethylation in the spleen, yet not in the pancreas. High blood glucose is often [...] Read more.

The LEW.1AR1-iddm rat is an animal model of human type 1 diabetes (T1D). Previously, we have shown that combination with anti-TCR/anti-TNF-α antibody-based therapy re-established normoglycemia and increased proteinic arginine-dimethylation in the spleen, yet not in the pancreas. High blood glucose is often associated with elevated formation of advanced glycation end-products (AGEs) which act via their receptor (RAGE). Both anti-TCR and anti-TNF-α are inhibitors of RAGE. The aim of the present work was to investigate potential biochemical changes of anti-TCR/anti-TNF-α therapy in the LEW.1AR1-iddm rat. We determined by stable-isotope dilution gas chromatography-mass spectrometry (GC-MS) the content of free and proteinic AGEs and the N^ε-monomethylation of lysine (Lys) residues in proteins of pancreas, kidney, liver, spleen and lymph nodes of normoglycemic control (ngCo, n = 6), acute diabetic (acT1D, n = 6), chronic diabetic (chT1D, n = 4), and cured (cuT1D, n = 4) rats after anti-TCR/anti-TNF-α therapy. Analyzed biomarkers included Lys and its metabolites N^ε-carboxymethyl lysine (CML), furosine and N^ε-monomethyl lysine (MML). Other amino acids were also determined. Statistical methods including ANOVA, principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to evaluate the effects. Most statistical differences between the study groups were observed for spleen, pancreas and kidney, with liver and lymph nodes showing no such differences. In the pancreas, the groups differed with respect to proteinic furosine (p = 0.0289) and free CML (p = 0.0023). In the kidneys, the groups differed with respect to proteinic furosine (p = 0.0076) and CML (p = 0.0270). In the spleen, group differences were found for proteinic furosine (p = 0.0114) and free furosine (p = 0.0368), as well as for proteinic CML (p = 0.0502) and proteinic MML (p = 0.0191). The acT1D rats had lower furosine, CML and MML levels in the spleen than the rats in all other groups. This observation corresponds to the lower citrullination levels previously measured in these rats. PCA revealed diametric associations between PC1 and PC2 for spleen (r = −0.8271, p < 0.0001) compared to pancreas (r = 0.5805, p = 0.0073) and kidney (r = 0.8692, p < 0.0001). These findings underscore the importance of the spleen in this animal model of human T1D. OPLS-DA showed that in total sixteen amino acids differed in the experimental groups. Full article

(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease 2.0)

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14 pages, 2130 KiB

Open AccessArticle

A High-Methionine Diet for One-Week Induces a High Accumulation of Methionine in the Cerebrospinal Fluid and Confers Bipolar Disorder-like Behavior in Mice

by Isao Ishii, Shotaro Kamata, Saki Ito, Aya Shimonaga, Maika Koizumi, Maiko Tsushima, Asumi Miura, Tomoko Nagata, Yuka Tosaka, Haruka Ohtani, Waka Kamichatani and Noriyuki Akahoshi

Int. J. Mol. Sci. 2022, 23(2), 928; https://doi.org/10.3390/ijms23020928 - 15 Jan 2022

Cited by 5 | Viewed by 3100

Abstract

Methionine (Met) is considered the most toxic amino acid in mammals. Here, we investigated biochemical and behavioral impacts of ad libitum one-week feeding of high-Met diets on mice. Adult male mice were fed the standard rodent diet that contained 0.44% Met (1×) or [...] Read more.

Methionine (Met) is considered the most toxic amino acid in mammals. Here, we investigated biochemical and behavioral impacts of ad libitum one-week feeding of high-Met diets on mice. Adult male mice were fed the standard rodent diet that contained 0.44% Met (1×) or a diet containing 16 graded Met doses (1.2×–13×). High-Met diets for one-week induced a dose-dependent decrease in body weight and an increase in serum Met levels with a 2.55 mM peak (versus basal 53 µM) on the 12×Met diet. Total homocysteine (Hcy) levels were also upregulated while concentrations of other amino acids were almost maintained in serum. Similarly, levels of Met and Hcy (but not the other amino acids) were highly elevated in the cerebrospinal fluids of mice on the 10×Met diet; the Met levels were much higher than Hcy and the others. In a series of behavioral tests, mice on the 10×Met diet displayed increased anxiety and decreased traveled distances in an open-field test, increased activity to escape from water soaking and tail hanging, and normal learning/memory activity in a Y-maze test, which were reflections of negative/positive symptoms and normal cognitive function, respectively. These results indicate that high-Met ad libitum feeding even for a week can induce bipolar disorder-like disease models in mice. Full article

(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease 2.0)

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19 pages, 1656 KiB

Open AccessArticle

Identification and Determination of 1,3-Thiazinane-4-carboxylic Acid in Human Urine—Chromatographic Studies

by Justyna Piechocka, Natalia Litwicka and Rafał Głowacki

Int. J. Mol. Sci. 2022, 23(2), 598; https://doi.org/10.3390/ijms23020598 - 6 Jan 2022

Cited by 3 | Viewed by 2328

Abstract

It is well established that homocysteine (Hcy) and its thiolactone (HTL) are reactive towards aldehydes in an aqueous environment, forming substituted thiazinane carboxylic acids. This report provides evidence that Hcy/HTL and formaldehyde (FA) adduct, namely 1,3-thiazinane-4-carboxylic acid (TCA) is formed in vivo in [...] Read more.

It is well established that homocysteine (Hcy) and its thiolactone (HTL) are reactive towards aldehydes in an aqueous environment, forming substituted thiazinane carboxylic acids. This report provides evidence that Hcy/HTL and formaldehyde (FA) adduct, namely 1,3-thiazinane-4-carboxylic acid (TCA) is formed in vivo in humans. In order to provide definitive proof, a gas chromatography–mass spectrometry (GC–MS) based method was elaborated to identify and quantify TCA in human urine. The GC–MS assay involves chemical derivatization with isobutyl chloroformate (IBCF) in the presence of pyridine as a catalyst, followed by an ethyl acetate extraction of the obtained isobutyl derivative of TCA (TCA-IBCF). The validity of the method has been demonstrated based upon United States Food and Drug Administration recommendations. The assay linearity was observed within a 1–50 µmol L⁻¹ range for TCA in urine, while the lowest concentration on the calibration curve was recognized as the limit of quantification (LOQ). Importantly, the method was successfully applied to urine samples delivered by apparently healthy volunteers (n = 15). The GC–MS assay may provide a new analytical tool for routine clinical analysis of the role of TCA in living systems in the near future. Full article

(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease 2.0)

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16 pages, 3938 KiB

Open AccessArticle

A Study on How Methionine Restriction Decreases the Body’s Hepatic and Lipid Deposition in Rice Field Eel (Monopterus albus)

by Yajun Hu, Minglang Cai, Huan Zhong, Wuying Chu and Yi Hu

Int. J. Mol. Sci. 2021, 22(24), 13379; https://doi.org/10.3390/ijms222413379 - 13 Dec 2021

Cited by 8 | Viewed by 3136

Abstract

Methionine restriction reduces animal lipid deposition. However, the molecular mechanism underlying how the body reacts to the condition and regulates lipid metabolism remains unknown. In this study, a feeding trial was performed on rice field eel Monopterus albus with six isonitrogenous and isoenergetic [...] Read more.

Methionine restriction reduces animal lipid deposition. However, the molecular mechanism underlying how the body reacts to the condition and regulates lipid metabolism remains unknown. In this study, a feeding trial was performed on rice field eel Monopterus albus with six isonitrogenous and isoenergetic feeds that included different levels of methionine (0, 2, 4, 6, 8, and 10 g/kg). Compared with M0 (0 g/kg), the crude lipid and crude protein of M. albus increased markedly in M8 (8 g/kg) (p < 0.05), serum (total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and non-esterified free fatty acids), and hepatic contents (hepatic lipase, apolipoprotein-A, fatty acid synthetase, total cholesterol, triglyceride, and lipoprteinlipase). However, in the serum, very-low-density lipoprotein and hepatic contents (hormone-sensitive triglyceride lipase, Acetyl CoA carboxylase, carnitine palmitoyltransterase, and mirosomal triglygeride transfer protein) decreased markedly in M8 (p < 0.05). The contents of hepatic C18:2n-6, C22:6n-3, and n-3PUFA in the M8 group were significantly higher than those in M0 (p < 0.05), and the contents of lipid droplets in M8 were higher than those in M0. Compared with M0, the hepatic gcn2, eif2α, hsl, mttp, ldlrap, pparα, cpt1, and cpt2 were remarkably downregulated in M8, while srebf2, lpl, moat2, dgat2, hdlbp, srebf1, fas, fads2, me1, pfae, and icdh were markedly upregulated in M8. Moreover, hepatic SREBP1 and FAS protein expression were upregulated significantly in M8 (p < 0.01). In short, methionine restriction decreased the lipid deposition of M. albus, especially for hepatic lipid deposition, and mainly downregulated hepatic fatty acid metabolism. Besides, gcn2 could be activated under methionine restriction. Full article

(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease 2.0)

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Review

Jump to: Editorial, Research

11 pages, 1144 KiB

Open AccessReview

Role of Branched-Chain Amino Acid Metabolism in Type 2 Diabetes, Obesity, Cardiovascular Disease and Non-Alcoholic Fatty Liver Disease

by Paola Cuomo, Rosanna Capparelli, Antonio Iannelli and Domenico Iannelli

Int. J. Mol. Sci. 2022, 23(8), 4325; https://doi.org/10.3390/ijms23084325 - 13 Apr 2022

Cited by 43 | Viewed by 6259

Abstract

Branched-chain amino acids (BCAAs) include leucine, isoleucine, and valine. Mammalians cannot synthesize these amino acids de novo and must acquire them through their diet. High levels of BCAAs are associated with insulin resistance; type 2 diabetes; obesity; and non-metabolic diseases, including several forms [...] Read more.

Branched-chain amino acids (BCAAs) include leucine, isoleucine, and valine. Mammalians cannot synthesize these amino acids de novo and must acquire them through their diet. High levels of BCAAs are associated with insulin resistance; type 2 diabetes; obesity; and non-metabolic diseases, including several forms of cancer. BCAAs—in particular leucine—activate the rapamycin complex1 mTORC1, which regulates cell growth and metabolism, glucose metabolism and several more essential physiological processes. Diets rich in BCAAs are associated with metabolic diseases (listed above), while diets low in BCAAs are generally reported to promote metabolic health. As for the dysregulation of the metabolism caused by high levels of BCAAs, recent studies propose that the accumulation of acyl-carnitine and diacyl-CoA in muscles alters lipid metabolism. However, this suggestion is not broadly accepted. On clinical grounds, pre- and post-operative metabolic profiles of candidate patients for bariatric surgery are being used to select the optimal procedure for each individual patient. Full article

(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease 2.0)

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16 pages, 900 KiB

Open AccessReview

N-Acetyl-Aspartyl-Glutamate in Brain Health and Disease

by Cecilie Morland and Kaja Nordengen

Int. J. Mol. Sci. 2022, 23(3), 1268; https://doi.org/10.3390/ijms23031268 - 23 Jan 2022

Cited by 38 | Viewed by 7818

Abstract

N-acetyl-aspartyl-glutamate (NAAG) is the most abundant dipeptide in the brain, where it acts as a neuromodulator of glutamatergic synapses by activating presynaptic metabotropic glutamate receptor 3 (mGluR3). Recent data suggest that NAAG is selectively localized to postsynaptic dendrites in glutamatergic synapses and [...] Read more.

N-acetyl-aspartyl-glutamate (NAAG) is the most abundant dipeptide in the brain, where it acts as a neuromodulator of glutamatergic synapses by activating presynaptic metabotropic glutamate receptor 3 (mGluR3). Recent data suggest that NAAG is selectively localized to postsynaptic dendrites in glutamatergic synapses and that it works as a retrograde neurotransmitter. NAAG is released in response to glutamate and provides the postsynaptic neuron with a feedback mechanisms to inhibit excessive glutamate signaling. A key regulator of synaptically available NAAG is rapid degradation by the extracellular enzyme glutamate carboxypeptidase II (GCPII). Increasing endogenous NAAG—for instance by inhibiting GCPII—is a promising treatment option for many brain disorders where glutamatergic excitotoxicity plays a role. The main effect of NAAG occurs through increased mGluR3 activation and thereby reduced glutamate release. In the present review, we summarize the transmitter role of NAAG and discuss the involvement of NAAG in normal brain physiology. We further present the suggested roles of NAAG in various neurological and psychiatric diseases and discuss the therapeutic potential of strategies aiming to enhance NAAG levels. Full article

(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease 2.0)

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12 pages, 1096 KiB

Open AccessReview

Catabolism of Hydroxyproline in Vertebrates: Physiology, Evolution, Genetic Diseases and New siRNA Approach for Treatment

by Ruth Belostotsky and Yaacov Frishberg

Int. J. Mol. Sci. 2022, 23(2), 1005; https://doi.org/10.3390/ijms23021005 - 17 Jan 2022

Cited by 10 | Viewed by 4411

Abstract

Hydroxyproline is one of the most prevalent amino acids in animal proteins. It is not a genetically encoded amino acid, but, rather, it is produced by the post-translational modification of proline in collagen, and a few other proteins, by prolyl hydroxylase enzymes. Although [...] Read more.

Hydroxyproline is one of the most prevalent amino acids in animal proteins. It is not a genetically encoded amino acid, but, rather, it is produced by the post-translational modification of proline in collagen, and a few other proteins, by prolyl hydroxylase enzymes. Although this post-translational modification occurs in a limited number of proteins, its biological significance cannot be overestimated. Considering that hydroxyproline cannot be re-incorporated into pro-collagen during translation, it should be catabolized following protein degradation. A cascade of reactions leads to production of two deleterious intermediates: glyoxylate and hydrogen peroxide, which need to be immediately converted. As a result, the enzymes involved in hydroxyproline catabolism are located in specific compartments: mitochondria and peroxisomes. The particular distribution of catabolic enzymes in these compartments, in different species, depends on their dietary habits. Disturbances in hydroxyproline catabolism, due to genetic aberrations, may lead to a severe disease (primary hyperoxaluria), which often impairs kidney function. The basis of this condition is accumulation of glyoxylate and its conversion to oxalate. Since calcium oxalate is insoluble, children with this rare inherited disorder suffer from progressive kidney damage. This condition has been nearly incurable until recently, as significant advances in substrate reduction therapy using small interference RNA led to a breakthrough in primary hyperoxaluria type 1 treatment. Full article

(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease 2.0)

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Open AccessReview

Role of Hydrogen Sulfide, Substance P and Adhesion Molecules in Acute Pancreatitis

by Ayush Kumar and Madhav Bhatia

Int. J. Mol. Sci. 2021, 22(22), 12136; https://doi.org/10.3390/ijms222212136 - 9 Nov 2021

Cited by 9 | Viewed by 2450

Abstract

Inflammation is a natural response to tissue injury. Uncontrolled inflammatory response leads to inflammatory disease. Acute pancreatitis is one of the main reasons for hospitalization amongst gastrointestinal disorders worldwide. It has been demonstrated that endogenous hydrogen sulfide (H₂S), a gasotransmitter and [...] Read more.

Inflammation is a natural response to tissue injury. Uncontrolled inflammatory response leads to inflammatory disease. Acute pancreatitis is one of the main reasons for hospitalization amongst gastrointestinal disorders worldwide. It has been demonstrated that endogenous hydrogen sulfide (H₂S), a gasotransmitter and substance P, a neuropeptide, are involved in the inflammatory process in acute pancreatitis. Cell adhesion molecules (CAM) are key players in inflammatory disease. Immunoglobulin (Ig) gene superfamily, selectins, and integrins are involved at different steps of leukocyte migration from blood to the site of injury. When the endothelial cells get activated, the CAMs are upregulated which leads to them interacting with leukocytes. This review summarizes our current understanding of the roles H₂S, substance P and adhesion molecules play in acute pancreatitis. Full article

(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease 2.0)

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